By: Dr Nita Mawar Deputy Director (Sr. Gr.) National AIDS Research Institute (ICMR), Pune 411026

1. Inducement and conflict of interestsCapacity Building Workshop: Ethical issues in HIV/AIDS ResearchUNICEF-NACO sponsored at NARI from 13th -15th Sept 2011Presented on 15th September 2011 By: Dr Nita Mawar Deputy Director (Sr. Gr.) National AIDS Research Institute (ICMR), Pune 411026 nmawar@nariindia.org NARI CBWS Inducement and COI NACO-UNICEF

2. Concepts • Payment for participation • Compensation for actual costs • Compensation for inconvenience /discomfort • Incentives for participation • Inducement and Undue inducement by Coercion, persuasion, manipulation • Conflicts of Interest • Situations in which financial/ other personal considerations may compromise professional judgment in conducting or reporting research NARI CBWS Inducement and COI NACO-UNICEF

3. Compensation of Human Participants • Reimbursement for travel cost and loss of wages • Amount of compensation is often proportional to risks and inconveniences posed by participation in study • Minor inconvenience or discomfort - Modest payment • Significant risk - Greater payment, but not so great to exert undue inducement • Many studies, e.g., Phase I trials are lengthy & tedious • Reasonable to pay over and above reimbursement of expenses incurred for time, inconvenience or discomfort NARI CBWS Inducement and COI NACO-UNICEF

4. Non-Financial Altruism - act of love Seek treatment/ cure Manipulative suggestions Freedom to prisoners Academic credits Emotional appeals Negative or Positive encouragement Threats Open Suggestive Discrete Financial Rewards Offers Payments Compensation- just/ unjust Payments – large or even small sums in resource poor settings Incentives (toys/Travel vouchers etc) Free medication- expensive drugs for terminally ill Influences & Inducements NARI CBWS Inducement and COI NACO-UNICEF

5. Inducement to Participants • For enrollment • Relate to level of participation • Relate to degree of risks • Cash/Kind/Services • Inducement to Researchers • For number of enrolments /CROs in business • Individuals/Research team/Institution • Cash/Kind • Per research subject / research procedure • Incentives/schemes for Fast recruitment NARI CBWS Inducement and COI NACO-UNICEF

6. Ethical Issues • Decreases voluntariness for participation: in research both for research organization,indiv dual researchers and then comes to research subjects. • Economically disadvantaged or marginalised population bear a larger share of risks and burdens • Subject will care about money rather than understand goal of study- defeats Informed consent purpose • Researcher subject relationship - a commercial relationship NARI CBWS Inducement and COI NACO-UNICEF

7. Financial Transactions and Inducement Offer of otherwise unobtainable treatment • Consider to disapprove Offer of superior care and attention • Improved care should not be offered as an inducement to participate • Insurance – can it be an inducement?? Fees to participants, department, institution, University • The participant must be assured • free to decline to take part • refusal will be accepted without question • his care will then continue as routinely followed NARI CBWS Inducement and COI NACO-UNICEF

8. Models of payment • Market Model • Larger payments/ incentives for faster recruitments • Wage Model • Fairly low, unskilled labor: eg study on S&D in HCP: EC permitted compensation for ward boys and nurses not doctors not even a pen • Reimbursement Model • Covers only expenses, no compensation for time, efforts, discomfort NARI CBWS Inducement and COI NACO-UNICEF

9. Guidelines • WHO Operational Guidelines • “a statement describing any compensation for study participation (including expenses and access to medical care) to be given to research participants;” • Declaration of Helsinki • The design and performance of each experimental procedure involving human subjects ….., which must be independent of the investigator, the sponsor or any other kind of undue influence ……The researcher should also submit to the committee, for review, information regarding funding, sponsors….and incentive for subjects. • CIOMS • Subjects may be paid for inconvenience and time spent, and should be reimbursed for expense incurred, in connection with their participation in research; they may also receive free medical services. However, the payments should not be so large or the medical services so extensive as to induce prospective subjects to consent to participate in the research against their better judgment (“undue inducement”) NARI CBWS Inducement and COI NACO-UNICEF

10. ICMR Guidelines • Subjects may be paid for inconvenience & time spent & reimbursed for expenses incurred, in connection with their participation in research. • They may also receive free medical services. • Payments should not be so large or medical services so extensive as to induce prospective subjects to consent against their best judgment (inducement). • All payments, reimbursement and medical services to be provided to research subjects should be approved by IEC. • Care should be taken: • When a guardian is asked to consent on behalf of incompetent persons, no remuneration should be offered except a refund of out of pocket expenses • When a subject is withdrawn from research for medical reasons related to the study the subject should get the benefit for full participation • When a subject withdraws for any other reasons s/he should be paid in proportion to the amount of participation NARI CBWS Inducement and COI NACO-UNICEF

