clinical research guide

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Clinical Trial Guide explains clinical trial phases and the process of clinical trial research for patients and their loved ones. We seek to transform the way patients and their caregivers learn and navigate the often overly complicated process of information-gathering, selection, and enrollment.

Do I Qualify for a Clinical Trial?

It is important to be aware of the eligibility criteria of a specific trial before looking further into a study for your condition, as they are the...

Procedures and Ethical Standards

This article focuses on answering the questions or concerns many people face when considering joining a trial, such as how long it will last, legal...

Navigate Through the Clinical Trial Process

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Introduction to Clinical Trials

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Questions to Ask Before Joining a Clinical Trial

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Nih clinical research trials and you.

The NIH Clinical Trials and You website is a resource for people who want to learn more about clinical trials. By expanding the below questions, you can read answers to common questions about taking part in a clinical trial. 

What are clinical trials and why do people participate?

Clinical research is medical research that involves people like you. When you volunteer to take part in clinical research, you help doctors and researchers learn more about disease and improve health care for people in the future. Clinical research includes all research that involves people.  Types of clinical research include:

• Epidemiology, which improves the understanding of a disease by studying patterns, causes, and effects of health and disease in specific groups.
• Behavioral, which improves the understanding of human behavior and how it relates to health and disease.
• Health services, which looks at how people access health care providers and health care services, how much care costs, and what happens to patients as a result of this care.
• Clinical trials, which evaluate the effects of an intervention on health outcomes.

What are clinical trials and why would I want to take part?

Clinical trials are part of clinical research and at the heart of all medical advances. Clinical trials look at new ways to prevent, detect, or treat disease. Clinical trials can study:

• New drugs or new combinations of drugs
• New ways of doing surgery
• New medical devices
• New ways to use existing treatments
• New ways to change behaviors to improve health
• New ways to improve the quality of life for people with acute or chronic illnesses.

The goal of clinical trials is to determine if these treatment, prevention, and behavior approaches are safe and effective. People take part in clinical trials for many reasons. Healthy volunteers say they take part to help others and to contribute to moving science forward. People with an illness or disease also take part to help others, but also to possibly receive the newest treatment and to have added (or extra) care and attention from the clinical trial staff. Clinical trials offer hope for many people and a chance to help researchers find better treatments for others in the future

Why is diversity and inclusion important in clinical trials?

People may experience the same disease differently. It’s essential that clinical trials include people with a variety of lived experiences and living conditions, as well as characteristics like race and ethnicity, age, sex, and sexual orientation, so that all communities benefit from scientific advances.

See Diversity & Inclusion in Clinical Trials for more information.

How does the research process work?

The idea for a clinical trial often starts in the lab. After researchers test new treatments or procedures in the lab and in animals, the most promising treatments are moved into clinical trials. As new treatments move through a series of steps called phases, more information is gained about the treatment, its risks, and its effectiveness.

What are clinical trial protocols?

Clinical trials follow a plan known as a protocol. The protocol is carefully designed to balance the potential benefits and risks to participants, and answer specific research questions. A protocol describes the following:

• The goal of the study
• Who is eligible to take part in the trial
• Protections against risks to participants
• Details about tests, procedures, and treatments
• How long the trial is expected to last
• What information will be gathered

A clinical trial is led by a principal investigator (PI). Members of the research team regularly monitor the participants’ health to determine the study’s safety and effectiveness.

What is an Institutional Review Board?

Most, but not all, clinical trials in the United States are approved and monitored by an Institutional Review Board (IRB) to ensure that the risks are reduced and are outweighed by potential benefits. IRBs are committees that are responsible for reviewing research in order to protect the rights and safety of people who take part in research, both before the research starts and as it proceeds. You should ask the sponsor or research coordinator whether the research you are thinking about joining was reviewed by an IRB.

What is a clinical trial sponsor?

Clinical trial sponsors may be people, institutions, companies, government agencies, or other organizations that are responsible for initiating, managing or financing the clinical trial, but do not conduct the research.

What is informed consent?

Informed consent is the process of providing you with key information about a research study before you decide whether to accept the offer to take part. The process of informed consent continues throughout the study. To help you decide whether to take part, members of the research team explain the details of the study. If you do not understand English, a translator or interpreter may be provided. The research team provides an informed consent document that includes details about the study, such as its purpose, how long it’s expected to last, tests or procedures that will be done as part of the research, and who to contact for further information. The informed consent document also explains risks and potential benefits. You can then decide whether to sign the document. Taking part in a clinical trial is voluntary and you can leave the study at any time.

What are the types of clinical trials?

There are different types of clinical trials.

• Prevention trials look for better ways to prevent a disease in people who have never had the disease or to prevent the disease from returning. Approaches may include medicines, vaccines, or lifestyle changes.
• Screening trials test new ways for detecting diseases or health conditions.
• Diagnostic trials study or compare tests or procedures for diagnosing a particular disease or condition.
• Treatment trials test new treatments, new combinations of drugs, or new approaches to surgery or radiation therapy.
• Behavioral trials evaluate or compare ways to promote behavioral changes designed to improve health.
• Quality of life trials (or supportive care trials) explore and measure ways to improve the comfort and quality of life of people with conditions or illnesses.

What are the phases of clinical trials?

Clinical trials are conducted in a series of steps called “phases.” Each phase has a different purpose and helps researchers answer different questions.

• Phase I trials : Researchers test a drug or treatment in a small group of people (20–80) for the first time. The purpose is to study the drug or treatment to learn about safety and identify side effects.
• Phase II trials : The new drug or treatment is given to a larger group of people (100–300) to determine its effectiveness and to further study its safety.
• Phase III trials : The new drug or treatment is given to large groups of people (1,000–3,000) to confirm its effectiveness, monitor side effects, compare it with standard or similar treatments, and collect information that will allow the new drug or treatment to be used safely.
• Phase IV trials : After a drug is approved by the FDA and made available to the public, researchers track its safety in the general population, seeking more information about a drug or treatment’s benefits, and optimal use.

What do the terms placebo, randomization, and blinded mean in clinical trials?

In clinical trials that compare a new product or therapy with another that already exists, researchers try to determine if the new one is as good, or better than, the existing one. In some studies, you may be assigned to receive a placebo (an inactive product that resembles the test product, but without its treatment value).

Comparing a new product with a placebo can be the fastest and most reliable way to show the new product’s effectiveness. However, placebos are not used if you would be put at risk — particularly in the study of treatments for serious illnesses — by not having effective therapy. You will be told if placebos are used in the study before entering a trial.

Randomization is the process by which treatments are assigned to participants by chance rather than by choice. This is done to avoid any bias in assigning volunteers to get one treatment or another. The effects of each treatment are compared at specific points during a trial. If one treatment is found superior, the trial is stopped so that the most volunteers receive the more beneficial treatment.  This video helps explain randomization for all clinical trials .

" Blinded " (or " masked ") studies are designed to prevent members of the research team and study participants from influencing the results. Blinding allows the collection of scientifically accurate data. In single-blind (" single-masked ") studies, you are not told what is being given, but the research team knows. In a double-blind study, neither you nor the research team are told what you are given; only the pharmacist knows. Members of the research team are not told which participants are receiving which treatment, in order to reduce bias. If medically necessary, however, it is always possible to find out which treatment you are receiving.

Who takes part in clinical trials?

Many different types of people take part in clinical trials. Some are healthy, while others may have illnesses. Research procedures with healthy volunteers are designed to develop new knowledge, not to provide direct benefit to those taking part. Healthy volunteers have always played an important role in research.

Healthy volunteers are needed for several reasons. When developing a new technique, such as a blood test or imaging device, healthy volunteers help define the limits of "normal." These volunteers are the baseline against which patient groups are compared and are often matched to patients on factors such as age, gender, or family relationship. They receive the same tests, procedures, or drugs the patient group receives. Researchers learn about the disease process by comparing the patient group to the healthy volunteers.

Factors like how much of your time is needed, discomfort you may feel, or risk involved depends on the trial. While some require minimal amounts of time and effort, other studies may require a major commitment of your time and effort, and may involve some discomfort. The research procedure(s) may also carry some risk. The informed consent process for healthy volunteers includes a detailed discussion of the study's procedures and tests and their risks.

A patient volunteer has a known health problem and takes part in research to better understand, diagnose, or treat that disease or condition. Research with a patient volunteer helps develop new knowledge. Depending on the stage of knowledge about the disease or condition, these procedures may or may not benefit the study participants.

Patients may volunteer for studies similar to those in which healthy volunteers take part. These studies involve drugs, devices, or treatments designed to prevent,or treat disease. Although these studies may provide direct benefit to patient volunteers, the main aim is to prove, by scientific means, the effects and limitations of the experimental treatment. Therefore, some patient groups may serve as a baseline for comparison by not taking the test drug, or by receiving test doses of the drug large enough only to show that it is present, but not at a level that can treat the condition.

Researchers follow clinical trials guidelines when deciding who can participate, in a study. These guidelines are called Inclusion/Exclusion Criteria . Factors that allow you to take part in a clinical trial are called "inclusion criteria." Those that exclude or prevent participation are "exclusion criteria." These criteria are based on factors such as age, gender, the type and stage of a disease, treatment history, and other medical conditions. Before joining a clinical trial, you must provide information that allows the research team to determine whether or not you can take part in the study safely. Some research studies seek participants with illnesses or conditions to be studied in the clinical trial, while others need healthy volunteers. Inclusion and exclusion criteria are not used to reject people personally. Instead, the criteria are used to identify appropriate participants and keep them safe, and to help ensure that researchers can find new information they need.

What do I need to know if I am thinking about taking part in a clinical trial?

Risks and potential benefits

Clinical trials may involve risk, as can routine medical care and the activities of daily living. When weighing the risks of research, you can think about these important factors:

• The possible harms that could result from taking part in the study
• The level of harm
• The chance of any harm occurring

Most clinical trials pose the risk of minor discomfort, which lasts only a short time. However, some study participants experience complications that require medical attention. In rare cases, participants have been seriously injured or have died of complications resulting from their participation in trials of experimental treatments. The specific risks associated with a research protocol are described in detail in the informed consent document, which participants are asked to consider and sign before participating in research. Also, a member of the research team will explain the study and answer any questions about the study. Before deciding to participate, carefully consider risks and possible benefits.

Potential benefits

Well-designed and well-executed clinical trials provide the best approach for you to:

• Help others by contributing to knowledge about new treatments or procedures.
• Gain access to new research treatments before they are widely available.
• Receive regular and careful medical attention from a research team that includes doctors and other health professionals.

Risks to taking part in clinical trials include the following:

• There may be unpleasant, serious, or even life-threatening effects of experimental treatment.
• The study may require more time and attention than standard treatment would, including visits to the study site, more blood tests, more procedures, hospital stays, or complex dosage schedules.

What questions should I ask if offered a clinical trial?

If you are thinking about taking part in a clinical trial, you should feel free to ask any questions or bring up any issues concerning the trial at any time. The following suggestions may give you some ideas as you think about your own questions.

• What is the purpose of the study?
• Why do researchers think the approach may be effective?
• Who will fund the study?
• Who has reviewed and approved the study?
• How are study results and safety of participants being monitored?
• How long will the study last?
• What will my responsibilities be if I take part?
• Who will tell me about the results of the study and how will I be informed?

Risks and possible benefits

• What are my possible short-term benefits?
• What are my possible long-term benefits?
• What are my short-term risks, and side effects?
• What are my long-term risks?
• What other options are available?
• How do the risks and possible benefits of this trial compare with those options?

Participation and care

• What kinds of therapies, procedures and/or tests will I have during the trial?
• Will they hurt, and if so, for how long?
• How do the tests in the study compare with those I would have outside of the trial?
• Will I be able to take my regular medications while taking part in the clinical trial?
• Where will I have my medical care?
• Who will be in charge of my care?

Personal issues

• How could being in this study affect my daily life?
• Can I talk to other people in the study?

Cost issues

• Will I have to pay for any part of the trial such as tests or the study drug?
• If so, what will the charges likely be?
• What is my health insurance likely to cover?
• Who can help answer any questions from my insurance company or health plan?
• Will there be any travel or child care costs that I need to consider while I am in the trial?

Tips for asking your doctor about trials

• Consider taking a family member or friend along for support and for help in asking questions or recording answers.
• Plan what to ask — but don't hesitate to ask any new questions.
• Write down questions in advance to remember them all.
• Write down the answers so that they’re available when needed.
• Ask about bringing a tape recorder to make a taped record of what's said (even if you write down answers).

This information courtesy of Cancer.gov.

How is my safety protected?

Ethical guidelines

The goal of clinical research is to develop knowledge that improves human health or increases understanding of human biology. People who take part in clinical research make it possible for this to occur. The path to finding out if a new drug is safe or effective is to test it on patients in clinical trials. The purpose of ethical guidelines is both to protect patients and healthy volunteers, and to preserve the integrity of the science.

Informed consent

Informed consent is the process of learning the key facts about a clinical trial before deciding whether to participate. The process of providing information to participants continues throughout the study. To help you decide whether to take part, members of the research team explain the study. The research team provides an informed consent document, which includes such details about the study as its purpose, duration, required procedures, and who to contact for various purposes. The informed consent document also explains risks and potential benefits.

If you decide to enroll in the trial, you will need to sign the informed consent document. You are free to withdraw from the study at any time.

Most, but not all, clinical trials in the United States are approved and monitored by an Institutional Review Board (IRB) to ensure that the risks are minimal when compared with potential benefits. An IRB is an independent committee that consists of physicians, statisticians, and members of the community who ensure that clinical trials are ethical and that the rights of participants are protected. You should ask the sponsor or research coordinator whether the research you are considering participating in was reviewed by an IRB.

Further reading

For more information about research protections, see:

• Office of Human Research Protection
• Children's Assent to Clinical Trial Participation

For more information on participants’ privacy and confidentiality, see:

• HIPAA Privacy Rule
• The Food and Drug Administration, FDA’s Drug Review Process: Ensuring Drugs Are Safe and Effective

For more information about research protections, see: About Research Participation

What happens after a clinical trial is completed?

After a clinical trial is completed, the researchers carefully examine information collected during the study before making decisions about the meaning of the findings and about the need for further testing. After a phase I or II trial, the researchers decide whether to move on to the next phase or to stop testing the treatment or procedure because it was unsafe or not effective. When a phase III trial is completed, the researchers examine the information and decide whether the results have medical importance.

Results from clinical trials are often published in peer-reviewed scientific journals. Peer review is a process by which experts review the report before it is published to ensure that the analysis and conclusions are sound. If the results are particularly important, they may be featured in the news, and discussed at scientific meetings and by patient advocacy groups before or after they are published in a scientific journal. Once a new approach has been proven safe and effective in a clinical trial, it may become a new standard of medical practice.

Ask the research team members if the study results have been or will be published. Published study results are also available by searching for the study's official name or Protocol ID number in the National Library of Medicine's PubMed® database .

How does clinical research make a difference to me and my family?

Only through clinical research can we gain insights and answers about the safety and effectiveness of treatments and procedures. Groundbreaking scientific advances in the present and the past were possible only because of participation of volunteers, both healthy and those with an illness, in clinical research. Clinical research requires complex and rigorous testing in collaboration with communities that are affected by the disease. As research opens new doors to finding ways to diagnose, prevent, treat, or cure disease and disability, clinical trial participation is essential to help us find the answers.

This page last reviewed on October 3, 2022

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NIH Policies & Guidelines and Other Federal Regulations for Clinical Research

The NIH and other federal agencies have developed policies, regulations, and guidelines for investigators to follow for conducting safe, ethical, and high-quality clinical research. This page provides information that includes but is not limited to federal and NIH human subjects research policies and guidelines for monitoring clinical research, education and training for investigators, and privacy and protecting confidentiality. For further guidance or questions, reach out to the NIAMS Clinical Management Team at [email protected] .

NIH Human Subjects Policy and Guidance

Policies and guidelines for monitoring clinical research.

• Education and Training for Investigators Conducting Clinical Research
• Protecting Confidentiality
• Office for Human Research Protections and General Human Subjects Guidelines

U.S. Food and Drug Administration (FDA) Guidelines for Conduct of Clinical Trials

• Gene Therapy, Stem Cells and Fetal Tissue

The NIH has policies that govern the conduct of studies that involve human subjects. We encourage you to review the following guidelines for human subjects research and policies for inclusion of women, children, and individuals across the lifespan in studies. Additionally, this section contains information about single Institutional Review Board (sIRB) and requirements for registering clinical trials on ClinicalTrials.gov.  

• NIH Human Subjects Research Policies
• NIH Listing of Select Human Subjects Policy Statement Notices
• NIH Clinical Research Policy 
• Removal of the Requirement for IRB Review of NIH Grant Applications Contract
• NIH Policy on the Dissemination of NIH-Funded Clinical Trial Information 
• Requirements for Registering Clinical Trials into ClinicalTrials.gov  
• Steps to Compliance for NIH awardees
• NIH Grant Application and Proposal Considerations for Human Subjects Research
• Human Subjects System (HSS)
• Annotated Forms Set for NIH Grant Applications-FORMS-F-Series (Human Subjects on Page 32)
• NIH Inclusion Across the Lifespan Policy  
• NIH Policy and Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research
• Single IRB (sIRB) Policy for Multi-site Research
• Frequently Asked Questions (FAQs), General Questions about Human Subjects

Review the NIH and other federal agency policies for data and safety monitoring in the conduct of clinical trials to ensure the safety of research participants and the appropriate and ethical conduct of the study. Learn the NIAMS requirements and guidelines for reportable events as well as reviewing and reporting unanticipated problems involving risks to human subjects or others and adverse events.

• NIH Policy for Data and Safety Monitoring – June 1998
• Further Guidance on Data and Safety Monitoring for Phase I and II Clinical Trials – June 2000
• NIAMS Data and Safety Monitoring Guidelines and Policies
• NIAMS Safety Reporting Assessment Flowchart
• Guidance on Reporting Incidents to Office for Human Research Protections  
• FDA Guidance for Clinical Trial Data Monitoring Committees – March 2006

Human Subjects Education, Training and Resources for Investigators Conducting Clinical Research 

NIH investigators and those involved with conducting NIH supported clinical research are expected to be trained and maintain up to date certification on human subjects protection education and good clinical practice (GCP). Here are some useful resources that investigators can refer to which will help them understand the education and training requirements and offer resources to gain knowledge in the various topics related to the safe and ethical conduct of human subjects research.  

• Policy on Good Clinical Practice Training for NIH Awardees Involved in NIH-funded Clinical Trials
• NIH Human Subjects Protections Training & Resources
• Training Resources in the Responsible Conduct of Research (RCR) – HHS ORI 
• CITI Program Training & Resources 
• National Institute of Allergy and Infectious Diseases (NIAID) GCP Learning Center
• National Drug Abuse Treatment Clinical Trials Network (NDAT CTN) GCP Course
• Society of Behavioral Medicine GCP Training for Social and Behavioral Research
• NIH Frequently Asked Questions (FAQs) on Human Subjects Education

Privacy and Confidentiality

Learn more about the policies and guidance for ensuring the confidentiality of individuals who participant in clinical research studies.

• The Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule 
• HIPAA Administrative Simplification Statute and Rules
• Impact of the HIPAA Privacy Rule on NIH Processes
• NIH Certificates of Confidentiality (CoC) - Human Subjects

OHRP and General Human Subjects Regulations

Learn the procedures investigators must follow in order to protect human subjects who participate in clinical research studies. 

• Title 45 Code of Federal Regulations Part 46 – Protection of Human Subjects   
• 2020 Edition of International Compilation of Human Research Standards
• OHRP Policy and Guidance Index
• Belmont Report 1979 – Ethical Principles and Guidelines for the Protection of Human Subjects of Research
• International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH): Regulatory Guidance 
• ICH Guidance for Industry: E6 (R2) Good Clinical Practice

Understand the FDA’s policies and guidance for the conduct of clinical trials as they relate to drugs, devices, and biologics.

• Title 21 Code of Federal Regulations – Food and Drugs
• FDA Clinical Trial Guidance Documents Directory  
• Information for Clinical Investigators-Drugs (CDER)
• Information for Clinical Investigators-Devices (CDRH)
• Information for Clinical Investigators-Biologic (CBER)
• FDA Encourages More Participation, Diversity in Clinical Trials
• Notice to NIH Grantees Regarding Letters or Notices from the FDA

Additional Resources:  

• Collection of Race and Ethnicity Data in Clinical Trials
• Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Product
• Investigational New Drug Applications (INDs) - Determining Whether Human Research Studies Can Be Conducted Without an IND
• Financial Disclosure by Clinical Investigators
• IRB Responsibilities for Reviewing the Qualifications of Investigators, Adequacy of Research Sites, and the Determination of Whether an IND/IDE is Needed
• FDA and OHRP Final Guidance: Use of electronic Informed Consent & Questions and Answers
• Elaboration of Definitions of Responsible Party and Applicable Clinical Trial

Gene Therapy, Stem Cells, and Fetal Tissue

Learn the policies and guidelines for conducting clinical research studies that involve gene therapy, stem cells, or fetal tissue.

• NIH Stem Cell Research
• NIH Biosafety, Biosecurity and Emerging Biotechnology 
• New Initiatives to Protect Participants in Gene Therapy Trials
• NIH Biosafety Guidelines
• Approval Process for the Use of Human Pluripotent Stem Cells in NIH-Supported Research
• Informed Consent on Use of Human Fetal Tissue
• Changes to Requirements on Human Fetal Tissue Research 
• Research on Dried Blood Spots Obtained Through Newborn Screening

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• v.10(2); Apr-Jun 2020

How to read a published clinical trial: A practical guide for clinicians

Mohamad b sonbol.

1 Mayo Clinic Cancer Center, Phoenix, Arizona, USA

Belal M Firwana

2 Heartland Cancer Research, National Cancer Institute Community Oncology Research Program (NCORP), Missouri Baptist Medical Center, St. Louis, Missouri, USA

Talal Hilal

3 University of Mississippi Medical Center, Jackson, Mississippi, USA

Mohammad Hassan Murad

4 Evidence-Based Practice Center, Mayo Clinic, Rochester, Minnesota, USA

Over the last 5 years, there have been more than 140 new drug approvals in the field of Oncology alone, all based on newly published clinical trials. These approvals have led to an ongoing change in clinical practice, offering new therapeutic options for patients. Therefore, it is important for healthcare providers to be able to appraise a clinical trial and determine its validity, understand its results, and be able to apply such results to their patients. In this guide, we provide a simplified approach tailored to practicing clinicians and trainees. The same concepts and principles apply to other medical specialties.

INTRODUCTION

The modern practice of oncology is based on clinical trials, which have been increasingly conducted and published in the last 20 years. Over the last 5 years, there have been more than 140 anticancer drug approvals in the United States.[ 1 ] These approvals have led to an ongoing change in clinical practice, offering new therapeutic options for patients with cancer. Therefore, it is important for physicians to be able to appraise a clinical trial and determine its validity, understand its results, and be able to apply such results to their patients. In this guide, we provide a simplified approach based on the User’s Guide to the Medical Literature series tailored to practicing clinicians and trainees.[ 2 ] Although most of the included examples are from the oncology literature, the same concepts and principles would apply to other medical and surgical specialties.

Clinical case

A 56-year-old man with a history of diabetes mellitus who was recently diagnosed with metastatic non-small cell lung cancer comes to your oncology clinic for clinical care. You decide to start him on chemotherapy with carboplatin and pemetrexed. He is otherwise healthy and asymptomatic. His body mass index (BMI) is 41. He has reasonable functional status as measured by the Eastern Cooperative Oncology Group (ECOG) performance status (PS) score value of 1. His mother recently died of a pulmonary embolism (PE) and he is asking you about prevention of PE. You calculate his risk for chemotherapy-associated thrombosis using the Khorana score[ 3 ] and find it to be 2, which suggests an intermediate risk for venous thromboembolism. You are contemplating thromboprophylaxis and proceed to review the evidence.

What is a clinical trial?

A clinical trial is any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes. Therefore, a clinical trial can be randomized (i.e., a randomized controlled trial [RCT]) or nonrandomized. For inference purposes, nonrandomized trials are at similar risk of bias to that of observational studies and can be appraised by focusing on cohort selection, comparability of study groups, and adjustment for confounders (discussed in the Comparability of the groups at the baseline section) (i.e., just like an observational study). For the most part, when clinicians think about trials, they are usually referring to RCTs which are the gold standard study design to ascertain the effect of therapy. The RCT design creates groups of patients that are similar in all known and unknown prognostic factors (i.e., confounders) except the intervention. RCTs can randomize the patients to groups and follow them prospectively (parallel RCTs) or can switch patients at random to different treatment regimens during the course of the trial (crossover RCTs). This guide will focus on parallel-design RCTs because they are more common and are critical for the practice of internal medicine and oncology. We will also focus on an example of a superiority trial for simplicity (i.e., a trial that aims to evaluate if the experimental treatment is better than the standard treatment or placebo), although many of the constructs and principles discussed here apply to noninferiority trials (i.e., a trial that aims to evaluate whether an experimental treatment is not importantly worse than a standard treatment).

Lastly, although we are discussing an approach to appraise and apply an RCT, it is important to keep in mind that having a systematic review and meta-analysis of multiple RCTs would likely give more precise and valid estimates and would be preferred if available.[ 4 ] Moreover, the fundamental principles of evidence-based medicine (EBM) are assumed, which include formulating an answerable question, identifying the best evidence, critically appraising the evidence, applying the evidence, and integrating clinical expertise and patient’s values with the evidence.[ 5 ] In this concise guide, we will critically appraise an RCT that aims to answer the following clinical question: What is the evidence supporting prophylactic anticoagulation in patients with cancer?

When reading a manuscript reporting the conduct and results of an RCT, one should ask three questions. How valid are the results (which is also expressed as to what extent does the risk of bias affect the trustworthiness of the results)? What are the results? How do I apply these results to patient care? This simplified approach is based on the User’s Guide to the Medical Literature series and also adapted in oncology.[ 2 , 6 ]

We have identified one RCT that addresses the clinical question of interest to our patient––“Apixaban to Prevent Venous Thromboembolism in Patients with Cancer”––the AVERT trial.[ 7 ]

The trial evaluates the efficacy and safety of apixaban (2.5mg twice daily) for thromboprophylaxis in ambulatory patients with cancer who were at intermediate-to-high risk for venous thromboembolism (Khorana score, ≥2) initiating chemotherapy.”[ 7 ]

How valid are the results (to what extent does the risk of bias affect the trustworthiness of the results)?

The validity of the RCT focuses on how well the study is conducted and addresses different types of bias.[ 8 ] Appraising the study’s internal validity can be achieved by evaluating the methods section and following a stepwise approach. Did the study: start well, run well, and finish well?[ 6 ] [ Figure 1 ].

A framework summarizing the steps in critically appraising a randomized controlled trial.

ITT = intention to treat

Was the allocation sequence random?

Randomization (also known as allocation sequence generation) ensures that the study participants have an equal chance of being assigned to either the intervention group or the control group, thereby decreasing the likelihood of an imbalance in baseline prognostic factors which can cause what is called selection bias. For example, if the fit and younger patients were assigned to one arm of a study, this arm will have better outcomes that are not caused by the intervention. Randomization is commonly performed using a computer-generated algorithm.

In the AVERT trial, the authors state in the methods section “eligible patients underwent randomization by means of a centralized, web-based randomization system to receive apixaban or placebo in a 1:1 ratio.”[ 7 ] The randomization in this trial is adequate.

Was the allocation sequence concealed until participants were enrolled and assigned to interventions?

When appraising the validity of a study, it is important to look at the method of randomization and whether it can prevent the predictability of the allocation (also known as concealment). Concealment means that both study participants and investigators are not aware, and cannot predict, which group the study participant (patient) will be assigned to. This is not to be confused with blinding of assigned interventions (discussed below). Allocation concealment happens prior to and at the time of randomization. Conversely, blinding occurs after randomization[ 9 , 10 , 11 , 12 ] [ Figure 2 ]. Patient enrolment can be concealed but not blinded. An example of that is the biliary tract cancer (BILCAP) trial, where treatments were not masked but allocation concealment was achieved.[ 13 ]

A flow diagram showing blinding, concealment, and randomization

In the AVERT trial, the authors used a “centralized, web-based randomization” method which ensures that both participants and investigators could not foresee assignment.[ 7 ]

Comparability of the groups at the baseline

The benefit of randomization is in minimizing the imbalance and differences in baseline characteristics and prognostic factors between the groups. These differences are sometimes referred to as “confounders.” These baseline characteristics are almost always reported in Table 1 in RCTs. When detected, it is important to evaluate the importance of the prognostic factor imbalances (confounding) by asking the following questions: (1) Does the prognostic factor affect the outcome?; (2) If yes, which group is favored?; (3) Does this change the conclusion? This accounts for known confounders, but unknown confounders can always introduce bias. Potential unknown confounder imbalance can be minimized with appropriate randomization.

Primary efficacy and safety outcomes of the AVERT trial

N = total number of patients, n = number of events, RR = relative risk, ARR = absolute risk reduction, RD = risk difference, NNT = number needed to treat, HR = hazard ratio, CI = confidence interval

*Value calculated

† Value exported from reported trial results

In the AVERT trial, table 1 shows how the groups were comparable at the baseline, in terms of tumor type, Khorana score, PS, and others, including the use of concomitant antiplatelet medications.[ 7 ] It is important to look at the proportions in table 1 and determine whether they are clinically meaningful, and not to depend on reported P values. These P values are not meaningful (although commonly reported) because the trial is often underpowered to show significant differences in these variables.

This series of questions concerns performance bias and bias due to deviations from intended intervention and includes blinding, contamination, co-intervention, and compliance [ Figure 1 ].

Were participants and investigators aware of their assigned intervention during the trial?

Blinding refers to the process by which the study participants (patients), providers (nurses and physicians), investigators, and outcome assessors are kept unaware of treatment assignment throughout the study.[ 8 , 14 ] Blinding of patients and study personnel help in reducing performance bias that could occur upon the knowledge of the assignment. Performance biases arise from deviations from intended interventions. For example, if a study investigator is aware of treatment assignment, they might elect to monitor and see the patient in the novel therapy group more frequently than the control group. In addition, blinding of study participants helps in reducing the risk of the “placebo-effect” that can be detected in more subjective outcomes such as pain.[ 15 , 16 ] For example, in an RCT of patients with nasopharyngeal carcinoma, acupuncture significantly lowered radiation-induced xerostomia compared to standard care group (no acupuncture).[ 17 ] In this example, blinding of participants was not performed; however, it is hard to draw a clear conclusion from such trial when the outcomes (xerostomia and quality of life [QOL]) are subjective and could be affected by the “placebo-effect.” This has been described before where trials of acupuncture found benefit in treating pain compared to no treatment. However, this benefit was less significant when acupuncture was compared with sham control.[ 18 ] The effect of blinding in a study should be assessed for each individual outcome; it may be less important in more objective outcomes such as overall survival (OS).

In the AVERT trial, the authors state that “The AVERT trial was a randomized, placebo controlled, double-blind clinical trial.”[ 8 ] One can assume that “double blind” implies that patients and investigators were blinded. However, it is important to read the methods section to find out who was actually blinded.[ 19 ]

Was there any contamination or co-intervention

The study protocol usually specifies the intended interventions in each study group. When a study participant (patient) receives a non-protocol intervention, it is usually referred to as “co-intervention.” On the contrary, when a study participant receives the intervention that is assigned to the other study group, it is referred to as “contamination.”

In the AVERT trial, 23% and 22.6% of patients in the apixaban and placebo groups, respectively, received a concomitant antiplatelet medication (a co-intervention), which could potentially affect the primary outcomes of bleeding and clotting in such trial.[ 8 ] However, as both groups equally received this co-intervention, this will unlikely bias the results.

Was there nonadherence to the assigned intervention regimen that could have affected participants’ outcomes?

Compliance of the study participants to the intervention they are assigned to is referred to as “adherence.” It is important when appraising a trial to look at the reported adherence and whether there is a significant difference between groups. This is especially important in oncology RCTs where adverse events and safety profile of the studied medications play a major role in patients’ compliance.[ 20 ] For example, in the recently reported BILCAP trial studying the effect of adjuvant capecitabine compared to observation following surgery in patients with BILCAP, only half of the patients (55%) completed the planned eight cycles of capecitabine with third of the patients discontinuing treatment secondary to toxicity.[ 13 ]

In the AVERT trial, the authors state that “The rate of adherence to the trial regimen was high in both groups, at 83.6% in the apixaban group and 84.1% in the placebo group.”

