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.
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).
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.
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.
Stage I: Bioethics in Basic Research 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 public's continued participation in and support of clinical trials that advance scientific knowledge. Over the past three decades, a plethora 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 available 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 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 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 availability 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 management 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 single 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 management 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 preventing fetal exposure to Accutane. In those discussions, conflicting 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, bioethics input was critical in framing and analyzing questions such as the following: At what point do prescribing limitations unduly interfere with patients’ ability to receive treatment they need and desperately want? To the extent risk management programs involve 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?
The urgency of clinical and translational science is clearly acknowledged 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 incorporation 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 incorporated 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 identified 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?
▪ 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.