Computer–Based Training for NIH IRB Members

1. Computer–Based Training for NIH IRB Members Lesson 1Introduction Lesson 2Using NIH IRB Review Standards Lesson 3Continuing IRB Review, IRB Minutes, and Other Issues

2. Computer–Based Training for NIH IRB Members Lesson 1: Introduction

3. Computer–Based Training for NIH IRB Members: Introduction This computer-based training course is designed to help you understand the responsibilities of NIH's Institutional Review Boards (IRBs). It is designed primarily for NIH IRB members but its content is also useful for clinical researchers submitting protocols for review by an NIH IRB. The NIH values highly the important work of its IRBs and appreciates your willingness to serve as a member. NIH's IRBs are critically important to its overall system of human subject protections. Before we focus entirely on IRBs let's review some general issues about the NIH's overall system for the protection of human subjects.

4. Computer–Based Training for NIH IRB Members: Introduction Upon completing this lesson you should know: • The basic ethical and regulatory foundations of NIH's system for the protection of human research subjects • The importance of NIH's Institutional Review Boards (IRBs) to this overall system, and • Some unique features of NIH's IRB system.

5. Computer–Based Training for NIH IRB Members: Introduction The National Institutes of Health (NIH) is the Federal Government's primary agency for advancing knowledge in the biomedical and behavioral sciences. It has a long and distinguished history of rapidly applying basic scientific discoveries in the laboratory to the design and conduct of clinical research at the bedside.

6. Computer–Based Training for NIH IRB Members: Introduction The NIH is funded by the American taxpayer and is held publicly accountable for the scientific worth and ethical integrity of its research activities, including those involving human subjects. The NIH expects researchers in its Intramural Research Program (IRP) to share its commitment to the conduct of high quality research that promotes the rights and welfare of research subjects. The IRP consists of researchers working on the NIH's Bethesda campus and other sites in Maryland, Montana, North Carolina and Arizona.

7. Computer–Based Training for NIH IRB Members: Introduction Research investigators have a fundamental responsibility to safeguard the rights and welfare of people participating in their research activities. Also, in the U.S. it has been decided that prospective review of research activities involving human subjects by a group of diverse individuals, not involved in the conduct of the research, is most likely to protect human subjects and promote ethically sound research. Generally this review is performed by committees called Institutional Review Boards (IRBs).

8. Computer–Based Training for NIH IRB Members: Introduction The NIH IRP has established a system to help IRP researchers understand and fulfill their responsibilities when they conduct or collaborate in research involving humans. IRBs are an important part of this system. The NIH's system for the protection of human subjects is described in its Human Research Protection Program (HRPP). You should be familiar already with the NIH HRPP. It was discussed in the NIH's Computer-Based Training(CBT) Course on Protecting Human Research Subjects. If you would like to review the CBT lesson on the NIH HRPP, you may go to the Web site of NIH's Office of Human Subjects Research (OHSR) at http://ohsr.od.nih.gov and click on “Training for NIH Researchers”.

9. Computer–Based Training for NIH IRB Members: Introduction The HRPP incorporates the basic ethical principles of The Belmont Report and is consistent with requirements provided in Title 45 Code of Federal Regulations, Part 46, Protection of Human Subjects (45 CFR 46). The Belmont Report and 45 CFR 46 are available for review and for printing from the OHSR Web site.

10. Computer–Based Training for NIH IRB Members: Introduction The NIH HRPP provides policies and procedures for research involving human subjects and describes the responsibilities of: • NIH officials who oversee human subjects research; • Intramural researchers, and other NIH employees, who conduct, support or collaborate in research involving human subjects at the NIH or elsewhere; • NIH's IRBs, and • The NIH's Office of Human Subjects Research (OHSR).

