2013 evolution of irb regulations 1900 - 2002 bioshield-36

Biological Threat Reduction
Biological Weapons
Program
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.

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PR-13-015 Biological Weapons
Proliferation Prevention Program

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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ProliferationProgram Program
Prevention

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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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
Major 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.
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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.
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1939 U.S. Unprepared For BW
The 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
Memory of the millions of WWII.
deaths from influenza
and pneumonia during  This was a successful venture, and
World War I haunted the Flu vaccine was approved by the
founders of the AFEB UPHS in 1944 with this data

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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
23 Nazi Doctors were
convicted of Murder at conduct in research involving
The Nuremberg Trials human subjects.

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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 withdraw
10. 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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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.
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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 Definitions
3. 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
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

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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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OHU&E
Arthur O. Anderson MD
Chief, Office of Human Use and Ethics
artnscience@yahoo.com

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Prevention

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