Risk Benefit Analysis

1. Risk Benefit Analysis Dr.R.R.Gangakhedkar, National AIDS Research Institute, Pune

2. What is risk & Benefit • Types of risks & benefit • How does one evaluate risk benefits • Challenges in measuring risk benefits • What is risk management • Strategies to minimise risks

3. Research adheres to …. • Respect for Persons • Individual autonomy • Beneficience • Maximise benefits & minimise risks • Justice • Equity including that for risks & benefits

4. What is risk and benefit? • Risk is an effect that is harmful to the patient’s or public’s health and which can relate to safety, efficacy or quality of a product • Benefit is “something that promotes well being” – Webster Dictionary

5. What is the difference between risk & hazard? • Hazard is an event that has a potential to cause harm • Risk is a likelihood of a harm being caused by occurrence of hazard

6. Broad principle for evaluating the risk… • Risk = Severity of harm X probability of occurrence of hazard

7. Is it easy to measure through such an equation? • In principle yes, but there may be many practical challenges; • There could be differences in • Real Risk ~ may be measurable • Perceived Risk ~ multidimensional • Risk denial as you see among adolescents • Assessed Risk ~ may vary between people

8. Risks Identified in Belmont Report • Psychological: Boredom, anxiety, embarrassment, or psychotic relapse • Physical:Sexual dysfunction, high blood pressure, or death • Legal:Fines or imprisonment • Social:Stigmatization, harm to reputation, or divorce • Economic:Lost time at work, loss of employment, legal fees or medical bills for harms incurred in research

9. If you recall the different types of risks, certain issues become apparent.. • Even in “Real Risk”, interpretations from scientific data can potentially be subjective leaving a room for ‘understatement’. Complexity of scientific data & its ‘generalisability’ limitations • Data on post-sexual exposure prophylaxis & risk of transmission • Indigenous research ~ no study in India • Approved in US for certain situations but not in India ….

10. Comparisons for risks and benefits are not easy. As the measures of risks & benefits are not same. • Eg. Is ART equally efficacious in controlling CMV disease vs conventional treatment? Challenges in assessing risks. IRIS. • They may also have a temporal perspective that is anticipatory in nature and brings element of uncertainty • Immediate benefits vs long-term risks • Long term benefits vs short-term risks

11. One cannot easily weigh one harm/risk with multiple minor benefits that may accrue • Most often these comparisons depend on the investigator and ‘empowered’ persons and it can potentially lead to a conflict. • Example: “Stopping HPV Vaccine Trial”, ‘Jaitapur Nuclear Power Plant’

12. Quite often, disagreements are seen among scientists & researchers & … Best example; IPT for TB among HIV infected persons or;

13. A trial proposes to assess efficacy of r/LPV monotherapy among patients who have failed first-line ART in India… Risks… and Benefits Do you think it will be easy to get approval from IEC?

14. Importantly, risk for an individual may not be perceived as risk by another However, one needs make efforts to ensure that both will be able to assess it will with provision of scientific information on what does the risk mean and how commonly can it occur

15. Concept of average risk vs relative risk • Generally the statistics that one would have, will speak of average risk arrived from the mean from different people • However, for some people the ‘background risk’ that they commonly encounter is so high that they feel it is low compared to the perception of ‘others’. Ex. Sex workers did not feel that risk of acquiring HIV is as high since they would have to buy condoms vs that of not having money or being in the profession • This to me is a sign of vulnerability that needs to be dealt with appropriately. • But the wider issue is~ should their be different standards for risk evaluation for different groups?

16. Importantly… • Everybody does not perceive risk similarly; • Researcher ~ will know best about average risk+ may guess/ anticipate unknown risk • Study participant ~ may compare the informed risk with known risks through life experiences • These assume importance as in certain set of studies – there will avoidable risks & some unknown, unavoidable but sometimes recognisable risks in early stages

17. Not only is it the duty of investigator to empower potential participants with knowledge about the risk, but.. Responsibility of IEC to ensure risk benefit evaluation that may need appropriate steps for risk mitigation

18. What is minimal risk? • 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 during the performance of routine physical or psychological examinations or tests.

19. Minimal risk is… • Risks encountered during routine physical and psychological exams • Other examples of routinely encountered risks: • Dealing with a child’s routine illness • Having a minor argument at work • Losing something important eg. keys. • Having a tooth filled UIC

20. Omeract 3X3 table for risk assessment

21. By and large a lifetime involuntary risk on the order of 1:1,000,000 (1: 1 million) is considered small enough to be acceptable or is a tolerable risk., That is also a reason why EFV based ART is not yet researched during first trimester of pregnancy !

