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Ethical Considerations in Clinical Trials

Ethical Considerations in Clinical Trials.

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Ethical Considerations in Clinical Trials

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  1. Ethical Considerations in Clinical Trials

  2. “The Clinical Trial: Deceitful, Disputable, Unbelievable, Unhelpful, and Shameful – What Next?”Horton R, Cont Clin Trials 2001.“Clinical Trials: Discerning Hype from Substance”Fleming T, Ann Intern Med 2010.“The Good Clinical Practice guideline: a bronze standard for clinical research”Grimes D et al, Lancet 2005.“Damage to important clinical trials by overregulation”Yusuf S, Clin Trials 2010.

  3. Finding the Balance • Many regulations have been created in response to unethical behavior. • Regulations are applied to publically funded studies as well as to studies sponsored by industry. • Around the world, regulations are not harmonized. • Many regulations and guidelines increase the costs of trials.

  4. Guidelines and Regulations to Ensure the Ethical Conduct of Research • Nuremburg Code (1949) – informed consent required. • Declaration of Helsinki (1964) – clinical research should be preceded by animal studies, careful assessment of risks and benefits, fully informed consent, conducted by medically qualified people. • Greenberg Report (1967) • Belmont Report (1979) – produced by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research which was established following the Tuskegee scandal; report addresses principles of respect (autonomy of clear informed consent), beneficence (beneficial and do no harm), and justice (benefits to some must be balanced against the risks to subjects). • International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines (1990) • Common Rule (1991) – adoption of 45 Code of Federal Regulations (CFR) 46 subpart A by multiple agencies (IRB procedures). • FDA Guidance on DMCs (2006) • Trial registration and publication of summary results on ClincalTrials.gov (FDA Amendments Act 2007)

  5. Structure for Cooperative Studies (Greenberg Report, 1967) Policy BoardorAdvisory Committee National Advisory Heart Council Initialreviewgroup Institutestaff Executive CommitteeorSteering Committee CoordinatingCenter Participating Units Reprinted in Cont Clinical Trials 9:137-48, 1988.

  6. Some Examples Where Reform is Needed • Annual reviews • Drug importation • Review of multi-site studies • Adverse events • Length of informed consent forms • Use of biospecimens • Sponsorship and insurance • GCP (e.g., site monitoring) See Emanuel E and Menikoff J for some proposed revisions to the Common Rule, N Engl J Med 2011

  7. Conflicting International and US Regulations • Conflict with US regulations (45 CFR 46) • Continuing Review (CR) – local international requirements allow for annual IRB continuing review by the IRB Chair (or select members), but not by the convened IRB as required by 45 CFR 46 • Conflict with the EU Clinical Trial Directive • Indemnification - NIH cannot serve as a sponsor for trials in the EU requiring NIH to indemnify Clinical Trials 2010; 7:705-718 and Editorial 622-625.

  8. Continuing Review of Protocols • The U.S. Office of Human Research Protections (OHRP) oversees research supported by the DHHS. • OHRP regulations require an annual review of each research protocol by the majority of IRB/EC members (regulations apply to foreign countries if they receive federal support). • Other countries do not require full-board reviews of each protocol annually.

  9. Exemption Requested by UK • Chair of central ethics committee reviews the protocol annually. • Enrollment in trial halted for 3-4 months. • Restriction lifted but “…to date, the Secretary has not made any determinations that other procedures provide equivalent protections”.

  10. EU Guidance on Sponsorship • Sponsor must provide the insurance or indemnity to cover the liability of the investigator and sponsor. • Variable implementation of this requirement by EU Member States. • In most cases, the sponsor is the funder.

  11. Sponsorship of Publically Funded Studies • As funder, NIH is usually legal sponsor of trial. • After a year of planning for a 4,000 patient international trial, NIH Counsel determined in July 2008 that NIH could not sponsor the trial due to insurance and indemnification requirements of the EU Directive. • NIH notifies U of M they will fund but not sponsor the trial. • After much deliberation, U of M assumes role as sponsor

  12. WHAT IF YOU ARE INJURED? If you are injured because of being in this study, {Insert the name of the clinic] will give you immediate necessary treatment for your injuries. The cost for this treatment will be charged to you or your insurance company. You will then be told where you may receive additional treatment for your injuries. There is no program for monetary compensation. You do not give up any of your legal rights by signing this form. Sample NIH Informed Consent Template

