From Another Member of the Rutland Ethics Alliance...
>> Wednesday, December 18, 2013
 |
| Jennifer L. Mallory |
JUSTICE
DELAYED: THE ETHICS OF EXCLUDING WOMEN
AND MINORITIES FROM CLINICAL TRIALS
In the spring of 1979, nearly 15 years after the
Civil Rights Act but many years before diversity affinity groups became the
norm, the National Commission for the Protection of Human Subjects of
Biomedical and Behavioral Research put ethical treatment of all people first,
even before science. On April 18, 1979,
that group issued the Belmont Report:
Ethical Principles and Guidelines for the Protection of Human Subjects
of Research. The report outlined three
ethical principles to guide studies to be conducted on humans in the United
States: (1) respect, (2) beneficence,
and (3) justice—for all persons, regardless of race, ethnicity, gender, or sex.[i] Despite the report's guidance for scientists,
members of Institutional Review Boards, and Federal employees, the ethical
principle of justice has remained elusive for women and minorities. This article explores the application of
justice to clinical trials, the historical treatment of women and minorities in
research, and efforts to rectify the persistent inequity borne by women and
minorities in this area.
JUSTICE AND THE ETHICAL CLINICAL TRIAL
In
1974, the National Research Act was signed into law.[ii] That law, inter
alia, created the National Commission for the Protection of Human Subjects
of Biomedical and Behavioral Research (the “Commission”). The Commission, as the first recognized
national bioethics commission, was directed to "identify the basic ethical
principles that should underlie the conduct of biomedical and behavioral
research involving human subjects and to develop guidelines which should be
followed to assure that such research is conducted in accordance with those
principles."[iii]
As part of those
efforts, the Commission determined that "justice" was a principle or
"general prescriptive judgment" relevant to all research involving
all people.[iv] While recognizing that the ethical
principles, including justice, could "not always be applied so as to
resolve beyond dispute particular ethical questions," the Commission's
goal was "to provide an analytical framework that will guide the
resolution of ethical problems" in clinical trials.[v]
In providing that
framework for the ethical principle of justice, the Commission's starting point
was a question: “[w]ho ought to receive
the benefits of research and bear its burdens?”[vi] The Commission answered that justice requires
"fairness in distribution."[vii] In clinical trials, as elsewhere, the
Commission also noted that “[a]n injustice occurs when some benefit to which a
person is entitled is denied without good reason or when some burden is imposed
unduly.”[viii] Using the Commission's analytical
framework, a choice in favor of justice would reject exploitation of people in clinical trials simply because "of
their easy availability, their compromised position, or their
manipulability."[ix] A choice for justice also would reject exclusion of people from clinical trials
simply because they are not easily available or would be more difficult to sign
up for those trials.
Despite the promise of
justice in the Belmont Report, the benefits and the burdens of clinical
research have not been fairly distributed across society. Instead, the burden of inequitable
distribution has been shouldered by women and minorities. To illustrate, because women and minorities
often have not participated in clinical trials in a statistically meaningful
way, at times, those groups have been excluded from equal access to promising
new treatments.[x] Moreover,
their absence or exclusion has dealt a blow to science and advances in
personalized medicine, as differences in therapy responses, toxicity, and
survival between racial/ethnic and sex/gender populations may remain unknown
and untested.[xi] Accordingly, not only have those groups
been excluded from the early benefits of research, they continue to be excluded
from the long-term benefits as well.
HISTORICAL TREATMENT
1. Women in Clinical Trials
For a drug or treatment likely to be prescribed
across the adult population, justice and science seemingly would require
testing of that drug or treatment on men and women. Unfortunately, however, medical tragedies
overwhelmed the logical conclusion that women should participate in all
clinical trials. Thalidomide struck the
first blow. From the late 1950s through
the early 1960s, Thalidomide was marketed and used to treat nausea in pregnant
women.[xii] However, "[i]t became apparent in the
1960s that thalidomide treatment resulted in severe birth defects in thousands
of children."[xiii]
In the
1970s, politicians and federal regulators reacted to the terrible effects of
Thalidomide and other drugs in pregnant women.
