Managing Your Research Hat While Wearing Your Clinical Hat Thomas J. J. Blanck, MD, PhD

1. NYU School of Medicine HRPP PI Lecture Series Managing Your Research Hat While Wearing Your Clinical Hat Thomas J. J. Blanck, MD, PhD IRB Chairman NYU SoM PI Lecture Series 2010

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3. Tuskegee Study of Untreated Syphilis • 400 African Americans. • 1932-1972. • Sponsored and supported by the USPHS ultimately forming the CDC. • Exposed in lay literature. • 20% increase in mortality. NYU SoM PI Lecture Series 2010

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5. “The men’s status did not warrant ethical debate. They were subjects not patients; clinical material, not sick people.” 1976 quote from the 1943-1948 PHS Director of Venereal Diseases NYU SoM PI Lecture Series 2010

6. President Clinton 1997 Apology for Tuskegee Study So today America does remember the hundreds of men used in research without their knowledge and consent. We remember them and their family members. Men who were poor and African American, without resources and with few alternatives, they believed they had found hope when they were offered free medical care by the United States Public Health Service. They were betrayed. Medical people are supposed to help when we need care, but even once a cure was discovered, they were denied help, and they were lied to by their government. Our government is supposed to protect the rights of its citizens; their rights were trampled upon. Forty years, hundreds of men betrayed, along with their wives and children, along with the community in Macon County, Alabama, the City of Tuskegee, the fine university there, and the larger African American community. NYU SoM PI Lecture Series 2010

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8. War Crimes • A) High-Altitude ExperimentsB) Freezing ExperimentsC) Malaria ExperimentsD) Lost (Mustard) Gas ExperimentsE) Sulfanilamide ExperimentsF) Bone, Muscle, and Nerve Regeneration and Bone Transplantation ExperimentsG) Sea-Water ExperimentsH) Epidemic Jaundice ExperimentsI) Sterilization ExperimentsJ) Spotted Fever (Fleckfieber) ExperimentsK) Experiments with PoisonL) Incendiary Bomb Experiments NYU SoM PI Lecture Series 2010

9. Nuremberg Code 1947 • Informed Consent of Volunteers must be obtained without coercion. • Human experiments should be based upon prior animal experiments. • Anticipated scientific results should justify the experiment. • Only qualified scientists should conduct medical research. • Physical and mental suffering and injury should be avoided. • There should be no expectation of death or disabling injury. NYU SoM PI Lecture Series 2010

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11. Human Radiation Experiments • 1993 Albuquerque Tribune • Under government sponsorship researchers at several major universities had injected plutonium into subjects. • 1993 Congressional report • describes 13 cases of intentional release of radiation for government experiments. • 2000-2010 CDC LAHDRA review. • “LANL operations have not proceeded without health hazards or environmental impacts,” the interim report reads. “Approximately 30 people have been killed in incidents including criticality experiments and accidents with high explosives. Significant quantities of plutonium, uranium, and a wide variety of other toxic substances have been processed and released to the environment in quantities that in some cases are not well known.” NYU SoM PI Lecture Series 2010

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13. Willowbrook Study • State school for the mentally challenged. • Overcrowded. • 100% development of Hepatitis A within 6 months. • PI Dr Saul Krugman. • Pediatric subjects injected with hepatitis virus along with treatment with gamma globulin. NYU SoM PI Lecture Series 2010

14. Krugman's Defense • There was no additional risk for the subjects. Under the normal conditions at the institution the subjects would have been exposed to the same strains of hepatitis. • Experimental subjects had a lowered risk of complications since they were housed in a special unit where there was little danger of exposure to other diseases. • Experimental subjects had the chance of benefiting from immunization. • Experimental subjects were obtained only with informed consent from parents. NYU SoM PI Lecture Series 2010

15. Informed Consent • A description of any reasonably foreseeable risks or discomforts to the subject. • Participation is voluntary without negative consequences if you don’t participate. NYU SoM PI Lecture Series 2010

16. Letter to the Parents Willowbrook State School Office of the Director Staten Island, New York November 15, 1958 Dear_______________: We are studying the possibility of preventing epidemics of hepatitis on a new principle. Virus is introduced and gamma globulin given later to some, so that either no attack or only a mild attack of hepatitis is expected to follow. This may give the children immunity against this disease for life. We should like to give your child this new form of prevention with the hope that it will afford protection. Permission form is enclosed for your consideration. If you wish to have your child given the benefit of this new preventative, will you so signify by signing the form.  Sincerely, H. H. Berman, MD Director NYU SoM PI Lecture Series 2010

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18. "An experiment isethical or not at its inception. It does not become ethicalpost hoc — ends do not justify means." Henry K. Beecher, “Ethics and Clinical Research” NEJM 274:1354-60 (1966). NYU SoM PI Lecture Series 2010

19. Ethical Principles & Guidelines for Research Involving Human Subjects National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research 1979 NYU SoM PI Lecture Series 2010

20. The Belmont Report A. Boundaries Between Practice and Research • Doctor/Patient • Investigator/Subject B. Ethical Principles • Respect • Justice • Beneficence NYU SoM PI Lecture Series 2010