11. Conflicts of Interests (COI)- Examples • Italian scientist Giuseppe Sanarelli’s desire for fame - he discovered bacillus of yellow fever and produced yellow fever in 5 patients in 1897 • “To deliberately inject a poison of known high degree of virulence, unless you obtain that man’s sanction is not ridiculous, it is criminal”- Osler 1898 • WW-II Nazi doctors promotion of the War Effort, 1939-45 • prisoners of war crimes were exploited and used for benefit of others NARI CBWS Inducement and COI NACO-UNICEF

12. Fred Hutchinson Cancer Research Center (FHC), Seattle (1981-1993, 1990-98) • Bone marrow transplantation & breast cancer study- 20/82 died • Key researchers including Nobel Prize winner Donald Thomas had stock shares & commercial rights to antibodies produced by him • Financial and professional COI of PI & Instt, deception of patients, coercion of IRB members Duke’s University • In1999 Duke’s University was shut down as Grant Officer was on IRB who should not have been a voting member. Thus there was inadequate IRB supervision of human subject experiments NARI CBWS Inducement and COI NACO-UNICEF

13. University of Pennsylvania Death of Jesse Gelsinger, 1999 • Death of 18yr old with ornithine transcarbamylase deficiency, a genetic disorder. Underwent gene therapy and was injected with adenovirus carrying OTCgene - died in 4 days. Later it was found that 2 Rhesus monkeys had died in similar tests; 4 other human patients had suffered toxicity to their livers earlier • PI as well as Head of Instt had 30% shares in the company Genovo sponsoring its product ‘gene-altered adenovirus’ Example from India • PI of a clinical trial on chronic hepatitis was found to have 30% stake in the sponsoring Pharma company but did not disclose it to the Ethics Committee. • Once information was known he was asked to withdraw as PI of study NARI CBWS Inducement and COI NACO-UNICEF

14. Understanding Conflicts of Interest • Any professional has a primary as well as secondary interests • Primary Interests • Patient Health and well being • Clinical Research • Education of future health professionals • A conflict of interest occurs when secondary interests “unduly influence” the “professional judgments concerning a primary interest” • Secondary Interests • Financial gain • promotion • grants for research • publication of research results • desire of fame • family obligations NARI CBWS Inducement and COI NACO-UNICEF

15. Conflicts • Secondary Interest are usually not illegitimate but frequently necessary and desirable • Problem occurs when secondary interests dominate, unduly influence, distort, corrupt the integrity of a physician’s judgment in relation to patients health, clinical research or medical education • Fortune, fame, family preference threaten the integrity of the professional judgment Dennis F Thompson. Understanding Financial Conflicts of Interest, NEJM 329 (1993): 573-76 NARI CBWS Inducement and COI NACO-UNICEF

16. Evaluating Conflicts of Interests • Risk Benefit Compromise ? • Subjects safety may be compromised • Knowledge produced may be biased eg differentfollow-up rates for developing and developed countries • Probability that judgment will be distorted • If the secondary interest is small & unlikely to corrupt decision making • Large financial incentive influence is great • Potential magnitude of harm • If small or transient in nature, concern is less • If the harm is life threatening or disabling concern is heightened NARI CBWS Inducement and COI NACO-UNICEF

17. Conflicts of Interest • Institutional • Ethics Committee members • Investigators NARI CBWS Inducement and COI NACO-UNICEF

18. Institutional COI • Administrative conflicts - Instt may enter into a contractual relationship with a company that presents a conflict • with its academic mission • its non-profit status • the activities of its board members • its need to be objective in its dealings with faculty • its obligations to other organizations • Decisions regarding institutional conflicts of interest must be made by the governing board. NARI CBWS Inducement and COI NACO-UNICEF

19. Ethics Committee Members – Conflict of Interest • Principal of Medical College/ Head of Institution/ Dean as Chairman IEC - biggest inherent COI eg EC members in SE asian countries were spouses • IEC members reviewing their own protocols, protocols of colleagues, friends, rivals from same deptt/ working on similar research areas or own student’s proposals NARI CBWS Inducement and COI NACO-UNICEF

