1. Ethical Use of Human Subjects
in Infectious Disease Research
Arthur O. Anderson MD
Office of Human Use and Ethics
Lecture for BCLT & BHBLS March 18, 2015
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 15-149 (+)

2. Few choices in life are:
Ethical, Legal & Moral
Ethical Moral Legal

3. Responsibility and
Accountability in Research
Involves:
 Ethical Behavior
 Morality and
 Lawfulness
 Guided by:
 Values , Principles and Beliefs

4. What Values You Choose
May Influence Ethical Decisions:
Group A
1. Trust
2. Integrity
3. Courage
4. Honesty
5. Duty
6. Justice
7. Honor
Group B
1. Loyalty
2. Duty
3. Respect
4. Selfless-service
5. Honor
6. Integrity
7. Personal Courage

5. Values: Subjects Expect
Principal Investigators to Be:
Trustworthy
Loyal
Helpful
Friendly
Courteous
Kind

6. Values: Researchers Hope
Volunteer Subjects to Be:
Obedient
Cheerful
Thrifty
Brave
Clean
Reverent

7. Decisional Ethics Process:
Identify your intention(s)
Determine actions to achieve intention(s)
What are possible consequences of the
intention or of taking specific actions
Determine which intentions/actions give
greatest benefits and result in least harms
The context, cultural values and limits to
available choices effect final determination

8. Applied Ethics Practices
Organizational ethics:
 Safety, Security, Equitable Compensation, Work Time,
Transparency, etc.
Research ethics is individualistic:
 Respect for Persons, Beneficence, Distributive Justice
Clinical ethics is individualistic:
 Do no harm, Beneficence, Duty to Care, Evidence Based
Public Health ethics is societal not individualistic:
 "Public health ethics involves a systematic process to clarify,
prioritize and justify possible course of public health action
based on ethical principles, values and beliefs of stakeholders,
and scientific and other information” (from Powers and Faden 2006)
 Public Health actions are both prudential and humanitarian
Principle of least infringement, respects and protects individual &
society/community needs, interests, rights and liberties.
Individual rights and welfare may be subordinate to those of the
population if the individual’s actions endanger others. (Harm Principle)

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

10. 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 (barrier)
Environmental Safety
by control of Ambient
Air Pressures was
developed and tested
at Detrick (isolation)
Masks and biohazard
suits were developed
and tested at Detrick

11. WWII Human Experimentation
Detrick – Occupational Safety
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

12. Nuremberg War Crimes Trial
By 1947 Andrew Ivy & Leo
Alexander released a 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

13. 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

14. 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.

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, a prototype
aerosol study and instructions for compensating subjects
for injuries resulting from participation in research
AR70-25 was Nuremberg Code Based from 1962-1990

16. USAMU ‘56 / USAMRIID ‘69 was established 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

17. 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.
These wooden buildings resemble what may
be found in Africa as care stations. They were
safe and secure because of disinfectant sprays
and partitioned space, i.e. hot, warm & cold

18. CD-22 & Operation Whitecoat
were 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.

19. 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

20. 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.

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

22. 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

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

24. Ethical Accomplishments of
CD-22 & Operation Whitecoat
Effectively Used Nuremberg Code Principles
in creating USAMU and in planning studies
Created Effective Informed Consent Process
Involved “Community” of the SDA Volunteers
Local and Extramural Oversight / Monitoring

25. 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.

26. 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

27.  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

28. 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 Emergency

29. 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” - AKA - ”The Common Rule”
NIH uses 45 CFR 46 | DoD uses 32 CFR 219

30. Common Rule Principles 1979
BENEFICENCE JUSTICE
RESPECT FOR PERSONS
Privacy & Confidentiality
Protection of subjects
(especially vulnerable
populations)
Informed consent
Surrogate consent
Assent
Risk/Benefit Analysis
Experimental Design
Qualifications of PI
Subject selection
Inclusion/exclusion
Recruitment
J. Cooper, Albany Medical Center

32. USAMRIID Research Influenced by
News Events and World Affairs
“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.
MRVS Program Tested Safety of WRAIR & USAMRIID
Vaccines & Drugs Through 2001
Post September 11, 2001 Anthrax Letters and Bioterrorism
fears caused U.S. to increase Biodefense infrastructure

33. 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.

