2013 evolution of irb regulations 1900 - 2002 bioshield-36

Biological WeaponsProliferation Prevention

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Biological WeaponsProliferation Prevention Program

Biological Threat Reduction 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.

PR-13-015

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Proliferation Prevention Program


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Objectives

During 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

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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

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Army Surgeon GeneralGeorge M. Sternberg

Major Walter Reed Hospital Corps Detachment at Camp Columbia, Havana, Cuba, September 1900 served as YF research subjects

“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.

Yellow Fever Commission Cuba 1900Yellow Fever 1st Consent

Form.

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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.

Laws and Regulations needed to assure Safe Drugs and Biologics

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1939 U.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

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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

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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

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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

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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

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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

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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

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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

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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.

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1954 CD-22 & 1955 Operation Whitecoat:

Start Aerosol Human Efficacy Studies

Q-fever and Tularemia were approved for these studies because safety criteria were met and cure was assured.

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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.

FDA Milestone

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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

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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.

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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.

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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.

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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

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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

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Common Rule Principles

BENEFICENCE JUSTICE

RESPECT FOR PERSONS

Privacy & Confidentiality

Protection of subjects (especially vulnerable

populations)

Informed consentSurrogate consent

Assent

Risk/Benefit AnalysisExperimental DesignQualifications of PI

Subject selectionInclusion/exclusion

Recruitment

J. Cooper, Albany Medical Center

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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

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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.

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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.

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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

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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

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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.

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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

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Ethical Dichotomy Intrinsic to National Biodefense

Program: Emergency circumstances may affect outcomes of

ethical analyses by weighting different values, thus favoring mitigating actions over caution

Choices: 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.

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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

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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)

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USAMRIID

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Arthur O. Anderson MD

Chief, Office of Human Use and Ethics

[email protected]

OHU&E

2013 evolution of irb regulations 1900 - 2002 bioshield-36

Documents

bw threat

reporton threat of bw

army medical research

valid research

yf research subjects

yellow fever vaccine

yellow fever commission

yellow fever virus