Biowarfare to Biodefense:Operation Whitecoat &

USAMRIID HistoryArthur O. Anderson MD

Office of Human Use and Ethics

CD-22 Exp 25 Jan 1955, USAMU Est 20 Jun 1956, USAMRIID Est 27 Jan 1969

Lecture for FDA 27 February 2013

PR-13-015

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.

U.S. Not Prepared For BW in 1941

Europeans Had Chemical Warfare Experience in WWI. As WW II Approached, U.S. Worried That Nazis Had Prepared For BioWarfare

Detrick Field Was An Air National Guard

Training Center

Detrick Field Was An Air National Guard

Training Center

It Became A Bio- Warfare Center

as Camp Detrick

It Became A Bio- Warfare Center

as Camp Detrick

Scientific Director, Dr. Ira Baldwin, [U.Wisc] planned operations 1942-44

LTC William S. Bacon, CMLC was first Commander of Camp Detrick

Scientific Director, Dr. Ira Baldwin, [U.Wisc] planned operations 1942-44

LTC William S. Bacon, CMLC was first Commander of Camp Detrick

April 19431931

Biosafety invented at Camp Detrick before

bioweapons developed

Biosafety invented at Camp Detrick before

bioweapons developed

A.G. Wedum MD - Safety “S” Division - first division to be activated in 1943A.G. Wedum MD - Safety “S” Division - first division to be activated in 1943

Organizational Ethics:Organizational Ethics:

Nonpathogenic Simulants were used in Human Studies of Safety Practices

Worker safety tests were done to test air purification systems such as mechanical and electrostatic filters, air incinerators and washersEnvironmental Safety by Regulation of Ambient Air Pressures was developed and tested at Detrick.

Masks and biohazard suits were developed and tested at Detrick

Camp Detrick – Worker Safety Practices: Organizational Ethics

Occupational Safety by “S” Division 1943

Training Program, Posters, Constant Survey of Safety Practices

Personnel Inspection and First Aid First Aid room near hot suite change rooms

held personnel who inspected workers leaving suites for breaks in skin or clinical signs and symptoms of disease

WWII Human Experimentation Camp Detrick - Safety Practices Immunization*

Vaccination routine called “special procedures” instituted by Biological Protection Branch of S Division

Primary Objective was to protect workers Secondary Objectives:

Determine most efficacious immunization methodsDetermine effectiveness of available preparations

No existing vaccines for some agentsOnly experimental vaccines available for others

* Ltr (S), CO CD to Post Surgeon CD, 22 Jan 44, Sub: Immunization. SPCYF 400.12. In Hq CD (720.3)* Sp Rpt 15, Immunological Protection of Personnel Against B.W. Agents (Oct 46), p.2

Special Procedures - SIPMost 1950’s Fort Detrick alumni remember Nurse Betty Grable, Dr. Paul Kadull & the “shot shop”, which is what they called the building where all workers and research subjects received their vaccines prescribed by “Special Procedures”.

Most 1950’s Fort Detrick alumni remember Nurse Betty Grable, Dr. Paul Kadull & the “shot shop”, which is what they called the building where all workers and research subjects received their vaccines prescribed by “Special Procedures”.

Both groups got the same IND vaccines but only the research volunteers were given the choice with informed consentBoth groups got the same IND vaccines but only the research volunteers were given the choice with informed consent

Fort Detrick - Fully Engaged

Equipment needed was invented on site by a brilliant design and fabrication team

Equipment needed was invented on site by a brilliant design and fabrication team

Human Subjects Research at Fort Detrick 1943 - 1946

The station hospital, originally activated in 1943, provided a “unique opportunity to study the inception, course and therapeutics of many rare diseases in patients whose baseline health data was known” LTC Abram Benenson MC

This was primarily “opportunist” research that depended upon occupational incidents among workers in the various biowarfare facilities

Nuremberg War Crimes Trial

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 for ethical research with humans

23 Nazi Doctors were convicted of Murder at The Nuremberg Trials

Nuremberg Code of 1947 1. Voluntary Consent absolutely essential.

2. Valid research for good of society – by no other means.

3. Human studies preceded by knowledge survey & research with animal models to identify potential risks and benefits.

4. Avoid unnecessary physical and mental suffering & injury.

5. Prohibits research with apriori risk of death or disabling injury.

6. Degree of risk never to exceed benefit or humanitarian value

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

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.

