Shapiro and Layde ■ Integrating Bioethics into CTS Research

Integrating Bioethics into Clinical and Translational Science Research: A Roadmap

Robyn S. Shapiro and Peter M. Layde1

Abstract
Recent initiatives to improve human health emphasize the need to effectively and appropriately translate new knowledge gleaned
from basic biomedical and behavioral research to clinical and community application. To maximize the beneficial impact of scientific
advances in clinical practice and community health, and to guard against potential deleterious medical and societal consequences
of such advances, incorporation of bioethics at each stage of clinical and translational science research is essential. At the earliest
stage, bioethics input is critical to address issues such as whether to limit certain areas of scientific inquiry. Subsequently, bioethics
input is important to assure not only that human subjects trials are conducted and reported responsibly, but also that results are
incorporated into clinical and community practices in a way that promotes and protects bioethical principles. At the final stage of
clinical and translational science research, bioethics helps to identify the need and approach for refining clinical practices when safety
or other concerns arise. The framework we present depicts how bioethics interfaces with each stage of clinical and translational
science research, and suggests an important research agenda for systematically and comprehensively assuring bioethics input into
clinical and translational science initiatives.
Keywords: bioethics, scientific inquiry, ethical issues

Introduction
Recent initiatives to improve human health emphasize the
need to efficiently and appropriately translate new knowledge
gleaned from basic biomedical and behavioral research to
clinical and community application. This emphasis is embodied
in the discipline of clinical and translational science, which
is championed in the National Institutes of Health’s recently
announced “Institutional Clinical and Translational Science
Award” (“CTSA”) program. As acknowledged in the CTSA
program, central to the appropriate translation of biomedical
and behavioral knowledge to clinical care and community
health is identification, analysis, and resolution of the important
bioethics issues that present along the way. Challenging ethical
issues are posed at each stage of clinical and translational
science—i.e., in basic (or “preclinical”) research studies (Stage
I), in subsequent human subjects trials (Stage II), in adoption of
best practices in the community (Stage III), and then in refinement
of best clinical practices in the community (Stage IV). Integrating
bioethics—the interdisciplinary study of ethical implications of
scientific discoveries and biomedical advances—into clinical and
translational science research is critical in order for the promises
of such research to be attained.
This commentary identifies and discusses, through case
examples, the critical role of bioethics in each stage of clinical and
translational science research, as graphically illustrated in Figure 1,
and makes recommendations for assuring the incorporation of
bioethics throughout the spectrum of this evolving discipline.
St age I : B ioe t hic s in B asic Re searc h Studies ;
Case Illustration: Cloning
While the freedom of scientific inquiry is essential for the
development of medical breakthroughs, high profile abuses in the
medical research context, such as the injection of live cancer cells
into patients at the Jewish Chronic Disease Hospital in Brooklyn,
and the Tuskegee syphilis study, are glaring reminders that the
right of scientific inquiry cannot be absolute. Some contend that
limits on scientific inquiry must include not only how research is
conducted, but also what research questions are asked.
Cloning is one recent example of debate on the ethical limits
of scientific research. The U.S. House of Representatives has voted
twice to ban all human-cloning research1; and numerous state
laws to control or prohibit this research have been adopted or
proposed.2 A number of ethical issues surround these legislative
developments. When is it justifiable to curtail freedom of scientific
inquiry? Do the potential dangers of reproductive cloning so
outweigh the benefits as to warrant prohibition of reproductive
cloning research? Does the availability of alternative means to
achieve parenthood sufficiently bolster the case for imposing
restrictions on reproductive cloning research? Do the dangers of
reproductive cloning justify a ban of all forms of cloning research?
In evaluating whether a cloning ban can be morally justified
and whether it would be a good social policy, bioethics input is
critical to adequately frame and address these questions—as well
as others that are encountered in the very early stages of clinical
and translational science research.
Stage II: Transferring Discoveries Generated in Preclinical
Studies to Trials in Humans
Applying general research ethics guidelines to the review and
approval of clinical trials in humans
Bioethics is critical to the responsible conduct and reporting of
human subjects research, which in turn is critical to the public’s
trust; and the public’s trust, in its turn, is critical to the pub-
lic’s continued participation in and support of clinical trials that

