Computer Based Training for

Transcription

1 Computer Base Training for NIH IRB Members Lesson 1 Lesson 2 Lesson 3 Introuction Using NIH IRB Review Stanars Continuing IRB Review, IRB Minutes, an Other Issues

2 Members Lesson 1: Introuction ti

3 Members: Introuction ti This computer-base training course is esigne to help you unerstan the responsibilities of NIH's Institutional Review Boars (IRBs). It is esigne 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 an 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 Members: Introuction ti Upon completing this lesson you shoul know: 1. The basic ethical an regulatory founations of NIH's system for the protection of human research subjects 2. The importance of NIH's Institutional Review Boars (IRBs) to this overall system, an 3. Some unique features of NIH's IRB system.

5 Members: Introuction ti The National Institutes of Health (NIH) is the Feeral Government's primary agency for avancing knowlege in the biomeical an behavioral sciences. It has a long an istinguishe history of rapily applying basic scientific iscoveries in the laboratory to the esign an conuct of clinical i l research at the besie.

6 Members: Introuction ti The NIH is fune by the American taxpayer an is hel publicly l accountable for the scientific worth an ethical integrity of its research activities, incluing those involving human subjects. The NIH expects researchers in its Intramural Research Program (IRP) to share its commitment to the conuct of high quality research that promotes the rights an welfare of research subjects. The IRP consists of researchers working on the NIH's Bethesa campus an other sites in Marylan, Montana, North Carolina an Arizona.

7 Members: Introuction ti Research investigators have a funamental responsibility to safeguar the rights an welfare of people participating in their research activities. Also, in the U.S. it has been ecie that prospective review of research activities involving human subjects by a group of iverse iniviuals, not involve in the conuct of the research, is most likely to protect human subjects an promote ethically soun research. Generally this review is performe by committees calle Institutional Review Boars (IRBs).

8 Members: Introuction ti The NIH IRP has establishe a system to help IRP researchers unerstan an fulfill their responsibilities i when they conuct 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 escribe in its Human Research Protection Program (HRPP). You shoul be familiar alreay with the NIH HRPP. It was iscusse in the NIH's Computer-Base Training(CBT) Course on Protecting Human Research Subjects. If you woul 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 an click on Training for NIH Researchers.

9 Members: Introuction ti The HRPP incorporates the basic ethical principles p of The Belmont Report an is consistent with requirements provie in Title 45 Coe of Feeral Regulations, Part 46, Protection ti of Human Subjects (45 CFR 46). The Belmont Report an 45 CFR 46 are available for The Belmont Report an 45 CFR 46 are available for review an for printing from the OHSR Web site.

10 Members: Introuction ti The NIH HRPP provies policies an proceures for research involving human subjects an escribes the responsibilities of: NIH officials who oversee human subjects research; Intramural researchers, an other NIH employees, who conuct, support or collaborate in research involving human subjects at the NIH or elsewhere; NIH's IRBs, an The NIH's Office of Human Subjects Research (OHSR).

11 Members: Introuction ti Overall responsibility for the NIH HRPP rests with the Deputy Director for Intramural Research (DDIR), Office of the Director (OD), NIH. Other NIH Institute an Center officials who share this responsibility inclue: the Director of the Clinical Center, Clinical an Scientific Directors; Laboratory, Branch an Section Chiefs; research investigators, an other research personnel. All IRP personnel who oversee, conuct or collaborate in research involving human subjects are expecte to be familiar with the NIH HRPP. Dr. Michael Gottesman, Deputy Director for Intramural Research (DDIR)

12 Members: Introuction ti Although you shoul be familiar with the HRPP, the Chair of your IRB is an important resource on its content an how it applies to the work of the IRBs in protecting human subjects. For more information or questions about issues relate to the protection of human subjects, you may call the Office of Human Subjects Research (OHSR). OHSR's aress is: NIH Builing 10 Room 2C-146 Bethesa, MD The phone number is:

13 Members: Introuction ti OHSR works for the DDIR. It is the IRP's central office for information an eucation about the protection of human research subjects. OHSR's Web site at contains much information about research involving human subjects at the NIH. You will be given an opportunity to go irectly to this Web site at the en of the CBT.

14 Members: Introuction ti 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 compose of over 180 members with expertise in science, ethics, an other non-scientific areas. This iversity fosters a comprehensive approach to safeguaring the rights an welfare of subjects involve in NIH IRP research activities. When reviewing research protocols, regarless of their professional backgrouns, or on which of the NIH's IRBs they serve, IRB members are responsible for assuring that minimal regulatory review requirements are met an that these requirements are properly ocumente in the IRBs' minutes. In the next lesson we will iscuss the IRB review stanars an how IRB In the next lesson we will iscuss the IRB review stanars an how IRB members can implement them in a methoical way.