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22. www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm Code of Federal Regulations TITLE 45PUBLIC WELFARE DEPARTMENT OF HEALTH AND HUMAN SERVICES PART 46PROTECTION OF HUMAN SUBJECTS [PDF 215 KB] * * * Revised January 15, 2009Effective July 14, 2009 * * * NYU SoM PI Lecture Series 2010

23. Henry K. Beecher, “Ethics and Clinical Research” NEJM 274:1354-60 (1966). “ A far more dependable safeguard than consent is the presence of a truly responsible investigator.” NYU SoM PI Lecture Series 2010

24. Hierarchy of Research The PI is the leader of the research team. NYU SoM PI Lecture Series 2010

25. PI as Leader of the Research Team • Primarily responsible for safety of subjects. • Responsible for the conduct of objective research that generates independent, high quality and reproducible results. • Responsible for management and integrity of research design. • Responsible for direction and oversight of compliance. NYU SoM PI Lecture Series 2010

26. Co-I and Research Staff • PI delegates responsibility for some of the daily research tasks. • Research Team is responsible to report to the PI all AE’s and SAE’s – the PI determines relationship and causality. • Research Team reports to the PI on all aspects of the project. NYU SoM PI Lecture Series 2010

27. What is the Human Research Protection Program? The Mission of the HRPP is to protect the rights and welfare of subjects. NYU SoM PI Lecture Series 2010

28. A Collaborative Relationship The ability of the PI to work with HRPP and for HRPP to support the PI is critical for the safety of research subjects and for the successful completion of research. NYU SoM PI Lecture Series 2010

29. Doctor/Patient Relationship • “Practice” refers to interventions that are designed solely to enhance the well-being of an individual patient or client. • Reasonable expectation of success • Purpose of practice is to provide diagnosis, preventive treatment or therapy • Treatments based on standards of care NYU SoM PI Lecture Series 2010

30. Doctor/Patient Relationship Refer to the person you care for as your PATIENT NYU SoM PI Lecture Series 2010

31. Definition of Human Subject An individual about whom an investigator conducting research obtains • Data through intervention or interaction • Identifiable private information NYU SoM PI Lecture Series 2010

32. Investigator/Subject • “Research” - an activity designed to test an hypothesis, permits conclusions to be drawn, and thereby to develop or contribute to generalizable knowledge. • New procedures which are presented in the form of a research protocol – deviate from the “standard of care”. NYU SoM PI Lecture Series 2010

33. Investigator/Subject • Research often presents no direct benefit to subject. • Often hypothesis/protocol are conducted on healthy volunteers. • Research may have unknown risks and could place subject in some harm – mostly of the unknown. NYU SoM PI Lecture Series 2010

34. Investigator/Subject Relationship Refer to the person in a study As your SUBJECT NYU SoM PI Lecture Series 2010

35. The Clinician and Investigator • Maintaining both roles. • Keeping the disparate goals of practice and research in mind. • Complicated because of your relationship with your patients. • Important to separate your roles. NYU SoM PI Lecture Series 2010

36. What Happens When The Lines of Research and Practice Blur? • Tenets of research may be forgotten. • Researchers do not follow protocols. • Human Subjects may not be protected. • Subject risks are not minimized. • OHRP and FDA perform audits • Determination Letters are sent • Human Subject Research is interrupted…….. NYU SoM PI Lecture Series 2010

37. Office for Human Research Protections (OHRP) Compliance Oversight Overview • OHRP's Division of Compliance Oversight (DCO) reviews institutional compliance with federal regulations 45 CFR 46. • DCO evaluates all written substantive complaints. If complaints arise regarding an institution's human subject protection practices, OHRP opens a formal evaluation. • During the course of an evaluation DCO issues findings of noncompliance in the form of determination letters. NYU SoM PI Lecture Series 2010

38. PI OHRP Inspection NYU SoM PI Lecture Series 2010

39. OHRP Inspection NYU SoM PI Lecture Series 2010

40. OHRP Determination Letter Scottsdale Healthcare March 2009 Research Project: Molecular and Genomic Rationale for Adjunctive Hyperbaric Oxygen Therapy of Selected Crush Injuries Using DNA Microarray Analysis (CRUSH Study) and HOLLT Study Principal Investigator: Dr. Dennis Weiland “the HOLLT Study was to be a retrospective chart review. (PI) enrolled subjects into the “full” HOLLT study (a randomized controlled trial of hyperbaric oxygen in lower limb trauma) by using an altered CRUSH study consent form. informed consent was not appropriately documented by a written consent form reviewed and approved by the IRB NYU SoM PI Lecture Series 2010

41. OHRP Determination Letters Oklahoma Health Science Center Human Research Project: A Phase III Study for the Treatment of Children and Adolescents with Newly Diagnosed Low Risk Hodgkin Disease Principal Investigator: Rene McNall, M.D. (d). informed consent documents …..failed to include a complete explanation of the purposes of the research and identification of procedures which were experimental ….. (2) A complainant alleged, and we determine, that the informed consent document for this study failed to include an adequate description of any reasonably foreseeable risks and discomforts,… (4) the investigator implemented the following changes without first obtaining IRB review and approval …… NYU SoM PI Lecture Series 2010