Human Vulnerability to BW Aerosols Not Previously Tested

In 1952, the Armed Forces Medical Policy Council wanted information on human vulnerability and countermeasures to biological warfareArmy SG met with Chief Chemical Officer at the same time that Secretaries of Defense & Army, Army Chief of Staff and Chemical and Medical elements were meeting to discuss possible use of humans in biowarfare defense research.

In 1952, the Armed Forces Medical Policy Council wanted information on human vulnerability and countermeasures to biological warfareArmy SG met with Chief Chemical Officer at the same time that Secretaries of Defense & Army, Army Chief of Staff and Chemical and Medical elements were meeting to discuss possible use of humans in biowarfare defense research.

Wilson Memorandum of 1953The Nuremberg Code* was incorporated into the Wilson Memorandum to the Secretaries of the Army, Navy and Air Force dated 26 February 1953

* Use of its principles was promoted before any human research related to biological warfare defense were officially planned or 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

AR70-25 was Nuremberg Code Based from 1962-1990

CS-385 (30 June 1953)“Use of Volunteers in

Research”

This document, prepared for the Army Chief of Staff by BG John C. Oakes, became the first government directive prescribing policies and procedures for ethical use of volunteers in atomic biological and chemical warfare defense research.

The original document resides at USAMRIID. Five carbon copies went to other USAMRDC Laboratories.

Multifaceted CD-22 (1954-55)was designed to determine:

Human vulnerability in realistic BW scenarios, i.e. outdoor aerosol delivery to human subjects

Effective prevention and treatment of BW casualties.

Determination of minimal infective doses.

Effectiveness of vaccines and drugs.

Serological responses to infections, and.

Clinical effects of various doses of infectious agents.

The CD-22 program focused on Human responses to prototypes:

Q fever and Tularemia were regarded by CES of AFEB as acceptable prototypical BW agents for testing in Humans that satisfied limiting characteristics* of low lethality, no serious chronicity anticipated, effective therapy available and there was adequate animal experimental data on safety and protective efficacy *[also described in cs-385].

Q fever and Tularemia were regarded by CES of AFEB as acceptable prototypical BW agents for testing in Humans that satisfied limiting characteristics* of low lethality, no serious chronicity anticipated, effective therapy available and there was adequate animal experimental data on safety and protective efficacy *[also described in cs-385].

USAMU was established in 1956 to develop the means to diagnose, treat and prevent diseases caused by biological warfare agents. Approval of the cs-385 directive for ethical operation, plans for organization of the institute, preparation of CD-22 protocols and the Dugway study preceded by 3-6 months the creation of USAMU.

The US Army Medical Unit at Fort Detrick

USAMU - USAMRIID

The station hospital was built in 1957. It was linked via walkways to support laboratories (vir, bact, clin lab, etc) and USAMU. The 8-ball is at upper left and the BL-4 suite called ”black moriah” is at upper right.

The station hospital was built in 1957. It was linked via walkways to support laboratories (vir, bact, clin lab, etc) and USAMU. The 8-ball is at upper left and the BL-4 suite called ”black moriah” is at upper right.

COL W.D. Tigertt USAMU

Community ConsultationOctober 1954 Colonel Tigertt contacted Dr. Theodore R. Flaiz of Seventh Day Adventist General Conference about seeking 1A-O SDA volunteer subjects.General Conference of SDA Church approved recruitment of drafted SDA volunteer subjects into Operation Whitecoat

Between 1954 and 1973 2,300 Seventh Day Adventist participants of Operation Whitecoat served at Fort Detrick and associated locations.

Operation Whitecoat Volunteers were SDA “Conscientious Objectors” recruited from

Medic Training school at Fort Sam Houston

Operation Whitecoat Volunteers were SDA “Conscientious Objectors” recruited from

Medic Training school at Fort Sam Houston

Operation Whitecoat Volunteers at Forest Glenn Ballroom 1956

Protocol Review during Operation Whitecoat

• The Medical investigator prepared protocol.• It was Reviewed for approval at a “Protocol

Meeting” attended by Commander, Scientific Advisor, and the Research Division Chiefs.