15 NIH IRB CONTACTS Institute: Chair: Coorinator: Phone: Aress: CNS W: NIAAA, NIMH Barbara Karp Jeanne Racliffe, Cathy CRC CNS B: NINDS, NIDCD, NIA, NIE Barbara Karp Little, Donna Howar, Jennifer Morris, Marge Gillespie, Alex Noury, Latasha Terrell, Nanette Suksta, Mike Chapple NCI Wana Salzer Lina Aams /117 NCIss Nancy Potischman Lynn Sayers, Suzan Privot EPN/5143 NHLBI Alison Wichman Melissa Bryant, Patty Sweet CRC NIAID V. Koneti Rao Doreen Chaitt B Rocklege Room 1116 NICHD Gilman Grave Lin Aspinall CRC NIDA Barbara Karp Anne Gupman, Cecile Shinell Bayview Blv., Suite 200 Baltimore, MD NIDDK/NIAMS Howar Austin Glynnis Vance CRC NIDCR Reuben Siraganian Rachel Topper-Greco CRC NIEHS Davi Resnik Jane Lambert, Craig Nottingham Room 275 Wlayka NHGRI Fabio Canotti Victoria Willits /1C118

16 Members: Introuction ti These IRBs oversee about 1300 active protocols being conucte in the Clinical Center (CC) an about 200 protocols for research collaborations in which the human subjects are locate at omestic non-nih sites an at many sites aroun the worl.

17 Members: Introuction ti It is unusual for one research institution to have so many IRBs. This large number of IRBs reflects the history an organization of the NIH IRP in which the various NIH Institutes have a high egree of freeom in the kins of research they conuct an in the aministration of their programs. There are relative avantages an rawbacks to the NIH's multi-irb system.

18 Members: Introuction ti Some avantages of the NIH's multi-irb system: It allows for IRB members who have specialize scientific an ethical expertise in the area of the Institutes' research activities. For example, persons with expertise in the scientific, ethical an legal aspects of research on the human genome are important to an IRB that reviews genetic research. On the other han, an IRB that reviews cancer clinical trials using highly experimental rugs is better serve by having members with expertise in the scientific, ethical, statistical, an nursing aspects of clinical trials involving persons with cancer.

19 Members: Introuction ti Some avantages of the NIH's multi-irb system: A lighter work loa for each IRB allows time for more thorough, thoughtful review of research protocols. In many other research institutions the IRB workloa is much higher. For example, in 1996, the Chair of one University IRB reporte that at its monthly meetings it reviewe 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 Members: Introuction ti Some rawbacks to the multi-irb system: Even though each NIH IRB is governe by the policies an proceures of NIH's MPA, as well as some Clinical Center policies, the IRBs vary in how they implement these policies. i Some egree of flexibility is esirable because it allows IRBs to apply the policies in ways that are most relevant an appropriate to their particular research population an environment. However, all NIH IRBs are expecte to fulfill basic requirements for the review an approval of research. Therefore, the NIH has implemente minimal review stanars for its IRBs. You will learn more about the IRB review stanars an how to apply them in the next lesson.

21 Members: Introuction ti Some rawbacks to the multi-irb system: Eucating new IRB members, proviing continuing eucation an oversight of so many IRBs is a formiable task. Currently, minimal NIH eucational requirements for all of its new IRB members inclue: Completion of the NIH's computer-base training program (CBT) on Protecting Human Research Subjects; Completion of this CBT (CBT for IRB members), an A one-on-one orientation session with a member of the OHSR staff.

22 Members: Introuction ti Summary points: The NIH's overall system for the protection of human subjects is escribe in its Human Research Protection Program; NIH's IRBs are a critical element in this overall system; The major manate of IRBs is to protect the rights an safeguar the welfare of the subjects, an The NIH epens on the knowlege an jugment 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 ).

23 Members Lesson 2: Using NIH IRB Review Stanars

24 Members: Using NIH IRB Review Stanars Upon completing this lesson you shoul know: 1. Unerstan that the NIH IRB review stanars incorporate minimal regulatory requirements for the review an approval of research protocols; 2. Unerstan that the stanars were evelope to help NIH IRB members aress these requirements methoically an consistently; 3. Unerstan how to apply the stanars when reviewing research protocols, an 4 A i t th NIH' i t th t f h t l th i NIH 4. Appreciate the NIH's requirement that, for each protocol they review, NIH IRBs' iscussions of the review stanars are ocumente in their minutes.

25 Members: Using NIH IRB Review Stanars NIH IRB review stanars were evelope to: 1. Assure that regulatory requirements for the review an approval of research protocols are aresse by an ocumente consistently in the minutes of all NIH IRBs; 2. Improve NIH IRBs' efficiency an save IRB members' time; 3. Assure NIH's leaership that NIH IRBs' proceures an minutes can withstan evaluation an/or auit by the NIH, other governmental, regulatory or private groups.

