Ethics A. Statistical Consultant B. Human Subjects Research

1. EthicsA. Statistical Consultant B. Human Subjects Research

2. Statistical Ethics • Professional conduct of statistical analyses essential to society • Use statistics in • Medical diagnoses / biomedical research • Environment / Agriculture • Economy / market research / quality control • Government policy decisions • Scientific and engineering research

3. Ethical problems may arise in research from: • deliberate fraudulent behavior • use of incorrect procedures • omitting data which do not support the researcher’s ideas • misuse of statistics in the analysis and interpretation phase

4. Statistical Ethics • American Statistical Association has Ethical Guidelines for Statistical Practice • Applies to all • Statisticians (and/or those doing the analyses) • Researchers / Funders / Employers • Interested audience • Not followed in practice due to conflict of interest / poor science / lack of knowledge

5. Statistical Ethics • Statistical ethics and statistical validity are highly interdependent • Poor use of statistics and the increased availability to information creating “hard-nosed” skeptics and “lazy” practitioners • Guidelines focus on 8 topic areas • Professionalism • Responsibility to funders / employers • Responsibilities in publications and testimony

6. Professionalism • Strive for practical significance, not just statistical significance • Competent understanding of subject matters • Disclose conflicts of interest and resolve them • Use statistical methodologies suitable to the data

7. Responsibility to Funders • Apply statistical sampling and analysis procedures objectively • Explain potential biases created by altering the sampling /design plan • Clarify respective roles in studies • Where appropriate present Funders choices of statistical approaches that vary in cost, precision, scope

8. Responsibilities to Publications • Maintain personal responsibility for all work bearing one’s name • Report statistical and substantive assumptions made in a study • Report the sources of information and if possible share the data • Fully report statistical methods used • Report limits of inference

9. Statistics and Ethics • Hypothesis testing and statistical significance • Role of the null and alternative hypotheses • The nature of the conclusion • Properties of procedures described in terms of a single use • Special cases, e.g. bioequvalence

10. Multiplicity • What happens when we have many outcomes and do many tests? • Some technical adjustments are possible, e.g. multiple comparisons procedures

11. Other issues • Outliers • Other rules for excluding data • “Intent to treat” • LOCF • Transformations • Data mining

12. Some principles • Transparency • Free from pretense of deceit, readily understood • Often applied to decision making • It can be applied to the use of statistics • Issues related to selective reporting • Analyses to understand the data • Analyses to present the findings

13. Old I teach formulas and procedures I consult I calculate power I analyze data I do tables, not words New My students learn to use concepts I collaborate I plan studies I draw conclusions I do words and tables Roles of statisticians

14. Ethics implications • In the old scenario, my ethical responsibility is to do good statistics • In the new scenario, my ethical responsibility is much greater

15. History of Human Subject Research • First documented trials in 1700’s • Vaccination trials • Researchers and family members as subjects • Generally, human subject studies carefully scrutinized • Consent of subject key • Generally high regard for medical profession

16. Nuremberg Code • After war, 23 Nazi doctors and scientists put on trial • Used concentration camp inmates as subjects • Study commonly led to the death of subject • As part of sentences, 10 points describing required elements for research with humans

17. Nuremberg Code • Informed consent in essential • Prior animal work is essential • Risks should be justified by anticipated benefits • Only qualified scientists conduct research • Physical/mental suffering be avoided • Research in which death or severe injury likely should not be performed

18. Benefits vs Risks • Benefits: positive value of advantage of being in study • Could be direct effect to individual • Could be more of a societal benefit • Risks: outcomes that potentially harm the subject • Must assess magnitude and probability • Easy to quantify physical risk • Harder to assess social, legal, financial, psychological

19. Declaration of Helsinki • Nuremberg code: Limited effect in US • Medical profession already “knew better” • No real law enacted • World Medical Association developed code of research ethics (1964) • Focused more on research with therapeutic intent • Journal editors required this code be followed • Birth of institutional review boards (IRBs)

20. Beecher Article • Was an anesthesiologist • Wrote article in 1966 (NEJM) • Described 22 examples of studies with controversial ethics • Heightened awareness of researchers, public, and press to the problem of unethical research ethics • Possible to happen anywhere

21. Beecher Article • Problems • Lack of informed consent / withholding info • Coersion/undue pressure on volunteers • Use/exploitation of vulnerable population • Withholding available treatments • Deception • Risks outweigh benefits

22. Willowbrook Hepatitis Study • 1956 study to determine • natural history of viral hepatitis • Inoculation against hepatitis • Children at institution for mentally retarded deliberately infected with mild form of hepatitis • Lack of full disclosure of risks • Possible coersion • Use of vulnerable population

23. San Antonio Contraception Study • 1971 study to determine side effects of an oral contraceptive • Crossover design with half the women getting oral contraceptive and half getting placebo • Problems • Informed consent – weren’t told this would happen • Risks outweigh benefits • Vulnerable group

24. Tuskegee Syphilis Study • Public Health Service study (1932-1971) • Study to document natural history of syphilis in African-American men • Initially enrolled men with and without syphilis • Men were denied antibiotics (1940 penicillin) • Problems • Lack of informed consent • Deception • Withholding available treatment

25. Government Involvement • Syphilis study resulted in Congress getting involved • Recommended federal regulations be put into place • 1974 National Commission put into place and asked to identify basic ethical principles of human subject research and develop guidelines • 1979: Published Belmont Report

26. Belmont Report • Required reading for anyone involved in human subject research • Identified three basic principles • Respect for persons • Beneficence • Justice • Each should have equal moral force when determining merits of research

27. Respect for Persons • Treat individuals as autonomous human beings • Let them choose for themselves • Provide extra protection for those with limited autonomy • Limited mental capacity • Lack of freedom or influence of others • Informed Consent / Respect of Privacy

28. Beneficence • Minimize harms and maximize benefits • Best possible research design to maximize benefits / minimize harms • Need favorable risk-benefit ratio • Capable researchers to perform procedures

29. Justice • Treat people fairly and design studies so the burdens and benefits are shared equitably • Subject selection • Avoid exploitation of vulnerable populations

30. More Recent Events • 1996- Death of Normal Volunteer • Underwent bronchonsopy • Was difficult procedure requiring numerous doses of lidocaine • Subject “nodded” yes when asked to continue • Later had cardiac arrest due to overdose of lidocaine • Issues • Doses / limit of lidocaine not in protocol • Subject not observed after procedure • Complete autonomy?

