Lecture given for FDA OCET on 27 February 2013

1. PR-13-015
Lecture for FDA 27 February 2013
Biowarfare to Biodefense:
Operation Whitecoat &
USAMRIID History
Arthur O. Anderson MD
Office of Human Use and Ethics
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.
CD-22 Exp 25 Jan 1955, USAMU Est 20 Jun 1956, USAMRIID Est 27 Jan 1969

2. 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

3. Detrick Field Was An It Became A Bio-
Air National Guard Warfare Center
Training Center as Camp Detrick
1931 April 1943
Scientific Director, Dr. Ira Baldwin, [U.Wisc] planned operations 1942-44
LTC William S. Bacon, CMLC was first Commander of Camp Detrick

4. Organizational Ethics: Biosafety invented at
Camp Detrick before
bioweapons developed
A.G. Wedum MD - Safety “S” Division - first division to be activated in 1943

5. 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 washers
Environmental Safety
by Regulation of
Ambient Air Pressures Masks and biohazard
was developed and suits were developed
tested at Detrick. and tested at Detrick

6. 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

7. 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 methods
Determine effectiveness of available preparations
No existing vaccines for some agents
Only 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

8. Special Procedures - SIP
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 consent

9. Fort Detrick - Fully Engaged
Equipment needed was
invented on site by a brilliant
design and fabrication team

10. 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

11. 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.
23 Nazi Doctors were The Code became the
convicted of Murder at standard for ethical
The Nuremberg Trials research with humans

12. 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

13. 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.

14. 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 warfare
Army 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.

15. 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 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

16. 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.

17. 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.

18. 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].

19. The US Army Medical Unit at Fort Detrick
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.

20. 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.

21. COL W.D. Tigertt USAMU
Community Consultation
October 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

22. Operation Whitecoat Volunteers were SDA
“Conscientious Objectors” recruited from
Medic Training school at Fort Sam Houston
Operation Whitecoat Volunteers
at Forest Glenn Ballroom 1956
Between 1954 and 1973 2,300 Seventh Day Adventist participants of
Operation Whitecoat served at Fort Detrick and associated locations.

23. 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.

24. Review and Approval Process
USAMU 1955-73 vs USAMRIID
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.

25. Protocol Briefing

26. 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.

27. 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).

28. Aerosol Efficacy Studies in 8 Ball
Q-fever and Tularemia were approved for these studies
because safety criteria were met and cure was assured.

29. 1955 Whitecoat: Aerosol Human
Study in Realistic BW Scenario
Dugway Q-fever trial men seemed
to have mysteriously disappeared
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
Outdoor Q-fever Study - Dugway studies like this were never done again.

30. Experimental Risks Minimized by
Availability of Effective Treatment
The men were
assured that no dose
of bacteria would be
fatal, and effective
antibiotics would stop
infection immediately
after it developed.
"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.

31. 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.

32. 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

33. 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.

34. Volunteers in RVF Vaccine Trial

35. 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
Emissaries from Egypt RVF Vaccine was an
and Israel requested important bargaining
RVFV as Sadat & Begin chip to both parties.
met at Camp David. N Meyers - Nature 1986 Jan 9; v319(6049): p91

36. FDA Milestone
 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.

37. 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.

38. 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.

39. 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

40. 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.

41. 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.

42. 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

43. 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.

44. 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

45. 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)

46. 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.

47. Arthur O. Anderson MD
Director, Office of Human Use and Ethics
US Army Medical Research Institute of Infectious Diseases