26 Members: Using NIH IRB Review Stanars IRB Review Stanars Goal #1: Assure that minimal requirements for the review an approval of research protocols are aresse by an ocumente consistently in the minutes of all NIH IRBs. IRB ecisions are matters of jugment an therefore they epen on an unerstaning an wise application of ethical guielines an 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 iscuss an ocument them in their minutes for each new protocol.

27 Members: Using NIH IRB Review Stanars IRB Review Stanars Goal #2: To improve NIH IRBs' efficiency an save IRB members' time. IRB agenas are often long. Implementing review stanars will focus IRBs' attention on basic review requirements an therefore streamline their activities.

28 Members: Using NIH IRB Review Stanars IRB Review Stanars Goal #3: Assure NIH's leaership that NIH IRBs' proceures an minutes can withstan evaluation an/or auit by the NIH, other governmental, regulatory or private groups. As iscusse in the Introuction, the NIH is a publicly fune institution an therefore many of its recors, incluing research protocols an IRB minutes, are available for review uner the Freeom of Information Act (FOIA). Also, the NIH's clinical research an IRB activities receive close scrutiny by NIH an non-nih groups; therefore, it is particularly important that NIH IRBs ecisions are properly ocumente in their minutes an reflect an unerstaning an appreciation of minimal regulatory requirements.

29 Members: Using NIH IRB Review Stanars The NIH IRB review stanars are base on "Criteria for IRB approval of research" as provie in 45 CFR This lesson is esigne to familiarize you with the require NIH IRB review stanars an to provie some avice on how to apply them when you are reviewing protocols.

30 Members: Using NIH IRB Review Stanars Practice will guie new IRB members to the most effective ways of applying the stanars when they review protocols an investigators when they write protocols. However, it is important to remember that for each new protocol an IRB reviews, it is expecte to iscuss an ocument in its minutes EACH review stanar.

31 Members: Using NIH IRB Review Stanars The following pages will provie an overview of the NIH IRB review stanars. The rest of this lesson is evote to a iscussion of each The rest of this lesson is evote to a iscussion of each stanar.

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34 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #1: The propose research esign is scientifically soun an will not unnecessarily expose subjects to risk.

35 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #1: The propose research esign is scientifically soun an will not unnecessarily expose subjects to risk. NIH's leaership expects all research protocols to receive substantive scientific review before they are reviewe by an NIH IRB. It is NIH HRPP policy that its IRBs will review only research which has been reviewe by the appropriate Institute or Center (IC) an foun to be scientifically meritorious, well esigne, an in keeping with ethical guielines, program relevance, an public responsibility.

36 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #1: The propose research esign is scientifically soun an will not unnecessarily expose subjects to risk. Each NIH Institute an Center (IC) is expecte to have a system for aequate scientific review of research protocols before they are sent to an NIH IRB for review. However, ICs are given wie iscretion in how to accomplish this task. For example, some have pre-irb scientific review committees, some sen their protocols out for scientific review by outsie (non-nih) experts, an some have intramural experts evaluate protocols.

37 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #1: The propose research esign is scientifically soun an will not unnecessarily expose subjects to risk. Aequate pre-irb scientific review is important because: An IRB's main manate is to protect the rights an safeguar the welfare of research subjects. Although NIH's IRBs have members with scientific expertise, they are not constitute to act as primary scientific review committees. If a research protocol is poorly esigne an not likely to obtain meaningful information, it is not ethically justifiable to expose subjects to any risk, iscomfort or inconvenience. Therefore, IRBs eserve some assurance that the research they are aske to review has receive prior, aequate review by scientific experts.

38 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #1: The propose research esign is scientifically soun an will not unnecessarily expose subjects to risk. IRBs shoul assure themselves that t all new research protocols they review have receive pre-irb scientific review. However, for each protocol they review, IRBs are expecte to etermine an ocument in the minutes that: 1. The hypothesis is clear; 2. The stuy esign is appropriate to prove the hypothesis, an 3. The research will contribute to generalizable knowlege an that it is justifiable to expose subjects to (any) risk, iscomfort, or inconvenience.

39 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #1: The propose research esign is scientifically soun an will not unnecessarily expose subjects to risk. If an IRB etermines that a protocol is not scientifically soun - the hypothesis is not clear, the stuy is poorly esigne (i.e., statistically not vali) - its courses of action inclue: 1. It may attempt to resolve the major scientific issues, keeping in min that its main task is to protect the rights an welfare of human research subjects an that it is not constitute to be a scientific review committee. If the IRB chooses this approach, its minutes will contain a number of stipulations (require changes) to which the PI must respon aequately before the protocol is consiere for re-review. 2. It may table the protocol an refer it back to the PI. 3. It may choose to ask the pre-irb scientific review group to re-review review the protocol or it may request that an a hoc consultant(s) review the protocol an provie guiance in writing an/or by attening an IRB meeting to iscuss it. 4. It may isapprove the research protocol.