To ensure that pregnant women would be exposed to the least possible
risk, federal regulators divided women into two categories for clinical trial
purposes: (1) women of childbearing
potential, and (2) women not of childbearing potential. The regulations defined a "woman of
childbearing potential" as
a premenopausal female
capable of becoming pregnant. This
includes women on oral, injectable, or mechanical contraception; women who are
single; women whose husbands have been vasectomized or whose husbands have
received or are utilizing mechanical contraceptive devices. Women in certain institutions, e.g., prisons,
although of childbearing potential, could be considered as not in the
appropriate environment to become pregnant during administration of
investigational drug. However, women in
mental institutions could become pregnant.[xiv]
Using that definition, regulators excluded a significant portion
of the female population from most Phase I and early Phase II clinical
trials.
Not only did this regulatory approach fail to acknowledge the
fundamental right of women to be treated as autonomous agents, but it also
mandated "continued gaps in our scientific knowledge, as important
information about metabolic activity and drug interactions in this group of
subjects [was] not readily available."[xv] Because the regulations prohibited study of
effects on women of childbearing potential, the FDA had no actual data to
assess the impact of study drugs or treatments on women and their
offspring. Even without that important
data, the FDA moved forward and approved drugs and treatments for use by women
of childbearing potential.
Consequently, the original unjust exclusion ultimately exposed
more women and their offspring to a greater risk of harm than if women
initially had been allowed to participate in the clinical trials. Thus, one injustice begat more
injustices.
2. Minorities
in Clinical Trials
While a damaging paternalism
dominated treatment of women in clinical trials, tyranny dictated the
historical treatment of minorities in clinical trials. In 1932, the Public Health Service joined
with the Tuskegee Institute to commence the “Tuskegee Study of Untreated
Syphilis in the Negro Male.”[xvi] The study, which lasted 40 years, violated
fundamental ethical principles, including respect for persons, beneficence, and
justice. The damage inflicted by those
ethical violations persists.
To illustrate, the researchers
failed to provide the participants with a clear and meaningful explanation of
the subject or purpose of the study.[xvii] Rather, the evidence indicated that the
researchers actually misled the participants.[xviii] Additionally, the participants never
received appropriate treatment for the disease.[xix] In fact, even when penicillin became the
standard of care for treating syphilis, the researchers did not offer it to the
participants.[xx] Further, the researchers did not inform the
participants that an effective treatment was available outside the study or
that the participants were free to leave the study at any time.[xxi]
In 1972, the Associated Press
published a story that exposed the Tuskegee Study and led to a public outcry.[xxii] In reaction, the Assistant Secretary for
Health and Scientific Affairs appointed an Ad Hoc Advisory Panel.[xxiii] In October 1972, the advisory panel
determined that the study was “ethically unjustified.”[xxiv] One month later, the Tuskegee Study was
ended.[xxv] In 1973, the study participants and their
families filed a class action lawsuit.[xxvi]
While the lawsuit resulted in a
settlement, including lifetime health and medical benefits and burial services
for all living participants, their wives, widows, and offspring, the harm of
the study endures. Today, it can be seen
in deep mistrust of clinical trials in at least some segments of the African
American population. As noted by Dr.
