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HRC 101

HRC 101. History of Human Subjects Research Amy Gibbs, January 25, 2006. History Hippocratic Oath. Original written 400 B.C. by Hippocrates, a Greek physician Emphasis on duty, virtue, gentlemanly conduct Principle of ‘first, do no harm’ is not in original oath

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HRC 101

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  1. HRC 101 History of Human Subjects Research Amy Gibbs, January 25, 2006

  2. HistoryHippocratic Oath • Original written 400 B.C. by Hippocrates, a Greek physician • Emphasis on duty, virtue, gentlemanly conduct • Principle of ‘first, do no harm’ is not in original oath • Included now controversial pledges never to perform euthanasia or abortion • Modern oath • Written in 1964 by Louis Lasagna, Dean of Tufts Medical School • Version varies by medical school • Includes pledges to: • Act in a compassionate manner • Share knowledge and recognize shortcomings • Protect privacy • Prevent disease

  3. HistorySignificant Events • 1900: Walter Reed Yellow Fever • Injected American soldiers in Panama with agent for yellow fever; paid them $100 if they survived and $200 if they contracted a disease • Introduced use of consent ‘contracts’ to augment verbal consent, also use of healthy human subjects in medical research • Minimized consequences (ie, possibility of death) of yellow fever • Alluded to inevitability of contracting disease outside of study • 1937: Sulfanilamide Elixir • Used to treat strep infections • 107 people, mostly children, died due to dilutent (diethylene gylcol) • At the time, pre-marketing toxicity testing wasn’t required • 1938: Food, Drug, Cosmetic Act passed requiring safety testing

  4. HistorySignificant Events • 1941-1945: Concentration Camp Experiments • Numerous experiments (sterilization, typhus, high altitude/low pressure, bone regeneration and transplantation, freezing, malaria, phosphorus burn) performed on prisoners • 1962: Thalidomide • Used as a sleeping pill, caused birth defects in thousands of western European babies • 1962: New Drug Amendment passed also requiring efficacy testing • 1962: Stanley Milgram Obedience Experiments • Tested obedience to authority • Subjects told to administer shocks to another person – despite increasing pain, subjects continued to administer shocks as instructed • Deceived subjects about objective of study, filmed them without consent, deprived them of ability to withdraw from the study

  5. HistorySignificant Events • 1963-1966: Willowbrook • Introduced benign hepatitis into mentally ill children with coerced parental consent to study the natural course of the disease • Investigators argued most of the children would have acquired the infection anyway • 1966: Beecher paper in NEJM • Physician at Harvard Medical School • Called 22 studies published in NEJM unethical because risk/benefit ratio unknown to subjects • Examples: injecting live cancer cells into nursing home patients, withholding antibiotics from men with rheumatic fever, transplanting melanoma into relatives

  6. HistorySignificant Events • 1929 – 1972: Tuskegee syphilis study • Study to observe course of untreated syphilis, primarily in poor African-American men in the South • Patients weren’t told they had the disease and were excluded from receiving treatment even after the US Public Health Service began using penicillin in 1943 • Study stopped in 1972 after 100 patients (25%) had died from disease • US government settled out of court for $10 million • President Clinton issued formal apology in 1997

  7. HistoryRegulatory Guidelines • 1947: Nuremberg Code • Established conditions for the ethical conduct of research involving human subjects, with an emphasis on voluntary consent • 1964: Declaration of Helsinki (DoH) • Ethical guidelines for physicians engaged in research • Independent review of protocol, consent by legal guardian • 1979: Belmont Report • Set boundaries between research and practice • Principles: Respect for persons, beneficence, justice

  8. HistoryRegulatory Guidelines • 1982: International Ethical Guidelines for Biomedical Research Involving Human Subjects • Application of DoH in developing countries • Community health priorities, compensation for injury • 1991: Common Rule (Title 45, Part 46 of CFR) • Applies to research or institutions receiving federal funds • Oversight for DHHS provided by OHRP • Guidelines for informed consent, IRB composition and review, plus subparts for research on fetuses, pregnant women, prisoners, children • Also issued by FDA in 21 CFR parts 50 and 56