1
Center for the Study of Bioethics, Department of Population Health, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, USA
Correspondence: RS Shapiro (rshapiro@mcw.edu)
1
See The Human Cloning Prohibition Act of 2003, HR 234; and The Human Cloning Prohibition Act of 2001, HR 2505, which would make it a crime, punishable by a $1 million fine
and up to 10 years in prison, for anyone knowingly (1) to perform or attempt to perform human cloning, whether reproductive cloning or research cloning; (2) to participate in an
attempt to perform human cloning; or (3) to ship or receive for any purpose an embryo produced by human cloning or any product derived from such embryo.
2
See, e.g., Calif. Health and Safety Code sec. 24185 (prohibits cloning of human beings and sale and purchase of ovum, zygote, embryo, or fetus for the purpose of cloning a human being);
La. Rev. Stat., title 40, sect. 1299.36.2 (prohibits cloning of human being, attempts to clone human being, and sale or purchase of ovum, zygote, embryo, or fetus with the intent to clone a
human being; does not prohibit “scientific research or a cell based therapy not specifically prohibited elsewhere by this Part”); Mich. Comp. Laws Ann., chp. 333, sec. 333.16274 (prohibits
human cloning and attempts to engage in human cloning); Gen. Laws of R.I. Ann., title 23, sect. 23–16.4–2 (prohibits cloning of human beings); and Va. Code Ann., sect. 32.1–162.22
(prohibits human cloning and implantation or attempt to implant product of somatic cell nuclear transfer into uterine environment so as to initiate pregnancy).

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Shapiro and Layde ■ Integrating Bioethics into CTS Research
Figure 1. Bioethics in clinical and translational science research: a roadmap.
advance scientific knowledge. Over the past three decades, a pleth-
ora of federal and state laws, regulations, policies, and guidelines
addressing responsible research practices have been developed.
Yet, ethical issues that are not specifically addressed in law or avail-
able guidance continually arise in human subjects research.
For example, while in recent years greater attention has
been paid to ethical issues that arise from conflicts of interest in
human subjects research, there is no comprehensive guidance to
resolve these issues. These issues are of particular significance in
translational research. Industry collaboration is often essential
in realizing the promise of translational research and has figured
prominently in many suc­cesses, including recombinant growth
hormone, angioplasty, and stenting for coronary artery disease.1
This collaboration, however, can occasion conflicting obligations
among researchers, their employers, and their industry sponsors
(e.g., if a researcher receives consulting income or equity in
exchange for service on a scientific advisory board of a company
that sponsors clinical research in his/her lab). While some
governmental regulations have been issued, and many research
institutions now have policies in place to guide management
of some aspects of researchers’ personal financial interests in
research, as a gen­eral rule, institutional management of conflicts
of interest in research remains variable, unclear, and plagued by
lack of accountability.2–7 Bioethics expertise—for training of IRB
members on the topic, policy development, and consultation
in individual cases—is criti­cal to effectively address these
shortcomings that surround this crit­ical aspect of clinical and
translational science research.
Applying bioethics guidance to appropriately modify proposed
clinical trials in humans; Case illustration: PolyHeme
In some cases, bioethics input is necessary to provide guidance
on appropriate alterations of proposed human subjects research.
One recent example is the PolyHeme waived-consent study,
sponsored by Northfield Laboratories. The protocol provides that
trial subjects—trauma patients in the field suffering hemorrhagic
68 Volume 1 • Issue 1
shock—randomly receive either saline solution or PolyHeme,
an experimental oxygen-carrying blood substitute (“Phase I”
of the trial). Subject enrollment occurs under a waived-consent
exception found in FDA regulations.8 When the trial participants
arrive at the hospital, those in the control (saline) arm receive
blood as necessary; and participants in the experimental arm
continue to receive PolyHeme instead of blood for oxygen
delivery—up to six units for up to 12 hours (“Phase II” of the
trial). Once the allotted time has lapsed or six units of PolyHeme
have been administered (whichever occurs first), participants in
the experimental arm receive blood as necessary.
Bioethicists have raised ethical concerns about this protocol
and have urged that it be limited to the out-of-hospital component
(i.e., Phase I).9 Specifically, it has been argued that informed
consent, an important human subjects protection, may be waived
only where prospective subjects are in life-threatening situations
and available treatments are unproven or unsatisfactory; and in
Phase II of the PolyHeme trial (i.e., once participants have arrived
at the hospital), they have ready access to blood transfusion, a
proven and satisfactory treatment for interrupting the natural
course of hemorrhagic shock. Based on this analysis, some
investigators asked the sponsor to change the protocol so that
Phase II would be permitted only when individual consent could
be obtained from the subject or surrogate10; and some IRBs
withheld approval of the PolyHeme study.11
Stage III: Incorporating Human Subjects Research
Results into Clinical and Community Best Practices;
Case Illustration: Advances in Genetic Testing
Human subjects trials can raise serious ethical and legal questions
in the clinical setting about uses that will and should be made
of the information gleaned from the research, as illustrated by
our rapidly advancing genetic testing capabilities. For example,
to evaluate protection of patients’ autonomy, it is important
to know whether women who test positive for the BRCA-1
gene understand that, nonetheless, they may never get breast
www.ctsJOURNAL.com

