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Ethical and Legal Dilemmas in Biodefense Research

Chapter 24

ETHICAL AND LEGAL DILEMMAS IN

BIODEFENSE RESEARCH

JEFFREY E. STEPHENSON, P h D * ; a n d ARTHUR O. ANDERSON, MD †

INTRODUCTION

OVERVIEW OF THE HISTORY OF BIODEFENSE DEVELOPMENT

AND MEDICAL ETHICS

Biodefense and Ethics in the 18th and 19th Centuries

Biodefense, Ethics, and Research in the 20th Century

IMPACT OF REGULATING AGENCIES ON STRATEGIC RESEARCH

CONFLICT BETWEEN REGULATIONS AND ETHICAL RESPONSIBILITIES

Department of Defense/Food and Drug Administration Memorandum of

Understanding (1987)

Investigational New Drug Status of Vaccines

Summary Points

OPTIONS FOR FULFILLING MISSION AND ETHICAL RESPONSIBILITIES

TO MILITARY PERSONNEL

Option 1: Continue to Use Investigational New Drug Products Without

Full Compliance

Option 2: Negotiate for Accelerated Licensure

Option 3: Institute Waiver of Informed Consent

CURRENT MOVEMENTS IN THE REGULATORY ENVIRONMENT

The Public Health Security and Bioterrorism Preparedness and Response

Act of 2002

The Animal Efficacy Rule

BioShield Act of 2004

The Turner Bill

Biodefense and Pandemic Vaccine and Drug Development Act of 2005

SUMMARY

* Regulatory Compliance Specialist, US Army Medical Research and Materiel Command, Telemedicine and Advanced Technology Research Center, Fort

Detrick, Maryland 21702; formerly, Institutional Review Board Administrator, US Army Medical Research Institute of Infectious Diseases, 1425 Porter

Street, Fort Detrick, Maryland

† Colonel, Medical Corps, US Army (Ret); Director, Office of Human Use and Ethics, US Army Medical Research Institute of Infectious Diseases, 1425

Porter Street, Fort Detrick, Maryland

559

Medical Aspects of Biological Warfare

INTRODUCTION

The anthrax attacks of October 2001 made the nation

acutely aware of not just the possibility of a large-

scale biological weapons attack on US soil, but also

has brought to the forefront concerns over the proper

measures to be implemented to prepare for such

biological warfare scenarios. It is evident that drugs

and vaccines may be needed immediately to respond

appropriately to emergency or battle situations.

Government regulatory agencies, the pharmaceutical

industry, and the armed services must work together

more effectively so that vaccines and drugs that are

not yet approved for marketing but have preclinical

evidence of efficacy may be considered and used in

the event of bioterrorist attacks or in times of war.

The pharmaceutical industry is not accustomed to

responding to such situations; it is in the business of

developing drugs to treat natural diseases afflicting

patients of the civilian healthcare industry. Profit

considerations and sustained business growth are,

understandably, the primary objectives of pharma-

ceutical companies, so drugs are more likely to be

developed for common rather than rare diseases. For

such naturally occurring, often relatively common

diseases, many potential test subjects are ready and

willing to participate in drug safety and efficacy trials

because of the possibility that the new drug might

cure their diseases or help future patients.

This is not the case for products required as coun-

termeasures against biological warfare agents. These

infectious disease agents and toxins are usually found

in areas of the world where humans have learned it is

not safe to settle, or they occur in sporadic, small epi-

demics that kill everyone affected and fail to spread.

In any case, there are rarely enough “naturally”

occurring disease outbreaks of this kind to conduct

clinical trials yielding substantial evidence of human

clinical efficacy.

Over the past 60 years the conditions that must be

met in order to use many of these drugs and vaccine

products have become more restrictive. Until the ap-

proval of an animal efficacy rule and passage of the

Project BioShield Act of 2004, Food and Drug Admin-

istration (FDA) regulations originating in the 1938

Food, Drug, and Cosmetic Act made emergent medical

responses to bioterrorist attacks extremely complex by

prohibiting use of investigational products until there

was substantial evidence of human clinical efficacy.

Gathering evidence in a scientifically valid clinical trial

requires the participation of large numbers of subjects

who have or are at risk of acquiring the disease, and

accumulating these clinical observations takes a long

time. Although some disease agents cause sporadic

epidemics, others only infect individuals randomly

when they happen upon a reservoir of contagion.

Biowarfare attacks involving these uncommon agents

would likely affect many people suddenly, permitting

neither the opportunity to enroll enough subjects in a

study nor the time for observation. Although FDA re-

strictions are meant to protect the public from possible

harm, delaying use of potentially beneficial products

until outcomes are known can be detrimental in the

event of a widespread biowarfare attack. Throughout

most of the 20th century and into the 21st century,

successful animal studies followed by substantial evi-

dence of efficacy from human clinical trials have been

required before a drug could be approved for market.

In an emergency, however, it may be beneficial to allow

animal study evidence to suffice if the circumstances

cannot permit valid human clinical trials.