FINISH WELL

The method of analysis and completion of follow-up are important factors that affect trial validity.

Were all patients who entered the trial accounted for? And were they analyzed in the groups to which they were randomized? Were there any lost to follow-up?

The principle of intention to treat (ITT) analysis indicates that participants should be analyzed based on the intervention group to which they were assigned, regardless of their adherence to the intervention or lost to follow-up (participant cannot be located).[ 21 ]

This is in contrast to the per-protocol analysis, which only analyzes the individuals who adhered to the intervention. ITT analysis maintains the benefit of randomization in minimizing any prognostic differences between groups. In contrast, the problem with the per-protocol analysis is that prognostic factors might influence whether individuals receive their allocated intervention. In RCTs assessing a superiority outcome, ITT is suggested for the most part. Some trials report both ITT and per-protocol analysis; for example, the previously mentioned BILCAP trial reported the OS results using both ITT and per-protocol analyses, with significant improvement in outcome seen with per-protocol analysis, but not with ITT analysis, reducing the trustworthiness or believability of the results.[ 13 ]

In some trials, instead of reporting ITT, a modified intention to treat (mITT) is reported. The definition of such an analysis is variable between trials and mostly generates post-randomization exclusions that potentially bias results making interpretation of such analyses challenging.[ 22 ]

In the AVERT trial, the primary analysis was performed in the “modified intention-to-treat” population, which included all patients who undergone randomization and received at least one dose of apixaban or placebo on or before day180.[ 7 ] Although ITT is the preferred approach, in this study the mITT is likely adequate and would not be expected to greatly alter the observed effect size compared to ITT. This modification––analyzing patients who received at least one dose of the study drug––is commonly seen in studies assessing differences in adverse drug events between treatment groups because it could be considered inappropriate to attribute an adverse drug event to a medication never received by the patient.[ 23 ] Although a threshold of >20% patients lost to follow-up is sometimes used to assess whether the number of patients of lost to follow-up is not acceptable, these arbitrary cutoffs can sometimes be misleading. It is important to compare the proportion lost to follow-up to the event rate in the trial. It is also important to conduct what is called a worst-case scenario in which we assume that patients lost to follow-up had bad outcome. If this new analysis shows results that are different from the original analysis, validity is then reduced.

Was outcome assessment blinded?

As described above, in addition to blinding patients and investigators, it is important to have blinding of outcome assessors. Indeed, the effect of blinding in a study should be assessed for each individual outcome as it is probably less important in objective outcomes as OS (death or alive) compared to progression-free survival.[ 24 ]

In the AVERT trial, outcomes were assessed by blinded investigators “All trial outcomes were adjudicated by an independent adjudication committee whose members were unaware of the treatment assignment.”

WHAT ARE THE RESULTS?

Once trial validity is established (i.e., risk of bias is low or unlikely to impact the conclusions), results need to be interpreted by asking about the magnitude of the effect and its precision.

What is the magnitude of the treatment effect?

There are several commonly used methods that are referred to as “measures of association” to assess the magnitude of treatment effect in clinical trials, including but not limited to relative risk (RR), odds ratio (OR), risk difference (RD), and hazard ratio (HR).

Relative risk and relative risk reduction

RR is the risk of disease or outcome in the treatment or exposed arm compared (relative) to the risk of the outcome in the control arm, hence the name RR.

On the contrary, relative risk reduction (RRR) is an estimate of the percentage of baseline risk (the control arm risk) that is reduced by receiving the experimental therapy, which is calculated as subtracting RR from 1 (1 – RR). For example, looking at the outcome table for the AVERT trial [ Table 1 ], the risk of venous thromboembolism (VTE) in apixaban group is 12/288 = 4.2% (also known as experimental event rate or EER) and the risk of VTE in placebo group is 28/275 = 10.2% (also known as control event rate or CER). Compared to patients in the placebo group, patients assigned to the apixaban group have almost half of the risk (41%) of the patients in the placebo group 4.2/10.2 = 41%. This is also known as RR. In other words, this means that apixaban decreased the RR by 1–0.41 (41%) = 59%. This is known as RRR.

One example of using RR in cancer clinical trials is when assessing response rates in the experimental and control arms. For example, in the Keynote-189 trial, comparing pembrolizumab plus chemotherapy versus chemotherapy alone in metastatic non-small-cell lung cancer,[ 25 ] objective response rates were 47.6% versus 18.9%, with an RR of 2.5, meaning that the experimental regimen results in 2.5 times better responses compared to the control arm.

OR is another relative association measure that is similar to RR. However, it is a ratio of odds, not risks. Odds are events/nonevents, whereas risk is events/total exposed sample. When the event rate is low (<10%), OR and RR become very similar.[ 26 ]

Risk difference

Although relative measures (RR and RRR, OR and HR) are very helpful to depict the direction of the association, they do not give the full picture, especially when interpreting data or discussing with patients. Therefore, reporting absolute measures is as important, namely the RD, which is the proportion of the event in the experimental arm subtracted from the proportion of the even in the control arm. In other words, it is the proportion of patients who are spared the undesired outcome having received the experimental rather than the control treatment. RD of 0 means the events occurred equally in both groups. RD is sometimes called absolute risk reduction (ARR) or absolute risk increase (ARI) based on the direction of the effect. When interpreting RCTs, it is important to look at both ARR and RRR, as looking at relative measures can be deceiving and tends to overestimate results. In a hypothetical example, an RR of 50% could represent an ARR of 30% (if the absolute risk improved from 60% to 30%), or that same RR of 50% could represent and ARR of 2% (if the absolute risk improved from 4% to 2%).

In our example [ Table 1 ], in the AVERT trial: baseline risk of VTE in the placebo group is 10.2% and is decreased to 4.2% in the apixaban group. Therefore, giving apixaban decreased the risk of VTE by 10.2–4.2 = 6%, which is the RD.

Number needed to treat/harm

Another important measure of association is the number needed to treat (NNT). This reflects the number of patients who needs to be treated in order to prevent one event (in this case, VTE). NNT = 1/ARR (when ARR is in percentage, this would be NNT = 100/ARR). In the AVERT trial, the NNT = 100/6 = 16.6 patients. In the same way, we can calculate the number needed to harm (NNH), which is the number of patients who need to be treated in order to harm one patient or cause one undesired event. The risk of bleeding in the apixaban group is 3.5% and in the placebo group it is 1.8%. The RD is 1.7% (3.5–1.8). For 100 patients treated, 1.7% get harmed. The NNH = 100/1.7 = 58.8 patients.

These numbers are useful when evaluating the magnitude of effect and safety of the intervention by comparing NNH and NNT. For apixaban, for each 16 patients we treat we benefit 1, and for each 58 patients we treat, 1 would be harmed. We obviously seek drugs with low NNT and high NNH.

Hazard ratio

The HR is a relative association measure used for outcomes of survival in cancer clinical trials. Although calculated differently,[ 27 ] for practical purposes it can be interpreted as an RR averaged over the course of a trial and can be expected at any given time during the follow-up. The calculation of HR includes the element of time (i.e., how long an event took to occur vs. did it occur or not). HR of 1 means no effect; HR of 2 means that the intervention doubles the risk of outcome; and HR of 0.5 means that the intervention halves the risk of outcome. HR should always be interpreted with consideration of the associated length of survival. In the trial of erlotinib plus gemcitabine compared with gemcitabine in patients with advanced pancreatic cancer,[ 28 ] median survival time was 6.24 months in the experimental arm of combination therapy versus 5.91 months in the gemcitabine arm. Thus, although the HR of 0.82 suggests improved survival, the actual difference in survival could be trivial.

How precise is the estimate of treatment effect?

Confidence intervals (CIs) in RCTs identify a range of values within which it is probable that the true effect of treatment lies. In most trials, 95% CI is estimated to indicate that if the trial was repeated 100 times, 95% of the CI would include the true effect; the wider the CI, the less precise the estimate. For example, in the Keynote-189 trial, the HR for death was 0.49 with a reported P < 0.001 (which means that this effect is statistically significant because it is <0.05, the arbitrary cutoff for significance). This HR of 0.49 had a 95% CI of 0.38–0.64. When making a decision, one should consider precision. If our decision would be the same whether the lower or the upper boundaries were the truth, then the results are sufficiently precise. In this case, the precision is adequate.

HOW DO I APPLY THE RESULTS TO MY PATIENTS?

Applicability is a form of external validity.[ 29 ] To assess applicability, one should ask the following questions:

Were the study patients similar to my patients?

This question can be answered by looking at inclusion and exclusion criteria for the RCT and compare them to the characteristics of the patient of interest. RCTs with long lists of exclusion criteria (e.g., comorbid conditions) may be less applicable in real practice. Furthermore, RCTs in oncology can be regional, a few countries in the same region, or international, spanning multiple regions and countries, which makes generalizability variable depending on the regions where the RCT was conducted. For example, the oral fluoropyrimidine, S-1, was shown to improve OS as an adjuvant chemotherapy option in patients with curatively resected gastric cancer in Japan only.[ 30 ] It has yet to be approved in the United States due to this regional variation, which limits generalizability of drug metabolism and efficacy data to Western patients. However, we should not expect a perfect match and we should anticipate that most of the time relative treatment effects apply to patients with various characteristics.

In the AVERT trial, one of the inclusion criteria was a Khorana score of 2, an intermediate risk category associated with only 1%–2% risk of VTE.[ 3 ] Approximately two-thirds of participants in the AVERT trial had a Khorana score of 2. Using apixaban in this group of patients may be associated with greater harm than benefit as the baseline risk of VTE is very small.

Were all clinically meaningful outcomes considered?

When a drug produces small increments in hemoglobin level, or that a chemotherapy agent causes tumors to shrink above a specific threshold (i.e., response rate), this may not provide sufficient justification for recommending these interventions to patients. These are surrogate outcomes that may or may not lead to an improvement in clinically meaningful, patient-important outcomes, such as QOL or OS.

In the AVERT trial, investigators preemptively evaluated for the presence of VTE with imaging in the absence of symptoms or signs of VTE, a practice that is not commonly performed or indicated for most VTEs. This probably led to the diagnosis of many incidental VTE, which otherwise may have not been found or caused important morbidity or mortality.

Do treatment benefits outweigh the potential risks (harm and costs)?

We evaluate the patient’s baseline risk to determine whether introducing an intervention would be worthwhile. A low baseline risk usually means the RD will be low and NNT will be high. Knowing these absolute measures can assist clinicians in helping patients weigh the benefits and risks of each potential intervention. Ultimately, the values and preferences for each individual patient need to be considered before recommending one therapy over another.

CONCLUSION OF THE CLINICAL SCENARIO

After applying the framework [ Figure 1 ], you found that this RCT (AVERT trial) was at low risk of bias. However, after you discuss the efficacy data along with the underlying risk of bleeding in this patient, the patient decided not to start the medication. A different patient with similar characteristics (Khorana score of 2) might elect to accept such risk in return to the benefits seen. This emphasizes the importance of shared-decision making when applying evidence to individual patients.

Financial support and sponsorship

Conflicts of interest.

There are no conflicts of interest.

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• The Drug Development Process

Step 3: Clinical Research

While preclinical research answers basic questions about a drug’s safety, it is not a substitute for studies of ways the drug will interact with the human body. “Clinical research” refers to studies, or trials, that are done in people. As the developers design the clinical study, they will consider what they want to accomplish for each of the different Clinical Research Phases and begin the Investigational New Drug Process (IND), a process they must go through before clinical research begins.

On this page you will find information on:

Designing Clinical Trials

Clinical Research Phase Studies

The Investigational New Drug Process

Asking for FDA Assistance

FDA IND Review Team

Researchers design clinical trials to answer specific research questions related to a medical product. These trials follow a specific study plan, called a protocol , that is developed by the researcher or manufacturer. Before a clinical trial begins, researchers review prior information about the drug to develop research questions and objectives. Then, they decide:

Who qualifies to participate (selection criteria)

How many people will be part of the study

How long the study will last

Whether there will be a control group and other ways to limit research bias

How the drug will be given to patients and at what dosage

What assessments will be conducted, when, and what data will be collected

How the data will be reviewed and analyzed

Clinical trials follow a typical series from early, small-scale, Phase 1 studies to late-stage, large scale, Phase 3 studies.

What are the Clinical Trial Phases?

Watch this video to learn about the three phases of clinical trials.

Study Participants: 20 to 100 healthy volunteers or people with the disease/condition.

Length of Study: Several months

Purpose: Safety and dosage

During Phase 1 studies, researchers test a new drug in normal volunteers (healthy people). In most cases, 20 to 80 healthy volunteers or people with the disease/condition participate in Phase 1. However, if a new drug is intended for use in cancer patients, researchers conduct Phase 1 studies in patients with that type of cancer.

Phase 1 studies are closely monitored and gather information about how a drug interacts with the human body. Researchers adjust dosing schemes based on animal data to find out how much of a drug the body can tolerate and what its acute side effects are.

As a Phase 1 trial continues, researchers answer research questions related to how it works in the body, the side effects associated with increased dosage, and early information about how effective it is to determine how best to administer the drug to limit risks and maximize possible benefits. This is important to the design of Phase 2 studies.

Approximately 70% of drugs move to the next phase

Study Participants: Up to several hundred people with the disease/condition.

Length of Study: Several months to 2 years

Purpose: Efficacy and side effects

In Phase 2 studies, researchers administer the drug to a group of patients with the disease or condition for which the drug is being developed. Typically involving a few hundred patients, these studies aren't large enough to show whether the drug will be beneficial.

Instead, Phase 2 studies provide researchers with additional safety data. Researchers use these data to refine research questions, develop research methods, and design new Phase 3 research protocols.

Approximately 33% of drugs move to the next phase

Study Participants: 300 to 3,000 volunteers who have the disease or condition

Length of Study: 1 to 4 years

Purpose: Efficacy and monitoring of adverse reactions

Researchers design Phase 3 studies to demonstrate whether or not a product offers a treatment benefit to a specific population. Sometimes known as pivotal studies, these studies involve 300 to 3,000 participants.

Phase 3 studies provide most of the safety data. In previous studies, it is possible that less common side effects might have gone undetected. Because these studies are larger and longer in duration, the results are more likely to show long-term or rare side effects

Approximately 25-30% of drugs move to the next phase

Study Participants: Several thousand volunteers who have the disease/condition

Purpose: Safety and efficacy

Phase 4 trials are carried out once the drug or device has been approved by FDA during the Post-Market Safety Monitoring

Learn more about Clinical Trials .

Drug developers, or sponsors , must submit an Investigational New Drug (IND) application to FDA before beginning clinical research.

In the IND application, developers must include:

Animal study data and toxicity (side effects that cause great harm) data

Manufacturing information

Clinical protocols (study plans) for studies to be conducted

Data from any prior human research

Information about the investigator

Drug developers are free to ask for help from FDA at any point in the drug development process, including:

Pre-IND application, to review FDA guidance documents and get answers to questions that may help enhance their research

After Phase 2, to obtain guidance on the design of large Phase 3 studies

Any time during the process, to obtain an assessment of the IND application

Even though FDA offers extensive technical assistance, drug developers are not required to take FDA’s suggestions. As long as clinical trials are thoughtfully designed, reflect what developers know about a product, safeguard participants, and otherwise meet Federal standards, FDA allows wide latitude in clinical trial design.

The review team consists of a group of specialists in different scientific fields. Each member has different responsibilities.

Project Manager: Coordinates the team’s activities throughout the review process, and is the primary contact for the sponsor.

Medical Officer: Reviews all clinical study information and data before, during, and after the trial is complete.

Statistician: Interprets clinical trial designs and data, and works closely with the medical officer to evaluate protocols and safety and efficacy data.

Pharmacologist: Reviews preclinical studies.

Pharmakineticist: Focuses on the drug’s absorption, distribution, metabolism, and excretion processes.Interprets blood-level data at different time intervals from clinical trials, as a way to assess drug dosages and administration schedules.

Chemist: Evaluates a drug’s chemical compounds. Analyzes how a drug was made and its stability, quality control, continuity, the presence of impurities, etc.

Microbiologist: Reviews the data submitted, if the product is an antimicrobial product, to assess response across different classes of microbes.

The FDA review team has 30 days to review the original IND submission. The process protects volunteers who participate in clinical trials from unreasonable and significant risk in clinical trials. FDA responds to IND applications in one of two ways:

Approval to begin clinical trials.

Clinical hold to delay or stop the investigation. FDA can place a clinical hold for specific reasons, including:

Participants are exposed to unreasonable or significant risk.

Investigators are not qualified.

Materials for the volunteer participants are misleading.

The IND application does not include enough information about the trial’s risks.

A clinical hold is rare; instead, FDA often provides comments intended to improve the quality of a clinical trial. In most cases, if FDA is satisfied that the trial meets Federal standards, the applicant is allowed to proceed with the proposed study.

The developer is responsible for informing the review team about new protocols, as well as serious side effects seen during the trial. This information ensures that the team can monitor the trials carefully for signs of any problems. After the trial ends, researchers must submit study reports.

This process continues until the developer decides to end clinical trials or files a marketing application. Before filing a marketing application, a developer must have adequate data from two large, controlled clinical trials.

Posters advertising a variety of clinical research trials at Penn State College of Medicine are seen on a College bulletin board in summer 2016. The image shows five posters in a line, with the center one in focus and the others out-of-focus in the background.

• Clinical Research Guidebook

See all COVID-19 research updates, including updated human-subjects research guidance and participant screening script, here.

This clinical research guidebook has been developed for faculty and staff members engaged in clinical research at Penn State College of Medicine/Penn State Health Milton S. Hershey Medical Center. It has been adapted from the materials created and released by The Clinical Trials Resource Group at the University of California – Davis CTSC.

Researchers at University Park may wish to view University Park-specific guidebook information .

Request clinical research project help here

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Resources and training.

Penn State Health and Penn State College of Medicine conduct a variety of clinical research studies in accordance with the applicable regulations relevant to the protection of human subjects. For FDA-regulated research, Penn State commits to apply the “International Conference on Harmonisation – Good Clinical Practice as adopted by the U.S. FDA and as required by sponsors. Standardized training and continuing skill development of all clinical research professionals is an important part of preparation for clinical research. It is the responsibility of all staff and investigators to know, understand and maintain sufficient knowledge of the federal, state and local requirements protecting research subjects.

The U.S. Department of Health and Human Services (HHS) is the government’s principal agency for protecting the health of all Americans. It comprises several public health services agencies including the FDA (Food and Drug Administration), OHRP (Office of Human Research Protection), the NIH (National Institutes of Health), and the Centers for Medicare and Medicaid Services (CMS).

Food and Drug Administration (FDA, fda.gov ) is responsible for protecting and promoting public health through the regulations and supervision of food safety, tobacco products, dietary supplements, prescription and over-the-counter pharmaceutical drugs (medications), vaccines, biopharmaceuticals, blood transfusions, medical devices, electromagnetic radiation emitting devices (ERED), veterinary products, and cosmetics. Understanding these rules is critical for any investigator who conducts human subject studies with drugs, devices or dietary supplements, whether already approved on the market, or still investigational.

Office of Human Research Protection (OHRP, hhs.gov/ohrp ) provides leadership, guidance, and education in the protection of the rights, welfare, and well-being of subjects involved in research conducted or supported by the HHS. OHRP performs these services through providing clarification and guidance, developing educational programs and materials, maintaining regulatory oversight, and providing advice on ethical and regulatory issues in biomedical and social-behavioral research. Detailed regulations for human subject protection are listed on the OHRP website . OHRP rules guide the Institutional Review Boards (IRBs).

National Institutes of Health (NIH, nih.gov ) seeks to provide fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce the burdens of illness and disability. As part of this mission NIH provides leadership and direction to programs designed to improve health and provides support for research.

As of December 2017 2017, the NIH funds 57 Clinical and Translational Science Centers across the country. Working together as a national consortium, Clinical Translational Science Award (CTSA) institutions share a common vision to improve human health by transforming the research and training environment to enhance the efficiency and quality of clinical and translational research. The CTSA program is supported by the National Center for Advancing Translational Science (NCATS), part of the National Institutes of Health.

The CTSA program has the following overriding objectives:

• Provide a comprehensive array of essential tools and services to spark clinical and translational research.
• Ensure the training of a well prepared workforce of trainees, staff, and investigators.
• Effectively communicate the many tools, services, and training opportunities to ensure innovative translational science advances that will improve human health.

Today, Penn State Clinical and Translational Science Institute ( ctsi.psu.edu ) offers resources that faculty, trainees and staff across the scientific and medical spectrum can use to enhance research and improve health and healthcare delivery.

Centers for Medicare and Medicaid Services (CMS, cms.gov ) is the federal agency which administers Medicare, Medicaid, and the Children’s Health Insurance Program. On June 7, 2000, the President of the United States issued an executive memorandum directing the Secretary of Health and Human Services to “explicitly authorize [Medicare] payment for routine patient care costs… and costs due to medical complications associated with participating in clinical trials.” CMS responded to the executive order with the clinical trial policy – National Coverage Determination (NCD). Medicare State fiscal intermediaries also issue Local Coverage Determinations (LCD). Our intermediary is Novitas Solutions, Inc.

Understanding Coverage Rules is critical for generating correct billing claims for clinical research participants. At Penn State Health/Penn State College of Medicine, the tool and the process of applying CMS rules to each individual study is called Coverage Analysis . This information is reviewed in detail in the Preparing Documents section of this guidebook.

The Code of Federal Regulations (CFR) is a compendium of the general and permanent rules and regulations published in the Federal Register by the federal executive departments and agencies. The CFR is divided into 50 titles that represent broad areas subject to Federal regulations. Title 45 CFR encompasses regulation of Public Welfare. Title 21 CFR is administered by the FDA and covers regulations of Food and Drugs.

Title 45 CFR 46 ( The Common Rule ) is a core set of regulations defining protection of Human Subjects in clinical research. 45 CFR part 46 includes four subparts:

• Subpart A , also known as the Federal Policy or the “Common Rule”
• Subpart B , additional protections for pregnant women, human fetuses and neonates
• Subpart C , additional protections for prisoners
• Subpart D , additional protections for children

Through a system of IRB registration and assurances , the Department of Health & Human Services (DHHS) regulations require institutions to commit to compliance with 45 CFR 46 before initiating participation in DHHS-conducted or -supported research involving human subjects. A Federalwide Assurance (FWA) is the institution’s commitment to apply 45 CFR 46 as required. Penn State College of Medicine’s FWA is 00004251 . In the FWA, Penn State Health is listed as a component of Penn State College of Medicine.

Title 21 CFR: The FDA regulations (Title 21 CFRs) are applicable when research is being conducted to develop a medical product that will be licensed for sale in the United States. Certain federally sponsored and privately sponsored research is subject to the regulations of the FDA according to 21 CFR Parts 50 and 56. Title 21 CFR part 50 defines regulations for informed consent and 21 CFR part 56 defines regulations for IRBs. These regulations largely overlap but are not identical with the Common Rule. Investigators need to know both sets of regulations to apply them appropriately.

Title 21 CFR 312 details the regulations for human research done with investigational drugs. This Title includes, but is not limited to, the regulations for applying to FDA to conduct research under an Investigational New Drug (IND) application (21 CFR 312 Subpart B), responsibilities of Sponsors and Investigators under an IND (21 CFR 312 Subpart D), and expanded access to Investigational Drugs (21 CFR 312 Subpart I). The IND and IDE Submissions section of this guidebook discusses the drug development process in more detail.

Title 21 CFR 812 details the regulations for human research with investigational devices. The regulations lay out the framework for applying to FDA to conduct human subjects research with Investigational Devices (21 CFR 812 Subpart B), responsibilities of Sponsors (21 CFR 812 Subpart C) and Investigators (21 CFR 812 Subpart E), and IRB approval 21 CFR 812 Subpart D).

The IND and IDE Submissions section of this guidebook discusses the drug development process in more detail.

This guidebook is updated on an annual basis at minimum to provide updates and new information. Always reference this website, not printouts, for the most recent information.

HRP-103 – Investigator Manual is designed to guide investigators and study team members through policies and procedures related to the conduct of Human Research that are specific to this institution. General information regarding Human Research protections and relevant federal regulations and guidance is incorporated into the required human protections training.

It is recommended that all study team members review the Investigator Manual and become familiar with its contents. The manual is updated regularly and can serve as an initial source of information when questions arise regarding policies and procedures.

The manual can be located from the link below or accessed through the CATS IRB library.

Access the Investigator Manual

Penn State College of Medicine Clinical Trials Office (CTO) creates and maintains multiple Standard Operating Procedures (SOPs) and competencies related to conduct of clinical research at Penn State College of Medicine and Penn State Health.

The SOPs as well as links to other institutional research resources can be found, including coordinator competencies, can be found on the Penn State Health Policy Portal (ePass login required).

Penn State employs the Collaborative Institutional Training Initiative (CITI) program, a web-based training program to satisfy the training requirements for all personnel conducting human subject research as part of the University and/or Penn State Health.

For details on required modules, see IRB training and resources on the University Office of Research Protections website.

Penn State College of Medicine and Penn State Health have partnered with the Association of Clinical Research Professionals (ACRP) to support professional growth and development through providing membership accounts to users registered through the organizational account. User seats are currently capped at 50 members with anticipation to increase capacity based on need and utilization if funding permits. ACRP Membership through the organizational account immediately connects users with:

• 200-plus on-demand training, continuing education and ACRP Certification Exam preparation modules available in a Penn State College of Medicine and Penn State Health-branded learning environment
• Unlimited ACRP contact hours for ACRP certification renewal
• Breaking news and regulatory updates
• ACRP’s community and members-only discussion groups
• Plus, ACRP member pricing for ACRP certification and the ACRP annual conference

Please contact Liz Galgocy at [email protected] with questions, for access instructions or to be added to the waiting list for account access.

The institution provides a number of training opportunities to be sure our workforce members are HIPAA compliant. The courses are designed to satisfy accreditation, contractual and regulatory requirements, and they range from online courses used during New Employee Orientation, to introductory and refresher presentations available to employees through Compass. Cybersecurity and Privacy Annual Training is assigned yearly through Compass and completion is required to maintain compliance for continued employment (login required).

Required trainings include:

• CITI Yearly Biosafety Training
• Safety Annual Training 100
• Safety Annual Training College of Medicine 100
• Biological Shipping and Dry Ice Training
• COM Bloodborne Pathogens Training or Infection Prevention/Control Training

Lab Safety Training or Biological Safety, Chemical/Laboratory Safety, and Hazardous Waste Management and Minimization

Lab safety training is for research laboratory personnel in the Penn State College of Medicine. Every employee working in the research lab is required to take general safety training on an annual basis. Learn more on the Department of Safety section of the Infonet (login required).

Annual blood-borne pathogen training is required for labs currently using unfixed human and or non-human primate materials including human derived cell lines. Learn more on the Department of Safety section of the Infonet (login required).

SAA (Satellite Accumulation Area) training is required for each laboratory to have a representative registered and trained in the hazardous waste disposal and minimization program. Learn more on the Department of Safety section of the Infonet (login required).

CITI Biosafety/Biosecurity training is required by the Principal Investigator if operating a lab on the College of Medicine campus. The training is highly recommended for all laboratory personnel including technicians, technologists, postdoctoral scholars and visiting scientists. See more information at citi.psu.edu .

View more information about researching compliance training requirements

New Submitter Training is conducted by the IRB for submissions to the Centralized Application Tracking System Institutional Review Board (CATS IRB). This orientation provides detailed training on the ethical principles of human research, an explanation of the researcher’s primary responsibility for protecting research subjects and for complying with all applicable provisions of institutional, state and federal laws. It provides an explanation of the different levels of IRB review and describes the processes for IRB submissions. Find upcoming IRB trainings and workshops . The clinical trials management system, Study Tracking and Analysis for Research (STAR) , training is provided by the CTO. Learn more on the STAR Infonet section (login required). There may be additional training requirements based on your departmental requirements.

Information pertaining to Payer Coverage Analysis and clinical trial budgeting is available through the Clinical Trials Office .

All investigators who are engaged in research must complete Penn State University’s required FCOI training and submit a disclosure of significant financial interest. Per PSU Policy RP06, an investigator is defined as: “any individual, regardless of his or her title or position, whether faculty, staff, or student, who has the ability to make independent decisions related to the design, conduct or reporting of University Research, but not including individuals who perform only incidental or isolated tasks related to a University Research project.” Disclosure is required prior to the submission of an application for research funding, at least annually, and within 30 days of the discovery or acquisition of a new Significant Financial Interest. The Disclosure must identify significant financial interests of the investigator, spouses/partners, and dependent children that exceed the thresholds set by PSU and that relate to any of the investigator’s institutional responsibilities. Additionally, the College of Medicine has specific disclosure requirements for financial interest related to either human subjects research or purchasing responsibility. Both FCOI training and disclosure are completed via Penn State University’s electronic Conflict of Interest System, COINS ( coins.psu.edu ). As part of the electronic Disclosure Form, COINS requires investigators to complete FCOI training upon their first disclosure and again every four years. For details, please see the College of Medicine Conflict of Interest Program Overview and PSU Policy RP06 Disclosure and Management of Significant Financial Interests .

There are additional requirements for when a Penn State research project includes research procedures on-site in a Penn State Health or Penn State College of Medicine facility, and the onsite study team includes employees of Penn State who are not specifically a student or employee of the health system or College of Medicine. These requirements are not related to research, and do not apply to study team members that will never be in person at a Penn State Health or College of Medicine facility. These requirements are driven by the health system and requirements from the joint commission, the accrediting body for US health care organizations and programs. The joint commission requires that the exact same standards be applied to “all members of the workforce.” Anyone working on site at Penn State Health or Penn State College of Medicine for 5 or more days is considered a member of the workforce and must complete the same clearances as regular employees on campus.

View information related to the requirements and related guidance when these circumstances exist (in Sharepoint; Penn State Access ID login required).

The Penn State Research Portal (Pure) is a publicly-available system that captures and displays the research output of the University, both for investigators and units, and facilitates collaboration between investigators across the University and beyond. Pure is one of several applications by the company Elsevier. Pure aggregates research information from internal and external sources and enhances the visibility and discoverability of research at Penn State, both internally and externally. It provides detailed information on scholarly output, publications, networks, citation data from journals and social media citations.  See details about Pure here .

For further information, resources, and assistance in identifying collaborators and funding opportunities, please also visit the  Research Development website .

There are multiple central research administration support offices throughout the organization. Click on each link provided for information regarding each of these offices.

• Center for Medical Innovation (CMI)
• Clinical Trials Office (CTO)
• Human Research Protection Program (HRPP)
• Penn State Clinical and Translational Science Institute (CTSI)
• Office of Research Affairs (ORA)
• Research Development/Research Concierge
• Research Quality Assurance (RQA)

Study Development and Feasibility: CTSI Resources

Penn State Clinical and Translational Science Institute (CTSI) can provide a wide range of consultation services during all stages of studies, and specifically during the project development and start-up phases. The new Research Navigator service provides hands-on support in conducting research. See CTSI consultation services and request Research Navigator assistance.

The mission of the College of Medicine Clinical Trials Office is to enhance, foster and promote organized, high-quality clinical research within Penn State Health Milton S. Hershey Medical Center and Penn State College of Medicine.

By promoting clinical research, the Clinical Trials Office helps Penn State Health and Penn State College of Medicine meet its mission goals of excellence in patient care, education, research and community service.

Established in the 1990s, current services offered to support investigators include protocol and budget feasibility assessment, budget preparation and negotiation, regulatory and IRB submission and oversight, study coordinator services and clinical trial placement.

Learn more about the Clinical Trials Office .

Biostatistics support is provided by the Division of Biostatistics and Bioinformatics in the Department of Public Health Sciences. Statisticians can assist researchers with all sizes and types of projects, from simple data analyses to large multi-center clinical trials. Specific services include grant proposal preparation, study design/sample size calculation, development of a statistical analysis plan, data analysis and interpretation, manuscript review and preparation, response to reviewer comments and statistical advice only. Learn more and access the consultation form on the CTSI website .

