Evolving Research Regulation Advanced IRB Training- October 2006

1. Evolving Research RegulationAdvanced IRB Training- October 2006 Arthur O. Anderson MD

2. Objectives During this lecture you will: • Trace development of ethical principles for research involving human subjects from 1900 to the present. • Learn that both controversy and prior planning contributed to development of standards for ethical research involving human subjects. • Learn about specific milestone events that resulted in laws and regulations that protect the rights and safety of human research volunteer subjects

3. Human Research Regulation Evolution: Proactive Vs Reactive • Proactive Regulation: • Regulations that anticipate and minimize risk are part of comprehensive planning by commissions exploring future research intentions by institution • Reactive Regulation: • Regulations that follow legal action because of wrong doing by Dr, PI, Industry, Agency, etc

4. Yellow Fever Commission Cuba 1900 Yellow Fever 1st Consent Form. Army Surgeon General George M. Sternberg “Risk to the individual may be taken with his consent and full knowledge of the circumstances, as has been done in scores of cases, and we cannot honor too highly the bravery of such men as the soldiers who voluntarily submitted to the experiments on yellow fever in Cuba under the direction of Reed and Carroll.” * William Osler 1908 presentation on animal research vs antivivisectionists. Major Walter Reed Hospital Corps Detachment at Camp Columbia, Havana, Cuba, September 1900 served as YF research subjects

5. Laws and Regulations needed to assure Safe Drugs and Biologics • Prompted by Legal Action • malfeasance in manufacturing & marketing • 1902Biologics Control Act. • ensured purity and safety of serums, vaccines, and other biologic products for disease prevention and treatment. • 1906 Food and Drugs Act. • Regulated label content. • 1938 Food Drug and Cosmetic Act. • Drugs must be proven safe before marketing, one of new rules.

6. 1939U.S. Unprepared For BWThe folks in this photo are Europeans U.S. Concerned About The Possibility That The Nazis Were Preparing For BioWarfare As Entry into WW II Approaches

7. BW Threat & Start of WW II • 1939 Japanese scientists attempt to obtain virulent yellow fever virus from the Rockefeller university, but it was thwarted by scientists • 1941 War Department asks NAS WBC to report on Threat of BW and recommend actions. • 1942 WRS under George Merck Jr. created in FSA for Offensive and Defensive BW Effort

8. WW II - Soldier Deployment: Yellow Fever Vaccine Incident • A Yellow Fever vaccine developed by AEB was given to seven million deploying US troops January 1942. • By March 1942 tens of thousands of soldiers had hepatitis and scores died. (WRS-CMR and AEB Investigated). • The vaccine had been given to protect them against possible biologic attack, but it was contaminated with non-A Hepatitis viruses in human source materials. • 1944 Public Health Service Act is passed: • regulation of biologics and control of communicable diseases

9. Influenza Vaccine - WW II Soldier Deployment: • Army Commission determined that the Influenza pandemic of 1918 was amplified by troop movements during World War I. • The AEB Influenza Commission gave an experimental Flu Vaccine to 7 million soldiers deploying for WWII. • This was a successful venture, and Flu vaccine was approved by the UPHS in 1944 with this data Memory of the millions of deaths from influenza and pneumonia during World War I haunted the founders of the AFEB

10. Nuremberg War Crimes Trial - 1947 • By 1947 Andrew Ivy’s list of ten conditions required for permissible medical experiments in healthy subjects became the Nuremberg Code. • The Code became the standard measure of ethical conduct in research involving human subjects. 23 Nazi Doctors were convicted of Murder at The Nuremberg Trials

11. Nuremberg Code of 1947 1. Voluntary Consent of subject is absolutely essential* 2. Valid research for good of society – unprocurable by any other means and not random or unnecessary in nature 3. Human studies must be preceded by survey of existing knowledge and research with animal models to identify validity of approach and potential risks and benefits 4. Avoid unnecessary physical and mental suffering & injury 5. Prohibits research with apriori risk of death or disabling injury, except if physician scientist also volunteers 6. Degree of risk never to exceed that determined by the humanitarian importance of the problem to be solved 7. Prepare to minimize risk of injury, disability or death 8. Investigator must have credentials appropriate to study 9. Subjects must have freedom to withdraw 10. Scientist may terminate study to reduce serious risk

12. Nuremberg Code of 1947 - What is Voluntary Consent? *Voluntary Consent included this appended paragraph which defines what is needed for it to be voluntary • This means that the person involved should have legal capacity to give consent; should be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, over-reaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision. • This latter element requires that before the acceptance of an affirmative decision by the experimental subject there should be made known to him: the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; all inconveniences and hazards reasonably to be expected; and the effects upon his health or person which may possibly come from his participation in the experiment.