Keydron Guinn, post-doctoral fellow at the Baylor College of Medicine, “[w]hen
it comes to African Americans and clinical trials, there is this idea of a
trust issue. We are a lot less trusting
of clinical trials, because of what happened in the past…People don’t want to
be guinea pigs when it comes to pushing someone else’s agenda.”[xxvii]
That deep mistrust has grown into
another harmful legacy of the Tuskegee Study and another injustice: low minority participation in the very
clinical trials that could help to cure or treat diseases that plague minority
populations.[xxviii]
When minority populations are not represented in sufficient numbers in clinical
trials, then researchers may not be able to effectively examine “response to
therapy, toxicity, and even survival [that] may differ by racial/ethnic
subgroup independently of stage of diagnosis, treatment regimen, or other
prognostic indicators.”[xxix] Clinical study of these issues is “critical
to the development of effective…treatment and prevention, [and] cannot occur if
minority patients are underrepresented in clinical trials.”[xxx] The injustice does not impact one area of
medical research. Rather,
“underrepresentation of minorities occurs in all types of clinical research and
all therapeutic areas, including those diseases that predominantly affect
ethnic minorities.”[xxxi]
FEDERAL
EFFORTS TO INCREASE PARTICIPATION OF WOMEN AND MINORITIES IN CLINICAL TRIALS
The National Institutes of Health have taken significant steps
toward including women and minorities in research. Beginning in 1994, the NIH required women and
minorities to be included in “NIH-funded clinical research, unless a clear and
compelling rationale and justification establishes to the satisfaction of the
relevant Institute/Center Director that inclusion is inappropriate with respect
to the health of the subjects or the purpose of the research.”[xxxii] To promote inclusion of women and minorities,
the NIH further requires that their inclusion
must be addressed in
developing a research design or control proposal appropriate to the scientific
objectives of the study/contract. The research plan/proposal should describe
the composition of the proposed study population in terms of sex/gender and
racial/ethnic group, and provide a rationale for selection of such subjects. Such
a plan/proposal should contain a description of the proposed outreach programs
for recruiting women and minorities as participants.”[xxxiii]
Additionally, the NIH
mandates that cost cannot be asserted as a legitimate basis for excluding women
and minorities as participants.[xxxiv]
The Food and Drug Administration has not taken steps that mirror
those of the NIH. Instead, the FDA has
taken a more incremental approach. For
example, in the 1993, the FDA withdrew the prohibition against including women
of childbearing potential in clinical trials.[xxxv] Thereafter, in 1998, the FDA mandated that
sponsors are required to document safety and effectiveness of new drugs for
demographic subgroups and stated that it might withhold final approval of a new
drug if the approval application did not analyze the clinical data according to
the subgroup data.[xxxvi] While this is not tantamount to requiring
inclusion of women and minorities in studies, it represents a step in that
direction.
More recently, on July 9, 2012, the Food and Drug Administration
Safety and Innovation Act (FDASIA) became law.
Section 907 of FDASIA called for preparation and publication of a
"report addressing demographic subgroup participation in clinical trials
submitted to FDA in support of product applications" and describing
"demographic data collection, subset analysis, and public communication of
this information."[xxxvii] The FDA issued the required report in August
2013. The report concluded that
"statutes, regulations, and policies currently in place generally give
product sponsors a solid framework for providing data in their applications on
the inclusion and analysis of demographic subgroups."[xxxviii] While not a significant step forward, the
report reflects continuing FDA and federal focus on inclusion of women and
minorities in clinical trials.
CONCLUSION
Clinical trials may take place today without including women and
minorities. While the FDA does not mandate their inclusion, even NIH-funded
clinical trials may exclude women and minorities under certain circumstances.[xxxix] However, biopharmaceutical industry members[xl],
including research centers, hospitals, and universities, are not waiting for
the federal government to act.[xli] Those industry members are actively including
and recruiting women and minorities, potentially rectifying historical
injustices even more than federal action to date. As the economic benefits of clinical trials
continue to be seen,[xlii]
and the call for personalized medicine intensifies, industry members may become
even more incentivized to encourage and require the ethical inclusion of women
and minorities in clinical trials.[xliii]
** If you have an article that you would like to
submit for consideration for a future edition, please forward to Linda
Gallicchio, lgalli@clemson.edu.**
[i] See
The Belmont Report (April 18, 1979), available at
http://www.hhs.gov/ohrp/policy/belmont.html.
[ii] Id.
[iii] Id.
[iv] Id.
[v] Id.
[vi] Id.
[vii] Id.
[viii] Id.
[ix] Id.
[x] See,
e.g., Worta McCaskill-Stevens, Harlan Pinto, Alfred C. Marcus, Robert
Comis, Randall Morgan, Kathy Plomer, and Sarah Schoentgen, “Recruiting Minority
Cancer Patients Into Cancer Clinical Trials:
A Pilot Project Involving the Eastern Cooperative Oncology Group and the
National Medical Association,” Amer.
Society of Clinical Oncology, Vol. 17, No. 3, at 1029-1039 (March
1999).
