1. Consideration of Risks and Benefits at Initial Review

2. Consideration of Risks and Benefits What does it mean?

3. Why Consider Risks & Benefits The main charge of an IRB is their responsibility to protect the rights and welfare of human subjects in research Practical aspect: in addition to the ethical/moral responsibilities there is a legal aspect  NOT protecting the rights and welfare of human subjects invites bad press, lawsuit, even the shutting down of an institution

4. Risk: What is it? The probability of harm or injury occurring as a result of participation in a research study Prediction of some future occurrence of harm Consideration of probabilities: what has happened before?

5. Minimal Risk Risk level is determined by the IRB A risk is minimal where the probability and magnitude of harm or discomfort anticipated in the proposed research are not greater, in and of themselves, than those ordinarily encountered in daily life or during the performance of routine or psychological examinations or tests. (38 CFR 16.102i)  For research to be exempt from IRB review it MUST be minimal risk

6. Risks: Types of Risk Physical Psychological Social Economic Legal

7. Risks and Benefits: IRB Approval Criteria Risks to subjects are minimized: (i) by using procedures which are consistent with sound research design and which do not unnecessarily expose subjects to risk, and (ii) whenever appropriate, by using procedures already being performed on the subjects for diagnostic or treatment purposes. Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result. 38 CFR 16.111(a)(1-2)

8. Risks: Types of Risk Physical Psychological Emotional Loss of dignity Embarrassment Social Loss of confidentiality Loss of social status Threat to privacy Harassment Economic Threat to employment Insurability and insurance costs Legal

9. Risks: Types of Research Case example: August 21, 2008 Allegation sent to OHRP regarding failure of IRB to determine that criteria for IRB approval are satisfied: “Risks to subjects were not minimized because all subjects were required to undergo Modified Radical Mastectomy (MRM).” Source: 8/21/2008 OHRP Determination Letter: RUMC and CCBHS

10. Risks: Types of Research How does one evaluate risks in a research protocol when usual care is involved?

11. Risks: Description in Informed Consent Basic Element of Informed Consent: A description of any reasonably foreseeable risks or discomforts to the subjects including for example, privacy risks (legal, employment, and social). VHA 1200.05 Appendix C, 2(a)(7) What is meant by reasonably foreseeable?

12. Issues in Describing Risks: Informed Consent What level of detail? How much is too much? Does one include everything in an Investigator’s Brochure? How does one make it understandable? Percentages Tables

13. Benefit: What is it? A valued or desired outcome; an advantage The probability of hoped for benefits

14. Benefit: IRB Approval Criteria Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result. 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 therapies subjects would receive even if not participating in the research). The IRB should not consider possible long range effects of applying knowledge gained in the research (for example, the possible effects of the research on public policy) as among those research risks that fall within the purview of its responsibility. 38 CFR 16.111(a)(2)

15. Benefit: Hoped for benefits? Two Major Categories: Benefits to participants Therapeutic Benefits to society Nontherapeutic

16. Benefit: Nontherapeutic Long-term Question: Can one ethically justify enrolling subjects into a study solely based on nontherapeutic benefits to the subject?

17. Benefits: Description in Informed Consent Basic Element of Informed Consent: A description of any benefits to the subject, or to others, which may reasonably be expected from the research. VHA 1200.05 Appendix C, 2(a)(9) What is meant by reasonably be expected?

18. Benefits: Issues in Informed Consent How does one prevent statements from being coercive? Is this coercive? It may be a way to get an experimental treatment for a life threatening illness before it is approved and available. Compensation confused with benefit Is this a benefit? You will receive a $25 gift card following each study visit? Is care received as a research subject a benefit? Is this a benefit? Researchers may check your physical condition frequently, because they need data to make comparisons in a trial.