40 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #1: The propose research esign is scientifically soun an 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 etails of the scientific esign. Regarless of which of these approaches it takes, before approving a research protocol, the IRB must assure itself, an ocument in its minutes, that the propose research esign is scientifically soun an will not unnecessarily expose subjects to risk.

41 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #2: Risks to subjects are reasonable in relation to Risks to subjects are reasonable in relation to anticipate benefits, if any, to subjects an the importance of knowlege that may reasonably be expecte to result.

42 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #2: Risks to subjects are reasonable in relation to anticipate benefits, if any, to subjects an the importance of knowlege that may reasonably be expecte to result. As iscusse in The Belmont Report, the ethical principle of beneficence requires researchers, an others, to protect research subjects by maximizing possible benefits an minimizing possible harms of research participation. This principle requires that researchers an IRBs have aequate information concerning, an give careful consieration to, the risks an benefits of research participation. To review the Belmont Report, go to OHSR's web site at

43 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #2: Risks to subjects are reasonable in relation to anticipate benefits, if any, to subjects an the importance of knowlege that may reasonably be expecte to result. In aressing this review stanar, the NIH IRB, in consultation with the Principal Investigator (PI) of the protocol being reviewe, is responsible for etermining: The risk(s), iscomfort(s) an inconvenience(s) to subjects, The level of risk to research subjects, an Whether or not there is prospect of irect benefit to iniviual research subjects. Therefore, NIH PIs are require to provie a section in their research protocols entitle "Human Subjects Protections" which inclues an evaluation of research-relate benefits (to the subjects or to others) an the research-relate risks, iscomforts an inconveniences. NIH IRBs ought not approve research protocols which o not contain this section.

44 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #2: Risks to subjects are reasonable in relation to anticipate benefits, if any, to subjects an the importance of knowlege that may reasonably be expecte to result. However, keep in min two things: 1. In evaluating risks an benefits, the IRB shoul consier only those risks an benefits that t may result from the research (as istinguishe i from risks an benefits of proceures or interventions subjects woul receive even if not participating in research).

45 Members: Using NIH IRB Review Stanars

46 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #2: Risks to subjects are reasonable in relation to anticipate benefits, if any, to subjects an the importance of knowlege that may reasonably be expecte to result. However, keep in min two things: 2. The IRB shoul not consier possible long-range effects of applying knowlege gaine in the research (for example, the possible effect of research on public policy) as among those research relate risks that fall within the purview of its responsibility.

47 Members: Using NIH IRB Review Stanars

48 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #2: Risks to subjects are reasonable in relation to anticipate benefits, if any, to subjects an the importance of knowlege that may reasonably be expecte to result. Let's evaluate further the IRB's responsibility for etermining level of risk to research subjects an review what guiance is provie in the regulations (45 CFR 46). Minimal risk means that the probability an magnitue of harm or iscomfort anticipate in the research are not greater in an of themselves than those orinarily encountere in aily life or the performance of routine physical, psychological examinations or tests (45 CFR {i}). A efinition of minimal risk is provie because some research activities etermine to be of minimal risk are eligible for IRB review through expeite review proceures. This means that the IRB Chair, (an/or other IRB members esignate by the Chair) may approve the research on behalf of the IRB. If you woul like to review a list of proceures that are eligible for review uner expeite review proceures, go to OHSR's Web site at an click on NIH Multiple Project Assurance.

49 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #2: Risks to subjects are reasonable in relation to anticipate benefits, if any, to subjects an the importance of knowlege that may reasonably be expecte to result. The IRB is responsible for etermining the level of risk to research subjects. For each new protocol they review through their regular review proceures (nonexpeite proceures), NIH IRBs are require to etermine an ocument in their minutes which of the following applies: 1. The research involves no more than minimal risk to subjects, 2. The research involves more than minimal risk to subjects an the risks represent a minor increase over minimal risk, or 3. The research involves more than minimal risk to subjects an risks represent more than a minor increase over minimal risk.

50 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #2: Risks to subjects are reasonable in relation to anticipate benefits, if any, to subjects an the importance of knowlege that may reasonably be expecte to result. The IRB is responsible for etermining the level of risk to research subjects. Feeral regulations efine only "minimal risk" an therefore what constitutes "minor increase over minimal risk" an "greater than minimal risk" are for the IRB to juge on a protocol-by-protocol basis. Although Feeral regulations require IRBs to categorize research activities accoring to level of risk only when chilren are research subjects, it is an NIH stanar that its IRBs categorize all research protocols into one of these risk levels an ocument their ecisions in the minutes. Research-relate risks refer to the probability of harm to subjects an may vary in magnitue. Ambiguous terms such as "small or low risk" an "high risk" are best avoie by IRBs.