31. More Recent Events • 1999: Death in Gene Therapy Trial • 18-year-old James Gelsinger died during a gene-therapy study to treat enzyme disorders • Issues • Conflict of interest • Researcher James Wilson held a 30-percent equity stake in the company that owned the rights to license the drug that Wilson was testing. • Data safety monitoring • Informed consent

32. More Recent Events • 2001: At Johns Hopkins, Ellen Roche, an otherwise healthy woman, died of respiratory failure after breathing in a chemical that was designed to help scientists study the effects of asthma. • Later, investigators uncovered evidence that the chemical could be unsafe, evidence the researcher had not found in his literature search. Moreover, the consent forms signed by Roche and other patients made the chemical seem like a benign and federally approved product.

33. More Recent Events • After a man died during a gene-therapy experiment at the St. Elizabeth Medical Center in Boston in 2001, his family filed a wrongful-death suit, alleging that the man would never have entered the experiment had he been told about the 20 percent financial interest that the researcher and hospital had in the product being tested.

34. Data Safety and Monitoring Board • DSMB monitors patient safety and evaluates the efficacy of the intervention • Initial responsibility is to approve the initiation of a clinical trial • After approval, and at periodic intervals during the course of the trial, the DSMB responsibilities are to: • review the research protocol, informed consent documents and plans for data safety and monitoring; • evaluate the progress of the trial, including periodic assessments of data quality and timeliness, participant recruitment, accrual and retention, participant risk versus benefit, performance of the trial site, and other factors that can affect study outcome; • if appropriate, conduct interim analysis of efficacy in accordance with stopping rules which are clearly defined in advance of data analysis; • Consider factors external to the study when relevant info becomes available, such as scientific or therapeutic developments that may have an impact on the safety of the participants or the ethics of the trial;

35. What is an IRB? • Committee of at least 5 members • Varied professions / expertise • Obtain special competencies from outside consultants • Sensitive to community attitudes • Sensitive to vulnerable populations • Trained in institutional regulations, standards of professional conduct

36. What Does an IRB do? • Approve, disapprove, or modify current human subjects research • Conduct continuing reviews • Observe, monitor, audit • Suspend or terminate approval • What constitutes human subjects research?

37. Definitions • Human Subject • Living individual about whom and investigator conducting research obtains • Data through intervention or interaction with an individual • Identifiable private information • Research • A systematic investigation designed to develop or contribute to generalizable knowledge

38. Criteria for Approval45 CFR 46.111 • Minimizes the risks • Has reasonable risk/benefit ratio • Equitable subject selection • Vulnerable populations addressed • Informed consent process / documentation • Confidentiality / privacy maintained • Data monitored for safety

39. Level of Review • 1. Exempt • Low-risk research (as defined by Federal criteria) • Fits one of 6 categories • Involves only non-vulnerable population • Does not involve “sensitive” issues • No permanent record of individual • Does not have to initially be anonymous • Destroy links once data obtained and processed

40. Six Categories • Typical education practices • Educational tests, survey procedures, interview procedures, or observation of public behavior, unless: • human subjects can be identified directly (or linked) and information is sensitive • Existing data if publicly available or unidentifiable • Research with public officials or candidates • Evaluation of public or service programs • Taste and food quality evaluations, consumer acceptance

41. Level of Review • 2. Expedited • Meets criteria for minimal risk • Involves activities in one of nine categories • Non-vulnerable populations • Non-sensitive issues • Minimal risk : No substantive increase beyond risks of ordinary life – IRB needs to be very careful to consider all potential risks

42. Expedited Review • Reviewed at same rigor as Full but with a limited number of reviewers • Must go to full review if research to be disapproved • Selected categories • Focus groups, collected data not for research purposes, blood samples, voice or video data, noninvasive collection of biological samples

43. Level of Review • Full • Research greater than minimal risk • Research involving vulnerable populations • Sensitive topics (will vary by community) • All IRB members review protocol

44. Study #1 • Want to determine prevalence of illicit drug use in pregnant women • Subjects will be from 10 rural and 10 hospitals in Arizona • Collect urine drug screening , demographics • Subject identifiers will be stripped • Waiver of consent is requested

45. Study #2 • Want to determine prevalence of illicit drug use in a high school • Subjects 16-18 from one urban school • Will screen existing urine samples from previous protein study • Samples will be stripped of identifiers • Researchers claim this is exempt research Research involving the collection or study of existing data, documents, records, pathological specimens, or diagnostic specimens, if these sources are publicly available or if the information is recorded by the investigator in such a manner that subjects cannot be identified, directly or through identifiers linked to the subjects

46. Study #3 • Find risk factors for pancreatic cancer • Registry will be established involving 20 major health centers • Patients will provide extensive health history information • Asked to provide health information on family members (1st and 2nd order relatives) • Are the family members also research subjects?