Current regulations governing research related to

biodefense development cover a wide swath of legal

and ethical ground. However, the relationship between

the military and the FDA is a complex one, partly be-

cause of the institutions’ different missions. The FDA

regulates the manufacture, testing, promotion, and

commerce of medical products, and it makes a legal

distinction between products that are approved and

not approved for marketing. Products not approved for

marketing are classified as investigational new drugs

(INDs). FDA regulations specify what is necessary to

change from the latter status to the former.

Because members of the armed services are at the

greatest risk for biowarfare attack, it is prudent for the

military to research and develop effective biological

defenses that may also be used for treatment in the

civilian population in an emergency. But in the military

context, FDA regulations pose three significant legal

hurdles to the military’s ethical responsibility to pro-

tect military personnel. First, because diseases that are

potential weapons, such as Ebola or Rift Valley fever ,

are both rare in nature and can be life threatening, it is

immoral to conduct clinical trials to determine clinical

efficacy because of the inherent risk to participants.

Second, outside of clinical trials, the systematic use of

INDs (as opposed to single use instances) in emergency

life-threatening situations, is illegal. Third, it is illegal to

systematically use licensed drugs in large numbers of

persons for uses other than those indicated on the label.

Ultimately, however, researchers must find ways to cir-

cumvent these limitations so that the FDA and Depart-

ment of Defense (DoD) can fulfill their respective execu-

tive branch responsibilities while minimizing conflicts.

Federal regulations serve as practical and praise-

worthy legal and ethical safeguards for the conduct of

human subjects research. However, as detailed above,

regulations governing the conduct of human subjects

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Ethical and Legal Dilemmas in Biodefense Research

research can also have the unintended consequence

of slowing the development and advancement of

biodefense-related medicine. When the letter of the

law is applied, the interests of military personnel may

be lost in the shuffle, leaving the following ethical

dilemma: on one hand, the military has the duty to

adhere to regulations and obey the country’s laws;

on the other hand, the military has the duty to use all

available means to protect its personnel and civilians

and accomplish the mission at hand. Some way to

bridge the two horns of this dilemma is needed; in

particular, there must be a legal way to make protec-

tive drugs and vaccines available when the normally

required clinical trials cannot be carried out.

This chapter will demonstrate ways to protect mili-

tary personnel and possibly even the civilian popula-

tion. The history of the development of biodefense in

military medicine and the ethics of biomedical research

will be covered. In addition, a summary of the evolution

of regulations that influence or inform human subjects

research, including research intended and designed in

part to meet the needs of the military personnel, will be

presented. Then an analysis and discussion of the con-

flict between regulatory requirements and adherence to

ethical principles in the military setting will demonstrate

three options the DoD might pursue in relation to the

issues outlined. Some of the legislated solutions recently

proposed or implemented will also be included.

OVERVIEW OF THE HISTORY OF BIODEFENSE DEVELOPMENT AND MEDICAL ETHICS

Advances in biomedical research have led to

considerable breakthroughs in the treatment of

diseases that military personnel face. Although

the focus of this chapter is on biodefense, the his-

tory of research to protect military personnel from

disease has frequently targeted naturally occurring

diseases unfamiliar to US troops. The need for de-

velopment of medical treatment in military settings

has frequently been the impetus for conceptual

breakthroughs in the ethics of human participation

in research. Biomedical research involving human

subjects in military research facilities must be con-

ducted with oversight from an institutional review

board (IRB), per 32 CFR 219.109. 1 Acknowledgment

of ethical dimensions in biodefense research requires

the cooperation of all military personnel. However,

the ethical principles that serve as the foundations

of current ethical practices in military medical re-

search did not come about de novo, and neither did

the biodefenses and protections. Military medical

ethics standards evolved over centuries, often in

tandem with or in reaction to biodefense needs, or in

response to ethical lapses or controversies. At times

the military has assumed the lead in establishing

human subjects research ethics precedence.

placed into crowded camps, mingling with local civil-

ian populations, which expanded variola transmission

even further into vulnerable populations. 3 Washing-

ton proclaimed smallpox to be his “most dangerous

enemy,” and by 1777 he had all his soldiers variolated

before beginning new military operations. In doing

so, Washington fulfilled the ethical responsibility of

ensuring the health of his military personnel, which

in turn served to fulfill his professional responsibility

as commander of a military force to preserve the na-

tion. However, his actions were criticized by a public

unfamiliar with the stakes or conditions weighing on

this choice (Figure 24-1).

Biodefense and Ethics in the 18th and 19th Centuries

In 1766, while still a general for England, George

Washington and his soldiers were unable to take Que-

bec in the French and Indian War. In part this failure

was due to smallpox outbreaks that affected his troops. 2

Later when Washington led Continental Army troops

against the British, a smallpox epidemic reduced his

healthy troop strength to half while the British troops,

who had been variolated, were already immune to

the spreading contagion. Troops were often gathered

together from remote parts of the fledgling nation and

Fig. 24-1. George Cruikshank, Vaccination against Small Pox or

Mercenary and Merciless spreaders of Death and Devastation

driven out of Society! London, England: SW Fores, 1808. Gen-

eral George Washington was strongly criticized in the press

because of the risks and his decision to go ahead with forced

variolation despite concerns. A political cartoon, published in

the 1800s, shows how critically forced variolation was seen by

the public despite the Army’s intent to benefit its soldiers.