51 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #2: Risks to subjects are reasonable in relation to anticipate benefits, if any, to subjects an the importance of knowlege that may reasonably be expecte to result. The IRB is responsible for etermining the level of risk to research subjects. When etermining the magnitue of risks presente by research proceures or interventions whether risks are minimal, a minor, or more than a minor increase above minimal risk the IRB may want to consier at least four approaches: 1. A common-sense estimation of risk; 2. An estimation base upon investigators' or others' experience with similar interventions or proceures; 3. Any statistical information (or other information in the meical literature) that is available regaring such interventions or proceures, an 4. The situation of the propose research subjects; for example, are potential subjects ill, healthy, young, institutionalize, etc.

52 Members: Using NIH IRB Review Stanars

53 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #2: Risks to subjects are reasonable in relation to anticipate benefits, if any, to subjects an the importance of knowlege that may reasonably be expecte to result. The IRB is responsible for etermining the level of risk to research subjects. In etermining risks an potential harms to research subjects, the IRB nees to consier not only physical harms but also psychological, social an economic harms an other aspects of the research stuy which may weigh in a negative fashion in the research participant's ecision making process.

54 Members: Using NIH IRB Review Stanars

55 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #2: Risks to subjects are reasonable in relation to anticipate benefits, if any, to subjects an the importance of knowlege that may reasonably be expecte to result. Now let's briefly consier what is meant by research-relate benefits. Benefit is use in the research context to refer to something of positive value relate to health or welfare. Benefits of research fall into two major categories: Direct benefits to subjects an Benefits to others (an to society by the avancement of knowlege through research).

56 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #2: Risks to subjects are reasonable in relation to anticipate benefits, if any, to subjects an the importance of knowlege that may reasonably be expecte to result. The IRB is responsible for etermining if there is prospect p of irect benefit to iniviual research subjects. In some research stuies, the subjects are unergoing examination, iagnosis or treatment for an illness or an abnormal conition. Therefore their research participation may hol out the prospect of irect benefit to them by ameliorating their conition or proviing a better unerstaning of their isorer. On the other han, patients an healthy iniviuals may agree to participate in research that either is not relate to any illness they might have or that is relate to their conition(s) but not esigne to provie any iagnostic or therapeutic benefit to them. This type of research is not intene to benefit the subjects irectly but nonetheless may benefit others in the future with the same isease as well as society as a whole. These benefits take the form of increase knowlege, improve safety, technological avances an better health for persons in the future.

57 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #2: Risks to subjects are reasonable in relation to anticipate benefits, if any, to subjects an the importance of knowlege that may reasonably be expecte to result. The IRB is responsible for etermining if there is prospect p of irect benefit to iniviual research subjects. Monetary payment (or other material compensation such as coupons, etc.) for research participation shoul not be consiere a benefit to subjects but rather remuneration for research-relate inconveniences an iscomforts. When a research protocol calls for monetary payments or other compensations, IRBs are expecte to review an approve the propose amount, timing of payments, etc. This is to assure that the remuneration is not so high as to inuce potential subjects to take on risks or iscomforts which they woul not accept without payment. The amount of monetary payment or other compensation shoul be isclose in the consent ocument.

58 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #2: Risks to subjects are reasonable in relation to anticipate benefits, if any, to subjects an the importance of knowlege that may reasonably be expecte to result. The IRB is responsible for etermining if there is prospect of irect benefit to iniviual research subjects. For each protocol it reviews, an NIH IRB is expecte to iscuss an ocument in its minutes whether: 1. The research involves the prospect of irect benefit to iniviual subjects, OR 2. The research involves no prospect of irect benefit to iniviual subjects, but is likely to contribute to generalizable knowlege.

59 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #2: Risks to subjects are reasonable in relation to anticipate benefits, if any, to subjects an the importance of knowlege that may reasonably be expecte to result. When reviewing a research protocol, not only is the IRB responsible for ientifying research-relate risks an benefits, but also for etermining if the risks are reasonable in relation to anticipate benefits. An IRB's risk/benefit assessments are jugments mae on a protocol-by protocol basis an begin with its etermination of whether the research esign will yiel useful ata (see NIH IRB review stanar #1, above). While goo scientific esign may not itself eraicate or reuce risks to subjects, poor or faulty research esign inicates that the risks are not reasonable in relation to the benefits.

