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 EthicsThis presentation represents the views of the author. The information or content presented does notrepresent 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
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 It Became A Bio- Air National Guard Warfare Center Training Center as Camp Detrick1931 April 1943 Scientific Director, Dr. Ira Baldwin, [U.Wisc] planned operations 1942-44 LTC William S. Bacon, CMLC was first Commander of Camp Detrick
Organizational Ethics: Biosafety invented at Camp Detrick before bioweapons developed A.G. Wedum MD - Safety “S” Division - first division to be activated in 1943
Nonpathogenic Simulants were used in Human Studies of Safety PracticesWorker safety testswere done to test airpurification systemssuch as mechanicaland electrostaticfilters, air incineratorsand washersEnvironmental Safetyby Regulation ofAmbient Air Pressures Masks and biohazardwas developed and suits were developedtested at Detrick. and tested at Detrick
Camp Detrick – Worker SafetyPractices: 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 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
Special Procedures - SIPMost 1950’s Fort Detrickalumni remember NurseBetty Grable, Dr. PaulKadull & the “shot shop”,which is what they calledthe building where allworkers and researchsubjects received theirvaccines prescribed by“Special Procedures”.Both groups got the same IND vaccines but only the researchvolunteers were given the choice with informed consent
Fort Detrick - Fully EngagedEquipment needed wasinvented on site by a brilliantdesign and fabrication team
Human Subjects Researchat 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.23 Nazi Doctors were The Code became theconvicted of Murder at standard for ethicalThe Nuremberg Trials research with humans
Nuremberg Code of 19471. 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 value7. Prepare to minimize risk of injury, disability or death8. Investigator must have credentials appropriate to study9. Subjects must have freedom to withdraw10. 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 BWAerosols Not Previously TestedIn 1952, the Armed Forces Medical PolicyCouncil wanted information on humanvulnerability and countermeasures tobiological warfareArmy SG met with Chief Chemical Officerat the same time that Secretaries ofDefense & Army, Army Chief of Staff andChemical and Medical elements weremeeting to discuss possible use of humansin biowarfare defense research.
Wilson Memorandum of 1953The Nuremberg Code* was incorporated into the WilsonMemorandum to the Secretaries of the Army, Navy and AirForce dated 26 February 1953* Use of its principles was promoted before anyhuman research related to biological warfaredefense were officially planned or conductedArmy Directive CS-385 issued 30 June 1953 addedconsent in writing, additional safeguards, and instructionsfor compensating subjects for injuries resulting fromparticipation in researchAR70-25 was Nuremberg Code Based from 1962-1990
CS-385 (30 June 1953)“Use of Volunteers in Research”This document, prepared forthe Army Chief of Staff byBG John C. Oakes, becamethe first government directiveprescribing policies andprocedures for ethical use ofvolunteers in atomicbiological and chemicalwarfare defense research.The original documentresides at USAMRIID. Fivecarbon copies went to otherUSAMRDC Laboratories.
Multifaceted CD-22 (1954-55) was designed to determine:Human vulnerability in realistic BW scenarios,i.e. outdoor aerosol delivery to human subjectsEffective 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 onHuman responses to prototypes:Q fever and Tularemia were regarded byCES of AFEB as acceptable prototypicalBW agents for testing in Humans thatsatisfied limiting characteristics* of lowlethality, no serious chronicityanticipated, effective therapy availableand there was adequate animalexperimental data on safety andprotective efficacy *[also described in cs-385].
The US Army Medical Unit at Fort DetrickUSAMU 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 fororganization of the institute, preparation of CD-22 protocols and theDugway study preceded by 3-6 months the creation of USAMU.
USAMU - USAMRIIDThe station hospital was built in 1957. It was linked via walkways tosupport laboratories (vir, bact, clin lab, etc) and USAMU. The 8-ball isat upper left and the BL-4 suite called ”black moriah” is at upper right.
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
Operation Whitecoat Volunteers were SDA “Conscientious Objectors” recruited from Medic Training school at Fort Sam HoustonOperation Whitecoat Volunteersat Forest Glenn Ballroom 1956 Between 1954 and 1973 2,300 Seventh Day Adventist participants of Operation Whitecoat served at Fort Detrick and associated locations.
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 theResearch Division Chiefs.• Approved protocols were forwarded to HQDA (SGRD-DR)for further approval. This could have entailed review by CESof AFEB (before 1962) or HSRRB (after 1962 *).• When final approval was given, Whitecoat volunteers werebriefed, attended a project interview, and informed consentdocuments were signed after at least 24 hours.•*AR 70-25 published in 1962 was identical to cs-385.