  13. Compensation for Research Related Injury “[D]espite decades of discussion and studies by a number of federal commissions, there remains little quantitative information regarding the number and severity of potentially compensable injuries and about the costs of implementing compensation programs.” (Responsible research. A systems approach to protecting research participants. IOM 2002, page 191)

  14. Anti-Deficiency Act and Adequacy of Appropriations Act Forbid the government from obligating itself for payments that are not appropriated or funded Form the basis of current NIH policy not to compensate injured research participants Potential Legal Barriers

  15. Insurance Requirements for START HIV Study by Country

  16. New Regulations for Trials in India • Announced by Ministry of Health and Family Welfare on January 30, 2013 • “Any injury or death of the subject occurring in clinical trial due to the following reasons shall be considered as clinical trial related injury or death and the subject or his/her nominee(s), as the case may be, are entitled for financial compensation…failure of investigation product to provide intended therapeutic effect…use of placebo in a placebo controlled trial...”

  17. Current Situation • NIH trials puts hold on new enrollments for trials in India (March 17). • Efforts by investigators in India and NIH to have regulations modified; amendments to be considered on April 8. • Plans for terminating studies in India being considered. • As, sponsor of a trial with 2 sites in India, similar considerations by U of M.

  18. Definition: Misconduct in Science according to a National Academy of Science Report Misconduct in science is defined as fabrication, falsification, or plagiarism, in preparing, performing, or reporting research. Misconduct in science does not include errors of judgment; errors in the recording, selection or analysis of data; differences in opinions involving the interpretation of data; or misconduct unrelated to the research process. “Intent-to-Cheat”

  19. Research Misconduct as Defined in Federal Register, May 17,200542 C.F.R § 50 and 93 (U.S. Office of Science and Technology Policy) • Research misconduct means fabrication, falsification, or plagiarism in proposing or reviewing research, or in reporting research results - Fabrication is making up data or results and recording or reporting of them. - Falsification is manipulating research materials, equipment , or processes, or changing or omitting data or results such that the research is not accurately represented in the research record. - Plagiarism is the appropriation of another person’s ideas, processes, results, or words without giving appropriate credit. - Does not include honest error or differences of opinion.

  20. Three Conditions For Misconduct According to Federal Policy • A significant departure from accepted practices in the scientific community. • Be committed intentionally, or knowingly in reckless disregard for accepted practices. • Allegation must be proven by a preponderance of evidence.

  21. Spectrum of Scientific Misconduct: Big Sins, Little Sins and Other Types of Bad Behavior Data Collection • Data fabrication • Data alteration • Sloppy methods • Maintenance of inadequate research records Reporting • Plagiarism • Duplicate publication • Incomplete reporting of data (25-50% of trials not published; 50% of trials to support drug approval – PLoS Med 2008) • Honorary or “ghost” authorship • Authorship credit

  22. Prevalence ofMisconduct in Science • Between March 1989 and March 1991, 200+ allegations of misconduct were recorded by U.S. government offices • 26,000 research projects supported annually by NIH Source: Responsible Science - Ensuring the Integrity of the Research Process, Vol. I, Nat’l. Academy of Sciences, IOM, 1992.

  23. Misconduct and Retracted Publications • 2,047 articles identified in May 2012 on PubMed (among 25 million articles); earliest was in 1973. • Fabrication/falsification – 697 • Suspected fraud – 192 • Plagiarism – 200 • Duplicate publication – 290 • Error – 437 • Other/unknown -- 290 • More retractions in high impact journals. • Marked rise in frequency of retraction over time. • Recommendations: more vigilance by editors and reviewers; more attention to ethics in training of scientists; changes to incentive systems in science. Fang FC, Steen RG, Casadevall A. PNAS 2012.

  24. Fraud in Medical ResearchA Survey of Biostatisticians Percent knowing of at least one fraudulent project in their proximity in past 10 years 37% of respondents 18% of members Fraud (def.) – A deliberate attempt to mislead others in the design, conduct, analysis, or the reporting of a scientific study. Ranstam J et al., Cont Clin Trials, 21:415-427, 2000.