cancer; and whether those who test negative understand that the
finding is not a guarantee that breast cancer will never develop.
Furthermore, does the age, socioeconomic status, cultural
background, or educational background of the patient impact
her understanding of the test’s meaning? From the perspective of
the ethical principles of beneficence, which bids us to foster the
interests and happiness of other persons, and nonmaleficence,
pursuant to which we are to refrain from harming others, what
impact do BRCA-1 test results have on the patient’s psychological
well-being, healthcare decisions and behaviors, or on the
psychological well-being, healthcare decisions and behaviors
of her sisters and daughters? What should healthcare providers
do if a patient tests positive for BRCA-1 but refuses to reveal the
results to her sisters and daughters?
The manner in which such questions are addressed and
resolved has far-reaching implications for doctors and patients and
for society at large. Yet, to date, there is a lack of comprehensive
data and focused analyses about genetic test referrals, genetic
test decision-making, and genetic test result implications relative
to the ethical principles of patient autonomy and beneficence/
nonmaleficence. This is but one example of the need for additional
bioethics studies at this stage of clinical and translational science to
assure that the adoption of research data at the bedside promotes
ethical principles.
Stage IV: Bioethics in Refining Best Clinical Practices;
Case Illustration: Accutane
On occasion, safety signals or other concerns arise with respect
to established clinical practices. Examples include adverse effects
of approved drugs or devices that have been on the market and
utilized in clinicians’ practices for a time. At that point, bioethics
input can help to resolve the tension between continued avail-
ability of a treatment modality that many may consider useful,
and imposing limitations on such availability due to suspected
longer-term dangers or risks.
One illustration of this tension is the Accutane risk manage-
ment program. In 1982, the FDA approved Accutane for use in the
treatment of severe, recalcitrant nodular acne that is unresponsive
to conventional therapy. Accutane is uniquely effective in treating
patients with this disease and in many cases is curative after a sin­
gle 4- or 5-month treatment course; but when taken by pregnant
patients, Accutane can cause serious birth defects—including
hydrocephaly, microcephaly, mental retardation, heart defects,
ear and eye abnormalities, cleft lip and palate, and other facial
deformities. Despite implementation of an Accutane Pregnancy
Prevention Program in 1989, between 1982 and 2000 there were
1995 pregnancy exposures and 383 live births involving women
taking Accutane. In response, the FDA worked with the drug
manufacturer to implement a more comprehensive program
aimed at preventing pregnancies among Accutane users, which
included restrictions on pharmacists’ dispensing practices and
distribution of a special patient Medication Guide. Unfortunately,
as of 2004, despite the implementation of the enhanced risk man-
agement program, the FDA determined that at least 100 women
per year were taking the drug while pregnant. Accordingly, in
February 2004, the FDA convened two of its advisory committees
to discuss modified risk management approaches for prevent-
ing fetal exposure to Accutane. In those discussions, conflict-
ing interests of patients, physicians, the drug manufacturer, and
persons-yet-to-be were discussed. To assist in the development
of a morally justifiable and socially effective risk management
approach, compatible with professional responsibilities, bioeth-
ics input was critical in framing and analyzing questions such as
the following: At what point do prescribing limitations unduly
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Shapiro and Layde ■ Integrating Bioethics into CTS Research
interfere with patients’ ability to receive treatment they need and
desperately want? To the extent risk management programs in-
volve patients’ required disclosure of details about their sex lives,
do they unduly infringe privacy interests? To the extent that a
prescribing physician is required to report a patient’s violations
of rules about sexual activity, is there a deleterious impact on the
physician–patient relationship?
Implications/Conclusion
The urgency of clinical and translational science is clearly ac-
knowledged in the medical and health policy literature, and in
significant governmental and private sector funding initiatives. To
maximize the beneficial impact of scientific advances in clinical