13. Wilson Memorandum of 1953 The Nuremberg Code* was incorporated into the Wilson Memorandum to the Secretaries of the Army, Navy and Air Force dated 26 Feb 1953 * Use of its principles was promoted before non-clinical research experiments related to warfare defense were planned and conducted Army Directive CS-385 issued 30 June 1953 added consent in writing, additional safeguards, and instructions for compensating subjects for injuries resulting from participation in research

14. FDA Historic Milestones • 1953 Federal Security Agency becomes Department of Health, Education, & Welfare (HEW). • Factory Inspection Amendment clarifies previous law and requires FDA to give manufacturers written reports of conditions observed during inspections and analyses of factory samples. • 1955 The Division of Biologics Control became an independent entity within the NIH, after polio vaccine thought to have been inactivated is associated with about 260 cases of polio.

15. 1955 Start of Operation Whitecoat: Aerosol Human Efficacy Studies Q-fever and Tularemia were approved for these studies because safety criteria were met and cure was assured.

16. FDA Milestone • Kefauver-Harris Drug Amendments passed in 1962 to ensure drugs tested for greater safety and for efficacy as well • For the first time, drug manufacturers required to prove to FDA the efficacy of their products before marketing them.

17. Declaration Of Helsinki 1964 • Distinguished between Medical Practice and Research, and between therapeutic and non-therapeutic research. • Allowed “compassionate use” of test agent. • Provided remedies to bans on use of minors, sick people, and impaired persons in research if conditions met. • It described those conditions for Medical Research combined with patient care and for non-therapeutic research.

18. Major Regulatory Milestones • 1972 Regulation of biologics (serum, vaccine, blood). • regulatory function is transferred from NIH to FDA • 1972 Title 10 USC 980 in DOD Appropriations bill • 1976 Medical Device Amendments passed to ensure safety and effectiveness of medical devices, including diagnostic products.

19. USPHS Tuskegee Syphilis Study Scandal of 1972 Led To New Regulations: • National Research Act of 1974 requiring new regulations for protection of human subjects • Informed consent requirements • Review of research by IRBs • Created the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research • 1979: National Commission wrote the “Belmont report” …45 CFR 46

20. Belmont Report - 1979 • Boundaries Between Practice and Research • Basic Ethical Principles • Respect for Persons • Beneficence • Justice (benefits & burdens equitably distributed) • Applications • Informed Consent • Assessment of Risk and Benefits • Selection of Subjects

21. BENEFICENCE JUSTICE RESPECT FOR PERSONS Privacy & ConfidentialityProtection of subjects (especially vulnerable populations) Informed consent Surrogate consent Assent IRB Decision Matrix Subject selection Inclusion/exclusion Recruitment Risk/Benefit Analysis Experimental Design Qualifications of PI J. Cooper, Albany Medical Center

22. The Common Rule - 1981 • 1981: DHHS & FDA published convergent regulations based on Belmont principles • 1991: 17 federal departments & agencies agreed to adopt the basic human subject protections • All federally sponsored research covered by a common set of protective mechanisms • Review of research by an IRB • Informed consent of subjects • Institutional assurances of compliance

24. FDA Historic Milestones • 1987 Investigational Drug Regulations Revisedto expand access to experimental drugs for patients with serious diseases with no alternative therapies. (Fast Track System – AIDS activists) • 1988 Food and Drug Administration Act establishes FDA as an agency of DHHS with a Commissioner of Food and Drugs appointed by the President with the advice and consent of the Senate, and broadly spells out the responsibilities of the Secretary and the Commissioner for research, enforcement, education, and information.

25. President’s Advisory Committee On Human Radiation Experiments (ACHRE) • Created by Clinton in 1994 to investigate reports of federally sponsored human research involving radioactive materials & to assess current human subjects protections • Issues raised by ACHRE • Variability in the quality of IRBs • Confusion among human participants as to whether they were involved in research or therapy • Insufficient attention to implications of diminished decision-making capacity in the consent process • Need for national advisory group to study the issues

26. IRBs - Time for Reform: NIH Office of Inspector General – June 1998 • Institutional review boards (IRBs) . . . • Review too much, too quickly, and often lack expertise. • Have a problem with continuing reviews. • Provide inadequate education for. • IRB members. • Researchers. • Research support staff. • Conflicts within organizations affect the independence of the IRBs. • IRBs are under stress & their human subject protection work is compromised.

27. USAMRIID

28. OHU&E Arthur O. Anderson MD Chief,Office of Human Use and Ethicsart@artandersonmd.com