60 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #2: Risks to subjects are reasonable in relation to anticipate benefits, if any, to subjects an the importance of knowlege that may reasonably be expecte to result. Risks are reasonable in relation to anticipate benefits Risk/benefit assessments take into account a number of other factors incluing prevailing community stanars, subjective eterminations of, an currently available information about, risks an benefits, as well as the egree of confience about this information. For example, information rawn from animal research may be highly suggestive of the risks an benefits to be expecte in humans but it may not be conclusive (because human responses may iffer from those of animals). Similarly, absence of information concerning risks oes not necessarily mean that there are no risks.

61 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #2: Risks to subjects are reasonable in relation to anticipate benefits, if any, to subjects an the importance of knowlege that may reasonably be expecte to result. Risks are reasonable in relation to anticipate benefits Also, the relation of risks an anticipate benefits must take into account the propose subjects of the research (chilren, terminally ill) an other consierations which may influence subjects' ieas about research-relate relate risks an benefits.

62 Members: Using NIH IRB Review Stanars

63 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #2: Risks to subjects are reasonable in relation to anticipate benefits, if any, to subjects an the importance of knowlege that may reasonably be expecte to result. Risks are reasonable in relation to anticipate benefits Risk/benefit assessments will be influence strongly by whether or not the research hols out the prospect of irect benefit to iniviual subjects. If research subjects stan to benefit irectly from participation in the research (because they are receiving treatment or iagnostic proceures), higher risks an iscomforts may be justifiable. On the other han in research where no irect benefits to subjects are On the other han, in research where no irect benefits to subjects are anticipate, the IRB must evaluate whether the risks to subjects presente by proceures/interventions solely to obtain generalizable knowlege are ethically acceptable.

64 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #3: Risks to subjects are minimize

65 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #3: Risks to subjects are minimize This IRB Review Stanar is closely relate to an most likely will be iscusse along with IRB Review Stanars #1 an #2. Even when research risks are justifiable an unavoiable, often they can be reuce or manage effectively. Precautions, safeguars, an/or alternatives can be incorporate into the protocol to reuce the probability of harm or reuce its severity. IRBs are responsible for assuring that risks are minimize to the extent possible.

66 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #3: Risks to subjects are minimize In orer to minimize risks, IRBs may want to ask: 1. Are aequate safeguars incorporate into the protocol? 2. Is the monitoring of ata propose in the research protocol appropriate? 3. Are the investigators competent in the area(s) being stuie? 4. Do investigators serve ual roles (e.g., treating physician, teacher, employer) in aition to researcher that may complicate their interactions with the subjects?

67 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #3: Risks to subjects are minimize 1. Are aequate safeguars incorporate into the protocol? Examples of safeguars inclue appropriate clinical an laboratory monitoring of subjects enrolle in the protocol, establishment of en an stopping points, proper storage of ata to protect confientiality, the presence of traine personnel to respon to emergencies, an written proceures for ientification an reporting of averse events(aes) to the IRB. At a minimum, all NIH protocols must efine an "averse event" an IRBs are expecte to assure that the PI's plans for ientifying an graing AEs an the time-frame for reporting them to the IRB are appropriate for the protocol uner consieration. Also, it may be necessary to exclue iniviuals or classes of subjects (e.g., pregnant y y j ( g p g women, persons with iabetes or hypertension) whose sensitivity to a rug or proceure may increase their risks. Therefore, in orer to minimize risks to subjects the IRB shoul always evaluate carefully the inclusion (eligibility) an exclusion criteria for the protocol.

68 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #3: Risks to subjects are minimize 1. Are aequate safeguars incorporate into the protocol? Bline, ranomize stuies require special attention. Ranom assignment an blining are methos use in clinical trials to reuce bias an enhance stuy valiity. However, both require justification because when ranomize an bline, subjects neither have a say in their choice of experimental treatment nor o they (or the researcher(s)) have information about what experimental treatment(s) they are receiving. In orer to balance the nee for scientific objectivity with the concern for subject safety, the protocol shoul iscuss conitions in which the blin may be broken to treat averse events. Discussion might inclue ientification of where the coe is locate, the circumstances in which it may be broken, who will break it, how information will be hanle (will the investigator, subject, IRB, treating physician be informe?), an how breaking of the blin will influence analysis of ata. More about these issues can be foun in OHSR Information Sheet #13, "Issues Regaring Bline, Ranomize Stuies in the Intramural Research Program" which is available on OHSR's Web site.

69 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #3: Risks to subjects are minimize 2. Is the monitoring of ata propose in the research protocol appropriate? The Principal Investigator (PI) of the protocol is responsible for monitoring research ata an the clinical status of the subjects. Also, feeral regulations require that research protocols receive continuing review by an IRB at least annually. However, an IRB may etermine that more frequent monitoring of research ata is necessary in some types of research. More about these issues can be foun in OHSR Information Sheet #13 "Issues More about these issues can be foun in OHSR Information Sheet #13, "Issues Regaring Bline, Ranomize Stuies in the Intramural Research Program" which is available on OHSR's Web site.