practice, and to guard against potential deleterious medical and
societal consequences of such advances, the appropriate incor-
poration of bioethics at each stage of clinical and translational
science research is essential. Given the greatly enhanced speed
with which knowledge generated in basic science is, and will be,
translated to clinical application, and given the importance of
the bioethics issues that permeate this translational process, a
systematic approach to assuring appropriate bioethics input (as
suggested in our graphic framework) should be firmly incorpo-
rated into clinical and translational science initiatives.
The primary purpose of the framework that we present is not
to provide resolution of all of the bioethical issues that arise in
clinical and translational science research. Rather, its purpose
is to serve as a tool for assuring that bioethics issues are identi-
fied and addressed throughout the clinical and translational
science continuum.
The framework that we present also may be useful in identifying
a specific bioethics research agenda that could promote progress
in clinical and translational science, including the following:
1. With respect to pre-clinical ethical issues (e.g., whether
limitations on certain areas of scientific inquiry should be
imposed) (Stage I):
■■ At an institutional level, should the role of IRBs be expanded
to include consideration of such issues? If so, how should the
scope of such issues be defined, and how should IRB member
training on such issues be accomplished? Is it realistic,
appropriate, and/or fair to expect already-overburdened IRBs
to take on such additional responsibilities?
■■ At a community level, should research institutions collaborate
with others to address common pre-clinical ethical issues?
How can the legal, political, and administrative barriers to
such collaboration be overcome?
■■ At a policy level, should pre-clinical ethical issues be addressed
by regulators, legislatures, and/or professional organizations,
and if so, in what manner? (For example, should the American
Bar Association, the National Commission on Uniform State
Laws, or other appropriate organizations provide guidance
addressing the range of ethical and legal issues that surround
legislative research restrictions?)
2. With respect to bioethics-related issues that arise in human
subjects trials (Stage II):
■■ At an institutional level, what type of IRB member training
and support is required to enable IRBs to appropriately
address currently unaddressed bioethics-related clinical and
translational science research issues? For example, in their
review of proposed clinical trials, it is uncommon for IRBs
to consider research methodology and its effect on human
subjects protection issues. How should health professional
and bioethics training programs be structured so as to assure
adequate instruction on research methodology and attendant
bioethics considerations?
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Shapiro and Layde ■ Integrating Bioethics into CTS Research
■■ At a community level, should consideration be given to
creating an IRB registry or networking group that would allow
research institutions’ IRBs to collaboratively identify and/or
address their ethics-related concerns relating to multi-center
trials and/or to community-based research initiatives?
3. With respect to bioethics issues that accompany adoption of
best practices in the community (Stage 3):
■■ At the institutional level, how should healthcare providers
assure the availability of bioethics expertise to identify and
consider ethical issues raised by the adoption of scientific
developments (including but not limited to advances in
genetics) at the bedside and in the community?
4. At the policy level, how should research grantors assure
that grant reviews include adequate bioethics input relating
not only to the research question at issue in the protocol
but also to implications of adoption of research results in
clinical practice?
5. With respect to bioethics issues that accompany alteration of
best clinical practices in the community (Stage 4):
■■ How should government regulatory entities and their
advisory committees, and industry DSMBs utilized in post-
marketing drug and device safety studies, be structured to
assure adequate bioethicist input?
These questions, which are prompted by the bioethics roadmap we
present, highlight the need for and content of additional bioethics
research for further identification, analysis, and resolution of the
important ethics issues that permeate clinical and translational
science research.
70 Volume 1 • Issue 1
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