• Approved protocols were forwarded to HQDA (SGRD-DR) for further approval. This could have entailed review by CES of AFEB (before 1962) or HSRRB (after 1962 *).

• When final approval was given, Whitecoat volunteers were briefed, attended a project interview, and informed consent documents were signed after at least 24 hours.

• *AR 70-25 published in 1962 was identical to cs-385.

• The Medical investigator prepared protocol.• It was Reviewed for approval at a “Protocol

Meeting” attended by Commander, Scientific Advisor, and the Research Division Chiefs.

• Approved protocols were forwarded to HQDA (SGRD-DR) for further approval. This could have entailed review by CES of AFEB (before 1962) or HSRRB (after 1962 *).

• When final approval was given, Whitecoat volunteers were briefed, attended a project interview, and informed consent documents were signed after at least 24 hours.

• *AR 70-25 published in 1962 was identical to cs-385.

1955 – 73 USAMU Protocol Meeting Minutes were one page long with only one sentence for the committee decision. Issues were not documented.

1976 – USAMRIID IRB Minutes 5 pages long, 4 of which were Q&A that documented issues.

Presently – USAMRIID IRB Minutes are > 14 pages long with 2 pages of narrative summary, 2.5 pages of Q&A per protocol with decision plus 9 pages of expedite approval ratifications, continuing review and SAE discussion.

1955 – 73 USAMU Protocol Meeting Minutes were one page long with only one sentence for the committee decision. Issues were not documented.

1976 – USAMRIID IRB Minutes 5 pages long, 4 of which were Q&A that documented issues.

Presently – USAMRIID IRB Minutes are > 14 pages long with 2 pages of narrative summary, 2.5 pages of Q&A per protocol with decision plus 9 pages of expedite approval ratifications, continuing review and SAE discussion.

Review and Approval ProcessUSAMU 1955-73 vs USAMRIID Review and Approval Process

USAMU 1955-73 vs USAMRIID

Protocol Briefing

Operation Whitecoat served as a model of the ethical use of human subjects in research. The three step process of informed consent - by which research subjects become familiar with the purpose of a study in order to understand the risks and potential benefits involved before agreeing to participate - was successfully implemented from the program’s inception. The soldiers were not required to participate in any of the studies, only to be present for briefings by principal investigators seeking volunteers. Two more steps occurred before subjects were asked to consent. About 20 percent of the men did not participate in any studies during their tenure at Fort Detrick.

Operation Whitecoat served as a model of the ethical use of human subjects in research. The three step process of informed consent - by which research subjects become familiar with the purpose of a study in order to understand the risks and potential benefits involved before agreeing to participate - was successfully implemented from the program’s inception. The soldiers were not required to participate in any of the studies, only to be present for briefings by principal investigators seeking volunteers. Two more steps occurred before subjects were asked to consent. About 20 percent of the men did not participate in any studies during their tenure at Fort Detrick.

Vaccines that were tested under approved protocols included those for Q fever, Tularemia (safety & efficacy), Yellow Fever, Eastern, Western and Venezuelan equine encephalitis (EEE, WEE & VEE), Hepatitis, Plague and Rift Valley fever (safety only).

Vaccines that were tested under approved protocols included those for Q fever, Tularemia (safety & efficacy), Yellow Fever, Eastern, Western and Venezuelan equine encephalitis (EEE, WEE & VEE), Hepatitis, Plague and Rift Valley fever (safety only).

Aerosol Efficacy Studies in 8 Ball

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

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

1955 Whitecoat: Aerosol Human Study in Realistic BW Scenario

Outdoor Q-fever Study - Dugway

Merlin Neff described being in the study at Dugway. "They put two of us at each station along with several monkeys and guinea pigs and mice and air sampling apparatus,“ This study satisfied the AFMPC and outdoor studies like this were never done again.

Dugway Q-fever trial men seemed to have mysteriously disappeared

Experimental Risks Minimized by Availability of Effective TreatmentExperimental Risks Minimized by Availability of Effective Treatment

"They knew that they were going to inhale a certain number of organisms, and that as soon as they became ill, they would be treated with appropriate antibiotics," said Dr. Peter Bartelloni, who was involved in the research.

"They knew that they were going to inhale a certain number of organisms, and that as soon as they became ill, they would be treated with appropriate antibiotics," said Dr. Peter Bartelloni, who was involved in the research.