The Clinical Research Center (CRC) provides clinical research resources and expertise to investigators who conduct research with human subjects.  The 6,800-square-foot CRC in Hershey is located on the fourth floor of Penn State Health Milton S. Hershey Medical Center and includes clinical exam rooms, private subject beds, procedure space, an observational study suite, consultation space, infusion sleep rooms, negative pressure rooms, DXA scanner and specimen processing and storage space.  The unit is staffed by research nurses who implement protocol-specific requirements including drug administration, timed blood draws, electrocardiograms and assistance with various study-related procedures.  They are certified in chemotherapy/biotherapy administration.  CRC nursing is available 7:30 a.m. to 4 p.m. Monday-Friday.  Nursing assistance may be available outside of these times with adequate notice.  The unit is available by badge access to investigators and their study teams 24 hours a day.

The Exercise Research Center (ERC) is a 4,500-square-foot, state-of-the-art facility conveniently located at the Hershey Center for Applied Research (HCAR) for easy access for participants. Resources include four separate testing areas, a reception and waiting area, exam room and secure file room. The Exercise Research Center has a fee-for-service basis and provides highly skilled and trained exercise physiologists and CRC nursing support to conduct body composition and exercise assessments.

Body Composition equipment includes:

• DXA scanner
• Resting metabolic analyzer
• Bioelectrical impedance analysis (BIA)
• Anthropometric measurers

Exercise Physiology equipment includes:

• Metabolic gas analysis system
• Biodex dynamometer
• Multistation resistance training unit
• Strength training equipment
• Pulmonary function tests
• Treadmills, bikes and arm ergometers

Clinical Research Nurses: Highly skilled clinical research nurses implement protocol-specific procedures and provide direct nursing care for all subjects enrolled in research studies. CRC nurses are committed to subject safety and protocol fidelity. CRC nurses are certified in chemotherapy administration, conscious sedation and ACLS. Learn more about the CRC and request a consultation with the CRC.

The Research Ethics Consultation Service is a free service available to all biomedical researchers at Penn State who seek advice regarding ethically complex aspects of their biomedical research. Learn more on the CTSI website .

The Community Engagement Consultation Service provides opportunities for researchers and community members interested in healthcare research to get expert feedback on how to engage communities around research ideas, proposals, evaluations, and ongoing projects. Learn more on the CTSI website .

CHEER – the Community Health Equity & Engagement in Research program

CHEER is a partnership between the  Social Science Research Institute  (SSRI) and the  Clinical and Translational Science Institute  (CTSI) at Penn State. The CHEER program promotes community-engaged research (CEnR) across Penn State, spanning many disciplines, with the overall goal of enhancing wellness and reducing health disparities. It serves as the landing place for faculty who seek to engage communities in their research and for community organizations and members to engage with  Penn State  expertise. The CHEER team is here to jumpstart your career in CEnR, connect you with community partners based on shared interests, and provide resources and educational programming in an effort to promote meaningful and sustainable partnerships.

The CHEER Researcher Toolkit is designed to educate learners about the importance of community-engaged research (CEnR), guiding CEnR principles to support meaningful engagement and strategies to develop and maintain successful community-academic partnerships. Weaved throughout each section are real-world, evidence-based best practices and resources.

REDCap (Research Electronic Data Capture) is a secure web application for building and managing online surveys and databases. It is a novel workflow methodology and software solution designed by Vanderbilt University for rapid development and deployment of electronic data capture tools to support clinical and translational research. Using REDCap’s streamlined process for rapidly developing projects, you may create and design projects using:

• the online method from your web browser using the Online Designer
• the offline method by constructing a “data dictionary” template file in Microsoft Excel, which can be later uploaded into REDCap

Both surveys and databases (or a mixture of the two) can be built using these methods. REDCap provides audit trails for tracking data manipulation and user activity, as well as automated export procedures for seamless data downloads to Excel, PDF, and common statistical packages (SPSS, SAS, Stata, R). Also included are a built-in project calendar, a scheduling module, ad hoc reporting tools, and advanced features, such as branching logic, file uploading, and calculated fields. REDCap has a quick and easy software installation process, so that you can get REDCap running and fully functional in a matter of minutes. Learn more about REDCap on the CTSI website . The staff of the Data Management Unit at the Department of Public Health Sciences offers REDCap configuration services to allow investigators to more easily develop and implement a fully operational and customized REDCap project based on the needs of their study. Services include:

• REDCap project design ( e.g., longitudinal studies and cross-sectional surveys)
• Development of case report forms, data entry forms and surveys
• Creation of REDCap randomization models as well as backup randomization processes
• Creation of data quality rules and data flow processes
• Customization and implementation of study’s Electronic Regulatory Binder

The Trial Innovation Network is a new collaborative initiative within the Clinical and Translational Science Awards (CTSA) Program and is composed of three key organizational partners – the CTSA Program Hubs, the Trial Innovation Centers (TICs), and the Recruitment Innovation Center (RIC). All are key partners of the Trial Innovation Network and make unique and essential contributions. Other important partners include NIH institutes, other federal and non-federal stakeholders, researchers, patients, providers and the public. The local Penn State Hub Liaison Team works together to provide support and resources for investigators to develop proposals into protocols, optimize study operations, and enhance recruitment and enrollment. Investigators must contact their local Trial Innovation Liaison Team to discuss their proposal and obtain a brief consultation prior to submission. A consultation with the local Trial Innovation Liaison Team is important because these teams will directly connect the local hubs to the national network and provide advice and input on proposals. Learn more on the CTSI website  and  the Trial Innovation Network national site .

The Exercise Research Center provides space, equipment and trained personnel to Penn State investigators. Resources include unique facilities and equipment, as well as highly experiences staff who are trained in human subjects’ protection, good clinical practices, protocol implementation and compliance. The facilities are approximately 4,500 square feet and include a DXA scanner, resting metabolic rate system, BODPOD, anthropometric measures, skinfold calipers and bioelectrical impedance analysis. Exercise testing equipment includes stationary and portable VO2 metabolic systems, a Biodex, resting ECG, treadmills, weight machines, bikes and a multi-station, resistance training unit.

Exercise Physiologist: A highly skilled exercise physiologist staffs the ERC and can provide oversight of all of the tests that can be conducted at the facility. The ERC exercise physiologist is committed to subject safety.

Learn more about the Exercise Research Center on the Clinical Research Center website .

Study Development and Feasibility

A pool of potential study subjects can be estimated using TriNetX. Through TriNetX, users search for patients meeting specified criteria in a de-identified database, without prior Institutional Review Board (IRB) approval. Data are presented as unique patient counts, and a patient is counted only once. Data in TriNetX also exclude patients with only a medical record number or without diagnoses or codes. Such a search can help researchers determine whether enough potential patients are available to properly conduct a research study. With IRB approval and an enterprise information management request, patient-level data can be requested.

TriNetX also offers chart and graph options for data visualization and includes a rate-of-arrival algorithm. This algorithm determines how many patients matching certain criteria visited Penn State Health within the past three years, and then predicts how many potential visits will happen each quarter over the next year. A Trial Connect feature allows clinical research organizations and industry sponsors to determine and connect with potential study sites.

Learn more at Penn State Clinical and Translational Science Institute’s website .

(45 CFR 164.512(i)(1)(ii))

If it is necessary to access identifiable patient data to determine if a research project is feasible, investigators must submit a Review Preparatory to Research Form to the Penn State IRB, which serves as the Penn State Health Privacy Board, prior to reviewing any records.

The Review Preparatory to Research Form should be used if the investigator wishes to look at identifiable health information for a research purpose prior to IRB submission, i.e. , to determine whether a research project is feasible, or to aid in drafting study forms or protocols. Investigators do not need to file this form to access de-identified data through TriNetX .

In order to remain compliant with the privacy laws, investigators are strongly encouraged to utilize de-identified data, when possible, and access such data through TriNetX. In cases where accessing de-identified data is not sufficient, the Review Preparatory to Research Form should be submitted to the Human Research Protection Program using the link above.

For all preparatory requests, the following rules apply:

• The investigator must attest that the work is solely to review PHI to prepare a research protocol or for similar purposes preparatory to research.
• The investigator must provide a statement affirming that no PHI will be removed from the covered entity by the researcher in the course of the review. This means that the data retrieved cannot be shared, in an identifiable fashion, with any person or third-party agency.
• The investigator may only access the information necessary to reach their research goals in accordance with the Minimum Necessary Rule.
• The investigator must agree that any access to PHI without a signed HIPAA authorization will be tracked by the individual accessing the information.

This activity is required for industry-sponsored clinical studies and investigator-initiated clinical studies with funding from industry. In many instances a sponsor sends a Confidential Disclosure Agreement (CDA) prior to sharing a protocol or confidential documents. If a CDA is not provided by industry, a PI may request that the Office of Research Affairs send a CDA to the industry representative. If a PI receives a CDA or would like to send a CDA, the request should be submitted via this online form (Penn State Access ID login required). The Office Research Affairs reviews CDAs in great detail and ensures that it complies with the Penn State Health and Penn State College of Medicine rules for confidentiality, data retention and information ownership. CDAs require an authorized signature of Penn State College of Medicine, as well as a signature from the PI acknowledging the confidentiality obligations. See the “Submitting Contracts for Approval” section of this guidebook for other industry contract-related activities.

The Department of Medicine, under the direction of Dr. Christopher Sciamanna, operates a grant preparation service for investigator-initiated clinical trials. The group works with faculty who are at the point in their career where they have some pilot data, a compelling clinical trial question to answer and the ability to do the work if funded. The team includes a PhD with experimental research training who works closely with Dr. Sciamanna and a grants management specialist to address budgetary and other grant requirements. This is not solely a grant preparation service and works closely with investigators to help them design the trial so that it has the greatest possible chance of external funding. This group focuses the grants toward large federal funders (NIH, PCORI, etc) but is not opposed to other sources, assuming they are large enough to conduct a properly powered clinical trial. The first step to using this service is to speak to Dr. Sciamanna ( [email protected] ). The group works with investigators in departments other than Medicine, and the service has been operational since 2016.

The Department of Public Health Sciences has been serving as a data coordinating center for NIH-funded multi-site clinical trials since 1993. Through this experience, the department has developed the following areas of expertise:

• Data management
• Biostatistics
• Research computing
• Project management

After consulting with you and assessing the scope of the project, an experienced individual, or a full team of qualified researchers, can be assigned to work with you to efficiently handle all aspects of your project. Services include protocol development, project management (both administrative and clinical), forms development, data management, REDCap development, custom application development, IND/IDE submissions, manual of operations (MOP) development, statistical consultations, and snalysis and manuscript preparation and review. Learn more about services from the Department of Public Health Sciences .

Some no-cost support is available through the Biostatistics, Epidemiology and Research Design (BERD) core within the Clinical and Translational Science Institute (CTSI). Request a consultation for all BERD services here .

Monitoring is the act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, SOPs, GCPs, and the applicable regulatory requirement(s).

Typically, academic sites are familiar with monitors assigned by a sponsor or a contract research organization (CRO). However, GCP requires that investigator-initiated trials enrolling human subjects also provide a monitoring plan to assure that the data collected throughout the study are accurate. In addition, the Code of Federal Regulations requires monitoring under 21CFR 312 subpart D (for INDs) and 21CFR 812 subpart C (for IDEs).

Sponsors (including Sponsor-Investigators) of clinical investigations conducted under an IND or IDE are required to provide oversight to ensure adequate protection of the rights, welfare, and safety of human subjects and the quality and integrity of the resulting data submitted to FDA.

This oversight is maintained through the regular review of the source data, case report forms, informed consents, regulatory documents and any other essential documents by a monitor.

During a monitoring visit, a monitor reviews individual subject records and source documents, regulatory binder(s), and other essential documents and compares the information with data recorded on the case report forms (CRF) or entered in the electronic case report form (eCRF).

The monitor is obligated to ensure the following:

• Subjects meet eligibility requirements
• The rights and safety of human subjects are protected
• Informed consent has been obtained and documented appropriately
• Conduct of trial is in compliance with protocol, good clinical practice (GCP), and applicable regulatory requirements
• Subject was followed and treated according to the protocol
• Reported trial data are accurate, complete, and 100% verifiable from source documents; all pertinent information in the subject records must be accurately recorded on the CRF
• The CRF is complete, legible, and consistent throughout visits

Typically, in an industry-sponsored study, the pharmaceutical company will provide the monitor for the study. However, in the case of a study conducted by a Sponsor-Investigator, the Investigator takes on the responsibility of ensuring that the study is being monitored.

For industry-sponsored studies a monitoring plan will often be used to guide the frequency of monitoring visits to investigative sites whereas in an Investigator-initiated study the Investigator and/or study staff should develop a monitoring plan.

The frequency of visits is affected by the complexity of the study and the rate of enrollment. Monitoring plans can be updated during the course of the study if, for example, enrollment is faster than expected. When a monitor comes to a clinical site to conduct a monitoring visit, they will need access to all source documents, including the Electronic Medical Record (EMR).

Learn more about the process for requesting monitoring access to the EMR via the Clinical Trials Office .

Clinical Trial Monitoring Services are required by Penn State College of Medicine Institutional Review Board (IRB) and Research Quality Assurance (RQA) offices for investigational drug/devices (IND/IDE), multisite and high-risk clinical trials. The Data Management Unit of the Department of Public Health Sciences receives institutional support to provide no-cost monitoring services, as directed by the IRB and RQA offices, to Penn State investigators conducting clinical research. Additionally, budget estimates can be prepared for other types of human subject research interested in data monitoring services. Estimates should be obtained early in the protocol development and feasibility process. Clinical Trial Monitoring services provided by the Data Management Unit help the investigator ensure that:

• All clinical trial activities follow the research protocol
• Participants’ rights, welfare, and safety are protected
• Quality, reliability, and integrity of data collected are maintained throughout the study
• Liability risk to the institution is minimized

Services include:

• Creation of a customized data monitoring plan
• Source document verification
• Review of regulatory documents
• Tracking of investigational products
• Data monitoring visits

See the Department of Public Health Sciences for details .

This section describes the roles, responsibilities and operating procedures of Data Monitoring Committees (DMCs) (also known as Data and Safety Monitoring Boards (DSMBs) or Data and Safety Monitoring Committees (DSMCs) that may carry out important aspects of clinical trial monitoring. A clinical trial Data Monitoring Committee is a group of individuals with pertinent expertise that reviews on a regular basis accumulating data from one or more ongoing clinical trials. The DMC advises the investigator regarding the continuing safety of trial subjects and those yet to be recruited to the trial, as well as the continuing validity and scientific merit of the trial. DMCs have the practical position of seeing data and safety information in more frequent intervals and with typically more statistical expertise to make enhanced assessments about a study’s progress and determine the study’s future.

DMC/B: What do they do?

DMC/Bs perform the following general functions:

• Objectively appraise a study’s progress
• Assess data quality via a formal and planned process
• Provide analytical expertise and rigor
• Determine the statistical significance of efficacy and/or risk‐benefit ratio
• Serve as “another set of eyes”

In accordance with its analytic and ethical responsibilities, a DMC is tasked to determine whether a study can proceed with enrollment, as designed. It has the authority to halt a study, suspending enrollment, pending crucial changes to the protocol’s design, recruitment strategy, risk minimization, or other modification. It can also terminate a study due to statistically significant efficacy or increased risk of harm to participants.

DMC/Bs: When are they needed?

A fundamental reason to establish a DMC/B is to enhance the safety of trial participants in situations, in which safety concerns may be unusually high, in order that regular interim analyses of the accumulating data are performed. All clinical trials require safety monitoring, but not all trials require monitoring by a formal DSMC/B. DMC/Bs are established for large, randomized multisite studies that evaluate treatments intended to prolong life or reduce risk of a major adverse health outcome such as a cardiovascular event or recurrence of cancer. DMC/Bs are generally recommended for any controlled trial of any size that will compare rates of mortality or major morbidity. Formal data and safety monitoring is also necessary to assure confidence in a study’s interim and final outcomes:

• To verify or validate efficacy and/or safety information significant to a novel therapy
• To gauge data quality to confirm the research question/ hypothesis in developing treatments
• To assess efficacy and safety when “lives and wellbeing depend on valid results”

The FDA recommends that sponsors consider using a DMC/B when:

• The study endpoint is such that a highly favorable or unfavorable result, or even a finding of futility, at an interim analysis might ethically require termination of the study before its planned completion
• There are a priori reasons for a particular safety concern, as, for example, if the procedure for administering the treatment is particularly invasive
• There is prior information suggesting the possibility of serious toxicity with the study treatment
• The study is being performed in a potentially fragile population such as children, pregnant women or the very elderly, or other vulnerable populations, such as those who are terminally ill or of diminished mental capacity
• The study is being performed in a population at elevated risk of death or other serious outcomes, even when the study objective addresses a lesser endpoint
• The study is large, of long duration, and multi-center

In studies with one or more of these characteristics, the additional oversight provided by a DMC/B can further protect study participants. In other studies, such as short-term studies for relief of symptoms as noted above, such committees are generally not warranted. ( FDA Guidance: The Establishment and Operation of Clinical Trial Data Monitoring Committees for Clinical Trial Sponsors – Guidance for Clinical Trial Sponsors – Establishment and Operation of Clinical Trial Data Monitoring Committees )

DMC/B Charters

DMC/Bs typically operate under a written charter that includes well-defined standard operating procedures. Such charters are important for the same reason that study protocols and analytical plans are important—they document that procedures were pre-specified and thereby reduce concerns that operations inappropriately influenced by interim data could bias the trial results and interpretation. The sponsor may draft this charter and present it to the DMC/B for agreement, or the DMC/B may draft the charter with subsequent concurrence by the sponsor. Topics to be addressed would normally include a schedule and format for meetings, format for presentation of data, specification of who will have access to interim data and who may attend all or part of DMC/B meetings, procedures for assessing conflict of interest of potential DMC/B members, the method and timing of providing interim reports to the DMC/B, and other issues relevant to committee operations. FDA may request that the sponsor submit the charter to FDA well in advance of the performance of any interim analyses, ideally before the initiation of the trial (see 21 CFR 312.23(a)(6)(iii)(g); 21 CFR 312.41(a); 21 CFR 812.150(b)(10)). In such cases, FDA would usually consider the charter when FDA reviews the study protocol. ( FDA Guidance: The Establishment and Operation of Clinical Trial Data Monitoring Committees for Clinical Trial Sponsors – Guidance for Clinical Trial Sponsors – Establishment and Operation of Clinical Trial Data Monitoring Committees )

The Department of Radiology supports and encourages clinical research at Penn State Health and Penn State College of Medicine. If your protocol contains ionizing radiation procedures (standard of care and/or research-related procedures), you must complete the Radiation Review Form and include it with your IRB submission in CATS IRB. All research protocols/studies that involve non-routine radiation procedures must be reviewed by the Human Use of Isotope Committee (HUIC). It is also highly advised that you communicate with the CTO prior to starting your study or even at the protocol preparation step. CTO will work with Radiology to establish the exact process for your procedure and will provide a cost estimate. This is especially important if your experimental requirements deviate from the standard radiology procedures, i.e. require an unusual contrast agent. It is not uncommon that radiology services are not clearly detailed in the text of the protocol, potentially resulting in additional unanticipated charges at the point of service. See the Additional Approvals in the “Preparing Documents” section of this guidebook for details. HRP 903 Radiation Review Form is available in the CATS IRB library (login required).

The Department of Pathology is committed to excellence in patient care, education, and translational and basic research, and plays a vital and integral role in the medical center’s multifaceted missions. Through provision of high quality diagnostic services and the practice of laboratory medicine, the department supports the wide range of medical care provided at the institution.

Find Laboratory Licenses (such as CLIA) and Accreditations via the Clinical Trials Office .

Investigators planning to use any of the following specimens in their research project must complete the Use of Human Tissue for Research Form and include it with the CATS IRB Submission:

• Collection of tissue from surgical or biopsy procedures
• Collection of bone marrow from bone marrow biopsies and/or bone marrow aspirates
• Use of archival pathologic specimens stored in Anatomic Pathology
• Collection of tissue from cadavers
• Collection of placenta specimens

The completed form is reviewed by Anatomic Pathology during IRB review. After review and approval of the proposed tissue request, the Department of Pathology will notify the investigator and the IRB. Pathology approval will be required before the official IRB approval is issued.

No tissue will be released to an investigator without approval from Anatomic Pathology. See the Additional Approvals item in the “Preparing Documents” section of this guidebook for details.

General Information on Pathology

Any time human tissue is removed for research purposes, the specimen must pass through either the Surgical Pathology Laboratory or Autopsy Suite. Adequate diagnostic tissue will be retained in the laboratory prior to providing specimens for research. Therefore, Pathology is usually able to provide tissues from major surgical excisions but can only rarely provide tissues from small biopsies obtained for diagnostic purposes.

There is a charge per specimen to help defray the technical cost in obtaining research tissues. Please call the Department of Pathology at 717-531-8352 for the current charge to use when preparing the budget for a grant.

If the investigator is aware that a biopsy or excision of the desired tissue is scheduled, they should complete and submit to the Anatomic Pathology Gross Room (fax to 717-531-0831) a “Research Tissue Request Form” prior to the scheduled date of surgery. This form notifies the Gross Room staff that a specimen is a potential source of research tissue so that the specimen can be handled appropriately for that purpose.

A blank copy of this form can be obtained from the Gross Room; this blank form can be photocopied for multiple submissions.

See the “Investigational Drug Pharmacy (IDS)” section in this guidebook for a detailed description of the Investigational Drug Services (IDS), start-up requirements and fees.

The mission of the Clinical Research Biospecimen Core is to provide a centralized service for the processing and distribution of human subject research samples for all clinical research activities at Penn State College of Medicine and Penn State Health Milton S. Hershey Medical Center.

The goals of the Clinical Research Biospecimen Core (CRBC) are two-fold:

• First, by providing a centralized service for clinical research sample handling, more favorable study contract pricing with extramural research sponsors will be allowed.
• Second, by utilizing a centralized core service dedicated solely to this purpose, internal investigators will find it easier to budget and efficiently conduct their human subject research efforts.

IND and IDE Submissions

FDA’s Center for Drug Evaluation and Research (CDER) is responsible for regulating manufacturing, testing and importation of pharmaceutical drugs in the US. This includes new drug approvals, abbreviated new drug approvals (generics), over-the-counter drugs, animal drugs and biologics. A drug is defined as:

• substance intended for use in diagnosis, cure, mitigation, treatment, or prevention of the disease;
• substances (other than food)intended to affect the structure or any function of the body;
• substance intended for use as a component of a medicine but not a device or component of a device.

Other sections of this guidebook provide a brief summary of regulatory requirements for clinical research involving drugs, biologics or dietary supplements.

Preclinical testing begins after a potential drug has been identified in the lab. Preclinical testing involves lab and animal studies that evaluate the drug’s toxic and pharmacologic effects. Preclinical studies are also subject to the FDA regulations known as Good Laboratory Practices (GLP) for Nonclinical Laboratory Studies, 21 CFR 58. The GLP regulations specify minimum standards in such areas as personnel, facilities, equipment and operations.

Pre-clinical studies not performed under GLP conditions may not be accepted by the FDA. Recognition of this fact is particularly important for academic drug development. Please see “Roadmap for Academic Health Centers to Establish Good Laboratory Practice-Compliant Infrastructure”, Acad. Medicine, 2012 87(3):279-284

Preclinical testing includes pharmacokinetics, the study of how the drug moves through living organisms. Researchers examine absorption, distribution, metabolism and excretion (also abbreviated as ADME) to ensure that the drug reaches its intended target and passes through the body properly. In addition to the biological tests, researchers conduct chemistry tests to establish the drug’s purity, stability and shelf life. Manufacturing tests are conducted to determine the feasibility of producing the drug on a large scale and to explore dosing, packaging and formulation (e.g., pill, inhaler, injection). At the preclinical stage, the FDA will generally ask, at a minimum, that sponsors:

• develop a pharmacological profile of the drug;
• determine the acute toxicity of the drug in at least two species of animals, and
• conduct short-term toxicity studies ranging from two weeks to three months, depending on the proposed duration of use of the substance in the proposed clinical studies.

FDA Guidance for Industry: See Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-derived Products .

After preclinical testing is completed, a sponsor or sponsor-investigator (see below) files an IND with FDA prior to beginning any human testing. An IND is a request for FDA authorization to administer an investigational drug or biological product to humans. Such authorization must be secured prior to interstate shipment and administration of any unapproved drug or biological product that is not the subject of an approved New Drug Application or Biologics/Product License Application. The application must show results of preclinical experiments; the chemical structure of the compound; how it is thought to work in the body; any side effects found in animal studies; and how the compound is manufactured (chemistry, manufacturing and controls section). The IND must also include a detailed clinical trial plan, including how, where and by whom the studies will be conducted. Based on the information of the IND application, the FDA will determine if there is sufficient evidence to support initial human testing. The sponsor must wait 30 days after submitting the IND to the FDA for review. At the end of the 30 day review period, unless the FDA identifies a potential safety problem involving the use of the drug and asks for a delay, the sponsor may begin the proposed clinical testing. Per Penn State University Policy RP-05 “Research Quality in Human Participant Research,” it is required that the Research Quality Assurance (RQA) group be contacted to provide support for the submission process for INDs or IND Exemptions, and to perform an administrative review of the submission prior to being sent to the FDA. See Penn State University policy .

The terms “expanded access,” “compassionate use,” “treatment use” and “treatment IND” are used interchangeably to refer to use of an investigational drug when the primary purpose is to diagnose, monitor, or treat a patient’s disease or condition. Investigational drugs are new drugs that have not yet been approved by the FDA or approved drugs that have not yet been approved for a new use, and are in the process of being tested for safety and effectiveness. The distinction between administering an investigational drug in the setting of a “traditional” clinical trial versus expanded access lies in the intention. In a traditional clinical trial the intention is to understand the safety and effectiveness of the investigational drug; in expanded access the intention is treatment. There are four general guidelines for a drug to be considered for expanded-access use:

• Patients with a serious or immediately life-threatening disease or condition, where there is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the disease or condition.
• No comparable or satisfactory alternative therapy exists.
• The potential patient benefit justifies the potential risks of the treatment, and those risks are not unreasonable in the context of the disease or condition being treated.
• The expanded use of the investigational drug for the requested treatment will not interfere with the initiation, conduct, or completion of clinical investigations that could support marketing approval of the product.

The Human Research Protection Program (HRPP) should be contacted for further guidance as soon as a provider is considering using an investigational drug under any expanded access condition. See FDA details on expanded access .

After clinical trials have been completed demonstrating safety and effectiveness, the study sponsor (or drug manufacturer) will submit a New Drug Application (NDA) to the FDA for a license to market the drug for a specified indication. NDAs contain all of the information about all of the studies, including preclinical testing, all clinical trials, dosing information, manufacturing details and proposed labeling for the new medicine. Most academic drug development efforts do not progress to this stage. At NDA submission stage, FDA scientists review all the results from all the studies carried out over the years and determine if they show that the medicine is safe and effective enough to be approved. During this review, the FDA determines what the labeling should be and whether the sponsor can manufacture it properly and consistently. Once the drug is approved, it becomes available for physicians to prescribe for the indication approved by the FDA. The review process takes approximately 18 months.

Many academic investigators will want to conduct a clinical study with an already approved drug. This is often done to establish efficacy in a new disease indication. FDA provides provisions for conducting studies of lawfully marketed drugs through the use of an IND exemption. A clinical investigation of a drug is exempt from the IND requirements if all of the criteria for an exemption in 21CFR312.2(b) are met:

• The drug product is lawfully marketed in the United States;
• The investigation is not intended to be reported to FDA as a well-controlled study in support of a new indication and there is no intent to use it to support any other significant change in the labeling of the drug;
• The investigation is not intended to support a significant change in advertising to an existing lawfully marketed prescription drug product;
• The investigation does not involve a route of administration or dosage level or use in a patient population or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product;
• The investigation will be conducted in compliance with the requirements for institutional review set forth in FDA regulations 21 CFR 56, and requirements for informed consent as set forth in FDA regulations 21 CFR 50;
• The investigation will be conducted in compliance with FDA regulations 21 CFR 312.7: Promotion of investigational drugs.

Thorough documentation is required to support this exemption criterion and may include prior publications or other public disclosures. If such evidence cannot be provided, a physician should submit a research IND (limited in scope) to the FDA. The physician is now considered sponsor-investigator. FDA Guidance: See Investigational New Drug Applications (INDs) – Determining whether Human Research Studies can be conducted without an IND . Per Penn State University Policy RP-05 “Research Quality in Human Participant Research,” it is required that the Research Quality Assurance (RQA) group be contacted to provide support for the submission process for INDs or IND Exemptions, and to perform an administrative review of the submission prior to being sent to the FDA. See Penn State University policy .

Many clinical studies of academic investigators evaluate the effect of dietary supplements on the disease or physiological parameters. Some of these studies may require an IND submission. If the dietary supplements are investigated for diagnosis, cure, mitigation, treatment, or prevention of disease and are used to affect the structure or function of the body, then the dietary supplement will be considered a drug for the purposes of this study. The study will be the subject to the same regulations as any other unapproved drug. Specifically, the FDA will be paying particular attention to the composition of the dietary supplement, its origin and manufacturing processes. When preparing the INDs for dietary supplements, make sure that the supplement manufacturer is willing to provide this information. FDA Guidance: See Investigational New Drug Applications (INDs) – Determining whether Human Research Studies can be conducted without an IND .

FDA’s Center for Devices and Radiological Health (CDRH) is responsible for regulating manufacturing and importation of medical devices sold in the United States. In addition, CDRH regulates radiation-emitting electronic products (medical and non-medical) such as lasers, X-ray systems, ultrasound equipment, microwave ovens and color televisions.

If a product is labeled, promoted or used in a manner that meets the definition in section 201(h) of the Federal Food Drug & Cosmetic (FD&C) Act, it will be regulated as a medical device.

A device is: “an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is:

• “intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals,” or
• “intended to affect the structure or any function of the body of man or other animals, and which does not achieve any of its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes.”

This definition provides a clear distinction between a medical device and other FDA regulated products such as drugs. If the primary intended use of the product is achieved through chemical action or by being metabolized by the body, the product is usually a drug. In cases where it is not clear whether a product is a medical device the Division of Small Manufacturers, International and Consumer Assistance (DSMICA) can assist in making a determination.

FDA Guidance: See Frequently Asked Questions about Medical Devices .

See details via the Clinical Trials Office .

The FDA has established classifications for approximately 1,700 different generic types of devices and grouped them into 16 medical specialties referred to as panels. Each of these generic types of devices is assigned to one of three regulatory classes (Class I, Class II and Class III) based on the level of control necessary to assure the safety and effectiveness of the device.

The device classification defines the regulatory requirements for an approval of a new device. Regulatory control increases from Class I to Class II to Class III. Device classification depends on the intended use of the device and also upon indications for use. In addition, classification is risk-based, that is, the risk the device poses to the patient and/or the user is a major factor in the class it is assigned.

• Class I devices: elastic bandages, examination gloves and hand-held surgical instruments.
• Class II devices: powered wheelchairs, infusion pumps and surgical drapes.
• Class III devices: implantable pacemaker pulse generators and coronary stents.

To find the classification of a device, as well as whether any exemptions may exist, the classification regulation number should be determined for the device. One of the ways to accomplish this is to go directly to the FDA classification database and search for a part of the device name. Once the correct classification regulation has been identified, go to the device panel (medical specialty) to which the device belongs .

The search will provide the Device Classification and the appropriate CFR regulation for the device. If the device is not classified, similar devices can be researched on the FDA website (PMA and 510(k) databases) or pre-IDE consultation can be used for the FDA determination. The CTO has additional device information specific to our Medicare Administrative Contractor (MAC), Novitas Solutions, Inc.

Devices used on human subjects to conduct investigations of safety and effectiveness are considered “Investigational Devices” (Section 520(g) of FD&C Act). Significant Risk (SR) device presents a potential for serious risk to the health, safety and welfare of a subject, and:

• Intended to be used as an implant
• Purported to support or sustain human life
• Is used for substantial importance in diagnosing, curing, mitigating or treating disease, or
• Otherwise presents a potential for serious risk to the health, safety, or welfare of a subject.

Examples of SR devices include sutures, cardiac pacemakers, hydrocephalus shunts, and orthopedic implants. Conversely, non-significant risk (NSR) device studies do not pose a significant risk to patients. Non-significant risk should not be confused with “minimal risk,” a term used by the FDA to classify studies. Examples of NSR devices include most day-wear contact lenses and lens solutions, ultrasonic dental scalers, and foley catheters. SR devices must meet all regulatory requirements set in 21 CFR 812, including the requirement for approval by both IRB and the FDA before commencing the study. Significant risk devices require submission of an investigational device exemption (IDE) to CDRH. NSR device studies may commence without FDA approval, based solely on the IRB approval. However, the sponsor-investigator must follow abbreviated IDE requirements, which are, in essence, the same requirements as regular IDE only without FDA submission (21 CFR 812.2 (b)). The IRB acts as a surrogate overseer for the FDA. FDA Guidance: See Significant Risk and Non-significant Risk Medical Device Studies .