22. How can one measure risk? • Event Tree to assess probability. • Risk of providing post-exposure prophylaxis; • Risk of transmission X odds of protection X Risk of sexual exposure during receipt of ART X risk of encountering an HIV infected sexual partner X probability of not using condom X probability of the partner having STI X increase in risk of transmission of HIV due to STI X p of developing drug resistance in presence of ARV/s

23. Checking dose-response.. • Let us propose that HIV infected individuals who smoke are more likely to develop lung cancer • You may quantify the dose of exposure by measuring; • No cigarettes smoked per day • No. yrs of exposure • Type of cigarette smoked …. etc

24. Primary models used for assessment of non-threshold effects

25. However, quantifying risks is not all that easy.. • Most often “ dose” exposure does not occur at uniform frequency. Eg. Had 300 sex partners in lifetime but majority were two decades back, last 3 months and then yesterday ! • Difficulties in interpreting animal data. Eg. EFV & neural tube defect • Differences due to different routes of exposure. Eg. Vaccine studies in animal trials – route of exposure different than mucosal in humans

26. Limitations of analytical methods used earlier. Eg. Risk of transmission through contaminated blood transfusion is > 95% • Estimates of exposure are subject to many biases especially for disease that have low transmission efficiency such as HIV. Recall bias, social desirability bias and period effect. Ex. Risk of transmission in different types of needle stick injuries.

27. All these issues in estimating probability of risk may require an understanding of uncertainty as much! One can do sensitivity analysis to paint different scenario’s to assist in decision making One may also resort to Monte Carlo simulation that is based on randomness of all events

28. Study designs & importance of risk mitigation in HIV

29. Can you use objective methods to assess risks?Coplan 2011 • Assess relative weights • Stated choice methods • QALYs • Utilities • Value functions • Application of weighted approach in analysis • Net clinical benefit • Number needed to harm (NNH) • Multicriteria decision analysis

30. A new method~ 4-Step Process of Systematic Evaluation of Research Risks (SERR) Rid et al 2010 • Identify the potential harms posed by the research intervention. • Categorize the magnitude of each potential harm using harm scale. • Quantify or estimate the likelihood of each potential harm.

31. Compare likelihood of each potential harm from research intervention with likelihood of potential harms of the same magnitude occurring in an appropriate comparator activity • Based on a new approach called Harms Scale • Comparators developed with expert academicians, philosophers, research ethics, risk assessment, and patient advocacy , later bioethicists & IRB Chairs

33. Research adheres to …. • Respect for Persons • Individual autonomy • Beneficience • Maximise benefits & minimise risks • Justice • Equity including that for risks & benefits

34. Some may perceive that… • The risk benefit assessment is so difficult and may vary between people and blush the volatility index of Sensex. Some may worry how does IEC calculate the risk actually. • The truth is~ • Exhaustive approaches are for studies where not much is known • Commonly done has known risks and probabilities that can be intuitively handled • And there is a generic approach in risk mitigation • Implement measures to minimise occurrence of risk and its seriousness.

35. And also, IEC/ sponsors will try and assess relevance of research question • Those that are not based over sound theoretical basis • Has major flaws in study design • Has conflict of interest with partnering agencies such as Pharma company. Benefits ‘them’ rather than participants • May potentially dis-empower communities or individuals • Goes overboard in investigations for the stated objectives

36. Generic measures in risk management • Respect • Accurate Informed Consent form & Process • Respect for Privacy • Beneficence • Good study design & plan of implementation • Competent investigators/researchers • Favorable risk-benefit analysis • Justice • Equitable selections of subjects

37. Children ~ Risk levels (FDA) • Research is no greater than minimal risk • Research is greater than minimal risk with prospect of direct benefit • Research is greater than minimal risk with no prospect of direct benefit, but will contribute to knowledge about the subject’s condition. • Research otherwise not approvable, but may present an opportunity to understand, prevent, or alleviate a serious problem affecting children.

38. “ Beauty lies in the eyes of the beholder’ For risk mitigation “ Risk should lie in the eyes and mind of the beholder”

40. Risk Management = Risk Assessment + Risk Minimization

41. Principles of Prevention • Try a less riskier and manageable option • Reduce the chance of occurrence of the hazard • Early detection of before complete harm has occurred • Ensure that those who develop hazard receive appropriate treatment

42. Individual Vs Public Good • A big dilemma but the guiding principle should still revolve by levels of severity for children • Individual risk/benefits need to be protected most often • Only rarely would one like to weigh in favour for level 4 and 3 research • Few questions that help in decision making • “Can I reduce individual harm by excluding such ‘vulnerable’ individuals from the study/trial?’ • Is the study hypothesis so critical that it needs to be answered for public good? • Are there any alternate proxy’s or study designs that can reduce the harm?

43. A study proposes to use ‘test and treat’ strategy to control HIV epidemic? Issues in risks and benefits How will IEC evaluate the risk?

44. How should one inform the patient/ participant about the risks & benefits? • Are there studies that tell you the probability of these harms? • It is important that one recognises that patients find it difficult to understand a risk of SJS as 0.5 per thousand for a product • Simplify the numbers as much as possible. • Try to talk about the probability of commonly encountered risks & compare • Discuss treatability of these events & their sequelae • Inform them how to recognise them early • Assess comprehension and encourage them to ask any doubts that they may have. • And when they ask what should they do, inform them that they are now equally empowered with knowledge & encourage them to take decision

45. In conclusion~Assess, control and monitor risks