11. Computer–Based Training for NIH IRB Members: Introduction Overall responsibility for the NIH HRPP rests with the Deputy Director for Intramural Research (DDIR), Office of the Director (OD), NIH. Other NIH Institute and Center officials who share this responsibility include: the Director of the Clinical Center, Clinical and Scientific Directors; Laboratory, Branch and Section Chiefs; research investigators, and other research personnel. All IRP personnel who oversee, conduct or collaborate in research involving human subjects are expected to be familiar with the NIH HRPP. Dr. Michael Gottesman, Deputy Director for Intramural Research (DDIR)

12. Computer–Based Training for NIH IRB Members: Introduction Although you should be familiar with the HRPP, the Chair of your IRB is an important resource on its content and how it applies to the work of the IRBs in protecting human subjects. For more information or questions about issues related to the protection of human subjects, you may call the Office of Human Subjects Research (OHSR). OHSR's address is: NIH Building 10 Room 2C-146 Bethesda, MD 20892 The phone number is:    301-402-3444       

13. Computer–Based Training for NIH IRB Members: Introduction OHSR works for the DDIR. It is the IRP's central office for information and education about the protection of human research subjects. OHSR's Web site at http://ohsr.od.nih.gov contains much information about research involving human subjects at the NIH. You will be given an opportunity to go directly to this Web site at the end of the CBT.

14. Computer–Based Training for NIH IRB Members: Introduction Now, let's look at the role of IRBs in NIH's overall system to protect human subjects. As of January, 2007, the NIH has 12 IRBs which are composed of over 180 members with expertise in science, ethics, and other non-scientific areas. This diversity fosters a comprehensive approach to safeguarding the rights and welfare of subjects involved in NIH IRP research activities. When reviewing research protocols, regardless of their professional backgrounds, or on which of the NIH's IRBs they serve, IRB members are responsible for assuring that minimal regulatory review requirements are met and that these requirements are properly documented in the IRBs' minutes. In the next lesson we will discuss the IRB review standards and how IRB members can implement them in a methodical way.

15. NIH IRB CONTACTS

16. Computer–Based Training for NIH IRB Members: Introduction These IRBs oversee about 1300 active protocols being conducted in the Clinical Center (CC) and about 200 protocols for research collaborations in which the human subjects are located at domestic non-NIH sites and at many sites around the world.

17. Computer–Based Training for NIH IRB Members: Introduction It is unusual for one research institution to have so many IRBs. This large number of IRBs reflects the history and organization of the NIH IRP in which the various NIH Institutes have a high degree of freedom in the kinds of research they conduct and in the administration of their programs. There are relative advantages and drawbacks to the NIH's multi-IRB system.

18. Computer–Based Training for NIH IRB Members: Introduction Some advantages of the NIH's multi-IRB system: • It allows for IRB members who have specialized scientific and ethical expertise in the area of the Institutes' research activities. For example, persons with expertise in the scientific, ethical and legal aspects of research on the human genome are important to an IRB that reviews genetic research. On the other hand, an IRB that reviews cancer clinical trials using highly experimental drugs is better served by having members with expertise in the scientific, ethical, statistical, and nursing aspects of clinical trials involving persons with cancer.

19. Computer–Based Training for NIH IRB Members: Introduction Some advantages of the NIH's multi-IRB system: • A lighter work load for each IRB allows time for more thorough, thoughtful review of research protocols. In many other research institutions the IRB workload is much higher. For example, in 1996, the Chair of one University IRB reported that at its monthly meetings it reviewed up to 40 to 80 new protocols (JAMA November 27, 1996, Vol. 276, No. 20). In comparison, most NIH IRBs review no more than 5 new protocols per meeting.

20. Computer–Based Training for NIH IRB Members: Introduction Some drawbacks to the multi-IRB system: • Even though each NIH IRB is governed by the policies and procedures of NIH's MPA, as well as some Clinical Center policies, the IRBs vary in how they implement these policies. Some degree of flexibility is desirable because it allows IRBs to apply the policies in ways that are most relevant and appropriate to their particular research population and environment. However, all NIH IRBs are expected to fulfill basic requirements for the review and approval of research. Therefore, the NIH has implemented minimal review standards for its IRBs. You will learn more about the IRB review standards and how to apply them in the next lesson.

21. Computer–Based Training for NIH IRB Members: Introduction Some drawbacks to the multi-IRB system: • Educating new IRB members, providing continuing education and oversight of so many IRBs is a formidable task. Currently, minimal NIH educational requirements for all of its new IRB members include: • Completion of the NIH's computer-based training program (CBT) on Protecting Human Research Subjects; • Completion of this CBT (CBT for IRB members), and • A one-on-one orientation session with a member of the OHSR staff.