Important: Clinical study of a new indication or new patient population for an already marketed device falls under the IDE regulations. Per Penn State University Policy RP-05, “Research Quality in Human Participant Research,” it is required that the Research Quality Assurance (RQA) group be contacted to provide support for the submission process for IDEs or Study Risk Determinations, and to perform an administrative review of the submission prior to being sent to the FDA. See Penn State University policy . An investigational device exemption (IDE) is a regulatory submission to the CDRH. If approved, it allows the investigational device to be used in a clinical study in order to collect safety and effectiveness data. IDE requirements:

• Study approved by an institutional review board (IRB). If the study involves a significant risk device, the IDE must also be approved by FDA;
• Informed consent from all patients obtained and documented;
• The device is labeled “CAUTION- Investigational Device. Limited to investigational use only;”
• Sponsor-investigator complies with monitoring requirements;
• Records and reports are maintained;
• Investigator cannot promote or commercialize (charge for) the device.

FDA Guidance: See Investigational Device Exemptions (IDEs) for Early Feasibility Medical Device Clinical Studies, Including Certain First in Human (FIH) Studies . Two important elements of the guidance are:

• FDA approval of an IDE application for an early feasibility study, including some first-in-human studies, may be based on less nonclinical data than would be expected for other types of studies (e.g., traditional feasibility or pivotal).
• more types of modifications that can be made under a 5-day notification without prior FDA approval, as compared with other types of studies;
• a contingent approval process that permits changes contingent upon acceptable
• nonclinical test results without requiring additional FDA action; and
• interactive review of IDE supplements and amendments.

Studies of non-significant risk devices are subject to abbreviated IDE requirements. An IDE submission to the FDA is not required under the abbreviated requirements, but the requirements for labeling, IRB approval, informed consent, monitoring, records, reports and promotional practices contained in FDA regulations still apply (21 CFR 812.2(b)). In addition, the concept of “non-significant risk” to determine whether abbreviated IDE procedures are appropriate should not be confused with “minimal risk” to determine whether expedited IRB review is appropriate. For a device study to be eligible for expedited IRB review, it must be a non-significant risk device AND present no more than minimal risk to the subject (ref. 21 CFR 56.110). Requirements under abbreviated IDE:

• The sponsor will label the device in accordance with 21 CFR 812.5.
• The sponsor will obtain and maintain IRB approval throughout the investigation as a nonsignificant risk device.
• The sponsor will ensure that each investigator participating in an investigation of the device obtains and documents consent from each subject under the investigator’s care according to 21 CFR 50, unless documentation is waived by an IRB.
• The sponsor will comply with the requirements of 21 CFR 812.46 with respect to monitoring investigations.
• The sponsor will maintain the records required under 21 CFR 812.140(b) (4) and (5) and make the reports required under 21 CFR §812.150(b) (1) – (3) and (5) – (10); The sponsor will ensure that participating investigators will maintain the records required by 21 CFR 812.140(a)(3)(i) and make the reports required under 812.150(a) (1), (2), (5), and (7).
• The sponsor will comply with the prohibitions in 21 CFR 812.7 against promotion and other practices.

Some studies may be exempt from the IDE regulations. The exemption criteria is explained in 21 CFR 812.2(c), and briefly summarized here:

• A legally marketed device when used in accordance with its labeling;
• noninvasive;
• does not require an invasive sampling procedure that presents significant risk;
• does not by design or intention introduce energy into a subject;
• and is not used as a diagnostic procedure without confirmation of the diagnosis by another medically established diagnostic product or procedure.
• Consumer preference testing, testing of a modification, or testing of a combination of two or more devices in commercial distribution, if the testing is not for the purpose of determining safety or effectiveness and does not put subjects at risk;
• A device intended solely for veterinary use;
• A device shipped solely for research with laboratory animals;
• A custom device as defined in 812.3(b).

An unapproved medical device is a device that is utilized for a purpose, condition, or use for which the device requires, but does not have, an approved application for premarket approval or an approved IDE. Emergency use is permitted if the treating physician determines that:

• The patient has life-threatening condition that needs immediate treatment
• No generally acceptable alternative treatments exist
• Because of an immediate need to use the device, there is no time to use existing procedures to get FDA approval

Next, the treating physician needs to undertake the following protective measures:

• An independent assessment by an uninvolved physician
• Informed consent from the patient or legal representative
• Clearance from the institution as specified by their policies
• Approval of the IRB Chair
• Approval from the IDE sponsor, if an approved IDE exists for the device
• Prior FDA approval for shipment or emergency use of the investigational device is not required, but the use should be reported to the FDA by the IDE sponsor via a supplement within 5 working days from the time the sponsor learns of the use.

Note that if a physician who is faced with an emergency situation contacts the FDA to discuss their patient’s condition, in this situation the FDA will only act in an advisory role, rather than in an approving role. The responsibility for making the decision as to whether the situation meets the emergency use criteria and whether the unapproved device should be used lies with the physician. FDA Guidance: See Emergency Use Authorization of Medical Products . See detailed guidance about what to submit to the IRB/HSPO .

This type of use is not an emergency use. The compassionate use (or Single Patient/Small Group Access) provision allows access for patients who do not meet the requirements for inclusion in a clinical investigation but for whom the device may provide a benefit in treating and/or diagnosing their disease or condition. This provision is typically approved for individual patients but may be approved to treat a small group. Compassionate use requires the submission by the sponsor or investigator of an IDE Supplement as per 21 CFR 812.35 requesting approval in order to treat the patient(s). In order to permit this use, FDA will review the following information:

• The patient’s condition and the circumstances necessitating treatment
• Whether comparable alternative treatment exists, and the probable risk of using the investigational device is no greater than the probable risk from the disease or condition
• The protocol to be followed, or deviations from the approved clinical protocol that may be needed in order to treat the patient
• The patient protection measures that will be followed (informed consent, concurrence of IRB chairperson, clearance from the institution, independent assessment from uninvolved physician, authorization from IDE sponsor)
• Whether the preliminary evidence of safety and effectiveness justifies such use
• Whether such use would interfere with the conduct of ongoing clinical investigations

The investigator should not treat the patient identified in the supplement until FDA approves use of the device under the proposed circumstances.

This type of use is not an emergency use. A request for Treatment Use of an investigational device in the mitigation, diagnosis and treatment of a serious disease requires a Treatment IDE Submission as per 21 CFR 812.36. If approved, Treatment IDE enables a wider group of patients to receive the investigational device for the same indication as it is being studied under the sponsor IDE. During the course of the clinical trial, if the data suggests that the device is effective, then the trial may be expanded to include additional patients with life-threatening or serious diseases. Treatment IDE will remain open even after the sponsor trial has been completed. The following provisions have to be met:

• Life-threatening or serious disease or condition
• Device is investigated in a controlled clinical trial under IDE for the same use
• Sponsor is actively pursuing market approval
• No comparable alternative treatment exists
• The device is under investigation in a controlled clinical trial for the same use under an approved IDE, or such clinical trials have been completed.

Premarket approval (PMA) (21 CFR 814.39) is the FDA process of scientific and regulatory review to evaluate the safety and effectiveness of Class III medical devices. Due to the level of risk associated with Class III devices, FDA requires sufficient valid scientific evidence to assure that the device is safe and effective for its intended use(s). The content of PMA is similar to the NDA for new drugs, and contains manufacturing sections, pre-clinical laboratory studies and clinical investigations. Some devices (from Class I or Class II) may be able to be cleared under a different pathway referred to as premarket notification, or 510(k). The name refers to requirements outlined in section 510(k) of Food, Drug and Cosmetics Act. If the device is considered to be substantially equivalent to one or more similarly marketed devices (known as “predicate” devices), a claim of substantial equivalence can be made. A claim of substantial equivalence does not mean the new and predicate devices must be identical. Substantial equivalence is established with respect to intended use, design and other parameters.

A Humanitarian Use Device (HUD) is a “medical device intended to benefit patients in the treatment or diagnosis of diseases or conditions that affect or are manifested in fewer than 4,000 individuals in the United States per year.” (21 CFR 814). The request for HUD designation is described in the following FDA guidance: Humanitarian Use Device (HUD) Designations . The first step in seeking marketing approval of a HUD involves obtaining HUD designation of the device from FDA’s Office of Orphan Products Development. If the HUD request is granted, the investigator proceeds with the second step by submitting of a Humanitarian Device Exemption (HDE) application to the Office of Device Evaluation (ODE), Center for Devices and Radiological Health (CDRH), the Center for Biologics Evaluation and Research (CBER), or the Center for Drug Evaluation and Research (CDER), as applicable. An HDE is similar in both form and content to a premarket approval (PMA) application, but is exempt from the effectiveness requirements of a PMA. An HDE application is not required to contain the results of scientifically valid clinical investigations demonstrating that the device is effective for its intended purpose. The application, however, must contain sufficient information for FDA to determine that the probable benefit to health outweighs the risk of injury or illness, taking into account the probable risks and benefits of currently available devices or alternative forms of treatment. Additionally, the applicant must demonstrate that no comparable devices are available to treat or diagnose the disease or condition, and that they could not otherwise bring the device to market.

Sponsor-Investigator responsibilities under an IND or IDE are covered in 21 CFR Part 312 (for drugs) and 21 CFR Part 812 (for devices). FDA Guidance: Search for Investigator Responsibilities – Protecting the Rights, Safety and Welfare of Study Subjects .

The Research Quality Assurance (RQA) Group is available to assist with IND/IDE preparation, submission and maintenance.

Learn more about RQA .

The process and format for submitting an IND application is defined in 21 CFR 312.23, “IND Content and Format.”

The process and format for submitting an IDE application is defined in 21 CFR 812.20, “Investigational Device Exemptions – Application.”

Per Penn State University Policy RP-05, “Research Quality in Human Participant Research,” it is required that the Research Quality Assurance (RQA) group be contacted to provide support for the submission process for IDEs or Study Risk Determinations, and to perform an administrative review of the submission prior to being sent to the FDA.

See Penn State University policy .

See RQA contact details .

Preparing Documents

The purpose of these SOPs is to provide guidance to research personnel on how a clinical trial payer Coverage Analysis (CA) and budget negotiation process is under-taken in order to receive institutional and departmental approvals.

All clinical trials involving human subjects with potentially billable items and services, regardless of the funding source, should have a CA performed. Simply stated, a CA is required for studies that include services billable to insurance (i.e., when it is possible for a charge to be captured in the billing system).

The CA is not needed if a trial uses existing specimens or involves collecting data based on clinical progression. A survey, retrospective or observational study only includes a collection of forms during the patient’s standard of care. Since form collection is not billable to insurance, a CA is not required. The CA is necessary to assist in determining the responsibility of charges in a clinical trial.

A CA is a systematic review of study-related documents to determine the Medicare billing status of both the study and the items/services provided to research participants as part of a clinical research study. The CA process involves the following steps:

• Identifying studies required to undergo CA.
• Creating of the Coverage Analysis Review memo.
• Performing the “qualifying status” of the clinical trial.
• Identifying Routine Costs.
• Constructing the Study Billing Grid.
• Providing the Study Billing Grid as a tool for study team use.

Primary objective: To ensure all costs of a clinical trial are billed to the appropriate payer (sponsor, alternate funding source, institution/department, third-party payer, or participant) Medicare rules are used for various reasons. Foremost, it is not practical to budget on non-Medicare rules since Medicare drives the reimbursement rules in the United States. Medicare incorporates the “most favored nation” clause. This means that if a Medicare patient is enrolled in a clinical research study, the best deal must be given to the Medicare participant. Medicare rules for research coverage are being adopted by commercial payers, with many states already requiring commercial payers to follow rules similar to Medicare. Even pediatric studies go through the CA process since budget negotiations are based off of the coverage analysis results.

There are multiple benefits to performing a CA. It affords the institution an approach to tease out research-only charges from those items/services that are routine and/or customary care. Used as an asset in preparing a budget, it provides opportunities for increased revenue. Early detection of items/services that are not covered allows for appropriate negotiation. Additionally, we need to know the billing status of all trial procedures in order to perform a proper informed consent process. Participants are entitled to know what their financial responsibility will be during a clinical trial. Finally, it is necessary for compliant research billing processes. Errors in billing Medicare for items/services relative to clinical trials could result in allegations under the False Claims Act. Substantial fines and penalties may result. Loss of trust by sponsors and participants as well as loss of government funding may occur. Since clinical research often takes place in conjunction with the routine clinical care of patients, it is imperative to ensure that billing for both routine and research services/items are handled appropriately and in compliance with all applicable statutory requirements.

Determining coverage involves a multi-phased approach.

• If it is possible for a charge to be captured in the billing system, then a CA is performed.
• Examples of studies not requiring a CA: existing specimens, data collection on clinical progression.
• Initiate a Coverage Analysis Review memo to document and memorialize the evolution of coverage decisions.

Part 1: Identify if a clinical trial “qualifies” for Medicare coverage

• Non-device trials: Consult The Centers for Medicare and Medicaid Services (CMS) for coverage requirements (NCD 310.1: National Coverage Determination for Routine Costs in Clinical Trials).
• Device trials: CMS has established regulations for coverage of device trials. Consult the Code of Federal Regulations 42CFR 405.201 – 405.215 and 411.215 and 411.406. Additional information can be found on the Medicare Administrative Contractor’s website for our jurisdiction .

Part 2: Pinpoint items/services that are “routine costs” in the study and potentially billable

• Items or services that are typically provided absent a clinical trial (e.g., conventional care);
• Items or services required solely for the provision of the investigational item or service (e.g., administration of a non-covered chemotherapeutic agent, or surgery to implant an investigational device);
• Items or services required for the clinically appropriate monitoring of the effects of the item or service, or the prevention of complications (e.g., additional labs to monitor for side effects of the investigational product); and,
• Items or services needed for reasonable and necessary care arising from the provision of an investigational item or service, in particular for the diagnosis or treatment of complications.

Part 3: Review all statutes, regulations, national and local coverage determinations, Medicare manuals, and specialty specific practice guidelines

Analyzing items/services is solely done for billing purposes, not to judge what the provider should/should not be doing.

Further Details

Medicare/insurance will not cover items and services that are paid for by the sponsor, promised free in the informed consent document, not ordinarily covered by Medicare, and items/services used solely to satisfy data collection or analysis needs. In certain very specific instances CMS can be billed when the study is non-qualifying such as those trials that involve NO changes to medical management or treatment (i.e., observational, registry, or head-to-head). These types of quality trials do not fall under the scope of NCD 310.1. Every effort must take place to ensure that the usual, routine, medically necessary item is not provided based on protocol requirements, but rather would have been provided by the provider even in the absence of study participation.

Modifiers: A claim that contains an “investigational clinical service” must use the Q0 modifier on the HCFA 1450 form (for facilities) or on the HCFA 1500 form (for physicians). A claim that contains a “routine clinical service” must use the Q1 modifier on the forms. When Q1 is billed in conjunction with the ICD-10, Z00.6 diagnosis code, the Q1 modifier will serve as the provider’s attestation that the service meets the Medicare coverage criteria; i.e. was furnished to a beneficiary who is participating in a Medicare qualifying clinical trial and represents routine patient care, including complications associated with qualifying trial participation. National Clinical Trial (NCT) identifier or Clinicaltrials.gov Number: CMS requires ClinicalTrials.gov number on the claim when billing “routine costs” during a “qualifying clinical trial.” For clinical trial/registry/study claims with dates of service on and after January 1, 2014, this 8-digit clinical trial number must be included or claims will be returned as unprocessable. Study teams are responsible for providing sufficient information to add these identifiers to the claims. Medicare Advantage Plans (MAPs): If your study enrolls patients on the Medicare Advantage Plan, you need to be aware of special requirements for copays and claims processing. See the Medicare Managed Care Manual for details .

• Non-Device Trials: When enrolled in a qualifying clinical trial, Medicare pays for covered services as if in the original, traditional Medicare program (fee-for-service). Providers should split outpatient MAP claims and route the protocol-related “routine care” to traditional Medicare. Additionally, MAPs are responsible for copayments related to services paid under the traditional Medicare rules.
• The MAP is responsible for payment of routine care items and services in CMS-approved Category A IDE studies.
• The MAP is responsible for payment of routine care items and services, and potentially the Category B device under study in CMS-approved Category B IDE studies.

Education materials are available via the College of Medicine Clinical Trials Office’s section of this website. Additionally, in-person Clinical Research Skills Workshops are held annually.

While the clinical sites typically provide medical treatment to the subjects sustaining injury/complication on the study, who will cover the costs may not always be a clear decision. Industry sponsor, insurance or even self-pay options are considered. For privately sponsored studies that are conducted pursuant to a private sponsor’s protocol (industry sponsor), the sponsor of the study is required to pay for the reasonable cost of treating injuries or complications resulting from participation in the study, including injuries or complications resulting from the study material or research procedures performed pursuant to the study protocol, to the extent that injuries/complications were not a result of negligence, willful misconduct or failure to reasonably act on the part of the study personnel. Other costs that are incurred during conduct of the study but not resulting from the subject’s participation (i.e., typical for this type of disease or procedure) may be billed to private and government insurers, if consistent with their policies. However, in the case of injuries resulting from the natural progression of a disease or illness, the sponsor would be responsible for any injuries if, and to the extent, the progression resulted from participation in the study. In some cases, determination of whether the complication was directly or indirectly related may not be clear.

If an investigational medication is administered via an intravenous infusion, and the needle entry site became infected, it does not necessarily mean that this injury is directly related to the investigational drug administration. Other factors need to be considered. For instance, if the standard of care or alternative treatment is an oral medication, then the i.v. infection may be directly attributed to the investigational study drug. However, if the standard of care treatment is also intravenous, then the infection maybe construed as being a consequence of this typical intravenous procedure, and therefore, not directly related to the investigational drug administration.

When the trial is not conducted pursuant to a private industry sponsor protocol, the costs of treating study subjects for injuries or complications resulting from a study material or research procedures will be the responsibility of the subject or the subject’s Medicare/private insurance plans. Further guidance is available under “Compensation for Injury” in the PSU Standard Consent Language.

It is not uncommon for participants to be paid for their participation in research, especially in the early phases of investigational drug, biologic or device development. Financial remuneration is often used when health benefits to participants are remote or non-existent. Payment to research participants for participation in studies is not considered a benefit, it is a recruitment incentive. However, the payment should appropriate to what is being asked of the participant to do during the study and relative to the potential harm/discomfort of participating in research. The payment should not unduly induce a person to participate.

The Institutional Review Board (IRB) should determine that the risks to participants are reasonable in relation to anticipated benefits [21 CFR 56.111(a)(2)] and that the consent document contains an adequate description of the study procedures [21 CFR 50.25(a)(1)] as well as the risks [21 CFR 50.25(a)(2)] and benefits [21 CFR 50.25(a)(3)]. Therefore, the IRB should review both the amount of payment and the proposed method and timing of disbursement to assure that either are coercive or present undue influence [21 CFR 50.20].

The amount and schedule of all payments should be presented to the IRB at the time of initial review. Any credit for payment should accrue as the study progresses and not be contingent upon the subject completing the entire study. Unless it creates undue inconvenience or a coercive practice, payment to participants who withdraw from the study may be made at the time they would have completed the study (or completed a phase of the study) had they not withdrawn. For example, in a study lasting only a few days, an IRB may find it permissible to allow a single payment date at the end of the study, even to participants who had withdrawn before that date.

While the entire payment should not be contingent upon completion of the entire study, payment of a small proportion as an incentive for completion of the study is acceptable to FDA, providing that such incentive is not coercive. The IRB should determine that the amount paid as a bonus for completion is reasonable and not so large as to unduly induce participants to stay in the study when they would otherwise have withdrawn. All information concerning payment, including the amount and schedule of payment(s), should be set forth in the informed consent document.

For further information, see FDA’s Guidance for Institutional Review Boards and Clinical Investigators; Payment to Research Participants Information Sheet.

Penn State University classifies participant payment into two categories: Stipend and Reimbursement. Stipend is payment for participant’s (and caregiver’s, if applicable) time to participate in research. Stipend can be paid as a flat amount or on a per-hour basis. This type of payment is subject to the U.S. Internal Revenue Service regulations, and may be deemed earned income. Reimbursement is for expenses incurred due to participation in research. Often reimbursement is for travel expenses, thus this category is referred to as “Travel.” Travel expenses can be mileage, gas, tolls, airline or train tickets, cab/rideshare fares, and parking. However, Reimbursement can include, but not limited to, hotel expenses related research visits, meals, and supplies/equipment necessary to participate in the research. Reimbursement can be paid as a flat amount or for actual cost upon submission of receipt.

For details, see Penn State’s research protections guideline Payments to Human Participants in Research (RPG03) .

The Penn State IRB Investigator Manual (HRP-103) provides a wealth of information about the IRB. It is advisable that the investigator consult this document prior to preparing the application. The IRB Investigator Manual is available in the CATS IRB Library. The Penn State IRB is an administrative body established to protect the rights and welfare of human research subjects recruited to participate in research studies conducted under the auspices of Penn State University and Penn State Health. The role of the IRB is to review and to make decisions on all research involving human subjects.

Types of regulatory review for research activities

Submitted research activities may fall into one of the following four regulatory classifications:

• Not “Human Research:” Activities must meet the organizational definition of “Human Research” to fall under IRB oversight. Activities that do not meet this definition are not subject to IRB oversight or review. Review the IRB “WORKSHEET: Human Research Determination (HRP-310)” for reference. Contact the IRB Office in cases where it is unclear whether an activity is Human Research.
• Exempt: Certain categories of Human Research may be exempt from regulation but require IRB review. It is the responsibility of the organization, not the investigator, to determine whether Human Research is exempt from IRB review. Review IRB “WORKSHEET: Exemption Determination (HRP-312)” for reference on the categories of research that may be exempt.
• Review using the Limited IRB Review Procedure: Certain categories of exempt Human Research require that the IRB assess some [46.111(a)(7)], but not all, of the 45 CFR 46.111 review criteria. Review IRB “WORKSHEET: Limited IRB Review (HRP-319)” for reference on the categories of research that may be eligible for a limited IRB review.
• Review Using the Expedited Procedure: Certain categories of non-exempt Human Research may qualify for review using the expedited procedure, meaning that the project may be approved by a single designated IRB reviewer, rather than the convened board. Review IRB “WORKSHEET: Eligibility for Review Using the Expedited Procedure (HRP-313)” for reference on the categories of research that may be reviewed using the expedited procedure.
• Review by the Convened IRB: Non-Exempt Human Research that does not qualify for review using the expedited procedure must be reviewed by the convened IRB.

Criteria for IRB Approval

In order to evaluate and potentially approve human subjects research, the Penn State IRB must review the protocol and determine that all of the federal requirements for approval, as outlined in 45 CFR 46.111(a)(1-7)(b), are satisfied. The criteria for IRB approval can be found in the “WORKSHEET: Criteria for Approval and Additional Considerations (HRP-314)” for non-exempt Human Research. The worksheet references other checklists that might be relevant. All checklists and worksheets can be found in CATS IRB Library.

What are the decisions the IRB can make when reviewing proposed research?

The IRB may approve research, require modifications to the research to secure approval, table research, or disapprove research:

• Approval: Made when all criteria for approval are met. See “Criteria for IRB Approval” above.
• Modifications Required to Secure Approval: Made when IRB members require specific modifications to the research before approval can be finalized.
• Deferred: Made when the IRB determines that the board is unable to approve research and the IRB suggests modifications the might make the research approvable. When making this motion, the IRB describes its reasons for this decision, describes modifications that might make the research approvable, and gives the investigator an opportunity to respond to the IRB in person or in writing.
• Tabled: Made when the IRB cannot approve the research at a meeting for reasons unrelated to the research, such as loss of quorum. When taking this action, the IRB automatically schedules the research for review at the next meeting.
• Disapproval: Made when the IRB determines that it is unable to approve research and the IRB cannot describe modifications the might make the research approvable. When making this motion, the IRB describes its reasons for this decision and gives the investigator an opportunity to respond to the IRB in person or in writing.

The IRB must review and approve all Human Research activities prior to the initiation of any research activities. Create an online application in CATS IRB, and submit it to the IRB along with all required documents. All research submissions must have a protocol attached to the online application in CATS IRB. The purpose of the protocol is to provide the IRB with sufficient information to conduct a substantive review. If a separate sponsor’s protocol exists, please submit it in addition to Local Site Plan for Human Subject Research (HRP-595) (see below). The IRB has provided multiple protocol templates, based on the type of research being conducted. Protocol templates can be accessed by navigating to CATS IRB (login required), clicking on the Library link in the left menu and then clicking on the templates tab on that page. The templates are referenced by number and include:

• For social science/non-biomedical/educational research
• For biomedical research studies not involving the use of a test article (drugs or devices)
• For biomedical research involving the use of a test article (drugs or devices, supplements, alternative medicines and/or chemicals)
• For biomedical research that falls under the FDA regulations
• For studies involving the use of a Humanitarian Use Device (HUD)
• For activities for which the need for IRB approval or determination is unclear, or
• For activities requiring written documentation of a not human research determination
• For multi-center research for which a protocol has been provided by the sponsor or director of the multi-center study. Upload both the sponsor-written protocol and HRP-595 for this type of project
• For studies involving the review of medical records (electronic medical records or paper charts) and/or the analysis of existing restricted data sets only . This protocol is not for the use of data that does not meet the definition of human subject research. Researchers who are not using human subjects data can complete protocol template HRP-594 – Protocol for Not Human Subjects Research Determination, when necessary.
• For all studies reviewed at Penn State College of Medicine, as a supplement to the main protocol document

Use a template protocol as a starting point for drafting a new protocol, and reference the instructions in italic text for information the IRB looks for when reviewing research. Here are some key points to remember when developing a protocol:

• The italicized bullet points included in the gray boxes in the protocol template serve as guidance to investigators when developing a protocol for submission to the IRB. All gray boxes should be left in the final document.
• If the study is a multi-center study, and the sponsor has provided a protocol, upload the sponsor’s protocol in CATS IRB and the Local Site Plan for Human Subjects Research (HRP-595).
• When writing a protocol, always keep an electronic copy. You will need to modify this copy when making changes to the protocol, or if the IRB requests changes.
• Note that, depending on the nature of your research, certain sections of the template may not be applicable to your protocol. Indicate this as appropriate.
• Adults unable to provide legally effective consent
• Individuals who are not yet adults (infants, children, teenagers)
• Pregnant women
• Neonates of uncertain viability or non-viable neonates
• Research studies using a community-based participatory research design
• Use of community advisory boards
• Use of subject advocates
• Partnerships with community-based organizations
• Appropriate human subject training for community partners engaged in the research

Supporting Documents

CATS IRB will prompt the user to upload documents throughout the submission form, including consent forms, protocols, recruitment materials, etc. In addition, any other study-specific documents should be uploaded in the “Local Site Documents” section of the form. Examples of common supporting documents include:

• Surveys/questionnaires
• Interview questions/focus group topics
• Observation checklists
• Videos or images that subjects may be asked to view (stimuli)
• Certificates of confidentiality from HHS Agency
• Scientific Review Memo
• HRP 903 Radiation Review Form – all research involving diagnostic or therapeutic radiation procedures involving ionizing radiation
• HRP 902 Human Tissue for Research Form – used when a project involves collection of tissue for research
• Enterprise Information Management (EIM) Design Specification Forms
• Completed checklist of Department of Energy requirements, if applicable
• Other IRB approvals
• Other study-related documents not previously uploaded

Informed Consent

The IRB has multiple consent templates, based on the type of research being conducted. Consent templates can be accessed by navigating to CATS IRB Library. Use one of the following templates:

• HRP-580 – HRPP Consent Form Template: For studies obtaining written informed consent (This is the standard long form consent document discussed in the next section)
• HRP-581 – HRPP Consent Form Addendum: To inform current subjects about new information that could affect the subject’s willingness to continue in the study
• HRP-582 – HRPP Consent Form for Emergency Use: To obtain written informed consent from patients receiving an unapproved drug, biologic or device in an emergency situation
• HRP-583 – HRPP Consent Short Form: Use this template for the short form consent documentation
• HRP-584 – HRPP Consent Guidance for Exempt Research: For the consent process in research projects that are exempt and involve interactions with research subjects
• HRP-585 – HRPP Minimal Risk Consent Form Template: For research in which verbal or implied consent will be obtained and which will not involve the use of protected health information
• HRP-586 – HRPP Pregnant Partner Consent Form: For research in which the partner of a subject becomes pregnant during participation in a clinical trial involving investigational drug(s). Note: this document does not have to be submitted with the initial study review but should be used if/when it becomes applicable.

Note that all long form consent documents and all summaries for short form consent documents must contain all of the required and all additional appropriate elements of informed consent disclosure. Review the “Long Form of Consent Documentation” section in the IRB’s “WORKSHEET: Criteria for Approval (HRP-314),” to ensure that these elements are addressed. The IRB requires that you date the revisions of your consent documents in the header to ensure that you use the most recent version approved by the IRB. The approved version will be watermarked by CATS IRB.

Common Mistakes in Informed Consent

• Incomplete and/or inconsistent information
• Language is too complex
• Recruitment and consent process is not well explained
• “De-identified” not a meaningful term by itself
• Standard of care procedures vs. research procedures are not clearly described
• Use of exculpatory language

Helpful Hints: Consent versus Clinical Trial Agreement (Contract)

The Consent Form

• Is not a contract for exchange of services for payment, but an acknowledgement
• It is between Penn State and the participant
• Necessary for regulatory compliance purposes
• Project-specific

The Clinical Trial Agreement (Contract)

• Is a contract for services by PSU/PSH in exchange for payment: required only when we are being paid by a Sponsor to conduct a trial
• It is between PSU/PSH and the Sponsor (the PI and the study subjects are not parties to the contract)
• It is necessary to cover the legal risks between the parties in exchanging services for payment
• May be a template or master and not project-specific

Approvals required prior to initiating research

Anatomic Pathology

Research involving the collection of tissues or use of pathologic specimens must receive approval from Anatomic Pathology. Include a copy of the Use of Human Tissue for Research Form with the application materials for research projects that involve any of the following:

• Collection of tissue from surgical or biopsy procedures;
• collection of bone marrow from bone marrow biopsies and/or bone marrow aspirates;
• use of archival pathologic specimens stored in Anatomic Pathology;
• collection of tissue from cadavers; and/or
• collection of placenta specimens.

There is a charge per specimen to help defray the technical cost in obtaining research tissues. Call the Department of Pathology at 717-531-8352 , for the current charge to use when preparing the budget for a grant. If the investigator is aware that a biopsy or excision of the desired tissue is scheduled, they should complete and submit to the Anatomic Pathology Gross Room (fax to 717-531-0831) a “Research Tissue Request Form” prior to the scheduled date of surgery. This form notifies the Gross Room staff that a specimen is a potential source of research tissue so that the specimen can be handled appropriately for that purpose. A blank copy of this form can be obtained from the Gross Room; this blank form can be photocopied for multiple submissions. Anatomic Pathology approval is required before the IRB will approve the study.

Human Use of Isotope Committee

All research involving radiation procedures (standard of care and/or research-related) must complete the Radiation Review Form and upload it on the Supporting Documents page in the CATS IRB application. If the study involves use of radiation procedures for research purposes, the study must receive approval from the Radiation Safety Committee – Human Use of Isotope Committee (HUIC). HUIC approval is required before the IRB will approve the study.

Clinical Research Center Advisory Committee

Research involving the use of services at the Clinical Research Center (CRC) for any reason, including the use of personnel as back up to the research team or plans to use personnel in the event of an emergency, need to be reviewed by the CRC Advisory Committee. CRC Advisory Committee approval is not required before the IRB will approve the study.

Conflict of Interest Committee (Individual)

Research studies in which a member of the study staff has a financial interest as defined by PSU policies must be reviewed by the Conflict of Interest Review Committee (CIRC-HY). IRB approval will not be granted until the IRB has reviewed the recommended management plan.

Conflict of Interest Committee (Institutional)

Research studies in which an institutional conflict may exist as defined by Penn State policies must be reviewed by the Institutional Conflict of Interest Review Committee. IRB approval will not be granted until the IRB has reviewed the recommended management plan.