  9. HistoryRegulatory Guidelines • 1996: Good Clinical Practice (GCP) • Unified standard for conduct of human clinical trials in EU, Japan, US • Should be followed when generating clinical data for submission to these authorities • Adopted by FDA in 1997 • 2001: EU Clinical Trials Directive • Streamline administrative process for clinical trials in EU

  10. HistoryRecent Human Subjects Research Cases • Univ. of Pennsylvania: Sept. 17, 1999 death of Jesse Gelsinger • Phase I gene ‘therapy’ study for OTCD • Jesse died of multiple organ failure 4 days after adenovirus was first injected into his liver • First death ever directly attributable to gene therapy • Investigation by FDA and OHRP (OPRR) found: • Did not adhere to inclusion/exclusion criteria • Inadequate SAE reporting to IRB and NIH • Insufficient consent – never informed subjects of animal deaths • Conflict of interest for PI, James Wilson, and Penn • FDA shut down gene therapy trials at Penn and elsewhere • Undisclosed civil suit

  11. HistoryRecent Human Subjects Research Cases • Johns Hopkins: June 2, 2001 death of Ellen Roche • Physiological study funded by NIH and designed to test how healthy volunteers vs. asthma patients recover from lung constriction • Ellen died of multiple organ failure after one dose of hexamethonium • Investigation by FDA and OHRP (OPRR) found: • Failure to submit IND • Subjects not informed of experimental nature of drug and risks • Failure to gain IRB approval of protocol amendment • Lack of documentation for IRB meetings • On July 19, OHRP suspended all federally-funded research for 3 days • Hopkins agreed to re-review all 2,000+ studies, create additional IRBs, further educate IRB members and researchers

  12. HistoryRecent Human Subjects Research Cases • Albany VAMC: March 15, 2002 death of Carl Steubing • Stomach cancer drug study funded by Aventis • VAMC paid $5,000 per subject • Paul Kornak altered blood results so Mr. Steubing could be enrolled in the study, even though his kidney and liver function were impaired • The subject died due to complications from experimental drug • In 2005, Kornak was convicted of criminally negligent homicide and sentenced to 71 months in jail • Altered records for at least 27 patients from 1999 – 2002 • Kornak had no valid medical license • VA instituting new oversight mechanisms and obtaining independent accreditation for all human research sites

  13. HRC 101 Human Subjects Compliance in Bioethics

  14. Human Subjects Compliance in BioethicsWhat is Bioethics? • Webster’s Dictionary (http://www.websters.com) • The study of the ethical and moral implications of new biological discoveries and biomedical advances, as in the fields of genetic engineering and drug research. • Cancerweb (http://cancerweb.ncl.ac.uk/) • Branch of ethics, philosophy and social commentary that discusses the life sciences and their potential impact on our society. • Discipline which examines the relationship between biology, science, and medicine and ethics, philosophy, and theology.

  15. Human Subjects Compliance in BioethicsWhat is Bioethics? Cloning Human subjects research Life support Stem cell research Allocation of public health resources Genetic testing Organ donation Genetically modified foods Genetic engineering Animal rights Conflicts of interest Tissue banking Assistedsuicide In vitro fertilization Health care access

  16. Human Subjects Compliance in BioethicsBackground in Philosophy • Ethical issues arise when moral dilemmas raise questions that cannot be answered with a simple rule • Moral philosophy outlines social conventions of what is right and wrong • Most of us do not subscribe to strictly one philosophy but rather are pragmatic in our approach