22. Computer–Based Training for NIH IRB Members: Introduction Summary points: • The NIH's overall system for the protection of human subjects is described in its Human Research Protection Program; • NIH's IRBs are a critical element in this overall system; • The major mandate of IRBs is to protect the rights and safeguard the welfare of the subjects, and • The NIH depends on the knowledge and judgment of its many IRB members to make this system work effectively. If you have any questions, comments or suggestions concerning your service as an NIH IRB member, please contact the Chair of your IRB or call OHSR (phone 301-402-3444).

23. Computer–Based Training for NIH IRB Members Lesson 2: Using NIH IRB Review Standards

24. Computer–Based Training for NIH IRB Members: Using NIH IRB Review Standards Upon completing this lesson you should know: • Understand that the NIH IRB review standards incorporate minimal regulatory requirements for the review and approval of research protocols; • Understand that the standards were developed to help NIH IRB members address these requirements methodically and consistently; • Understand how to apply the standards when reviewing research protocols, and • Appreciate the NIH's requirement that, for each protocol they review, NIH IRBs' discussions of the review standards are documented in their minutes.

25. Computer–Based Training for NIH IRB Members: Using NIH IRB Review Standards NIH IRB review standards were developed to: • Assure that regulatory requirements for the review and approval of research protocols are addressed by and documented consistently in the minutes of all NIH IRBs; • Improve NIH IRBs' efficiency and save IRB members' time; • Assure NIH's leadership that NIH IRBs' procedures and minutes can withstand evaluation and/or audit by the NIH, other governmental, regulatory or private groups.

26. Computer–Based Training for NIH IRB Members: Using NIH IRB Review Standards IRB Review Standards Goal #1: Assure that minimal requirements for the review and approval of research protocols are addressed by and documented consistently in the minutes of all NIH IRBs. IRB decisions are matters of judgment and therefore they depend on an understanding and wise application of ethical guidelines and regulatory requirements as well as an appreciation of specific requirements of the NIH HRPP. When reviewing research protocols, it is important that NIH's IRB members not only know the minimal regulatory requirements for the approval of research but also assure that IRBs thoroughly discuss and document them in their minutes for each new protocol.

27. Computer–Based Training for NIH IRB Members: Using NIH IRB Review Standards IRB Review Standards Goal #2: To improve NIH IRBs' efficiency and save IRB members' time. IRB agendas are often long. Implementing review standards will focus IRBs' attention on basic review requirements and therefore streamline their activities.

28. Computer–Based Training for NIH IRB Members: Using NIH IRB Review Standards IRB Review Standards Goal #3: Assure NIH's leadership that NIH IRBs' procedures and minutes can withstand evaluation and/or audit by the NIH, other governmental, regulatory or private groups. As discussed in the Introduction, the NIH is a publicly funded institution and therefore many of its records, including research protocols and IRB minutes, are available for review under the Freedom of Information Act (FOIA). Also, the NIH's clinical research and IRB activities receive close scrutiny by NIH and non-NIH groups; therefore, it is particularly important that NIH IRBs‘ decisions are properly documented in their minutes and reflect an understanding and appreciation of minimal regulatory requirements.

29. Computer–Based Training for NIH IRB Members: Using NIH IRB Review Standards The NIH IRB review standards are based on "Criteria for IRB approval of research" as provided in 45 CFR 46.111. This lesson is designed to familiarize you with the required NIH IRB review standards and to provide some advice on how to apply them when you are reviewing protocols.

30. Computer–Based Training for NIH IRB Members: Using NIH IRB Review Standards Practice will guide new IRB members to the most effective ways of applying the standards when they review protocols and investigators when they write protocols. However, it is important to remember that for each new protocol an IRB reviews, it is expected to discuss and document in its minutes EACH review standard.

31. Computer–Based Training for NIH IRB Members: Using NIH IRB Review Standards The following pages will provide an overview of the NIH IRB review standards. The rest of this lesson is devoted to a discussion of each standard.

34. Computer–Based Training for NIH IRB Members: Using NIH IRB Review Standards NIH IRB Review Standard #1: The proposed research design is scientifically sound and will not unnecessarily expose subjects to risk.