  25. Allegations of Fraud in Science • N Rays (1904) - Rene Blondlot of University of Nancy (perhaps more self-deception) • Path of gunshot wounds (1916) - James Shearer (sentenced to firing squad) • Mice experiment at Sloan-Kettering (1970s) - William Summerlin • Drug study in hyperactive children (1980s) - Richard Breuning • Cardiomyopathy studies (1980s) - John Darsee • Immunological research (1980s) - Imanishi-Kari and David Baltimore • HIV virus (1980s and 1990s) - Robert Gallo • Breast cancer trial (1990s) - Bernard Fisher • Bezwoda study (2000) – Warner Bezwoda • Korean cloner (2006) - Woo Suk Hwang • Chemotherapy prediction models (personalized cancer treatment) (2010) - Anil Potti at Duke University • Plagiarism by Serge Pangou (Science, 9 March 2012) detected with Turnitin antiplagiarism software • Improper sharing of articles in peer review • Conflicts of interest of individuals conducting and reporting research

  26. Readings 1. Committee on the Conduct of Science. National Academy of Sciences. On Being a Scientist, 3rd Edition, 2009 (see www.nap.edu/catalog.php?record_id=12192 (can read online) • Committee on the Responsible Conduct of Research of the Institute of Medicine. The Responsible Conduct of Research in the Health Sciences. National Academy Press. Washington, DC, 1989. • Woodward J, Goodstein D. Conduct, Misconduct and the Structure of Science. AmerScientists 1996; 479-90. • Conduct in Science. Science 1995; 268:1705-18. • Buyse M et. al. The role of biostatistics in the prevention, detection and treatment of fraud in clinical trials. Stat Med 18:3435-51, 1999. • Horton R. The clinical trial: deceitful, disputable, unbelievable, unhelpful, and shameful – what next? Cont Clin Trials 22:593-604, 2001. • Martinson BC et al. Scientists behaving badly. Nature 435:737-738, 2005. • Fang FC, et al. Misconduct accounts for the majority of retracted publications. PNAS 109:17028-17033, 2012. • Lo B, Field MJ. Conflict of interest in medical research, education, and practice. Washington DC, National Academies Press, 2009. • Responsible Research. A systems approach to protecting research participants. Institute of Medicine, The National Academies Press, 2003 (can read online). • The James Lind Library (NIH website)

  27. Encounters with Misconduct • Data alteration in MRFIT • Eligibility and consent violations in HIV trial • Duplicate publication • Conflicts of interest (def.: “a set of circumstances that creates a risk that professional judgment or actions regarding a primary interest will be unduly influenced by a secondary interest”, Conflict of Interest in Medical Research, Education, and Practice, IOM 2009) • Early termination of trials for business reasons (JAMA 2003; 289:2128)

  28. A Case SummaryofData Alteration in the Multiple Risk Factor Intervention Trial (MRFIT) Cont Clin Trials 1991; 12:731-740.

  29. Front Page Headline: St. Louis Globe – DemocratMay 3, 1976 “Federal investigation into heart research project here”

  30. MRFIT Background Recruitment period: 1973-1975 Number of clinical centers: 22 Average number of men screened to yieldone randomized participant (range): 15% rule: 19 (12-33) 10% rule: 35 (30-85) Randomization goal per center: 600 men Recruitment sources: places of employment, churches and civic groups, shopping centers, census tract (door-to-door)

  31. Calendar of Events Related to Data Alteration April and May 1975 Data alteration of screening forms Jan. or Feb. 1976 Local newspaper notified of alteration; investigation initiated March 1976 NHLBI notified of alterations to screening forms by newspaper reporters April 9, 1976 Detailed analyses of screening yields and risk factor distributions performed by Coordinating Center at NHLBI request April 14, 1976 Additional analyses of screening yields performed by Coordinating Center

  32. Calendar of Events Related to Data Alteration(cont’d.) April 22-23, 1976 Three members from Coordinating Center reviewed screening forms at clinical center April 28, 1976 Initial report of Coordinating Center reviewed May 3, 1976 Newspaper article June 16, 1976 Final report by Coordinating Center on “markouts” for randomized men June 28, 1976 MRFIT Data and Safety Monitoring Committee reviewed report prepared by Coordinating Center

  33. Number of Randomized Participants with Markouts and Changes in Eligibility No. with Markouts (%) Number Ineligible with Original Values (%) 2-74 to 3-75 306 42 (13.7) 2 (4.8) 4-75 56 26 (46.4) 15 (57.7) 5-75 41 9 (22.0) 7 (77.8) 6-75 to 9-75 141 36 (25.5) 3 (8.3) 544 113 (20.8) 27 (23.9) Month/Year of Initial Screen No. Randomized