70 Members: Using NIH IRB Review Stanars

71 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #3: Risks to subjects are minimize 2. Is the monitoring of ata propose in the research protocol appropriate? In certain types of clinical trials such as ouble-bline multi-center trials, monitoring by a single IRB may not be practicable an special provisions may nee to be mae for monitoring incoming ata from all the sites at set intervals. In these situations, the IRB or the sponsor of the research (the NIH, a pharmaceutical company, etc.) may choose to establish a ata an safety monitoring boar (DSMB) to review the incoming ata at state intervals. This is in orer to ensure the safety of subjects, to ensure that no group or subgroup is given a less effective treatment, an/ or to ensure that the trial oes not continue after reliable results have been obtaine.

72 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #3: Risks to subjects are minimize 4. Do investigators serve ual roles (e.g., treating physician, teacher, employer), in aition to researcher, that may complicate their interactions with the subjects? IRBs shoul pay particular attention to researchers' potential an/or real conflicts of interest. For example: Financial conflicts: for example, if researchers receive payment for enrolling subjects into protocols, or if they, their spouses or epenent chilren hol financial interest(s) in a pharmaceutical company that sponsors the research Conflicts experience when researchers serve in ual roles; for example, when the researcher is also the subject/patient's physician or when the researcher is the subject's teacher or employer.

73 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #3: Risks to subjects are minimize 4. Do investigators serve ual roles (e.g., treating physician, teacher, employer), in aition to researcher, that may complicate their interactions with the subjects? Although physicians an clinical researchers have similar long term goals to alleviate pain an suffering an to prevent an cure human iseases their roles are ifferent. As physicians or other health care professionals, they are eicate to promoting the welfare of iniviual patients. As researchers, they seek knowlege applicable to persons other than their iniviual patients. The secon goal may conflict with the first. IRBs have one paramount goal to protect the rights an safeguar the welfare of the human subjects. Therefore, IRBs nee to be particularly vigilant in ientifying an minimizing potential an real conflicts of interest when physicians are also researchers.

74 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #3: Risks to subjects are minimize 4. Do investigators serve ual roles (e.g., treating physician, teacher, employer), in aition to researcher, that may complicate their interactions with the subjects? The IRB may want to know more about the relationship of the researcher an patient/subject. If an investigator also serves as the patient's physician, the patient may feel oblige to participate in research out of a esire to please or fear that failure to o so will result in hostility or abanonment. In this case, the IRB may not allow the research or may require an iniviual not involve in the research to take over the patient's primary meical care uring participation in research. Because the CC is a research facility this problem is minimize. Generally, iniviuals are referre to the CC by their personal physicians. Therefore, when they are no longer participating in CC research they return to the care of their physicians. If you woul like to rea more about some ethical consierations involve when a physician is also a researcher, please call OHSR at

75 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #4: Subject selection is equitable.

76 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #4: Subject selection is equitable. The requirement for the equitable selection of subjects is base on the ethical principle of justice, which requires fair istribution of both the burens an benefits of research. In the past the burens of research in the Unite states often fell largely upon poor patients in public hospital wars an chronic care institutions, while the benefits flowe primarily to private patients. In the mi-1970s there was a national outcry against some researchers conucting stuies involving poor, elerly, or institutionalize persons. In large part, the Belmont Report an the implementation of feeral regulations for the protection of human subjects were a response to these an other research stuies which were thought to be unfair.

77 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #4: Subject selection is equitable. IRBs are require to give careful attention to subject selection to etermine whether some classes of subjects (e.g., welfare patients, racial an ethnic minorities, or persons confine to institutions) are being systematically ti selecte because of their easy availability, their compromise position or manipulability, rather than for reasons irectly relate to the problem being stuie.

78 Members: Using NIH IRB Review Stanars

79 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #4: Subject selection is equitable. Toay, special provisions are in place for research involving prisoners. If you are intereste in learning more, please see 45 CFR 46, Subpart C, Aitional DHHS Protections Pertaining to Biomeical an Behavioral Research Involving Prisoners as Subjects.

80 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #4: Subject selection is equitable. Defining the appropriate group of subjects to be stuie in a research protocol involves a variety of consierations-- requirements of scientific esign, consierations of practicability an fairness, potential subjects susceptibility to risk, an the likelihoo of irect benefits.

81 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #4: Subject selection is equitable. When reviewing a protocol for the first time (initial review), NIH IRBs are expecte to make a etermination that the selection of subjects is scientifically an ethically appropriate. They are assiste in this etermination by NIH PIs who, at a minimum, are require to provie in their protocols: The rationale for the subject selection base on a review of the gener/ethnic/race categories of persons at risk for the isease or conition being stuie in the protocol; Strategies/proceures for recruitment (incluing avertising, if applicable), an The rationale for the involvement of special classes of subjects, if any, such as fetuses, pregnant women, chilren, cognitively impaire iniviuals, prisoners or other institutionalize persons or others who are likely to be vulnerable to coercion or unue influence (iscusse further in Review Stanar #6). NIH IRBs shoul not accept for initial review protocols which o not contain this information. Let's briefly iscuss each of these requirements.