34. 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

35. 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)

36. USAMRIID Research on Medical
Countermeasures against Ebola
An update of the current situation
Why the current outbreak got so big so quickly?
How is Ebola virus transmitted?
 Is the virus transmitted by aerosol?
 Droplets of body fluids not Small Particle Aerosol
 Contact with Skin & mucus membranes & with
contaminated surfaces of objects
How do we stop the virus from spreading?
Do we have vaccines and therapeutics against
Ebola virus?
Do we know the reservoir(s) for Ebola virus?
Conclusions

37. Since the discovery of Ebola in 1976 until December 2013:
 23 outbreaks
 2388 human cases and 1590 deaths
As of 12 March 2015, Guinea, Liberia, Sierra Leone & 7 other
countries have reported over 24,544 cases and 10,111 deaths
→ This is the Largest Ebola Virus Disease outbreak ever recorded
Ebola Outbreak History
Country Year Number of
cases
Number of
deaths
Cote d’Ivoire 1994 1 0
Uganda 2012 7 4
Gabon 1994 52 31
DRC 2007 264 187
Uganda 2000 425 224
A few examples of
previous EVD
outbreaks

38. Barkedu is a very tightknit
community. (from NPR report)
If a neighbor gets sick, you
help him/her. If a highly
respected person gets sick,
everyone comes to help.
Barkedu’s first Ebola case
was Laiye Barwor, a favorite
son of the village. When he
got sick in early June, the
whole town took notice.
Unaware of Ebola, his family
brought him to traditional
healers - he died during the
journey.
At his funeral, more than 30
people helped wash and
prepare his body for burial –
(Important to Muslims)
All people who touched him
came down with Ebola. From
that one funeral, Ebola
spread like wildfire
Barkedu
From NY Times Report

39. Why did the current outbreak got
so big so quickly?
This was the first Ebola outbreak in West Africa:
 Lack of local knowledge of how to avoid Ebola Virus
 Lack of HCW experience with care vs contamination
 Limited manpower capacity for rapid response
High level of exposure in communities
 Through household care by family members (droplets)
 Traditional burial practices (touching, kissing, washing)
 Fear & Panic led to resistance to response measures
 Travel of patients / contacts to neighbouring communities
spread infection and impacted contact tracing
Lack of sufficient commitment of resources to the
epidemic in rural areas AND in large cities

40. Epidemiological
(human case data)
Direct contact with
bodily fluids
Respiratory
droplets
Blood/re-used
needles
Animal Experimental
Methods of Infection
• Oral
• Conjunctival
• Respiratory
• Intramuscular
• Intraperitoneal
• Submucosal
How is Ebola virus
transmitted?

41. Ebola virus is transmitted by
touch or body fluid droplets
Ebola Viral Antigen in NHP Lip
(L), Trachea (M) and Bowel (R).
In each image the virus is close
to or on the epithelial surface.

42. How do we stop the virus from
spreading?

43. How do we stop spread of Ebola?
Bleach and other anti-infectives, steam
sterilization, incineration of waste
Quickly Identify infected individuals & contacts
Liberty Restriction, Isolation / quarantine
Use of vaccines and therapeutics
Educating the public – engage community
Safe, Respectful Burial Practices
Enhance health care standard
Identifying the source (reservoir)

44. Anti-EBOV Therapeutic Portfolio Development
3 Synthetic Abs
Polymerase Inhib.
Polymerase Inhib.
Small interfering RNA
Antisense PM-oligomers
Nucleoside analog

45. Anti-EBOV Vaccine Portfolio Development

46. Conclusions
Ebola virus is extremely infectious & spreads
rapidly through personal contact and fluids
Fast multifaceted response needed to contain the
epidemic: community engagement, risk education,
patient isolation, contact tracing, quarantines
Protection of healthcare workers & staff with PPE
Public Health Ethics deliberations, community
collaboration and epidemic mitigation planning
need to occur long BEFORE the next outbreak
Protocols for IND Vaccines and Therapeutics must
be prepared, reviewed and ready BEFORE needed
There will be other outbreaks.

47. USAMRIID
Over the past 60 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.

48. USAMRIID Ebola Info Online
USAMRIID Targets Ebola, Other Infectious Diseases
 http://www.defense.gov/news/newsarticle.aspx?id=123530
 http://www.dvidshub.net/video/371474/us-military-leads-way-ebola-
containment#.VIBZ0WOa9bw
 http://www.dvidshub.net/video/371474/us-military-leads-way-ebola-
containment#.VIBZ0WOa9bw
USAMRIID Has Years of Ebola Drug Expertise
 http://www.defense.gov/news/newsarticle.aspx?id=123527
USAMRIID Contributes to Vaccine Development Effort
 http://www.defense.gov/news/newsarticle.aspx?id=123515
 http://www.dvidshub.net/video/371229/army-scientists-make-ebola-vaccine-
advances#.VIBZOmOa9bw
USAMRIID Develops Ebola Diagnostics
 http://www.defense.gov/news/newsarticle.aspx?id=123498

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