Financial Conflicts of Interest in Research: What do the data show?

1. Financial Conflicts of Interest in Research:What do the data show? Lindsay Hampson Department of Clinical Bioethics National Institutes of Health

2. Outline • Background • Interest in Conflicts of Interest • Definition • What is a Conflict of Interest? • Data • Conflicts of Interest and Research • Protections

3. Does Money Talk? • Would you interpret data differently in a lecture if a drug company were paying you $5,000 to give the lecture?

4. Interest in Conflict of Interest Why is there all the interest in researchers’ conflicts of interest? • Recent deaths have raised the question of whether researchers were more concerned about financial matters than patient safety • Gelsinger case at University of Pennsylvania • Fred Hutchinson Cancer Center

5. Interest in Conflict of Interest • Bayh-Dole act of 1980: Encouraged universities and medical schools to commercialize their research conducted with government funds

6. Interest in Conflict of Interest Industry has dramatically increased its funding of clinical research compared to the government • Phase I-III Trials: • -Pharmaceuticals $20 billion • -NIH $ 8 billion 62% 32%

7. DISCLAIMER The views expressed in this presentation do not represent the views of the NIH, DHHS, or any other government agency or official.

9. What is a Conflict of Interest? • Professionals have a primary interest—the goal of their profession • For researchers: • Producing generalizable knowledge • Ensuring the safety of research subjects • Disseminating research results

10. What is a Conflict of Interest? • Professionals also have secondary interests beyond their professional goals • Publishing • Spending time with his/her family • Obtaining a good income • Political activism or volunteerism • Obtaining future research funding • Pursuing other interests such as religion, traveling, social activities, etc.

11. What is a Conflict of Interest? • It is important to note that secondary interests on their own are not bad or unethical • Usually these secondary interests are good and often praiseworthy • Time devoted to one’s family • Lobbying for a political belief • Volunteering for a local charity

12. What is a Conflict of Interest? • What makes secondary interests problematic is their ability to unduly influence decisions about an individual’s primary interest • The key ethical issue is the relationship between a primary and a secondary interest

13. What is a Conflict of Interest? • A conflict of interest occurs when a secondary interest distorts or has the potential to distort a judgment related to a primary interest • A professional’s judgment does not necessarily have to be biased in order for that researcher to have a conflict of interest — even the appearance of a conflict of interest is ethically worrisome

14. How Does This Affect YOU? • Do not necessarily realize that your judgment is biased or that a conflict is occurring • It happens to everyone • Having a conflict of interest does not make you a bad person

15. Researcher Conflicts of Interest • For researchers, concern that some secondary interest might threaten: • Valid research design • Data integrity • Researchers’ interpretation of data • Dissemination of results • Patient safety

16. Financial Conflicts of Interest Why all the emphasis on financial conflicts of interest? • Money is… • Multi-purposed • Universally recognized as a good • A key motivating factor • Relatively easy to regulate

17. Frequency of Financial Interests How frequently do researchers have financial interest in their own research? • Not much data • Often, must rely on self-reporting

18. Frequency of Financial Interests • It seems that financial relationships between industry and researcher are relatively common:

19. Frequency of Financial Interests • In a survey of published randomized controlled trials, of authors that disclosed a financial interest… • 30% Employment • 22% Consultancies and Honorarium • 18% Grants • 7% Educational/Speaker’s Bureau • 7% Stock ownership • 5% Advisory Board • 1% Patents/Licenses Gross et al. JAMA 2003

20. Financial Conflicts of Interest and Research Design Do financial interests compromise research design? • Data indicate that industry-sponsored research is no worse methodologically than clinical research sponsored by non-profit organizations • In fact, industry-sponsored research studies may even be more methodologically rigorous

21. Assessing Methodological Quality • Instruments for assessing methodological quality of drug studies • Cho and Bero (JAMA 1994) • Oxman and Guyatt (J Clin Epidemiol 1991) • Jadad et al. (Controlled Clinical Trials 1996) • 5-point scale • For each question, yes = 1, no = 0; add/subtract extra point if method is appropriate or inappropriate • Look at the article and answer these questions • Was the study described as randomized? • Was the study described as double blind? • Was there a description of withdrawals and dropouts?

22. Financial Conflicts of Interest and Research Design • Liebeskind et al. 1999 (Stroke) • Used a 100-point scale to assess methodological quality • Randomization, outcome, inclusion/exclusion criteria, description of intervention, statistical analysis Industry 73.1 Non-industry 53.4 p<0.0001 • Industry-sponsored research was more likely to be double blind and to report adverse events

23. Financial Conflicts of Interest and Data Do financial interests compromise data collection? • Data suggest that industry funded clinical research leads to “positive results” more frequently than non-industry funded research

24. Financial Conflicts of Interest and Data • Of 11 meta-analyses, 9 reported that industry sponsored trials were significantly more likely to yield pro-industry results • Odds ratio of having industry sponsorship and pro-industry conclusion:OR=3.60 (2.63-4.91) Bekelman et al. JAMA 2003

25. Conflicts of Interest and Data • These data do not necessarily demonstrate bias or compromised studies • Is this a “pipeline” issue? • Industry commits resources only to clinical research that is likely to yield positive results • Industry terminates large randomized studies early that are likely to have side effects and less likely to be successful or to generate huge profits