82 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #4: Subject selection is equitable. 1.NIH PIs are require to provie in their protocols the rationale for the subject selection base on a review of the gener/ethnic/race categories of persons at risk for the isease or conition being stuie in the protocol. When the NIH funs research it expects the finings to be of benefit to all persons at risk for the isease, isorer or conition uner stuy. Therefore, aequate representation of women an minorities is particularly important in stuies of iseases, isorers an conitions that affect them. If a propose protocol inclues a stuy population in which women an minorities are not appropriately represente, the investigator must provie a clear, compelling reason for their exclusion or inaequate representation. If you want to learn more, go to the OHSR Web site an rea OHSR Information Sheet #11, Inclusion of Women an Minorities in Stuy Populations (Guiance for IRBs an Principal Investigators).

83 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #4: Subject selection is equitable. 2. NIH PIs are require to provie in their protocols strategies/proceures for recruitment, incluing avertising, if applicable. This requirement is to promote inclusion of a broa cross-section of research subjects an to promote fair recruitment practices. For example, the IRB may want to know if notices will be place on bulletin boars in grauate an/or unergrauate schools, in shelters for the homeless, or in meical clinics for persons who are inigent. If a researcher's s sole metho of recruitment is to write letters to private physicians, an unintene effect may be exclusion of persons without private physicians; therefore, aitional recruitment proceures may be warrante.

84 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #4: Subject selection is equitable. 2. NIH PIs are require to provie in their protocols strategies/proceures for recruitment, incluing avertising, if applicable. NIH IRBs are expecte to review all avertisements an recruitment notices associate with protocols they approve. Some institutions have guielines that prohibit professors from soliciting their stuents as subjects an supervisors from incluing their employees in research. The NIH has a policy that guies the involvement of its employees in NIH research. To receive a copy of this policy call OHSR at

85 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #4: Subject selection is equitable. 3. Explain the rationale for the involvement of special classes of subjects, if any, such as fetuses, pregnant women, chilren, cognitively impaire iniviuals, prisoners or other institutionalize persons or others who are likely to be vulnerable to coercion or unue influence (see Review Stanar #6). We will iscuss this in etail in the next section. However, when researchers request permission to stuy persons who are particularly vulnerable to coercion or unue influence, IRBs shoul etermine if these subjects are being systematically selecte for reasons irectly relate to the problem(s) being stuie or, for example, because of their easy availability, their compromise position or manipulability.

86 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #4: Subject selection is equitable. The principle of justice not only unerlies ethical consierations about who ought to be the subject of a research protocol but also the expectation that persons who accept the risks or burens of being research subjects shoul share in its benefits whenever possible. For example, those who have participate as research subjects shoul have the first opportunity to receive a therapy if the research emonstrates it to be safe an effective. (i.e., subjects of clinical trials who were either in a control group or recipients of a therapy that prove not to be superior shoul be offere the treatment that the trial emonstrate to be preferable).

87 Members: Using NIH IRB Review Stanars

88 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #5: Informe consent is obtaine from research subjects or their legally ll authorize representative(s).

89 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #5: Informe consent is obtaine from research subjects or their legally authorize representative(s). The principle of respect for persons is base on the ethical conviction that iniviuals shoul be treate as autonomous agents. An autonomous person is capable of eliberating about an acting upon personal choices. To respect autonomy is to give weight to his/her consiere choices. Therefore, proviing the opportunity for informe consent to research participation is one way to emonstrate respect for research subjects. We will iscuss briefly a few issues relate to subjects' informe consent.

90 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #5: Informe consent is obtaine from research subjects or their legally authorize representative(s). IRBs' consierations of informe consent generally inclue the following: Aequacy of the content an clarity of the written consent ocument; The process of informe ecision making; Documentation of informe consent, an Exceptions: Waiver or alteration of some or all of the requirements for written informe consent.

91 Members: Using NIH IRB Review Stanars NIH IRB Review Stanar #5: Informe consent is obtaine from research subjects or their legally authorize representative(s). Aequacy of the content an clarity of the written consent ocument. Except in specific circumstances approve by an IRB (which we will iscuss later), subjects' written informe consent is necessary. Therefore, IRBs give much attention to written informe consent ocuments to assure that they contain the require information in a manner that promotes unerstaning by prospective subjects. Feeral regulations give requirements for minimal research-relate information which h must be isclose to prospective subjects.