  17. Human Subjects Compliance in BioethicsMoral Philosophies • Deontology (Immanuel Kant) • Rights and duty-based system of analysis • Perfect duties – obligatory actions (don’t lie, don’t steal, etc.) • Imperfect duties – permissible actions (be kind, give to others, etc.) • May act on motives other than duty, but duty must be the primary motive in order for something to be morally worthy • Pros: recognizes sanctity of every human being • Cons: catastrophic clause, duties often conflict

  18. Human Subjects Compliance in BioethicsMoral Philosophies • Utilitarianism (Jeremy Bentham, John Stuart Mill) • An act/rule is morally right in proportion to the happiness it promotes • Decisions made by applying cost-benefit analysis to the situation • ‘Greatest good for the greatest number’ is morally desirable • Happiness defined as societal, not individual, good • Pros: simple, practical, and intuitive • Cons: sacrifice of a few to benefit many, motivation is irrelevant • Principlism (Belmont Report, Tom Beauchamp, James Childress) • Four principles arise from theory of common morality: respect for autonomy, non-maleficence, beneficence, justice (distributive) • Pros: easy to understand, practical • Cons: principles conflict all the time, why only 4 principles

  19. Human Subjects Compliance in BioethicsMoral Philosophies • Casuistry (Albert Jonsen, Stephen Toulmin) • Case-based reasoning: determine answers to moral dilemmas by drawing parallels to agreed upon paradigms • Pros: same reasoning is the basis of common law • Cons: idea of building knowledge has flaws, problem of interpretation • Virtue Ethics (Aristotle) • Emphasize virtuous character of the individual rather than the act • “Virtue is doing something at the right time for the right reason” • Pros: acknowledges role of inner character in ethical decision-making • Cons: lack of principles to help determine action, virtues conflict

  20. Human Subjects Compliance in BioethicsResearch Ethics Quotes • “Experiments that can only have harmful results are forbidden; those that are harmless are permitted; those that can do good are obligatory.” • Claude Bernard, 1860s • “An experiment is ethical or not at its inception; it does not become ethical post hoc – ends do not justify means.” • Henry Beecher, 1966 • “Obtaining informed consent does not ensure ethical research…” • Ezekiel Emanuel, 2000

  21. Human Subjects Compliance in Bioethics7 Requirements for Ethical Research • Social Value • Must lead to improvements in health or advancements in general knowledge • No value: not generalizable, duplicative, results not disseminated • Scientific Validity • Must be conducted in methodical and practical manner • No validity: underpowered, biased endpoints, unable to enroll • Fair Subject Selection • Science, not vulnerability or privilege, should guide inclusion / exclusion criteria • Should not exclude a group without a specific scientific reason

  22. Human Subjects Compliance in Bioethics7 Requirements for Ethical Research • Favorable risk-benefit ratio • Risks and benefits include physical, psychological, social, economic • If risks outweigh benefits, must be evaluated against benefit to society • Independent Review • Minimizes conflicts of interest and potential for harm to subjects • Informed Consent • Ensure individuals control whether they enroll in clinical research • Ensure the research is consistent with their values and preferences • Respect for Human Subjects • Ways to accomplish this: respect privacy, allow withdrawal without penalty, inform subjects of relevant new data, provide care if injured, and inform subjects of study results

  23. Human Subjects Compliance in Bioethics9 Problems with Clinical Research Inadequate informed consent • Many patients are too vulnerable • Power of physician’s opinion • Poor, uneducated, fearful • Difficulties with communication • Language barriers • Therapeutic misconception • Issues of competency • ~10% of US population is mentally ill • Another 5% is illiterate

  24. Human Subjects Compliance in Bioethics9 Problems with Clinical Research Inadequate oversight • IRBs/ECs don’t currently manage quality of consent process • Instead, labor extensively over consent form • Lack of auditing • IRBs/ECs typically only receive annual updates • May not be provided with critical safety/efficacy data from Data Safety Monitoring Boards (DSMBs) • Incomplete reporting and validation of adverse events • Patients have a disincentive to report AEs • Difficult to confirm relationship of AEs to drug