35. Computer–Based Training for NIH IRB Members: Using NIH IRB Review Standards NIH IRB Review Standard #1: The proposed research design is scientifically sound and will not unnecessarily expose subjects to risk. NIH's leadership expects all research protocols to receive substantive scientific review before they are reviewed by an NIH IRB. It is NIH HRPP policy that its IRBs will review only research which has been reviewed by the appropriate Institute or Center (IC) and found to be scientifically meritorious, well designed, and in keeping with ethical guidelines, program relevance, and public responsibility.

36. Computer–Based Training for NIH IRB Members: Using NIH IRB Review Standards NIH IRB Review Standard #1: The proposed research design is scientifically sound and will not unnecessarily expose subjects to risk. Each NIH Institute and Center (IC) is expected to have a system for adequate scientific review of research protocols before they are sent to an NIH IRB for review. However, ICs are given wide discretion in how to accomplish this task. For example, some have pre-IRB scientific review committees, some send their protocols out for scientific review by outside (non-NIH) experts, and some have intramural experts evaluate protocols.

37. Computer–Based Training for NIH IRB Members: Using NIH IRB Review Standards NIH IRB Review Standard #1: The proposed research design is scientifically sound and will not unnecessarily expose subjects to risk. Adequate pre-IRB scientific review is important because: • An IRB's main mandate is to protect the rights and safeguard the welfare of research subjects. Although NIH's IRBs have members with scientific expertise, they are not constituted to act as primary scientific review committees. • If a research protocol is poorly designed and not likely to obtain meaningful information, it is not ethically justifiable to expose subjects to any risk, discomfort or inconvenience. Therefore, IRBs deserve some assurance that the research they are asked to review has received prior, adequate review by scientific experts.

38. Computer–Based Training for NIH IRB Members: Using NIH IRB Review Standards NIH IRB Review Standard #1: The proposed research design is scientifically sound and will not unnecessarily expose subjects to risk. IRBs should assure themselves that all new research protocols they review have received pre-IRB scientific review. However, for each protocol they review, IRBs are expected to determine and document in the minutes that: • The hypothesis is clear; • The study design is appropriate to prove the hypothesis, and • The research will contribute to generalizable knowledge and that it is justifiable to expose subjects to (any) risk, discomfort, or inconvenience.

39. Computer–Based Training for NIH IRB Members: Using NIH IRB Review Standards NIH IRB Review Standard #1: The proposed research design is scientifically sound and will not unnecessarily expose subjects to risk. If an IRB determines that a protocol is not scientifically sound - the hypothesis is not clear, the study is poorly designed (i.e., statistically not valid) - its courses of action include: • It may attempt to resolve the major scientific issues, keeping in mind that its main task is to protect the rights and welfare of human research subjects and that it is not constituted to be a scientific review committee. If the IRB chooses this approach, its minutes will contain a number of stipulations (required changes) to which the PI must respond adequately before the protocol is considered for re-review. • It may table the protocol and refer it back to the PI. • It may choose to ask the pre-IRB scientific review group to re-review the protocol or it may request that an ad hoc consultant(s) review the protocol and provide guidance in writing and/or by attending an IRB meeting to discuss it. • It may disapprove the research protocol.

40. Computer–Based Training for NIH IRB Members: Using NIH IRB Review Standards NIH IRB Review Standard #1: The proposed research design is scientifically sound and will not unnecessarily expose subjects to risk. However, the best situation is for each IC to have high quality pre-IRB scientific review of protocols so that when an NIH IRB reviews a protocol, it can give most of its attention to the protection of the subjects rather than the details of the scientific design. Regardless of which of these approaches it takes, before approving a research protocol, the IRB must assure itself, and document in its minutes, that the proposed research design is scientifically sound and will not unnecessarily expose subjects to risk.

41. Computer–Based Training for NIH IRB Members: Using NIH IRB Review Standards NIH IRB Review Standard #2: Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects and the importance of knowledge that may reasonably be expected to result.