  34. Distribution of Difference (Original-Altered Value) in Diastolic BP (mmHg) for Randomized Participants Screened in April or May 1975 with Eligibility Change Due to Markouts of BP -5 to -9 6 27.2 -4 4 18.2 -3 3 13.6 -2 5 22.7 -1 1 4.5 0 1 4.5 1-3 0 0.0 4-5 2 9.1 TOTAL 22 100.0 Difference (Original-Altered) No. Percent No. <95 to ≥95 mmHg: 14 No. ≥115 to <115 mmHg: 2 Average difference: -3.0 mmHg

  35. Summary of Investigation 1. BP readings were altered over an approximately 3 week period in 1975 at one clinical center. 2. This was discovered approximately a year later following a telephone call to NIH and subsequent review of the original forms by the coordinating center. 3. The data alterations resulted in 22 participants being randomized who should not have been. 4. The alterations to BP levels were small and had little impact on trial design.

  36. Conclusions 1. It is unlikely that data alterations such as that described here can be detected with usual quality assurance procedures. 2. Care has to be taken so that pressure, particularly fiscal, to recruit participants does not result in actions which jeopardize the integrity of the trial. 3. Source documents, e.g., data collection forms, should be retained for several years beyond the end of a study. 4. Efforts should be directed at prevention rather than detection of data alteration.

  37. Another Case of Data Alteration: National Surgical Adjuvant Breast and Bowel Project (NSABP) • In a trial of 2,163 women, 6 of 254 patients at a site in Montreal had data altered to make them eligible. • Data reanalyzed and published in NEJM. • Investigator indicated “he felt the rules were meant to be understood as guidelines.” • Discussed at congressional hearings. • Led to formation of monitoring branch at NCI.

  38. Suggested Readings • NEJM letters, May 19, 1994. • “Clinical trial monitoring: hit or miss”, Science, June 10,1994. • Results of study audit - Christian M, NEJM 1995;333:1469-1474 • Peto R et al. “The trials of Dr. Bernard Fisher: a European perspective on an Americdan episode”, Cont Clin Trials, Feb 1997.

  39. Survey of 3,247 Early- and Mid-Career Scientists Funded by NIH “Our findings suggest that US scientists engage in a range of behaviors extending far beyond falsification, fabrication and plagiarism”. Nature 2005; 435:737-738.

  40. Top 10 Behaviors Reported

  41. Top 10 Behaviors, cont.

  42. Other Behaviors (Questionable Practices)

  43. Big Picture – What is the Truth? • Exclusions from analyses • Trials with no stopping rules • Inappropriate endpoints (poor surrogates instead of clinically meaningful outcomes) • Misleading subgroup analysis • Trial results that are not reported (even for NIH-funded research – see BMJ, 3 January 2012) • Biased or incomplete reporting; influence of source of funding (see Annals of Intern Med, 18 June 2013) (YODA Project) • Random high bias and regression to the mean

  44. Studies of Renal Flare in Patients with Systemic Lupus Erythematous (SLE) -1 • Trial 1: No overall effect of new drug (LJP 394) versus placebo on renal flares (19 versus 23 events; p=0.51) • Subgroup analysis revealed that in patients with high affinity antibody binding there were 7 versus 21 renal flares; p=0.007) • Abstract conclusion: “Treatment with LJP 394 with high-affinity antibodies to its DNA epitope prolonged the time to renal flare…” • No comment on overall results. Fleming TR. Ann Int Med 2010.

  45. Studies of Renal Flare in Patients with Systemic Lupus Erythematous (SLE) - 2 • Trial 2: Carried out in high affinity subgroup. • No difference in pre-specified primary analysis • Difference seen in 1st 12 months but not afterwards • Trial 3: Carried out in high affinity subgroup with 12 month follow-up. • No difference; trial terminated early for futility

  46. [There is an] idea that we all hope you have learned in studying science in school – we never explicitly say what this is, but just hope that you catch on by all the examples of scientific investigation… It’s a kind of scientific integrity, a principle of scientific thought that corresponds to a kind of utter honesty – a kind of leaning over backwards. For example, if you’re doing an experiment, you should report everything that you think might make it invalid – not only what you think is right about it; other causes that could possibly explain your results; and things you thought of that you’ve eliminated by some other experiment, and how they worked – to make sure the other fellow can tell they have been eliminated. …In summary, the idea is to try to give all the information to help others to judge the value of your contribution, not just the information that leads to judgment in one particular direction or another. R. Feynman, CAL TECH Commencement Address.

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