19. Benefits: Issues in Informed Consent How does one prevent statements from being coercive? Is this coercive? It may be a way to get an experimental treatment for a life threatening illness before it is approved and available. Compensation confused with benefit Is this a benefit? You will receive a $25 gift card following each study visit? Is care received as a research subject a benefit? Is this a benefit? Researchers may check your physical condition frequently, because they need data to make comparisons in a trial.

20. Risk/Benefit Analysis Risks and benefits are not parallel ideas Risks: often individual, immediate, measurable Benefit: often elusive, future, potential Need to maintain a favorable balance

21. What the Codes and Regulations Say The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment (Nuremberg 6) Biomedical research involving human subjects cannot legitimately be carried out unless the importance of the objective is in proportion to the inherent risk to the subject (Helsinki I.4) Risks to the subjects [must be] reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result 38 CFR 16.111(a)(1)

22. Belmont Report: it’s all about risk Three basic ethical principles in the Belmont Report guide the conduct of research with human subjects: 1.Respect for Persons 2.Beneficence 3.Justice

23. Identifying risks and benefits? NO ONE can be objective about their own work Underestimate risks Overestimate benefits IRB acts as objective referee

24. The IRB and the R&D Committee A Matter of Perspective  Is this how the committees view investigators? Or  Is this how investigators view the committees?

25. The Role of the IRB Review potential risks, discomforts, hazards, or inconveniences of protocol Probability, magnitude, duration, reversibility of risks Separate risks of research from standard of care risks e.g. Risks of surgery already scheduled Give special consideration to risks for research involving vulnerable populations Children, mentally impaired, prisoners, others

26. The Role of the IRB (cont.) Consider hoped for benefits Benefits can take the form of therapy, education, information, resources or empowerment Benefits can be directed at participants, their community, society, medical knowledge, medical technology Consider if risks reasonable in relation to possible benefits Balancing potential risks to participant/others against possible benefits to participant/society

27. The IRB: Balancing potential risks No benefit requires no risk to participants Little benefit requires low risk High risk studies require showing of significant benefit to participants To determine balance consider type of risk Physical, psychological, social, economic

28. The IRB: Balancing potential risks and benefits in informed consent Example: Here are some possible benefits in joining a clinical trial. Your participation may help others get a better treatment for their disease in the future. Researchers may check your physical condition frequently, because they need data to make comparisons in a trial. It may be a way to get an experimental treatment for a life threatening illness before it is approved and available.

29. The IRB: Balancing potential risks and benefits in informed consent Example: Here are some possible risks in joining a clinical trial. You may experience serious side effects, such as worsening of your asthma, other problems with your breathing, rashes, nausea, vomiting, headaches, trembling, difficulty speaking, fast heart beats, dizziness, difficulty moving, pain in your joints, mouth sores, and ringing in your ears. You could also experience other side effects that we do not know about because we do not know about this drug. You may not get the experimental treatment, but a standard treatment or a placebo instead. The experimental treatment may not be better or even as good as the standard treatment for your condition.

30. The IRB: Balancing potential risks and benefits in informed consent Even if a new procedure works for other people, it may not work for you. Keep in mind that a few people have increased their risk of getting another condition during experimental drug trials. For example, while testing the arthritis drug Vioxx as a treatment for polyps, researchers discovered that the drug increased the risk of heart attack and other cardiovascular problems. The drug has been taken off the market.

31. The IRB: Balancing potential risks and benefits in informed consent Another possible concern, though not a health risk, is that your health insurance or the trial may not cover all patient care costs.

32. The IRB: Balancing potential risks and benefits in informed consent Question: What is your impression as a potential subject of participating in this study?

33. Worth keeping in mind: IRB review of research is NOT an adversarial enterprise 1.With proper review, consideration of regulations, and inclusion of safeguards human subjects research relatively safe to participants 2.Human subjects research can be beneficial to improving health care at large and/or basic knowledge

34. All share the same mission The IRB should be working with investigators as part of a cooperative “Research Enterprise” whose goal is to advance society and its health Consideration of Risks and Benefits: part of overall review of Human Subjects research focusing on subject safety and welfare