The men were assured that no dose of bacteria would be fatal, and effective antibiotics would stop infection immediately after it developed.

The men were assured that no dose of bacteria would be fatal, and effective antibiotics would stop infection immediately after it developed.

In addition to the advances made in vaccine and drug development, Operation Whitecoat volunteers contributed to a better understanding of the signs, symptoms, and clinical diagnostic parameters in human disease associated with Q-fever, Tularemia, Sandfly fever, and staphylococcal enterotoxins.

In addition to the advances made in vaccine and drug development, Operation Whitecoat volunteers contributed to a better understanding of the signs, symptoms, and clinical diagnostic parameters in human disease associated with Q-fever, Tularemia, Sandfly fever, and staphylococcal enterotoxins.

Ethical Accomplishments of CD-22 & Operation Whitecoat

Effectively Used Nuremberg Code Principles

Created Effective Informed Consent Process

Involved “Community” of the SDA Volunteers

Local and Extramural Oversight / Monitoring

Medical Accomplishments:Operation Whitecoat

Licensed vaccines were developed, including yellow fever, hepatitis, and plague. Investigational New Drug (IND) vaccines were developed, including those for Venezuelan equine encephalitis (VEE), Rift Valley fever, Q fever, and tularemia. Effective systems for biological hazard containment were developed Rift Valley Fever Virus vaccine; used in 1977 outbreak in Egypt, effected 200,000 humans (2,000 deaths) and entire sheep population.

Volunteers in RVF Vaccine Trial

RVF Vaccine caused Peace to break out in the middle east

Therefore, a little known benefit that Operation Whitecoat Volunteers provided was to enable peace between Egypt and Israel to “break out” because obtaining RVF Vaccine was an important bargaining chip to both parties.

Emissaries from Egypt and Israel requested RVFV as Sadat & Begin met at Camp David. N Meyers - Nature 1986 Jan 9; v319(6049):

p91

Kefauver-Harris Drug Amendments passed in 1962 to ensure drug efficacy and greater drug safety. For the first time, manufacturers of drugs are required to show proof to the FDA of the efficacy of their products before they may be approved for marketing.

FDA Milestone

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.

Moral Dilemma: Comply with FDA law vs Intent to Benefit in BW EmergencyMoral Dilemma: Comply with FDA law

vs Intent to Benefit in BW Emergency

1962 Exemptions to AR 70-25: 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.

1974-1999 Research Influenced by News Events and World Affairs

“Cold War” imperatives continued into the 1980’s and we saw growth in Virology Research.Anthrax Research at RIID re-started after the outbreak in Sverdlovsk, (Ekaterinburg).“Yellow Rain” in Cambodia and Laos signaled the need to increase focus on Toxins and Toxinology was created from Physical Sciences Division.And Aum Shinrikyo warned that Bioterrorism was on the horizon just as the “Evil Empire” was crumbling. This prompted expansion of Rapid Diagnosis, using PCR & other dx technologies.

MRVS Program tested WRAIR & RIID Vaccines

FDA Historic Milestones1987 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.

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.

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

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.

Ethical Analysis vs Rules & Laws HHS Common Rule Regulates Research based on Ethical Principles but applied as

RulesFDA 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

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 - .650Additional 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)

USAMRIID still Evolving USAMRIID still Evolving

Over the past 56 years since the start of Operation Whitecoat, the U.S. Army Medical Research Institute of Infectious Diseases has grown considerably from what it was as the U.S. Army Medical Unit, yet It continues to conduct basic and applied research on biological threats resulting in medical solutions to protect military service members.

The present building was planned by COL Dan Crozier, and is named in his honor.

Over the past 56 years since the start of Operation Whitecoat, the U.S. Army Medical Research Institute of Infectious Diseases has grown considerably from what it was as the U.S. Army Medical Unit, yet It continues to conduct basic and applied research on biological threats resulting in medical solutions to protect military service members.

The present building was planned by COL Dan Crozier, and is named in his honor.

Arthur O. Anderson MDDirector, Office of Human Use and Ethics

US Army Medical Research Institute of Infectious Diseases 

Arthur O. Anderson MDDirector, Office of Human Use and Ethics

US Army Medical Research Institute of Infectious Diseases