42. OHRP Determination Letter Mt. Sinai Medical Center, Miami FL. May 27, 2009 Research Project: Trial to Assess Chelation Therapy (TACT) Principal Investigator: Gervasio A. Lamas, M.D. TACT protocol specified that infusions should be completed in no less than three hours to allow for safe infusion rates “whether any of the infusions that took less than three hours were completed infusions and explain why they were completed in less than three hours infusions identified in your review were associated with unanticipated problems involving risks to subjects. NYU SoM PI Lecture Series 2010

43. OHRP Determination Letters Howard University Research Project: Genetics of Early-Onset Depression Principal Investigator: William Lawson, MD HHS Protocol Number: 5R01MH075131 • HHS regulations at 45 CFR 46.116 We determine that the investigator initiated human subject research without obtaining legally effective informed consent of subjects and without the IRB appropriately waiving these requirements. • HHS regulations at 45 CFR 46.116(a) We determine that the informed consent documents reviewed and approved by the IRB for this study failed to include a description of any reasonably foreseeable risks and discomforts … • the protocol indicates that one of the risks of the research is violation of confidentiality which could be embarrassing to subjects and their relatives or could damage a subject’s reputation. We cannot locate this information in the informed consent document. NYU SoM PI Lecture Series 2010

44. OHRP Determination Letter to JHH Research Project: Mechanisms of Deep Inspiration-Induced Airway Principal Investigator: Dr. Alkis Togias July 2001 HHS Project Number: R01 HL61277 (Principal Investigator: Dr. Solbert Permutt) OHRP finds that the JHBMC IRB and the investigators conducting the research failed to ensure that risks to subjects were minimized and reasonable, as required by HHS regulations at 45 CFR 46.111(a)(1) and (2) Researchers did not do thorough literature review. Side effects in initial subject overlooked and not reported to the IRB. Side effects at another site in earlier clinical study not revealed in its publication. Result: • Federal research at Johns Hopkins suspended. • IRB structure and review process revamped. NYU SoM PI Lecture Series 2010

45. 1999 FDA investigation University of Pennsylvania • the scientists involved in the trial broke several rules of conduct • Inclusion of subject as a substitute for another volunteer who dropped out, despite having high ammonia levels that should have led to his exclusion from the trial • Failure by the university to report that two patients had experienced serious side effects from the gene therapy • Failure to mention the deaths of monkeys given a similar treatment in the informed consent documentation. NYU SoM PI Lecture Series 2010

46. FDA Warning Letter to Dr. Wilson at U of Pennsylvania “Notice of Initiation of Disqualification Proceeding and Opportunity to Explain” Dear Dr. Wilson …you failed to fulfill the responsibilities of a clinical investigator …you have repeatedly or deliberately violated regulations governing the proper conduct of clinical studies NYU SoM PI Lecture Series 2010

47. FDA Letter to Dr. Wilson • Failure to fulfill the general responsibilities of Investigator …you signed the FDA Form 1572, Statement of Investigator, in which you agreed to conduct the study in accordance with the protocol and applicable regulations. as the clinical investigator you were responsible for all aspects of the study. A. You failed to adequately protect the safety and welfare of subjects You failed to abide by the safety provisions required in the protocol You enrolled subjects who were not eligible You failed to obtain proper IRB approval for …modifications B. You failed to adequately protect the rights of subjects… NYU SoM PI Lecture Series 2010

48. FDA Letter to Dr. Wilson • Failure to ensure that an investigation is conducted according to the investigational plan …..you did not submit these protocol versions to FDA and they were therefore not part of the approved investigational plan. A. You did not follow the protocol requirement to stop the studyas described in protocol…”If a single patient develops Grade III or higher toxicity, the study will…be halted. B. Subjects who failed to meet eligibility criteria were allowed to participate in the clinical trial. Subjects were administered the investigational vector even though they should have been excluded. C. You did not perform protocol-required tests. NYU SoM PI Lecture Series 2010

49. FDA Letter to Dr. Wilson • You failed to assure that the Institutional Review Board would be responsible for the initial and continuing review of the clinical study by failing to submit accurate reports regarding the safety of the study. 4. You failed to accurately and completely identify changesto the research activity for Institutional Review Board review and evaluation. 5. Failure to obtain informed consent. 6. Failure to maintain adequate case histories of individuals treated with investigational drug. NYU SoM PI Lecture Series 2010

50. Requirements for IRB Approval (1) Risks to subjects are minimized. (2) Risks are reasonable . (3) Selection of subjects is equitable. (4) Informed consent sought from each prospective subject or legally authorized representative. (5) Informed consent will be appropriately documented. (6) Research plan makes adequate provision to monitor data to ensure subject safety . (7) There are adequate provisions to protect subject privacy and maintain data confidentiality . NYU SoM PI Lecture Series 2010