561

Medical Aspects of Biological Warfare

Advances in military medicine and hygiene

developed through experiences gained in battlefield

medicine during the American Civil War were adapted

as standards of medical care during the latter part of

the 19th century. New medical schools such as Johns

Hopkins sought advice about the most advanced

patient care facilities, medical practices, and medical

treatment lessons learned on the battlefield. The most

direct evidence of the influence of military medicine

on standard medical care practice is provided by John

Shaw Billings. 4 While serving in the office of the Army

surgeon general, he designed the Johns Hopkins Hos-

pital building, applying concepts he learned about the

importance of hygiene, light, and ventilation while

evaluating medical care in Civil War field hospitals.

Billings also created an indexing system for medi-

cal publications that was used for the Army surgeon

general’s library and became the nidus of the National

Library of Medicine. The Welch Medical Library at the

Johns Hopkins University School of Medicine adopted

this same system. Additionally, the Army ambulance

system was developed during the Civil War because

removing injured soldiers to field hospitals had a better

outcome than treating soldiers in the field. Further-

more, soldiers suffering war wounds frequently died

from infection. This lesson was not lost on military

physicians. As the end of the war neared, the fledgling

science of bacteriology and epidemiology became hot

topics of battlefield military medical research. Surgi-

cal techniques and use of anesthesia and antiseptics

became commonplace during the Civil War. 5-7

The Civil War was also a testing ground for medi-

cal education. One lesson learned from the war was

that many who served as military physicians did not

have the skills needed to save lives in the battlefield.

So the Army created its own medical school at what

later became the old Walter Reed Army Institute of

Research building. Those who created this school liked

the training being done at Johns Hopkins, where some

later became faculty. Later, civilian hospitals adopted

the same surgical techniques and treatment methods.

Johns Hopkins Medical School created new academic

standards not found at “proprietary” medical schools.

Thus, with the help and influence of military medical

experience, Johns Hopkins set the stage for medical

treatment in the modern era.

Surgeon General George Sternberg, who had been

trained as a bacteriologist at Johns Hopkins Medical

School, appointed Major Walter Reed, another Johns

Hopkins medical trainee, to the Yellow Fever Commis-

sion in 1900. Reed used “informed consent” statements

when he recruited volunteer subjects from among

soldiers and civilians during the occupation of Cuba at

the end of the Spanish-American War, and those state-

ments could be considered “personal service contracts”

(Figure 24-2). These documents clearly communicated

the risks and benefits of participation, described the

purpose of the study, provided a general timeline for

participation, and stated that compensation and medi-

cal care would be provided. All of these are standard

elements required in informed consent forms provided

to research participants today. Even if the yellow fever

statements did not directly influence the creation of

other military or civilian informed consent documents,

it is at least plausible to claim that documentation of

informed consent from research participants in the

military predates the practice in civilian medicine.

Biodefense, Ethics, and Research in the 20th Century

Ethical issues surrounding informed consent con-

tinued into the 20th century. At the same time, the

importance of strategic research was emphasized,

which influenced the growth of epidemiological and

infectious disease research. A 1925 Army regulation

(AR) promoting infectious disease research noted

that “volunteers” should be used in “experimental”

research. 8 In 1932 the secretary of the Navy granted

permission for experiments with divers, provided they

were “informed volunteers.” 9

The importance of strategic medical research was

not unwarranted. In 1939 Japanese scientists attempted

to obtain virulent strains of yellow fever virus from

Rockefeller University. The attempt was thwarted by

vigilant scientists, but it did not take long before the

threat of biological weaponry reached the War Depart-

ment. In 1941 Secretary of War Henry L Stimson wrote

to Frank B Jewett, president of the National Academy

of Sciences, and asked him to appoint a committee to

recommend actions. He wrote, “Because of the dan-

gers that might confront this country from potential

enemies employing what may be broadly described as

biological warfare, it seems advisable that investiga-

tions be initiated to survey the present situation and

the future possibilities.” 10 In the summer of 1942, the

War Research Service was established, under George

W Merck, Jr, in the civilian Federal Security Agency

to begin development of the US biological warfare

program with offensive and defensive objectives. On

October 9, 1942, the full committee of the War Research

Service endorsed the chairman’s statement on the use

of humans in research:

Human experimentation is not only desirable, but

necessary in the study of many of the problems of

war medicine which confront us. When any risks are

involved, volunteers only should be utilized as sub-

jects, and these only after the risks have been fully

explained and after signed statements have been

562

Ethical and Legal Dilemmas in Biodefense Research

Fig. 24-2. ( a ) English translation of the yellow fever informed consent document. ( b ) Spanish version of the yellow fever

informed consent documents. Major Walter Reed, who was appointed to the Yellow Fever Commission in 1900, used “in-

formed consent” statements when he recruited volunteer subjects from among soldiers and civilians during the occupation

of Cuba at the end of the Spanish-American War, which could be considered “personal service contracts.” However, these

( Figure 24-2 continues )

563

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