  25. Human Subjects Compliance in Bioethics9 Problems with Clinical Research Inadequate research ethics • Unfair subject recruitment • Research burden unfairly placed on poor because they are drawn to free care • Phase I studies unjustified • Never ethical to subject people to risk for no benefit • Significance of the last patient • Ethically speaking, noone should be the last patient because you usually already know the answer to the question and are just trying to achieve statistical significance • Avoid this problem through blinding

  26. Human Subjects Compliance in Bioethics9 Problems with Clinical Research  Rectified • Visual informed consent • CD rom or video presented by objective party • Nurse oversight of consent process • Split responsibilities of IRBs/ECs and DSMBs/Protocol Review Committees (PRCs) • IRBs/ECs focus on quality of consent, auditing, and institutional compliance with protocol and regulations • DSMBs focus on safety and efficacy monitoring • Use local IRBs for Phase I or non-randomized, small Phase II studies • National IRB/EC • Require subject advocates

  27. HRC 101 Case Studies

  28. Case Study #1Phase I Trial Compensation Healthy volunteers are typically paid for participating in a Phase I clinical trial. Cancer patients are not paid for participating in a Phase I clinical trial, even though the expectation of benefit is very small (response rate < 5%). • Should Phase I cancer or any other research subjects be paid for their participation? • If yes, why and how much? • If no, why not? • Do you think paying subjects will have any effect on their expectations from the research?

  29. Case Study #2Pharmacogenetics in Application Herbie participated in a prostate cancer study in which he donated a blood sample for pharmacogenetic testing. After a few months of research on his and other samples, it was discovered that Chinese men like Herbie don’t respond well to the study drug because of the presence of a SNP that interferes with drug absorption. The sponsoring company plans to proceed with a Phase III study in which men of Chinese descent are excluded. • Is this trial design fair and/or acceptable? • If follow-up data showed that individuals with this SNP were also more likely to develop a secondary cancer, should Herbie and other patients be notified? • Should we worry that as drugs become more tailored to specific populations, the healthcare of minority populations could suffer?

  30. Case Study #3HIV Vaccine Study Scientists develop a vaccine that is aimed at two of the most common strains of the HIV virus. They would like to test this vaccine in 10,000 healthy volunteers, including 5,000 in the US and 5,000 in Thailand. • Is it appropriate to test an HIV vaccine in healthy volunteers? • Is it appropriate to have a control group? • Should there be any procedural / ethical differences for testing the vaccine in Thailand vs. testing in US?

  31. Helpful ResourcesRegulatory Guidelines • Nuremberg Code (http://ohsr.od.nih.gov/guidelines/nuremberg.html) • Declaration of Helsinki (http://www.wma.net/e/policy/pdf/17c.pdf) • Belmont Report (http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.htm) • International Ethical Guidelines for Biomedical Research Involving Human Subjects (http://www.cioms.ch/frame_guidelines_nov_2002.htm) • Common Rule (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm) • Good Clinical Practice (http://www.fda.gov/cder/guidance/959fnl.pdf) • EU Clinical Trials Directive (http://europa.eu.int/eur-lex/pri/en/oj/dat/2001/l_121/l_12120010501en00340044.pdf)

  32. Helpful ResourcesOther Reference Websites • Bioethics.net (http://www.bioethics.net), American Journal of Bioethics • Weekly news updates sent via email • American Medical Association Ethics (http://www.ama-assn.org/ama/pub/category/2416.html) • AMA Code of Medical Ethics, policies, resources, and case studies • Wellcome Trust (http://www.wellcome.ac.uk) • Bioethics Library (http://bioethicsweb.ac.uk) • President’s Council on Bioethics (http://www.bioethics.gov) • Includes reports from current and past councils • Public Agenda.org (http://www.publicagenda.org/issues/frontdoor.cfm?issue_type=medical_research) • Facts and public opinion polls regarding medical research issues

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