26. Financial Conflicts of Interest and Researcher Interpretation Do financial interests bias researchers’ interpretation of data? • Data suggest that having financial ties with industry does distort the judgment of researchers • Not necessarily fabrication of data, but could influence interpretation of data

27. Financial Conflicts of Interest and Researcher Interpretation • Stelfox et al. study: reviewed all studies on the safety of Ca channel blockers in hypertension published in 1995-96 • 70 articles - 5 original research papers - 32 reviews - 33 letters to the editor

28. Financial Interests and Researcher Interpretation

29. Financial Conflicts of Interest and Researcher Interpretation Complex SituationMoney TalksMoney Affects JudgmentsNot Uniformly or Consistently

30. Financial Conflicts of Interest and Dissemination Do financial interests influence dissemination of research results? • Industry-funded clinical research that produces positive results are more likely to be published compared to government-funded clinical research

31. Conflicts of Interest and Dissemination • Analysis of 42 placebo-controlled trials of SSRI (selective serotonin reuptake inhibitors) drugs submitted to Swedish drug regulators • Results: • Experimental drug more effective than placebo: 19/21 published (90.5%) • Experimental drug not more effective than placebo: 6/21 published (28.6%)

32. Conflicts of Interest and Dissemination • Meta-analysis of data from randomized trials that evaluated a 5 SSRI’s against placebo in the treatment of depression in children • Articles reviewed were published in a peer-reviewed journal or unpublished (and reviewed by the Committee on Safety of Medicines) Whittington et al. Lancet 2004

33. Conflicts of Interest and Dissemination • Results: • When published data alone were considered, it appeared that there was a favorable risk-benefit profile for 5/5 drugs studied • Addition of unpublished data indicated that the risks outweigh the benefits for 4/5 drugs studied • Unknown if unpublished articles were not published due to publication bias against negative studies at major journals or the result of industry withholding negative data

34. Financial Conflicts of Interest and Dissemination • Multiple high profile attempts by industry to prevent publication of negative data: • The Olivieri case • Boot Pharmaceuticals-USCF synthroid case

35. Financial Conflicts of Interest and Patient Safety Do financial interests compromise patient safety and well-being? • No data • No data on overall safety of clinical research

36. Financial Conflicts of Interest and Patient Safety • In a bone marrow transplant protocol at Fred Hutchinson Cancer Research Center, 80/82 enrolled research subjects with metastatic breast cancer and leukemia died • Study investigators had $294 million of holdings in Genetic Systems, a drug company sponsoring part of the research

37. Conflicts of Interest and Patient Safety • This does not necessarily indicate that a conflict of interest impacted researchers’ judgment or patient safety • Need to be sure we do not draw unsubstantiated conclusions from the data • Raises questions and concerns, but deaths are not necessarily due to the presence of conflicts of interest

38. Why Do We Need Protections? • Protections aim to reduce: • Likelihood of harm: Limit the possibility of a harm occurring in the first place • Magnitude of harm:Lessen the negative consequences of the harm

39. Protections for Financial Conflicts of Interest • Disclosure • To institution/IRB/COI committee • To patients • In journals • Management • Data safety and monitoring boards (DSMBs) • Independent consent monitors • Prohibitions • Against types/amounts of financial interests • By removing researchers from study

40. Problems with Protections • No consistent standards for disclosure: • 2001 GAO study of 5 major research institutions • UCLA, UNC, UW, Washington University, Yale • Rules regarding disclosure and prohibitions of financial interests varied widely • Limits of financial interests varied from $10,000 to $100,000

41. Problems with Protections • Disclosed information is not well recorded and not readily available to the IRBs • Researchers are not aware or well-informed of disclosure policies • At UCSF and Stanford, 58% of researchers could not accurately describe the COI policy of their institution

42. Patient Worries aboutFinancial Conflicts of Interest • More and more people are talking about wanting to disclose financial interests of researchers to research participants • 2003 Boyd, Cho, Bero: ¼ of investigators felt that public disclosure was the best way to mitigate the ethical risks of COIs • In a 1995 study of post-marketing research: 75% of doctors and 86% of patients believed that their patients should be informed if their doctor was paid a fee for enrolling them in the study

43. Patient Worries aboutFinancial Conflicts of Interest • Disclosure, especially to research subjects, lets them know about a problem without tools to solve the problem (other than not participating in the research) • Places responsibility on subjects rather than on researchers and institutions, putting the onus on the least powerful group • No data that patients • Understand disclosure of financial interests • Understand how it might affect judgments • Will change their actions regarding participation in research

44. Patient Worries aboutFinancial Conflicts of Interest • At the NIH, currently conducting 2 studies interviewing research participants about their understanding and views about financial interests • How worried are they? • How would certain financial ties affect their participation in research studies (why)? • What do they want to know about financial ties? • Always know about financial ties • Know if only over a certain monetary limit • Never know about financial ties • Know about safeguards in place to protect subjects • If they could set limits, what would they allow?

45. Conclusions • Researcher financial interests are common: 25% to 33% of researchers • Financial interests • Do appear to influence researcher interpretation and data dissemination • Do not appear to influence research design • ? Influence data collection ? • ? Influence patient safety ?

46. Conclusions • Protections, but not without problems • Disclosure • Management • Prohibitions • Swift endorsement of disclosure to research subjects before this option has been fully thought out or shown to be of any benefit