42. Computer–Based Training for NIH IRB Members: Using NIH IRB Review Standards NIH IRB Review Standard #2: Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects and the importance of knowledge that may reasonably be expected to result. As discussed in The Belmont Report, the ethical principle of beneficence requires researchers, and others, to protect research subjects by maximizing possible benefits and minimizing possible harms of research participation. This principle requires that researchers and IRBs have adequate information concerning, and give careful consideration to, the risks and benefits of research participation. To review the Belmont Report, go to OHSR's web site at http://ohsr.od.nih.gov.

43. Computer–Based Training for NIH IRB Members: Using NIH IRB Review Standards NIH IRB Review Standard #2: Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects and the importance of knowledge that may reasonably be expected to result. In addressing this review standard, the NIH IRB, in consultation with the Principal Investigator (PI) of the protocol being reviewed, is responsible for determining: • The risk(s), discomfort(s) and inconvenience(s) to subjects, • The level of risk to research subjects, and • Whether or not there is prospect of direct benefit to individual research subjects. Therefore, NIH PIs are required to provide a section in their research protocols entitled "Human Subjects Protections" which includes an evaluation of research-related benefits (to the subjects or to others) and the research-related risks, discomforts and inconveniences. NIH IRBs ought not approve research protocols which do not contain this section.

44. Computer–Based Training for NIH IRB Members: Using NIH IRB Review Standards NIH IRB Review Standard #2: Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects and the importance of knowledge that may reasonably be expected to result. However, keep in mind two things: • In evaluating risks and benefits, the IRB should consider only those risks and benefits that may result from the research (as distinguished from risks and benefits of procedures or interventions subjects would receive even if not participating in research).

45. Computer–Based Training for NIH IRB Members: Using NIH IRB Review Standards

46. Computer–Based Training for NIH IRB Members: Using NIH IRB Review Standards NIH IRB Review Standard #2: Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects and the importance of knowledge that may reasonably be expected to result. However, keep in mind two things: 2. The IRB should not consider possible long-range effects of applying knowledge gained in the research (for example, the possible effect of research on public policy) as among those research related risks that fall within the purview of its responsibility.

47. Computer–Based Training for NIH IRB Members: Using NIH IRB Review Standards

48. Computer–Based Training for NIH IRB Members: Using NIH IRB Review Standards NIH IRB Review Standard #2: Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects and the importance of knowledge that may reasonably be expected to result. Let's evaluate further the IRB's responsibility for determining level of risk to research subjects and review what guidance is provided in the regulations (45 CFR 46). Minimal risk “means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or the performance of routine physical, psychological examinations or tests” (45 CFR 46.102{i}). A definition of “minimal risk” is provided because some research activities determined to be of minimal risk are eligible for IRB review through expedited review procedures. This means that the IRB Chair, (and/or other IRB members designated by the Chair) may approve the research on behalf of the IRB. If you would like to review a list of procedures that are eligible for review under expedited review procedures, go to OHSR's Web site at http://ohsr.od.nih.gov and click on NIH Multiple Project Assurance.

49. Computer–Based Training for NIH IRB Members: Using NIH IRB Review Standards NIH IRB Review Standard #2: Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects and the importance of knowledge that may reasonably be expected to result. The IRB is responsible for determining the level of risk to research subjects. For each new protocol they review through their regular review procedures (non- expedited procedures), NIH IRBs are required to determine and document in their minutes which of the following applies: • The research involves no more than minimal risk to subjects, • The research involves more than minimal risk to subjects and the risks represent a minor increase over minimal risk, or • The research involves more than minimal risk to subjects and risks represent more than a minor increase over minimal risk.

50. Computer–Based Training for NIH IRB Members: Using NIH IRB Review Standards NIH IRB Review Standard #2: Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects and the importance of knowledge that may reasonably be expected to result. The IRB is responsible for determining the level of risk to research subjects. Federal regulations define only "minimal risk" and therefore what constitutes "minor increase over minimal risk" and "greater than minimal risk" are for the IRB to judge on a protocol-by-protocol basis. Although Federal regulations require IRBs to categorize research activities according to level of risk only when children are research subjects, it is an NIH standard that its IRBs categorize all research protocols into one of these risk levels and document their decisions in the minutes. Research-related risks refer to the probability of harm to subjects and may vary in magnitude. Ambiguous terms such as "small or low risk" and "high risk" are best avoided by IRBs.