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Ethics in Clinical Research - Ethical Issues in Human Subjects ...


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Ethics in Clinical Research - Ethical Issues in Human Subjects ...

  1. 1. Ethical IssuesEthical Issues in Human Subjectsin Human Subjects ResearchResearch Judy Stone, MDJudy Stone, MD
  2. 2. The first step in the evolution of ethics is a sense of solidarity with other human eings. — Albert Sweiter
  3. 3. 1932–72 Tuskegee experiment on syphilis 1939–45 Nazi experiments 1944–74 Human radiation experiments by U.S. government 1946 Nuremberg Trial of doctors responsible for the Nazi experiments 1947 Nuremberg Code outlining ethical principles required for research 1948 United Nations adoption of Universal Declaration of Human Rights Milestones in Ethical DevelopmentMilestones in Ethical Development
  4. 4. Milestones in Ethical DevelopmentMilestones in Ethical Development  1953 NIH policy, the first U.S. federal policy introducing independent reviewers to  examine research, forerunners of the IRBs  1963–66 Willowbrook Study, involving hepatitis research on mentally retarded children,  raising issues access to care, consent, and coercion  1964 Declaration of Helsinki international agreement on recommendations for the ethical  conduct of medical research  1972 Public exposure of Tuskegee syphilis study  1974 First federal protections for human research participants
  5. 5. Milestones in Ethical DevelopmentMilestones in Ethical Development  1979 Belmont Report promoting three principles for research  1980 Food and Drug Administration regulations (CFR 21 (50)  1982 Council for the International Organization of Medical Sciences (CIOMS) publication of the International Ethics Guidelines for Biomedical Research Involving Human Subjects  1985 U.S. Public Health Service Task Force on Women’s Health issues report encouraging inclusion of women in research  1990 Society for Women’s Health Research
  6. 6. Milestones in Ethical DevelopmentMilestones in Ethical Development  1993 Public exposure of U.S. human radiation experiments  1993 NIH Revitalization Act mandating inclusion of women and minorities in research  1993 NIH Office of Research on Women’s Health
  7. 7. Milestones in Ethical DevelopmentMilestones in Ethical Development  1997 Food and Drug Modernization Act (FDAMA) requiring the FDA, NIH, and pharmaceutical industry to develop guidance on the inclusion of women and minorities in trials  1998 Pediatric Rule passed by Congress, stipulating that new drugs for children must include specific pediatric labeling information  2000 Further publicized ethical abuses prompting establishment of the Office of Human Research Protections (OHRP)
  8. 8. Belmont ReportBelmont Report  National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research  3 basic principles for research
  9. 9. Belmont ReportBelmont Report Respect for persons, or an individual’s autonomy- elements of the informed consent requiring that:  Information necessary to make a decision must be presented that is,the risks and benefits, if any, of participation.  The information must be presented at a level that can be understood by the patient or study subject.  Participation must be voluntary.
  10. 10. Belmont ReportBelmont Report Benificience, or benefit to the participantBenificience, or benefit to the participant Who decides whether there is benefit?Who decides whether there is benefit?
  11. 11. Belmont-BeneficenceBelmont-Beneficence Loss of substantial benefits that might be gained from research Paternalism Pregnancy Life-threatening illness (AIDS/Cancer)
  12. 12. Belmont-JusticeBelmont-Justice  Risks and benefits should beRisks and benefits should be equitably distributed among different populations  “Do onto others…” rather than taking advantage of Vulnerable populations
  13. 13. Vulnerable Populations  MilitaryMilitary  1944-1979: radiation, chemical,1944-1979: radiation, chemical,  Mustard gas, lewisiteMustard gas, lewisite  Venezuelan equine encephalitis virus and the nerve gas agent VX  Operation Whitecoat (tularemia, anthrax, Q fever)  1994 Congressional review: the Department of Defense “has demonstrated a pattern of misrepresenting the danger of various military exposures that continues today”
  14. 14. Vulnerable Populations  Unsuspecting civiliansUnsuspecting civilians  Radiation experiments: atomic weapons testing inRadiation experiments: atomic weapons testing in  South PacificSouth Pacific  Oak RidgeOak Ridge  Los AlamosLos Alamos  Hanford, WashingtonHanford, Washington  Plutoniaum injections (ACHRE report)Plutoniaum injections (ACHRE report)
  15. 15. Vulnerable PopulationsVulnerable Populations What studies are being done now under the guise of counter terrorism, hidden from the public by the “Patriot Act?”
