2013 evolution of irb regulations 1900 - 2002 bioshield-36


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2013 evolution of irb regulations 1900 - 2002 bioshield-36

  1. 1. Biological Threat Reduction Biological WeaponsProgram Proliferation Prevention Program Evolving Research Regulation Advanced IRB Training- 27 February 2013 Arthur O. Anderson MD This presentation represents the views of the author. The information or content presented does not represent the official position or policy of the U.S. Army Medical Research and Materiel Command, the U.S. Army Medical Department, the Department of Defense, or the U.S. Government. 1 PR-13-015 Biological Weapons Proliferation Prevention Program
  2. 2. ObjectivesDuring this lecture you will:1. Trace development of ethical principles for research involving human subjects from 1900 to the present.2. Learn that both controversy and prior planning contributed to development of standards for ethical research involving human subjects.3. Learn about specific milestone events that resulted in laws and regulations that protect the rights and safety of human research volunteer subjects Biological Threat Reduction Biological Weapons 2 2 ProliferationProgram Program Prevention
  3. 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 Biological Threat Reduction Biological Weapons 3 3 ProliferationProgram Program Prevention
  4. 4. Yellow Fever Commission Cuba 1900 Yellow Fever 1st Consent Form.Army Surgeon GeneralGeorge 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 ReedMajor Walter Reed Hospital Corps Detachment at Camp Columbia, Havana, and Carroll.” Cuba, September 1900 served as YF research subjects * William Osler 1908 presentation on animal research vs antivivisectionists. Biological Threat Reduction Biological Weapons 4 4 ProliferationProgram Program Prevention
  5. 5. Laws and Regulations needed to assure Safe Drugs and Biologics Prompted by Legal Action  malfeasance in manufacturing & marketing 1902 Biologics 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. Biological Threat Reduction Biological Weapons 5 5 ProliferationProgram Program Prevention
  6. 6. 1939 U.S. Unprepared For BW The folks in this photo are EuropeansU.S. Concerned About The Possibility That The Nazis Were Preparing For BioWarfare As Entry into WW II Approaches Biological Threat Reduction Biological Weapons 6 6 ProliferationProgram Program Prevention
  7. 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 Biological Threat Reduction Biological Weapons 7 7 ProliferationProgram Program Prevention
  8. 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 Biological Threat Reduction Biological Weapons 8 8 ProliferationProgram Program Prevention
  9. 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 forMemory of the millions of WWII.deaths from influenzaand pneumonia during  This was a successful venture, andWorld War I haunted the Flu vaccine was approved by thefounders of the AFEB UPHS in 1944 with this data Biological Threat Reduction Biological Weapons 9 9 ProliferationProgram Program Prevention
  10. 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 ethical23 Nazi Doctors wereconvicted of Murder at conduct in research involvingThe Nuremberg Trials human subjects. Biological Threat Reduction Biological Weapons 10 10 ProliferationProgram Program Prevention
  11. 11. Nuremberg Code of 1947 1. Voluntary Consent of subject is absolutely essential*(see next) 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 withdraw10. Scientist may terminate study to reduce serious risk Biological Threat Reduction Biological Weapons 11 11 ProliferationProgram Program Prevention
  12. 12. Nuremberg Code of 1947 - What is Voluntary Consent? 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. The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity Biological Threat Reduction Biological Weapons 12 12 ProliferationProgram Program Prevention
  13. 13. Wilson Memorandum of 1953The Nuremberg Code* was incorporated into the WilsonMemorandum to the Secretaries of the Army, Navy and AirForce dated 26 Feb 1953* Use of its principles was promoted before non-clinical research experiments relatedto warfare defense were planned and conductedArmy Directive CS-385 issued 30 June 1953 added consentin writing, additional safeguards, and instructions forcompensating subjects for injuries resulting fromparticipation in research Biological Threat Reduction Biological Weapons 13 13 ProliferationProgram Program Prevention