Review and Approval ProcessUSAMU 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.
Operation Whitecoat served as amodel of the ethical use of humansubjects in research. The threestep process of informed consent- by which research subjectsbecome familiar with the purposeof a study in order to understandthe risks and potential benefitsinvolved before agreeing toparticipate - was successfullyimplemented from the program’sinception. The soldiers were notrequired to participate in any ofthe studies, only to be present forbriefings by principal investigatorsseeking volunteers. Two moresteps occurred before subjectswere asked to consent. About 20percent of the men did notparticipate in any studies duringtheir tenure at Fort Detrick.
Vaccines that were tested under approved protocols includedthose 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 BallQ-fever and Tularemia were approved for these studiesbecause safety criteria were met and cure was assured.
1955 Whitecoat: Aerosol Human Study in Realistic BW ScenarioDugway Q-fever trial men seemedto 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 outdoorOutdoor Q-fever Study - Dugway studies like this were never done again.
Experimental Risks Minimized byAvailability 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 certainnumber of organisms, and that as soon as theybecame ill, they would be treated with appropriateantibiotics," said Dr. Peter Bartelloni, who wasinvolved in the research.
In addition to the advances made in vaccine and drug development, OperationWhitecoat volunteers contributed to a better understanding of the signs,symptoms, and clinical diagnostic parameters in human disease associatedwith Q-fever, Tularemia, Sandfly fever, and staphylococcal enterotoxins.
Ethical Accomplishments ofCD-22 & Operation WhitecoatEffectively Used Nuremberg Code PrinciplesCreated Effective Informed Consent ProcessInvolved “Community” of the SDA VolunteersLocal and Extramural Oversight / Monitoring
Medical Accomplishments: Operation WhitecoatLicensed vaccines were developed, includingyellow fever, hepatitis, and plague.Investigational New Drug (IND) vaccines weredeveloped, including those for Venezuelanequine encephalitis (VEE), Rift Valley fever, Qfever, and tularemia.Effective systems for biological hazardcontainment were developedRift Valley Fever Virus vaccine; used in 1977outbreak in Egypt, effected 200,000 humans(2,000 deaths) and entire sheep population.
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
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.
Moral Dilemma: Comply with FDA law vs Intent to Benefit in BW Emergency1962 Amendments to theFD&C Act requiring proofof efficacy of drugs andvaccines created a moraldilemma:Risk killing subjects in avalid clinical trial, versusWithholding potentially lifesaving drugs or vaccinesbecause they lackedsubstantial evidence ofhuman clinical efficacy.
1962 Exemptions to AR 70-25: 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.
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 DrugRegulations Revised to expand access toexperimental drugs for patients with serious diseaseswith no alternative therapies. (Fast Track System –AIDS activists)1988 Food and Drug AdministrationAct establishes FDA as an agency of DHHS with aCommissioner of Food and Drugs appointed by thePresident with the advice and consent of the Senate,and broadly spells out the responsibilities of theSecretary and the Commissioner for research,enforcement, education, and information.
1987 MOU with FDA Created Ethical and Legal Dilemma: Research vs TreatmentAbility to use products labeled IND to benefit warfighter and laboratory personnel becomes less clear.From 1964 through 1987 MOUs with the FDAallowed DoD to Self-Exempt certain IND productsfrom FDA requirements if they were to be used fortreatment of warfighter, i.e. with “intent to benefit” notfor generation of knowledge.Clinical Research with IND products to discover newtreatment applications rigorously followed DoD andFDA requirements.“Special Procedures” was used for worker safetyoutside 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 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.
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
Project BioShieldCDC, HHS & DoD may use HHS Project BioShield asspecified 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, 2004These legislative acts may resolve the dilemma associated with theneed for widespread use of FDA-unapproved products in for nationalbiodefense or war hazards when it is unethical to do FDA-mandatedhuman clinical efficacy studies. 21 CFR Part 314.600 - .650Additional legislation may be necessary to further define how these newlaws will operate through existing agencies without damaging the fabricof regulation protecting the public from unsafe and ineffective drugs.Federal Food Drug and Cosmetic Act, section 564 (EUA)
USAMRIID still EvolvingOver the past 56 years since the start of Operation Whitecoat, the U.S.Army Medical Research Institute of Infectious Diseases has grownconsiderably from what it was as the U.S. Army Medical Unit, yet Itcontinues to conduct basic and applied research on biological threatsresulting 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 MD Director, Office of Human Use and EthicsUS Army Medical Research Institute of Infectious Diseases