  16. 16. Vulnerable Populations-Children  Pint-size people vs. real dataPint-size people vs. real data  10 drugs most commonly prescribed for children that lacked pediatric labeling—drugs were prescribed more than 5 million times  HIV studies in foster children  Too vulnerable? vs denying access to potentially life-Too vulnerable? vs denying access to potentially life- saving drugssaving drugs  (all HIV + kids were being offered the trials)(all HIV + kids were being offered the trials)
  17. 17. Vulnerable Populations-Women  PregnancyPregnancy  PaternalismPaternalism  Woman vs FetusWoman vs Fetus
  18. 18. Daily Ethical Encounters Participants who are vulnerable from:Participants who are vulnerable from: Abuse from Doctor-patient relationshipAbuse from Doctor-patient relationship ““whatever you say, doc” syndromewhatever you say, doc” syndrome Indigent patientsIndigent patients
  19. 19. Daily Ethical Encounters  Financial Pressures and Conflict of InterestFinancial Pressures and Conflict of Interest  FinancialFinancial  Income for DepartmentIncome for Department  BonusesBonuses  Structure of grant (pay per visit or end-loaded)Structure of grant (pay per visit or end-loaded)  Pay for screeningPay for screening  Pay for quality of data, rather than # of patientsPay for quality of data, rather than # of patients  Avoid disincentives for dropping a patient (e.g., due toAvoid disincentives for dropping a patient (e.g., due to adverse reactionadverse reaction  Pressure re prestiege, publication, tenurePressure re prestiege, publication, tenure
  20. 20. Other Conflicts of InterestOther Conflicts of Interest at the Siteat the Site  Use of a class of drug in a study-e.g., Quinolones,Use of a class of drug in a study-e.g., Quinolones, that you might not use otherwisethat you might not use otherwise  Access to care for indigent patientsAccess to care for indigent patients  Access to novel drug (pt may lie)Access to novel drug (pt may lie)  Adverse event classificationAdverse event classification
  21. 21. Yet more COIYet more COI  IRB relatedIRB related  Voluntary, unpaidVoluntary, unpaid  Lack of trainingLack of training  Paid by drug companyPaid by drug company  Pressure from administrationPressure from administration  Personal competition/conflictPersonal competition/conflict
  22. 22. Mrs. G?Mrs. G?
  23. 23. Evaluating a StudyEvaluating a Study  Does the study ask an important/valuableDoes the study ask an important/valuable question?question?  Is the study design reasonable?Is the study design reasonable?  Would I be willing to be in this trial?Would I be willing to be in this trial?
  24. 24. Evaluating a Potential VolunteerEvaluating a Potential Volunteer  Level of understanding based onLevel of understanding based on  Education, life experienceEducation, life experience  MotivationMotivation  Financial needFinancial need  vs. ethics of lack of universal health carevs. ethics of lack of universal health care  What will happen to the pt when the study ends?What will happen to the pt when the study ends?  Stage of illnessStage of illness  Risk vs. BenefitRisk vs. Benefit  What do they have to lose?What do they have to lose?  Would I take this drug or give it to my family member?Would I take this drug or give it to my family member?
  25. 25. Politics of Research: WomenPolitics of Research: Women  Viewed as vulnerable populationViewed as vulnerable population  PaternalismPaternalism  Woman vs. fetusWoman vs. fetus  e.g. AIDs clinical trialse.g. AIDs clinical trials  ReligionReligion  Exclusion of women from participation due toExclusion of women from participation due to restrictions about contraceptive userestrictions about contraceptive use
  26. 26. Politics of Research: RacePolitics of Research: Race  one-fourth of the U.S. population is made up of “people of color”  Only 5% of trial participants  Legacy of distrust  Tuskeegee  HIV-foster children study (despite evidence)  Nigerian Pfizer meningitis trial => resistance to polio vacciination
  27. 27. Politics of Research: Race and Gender Overlap  1980 and 1983, fully one-fifth of contraceptive research was conducted in developing countries  Oral contraceptive research in Puerto Rico  Adverse events analysis was inadequate  Quinacrine  The effect of power inequities between men and women  Lack of social support for many women  Coercion by medical providers or government agencies
  28. 28. Quinacrine-Belmont PrinciplesQuinacrine-Belmont Principles  BeneficenceBeneficence  No safety or toxicity studies of intrauterineNo safety or toxicity studies of intrauterine installationinstallation  Distributive JusticeDistributive Justice  Almost all the women wereAlmost all the women were low income, poorly educated women of color in developing countries.  Respect for Persons, autonomy, self- determination  No explanation of experimental nature of quinacrine and no informed consent or offer of alternatives
  29. 29. Shifting ResearchShifting Research to Developing Countriesto Developing Countries  United States accounts for ~ 4 percent of the world’s population vs. 84% for dev. Countries  90 percent of $ is spent on the illnesses of the wealthiest countries, leaving 10 % of monies to care for 84 % of the global population
  30. 30. Vulnerable international populations • Limited economic development • Inadequate protection of human rights • Inadequate community and cultural experience with, or understanding of, scientific research • Limited availability of healthcare and treatment options • Limited ability of individuals in the community to provide informed consent due to illiteracy and language, educational, or cultural barriers
  31. 31. Vulnerable international populations What standards should apply?  Meningitis trialMeningitis trial  Maternal-fetal HIV transmission trialsMaternal-fetal HIV transmission trials  Absolute standard of care vs. local standard?Absolute standard of care vs. local standard?  What if the local standard is to do nothing?What if the local standard is to do nothing?  International consensus is that it is ethical if:International consensus is that it is ethical if: it is based on a valid scientific purpose for using a lesser standard, provides social benefits for the local host community, and shows a favorable risk-benefit ratio for the individual research participants
  32. 32. Vulnerable international populations  Distributive justice is violated  the local study populations will not significantly benefit from the research if the new therapies will not be affordable to them, although they are taking a higher proportion of the risk.