Departmental Scientific and Feasibility Review

All investigator-written research studies requiring review by the convened IRB must provide documentation of scientific review with the IRB submission. The scientific review requirement may be fulfilled by one of the following:

• external peer-review process (e.g., research studies funded by an NIH grant);
• departmental or institute scientific review committees; or
• scientific review by the Clinical Research Center Advisory Committee.

All research studies involving cancer patients, records and/or tissues or cancer prevention studies must be reviewed by the Penn State Cancer Institute Scientific Review Committee.

Institutional Animal Care and Use Committee

Research involving vertebrate animals must receive approval from the Institutional Animal Care and Use Committee. Investigators will need to complete an IACUC application. The IACUC approval is required before IRB approval will be issued.

Data Transfer Agreement Review

Research that involves any transfer of human research data to and/or from any third party requires review by the Office of Research Affairs. This approval is required before IRB approval will be issued. Requests for Data Use Agreements should be submitted via this form .

Data Security Plan Ancillary Review

Research in which the data security plan does not meet the requirements of the SOP Addendum – Security and Integrity of Human Research Data require review by the IT Security Group at Penn State Health. Also, research that involves the transfer of PHI or PII to and/or from a third party (exceptions: industry-sponsored, multi-center trials, oncology group studies and studies sharing data with NIH genomic databases) require review by the IT Security Group. The IT Security Group approval is required before IRB approval will be issued.

Medical Education Ancillary Review

Educational research enrolling any of the learner groups at Penn State College of Medicine must be reviewed by the Educational Research Review Committee (ERRC). The ERRC review must be complete before IRB approval will be issued.

IND/IDE Audit Ancillary Review

Research in which a Penn State Health or Penn State College of Medicine researcher holds the IND or IDE or intends to hold the IND or IDE must be reviewed by the Research Quality Assurance Office (RQA) to ensure sponsor-investigator is compliant with FDA sponsor requirements (including GMP when applicable). Also, RQA may be asked to review investigator-written research using marketed drugs in which the researcher does not have an IND and there is no exemption determination from the FDA. The RQA review must be completed before IRB approval will be issued.

Institutional Biosafety Committee

Research involving biohazardous materials (human biological specimens, biological toxins, carcinogens, infectious agents, recombinant viruses or DNA or gene therapy) must receive approval from the Institutional Biosafety Committee. Investigators will need to complete an IBC application. The IBC approval is required before IRB approval will be issued.

Biological Use Authorization

Institutional Biosafety Committee (IBC) at The Pennsylvania State University College of Medicine reviews research activities involving biological materials that may pose a risk to human, animal, or environmental health. IBC review and approval is required for research activities involving use of recombinant or synthetic nucleic acids, potential employee exposure to infectious agents, and generation of medical waste outside of clinical (patient care) environments.

Examples of research activities that require IBC review and approval include:

• Including use of human blood, tissues and patient samples for research purposes used in clinical trials
• Primary or established human-derived cell lines
• Biological toxins or carcinogens
• Infectious agents
• Recombinant infectious agents
• Recombinant DNA or synthetic DNA molecules
• Recombinant DNA in animals
• Biohazards in humans
• Biohazards in animals
• Genetically manipulated in animals
• Employee exposure to any of the aforementioned activities or materials, including product manipulation, pack, transporting and shipping

Researchers who plan on conducting research involving use of experimental recombinant or synthetic nucleic acid technologies in human subjects including all human gene transfer research are required to contact the Biosafety Office at the earliest stages of their research plan for advising by emailing [email protected] .

Penn State uses the CATS Safety electronic protocol submission system for all renewal and new submissions.

Approved protocols are valid for 3 years, after which the protocol must be resubmitted with any modifications for a full review by the IBC.

Principal Investigators must submit the protocol through the   CATS Safety system at researchsafety.psu.edu , prior to submission of 1) the IAF  for a grant application to the Office of Research Affairs, 2) animal protocols that involve work with biohazards to the Institutional Animal Care and Use Committee (IACUC), or 3) protocols that involve work with biohazards to the Institutional Review Board (IRB).

In addition, investigators must submit through the CATS safety system when beginning work with a new rDNA source (organism), new sequence (gene or gene region), recipient cell type for rDNA (host), or vector (plasmid or virus). All  changes to a protocol approved are to be amended at anytime to update work, add additional clinical trials, training and personnel updates appropriate.

CATS Safety includes an extensive reference section under the CATS Library button. Information includes the appropriate risk group summary, templates, policies , required training matrix and additional biosafety resources.

Activities conducted in clinical environments that are not used for research purposes, by employees covered under established health surveillance and infection control plans do not generally require IBC review.

The Principal investigator (PI) is responsible for completing all required training and for ensuring their employees complete required training commensurate with tasks performed. Required trainings include

• Blood Borne Pathogen (BBP) or Annual infection control training
• Annual Safety Training – Infonet (Penn State Health ePass login required)
• Biological Shipping and Dry Ice training – Infonet (Penn State Health ePass login required)

Questions regarding the IBC review process or training schedules and requirements should be directed to the Biosafety Officer at [email protected] .

Biosafety at Penn State College of Medicine is based on the two primary documents listed below

• The NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines)
• Biosafety in Microbiological and Biomedical Laboratories (BMBL; sixth edition)
• Penn State Policy RP11 Use of Regulated and Biohazardous Materials in Research and Instruction (formerly SY24)

Stem Cell Research Oversight Committee

The Institutional Biosafety Committee (IBC) provides administrative support on issues involving stem cell research.

Principle Investigators must add all appropriate information in the CATS safety submission regarding Human Embryonic Stem cell or pluripotent stem cell research.

• Human Embryonic Stem Cell (hESC) and/or Human Induced Pluripotent Stem Cell (hiPSC) Research must also be submitted in the CATS Safety protocol submission system .
• The submission will be reviewed by the Penn State ESCRO committee for formal review and approval.

All research laboratory information is available on the internal informational database, LabManager . As of Jan. 1, 2023, the LabManager system is being upgraded and only available to the Research Quality Assurance office

Technology Evaluation Process

Clinical research that requires implementation or use of new applications, systems or devices requires an IT Evaluation prior to the start of the study. This is necessary to determine whether or not the new technology may inadvertently create technical instability or create security risks for the institution. Some examples of research-related technologies that have been evaluated include:

• Mobile devices that are used to gather research data on human subjects
• Software that would be implemented on the Penn State network or that would be used to access the Penn State network
• Clinical devices that require network access or involve data transfer

It is important to note that an IT evaluation is restricted to a review of the technical stability, security and feasibility of technology used at the health system. Approval of applications, systems or devices does not signify a commitment of IT resources, implementation costs or financial approval. Learn more on the IT support section of the Infonet (internal access only; login required).

Submitting to IRB and Obtaining IRB Approval

The Human Research Protection Program (HRPP) accepts electronic submissions through CATS IRB, which is accessible at irb.psu.edu . The section of this guidebook on How to Submit a New Human Research Study to the IRB provides additional details regarding the submission of forms and documents through CATS IRB. To access CATS IRB, you must first have a Penn State Access Account. CATS IRB access is further limited to individuals with authorized CATS IRB user accounts. If, after WebAccess authentication, you receive the message “We are unable to display the requested page due to a problem verifying your authentication information,” you must request access to CATS IRB by emailing [email protected] . In addition, all Penn State faculty and staff members will be required to enroll in and use 2FA (Penn State’s Two-Factor Authentication) to log in to WebAccess (the University’s login authentication system for such services such as ESSIC, CATS IRB and many others). For more information, visit Get2FA.psu.edu . The IRB Researcher’s Quick Reference Guide that is available in the CATS IRB Help Center provides a step-by-step guide for the study staff for creating and submitting a study, responding to clarification requests, and getting started with modifications, continuing reviews, and new information reports.

The IRB will provide you with a written decision indicating that the IRB has approved the Human Research, or requires modifications to secure approval, or has disapproved the Human Research.

• If the IRB has approved the human research: The human research may commence once all other organizational approvals have been met. IRB approval is usually valid for a specific period of time and has an expiration date which is noted in the approval letter.
• If the IRB requires modifications to secure approval and you accept the modifications: Make the requested modifications and submit them to the IRB. If all requested modifications are made, the IRB will issue a final approval. Research cannot commence until this final approval is received. If you do not accept the modifications, write up your response addressing the specific modification(s) that are in question and submit it to the IRB.
• If the IRB defers the human research: The IRB will provide a statement of the reasons for deferral and suggestions to make the study approvable, and give you an opportunity to respond in writing. In most cases if the IRB’s reasons for the deferral are addressed in a modification, the human research can be approved.
• If the IRB disapproves the human research: The IRB will provide a statement of the reasons for disapproval and give you an opportunity to respond in writing.

In all cases, you have the right to address your concerns to the IRB directly at an IRB meeting.

See the section of this guidebook on documentation maintenance for details.

Submitting Contracts for Approval

The Office of Research Affairs (ORA) at Penn State College of Medicine oversees the proposal submission process and negotiates contractual terms and conditions of awards, all with the goal of promoting, fostering and sustaining excellence in basic and clinical research.

In collaboration with other offices, we strive to provide leadership which promotes the protection of human subject volunteers, the safety of research personnel, the humane treatment of research animals, the stewardship of research funds, the highest standards of ethics, integrity, and objectivity in the research process.

See details about the Office of Research Affairs .

ORA Receipt and Assignment

Once the contract packet is received by the contracts office it is assigned to a contract administrator contract administrator for review, negotiation and final execution. The contract administrator contract administrator will work with the Clinical Trials Office (CTO), and department contact if there are missing elements or delays with negotiations.

ORA Initial Review

The contract administrator contract administrator will review the contract for consistency with university policy, state and federal law, using the budget, protocol and internal forms as necessary. The contract administrator may also seek consultation with Risk Management, Legal, IRB, CTO, or other sources as necessary to complete the initial review.

ORA First Comments and negotiation to Sponsor

The contract administrator will send a marked copy of the agreement to the sponsor. The contract administrator will provide reasonable updates on the agreement to the study team.

End of Negotiation

Once there is agreement between the contract administrator and the sponsor, the contract administrator and the CTO perform final congruence between the agreement, internal and sponsor budgets and informed consent.

Once approved, the contract will be sent for signature, typically starting with the PI signature of acknowledgement to the contract. After the PI signs the contract, the authorized signatories of Penn State College of Medicine and/or Penn State Milton S. Hershey Medical Center or applicable Penn State Health entity sign the agreement on behalf of the institutions. Typically the Sponsor signs last and the agreement is then fully executed. However, the contract will not be awarded until the IRB has approved the project.

After the fully executed agreement is returned to ORA, and the IRB has approved the protocol, the ORA notifies the post-award central finance administrators. The post-award central finance administrators open the extramural account.

After the contract is executed, ORA and CTO will be responsible, upon request from the study team, to negotiate and execute amendments to the project period, budget, or other required changes to the contract as agreed between the sponsor and the institution. Such requests must originate from the study team, rather than directly from the sponsor.

Study Activation

For industry-sponsored and federal flow-through studies: Once the study is approved in the Internal Approval Form (IAF) and the Statement of Award (SOA) is issued internally, the IAF information is transmitted over into a form inSIMBA. SIMBAis the accounting and form processing system at Penn State College of Medicine. A notice is sent out to the financial contact for the study and the contact goes into SIMBA to enter information into various fields. The form is sent for final approval by University Park Research accounting. They return the form with a cost center and internal order.

The study team uses the cost center and internal order in order to apply expenses to the clinical research study. The financial contact allocates the total statement of award into different general ledgers. The Controller’s Office ensures that expenses and income falls within these different categories. These categories are established by the contract and budget with the sponsor. The amounts are negotiated by the pre-award analyst. The income and expense are reconciled by the post-award analyst.

The cost center and internal order is entered into CATS IRB so that the IRB can bill the appropriate study. This information is also entered into the Hospital Finance database so that study related charges can be applied to the account. Investigator effort is applied by adding this information to the salary assignment and allocated based on study activity. Study team effort is applied in a similar fashion depending if they are College of Medicine employees or Penn State Health employees.

The Coverage Analysis Review (CAR) memo and billing grid (BGRID) created by the College of Medicine Clinical Trials Office (CTO) will be the sole source of truth for determining the responsible payer for Penn State Health (PSH) billable items and services.

Study Tracking and Analysis for Research (STAR) is the sole clinical trial management system to be used for tracking PSH billable items and services for research participant’s visits.

The information entered into STAR will allow Patient Financial Services (PFS) to direct charges to the appropriate payer. On a monthly basis, reports are generated by PSH Finance and verified by the study team in order to bill the research services to the study.

See the Clinical Research Monthly Procedure Reports section of this guidebook for details.

The ClinicalTrials.gov  Protocol Registration and Results System (PRS) is a web-based tool used to submit clinical study information to ClinicalTrials.gov. Records submitted through the PRS are available to the public at ClinicalTrials.gov. Contact RQA at [email protected] for PRS account acquisition and any additional guidance or questions. Also see the User Guide (internal access only; login required) to ClinicalTrials.gov Registration at Hershey. ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. Title VIII of FDAAA, Public Law 110-85, amended the PHS Act by adding new section 402(j), 42 U.S.C. § 282(j). The new provisions require that additional information be submitted to ClinicalTrials.gov established by the National Institutes of Health (NIH)/National Library of Medicine (NLM). This includes expanded information on clinical trials and information regarding the results of clinical trials. This ClinicalTrials.gov registration requirement applies to:

• Any study initiated by an investigator under IND/IDE: The Sponsor-Investigator submits a certification (FDA Form 3674) attesting that the registration data will be submitted as per regulations. Results reporting would also be required for this type of study, due within one year of the study end date. Single-patient, emergency-use INDs do not fall under the referenced section, and therefore are not required to submit certification. Any study not conducted under an IND/IDE but involving drug or device. Most Phase 1 trials are not required to register.
• NIH-funded interventional clinical trials.
• Studies that intend to publish in scientific peer-reviewed journals need to be registered and results entered into ClinicalTrials.gov. Investigators intending to publish clinical studies results in an ICMJE journal (International Committee of Medical Journal Editors) must register before enrollment of first subject. The ICMJE clinical trial registration policy requires prospective registration of all interventional clinical studies, but does not require r results reporting for registered trials. In June 2007, the ICMJE adopted the WHO’s definition of clinical trial. Learn more about the definition and ICMJE publication on the ICMJE Clinical Trials Registration FAQs page and the ICMJE Publishing and Editorial Issues: Clinical Trial Registration page.

Potential Consequences of Non-Compliance

• Civil or criminal judicial actions
• Monetary penalties up to $11,383 per day
• Loss of current or future funding
• Rejection for manuscript publication for ICMJE journals

In 2013, the Centers for Medicare and Medicaid Services (CMS) issued a Transmittal requiring new mandatory reporting of the ClinicalTrials.gov clinical trial number (also known as NCT number) on all hospital and professional claims for related items/services. Effective Jan. 1, 2015, it became mandatory to report the clinical trial number on claims for items/services provided in all clinical trials that are qualified for coverage. In order for the NCT number to correctly appear on the claims, the study teams need to provide the NCT number in CATS IRB.

FDA Webinar Series – Overview of ClinicalTrials.gov

In a three-part webinar series, FDA provides a general overview of ClinicalTrials.gov and relevant definitions, laws, and regulations for complying with ClinicalTrials.gov registration and results information submission requirements. Participants will gain an understanding of CDER’s role and responsibilities with respect to ClinicalTrials.gov oversight and will hear examples of compliance and enforcement activities CDER has taken to encourage compliance.

Access the webinar series here

Other Relevant Links

• NIH Guidance on ClinicalTrials.gov Registration Requirements
• ClinicalTrials.gov Protocol Registration System

Clinical Engineering is primarily responsible for servicing and supporting technology used in the direct care and treatment of patients. The department also supports some minor clinical laboratory equipment and various devices used in the College of Medicine. The overall scope and responsibility of the Clinical Engineering Department extends into Penn State Health’s various off-campus practice sites including, but not limited to, Nyes Road, Elizabethtown, Palmyra, Fishburn Road, Front Street, Middletown, Erford Road, Lancaster, Silver Springs, State College and Wilkes-Barre. FDA-approved equipment used on human patients at Penn State Health requires evaluation and testing by Clinical Engineering. For instance, blood pressure monitors and EKG machines sent by an industry sponsor to support multicenter trials need to be evaluated. Another example would be if a researcher was studying (under an IRB-approved protocol) not-yet-approved ultrasound contrast material provided by a pharmaceutical company, while also using the pharmaceutical-company-owned, commercially available, ultrasound machine, the ultrasound machine would need to be checked by Clinical Engineering. Studies with medical devices that have not yet been FDA approved require an IRB approval, and the evidence of the IRB approval should be provided to Clinical Engineering. For more information, see the Clinical Engineering Infonet section (internal access only; login required) or call 717-531-8410 .

Institutional Policies and Procedures

• DE-06SPM, Medical Equipment Management Plan (login required)
• A-09 HAM, Patient Safety Event Reporting (login required)
• A-70 HAM, Failure of Medical Product or Device/Equipment (login required)

See the Maintain Study Documentation section of this guidebook for details.

Subject Recruitment

When an established patient is being considered for participation in a research study by a clinician involved in the patient’s care, the HIPAA rules can be confusing. HIPAA applies when a provider is reviewing a patient’s medical record for both treatment and research purposes. In general, under the HIPAA privacy rules, patient’s medical information may be accessed for treatment, payment or operational purpose without obtaining prior written authorization. Access to a patient’s medical record for any other purposes may require additional steps to be in compliance with privacy laws and rules. This means that when a provider looks at his or her patient’s medical record for research purposes, the research-related HIPAA rules apply.

If a patient’s record is reviewed for a treatment purpose ( e.g. , to view lab results or consult with a referring provider) the research-related rules do not apply. However, once a patient’s medical information is viewed for a research-related activity ( e.g. , to screen for eligibility or review, to review a unique case for possible study, or to collect data) the research-related HIPAA rules apply. For example, if a provider is reviewing a patient’s lab report for regular care, this access would be for treatment purposes and the research-related rules would not apply. However, if during this review, the provider notices that the lab value may make them a potential research subject and wants to review the chart further for eligibility; the research-related rules would need to be considered.

In general, before any patient information can be used for a research purpose, the patient must sign and date a study-specific consent form that includes the HIPAA authorization elements or a separate HIPAA authorization form which recites the patient’s privacy rights. This is true whether or not the patient is seen by the researcher/physician for medical care. Patient information cannot be used for research-related purposes without a signed patient authorization. There are two limited exceptions: if the IRB has granted a Waiver of Authorization or if the IRB has granted a “Preparatory to Research Authorization.” Important: Any study data obtained without the proper authorizations cited above may not be used for publication (i.e. journals, abstracts, etc.) or any other purpose and can be subject to notification requirements under state and/or federal laws.

See the section of this guidebook titled “Assessment of Potential Cohort for Feasibility or Recruitment” for details.

A HIPAA Waiver of Authorization can be obtained from the IRB if access to patient data is needed for recruitment purposes.

Describe the need in the “HIPAA Research Authorization and/or Waiver or Alteration of Authorization” section of the protocol template or the protocol site addendum. This section is reviewed by the IRB.

If a partial waiver of authorization for recruitment is granted, access to identifiable patient data to determine if a patient may be a potential research subject is permitted.

IRB approval is confirmed by issuance of the IRB approval memo for the study.

The requirement to obtain authorization may be waived or altered if certain criteria are met. Refer to “CHECKLIST: HIPAA Waiver of Authorization (HRP-441)” in the CATS IRB Library for a list of the criteria.

Authorization may be waived for all, or only some uses of protected health information (PHI) for a particular study. A partial waiver permits the use of PHI for recruitment purposes only, to allow identification and, as appropriate, contact of potential participants to determine their interest in study participation. The requirement to obtain authorization for use of PHI may also be altered or waived for a specific study. An alteration allows a change in certain authorization requirements, while still requiring authorization for the use of PHI. Examples include making an exception to the required language in an authorization or to the requirement to obtain a signed authorization. An alteration must meet the same criteria as a waiver or partial waiver.

To request a partial waiver of authorization for recruitment, you must complete the “HIPAA Research Authorization and/or Waiver or Alteration of Authorization” section in the protocol or protocol site addendum for the study. Appendix A-11 of the IRB Investigator Manual includes a list of informational elements that are considered to be identifiers according to the HIPAA regulations.

For additional information see Penn State Policy RP07 – HIPAA and Research at Penn State University .

An application for the use of PHI from decedents must be submitted to the HRPP prior to engaging in the research. In order to gain access to the PHI, the principal investigator needs to demonstrate that the use or disclosure being sought is solely for research on the PHI of decedents, adequate documentation of the death of such individuals, and that the PHI for which use or disclosure is sought is necessary for the purposes of the proposed research. Submit the Request for Research on Decedents’ Information located under “Forms.” If the research will include any identifiers linked to living persons, the project must be approved by the IRB in advance. For more information about the Privacy Rule and decedent research provisions go to: 45 CFR 160.103, paragraph (2)(iv) of the definition of “protected health information.”

Because it may be necessary for a researcher to obtain access to and review PHI in order to prepare a research study, HIPAA rules allow such a review upon compliance with specified criteria. Prior IRB approval must be obtained before accessing and reviewing PHI to prepare a study. Submit the Review Preparatory to Research Request located under “Forms” for IRB for review and approval.

HIPAA rules require that a record be made of a disclosure of any personally identifiable information that is made without an authorization by the research participant. Therefore, tracking of disclosures will have to be undertaken for all disclosures if a waiver of authorization, an approval for review preparatory to research or an approval for the use of a decedent’s PHI is obtained for purposes of research, and for any disclosures not previously specified in a signed authorization document. For purposes of this policy, “disclosure” means the release, transfer, provision of access to, or divulging in any other manner of PHI to any person, whether or not employed by Penn State Health, Penn State College of Medicine or Penn State University, who is not participating in carrying out the research protocol. The following information about any disclosure must be recorded and made available to the individual who is the subject of the PHI upon request:

• Date of disclosure;
• Name of person/entity that received the PHI;
• Description of what PHI was disclosed;
• Brief statement regarding the purpose of the disclosure.

If a research protocol requires multiple disclosures to the same outside party over a period of time, the following information is adequate:

• For the first disclosure, all of the above must be recorded;
• For subsequent disclosures, tracking can refer to the initial record of disclosure and should include the frequency, periodicity or the number of disclosures that will be made; and
• The date of the last disclosure must be documented.

Large Studies: When tracking is required and involves the disclosure of PHI from more than 50 people, HIPAA rules allow a modified tracking method. In this instance it is unnecessary to maintain a list of the specific persons about whom PHI has been disclosed, but the following information must be available upon the request of any individual whose information may have been included:

• The name and description of all protocols involving 50 or more people for which authorization has been waived, including the purpose of these and criteria for selecting records;
• Brief descriptions of types of PHI disclosed;
• Dates or time periods during which disclosures occurred;
• Contact information (name, address, telephone number) for sponsors and recipient researchers; and
• Statement that a specific individual’s PHI may or may not have been disclosed for a particular protocol or research activity.

In addition, the researcher must also assist in contacting the sponsor and recipient researcher if it is reasonably likely that an individual’s PHI was disclosed to them. Tracking information as required by HIPAA rules must be maintained by the principal investigator at least six years, and made available to the Privacy Officer.

The IRB must review and approve all materials for human subject recruitment before recruitment efforts begin. An advertisement to recruit subjects is any form of materials whose main purpose is to inform and invite the potential subjects to participate in a research study, including:

• Flyers and handouts
• Letters and emails
• Newspaper or magazine ads
• Radio, TV and cable
• Internet postings
• Phone scripts
• Facebook and other social media

The advertisement should be limited to the information prospective subjects need to determine their eligibility and interest, such as:

• Name and address of the investigator or research facility;
• The condition under study or purpose of the research;
• In summary form, the criteria that will be used to determine eligibility for the study;
• A brief list of participation benefits, if any;
• The time or other commitment required of all subjects;
• The location of the research and the phone number of the person or office to contact for further information.

For FDA-regulated research, the advertisement should not:

• Make claims, either explicitly or implicitly, that the drug, biologic or device is safe or effective for the purposes under investigation.
• Make claims, either explicitly or implicitly, that the test article is known to be equivalent of superior to any other drug, biologic or device.
• Use terms such as “new treatment,” “new medication” or “new drug” without explaining that the test article is investigational.
• Include a coupon good for a discount on the purchase price of the product once it has been approved for marketing.
• State or imply a certainty of favorable outcome or other benefits beyond what is outlined in the consent document and the protocol.
• Promise “free treatment” when the intent is only to say subjects will not be charged for a taking part in the research.
• Include exculpatory language.
• Emphasize the payment or the amount to be paid, by such means as larger or bold type.

Please reference “HRP-315 – Worksheet – Advertisements” in the CATS IRB Library for the IRB’s requirements regarding advertisements meant to be seen or heard by subjects. StudyFinder is also available to enhance recruitment efforts. StudyFinder is a web-based recruitment tool for Penn State researchers, managed and sponsored by Penn State Clinical Translational Science Institute (CTSI). It is available to all Penn State researchers actively recruiting participants or volunteers for studies. StudyFinder displays data in a way that is intuitive and user-friendly for the public. Learn more about the process for listing studies on StudyFinder .

Subject screening is the term used to describe research activities performed on participants after obtaining their informed consent. Usually screening activities are performed to ensure subjects are eligible to be enrolled in the study, i.e. that the participant meets the inclusion and exclusion criteria for the study. Screening activities include interactions with potential subjects to determine eligibility that would not otherwise have been performed if not for the study. Note that a screen failure is the term used to describe the circumstance in which a subject who has provided consent has subsequently failed to meet eligibility criteria for participation in the study based on screening procedures performed after informed consent was obtained. If some or all of the screening activities will take place before signing the consent form ( i.e. , by telephone) the screening script has to be approved by the IRB.

Please reference the following documents in the CATS IRB Library for the IRB’s policies regarding the informed consent process and the written documentation of consent:

• HRP-090 – SOP – Informed Consent Process for Research
• HRP-091 – SOP – Written Documentation of Consent

For all research participants who are also Penn State Health patients:

A copy of the signed informed consent form is to be included in the participant’s electronic medical records for all clinical research (regardless if the study meets the NIH definition of a clinical trial. A copy of the signed consent form is to be sent by inter-office mail to Health Information Services.

Documentation of consent is also to be included in the electronic medical record.

See institutional Clinical Research Standard Operating Procedure 401 for further details, which can be found on the Penn State Health Policy Management Portal (ePass login required).

Scheduling and Registration

Schedule training and optimization through CareConnect at [email protected] .

A patient should be associated with the study after signing the Informed Consent utilizing the Alerts Tab in PowerChart. The initial signed Consent Form and all Consent revisions (if a patient was re-consented), must be uploaded into the EMR for each patent enrolled in the study.

Health Information Services is responsible for the consent upload.

The signed paper copies may be sent to HIS by interoffice mail (see the “Submit Copy of Consent to Electronic Medical Record” section of this guidebook for details).

A member of the clinical trial research team is responsible for entering human subject participant information into the PowerChart “Alerts Tab” for all ongoing investigational drug or device clinical trials.

All new order sets or revisions to existing order sets in Connected must now be submitted by completing a form.

The form is available via the Clinical Trials Office .

The study coordinator, or another designated study team member, will receive a monthly report from Penn State Health (PSH) Finance summarizing the charges appearing in the billing system as research related charges for a designated study, including the amount being billed to the College of Medicine.

Study teams should expect to see all charges within two months of the items and services being rendered. If charges have not been listed, the study team is responsible for contacting PSH Finance to investigate further. If STAR entries are incorrect or not completed in a timely manner, misbilling can occur.

Charge reports are correct

Once the review of the report is complete, sign the report where indicated and return to the attention of PSH Finance by the due date. Send a copy to the appropriate central Financial Analyst as well. If clinical research monthly procedure reports are not signed and returned to PSH Finance within three months, the research charges will be deemed correct and billed to the respective study budget. PSH Finance will not adjust any charges after this time.

Charge reports need to revision

If there are services listed on the report that are not research related or not priced correctly, the study team member must notify PSH Finance immediately to have them corrected. Once the report is corrected, a revised copy will be sent for signature.

Revise/amend previous charge reports

Any changes requested to previously billed charges will only be made within three months of the original charge(s) in question. Changes after three months is at the sole discretion of PSH Finance.

Further information

See policy “Use of Clinical Research Funds” (PSHAM F-17) for further details, which can be found on the Penn State Health Policy Manager (ePass login required).

Investigational Drug Pharmacy (IDS)

An investigational drug is defined as a new drug or biological that is used in a clinical investigation and which has not been approved for general use by the U.S. Food and Drug Administration. It may also be a drug which is FDA-approved and is being used in a clinical investigation, possibly outside the use of the FDA-approved labeling. The FDA requires that the investigator or designee establish a record of receipt, storage, use/dispensation, and disposition of investigational drugs. At Penn State Health Milton S. Hershey Medical Center and Penn State College of Medicine, all investigational drugs are handled by the Investigational Drug Service (IDS) Pharmacy, a division of the Department of Pharmacy. IDS manages the receipt, storage, dispensation, return and disposal of study drugs in accordance with Good Clinical Practice Guidelines, the study protocol requirements, and all applicable rules and regulations.

Shipping address: Investigational Drug Service Pharmacy Penn State Health Milton S. Hershey Medical Center 500 University Dr. Room PG200, MC CH79 Hershey, PA 17033 Phone: 717-531-4976 Fax: 717-531-5705 Email: [email protected]

Contact IDS

• Site selection visit
• Budget estimate
• PI-initiated study consult

IRB Application

Setup study.

• Site initiation visit
• Create order template
• Order/receive study drug
• Build computer codes
• Randomization
• Drug compounding
• Staff training

Activate Study

• Order processing
• Drug preparation
• Drug accountability
• Monitor visit(s)

Close Study

• Drug return/destruction
• Close-out visit
• Study archive

The principal investigator instructs the sponsor to ship the study medication directly to the IDS Pharmacy. Upon receipt of study shipments, an IDS staff member will inventory/check the shipment using the shipping invoice, notating lot number, expiration date, breakage, storage condition, and total quantities. The shipping invoice will be signed and dated. The shipment will be recorded on the drug accountability log specific for that study. If applicable, the shipment will be activated in the Interactive Voice/Web Response system and/or the packing list will be faxed to the sponsor. The shipping invoice will be filed in the shipping file for that specific study. The study medication will be placed into the appropriate storage conditions, as designated by the sponsor.

Investigational drugs will be stored separately from other hospital medications, and will be marked (at a minimum) with the drug name, study short name, and IRB number. Dedicated investigational drug refrigerators and freezers will be utilized to store refrigerated and frozen investigational drugs. The outlets for the refrigerators and freezers are connected to the back-up generator. Minimum/maximum temperature logs or continuous electronic temperature monitoring logs for all storage conditions will be maintained daily. IDS will only utilize the institution’s approved, calibrated temperature monitoring device/system. Sponsor provided temperature monitoring devices will not be utilized to record temperature for specific studies during storage on site.

A perpetual inventory will be maintained for every study, to include drug receipt, dispensation, return, and destruction. The IDS pharmacy will not maintain drug accountability records for standard of care medications that are not supplied for the study. The inventory will be audited by the IDS Clinical Trials Assistant or designee. An appropriate minimum inventory will be maintained, based upon the rate of patient enrollment. At the end of a study, the perpetual inventory will be “zeroed out” and the drug will be disposed of/mailed back to the sponsor upon sponsor approval (refer to section 13.3 for additional information pertaining to study closure).

The pharmacy may dispense study drugs supplied for clinical trials only upon the receipt of a written physician order sheet or outpatient prescription signed by a physician-investigator authorized in the state of Pennsylvania to prescribe study drugs, as included on his/her clinical practice agreement. The ordering physician must be included on the study’s 1572 form as an investigator or co-investigator. In order for the drug to be dispensed, the prescription/physician order must contain ALL information required by state and federal law as well as the following information:

• Patient’s name
• Patient’s allergies
• Medical record number
• Protocol name
• IRB and/or PSHCI number
• Schedule of administration
• Quantity to dispense
• Physician name
• Physician signature

The initial order must also contain verification that the study participant signed the informed consent document by including one of the following:

• First page and signed Signature Page of the consent form
• Documentation on physician’s order sheet of date and time that the informed consent was signed

The drug will be prepared and dispensed per protocol specifications and established pharmacy policies. Dispensed study medication will be labeled with the Pharmacy Department’s computer-generated label, which conforms to state and federal law. The sponsor’s required labeling will be attached to the dispensed product in addition to the pharmacy label. No parts of the sponsor’s label will be obliterated by the pharmacy label. All study medications will be labeled with the caution, “For Investigational Use Only.” The administration of investigational drugs while in an Ambulatory Care Center, Infusion Room, or while admitted to the hospital, is the responsibility of the principal and co-investigators identified in the study protocol. An investigational medication may only be administered according to protocol and institutional specifications.