  14. 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. Biological Threat Reduction Biological Weapons 14 14 ProliferationProgram Program Prevention
  15. 15. 1954 CD-22 & 1955 Operation Whitecoat: Start Aerosol Human Efficacy StudiesQ-fever and Tularemia were approved for these studies becausesafety criteria were met and cure was assured. Biological Threat Reduction Biological Weapons 15 15 ProliferationProgram Program Prevention
  16. 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. Biological Threat Reduction Biological Weapons 16 16 ProliferationProgram Program Prevention
  17. 17. Moral Dilemma: Comply with FDA law vs Intent to Benefit in BW Emergency 1962 Amendments to the FD&C Act requiring proof of efficacy of drugs and vaccines created a moral dilemma:  Risk killing subjects in a valid clinical trial, versus  Withholding potentially life saving drugs or vaccines because they lacked substantial evidence of human clinical efficacy Biological Threat Reduction Biological Weapons 17 17 ProliferationProgram Program Prevention
  18. 18. Exemptions in Paragraph 3 of AR 70-25: Create Double Edged Sword of Definitions3. Exemptions to AR 70-25 (26 March 1962). The following categories of activities and investigative programs are exempt from the provisions of these regulations:a. Research and non-research programs, tasks, and tests which may involve inherent occupational hazards to health or exposure of personnel to potentially hazardous situations encountered as part of training or other normal duties, e.g., flight training, jump training, marksmanship training, ranger training, fire drills, gas drills, and handling of explosives. *exposure to chemical agent , cabin decompression and A-bomb blast were “training exercises”b. That portion of human factors research which involves normal training or other military duties as part of an experiment, wherein disclosure of experimental conditions to participating personnel would reveal the artificial nature of such conditions and defeat the purpose of the investigation. *unethical LSD experiments tested vulnerability to espionage.c. Ethical medical and clinical investigations involving the basic disease process or new treatment procedures conducted by the Army Medical Service for the benefit of patients. *justified clinical trials, force health protection, experimental infections and vaccine efficacy. Biological Threat Reduction Biological Weapons 18 18 ProliferationProgram Program Prevention
  19. 19. 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. Biological Threat Reduction Biological Weapons 19 19 ProliferationProgram Program Prevention
  20. 20. 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. Biological Threat Reduction Biological Weapons 20 20 ProliferationProgram Program Prevention
  21. 21. USPHS Tuskegee Syphilis Study 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 Biological Threat Reduction Biological Weapons 21 21 ProliferationProgram Program Prevention
  22. 22. 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 Biological Threat Reduction Biological Weapons 22 22 ProliferationProgram Program Prevention
  23. 23. Common Rule Principles BENEFICENCE JUSTICE Risk/Benefit Analysis Subject selection Experimental Design Inclusion/exclusion Qualifications of PI Recruitment RESPECT FOR PERSONS Informed consent Privacy & Confidentiality Surrogate consent Protection of subjects Assent (especially vulnerable populations)J. Cooper, Albany Medical Center Biological Threat Reduction Biological Weapons 23 23 ProliferationProgram Program Prevention
  24. 24. 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 Biological Threat Reduction Biological Weapons 24 24 ProliferationProgram Program Prevention
  25. 25. Biological Threat Reduction Biological Weapons 25 25ProliferationProgram Program Prevention
  26. 26. FDA Historic Milestones 1987 Investigational Drug Regulations Revised to 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. Biological Threat Reduction Biological Weapons 26 26 ProliferationProgram Program Prevention
  27. 27. 1987 MOU with FDA Created Ethical and Legal Dilemma: Research vs Treatment Ability to use products labeled IND to benefit war fighter and laboratory personnel becomes less clear. From 1964 through 1987 MOUs with the FDA allowed DoD to Self-Exempt certain IND products from FDA requirements if they were to be used for treatment of warfighter, i.e. with “intent to benefit” not for generation of knowledge. Clinical Research with IND products to discover new treatment applications rigorously followed DoD and FDA requirements. Special Procedures was used for worker safety outside of clinical research format through 1989. Biological Threat Reduction Biological Weapons 27 27 ProliferationProgram Program Prevention