20. COI management - Ethics Committees • IEC members requested to disclose potential conflicts of interests as part of the screening process for their selection • Required to sign ‘Confidentiality Agreements’ • IEC member should not be a faculty in a position to set university/ hospital policies, manage contracts, select equipment/ supplies, or have other administrative roles • In India- Chairman of IEC to be from outside the Instt • IEC member as investigator cannot vote on own protocol • Minutes should record that the person left the room and did not participate in discussions or decision making • Person shall not be counted as part of the quorum NARI CBWS Inducement and COI NACO-UNICEF

21. Role of Ethics Committee • To do the balancing • Payment for participation is not a research benefit • Maintaining Standards in Multicentric studies • Role to develop specific policies to determine type of cases and manner to pay subjects - local standardised rates • Research on Vulnerable needs special care • For e.g., Children- Given the magnitude of poverty prevalent in the country, it is possible that amount provided as compensation for participation could act as inducement and influence parental judgment regarding enrolling the child. (Indian Pediatrics, Feb, 2006) NARI CBWS Inducement and COI NACO-UNICEF

22. Researchers-Conflicts of Interest • Key issue to worry is that some interest might threaten • Valid research design • data integrity • patient safety • dissemination of results • Conflict of Time • May make a commitment but may not have enough time • Investigators motivation/ demotivation can affect particpant’s safety NARI CBWS Inducement and COI NACO-UNICEF

23. Influences of COI • Which treatments to test ? • Whether to have placebo? • Endpoints of the trial • Inclusion & exclusion criteria • Information in IC form and process • Rules for stopping trial if efficacy proven or adverse events • Whether clinical trial will be stopped due to evidence from other studies? • Which eligible patients will be enrolled? Baruch A. Brody “Conflicts of Interests and validity of clinical trials” in Conflicts of Interest in Clinical Practice and Research, ed Roy G Spece, David S Shimm, Allen E Buchanan (New york: Oxford University Press, 1996, 407-17. NARI CBWS Inducement and COI NACO-UNICEF

24. Financial COI • Financial ties between researchers & industry in US (by Dr E. Emmanuel, NIH) • 34% occasional speaking engagements • 33% consulting arrangements • 32% paid position on board of directors • 14% equity in company- mean value $100,000 • 1998- 34% publications had atleast 1 author with financial interest in results • Employment 30% • Consultancies and Honoraria 22% • Speaker’s Bureau 7% • Stock Ownership 7% • Advisory Boards 5% • 25% academic investigators receive industry funding • 43% receive research related gifts from Corporations NARI CBWS Inducement and COI NACO-UNICEF

25. Reviews and Meta-analysis • Clinical trials and meta-analyses sponsored by drug companies favored the product produced by the funder Lexchin et al. BMJ, 2003 • Conclusions of trials were significantly more likely to recommend the experimental drug as the treatment of choice if the trials were funded by for-profit organizations Nielsen et al. JAMA 2003 NARI CBWS Inducement and COI NACO-UNICEF

26. Management Strategies • Disclosure • Small amounts may be acceptable • Middle amounts need to be disclosed or watched • Large amounts need to be prohibited • IEC Management • Prohibition • Policies • Mediation • Elimination Approach • Conflict of Interest Committee NARI CBWS Inducement and COI NACO-UNICEF

27. Other Measures • NEJM requirement • “Authors of research articles should disclose at any financial arrangement they may have with the company whose product figures prominently in the submitted manuscript or with the company making a competing product” • “Because of the essence of reviews and editorials is selection and interpretation of literature, journal expects that authors of such articles will not have significant financial interest in a company that makes a product discussed in the article” NARI CBWS Inducement and COI NACO-UNICEF

28. Situation in India • Inherent COI - most IEC members come from within Institute • Survey- 60% IEC had Head of Institute as Chairman • Administrative Conflicts of interest of Institute • IEC member’s proposals discussed in meetings in their presence • COI Committee impractical at the moment • Financial interests of Independent Ethics Committee ?? NARI CBWS Inducement and COI NACO-UNICEF

29. Conclusions • Outsourcing of clinical trials leading to growing links between clinical researchers and industry, inducements as well as COI are likely to increase • Many potential COI situations may be acceptable with proper oversight and safeguard mechanisms developed by Institutions • In India there is a need to • 1.recognise, • 2.disclose and • 3. Manage COI with policies and regulation NARI CBWS Inducement and COI NACO-UNICEF

30. Acknowledge with thanks to Dr N Kumar and the IEC network • Thank you! NARI CBWS Inducement and COI NACO-UNICEF