The IDS Pharmacy staff will meet with study monitors/auditors in order to assure protocol compliance/adherence. The study coordinator or study monitor must schedule the monitoring visit with the IDS Pharmacy at least two weeks in advance. The IDS Pharmacy will schedule a maximum of three monitor visits or a total of five “monitoring hours” per day.

The investigator must provide the pharmacy with written permission to unblind a subject’s treatment. This may be in the form of a written order or an email. The IDS pharmacy will unblind the patient and place a copy of the written correspondence in the study file/binder.

IDS Pharmacy Policies may be viewed on the Infonet (internal access only; login required). The list below includes some of the available IDS policies:

• Ordering and Dispensing Investigational Drugs
• Temperature Monitoring of Investigational Drugs in the Pharmacy
• Essential Document Handling and Retention
• Cost Estimate
• Destruction of Investigational Drugs
• Dispensing Investigational Drugs to a Home Health Care Agency
• Drug Accountability, Inventory Management and Returns
• Handling Investigational Biosafety Level 2 Products BSL2
• Monitors and Auditors
• NCI-Registered Investigators to Prescribe CTEP-Supplied Agents
• Pharmacy Staff Training for Investigational Drug Studies
• Storage of Investigational Biosafety Level 2 BSL2
• Transport of Investigational Drugs by Penn State Health Milton S. Hershey Medical Center Pharmacy
• Use of Investigational Drugs

Clinical Trial Maintenance

Information items that fall into one or more of the categories listed below must be reported to the IRB within five business days of the investigator becoming aware of the information. These information items will be reviewed by the IRB to determine if they represent non-compliance, unanticipated problems involving risks to subjects or others, and/or result in suspension of IRB approval or termination of IRB approval. To submit an information item, click “Create Reportable New Information” in the CATS IRB system, answer the questions on each screen, attach all requested supporting documents and click the “Submit” activity in the workspace to send it to the IRB Office for review. Maintain electronic copies of all information submitted to the IRB. If the reportable new information is related to an updated Investigator’s Brochure (IB) or protocol amendment and/or revised consent form, you will also have to submit a modification for review and approval of the IB, protocol amendment and/or consent form.

• New information (e.g., an interim analysis, safety monitoring report, publication in the literature, sponsor report, or investigator finding) that indicates an increase in the frequency or magnitude of a previously known risk, or uncovers a new risk;
• Protocol violation that harmed subjects or others or that indicates subjects or others might be at increased risk of harm;
• Complaint of a subject that indicates subjects or others might be at increased risk of harm or at risk of a new harm;
• An investigator brochure, package insert, or device labeling is revised to indicate an increase in the frequency or magnitude or a previously known risk, or describe a new risk;
• Withdrawal, restriction, or modification of a marketed approval of a drug, device, or biologic used in a research protocol;
• Changes significantly affecting the conduct of the research.
• A harm is “unexpected” when its specificity or severity are inconsistent with risk information previously reviewed and approved by the IRB in terms of nature, severity, frequency, and characteristics of the study population.
• A harm is “probably related” to the research procedures if in the opinion of the investigator, the research procedures more likely than not caused the harm.
• Non-compliance with the federal regulations governing human research or with the requirements or determinations of the IRB, or an allegation of such non-compliance.
• Audit, inspection, or inquiry by a federal agency or other entity and any resulting reports (e.g., FDA Form 483)
• Written reports of study monitors.
• Failure to follow the protocol due to the action or inaction of the investigator or research staff.
• Breach of confidentiality.
• Change to the protocol done without prior IRB review to eliminate an apparent immediate hazard to a subject.
• Incarceration of a subject in a study not approved by the IRB to involve prisoners.
• Complaint of a subject that cannot be resolved by the research team.
• Premature suspension or termination by the sponsor, investigator or institution.
• Unanticipated adverse device effect; any serious adverse effect on health or safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the investigational plan or application (including a supplementary plan or application), or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of the subjects).

It is advisable that you consult the Penn State University IRB Investigator Manual (HRP-103) in the CATS IRB Library prior to preparing your application. You must report planned changes in a study and receive approval from the IRB prior to implementing these changes, except where necessary to eliminate apparent immediate hazards to the subjects. In the case of changes implemented to eliminate immediate hazards to the subjects, the emergency protocol changes must be reported to the IRB using a Reportable New Information submission. To request modifications to an approved study, click “Create Modification / CR” in the CATS IRB system, answer the questions on each screen, attach all requested supporting documents and click the “Submit” activity in the workspace to send it to the IRB Office for review. When revising previously approved documents, such as protocols, consent forms, recruitment materials, etc., use a tracked changes feature and a version date to denote all revisions. Maintain electronic copies of all documents submitted to the IRB in case revisions are required. Please note that research must continue to be conducted without inclusion of the modification until IRB approval is received. A protocol exception is a one-time, intentional action or process that departs from the IRB-approved study protocol, intended for one occurrence or applied to a single individual. This action must be approved prior to its implementation by the following:

• the sponsor or funding agency
• the FDA (if applicable)

An example of an exception may include: the potential enrollment, following approval of the sponsor, of a subject who fails to meet all of the protocol eligibility criteria. To request a protocol exception for an approved study, click “Create Modification / CR” in the CATS IRB system. In the modification summary section, provide the following information about the protocol exception:

• Description of the protocol exception, including a reference (page number or section) in the IRB-approved protocol that is being altered
• Justification for the protocol exception
• Discussion of the impact on the risks and/or benefits
• Discussion of the impact on the overall safety of the subject
• Discussion of the impact on the overall validity of the study
• Indication if the exception will be discussed with the subject and the rational for this decision
• Indication of when the approval of the protocol exception is needed

If applicable, attach the sponsor’s and/or FDA’s approval of the protocol exception on the Supporting Documents page in CATS IRB. Click the “Submit” activity in the workspace to send it to the IRB Office for review. See the IRB Investigator Manual for more information.

For any study that requires continuing review, a continuing review form must be submitted prior to the expiration date of IRB approval. Where continuing review is required, the approval letter will indicate this. The IRB sends out multiple courtesy notices starting at approximately 90 days prior to the approval expiration date. It is the Principal Investigator’s responsibility to ensure the required information is submitted by the administrative due date in order to receive renewed approval prior to the expiration date.It is advisable that you consult the Penn State University IRB Investigator Manual (HRP-103) in the CATS IRB Library prior to preparing the continuing review form. To submit a continuing review, click “Create Modification /CR/Admin Review” in the CATS IRB system, answer the questions on each screen, attach all required supporting documents and click the “Submit” activity in the workspace to send it to the IRB Office for review. Maintain electronic copies of all information submitted to the IRB in case revisions are required.

If the continuing review involves a minor modification to previously approved research (e.g., adding a study team member or correcting a typographical error on a consent document), choose ‘Modification and Continuing Review’ on the first screen and submit those modifications as part of the continuing review. IMPORTANT: If the requested changes are more than minor changes, you must complete and submit the ‘Continuing Review’ submission and a separate ‘Modification’ submission. Also note that combined Modification and Continuing Review submissions must be processed and reviewed together (i.e., a minor modification will be approved with the continuing review, not before). If you expect one submission to be reviewed and approved before the other, then submit separate submissions (one modification, and a separate continuing review).

If IRB approval lapses, all Human Research procedures related to the protocol under review must cease including recruitment, advertisement, screening, enrollment, consent, interventions, interactions, and collection or analysis of private identifiable information. Continuing Human Research procedures without IRB approval is a violation of institutional policy and in some cases a violation of federal regulations. If current subjects will be harmed by stopping Human Research procedures that are available outside the Human Research context, provide these on a clinical basis as needed to protect current subjects. If the PI believes that current subjects will be harmed by stopping Human Research procedures that are not available outside the Human Research context, immediately contact the HRPP at [email protected] and provide a written list of the currently enrolled subjects and why they will be harmed by stopping procedures. Remember that research data cannot be collected when a study has lapsed. In addition, the HRPP will administratively close any study that is in a lapsed state for more than 45 days. Once closed, these studies cannot be re-opened and a new submission would have to be completed to continue any human research activities.

Administrative Review

Certain studies approved on or after January 21, 2019, will not require a regulatory continuing review; however, investigators will be required to submit an administrative review form for such studies so that the HRPP can track these studies. Where administrative review is required, the approval letter will state this. Modifications and Reportable New Information submissions are still required for studies that do not require continuing review and the study must be kept active until such time that it meets the criteria for study closure. Investigators will receive reminders regarding the need to submit an administrative review form beginning 90 days prior to its due date. To submit an administrative review, click “Create Modification /CR/Admin Review” in the CATS IRB system, answer the questions on each screen, attach all requested supporting documents and click the “Submit” activity in the workspace to send it to the IRB Office for review. Maintain electronic copies of all information submitted to the IRB in case revisions are required.

Reporting under IND (Protocol Amendments)

You need to submit an IND Protocol Amendment if you have either of the following changes during the course of your study:

• New protocol
• Change in protocol
• New investigator (new site)

The study may begin after you obtain IRB approval based on the new or amended protocol and after the FDA receives the amendment. FDA does not issue “permissions” or “approvals” for protocol amendments, your changes are effective immediately upon the receipt of your amendment by the FDA. The IRB may request documentation of FDA review of amendments and may hold approval until documentation is received from the FDA. In these cases, the PI must request that the FDA provide documentation that the research may continue. For changes in the protocol , the IND Protocol Amendment consists of:

• Cover Letter identifying the submission as “Protocol Amendment: Change in Protocol” or “Protocol Amendment: New Protocol”
• Form 1571 – Check an appropriate box under Paragraph 11, “Protocol Amendments”
• A document outlining the differences between the new protocol and the original protocol

For changes in the investigators , the IND Protocol Amendment consists of:

• Cover letter identifying the submission as “Protocol Amendment: New Investigator”
• Form 1572 for the new investigator

If there are manufacturing or other changes, such as:

• Changes in chemistry, manufacturing and control,
• Changes in pharmacology/toxicology (new findings affecting safety and efficacy), or
• Decision to discontinue a clinical study,

the manufacturer (in many cases, industry sponsor) will notify you. Your responsibility is to notify the IRB and make a decision as to whether to proceed with your trial.

Reporting under IDE (IDE Supplements)

Any changes in the Investigational Plan should be approved by the FDA and, when appropriate, IRB, prior to implementing any change to a previously accepted Investigational Plan. The following types of protocol changes would require an approved IDE Supplement, because they are likely to have a significant effect on the scientific soundness of the trial design and/ or validity of the data resulting from the trial.

• Change in indication
• Change in type or nature of study control
• Change in primary endpoint
• Change in method of statistical evaluation
• Early termination of the study (except for reasons related to patient safety)
• Change in the number of investigational sites
• Change in the number of study subjects

However, if the modifications meet certain criteria, the sponsor of an IDE may modify the device and/or clinical protocol without prior FDA approval. The sponsor still needs to provide notice to FDA within five working days of making the change. These notices must be identified as a “notice of IDE change.”

• Emergency use: If PI deviates from the investigational plan to protect the life or physical well-being of a subject in an emergency. Such deviations should be reported to the IRB promptly after its occurrence, and to the FDA within five working days after the sponsor becomes aware of it.
• Certain changes to the device: Advance IRB notification is not required if the changes do not constitute a significant change in design or basic operation and are made in response to information gathered during the course of an investigation. Examples include: creditable data generated under the device control procedures (21 CFR Sec. 820.30), preclinical/animal testing, peer reviewed published literature, and clinical information gathered during a clinical trial or marketing.
• Certain clinical protocol changes: When they do not affect (i) the validity of the data or information resulting from the completion of the approved protocol, or the relationship of the likely patient risk to benefit ratio relied upon to approve the protocol; (ii) the scientific soundness of the investigational plan; or (iii) the rights, safety, or welfare of human subjects involved in the investigation.
• If changes will be submitted in the annual report: A sponsor may make minor changes to an Investigational Plan without prior FDA approval; provided that the respective changes are reported in the annual progress report for the IDE (see Annual Reports).

For details, see the RQA section of the Infonet (internal access only; login required).

Adverse Event (AE): An adverse event is an undesirable and unintended event occurring as a result of therapy or other intervention (e.g., headache following spinal tap or intestinal bleeding associated with aspirin therapy). It also includes any untoward or unfavorable medical occurrence in a human subject, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the subject’s participation in the research. Serious Adverse Event (SAE): Events are classified as serious if they meet any of the following criteria:

• Results in death or any life threatening event that places the subject at immediate risk of death from the event as it occurred.
• Any event that requires or prolongs in-patient hospitalization.
• Any event that results in persistent or significant disability/incapacity.
• Any congenital anomaly/birth defect diagnosed in a child of a subject who participated in the study and received study drug.
• Other medically important events that in the opinion of the investigator may jeopardize the subject or may require intervention to prevent one of the other outcomes listed in the definition above.

Unanticipated AE: Any adverse experience, the frequency or severity of which is not consistent with the current consent form or investigator brochure. Unanticipated Problem Involving Risk to Participants or Others: Any unanticipated event involving any aspect of a research study involving anyone (participants, research staff, or others not directly involved in the research) that increases the risk to the person involved. See DHHS Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events (includes flowcharts and diagrams)

Once an adverse event becomes serious, the site should inform the Sponsor by submitting an SAE report. Typically, the Sponsor will provide the report form to use and inform the study investigator/coordinator where and how (i.e. email, fax, etc.) to send the report. An SAE report should be submitted to the Sponsor no later than 24 hours after the site becomes aware of the event. As the site gains more information (i.e. admission records, hospital discharge summaries) updated SAE reports with the new information should be submitted to the Sponsor. In this case the Sponsor (Industry/cooperative group) holds the IND and is therefore responsible for deciding whether the SAE should be reported to the FDA.

IND Safety Reports

In cases where the PI is both the Investigator and the Sponsor, the PI assumes the responsibility of reporting certain SAEs to the FDA. Once it is determined that an SAE must go to the FDA an IND Safety Report is prepared (usually the PI, in association with the medical monitor, will determine whether an IND Safety Report needs to be prepared). An IND Safety Report is an expedited, written notification to the FDA of an adverse experience associated with the use of a study drug that is both serious and unexpected.

When to file:

• For any unexpected fatal or life threatening SAE associated with the use of the drug, the IND Sponsor-Investigator notifies the FDA of the SAE by telephone or fax as soon as possible, but no later than seven calendar days after initial receipt of the SAE. The investigator follows with the written report no later than 15 days after the occurrence.
• For serious and unexpected, but non-fatal adverse events, file as soon as possible and no later than 15 days after initial receipt of the SAE.

For more on filing requirements and follow-up, see IND Application Reporting: Safety Reports .

IDE Safety Reports

An unanticipated adverse device effect is any serious adverse effect on health or safety, any life-threatening problem or death caused by, or associated with a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the application; or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects. An investigator shall submit to the sponsor and to the reviewing IRB a report of any unanticipated adverse device effect occurring during an investigation as soon as possible, but in no event later than 10 working days after the investigator first learns of the effect. If the Investigator is a Sponsor-Investigator, he/she will notify the FDA and all participating investigators in a written IDE safety report of any unanticipated adverse device effects. The report is also provided to the device manufacturer and to the reviewing IRB as soon as possible, but no later than 10 working days after the Investigator first learns of the effect. Thereafter the sponsor (or Sponsor-Investigator) shall submit such additional reports concerning the effect as FDA requests. See IDE report details on the FDA website .

In many cases Sponsors will specify at the beginning of the study how they would like to handle protocol deviations. Minor deviations (as described elsewhere in this Guidebook) are usually recorded in the case report forms and tabulated by site at the end of the study. Most Sponsors do not require that minor deviations be reported in any immediate fashion. For major deviations the site often reports to the Sponsor are required. In the case where a site needs a deviation in order to enroll a patient that is not otherwise eligible per the protocol inclusion/exclusion criteria, a Sponsor will request that a planned protocol deviation be filed requesting permission from the Sponsor for the site to enroll the patient. Sponsors will respond to this request in writing and this form along with documentation of all communication between the site and Sponsor should be kept in the patient’s source documentation. IRB approval is also needed for these one-time protocol exceptions.

Reporting Protocol Deviations under IND

(Information adapted from www.firstclinical.com ) FDA’s regulations have numerous references to “changes” or “amendments” to study protocols. For example, 21 CFR 312.30 addresses the responsibility of sponsors to submit amendments to their IND(s) to ensure that clinical investigations are conducted according to protocols included in the application. 21 CFR 312.30(b) specifically discusses changes in a protocol, and provides several examples of changes that would require sponsors to submit protocol amendments to the IND. However, the FDA regulations do not provide specific guidance on deviation reporting. A protocol deviation directed at eliminating an apparent immediate hazard to a research subject or group of subjects may be implemented immediately provided that the reviewing IRB is so notified. The respective protocol deviation should be addressed in the next Annual Report to the IND application. If the protocol deviation will be incorporated as a permanent change (i.e., revision) to the protocol, a respective Protocol Amendment must be submitted prospectively to the IND application/FDA and the revision to the protocol must be approved prospectively by the responsible IRB.

Reporting Protocol Deviations under IDE

FDA device regulations at 21 CFR 812.150(a)(4) discuss protocol deviations under IDE regulations. An investigator shall notify the sponsor and the reviewing IRB of any deviation from the investigational plan to protect the life or physical well-being of a subject in an emergency. Such notice shall be given as soon as possible, but in no event later than five working days after the emergency occurred. Except in such an emergency, prior approval by the sponsor is required for changes in or deviations from a plan, and if these changes or deviations may affect the scientific soundness of the plan or the rights, safety, or welfare of human subjects, FDA and IRB should be made aware in accordance with 812.35(a).

Annual Reports to CDER

For clinical trials being conducted under an IND, FDA requires an annual report from the Sponsor or Sponsor-Investigator. The annual report is due within 60 days of the anniversary date that the IND went effect (i.e., the date that the FDA permitted the study to begin). Required content is listed in 21 CFR 312.33. See the RQA Infonet section for details (internal access only; login required).

Annual Reports to CDRH

For clinical trials being conducted under an IDE, FDA requires Sponsors to submit progress reports, at regular intervals, and at least yearly. Reports must be submitted to all reviewing IRBs and in the case of significant risk devices the sponsor must also submit the progress report to FDA (21 CFR 812.150). See the RQA Infonet section for details (internal access only; login required).

“Essential documents are those documents which individually and collectively permit evaluation of the conduct of the trial and the quality of the data produced. These documents serve to demonstrate the compliance of the investigator, sponsor and monitor with the standards of Good Clinical Practice and with all applicable regulatory requirements.” (ICH Guideline E6) There are many ways to organize essential documents, and there is no gold standard for how to do this. For example, the ICH GCP E6 guideline recommends that the documents be grouped according to the stage of the trial, i.e. documents relevant to the trial before it commences, documents relevant to the trial during the conduct of the trial, and those documents relevant to the trial after completion or termination of the trial. See specific information here . The most important thing is that the documentation is organized and that all of the necessary documents are present. This section of the Guidebook provides examples of a potential system to organize essential documents. Essential documents also serve a number of other important purposes. Filing essential documents at the investigator/institution and sponsor sites in a timely manner can greatly assist in the successful management of a trial. These documents are also the ones which are usually audited by the independent audits and inspected by the regulatory authority(ies) as part of the process to confirm the validity of the trial conduct and the integrity of data collected. Another way to organize the essential documents into study binders is by the content of the binder. For example, many sites have a “source document binder,” a “case report form binder,” a “financial binder” and a “regulatory binder.”

Industry sponsors may provide investigators with a regulatory binder to be used to maintain the essential documents for the trial.

Investigators who are conducting investigator initiated trials are encouraged to use either of the two resources available to maintain essential documents.

These two resources are:

• The Virtual Regulatory Binder inserts for regulatory documents maintained in paper format.
• REDCap eRegulatory Binder for electronic storage and organization of regulatory documentation.

The binder tab inserts and instructions, as well as additional information regarding access and utilization of the REDCap eRegulatory Binder, can be found via the Clinical Trials Office .

The following list represents the required essential documents that must be filed in the regulatory binder. All essential documents must be available for audit/inspection by the sponsor and regulatory authorities.

The Virtual Regulatory Binder adapted from Partners Healthcare provides all essential tabs and information about what needs to go under each tab.

Delegation of Authority/Responsibilities Log

It is common practice for investigators to delegate certain study-related tasks to employees, colleagues, or other third parties (individuals or entities not under the direct supervision of the investigator).

However, the Principal Investigator (PI) is ultimately responsible for the conduct of the study.

When tasks are delegated by an investigator, the investigator is responsible for providing adequate supervision of those to whom tasks are delegated. A Delegation of Authority log should be created documenting delegated tasks to delegated individuals. The same applies to staff/contract organizations no in direct employ of the investigator.

Title of the study

Below the log, the PI should sign and date.

Training Log

The investigator has to assure that the staff has appropriate education, training and experience to perform delegated tasks.

The training log should also document that individuals have been trained on protocol-specific topics relevant to their job responsibilities. This training is documented in the training log.

The investigator should develop a plan for the supervision and oversight of the clinical trial at the site. Supervision and oversight should be provided even for individuals who are highly qualified and experienced.

Such a plan is outlined in the FDA Guidance on Investigator Responsibilities and may include routine meetings, procedures for reviewing staff performance, procedures for correction of protocol deviations, and procedures for ensuring quality control.

Per ICH GCP guideline E6 section 5.1 source data is identified as “all information in original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial.” This is the first recording of subject-related information. According to 21 CFR 312.62(b), and investigator is required to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual. Source documents must be complete, accurate, and valid. The regulatory authorities consider source documents to be the basis for al trial data and the adjudication of the outcome of events. The purpose of source documents/patient record binder:

• To document the existence of the participant and substantiate integrity of trial data collected.
• To include original documents related to the trial, medical treatment, history of participant, and participant’s condition while on-study or in follow-up.
• To provide an auditable link in the chain from the study database back to the original source (visit worksheet).
• To collect data for transfer to CRFs and then to the study database.
• To instruct study coordinators and other site personnel on what data to collect and information necessary to answer data queries.

According to ICH GCP EC 1.11, a case report form is a printed, optical, or electronic document designed to record all of the protocol required information to be reported on each trial subject. CRFs are designed by the sponsor or sponsor-investigator and maintained at the investigative site. Information documented on the CRF (or eCRF) must be supported by source documentation. At a minimum the CRF should record:

• Inclusion/exclusion criteria and assessment as to whether the subject met them
• Protocol-specific clinical laboratory testing (including EKGs, X-rays, eye exams, scans, etc.) documented by laboratory records
• All AEs, SAEs, concomitant therapies, and/or inter-current illnesses
• Assessment of severity of AEs, relationship to test article, and expectedness of the AE
• Report of all dropouts and the reasons

One of the most essential tasks performed by the Clinical Research Coordinator (CRC) is completing and/or ensuring the completion of the subject’s CRF. Most sponsors will provide instructions or a guide for CRF completion. Handwriting must be legible and should be completed in black ink. All data points must be addressed and for fields that cannot be completed, “not available,” “not done” or “unknown” should be marked in accordance with the sponsor’s instructions. The CRC will ensure that all required data are collected and entered on the CRF as soon as possible after, if not during, the visit. All CRFs should be checked for completeness and legibility. The CRFs should be reviewed and signed by the investigator prior to submission. Only those physicians identified on the 1572 may sign CRFs. When making a correction on a CRF, a single line should be drawn through the incorrect entry and the correct data should be entered above or next to the incorrect entry. The correction should be dated and initialed. White-out or eraser should never be used to correct an error. Blanks identified prior to the investigator’s review and sign-off on the CRF can simply be completed. Those identified after sign-off must be dated and initialed.

An electronic copy of the financial documents is kept in the individual study network folder. Studies are organized by department then by Investigator. The Controller’s office maintains electronic copies of all documents which include check copies, invoices, budget documents, etc. The documents in the network folder are kept separately from the negotiation items.

The following is an outline of the documents that should be kept in the financial binder:

An audit is a systematic and independent examination of trial-related activities and documents to evaluate whether the trial-related activities were conducted and the data were recorded, analyzed and accurately reported according to the protocol, Sponsor’s SOP, GCP and other applicable regulatory requirements. Auditors collect evidence and compare against standards, review documents, assess deviations and non-compliance and recommend actions.

The Bioresearch Monitoring Unit of the FDA may conduct inspections of medical research and testing facilities in order to ensure studies avoid bias and follow proper testing procedures.

The FDA inspector will review all case study data and may interview subjects and doctors. In all types of inspections, an FDA inspector checks the study for errors that affect the outcome.

Investigators may expect the following types of inspections:

• Routine Inspection may be conducted at random. It is sometimes triggered by abnormally high enrollment rate as well as large studies to promote a pivotal drug.
• For-Cause Inspections: FDA investigator has a reason to check out a research facility, i.e., subject complaint, a highly publicized drug, unqualified investigators, large AE clustering.

Once you receive notification of the FDA audit notify the appropriate research administration offices and IDS. Specific procedures to follow when preparing for an inspection and on the day of the inspection will be discussed with the research team prior to the inspection date and are outlined in the Standard Operating Procedures for Clinical Research, QA 601.

Also, see FDA guidance on FDA Inspection of Clinical Investigators for details.

Office of Research Quality Assurance (RQA) fulfills the auditor role for investigator-initiated studies. These audits are called Post Approval Reviews (PAR).

RQA conducts for-cause/directed reviews (requested by the IRB), random/routine reviews and self-evaluation assessments. The purpose of routine/random reviews is to assist investigators with achieving high quality of regulatory compliance. The reviews are meant to be more educational rather than punitive in nature.

RQA summarizes and reports the findings directly to the investigators. Investigators are required to submit all directed PAR reports to the IRB and significant findings in other PAR reports according to IRB Reportable New Information (RNI) reporting policy.

See RQA details.

If you have concerns about your preparedness for an audit, please contact the RQA office. RQA offers audit readiness assessment for both industry and investigator-initiated studies. This program helps ensure compliance with FDA, GCP, and IRB regulations, and institutional SOPs and policies and procedure as related to clinical research. The results of the pre-audit assessment will be provided for investigators and teams. For further information, contact RQA.

Billing and Invoicing

On a monthly basis the expense and income should be verified for the clinical research account. Reports are available via SIMBA, ran by the College of Medicine Research Accountant Supervisor. The COM Research Accountant, Department Financial Analyst and members of the study team should be certain that effort is being applied appropriately and that all income due is being tracked. The income and expenses in the accounting system should match the participant tracking document and any reports generated by hospital finance.

Within two business days, the study team is to enter participant visit information into STAR . In the event a research visit will take multiple days to complete, the study team should create the visit in STAR and record the date of the activities as they occur. The study team should not mark the visit as “completed” until all applicable items/services have been done. Since Patient Financial Services (PFS) is primarily focused on completed visits, it is recommended that the study team send the following message to PFS through STAR (edit as needed):

For this study, the XXX visit(s) will take place over an extended period (possibly xx weeks). I will keep the visit(s) updated and open as a snapshot of what has been done and what hasn’t occurred yet. I will not finalize the visit until it has been completed. Please feel free to call if you have any questions.

The study team should be reviewing the contract notes and notifying the financial contact of any events that require an invoice or any other items of interest.

For legacy studies (studies not in STAR)

On a weekly basis, the study team should enter the necessary visit information into the participant tracking Excel spreadsheet (on the shared network drive) and send to PFS and the central Financial Analyst (FA).

In the log, the first three columns should be filled out as listed. The rest of the columns, except for “Notes,” should be used to list the appropriate dates for that study. Any screening fails should be listed in notes and the appropriate subsequent dates grayed out. For questions filling out this Excel sheet, contact the Clinical Trials Office . A central FA uses this information to convert completed visits into Receivables by using the contracted amounts per visit/procedure. All costs for rescheduled visits, delayed procedures, adverse events and any other “invoiceable” items are also captured at this time.

In the event a research visit will take multiple days to complete, the study team should send the above referenced message PFS by email to [email protected] , notifying them of the extended visit period.

The COM Research Accountant should invoice the sponsor on a monthly or quarterly basis dependent upon the contract terms. The study team should collaborate with the COM Research Accountant in order to make sure all appropriate items are being invoiced. Communicate with the COM Research Accountant for more details in regards to invoices.

PI effort will be reviewed at a minimum of quarterly and applied where appropriate, in a timely manner, in accordance with the internal budget and subject accrual or protocol activity.

The following is to be used to determine what document is be used as the internal budget:

( Funding source: Document)

Grant: Budget document submitted as part of the grant application Industry contract: Budget Worksheet created by Clinical Trials Office Departmental funds: Department-specified document

Effort will be charged based on prorated accrual, not based on income received. Adjustments of actual effort vs. budgeted effort may not be greater than a 25 percent change, unless there is a contractual amendment to the agreement. Salary Assignment Schedules will be reviewed at a minimum of quarterly and updated to reflect appropriate effort, where applicable. For additional details, refer to the following policies:

• Policy: RAG64, Salary Caps
• Policy: RA30, Facilities and Administrative (F&A) Costs

Study Closure

Account Closure or Extension Forms (ACE Forms) are sent to the COM Research Accountant when an account has an end date in the accounting system. The Controller’s office receives a restricted fund report from Research Accounting at University Park with accounts that have end dates. The COM Research Accountant works with the investigator and study team to either extend the end date if the contract allows, request an amendment from the sponsor or close out the account in the accounting system. Communicate with the COM Research Accountant in order to obtain more details about the closure or extension of an account.

To request study closure, click “Create Modification/CR” in the CATS IRB system, answer the questions on each screen, attach all requested supplements and submit it to the IRB Office. Maintain electronic copies of all information submitted to the IRB in case revisions are required. Reference the Investigators Manual (HRP-103) in the CATS IRB Library for further information.

At the end of a trial, a close-out visit must be arranged by the study monitor. The monitor will perform the final drug reconciliation. The perpetual inventory will be “zeroed out” and the drug will be disposed of/mailed back per protocol. Copies of drug accountability records will be provided to the study monitor, which may be done by allowing the monitor access to Vestigo. Original records will not be released to the study monitor unless written permission from the study sponsor is obtained/provided by the study monitor. Once a study has been officially closed to accrual and all subjects at our institution have completed therapy with the supplied medication, the sponsor must perform final drug reconciliation within 30 days. After 30 days, any remaining drug will be destroyed per policy PAM 1406 (Investigational Drug Services: Destruction of Investigational Drugs.) Refer to the IDS section of this guidebook for additional information.

Once the project is terminated by the sponsor or the contract end date expires, the Controller’s Office receives a monthly report from Research Accounting. The Controller’s Office notifies the appropriate financial administrator for closeout or extension and provides an Account Closeout/Extension (ACE) form for completion. Once the financial administrator returns the ACE form to the Controller’s Office, the Controller’s Office notifies ORA of the expiration. ORA updates the SIMS database. Contracts must retain the agreement for the period of time designated in the agreement or if not so designated the period legally required The PI and department must retain the project records for the period of time designated in the agreement.

For drugs, according to 21 CRF 312.62(c), an investigator shall retain records required to be maintained under the part for a period of two years following the date a marketing application is approved for the drug for the indication for which it is being investigated; or, if no application is to be filed or if the applications is not approved for such indication, until two years after the investigation is discontinued and FDA is notified.

For devices, according to 21 CRF 812.140(d), an investigator or sponsor shall maintain the records required by this subpart during the investigation and for a period of two years after the latter of the following two dates: the date on which the investigation is terminated or completed, or the date that the records are no longer required for purposes of supporting a premarket approval application or a notice of completion of a product development protocol.

Study Sponsors may have additional document retaining provisions stipulated in the Contract.