  28. 28. 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 Biological Threat Reduction Biological Weapons 28 28 ProliferationProgram Program Prevention
  29. 29. 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. Response is Guidance that Increases Regulatory Burden Biological Threat Reduction Biological Weapons 29 29 ProliferationProgram Program Prevention
  30. 30. USAMRIID Research Influenced by News Events and World Affairs 1979 Anthrax Research at USAMRIID re-started after the outbreak in Sverdlovsk, (Ekaterinburg). “Cold War” imperatives continued until 1989, and the fall of the Berlin Wall but new threats on the horizon. 1993+ Virology Research Spurred by Emerging Diseases and Global Travel Disease Transmission Risks. 1995 Aum Shinrikyo signaled that Bioterrorism was Emerging, prompting expansion development of Rapid Diagnostics, i.e. PCR & other Advanced Technologies. 1997 Global Disease Surveillance & Response Planning raised concerns about ability to comply with FDA Re: Use of IND/IDE products in pipeline for emergency use. Biological Threat Reduction Biological Weapons 30 30 ProliferationProgram Program Prevention
  31. 31. Domestic Bioterrorism: Changed Priorities  Bioterrorism in the US was no longer theoretical after 2001  DHS, was created for domestic security and countermeasures  R&D for Biodefense medical countermeasures under DHHS  Present Bioterrorism response resembles US response to Bio- Warfare threat during WW II Biological Threat Reduction Biological Weapons 31 31 ProliferationProgram Program Prevention
  32. 32. Ethical Dichotomy Intrinsic to National Biodefense Program: Emergency circumstances may affect outcomes of ethical analyses by weighting different values, thus favoring mitigating actions over cautionChoices: I. Respect the rights and welfare of subjects who participate in research designed to discover, validate and gain FDA marketing approval for products to be used in prevention and treatment of possible bioterrorism casualties. Versus: II. Urgent need to use unapproved products reasonably thought to be beneficial for protection from - or immediate treatment of bioterrorism when there is an emergency and no approved alternatives are available. Biological Threat Reduction Biological Weapons 32 32 ProliferationProgram Program Prevention
  33. 33. Ethical Analysis vs Rules & Laws HHS Common Rule Regulates Research  based on Ethical Principles but applied as Rules FDA Regulates Product  FD&CA Law & FDA regulates development, labeling, marketing and use of drugs, biologics & devices  FDA defines use of product labeled IND / IDE as Research irrespective of intended use Nuremberg Code provides principles that may be applied in Ethical Analyses for Biodefense Research Biological Threat Reduction Biological Weapons 33 33 ProliferationProgram Program Prevention
  34. 34. Project BioShield CDC, HHS & DoD may use HHS Project BioShield as specified in the following legislation:  Passed: H.R. 2122 Project Bioshield Act - July 16 2003  Passed: S. 15 Project BioShield Act - May 19 2004  President Signed : Public Law No: 108-276 July 21 2004  Presented: H.R. 4258 Rapid Pathogen Identification to Delivery of Cures Act - May 3, 2004 These legislative acts may resolve the dilemma associated with the need for widespread use of FDA-unapproved products in for national biodefense or war hazards when it is unethical to do FDA-mandated human clinical efficacy studies. 21 CFR Part 314.600-650 Additional legislation may be necessary to further define how these new laws will operate through existing agencies without damaging the fabric of regulation protecting the public from unsafe and ineffective drugs. Federal Food Drug and Cosmetic Act, section 564 (EUA) Biological Threat Reduction Biological Weapons 34 34 ProliferationProgram Program Prevention
  35. 35. USAMRIID Biological Threat Reduction Biological Weapons 35 35ProliferationProgram Program Prevention
  36. 36. OHU&E Arthur O. Anderson MDChief, Office of Human Use and Ethics artnscience@yahoo.com Biological Threat Reduction Biological Weapons 36 36 ProliferationProgram Program Prevention