[xi] Id.
[xii] See
James H. Kim and Anthony R. Schialli, "Thalidomide: The Tragedy of Birth Defects and the
Effective Treatment of Disease," Toxicological
Sciences, Vol. 122, Issue 1 (April 2011).
[xiii] Id.
[xiv] "General Considerations for the Clinical
Evaluation of Drugs," U.S. Department of Health, Education, and Welfare,
Public Health Service, Food and Drug Administration (1974).
[xv] Eugene G. Hayunga, Karen H. Rothenberg, and
Vivian W. Pinn, "Women of Childbearing Potential in Clinical
Research: Perspectives on NIH Policy and
Liability Issues," Food, Drug,
Cosmetic and Medical Device Law Digest, Vol. 13, No. 1 at 7 (January
1996).
[xvi] See
“The Tuskegee Timeline,” Centers for Disease Control and Prevention, available
at http://www.cdc.gov/tuskegee/timeline.htm.
[xvii] Id.
[xviii] Id.
[xix] Id.
[xx] Id.
[xxi] Id.
[xxii] Id.
[xxiii] Id.
[xxiv] Id.
[xxv] Id.
[xxvi] Id.
[xxvii] Fia Curley, “The Minority Role in Clinical
Trials,” U.S. Department of Health and Human Services, The Office of Minority
Health, available at
https://minorityhealth.hhs.gov/templates/content.aspx?ID=5147 (hereinafter “The
Minority Role”).
[xxviii] See,
e.g., Worta McCaskill-Stevens, Harlan Pinto, Alfred C. Marcus, Robert
Comis, Randall Morgan, Kathy Plomer, and Sarah Schoentgen, “Recruiting Minority
Cancer Patients Into Cancer Clinical Trials:
A Pilot Project Involving the Eastern Cooperative Oncology Group and the
National Medical Association,” Amer.
Society of Clinical Oncology, Vol. 17, No. 3, at 1029-1039 (March
1999).
[xxix] Id.
at 1038.
[xxx] Id.
[xxxi] Alfonso J. Alanis, M.D. and Ken Getz, M.S.,
M.B.A., “Minority Participation in Clinical Trials: An Elusive Goal,” Increasing Minority Participation in Clinical Research, The Endocrine
Society, at 3 (December 2007)
[xxxii] NIH Policy and Guidelines on the Inclusion
of Women and Minorities as Subjects in Clinical Research—Amended, October,
2001, at Section II (“NIH Policy”).
[xxxiii] Id.
at II.A.
[xxxiv] Id.
[xxxv] See
"Collection, Analysis, and Availability of Demographic Subgroup Data for
FDA-Approved Medical Products," FDA Report, at 11 (August 2013)
(hereinafter "FDA Report"); see
also, Nancy E. Kass, Holly A. Taylor, Patricia A. King, "Harms of
Excluding Pregnant Women from Clinical Research: The Case of HIV-Infected Pregnant
Women," Journal of Law, Medicine,
& Ethics, 24:38 (1996).
[xxxvi] See FDA
Report at 11.
[xxxvii] Id.
at 8.
[xxxviii] Id.
at 2.
[xxxix] See,
e.g., NIH Policy at Section II.A.
[xl] See
"Dialogues on Diversifying Clinical Trials: Successful Strategies for Engaging Women and
Minorities in Clinical Trials," The Society for Women's Health Research
and U.S. F.D.A. Office of Women's Health, at v. (September 22-23, 2011) (
noting that "[b]iopharma industry leaders such as Eli Lilly and Johnson
& Johnson (J&J) are already making strides").
[xli] See
Lauren Sausser, "MUSC Researchers Discuss Barriers Keeping Minority
Patients from Clinical Trials," The
Post and Courier, Aug. 27, 2013.
[xlii] Id.
(stating clinical trials conducted in South Carolina since 1999 have generated
$2.4 billion in the state).
[xliii] See,
e.g., “Gender Studies in Product Development: Historical Overview,” available at
http://www.fda.gov/ScienceResearch/SpecialTopics/WomensHealthResearch/ucm134466.htm.
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