The National Institutes of Health (NIH) requires researchers to acknowledge federal funding in peer-reviewed publications by citing any NIH grants that supported the research process described in the publication. In addition, the NIH Public Access Policy requires that all investigators “funded by the NIH,” be it through direct funding or through use of resources of an NIH-funded center (such as Penn State Clinical and Translational Science Institute) submit an electronic version of their final, peer-reviewed manuscripts to PubMed Central (PMC) upon acceptance of publication. This policy ensures that the public has access to the published results of NIH-funded research. Failure to submit the manuscript to PMC within NIH-imposed deadlines may result in a delay of processing the grant awards of the researchers or centers whose grants were cited in the manuscript.

Resources about complying with the NIH Public Access Policy

• Details of the NIH PublicAccess Policy
• Directions and tutorials for submitting a manuscript to PMC through the NIH manuscript submission system
• Information about citing the CTSI in a publication

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• COVID-19 Research Guidance
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The Comprehensive Guide To Clinical Research: A Practical Handbook For Gaining Insight Into The Clinical Research Industry

Purchase options and add-ons.

• ISBN-10 1090349521
• ISBN-13 978-1090349521
• Publication date April 21, 2019
• Language English
• Dimensions 6 x 0.55 x 9 inches
• Print length 219 pages
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• Publisher ‏ : ‎ Independently published (April 21, 2019)
• Language ‏ : ‎ English
• Paperback ‏ : ‎ 219 pages
• ISBN-10 ‏ : ‎ 1090349521
• ISBN-13 ‏ : ‎ 978-1090349521
• Item Weight ‏ : ‎ 11.5 ounces
• Dimensions ‏ : ‎ 6 x 0.55 x 9 inches
• #15 in Medical Research (Books)
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About the author

My name is Dan Sfera and I am an entrepreneur currently involved in the clinical research industry. My first full length book is called "The Comprehensive Guide To Clinical Research". Throughout my career I have worked at the site, CRO, Sponsor and vendor levels of clinical research in some capacity. As a former study coordinator and current contract CRA and Site Owner, I am uniquely positioned to have a holistic perspective when it comes to the various intricacies of this industry. I enjoy writing about the clinical research industry as well as business in general.

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CLINICAL RESEARCH: Research Guide

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• Find Articles
• Organize & Write
• Cite Your Sources: AMA

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In This Section

In this section, you'll find:.

• Tips for finding theses and dissertations
• Taking good research notes
• Using citation managers
• Research and writing guides that can offer inspiration and advice

Find Theses & Dissertations

Option 1: library databases.

• Option 2: Institutional Repositories Through Google

We have a few library databases that contain theses and dissertations, although full-text options can be somewhat limited.

A comprehensive collection of dissertations and theses from around the world, offering millions of works from thousands of universities.

Option 2: Institutional Repositories through Google

Your next option is to search Google, specifically targeting educational institutional repositories, or IRs. Many universities have IRs where faculty, graduate students, and undergraduate students can submit capstone work like theses and dissertations. If you find citations for relevant dissertations in library databases, you might be able to find the full text through the publishing institution's IR.

Add keywords and site limiters

To search broadly for dissertations in Google, add  dissertation or thesis  and  site:.edu  to whatever subject you're looking for.

• For example, search: dialectical behavioral therapy dissertation site:.edu

Adding  site:.edu  to your search limits the sites that Google will comb through to only sites that end in .edu - so, the sites of educational institutions. You will still have to examine a few of the results to see if they really are theses and not dissertations (but you may even be able to tell from the search results list by looking at the gray blurbs under each result).

Staying Organized

• Take Good Research Notes
• Keep Track of Citations

Taking good research notes is a key part of staying organized.

Keep track of:.

• What search terms or keywords you used
• Where you were searching (database names, the library catalog, Google, etc.)
• When you were searching - databases and websites are constantly removing and adding content, and links change or break
• Full citation information for everything you save
• Permalinks or stable URLs (or DOIs) so you can get back to what you found

Have a system for:

• Organizing the articles you download, including naming PDFs (usually the file name automatically assigned at download is not helpful - you want to be able to quickly identify and find the articles you're using in your research) 
• Keeping track of summaries, quotes, or paraphrases from your sources, including exactly what pages those quotes or paraphrases come from

Citation managers are sometimes good tools for these types of notes, but using a text document or spreadsheet and folders on your computer, OneDrive, or Google Drive can work just as well. The important thing is finding a system that works for you, and then using it consistently.

Citation managers can help you keep track of large amounts of sources, as well as generate references lists and in-text citations. They can save you a lot of time and effort as you compile resources and integrate them into your writing.

Zotero is a free bibliographic manager available as a desktop application and browser plugin. Zotero collects, manages, and cites research from multiple types of sources and also has file management and notetaking capabilities. Through Zotero you can organize your research into different folders for different projects and create bibliographies using Word or OpenOffice. Zotero has a large user community with documentation and video tutorials to help you get started.

• Zotero Documentation

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Foundations of Clinical Research

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Research for the Health Professional

Your guide to research and evidence-based practice. This classic text explains the hows and whys of conducting and writing a research project.

Research Design: Qualitative, Quantitative, & Mixed Methods Approaches

Compares qualitative, quantitative, and mixed methods research design. Includes key elements of the research process, a literature review, an assessment of theory in research applications, and reflections about the importance of ethics in scholarly inquiry.

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The authoritative guide to dissertations and theses, now updated and revised to reflect changes to the APA's Publication Manual, Seventh Edition. ebook

Research Methods in Clinical Psychology

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Destination Dissertation

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Alternative routes into clinical research: a guide for early career doctors

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• Peer review
• Phillip LR Nicolson , consultant haematologist and associate professor of cardiovascular science 1 2 3 ,
• Martha Belete , registrar in anaesthetics 4 5 ,
• Rebecca Hawes , clinical fellow in anaesthetics 5 6 ,
• Nicole Fowler , haematology clinical research fellow 7 ,
• Cheng Hock Toh , professor of haematology and consultant haematologist 8 9
• 1 Institute of Cardiovascular Sciences, University of Birmingham, UK
• 2 Department of Haemostasis, Liaison Haematology and Transfusion, University Hospitals Birmingham NHS Foundation Trust, Birmingham
• 3 HaemSTAR, UK
• 4 Department of Anaesthesia, Plymouth Hospitals NHS Trust, Plymouth, UK
• 5 Research and Audit Federation of Trainees, UK
• 6 Department of Anaesthesia, The Rotherham NHS Foundation Trust, Rotherham Hospital, Rotherham
• 7 Department of Haematology, Royal Cornwall Hospitals NHS Trust, Treliske, Truro
• 8 Liverpool University Hospitals NHS Foundation Trust, Prescott Street, Liverpool
• 9 Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool
• Correspondence to P Nicolson, C H Toh p.nicolson{at}bham.ac.uk ; c.h.toh{at}liverpool.ac.uk

Working in clinical research alongside clinical practice can make for a rewarding and worthwhile career. 1 2 3 Building research into a clinical career starts with research training for early and mid-career doctors. Traditional research training typically involves a dedicated period within an integrated clinical academic training programme or as part of an externally funded MD or PhD degree. Informal training opportunities, such as journal clubs and principal investigator (PI)-mentorship are available ( box 1 ), but in recent years several other initiatives have launched in the UK, meaning there are more ways to obtain research experience and embark on a career in clinical research.

Examples of in-person and online research training opportunities

These are available either informally or formally, free of charge or paid, and via local employing hospital trusts, allied health organisations, royal colleges, or universities

Research training opportunities

Mentorship by PIs at local hospital

Taking on formal role as sub-investigator

Journal clubs

Trainee representation on regional/national NIHR specialty group

API Scheme: https://www.nihr.ac.uk/health-and-care-professionals/training/associate-principal-investigator-scheme.htm .

eLearning courses available at https://learn.nihr.ac.uk (free): Good clinical practice, fundamentals of clinical research delivery, informed consent, leadership, future of health, central portfolio management system.

eLearning courses available from the Royal College of Physicians. Research in Practice programme (free). www.rcplondon.ac.uk

eLearning courses available from the Medical Research Council (free). https://bygsystems.net/mrcrsc-lms/

eLearning courses available from Nature (both free and for variable cost via employing institution): many and varied including research integrity and publication ethics, persuasive grant writing, publishing a research paper. https://masterclasses.nature.com

University courses. Examples include novel clinical trial design in translational medicine from the University of Cambridge ( https://advanceonline.cam.ac.uk/courses/ ) or introduction to randomised controlled trials in healthcare from the University of Birmingham ( https://www.birmingham.ac.uk/university/colleges/mds/cpd/ )

This article outlines these formal but “non-traditional” routes available to early and mid-career doctors that can successfully increase research involvement and enable research-active careers.

Trainee research networks

Trainee research networks are a recent phenomenon within most medical specialties. They are formalised regional or national groups led by early and mid-career doctors who work together to perform clinical research and create research training opportunities. The first of these groups started in the early 2010s within anaesthetics but now represent nearly every specialty ( box 2 ). 4 Trainee research networks provide research training with the aim of increasing doctors’ future research involvement. 5

A non-exhaustive list of UK national trainee led research networks*

Acute medicine.

No national trainee research network

Anaesthesia

Research and Audit Federation of Trainees (RAFT). www.raftrainees.org

Cardiothoracic surgery

No national trainee-specific research network. National research network does exist: Cardiothoracic Interdisciplinary Research Network (CIRN). www.scts.org/professionals/research/cirn.aspx

Emergency medicine

Trainee Emergency Medicine Research Network (TERN). www.ternresearch.co.uk

Ear, nose, and throat

UK ENT Trainee Research Network (INTEGRATE). www.entintegrate.co.uk

Gastroenterology

No national trainee research network. Many regional trainee research networks

General practice

No national trainee-specific research network, although national research networks exist: Society for Academic Primary Care (SAPC) and Primary Care Academic Collaborative (PACT). www.sapc.ac.uk ; www.gppact.org

General surgery

Student Audit and Research in Surgery (STARSurg). www.starsurg.org . Many regional trainee research networks

Geriatric Medicine Research Collaborative (GeMRC). www.gemresearchuk.com

Haematology (non-malignant)

Haematology Specialty Training Audit and Research (HaemSTAR). www.haemstar.org

Haematology (malignant)

Trainee Collaborative for Research and Audit in Hepatology UK (ToRcH-UK). www.twitter.com/uk_torch

Histopathology

Pathsoc Research Trainee Initiative (PARTI). www.pathsoc.org/parti.aspx

Intensive care medicine

Trainee Research in Intensive Care Network (TRIC). www.tricnetwork.co.uk

Internal medicine

No national trainee-led research network. www.rcp.ac.uk/trainee-research-collaboratives

Interventional radiology

UK National Interventional Radiology Trainee Research (UNITE) Collaborative. https://www.unitecollaborative.com

Maxillofacial surgery

Maxillofacial Trainee Research Collaborative (MTReC). www.maxfaxtrainee.co.uk/

UK & Ireland Renal Trainee Network (NEPHwork). www.ukkidney.org/audit-research/projects/nephwork

No national trainee-led research network

Neurosurgery

British Neurosurgical Trainee Research Collaborative (BNTRC). www.bntrc.org.uk

Obstetrics and gynaecology

UK Audit and Research Collaborative in Obstetrics and Gynaecology (UKAROG). www.ukarcog.org

The National Oncology Trainee Collaborative for Healthcare Research (NOTCH). www.uknotch.com

Breast Cancer Trainee Research Collaborative Group (BCTRCG). https://bctrcguk.wixsite.com/bctrcg

Ophthalmology

The Ophthalmology Clinical Trials Network (OCTN). www.ophthalmologytrials.net

Paediatrics

RCPCH Trainee Research Network. www.rcpch.ac.uk/resources/rcpch-trainee-research-network

Paediatric anaesthesia

Paediatric Anaesthesia Trainee Research Network (PATRN). www.apagbi.org.uk/education-and-training/trainee-information/research-network-patrn

Paediatric haematology

Paediatric Haematology Trainee Research Network (PHTN). https://b-s-h.org.uk/about-us/special-interest-groups/paediatric-sig/phtn

Paediatric surgery

Paediatric Surgical Trainees Research Network (PSTRN). www.pstrnuk.org

Pain medicine

Network of Pain Trainees Interested in Research & Audit (PAIN-TRAIN). www.paintrainuk.com

Palliative care

UK Palliative Care Trainee Research Collaborative (UKPRC). www.twitter.com/uk_prc

Plastic surgery

Reconstructive Surgery Trials Network (RSTN). www.reconstructivesurgerytrials.net/trainees/

Pre-hospital medicine

Pre-Hospital Trainee Operated Research Network (PHOTON). www.facebook.com/PHOTONPHEM

Information from Royal College of Psychiatrists. www.rcpsych.ac.uk/members/your-faculties/academic-psychiatry/research

Radiology Academic Network for Trainees (RADIANT). www.radiantuk.com

Respiratory

Integrated Respiratory Research collaborative (INSPIRE). www.inspirerespiratory.co.uk

British Urology Researchers in Surgical Training (BURST). www.bursturology.com

Vascular surgery

Vascular & Endovascular Research Network (VERN). www.vascular-research.net

*limited to those with formal websites and/or active twitter accounts. Correct as of 5 January 2024. For regional trainee-led specialty research networks, see www.rcp.ac.uk/trainee-research-collaboratives for medical specialties, www.asit.org/resources/trainee-research-collaboratives/national-trainee-research-collaboratives/res1137 for surgical specialties, and www.rcoa.ac.uk/research/research-bodies/trainee-research-networks for anaesthetics.

Networks vary widely in structure and function. Most have senior mentorship to guide personal development and career trajectory. Projects are usually highly collaborative and include doctors and allied healthcare professionals working together.

Observational studies and large scale audits are common projects as their feasibility makes them deliverable rapidly with minimal funding. Some networks do, however, carry out interventional research. The benefits of increasing interventional research studies are self-evident, but observational projects are also important as they provide data useful for hypothesis generation and defining clinical equipoise and incidence/event rates, all of which are necessary steps in the development of randomised controlled studies.

These networks offer a supportive learning environment and research experience, and can match experience with expectations and responsibilities. Early and mid-career doctors are given opportunities to be involved and receive training in research at every phase from inception to publication. This develops experience in research methodology such as statistics, scientific writing, and peer review. As well as research skills training, an important reward for involvement in a study is manuscript authorship. Many groups give “citable collaborator” status to all project contributors, whatever their input. 6 7 This recognises the essential role everyone plays in the delivery of whole projects, counts towards publication metrics, and is important for future job applications.

Case study—Pip Nicolson (HaemSTAR)

Haematology Specialty Training, Audit and Research (HaemSTAR) is a trainee research network founded because of a lack of principal investigator training and clinical trial activity in non-malignant haematology. It has led and supported national audits and research projects in various subspecialty areas such as immune thrombocytopenia, thrombotic thrombocytopenic purpura, venous thrombosis, and transfusion. 8 9 10 Through involvement in this network as a registrar, I have acted as a sub-investigator and supported the principal investigator on observational and interventional portfolio-adopted studies by the National Institute for Health and Care Research (NIHR). These experiences gave me valuable insight into the national and local processes involved in research delivery. I was introduced to national leaders in non-malignant haematology who not only provided mentorship and advice on career development, but also gave me opportunities to lead national audits and become involved in HaemSTAR’s committee. 10 11 These experiences in leadership have increased my confidence in management situations as I have transitioned to being a consultant, and have given me skills in balancing clinical and academic roles. Importantly, I have also developed long term friendships with peers across the country as a result of my involvement in HaemSTAR.

Associate Principal Investigator scheme

The Associate Principal Investigator (API) scheme is a training programme run by NIHR to develop research skills and contribute to clinical study delivery at a local level. It is available throughout England, Scotland, Wales, and Northern Ireland for NIHR portfolio-adopted studies. The programme runs for six months and, upon completion, APIs receive formal recognition endorsed by the NIHR and a large number of royal colleges. The scheme is free and open to medical and allied healthcare professionals at all career grades. It is designed to allow those who would not normally take part in clinical research to do so under the mentorship of a local PI. Currently there are more than 1500 accredited APIs and over 600 affiliated studies across 28 specialties. 12 It is a good way to show evidence of training and involvement in research and get more involved in research conduct. APIs have been shown to increase patient recruitment and most people completing the scheme continue to be involved in research. 12 13

Case study—Rebecca Hawes

I completed the API scheme as a senior house officer in 2021. A local PI introduced me to the Quality of Recovery after Obstetric Anaesthesia NIHR portfolio study, 14 which I saw as a training opportunity and useful experience ahead of specialist training applications. It was easy to apply for and straightforward to navigate. I was guided through the six month process in a step-by-step manner and completed eLearning modules and video based training on fundamental aspects of running research projects. All this training was evidenced on the online API platform and I had monthly supervision meetings with the PI and wider research team. As well as the experience of patient recruitment and data collection, other important aspects of training were study set-up and sponsor communications. Key to my successful API scheme was having a supportive and enthusiastic PI and developing good organisational skills. I really enjoyed the experience, and I have since done more research and have become a committee member on a national trainee research network in anaesthesia called RAFT (Research and Audit Federation of Trainees). I’ve seen great enthusiasm among anaesthetists to take part in the API scheme, with over 150 signing up to the most recent RAFT national research project.

Clinical research posts

Dedicated clinical research posts (sometimes termed “clinical research fellow” posts) allow clinicians to explore and develop research skills without committing to a formal academic pathway. They can be undertaken at any stage during a medical career but are generally performed between training posts, or during them by receiving permission from local training committees to temporarily go “out of programme.” These positions are extremely varied in how they are advertised, funded, and the balance between research and clinical time. Look out for opportunities with royal colleges, local and national research networks, and on the NHS Jobs website. Research fellowships are a good way to broaden skills that will have long term impact across one’s clinical career.

Case study—Nicole Fowler

After completing the Foundation Programme, I took up a 12 month clinical trials fellow position. This gave me early career exposure to clinical research and allowed me to act as a sub-investigator in a range of clinical trials. I received practical experience in all stages of clinical research while retaining a patient facing role, which included obtaining consent and reviewing patients at all subsequent visits until study completion. Many of the skills I developed in this post, such as good organisation and effective teamwork, are transferable to all areas of medicine. I have thoroughly enjoyed the experience and it is something I hope to talk about at interview as it is an effective way of showing commitment to a specialty. Furthermore, having a dedicated research doctor has been beneficial to my department in increasing patient involvement in research.

Acknowledgments

We would like to thank Holly Speight and Clare Shaw from the NIHR for information on the API scheme.

*These authors contributed equally to this work

Patient and public involvement: No patients were directly involved in the creation of this article.

PLRN, MB, and CHT conceived the article and are guarantors. All authors wrote and edited the manuscript.

Competing interests: PLRN was the chair of HaemSTAR from 2017 to 2023. MB is the current chair of the Research and Audit Federation of Trainees (RAFT). RH is the current secretary of RAFT. CHT conceived HaemSTAR.

Provenance and peer review: Commissioned; externally peer reviewed.

• Downing A ,
• Morris EJ ,
• Corrigan N ,
• Bracewell M ,
• Medical Academic Staff Committee of the British Medical Association
• ↵ RAFT. The start of RAFT. https://www.raftrainees.org/about
• Jamjoom AAB ,
• Hutchinson PJ ,
• Bradbury CA ,
• HaemSTAR Collaborators
• ↵ National Institute for Health and Care Research. Associate Principal Investigator (PI) Scheme. 2023. https://www.nihr.ac.uk/health-and-care-professionals/career-development/associate-principal-investigator-scheme.htm
• Fairhurst C ,
• Torgerson D
• O’Carroll JE ,
• Warwick E ,
• ObsQoR Collaborators

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Part 1. Overview Information

National Institutes of Health ( NIH )

National Heart, Lung, and Blood Institute ( NHLBI )

National Institute on Aging ( NIA )

National Institute on Alcohol Abuse and Alcoholism ( NIAAA )

National Institute of Allergy and Infectious Diseases ( NIAID )

National Institute of Arthritis and Musculoskeletal and Skin Diseases ( NIAMS )

February 14, 2024 - Participation Added ( N0T-HD-24-007 ) Eunice Kennedy Shriver National Institute of Child and Human Development ( NICHD )

National Institute on Deafness and Other Communication Disorders ( NIDCD )

National Institute of Dental and Craniofacial Research ( NIDCR )

National Institute on Drug Abuse ( NIDA )

National Institute of Environmental Health Sciences ( NIEHS )

National Institute of General Medical Sciences ( NIGMS )

National Institute of Mental Health ( NIMH )

National Institute of Nursing Research ( NINR )

National Center for Advancing Translational Sciences ( NCATS )

National Center of Complementary and Integrative Health ( NCCIH )

All applications to this funding opportunity announcement should fall within the mission of the Institutes/Centers. The following NIH Offices may co-fund applications assigned to those Institutes/Centers.

Division of Program Coordination, Planning and Strategic Initiatives, Office of Disease Prevention ( ODP )

Office of Research on Women's Health ( ORWH )

UC2 High Impact Research and Research Infrastructure Cooperative Agreement Programs

• March 20, 2024 - Notice of Informational Webinar for PAR-23-144, STrengthening Research Opportunities for NIH Grants (STRONG): Structured Institutional Needs Assessment and Action Plan Development for Resource Limited Institutions (RLIs) (UC2 - Clinical Trial Not Allowed). See Notice NOT-MD-24-011
• February 14, 2024 - Notice of NICHD Participation in PAR-23-144 "Strengthening Research Opportunities for NIH Grants (STRONG): Structured Institutional Needs Assessment and Action Plan Development for Resource Limited Institutions"). See Notice NOT-HD-24-007
• August 31, 2023 - Notice of Correction to Eligibility Criteria of PAR-23-144, STrengthening Research Opportunities for NIH Grants (STRONG): Structured Institutional Needs Assessment and Action Plan Development for Resource Limited Institutions (RLIs) (UC2). See Notice NOT-MD-23-018
• May 12, 2023 - Notice of Participation of the NIAAA in PAR-23-144. See Notice NOT-AA-23-012 .
• April 25, 2023 - Notice of NCCIH Participation in PAR-23-144, "STrengthening Research Opportunities for NIH Grants (STRONG): Structured Institutional Needs Assessment and Action Plan Development for Resource Limited Institutions (RLIs) (UC2 - Clinical Trial Not Allowed). See Notice NOT-AT-24-004
• August 5, 2022 - Implementation Details for the NIH Data Management and Sharing Policy - see Notice NOT-OD-22-189 .
• August 8, 2022 - New NIH "FORMS-H" Grant Application Forms and Instructions Coming for Due Dates on or after January 25, 2023 - See Notice NOT-OD-22-195 .
• August 31, 2022 - Implementation Changes for Genomic Data Sharing Plans Included with Applications Due on or after January 25, 2023 - See Notice NOT-OD-22-198 .

See Section III. 3. Additional Information on Eligibility .

The STrengthening Research Opportunities for NIH Grants (STRONG): The STRONG-RLI program will support research capacity needs assessments by eligible Resource-Limited Institutions (RLIs). The program will also support the recipient institutions to use the results of the assessments to develop action plans for how to meet the identified needs.

RLIs are defined as institutions with a mission to serve historically underrepresented populations in biomedical research that award degrees in the health professions (and in STEM fields and social and behavioral sciences) and have received an average of $0 to $25 million per year (total costs) of NIH Research Project Grant (RPG) support for the past three fiscal years.

August 18, 2023

All applications are due by 5:00 PM local time of applicant organization.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

Not Applicable

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide , except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts).

Conformance to all requirements (both in the Application Guide and the NOFO) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV . When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review.

There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

• Use the NIH ASSIST system to prepare, submit and track your application online.
• Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.
• Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.

Part 2. Full Text of Announcement

Section i. notice of funding opportunity description.

Purpose: The purpose of the STRONG-RLI Notice of Funding Opportunity (NOFO) is to invite applications to conduct biomedical research capacity needs assessments by Resource-Limited Institutions (RLIs) and then to use the results of the assessments to create action plans for meeting identified needs. The program’s goal is to increase competitiveness in the biomedical research enterprise and foster institutional environments conducive to research career development. Awards are intended to support RLIs in analyzing their institutional research capacity needs and strengths. Resource-Limited Institutions (RLIs) are defined for this NOFO as institutions with a mission to serve historically underrepresented populations in biomedical research that award degrees in the health professions or the sciences related to health, in STEM fields including social and behavioral sciences, and have received an average of $0 to $25 million (total costs) per year of NIH research project grant (RPG) support for the past three fiscal years (as defined in Section III -Eligibility).

Background:

NIH’s ability to help ensure that the nation remains a global leader in scientific discovery and innovation is dependent upon a pool of highly talented scientists from diverse backgrounds who will help to further NIH's mission (see NOT-OD-20-031 ). NIH recognizes the importance of diversity in biomedical, clinical, behavioral, and social sciences (collectively termed "biomedical") research. This includes the diversification of NIH-funded institutions, where researchers with a wide range of skill sets and viewpoints can bring different perspectives, creativity, and individual enterprise to address complex scientific problems.

RLIs, as defined below, play an important role in supporting scientific research, particularly on diseases or conditions that disproportionately impact racial ethnic minority groups and other U.S. populations that experience health disparities. Although these institutions are uniquely positioned to engage underserved populations in research and in the translation of research advances into culturally competent, measurable and sustained improvements in health outcomes, they may benefit from enhancing their capacity to conduct and sustain cutting-edge health-related research.

NIH is committed to assisting RLIs in building institutional research capacity. Scientists at RLIs are critical to advancing knowledge in the biomedical research enterprise. NIH has many programs designed to support researchers at RLIs and broaden the participation of researchers through inclusive excellence across regions, institutions, and demographic groups. The role of RLIs in the nation’s overall competitiveness in research is integrally related to current resources, departmental and disciplinary strengths and capabilities, and campus research support systems and infrastructure. It is critical that RLIs recognize and utilize their research and organizational capabilities so they can leverage existing strengths and develop strategic approaches in areas that require additional attention. Structured needs assessments to examine research and organizational capabilities can offer metrics for short-term/long-term action plans. These assessments will enable institutions to develop benchmarks and action items to increase their competitiveness for NIH, Federal, and other funding opportunities.

RLIs face unique challenges depending on the institution type, resources, infrastructure, and policies as they seek to acquire NIH or other federal agency funding. The areas at RLIs that need to be identified and addressed to reduce the barriers to scientific advancement and increase independent research funding can best be determined by the institution itself. A fundamental principle for organizational development and change is the use of a structured assessment to understand these barriers.

This Funding Opportunity will provide resources to the institutions to 1) conduct the assessment of research infrastructure and other requirements that will enhance administrative and research resources, institutional policies, and expanded opportunities for faculty and students in the biomedical research enterprise; and 2) Use the results of these institutional assessments to develop action plans that will support the conduct of high-quality biomedical research.

Program Objectives:

The purpose of this NIH-wide initiative, STRONG-RLI, is to support research active RLIs to;1. conduct rigorous research capacity needs assessments.2. use the results of the assessments to develop action plans for how to meet the identified needs.

Because of the significant variability in the types of RLIs, two separate categories have been created for this initiative. Please refer to Section III for eligibility criteria for RLIs.

The two categories of research active RLIs are defined in Section III of the NOFO:

1) Low Research Active (LRA) : An RLI that is an undergraduate or graduate degree granting institution and has had less than six million dollars (total costs) in NIH research project grant (RPG) support per year in three of the last five years. In addition, undergraduate granting institutions must have at least 35% of undergraduate students supported by Pell grants.

2) High Research Active (HRA) : An RLI that grants doctoral degrees and has had between six million and 25 million dollars (total costs) in NIH RPG support per year in three of the last five years.

Both LRA and HRA RLIs must have a historical mission to support underrepresented groups in biomedical sciences. Each institution should describe the specific category into which they fit and provide documentation to verify those requirements.

Each RLI will provide details on how they plan to conduct their needs assessments and create/use/adapt/ instruments to study research capacity at the institution. Please note that institutional climate or culture assessment is not a priority for this funding announcement.

As part of the funding announcement , the recipient institutions are expected to use the results of needs assessments to develop action plans for short term and long term goals, to meet the identified needs . Applicants are encouraged to provide detailed approaches for conducting the needs assessment and action plan development. The action plan should include identification of possible sources of funding for increasing research capacity. The implementation of the action plan is beyond the scope of this funding opportunity.

A. Institutional Needs-Assessment for research capacity

NIH recognizes and values the heterogeneity in institutional settings and the students they serve. Applicants must describe their distinctive biomedical research and research training environment and the current services to support them.

Applicants for this needs assessment can use any available tools, or adapt existing tools, to fit their context and needs.

B. Development of Institutional Action Plans

• After completion of the needs assessment, the recipient institutions are expected to develop an action plan. The Institutional Action Plan for research capacity is intended to serve as a roadmap for enhancing the infrastructure and capacity at the applicant institution.
• The outcomes of the needs assessment should determine the capacity building interventions that the institution can undertake to strengthen the institutional framework and research capacity. The Institutional Action Plan that will be developed is expected to be supported by an institutional leader, e.g., the Provost or President (see Letters of Support).

C. Needs assessment topics may include (but are not limited to):

The institution will determine the needs assessment foci but may include broad categories such as administrative/research/student/faculty.

Administrative topics may include -

• Establishing or enhancing the Office of Sponsored Programs (OSP), examining efficiencies and staffing requirements and personnel needs for administrative support
• Available resources for effective business practices, automation, information dissemination, documentation and tracking progress for research activities,
• Process management and process improvement for grant application, grant award, and grant administration.

Research topics may include-

• Research infrastructure may include physical research facilities, lab equipment, and computing resources, core facility for technology, support staff, professional development, laboratories. Appropriate physical research facilities and skilled research support to enable competitiveness.
• Research readiness in areas, such as basic, behavioral or clinical research, grantsmanship support, seminars and workshops for grant writing, for sharing research ideas to enhance knowledge in the field. Potential and current scientific research areas of interest.
• Capacity to conduct Human Subjects Research
• Capacity for Community Engagement research
• Partnerships/ collaboration with other academic institutions, the public sector, and community-based organizations that are sustainable and equitable

Student and faculty topics may include-

• Training needs, Mentoring/Sponsorship, faculty development.
• Student resources for research, support for research experiences, and for post-bac and graduate career progression in biomedical research and in STEM topics
• Research staff recruitment and benefits packages, retention bonuses,
• Faculty teaching workloads that allow time for research pursuits, and department/college-based research staff and administrative support
• Institutional policies for assessment of teaching versus research assignments and support
• Tenure evaluations of faculty services for research, committee, community engagement, etc., protected time for research program development

Technical Assistance Webinar:

NIH will conduct a Technical Assistance Webinar for prospective applicants on July 21st from 2-3.30pm EST. Please join the webinar using the link below:

Join Zoom Meeting https://nih.zoomgov.com/j/1614627302?pwd=RmVXc0RjWjV2WTZsUzd1WmFSWU1NZz09&from=addon Meeting ID: 161 462 7302 Passcode: 919936 One tap mobile +16692545252,,1614627302#,,,,*919936# US (San Jose) +16468287666,,1614627302#,,,,*919936# US (New York)

See Section VIII. Other Information for award authorities and regulations.

Section II. Award Information

Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities. See Section VI.2 for additional information about the substantial involvement for this FOA.

The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types. Only those application types listed here are allowed for this NOFO.

Not Allowed: Only accepting applications that do not propose clinical trials.

Need help determining whether you are doing a clinical trial?

The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.

Application budgets for direct costs should not exceed $250,000/year.

The scope of the proposed project should determine the project period. The maximum project period is three years

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this NOFO.

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

For this funding opportunity, an applicant must be a Resource-Limited Institution (RLI), defined as an institution with a mission to serve historically underrepresented populations that awards degrees in the health professions (and related sciences) and has received an average of $0 to $25 million per year (total costs) of NIH Research Project Grants (RPG) support for the past three fiscal years.

A mission to serve historically underrepresented populations may be demonstrated by a documented historical and current mission to educate students from any of the populations that have been identified as underrepresented in biomedical research as defined by the National Science Foundation NSF, see http://www.nsf.gov/statistics/wmpd/ ) (i.e., African Americans or Blacks, Hispanic or Latino Americans, American Indians, Alaska Natives, Native Hawaiians, U.S. Pacific Islanders, and persons with disabilities) or by a documented record of recruiting, training and/or educating, and graduating underrepresented students as defined by NSF (see above), which has resulted in increasing the institution's contribution to the national pool of graduates from underrepresented backgrounds who pursue biomedical research careers.

RLIs, as defined above, are classified into the following two categories for this opportunity:

Institutional letters will attest to the category of the institution whether they are LRA or HRA and provide information to verify which can be included as an attachment.

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement , are not allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• Unique Entity Identifier (UEI)- A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registrations; all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities , NOT-OD-22-019 .

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

2. Cost Sharing

This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement.

3. Additional Information on Eligibility

Number of Applications

Only one application per institution (normally identified by having a unique UEI or NIH IPF number) is allowed

The NIH will not accept duplicate or highly overlapping applications under review at the same time, per 2.3.7.4 Submission of Resubmission Application . This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see 2.3.9.4 Similar, Essentially Identical, or Identical Applications ).

Only one application per institution (normally identified by having a unique UEI number or NIH IPF number) is allowed.

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide except where instructed in this notice of funding opportunity to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Letter of Intent

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information , prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Yujing Liu, MD, PhD National Institute on Minority Health and Health Disparities (NIMHD) Telephone: 301-827-7815 Email: [email protected]

Page Limitations

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this NOFO.

SF424(R&R) Cover

All instructions in the SF424 (R&R) Application Guide must be followed.

SF424(R&R) Project/Performance Site Locations

SF424(R&R) Other Project Information

SF424(R&R) Senior/Key Person Profile

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Travel costs for attending any in-person meetings and STRONG Executive Steering Committee (SESC) meetings must be included.

Funds may not be used for:

• Research infrastructure (such as laboratory supplies, laboratory equipment)
• Alterations or renovations
• Research projects or pilot projects

R&R Subaward Budget

PHS 398 Cover Page Supplement

PHS 398 Research Plan

Research Strategy:

Significance

Explain the needs for institutional research capacity and importance of the problem or critical barrier to progress that the proposed project addresses. Describe the benefits if the proposed aims are achieved with respect to enhanced biomedical research capacity.

Applicants should address the innovative aspects of the proposed needs assessment plans for research capacity. For this program, innovation is considered the use of existing products, tools or processes or creating or adapting evidence-based tools to fit the context and needs of the institutions.

A. Institutional Needs-Assessment for research capacity section describe:

• Physical research facility, research faculty support from institution, faculty teaching workload, human resources, Sponsored program
• Applicant must describe current methods of measuring student/faculty outcomes to take into consideration institutional missions, faculty investment, student populations, student needs, and institutional resource constraints.
• Tools and instruments for needs assessment, monitoring and evaluation of health research capacity development activities at the individual and organizational level
• The types of research facilities available for biomedical research and research training.
• The needs for research infrastructure to conduct biomedical, behavioral or clinical research, potential and current scientific research areas of interest.
• List and describe the outcomes of any capacity-building or infrastructure grants the institution has received over the past ten years, including the source and total costs of each award.
• The investigative team and their relevant expertise in conducting a needs assessment
• Student enrollment in the biomedical areas, including the number and percentage of undergraduate and graduate students, and the enrollment of students who are Pell-grant eligible (for LRA applications); and
• The current level of student and faculty participation in research.
• Describe the sponsored programs administration and how it will inform the needs assessment. The types of services provided by the existing sponsored projects administration (or similar entity). Current levels of sponsored programs productivity (e.g., number of applications submitted, number of applications funded, number of subcontracts).

Describe the approaches for developing an Institutional Action Plan after completing needs assessment for research capacity. The Institutional Action Plan for research capacity is intended to serve as a roadmap for enhancing the infrastructure and capacity at the applicant institution. This section of the application should describe steps that will be undertaken to ensure identified needs assessment activities lead to action plans for the long-term strengthening of research capacity. It must include an institutional commitment to achieving the goals and objectives of the proposed project and activities signed by institutional leadership (e.g., President, Provost, and Deans (see Letters of Support).

C. Governance and structure of steering committees

The Steering Committee (SC) will serve as the primary governing and oversight board for the cooperative agreement funded under this NOFO.

• Describe the composition and the activities of the steering committee. Describe the desired expertise of its members. Include the frequency of meetings and any other relevant information.
• The membership of the SC consists of the PD(s)/PI(s), the NIH Project Coordinator, and any additional stake holders deemed necessary.

Timeline and Milestones:

Describe the timeline for the needs assessment and action plan activities. The timeline should be realistic given the time needed to develop the approaches/tools and collect the proposed data. Describe how the program goals/aims will be aligned with milestones and metrics.

Letters of Support: Provide letters of support for the proposed needs assessment activities following instructions in the SF424 Application Guide.

A. Institutional Eligibility Letter (1-page maximum). S ubmit a letter from the Provost or similar official with institution-wide responsibility that certify that the applicant organization qualifies as one of the following two categories of research active RLI specified in this NOFO:

A mission to serve historically underrepresented populations may be demonstrated by a documented historical and current mission to educate students from underrepresented populations in biomedical research.

The two categories of research active RLIs are:

1) Low Research Active (LRA): An RLI that is an undergraduate or graduate degree granting institution, with at least 35% of undergraduate students supported by Pell grants, and that has had less than six million dollars in NIH research project grant (RPG) support per year in three of the last five years.

2) High Research Active (HRA): An RLI that grants doctoral degrees and has had less than 25 million dollars in NIH RPG support in three of the last five years.

B. Institutional Commitment Letter. The application must include an Institutional Commitment Letter from the President or designated high-ranking official such as the Provost, Vice President or Dean. Describe how the proposed project aligns with the broad institutional vision for enhancing biomedical research. The letter should include a commitment to achieving the goals and objectives of the proposed project and activities.

The letters of support must be included with the application. Applications which lack this letter will be considered incomplete and will be withdrawn and will not be reviewed.

Resource Sharing Plan : Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide.

The following modifications also apply:

Generally, Resource Sharing Plans are expected, but they are not applicable for this FOA.

• A Data Management and Sharing Plan is not applicable for this NOFO.

Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

• No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

PHS Human Subjects and Clinical Trials Information

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed.

PHS Assignment Request Form

3. Unique Entity Identifier and System for Award Management (SAM)

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

4. Submission Dates and Times

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday , the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons , NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement .

Pre-award costs are allowable only as described in the NIH Grants Policy Statement .

7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply Application Guide . If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile form . Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this NOFO for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review, NIH. Applications that are incomplete or non-compliant will not be reviewed.

In order to expedite review, applicants are requested to notify the NIMHD Referral Office by email at [email protected] when the application has been submitted. Please include the NOFO number and title, PD/PI name, and title of the application.

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in the policy

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

In addition, specific to this NOFO:

How well does the application provide a vision for how the project will serve as a foundation for future research capacity building? To what degree the application describes clear pathways between the need assessment and action plan development research activities and future research efforts? To what extent is the proposed project likely to enhance institutional research capacity to conduct biomedical research?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance, and organizational structure appropriate for the project?

To what extent do the PDs/PIs have the appropriate expertise to conduct the needs assessment, implement the proposed project, analyze the outcomes, and develop action plans?

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

How well does the applicant create approaches to fit their context and needs? Does the application employ novel approaches or methods to fulfill its purpose?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

To what extent does the applicant describe the tools and instruments for needs assessment, monitoring and evaluation of research capacity development activities? To what degree does the applicant identify metrics and indicators of success that will be used to assess the anticipated outcomes? Is the duration of the initial needs assessment stage adequate to develop action plans for short-term goals? To what degree isthe structure and governance plan likely to lead to implementation of the proposed plan? Are these goals feasible and well developed on the timeline of the award? How well are the program goals/aims aligned with yearly milestones and are the details provided adequate?

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment, and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

How strong is the level of institutional commitment to the project, including administrative and scientific support, to ensure the success of the project?

How well do the letters of support demonstrate a strong commitment to the proposed activities?

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

For research that involves human subjects but does not involve one of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects .

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research .

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animals Section .

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Not applicable

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Reviewers will comment on whether the Resource Sharing Plan(s) (e.g., Sharing Model Organisms ) or the rationale for not sharing the resources, is reasonable.

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NIMHD, in accordance with NIH peer review policy and procedures , using the stated review criteria . Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications will receive a written critique.

Applications may undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications . Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.
• Geographical distribution of the portfolio
• Balance between HRA and LRA awards

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons . Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement .

Section VI. Award Administration Information

1. Award Notices

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement .

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the recipient's business official.

Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this NOFO will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities , including of note, but not limited to:

• Federal wide Research Terms and Conditions
• Prohibition on Certain Telecommunications and Video Surveillance Services or Equipment
• Acknowledgment of Federal Funding

If a recipient is successful and receives a Notice of Award, in accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

Should the applicant organization successfully compete for an award, recipients of federal financial assistance (FFA) from HHS will be required to complete an HHS Assurance of Compliance form (HHS 690) in which the recipient agrees, as a term and condition of receiving the grant, to administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, age, sex and disability, and agreeing to comply with federal conscience laws, where applicable. This includes ensuring that entities take meaningful steps to provide meaningful access to persons with limited English proficiency; and ensuring effective communication with persons with disabilities. Where applicable, Title XI and Section 1557 prohibit discrimination on the basis of sexual orientation, and gender identity. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and https://www.hhs.gov/civil-rights/for-individuals/nondiscrimination/index.html

HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this NOFO.

• Recipients of FFA must ensure that their programs are accessible to persons with limited English proficiency. For guidance on meeting the legal obligation to take reasonable steps to ensure meaningful access to programs or activities by limited English proficient individuals see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.html and https://www.lep.gov .
• For information on an institution’s specific legal obligations for serving qualified individuals with disabilities, including providing program access, reasonable modifications, and to provide effective communication, see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html .
• HHS funded health and education programs must be administered in an environment free of sexual harassment, see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html . For information about NIH's commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what NIH's expectations are for institutions and the individuals supported on NIH-funded awards, please see https://grants.nih.gov/grants/policy/harassment.htm .
• For guidance on administering programs in compliance with applicable federal religious nondiscrimination laws and applicable federal conscience protection and associated anti-discrimination laws see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/index.html .

Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 and 2 CFR Part 200.206 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75 and 2 CFR Part 200, and other HHS, PHS, and NIH grant administration policies. The administrative and funding instrument used for this program will continue as a cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the recipients is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the recipients for the project as a whole, although specific tasks and activities may be shared among the recipients and the NIH as defined below.

The individual STRONG-RLI recipients will establish steering committees at their institutions with defined roles.

In addition, the PIs of the STRONG-RLI awards and involved NIH staff, and others as needed (ex-officio), will form a STRONG-RLI Executive Steering Committee (SESC) which will oversee the activities of the STRONG-RLI program recipients. There will be a yearly rotating chair of the SESC who will be nominated and selected from the PIs of the awards.

The PDs/PIs will have the primary responsibility for:

• Plan, organize, coordinate, and administer the described activities of the program, including setting project milestones with specific timelines and criteria for Institutional needs assessment and developing action plans.
• Establish Steering Committee, organize, and coordinate SESC meetings
• Ensure compliance with the applicable mandatory NIH regulations and policies
• Participate in the STRONG SESC meetings is a requirement for the PI/PDs.The purpose of the meeting is to share progress, best practices, and address common challenges.
• Work closely with the NIH Program Official and Project Coordinator (see below) in project coordination and management.
• Establish a separate site specific steering committee that will comprise of PI, institute leadership and NIH staff
• Evaluate progress using defined milestones and metrics. Recipients will provide NIH with progress reports at regular intervals as requested.
• Share needs assessment and action plan with the NIH during the award period.
• Recipients will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

NIH staff will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

The NIH Project Coordinator will :

Work closely with individual PIs and NIH program officials (POs) to facilitate collaborations.

• Interact with each recipient, help coordinate approaches, and contribute to the adjustment of projects/programs or approaches as warranted.
• Advise the recipient in performing project activities (e.g., coordination among RLI recipients for needs assessments; provide access to NIH supported resources; identify other resources for the project);
• Facilitate, not direct, activities.
• Participate on the Steering Committee (see below) or in other functions to help guide the course of the program (e.g., Annual Program Meeting and other Program related meetings).
• Ensure that the directions taken are consistent with the NIH missions and goals.

The Project Coordinator will not participate in the oversight of the funding opportunity announcement, application review, or programmatic and budgetary stewardship of the award.

The Program Official will be responsible for the normal programmatic stewardship of the award, including funding decisions, and will be named in the award notice. The Program Official will not serve as a voting member of the Steering Committee or partake of the duties of the Project Coordinator.

Areas of joint responsibility

The SECS is the governing and oversight body for the Program. Members, who are appointed by the PDs/PIs of the award, will be comprised of the following:

• The PI of each award will serve as the SESC member.
• NIH Project Coordinators.
• Additional members from the NIH may be appointed, but the total number of NIH votes may not exceed 1/3 of the Executive Steering Committee voting membership. Other government staff may attend the Steering Committee meetings, if their expertise is required for specific discussions.
• Each recipient must plan regular meetings (no less frequently than monthly) to discuss the progress and direction of its activities and to ensure that the necessary interactions are taking place. Recipients will be expected to participate in STRONG RLI program-wide meetings. These meetings may be in the form of phone teleconferencing, videoconferencing, and/or web conferencing, as well as face-to-face meetings. Unwillingness or a consistent inability of a PD/PI to attend may be the basis for administrative action including termination of the award.

The SESC will:

• Serve as the primary steering and oversight board for the awards funded under this NOFO.
• Decide on the schedule of regular and annual meetings. The Executive Steering Committee may also call meetings to address urgent needs and will participate in network meetings and teleconferences as needed.
• Contribute to the development of a cohesive and sustainable program.
• Provide advice on key issues such as needs assessment administration, approaches, and tools for research capacity, and opportunities for growth.
• Ensure that the implementation of the Institutional Needs Assessments and Development of Sustainable Action Plan is occurring on schedule and continues to align with the applicant institution's strategic vision for biomedical research and/or research training.
• Alert NIH to emerging needs and impediments.
• Prepare concise (1-2 page) summaries of the Executive Steering Committee recommendations, which will be delivered to the PDs/PIs and members of the group within 30 days after each meeting.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to dispute resolution. A Dispute Resolution Panel composed of three members will be convened. The three members will be a designee of the STRONG Executive Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two. In the case of individual disagreement, the first member may be chosen by the individual recipient. This special dispute resolution procedure does not alter the recipient's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

The NIH reserves the right to withhold funding or curtail the program (of an individual award) in accordance with NIH policy.

3. Data Management and Sharing

Note: The NIH Policy for Data Management and Sharing is effective for due dates on or after January 25, 2023.

Consistent with the NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement . Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

4. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement . NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 45 CFR Part 75.301 and 2 CFR Part 200.301.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for recipients of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All recipients of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over the threshold. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and 2 CFR Part 200.113 and Appendix XII to 45 CFR Part 75 and 2 CFR Part 200, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 and 2 CFR Part 200 Award Term and Condition for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: https://www.era.nih.gov/need-help (preferred method of contact) Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources) Email: [email protected] (preferred method of contact) Telephone: 301-480-7075

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace) Contact Center Telephone: 800-518-4726 Email: [email protected]

Brett Miller, PhD Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Telephone: 301-496-9849 Email: [email protected]

Rina Das, PhD. National Institute on Minority Health and Health Disparities (NIMHD) Telephone: 301-496-3996 Email: [email protected]

Behrous Davani, PhD. National Cancer Institute (NCI) Telephone: 240-276-6170 Email: [email protected]

Olga Kovbasnjuk, Ph.D. National Institutes of General Medical Sciences (NIGMS) E-mail: [email protected]

Kristopher Bough, PhD National Institute of Nursing Research (NINR) Telephone: 301-337-1372 Email: [email protected]

Anissa F Brown, PhD NIDCR - NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH Phone: 301-594-5006 E-mail: [email protected]

Melissa C. Green Parker, Ph.D. Office of Disease Prevention (ODP) Phone: 301-480-1161 E-mail: [email protected]

Erica K Rosemond NCATS - NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES Phone: (301) 594-8927 E-mail: [email protected]

Kristy M. Nicks, PhD National Institute of Arthritis and Musculoskeletal and Skin Diseases Tel: 301-594-5055 Email: [email protected]

Carol Shreffler, PhD National Institute of Environmental Health Sciences (NIEHS) Phone: 984-287-3322 E-mail: s [email protected]

Aria Crump NIDA - NATIONAL INSTITUTE ON DRUG ABUSE Phone: 301-443-6504 E-mail: [email protected]

Diane Adger-Johnson, MPH Office of Research Training and Special Programs (ORTSP) National Institute of Allergy and Infectious Diseases (NIAID) Telephone: 301-594-5945 Email: [email protected]

Damiya Eve Whitaker, PsyD, MA ORWH - Office of Research on Women's Health Phone: 301-451-8206 E-mail: [email protected]

Damali Martin, Ph.D., MPH NATIONAL INSTITUTE ON AGING (NIA) Division of Neuroscience (DN) Phone: 301-402-8310 E-mail: [email protected]

Judith Cooper NIDCD - NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS Phone: (301) 496-5061 E-mail: [email protected]

Xinzhi Zhang, M.D. National Heart, Lung, and Blood Institute Phone: 301-435-6865 Email: [email protected]

Brittany Haynes, Ph.D. National Institute of Mental Health (NIMH) Telephone: 301-496-2767 Email: [email protected]

Beda Jean-Francois, Ph.D. National Center for Complementary & Integrative Health (NCCIH) Phone: 202-313-2144 Email: [email protected]

Elizabeth Powell, PhD National Institute on Alcoholism and Alcohol Abuse ( NIAAA ) Telephone: 301-443-0786 Email: [email protected]

Margaret Young Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Telephone: 301-642-4552 Email: [email protected]

Priscilla Grant, JD National Institute on Minority Health and Health Disparities (NIMHD) Telephone: 301-594-8412 Email: [email protected]

Alania Foster NIGMS - NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES E-mail: [email protected]

Randi Freundlich National Institute of Nursing Research (NINR) Telephone: 301-594-5974 Email: [email protected]

Gabriel Hidalgo, MBA NIDCR - NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH Phone: 301-827-4630 E-mail: [email protected]

Leslie Le NCATS - NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES Phone: (301) 435-0856 E-mail: [email protected]

Jenny L Greer NIEHS - NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES Phone: 984.287.3332 E-mail: [email protected]

Pamela G Fleming NIDA - NATIONAL INSTITUTE ON DRUG ABUSE Phone: 301-480-1159 E-mail: [email protected]

Samuel Ashe National Institute of Allergy and Infectious Diseases ( NIAID ) Telephone: 301-435-4799 Email: [email protected]

Jeni Smits NATIONAL INSTITUTE ON AGING (NIA) E-mail: [email protected]

Anthony Agresti NHLBI - NATIONAL HEART, LUNG, AND BLOOD INSTITUTE Phone: 301-827-8014 E-mail: [email protected]

Tamara Kees National Institute of Mental Health (NIMH) Telephone: 301-443-8811 Email: [email protected]

Debbie Chen, Ph.D. National Center for Complementary and Integrative Health (NCCIH) Telephone: 301-594-3788 Email: [email protected]

Judy Fox National Institute on Alcoholism and Alcohol Abuse (NIAAA) Telephone: 301-443-4704 Email: [email protected]

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts . All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement .

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75 and 2 CFR Part 200.

Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files .

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A Researcher's Guide to Community Engaged Research: Association for Clinical and Translational Science 2024 Abstract Collection - Clinical Research Forum

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2024 Abstract and Publication Collection of the Journal of Clinical and Translation Science Topics Relative to Community Engaged Research

• The Community Research Liaison Model: Facilitating Community-Engaged Research The Community Research Liaison Model (CRLM) is a novel model to facilitate community-engaged research (CEnR) and community–academic research partnerships focused on health priorities identified by the community. This model, informed by the Principles of Community Engagement, builds trust among rural communities and expands capacity for community and investigator-initiated research. This publication describes the CRLM development process and how it is operationalized today. We followed a multi-phase process to design and implement a community engagement model that could be replicated. The resulting CRLM moves community–academic research collaborations from objectives to outputs using a conceptual framework that specifies our guiding principles, objectives, and actions to facilitate the objectives (i.e., capacity, motivations, and partners), and outputs. The CRLM has been fully implemented across Oregon.
• From Community Engagement, To Community-Engaged Research, To Broadly Engaged Team Science Abstract A foundational principle and practice for translational research is active participation of a range of disciplines, referred to as “team science.” It is increasingly apparent that to be relevant and impactful, these teams must also include stakeholders outside the usual academic research community, such as patients, communities, and not-for- and for-profit organizations. To emphasize the need to link the practices of team science and of community-engaged research, we propose a framework that has community members and stakeholders as integral members of the research team, which we term, “broadly engaged team science.” Such transdisciplinary and multi-stakeholder teams will be best suited to pose translational research questions, conduct the research, and interpret and disseminate the results. We think this will generate important and impactful science, and will support the public’s regard for, and participation in, research.
• Developing and Piloting a Community Scientest Academy to Engaged Communities and Patients in Research Abstract Introduction Effective translational research requires engagement and collaboration between communities, researchers, and practitioners. We describe a community scientist academy (CSA) developed at the suggestion of our Clinical and Translational Science Awards’ (CTSA) community advisory board to engage and capacitate community members by (1) increasing community members’ and patients’ understanding about the research process and (2) increasing their access to opportunities to influence and participate in research. A joint CTSA/community planning committee developed this 8-hour workshop including sessions on: (1) research definitions and processes; (2) study design; (3) study implementation; and (4) ways to get involved in research. The workshop format includes interactive exercises, content slides and videos, and researcher and community presenters.
• A Model for Academic Institution Support for Community-Engaged Research The promise of community-engaged research (CEnR) to improve the health and well-being of populations is increasingly recognized by academic institutions and the programs that support their work. The National Institutes of Health’s Clinical and Translational Science Awards calls for the development of partnerships with collaborators outside of academia (e.g., patients, nonprofit organizations, governmental agencies, community-based clinicians and delivery systems, industry), “where and when appropriate [1].” Recognizing that optimal ways to involve communities in each stage of the translational process are not yet clear, the program also charged the clinical and translational research institutes (“hubs”) that received funding, to “develop a methodological framework for discovering, demonstrating and disseminating successful collaboration models [1].”
• << Previous: Recorded Trainings on Community Engaged Research Practices
• Last Updated: Apr 23, 2024 8:08 AM
• URL: https://guides.mclibrary.duke.edu/CENR_researchers
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How to Implement eSource – A Guide for Clinical Research Sites

Increasingly, clinical research sites are replacing t raditional paper-based processes with Electronic Source ( eS ource ) technology in clinical trials . T he shift from paper-based processes to e Source represents a significant step forward in improving efficiency, accuracy, and compliance. As sites prepare to make t he transition , whether fro m paper or an existing vendor , it is essential to understand the steps involved, especially the pivotal phase of data migration. T his guide , “ How to Implement Electronic Source (eSource), ” aims to walk clinical research sites through the c rucial steps of implementation and data migration.  

What is Electronic Source (eSource)?

eSource refers to the use of electronic systems for the direct collection or transference of source data in clinical trials. This contrasts with traditional methods where data are first recorded on paper and then transcribed into electronic systems – a process prone to transcription errors and inefficiencies. T he transition to eSource data collecti on streamlines operations and offers many benefits for principal investigators and site staff. e Source is purpose-built t o manage studies more efficiently, lower protocol deviations and reduce FDA audit risks .    

According to research published in the International Journal of Medical Informatics studying the comparative effectiv eness of eSource for data capture , the overall average data capture time was reduced with eSource versus non-eSource methods (difference, 151 s per case; eSource, 1603 s ; non-eSource, 1754 s ; p = 0.051). The average data capture time for the demographic data was reduced (difference, 79 s per case; eSource, 133 s ; non-eSource, 213 s ; p < 0.001). This represents a 3 7% time reduction (95% confidence interval 27% to 47%). eSource data field transcription errors were also reduced (eSource, 0%; non-eSource, 9%) . 1  

Key Benefits of eSource for Clinical Research Sites

Improve efficiency in managing multiple studies.

eSource systems reduce the staff time spent on data entry and query resolution, allowing sites to manage multiple studies more effectively. By streamlining data collection and management processes, eSource enables principal investigators and site s taff to focus on more critical aspects of the trials, such as patient care and recruitment.

For instance, i n a recent case study by RealTime Software Solutions , a leading clinical research network was able to in c rease the number of studies managed by their coordinato rs by 42% . This increased capacity further resulted in 2850% revenue growth for the network.  

Reduce Protocol Deviations

Protocol deviations can compromise the integrity of a clinical trial and impact its outcomes. However, eSource technology offer s real-time data capture and validation checks, which significantl y reduces the likelihood of errors and deviations from the study protocol . I mmediate feedback is provided to site staff if data entered does not align with the protocol requirements . T his immediate feedback loop ensures that any potential deviations are addressed promptl y , maintain i ng the trial’s integrity.  

Lower Risk of FDA Audit Findings

FDA audits are a critical aspect of clinical trials, safeguarding that data integrity and patient safety are maintained . The FDA itself has recognized the value of electronic systems in improving the quality and integrity of clinical trial data. In its guidance on elect ronic source data in clinical investigations, the FDA advocates for the use of electronic systems to secure accurate , legible, and contemporaneous data capture, all of which contribute to a reduced risk of audit findings.  

Streamline Compliance and Enhance Data Integrity

eSource systems are designed to comply with FDA 21 CFR Part 11 and other relevant regulations, guaranteeing that electronic records and signatures are as valid and trustworthy as their paper counterparts. Thus, eSource improves data integrity and compliance by providing audit trails, secure data storage, and access controls. T hese powerful features strengthen the security of sensitive informati on and fac ilitate adherence to Good Clinical Practice (GCP) guidelines.    

The Data Migration Process

This section examines the intricate process of data migration. From planning and preparation to execution and validation, we unpack the critical steps involved in ensuring a smooth and successful transition.   

PHASE 1: PRE-MIGRATION

The first step in the data migration process is to make sure that all data within your current system is accurate , updated, and optimized for the transition.  

Database Cleanup

This stage is your opportunity to clean up your database, merging duplicate patient records and updating patient demographics and financial data. Remember, the quality of data migrated will directly affect your future operations.  

Obtaining Your Data File

If you are transferring data from an existing system, request a comprehensive data export from your vendor. This full export is vital as it encompasses all necessary information for a successful migration. Keep in mind:  

• Timing: The data acquisition process can be lengthy and may require patience as it may span weeks or months.  
• Data Backup: At RealTime Software Solutions, we highly recommend having a complete data backup, even if not all data is to be migrated. This backup serves as a vital historical reference, ensuring that valuable information is preserved and accessible whenever needed.

Vendor-Specific Requirements for Data File

Data File Formats: Ensure the data file format is compatible with the new eSource system (e.g.) Excel/.csv, SQL Database, or .xml formats.  

Custom Exports: Depending on your current system, you may need to request custom exports. This ensures all relevant financial and patient data is accurately captured.  

PHASE 2: MIGRATION

File Transfer: Securely transfer your data files to your new eSource system using a service like FileCloud. Ensure files are password-protected for security during the transfer.  

Project Proposal: After reviewing the initial data file for issues, request a Statement of Work (SOW). This ought to provide an outline of the project plan, timelines, and costs.

Development and QC Process: During migration, data are mapped and integrated into the new system and should be followed by a Quality Control (QC) process. This allows for a thorough review of the migrated data against the original files. It is important to ensure the accuracy and completeness of the migration before moving forward.  

PHASE 3: POST-MIGRATION

After completing the data migration process, it is essential to conduct a thorough review and make any necessary adjustments . This phase ensures that any discrepancies found during the QC process are addressed . It’s also a time to familiarize yourself with your new system, train staff and tweak workflows as needed. This allows your team to fully leverage the benefits of eSource. Ideally, your preferred software partner will extend support and services beyond the migration phase, focusing on data optimization and customization to tailor the platform to meet the unique needs of your site.  

Special Cases to Note  

• Post-migration, some manual cleanup might still be required. This ensures that the data within the new eSource system is organized logically and effectively.  
• Consider assigning staff members to QC specific sections of the data. This could include patient profiles, study information, financials, etc.  

Expert Advice: Tips for a Smooth Transition

Ensure compliance with regulatory standards file.

Confirm that your eSource solution is compliant with all relevant regulations, including FDA 21 CFR Part 11 in the United States and EMA Annex 11 in Europe. These regulations govern electronic records and signatures, ensuring data integrity and security.  

Select the Right eSource Solution

Choose an eSource platform that aligns with your trial’s specific needs. Consider factors such as ease of use, scalability, interoperability with other systems (like EDC, ePRO, and CTMS), and the ability to support remote monitoring. RealTime Software Solutions offers a suite of tools designed to integrate seamlessly, providing an efficient and comprehensive solution for your trials. Evaluate different eSource systems to find one that fits your site’s specific requirements, considering factors like user-friendliness, interoperability, and support services.  

Ensure Data Security and Privacy

Protecting patient data is paramount . Ensure your eSource system provides robust data encryption, user authentication, and access controls to safeguard against unauthorized access and data breaches. Regularly review security policies and compliance with data protection regulations like GDPR.  

Involve Stakeholders Early

Engaging stakeholders early in the process enhances adoption rates by ensuring their needs and perspectives are considered from the outset. Moreover, by involving clinical investigators, site staff, data managers, and IT personnel early on, organizations can gather valuable insights into user requirements, preferences, and pain points. This involvement allows for the customization of the system to better meet the specific needs of each stakeholder group, increasing their likelihood of embracing and actively using the new software.  

Train Your Team Thoroughly

Coordinate c omprehensive training for all users on how to use the eSource system . In fact, the FDA draft guidance on electronic systems recommends that staff be trained on every system used in the clinical trial and provide documentation fo r that training. Training should cover not just the technical aspects but also emphasize the importance of accurat e and timel y data entry, given its direct impact on study outcomes. Invest in thorough training for your staff to maximize the benefits of eSource . Furthermore, adequate training reduces resistance to change and enhances the system’s adoption.  

Plan for Data Migration

Ensure your eSource solution can integrate smoothly with other data systems you use, such as Clinical Trial Management Systems (CTMS). Efficient data flow between systems reduces manual data entry, minimizes errors, and improves data consistency.  

Monitor and Adapt

Equally important, after implementation, continuously monitor the system’s performance and user feedback. Be prepared to adapt and make changes to improve efficiency, user experience, and data quality. Regular audits can help identify areas for improvement.   

For clinical research sites, the shift to eSource is a strategic advantage. By enhancing efficiency, reducing protocol deviations, lowering the risk of FDA audit findings, and streamlining compliance, eSource empowers sites to effectively manage more studies while upholding the highest standards of data integrity and patient safety.  

Following the best practices outlined in this guide, sites can ensure a seamless and successful implementation that meets all stakeholders’ needs and supports the goal of bringing safe and effective treatments to patients faster and more efficiently. With proper preparation, the right technology partner, and a focus on data integrity, your site can realize the full potential of eSource, paving the way for more effective and compliant clinical research.   

Q: What are the long-term implications or benefits of transitioning to eSource technology for clinical research sites?   

A: Long-term benefits may include improved data quality and integrity, enhanced efficiency and productivity, increased patient safety, and greater regulatory compliance.  

Q: How can clinical research sites measure the return on investment (ROI) of implementing eSource technology?   

A: Measuring ROI may involve assessing factors such as time saved on data entry, reduction in protocol deviations, increased study efficiency, and improved regulatory compliance.  

Q: What platforms are compatible for data migration into eSource systems?    

A: Common systems include EMR, CTMS, eRegulatory, electronic documents, and spreadsheets.  

Q: How can clinical research sites ensure data quality and integrity throughout the eSource implementation process and beyond?   

A: Strategies include robust data validation processes, regular audits, adherence to regulatory standards, and ongoing staff training and support.  

Q: How long does migration typically take?    

A: While timelines vary, a standard migration can take 4-6 weeks, dependent on data complexity and volume.  

About RealTime Software Solutions

At RealTime , we’re dedicated to supporting our clients through every step of their e Source transition . Our comprehensive solutions and expert support team are here to ensure your success with the RealTime eClinical product suite . Trusted by over 3,000 clinical research sites worldwide, RealTime is at the forefront of modernizing clinical trials with site-based technology that helps sites improve the management of complex clinical trial workflows. D iscover more here .  

Read More: What is eSource in Clinical Trials?  

Read More: RealTime-eSOURCE: Fueling 28X Revenue Growth at the University of the Sunshine Coast  

References:  

Nordo, A.H., Eisenstein, E.L., Hawley, J., Vadakkeveedu, S., Pressley, M., Pennock, J., Sanderson, I. (2017). A comparative effectiveness study of eSource used for data capture for a clinical research registry. The International Journal of Medical Informatics (pp. 89-94).  

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