Chapter 12
ETHICAL AND LEGAL ISSUES IN THE CONDUCT OF CANCER CLINICAL TRIALS
Gerianne
J.
Sands* and Peggy A. Means**Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
NOTE: "Gerianne Sands is the Associate General Counsel at Fred Hutchinson Cancer Research Center. The views expressed here are those of the author and not that of Fred Hutchinson Cancer Research Center. Ms. Sands can be contacted by writing to the Office of the General Counsel, Fred Hutchinson Cancer Research Center, POB 19024, MS J6-205, Seattle, Washington 98109-1024 or by e-mail at gjsands@fhcrc.org. **Peggy Means is currently a consultant whose familiarity with the issues relating to the conduct of cancer clinical trials derived from her work at Fred Hutchinson Cancer Research Center in Seattle, Washington. Ms. Means recently concluded a 16-year tenure at Fred Hutchinson in which she held positions as the Chief Operating Officer and Senior Vice President for Strategic Planning.
The views expressed here are those of the author and not that of Fred Hutchinson Cancer Research Center.
1. INTRODUCTION
Cancer clinical trials like most research involving human participants are conducted within a complex regulatory environment. Much of that regulatory framework is designed to resolve the many ethical and legal issues that arise in the conduct of research involving humans. As discussed in other chapters of this book, the physician who elects to engage in cancer clinical trials research must become familiar with this complex regulatory environment to the fullest extent possible. But a familiarity with the regulations alone is not enough.
To
be a fully informed and actively engaged researcher in cancer clinical trials, it is crucial that the physician investigator also become familiar with the ethical and legal principles embraced in these regulations.Equally important to the physician investigator is the ability to make an informed decision as to the "right" cancer clinical trial(s) to select for the cancer patients being treated. The "right" cancer clinical trial is the one that will both best serve the interest of the patients under the physician's care and will match the physician investigator's capacity to meet (or exceed) the ethical and legal requirements imposed by the trial. The physician investigator must conduct the cancer clinical trial with a risk averse approach that is responsive to the heightened expectations and rigorous scrutiny of scientific and peer review bodies, ethical committees, patients and their families, as well as the public at large. To accomplish this, the physician investigator should seek assistance from resources provided by their home institutions and should participate in educational and training programs.
As those who have experienced the rigorous scrutiny of regulatory agencies, courts of law and the sting of public and media critics can attest, it is crucial that physician investigators and their supporting institutions embrace an anticipatory and proactive approach to the conduct of cancer clinical trials. For physician investigators who choose to initiate studies involving investigational new drug applications, it is important for them to understand that they will be held to a standard historically applied to pharmaceutical and biotech companies. If the supporting infrastructure is not available to the physician investigator to meet or exceed the regulatory standards, pressure should be applied to senior leadership and governing bodies to elevate these requirements in the institution's list of priorities. For investigator-initiated studies, if the institution is unwilling to invest the necessary resources, the investigator should consider collaboration with investigators at institutions or companies with access to these resources or consider hiring outside groups, such as clinical research organizations or consultants, to monitor their studies.
COMPLEX REGULATORY ENVIRONMENT
The regulatory framework in which cancer clinical trials are conducted today is complex and pervasive. Physician investigators at a minimum are required to complete a training program that provides a basic understanding of this regulatory environment. The majority of regulations affecting the conduct of cancer clinical trials are at the federal level in the United States.
The U.S. Department of Health and Human Services' Office of Human
Research Protections ("OHRP) is the principle regulatory oversight body
for most research involving human participants. The Food and Drug
Administration ("FDA") is also authorized to regulate research related to the
drugs or devices that it approves for use in cancer treatment. Although there
Ethical and legal issues in the conduct of cancer clinical trials 221
are similarities between these two regulatory schemes, they are not identical and physician investigators must be familiar with both.
In cases in which the physician investigator elects to act as a sponsor for an "investigator initiated" investigational new drug application
("IND"),additional requirements are imposed on that physician investigator1 as
"sponsor." The assumption of responsibility for these demanding "sponsor"
obligations should be carefully considered. Physician investigators engaged in cancer clinical trials involving devices not yet approved by the FDA must also become familiar with Investigational Device Exemption regulations.2 With increasing regularity, commercial sponsors of cancer clinical trials are also requiring adherence to international standards known as the "ICH
~ u i d e l i n e s . " ~
Federal regulations and policies imposed as a condition of funding for cancer clinical trials by agencies such as the National Institutes of Health ("NIH") must also be ~ b s e r v e d . ~ The Centers for Medicare and Medicaid Services ("CMS") impose restrictions on the extent to which the costs of participation in certain "qualifying" clinical trials can be recovered and define a key role for the physician investigator in the determination of which clinical trials are "qualifying."5
The physician investigator also plays a key role in ensuring compliance with federal regulations that require that any financial conflicts of interest held by physician investigators be managed, reduced or eliminated as a condition of support.6 As will be discussed later in this chapter, many comprehensive cancer centers and academic medical centers conducting cancer clinical trials have established conflict of interest policies that go well beyond the requirements imposed by federal law and state policies.
Another important federal law that affects cancer clinical trials is the Health Insurance Portability and Accountability Act ("HIPAA") and its implementing regulations.7 Also, as discussed more fully in other chapters of this book, all federally funded research is expected to conform with the highest standards for research integrity expressed in federal research misconduct regulatiom8 There are additional laws and regulations regarding research involving research, licensure and privacy that vary by state and investigators should request information from their institutional representatives about these rules because in some cases they vary substantially from federal requirements.
Clinical trial registration requirements have been imposed as a
prerequisite for publication of research findings by many scholarly journals9
and public access to clinical trial results may be required either by research
sponsors or more broadly as a result of Congressional action.''
3. SUPPORT SYSTEMS FOR REGULATORY COMPLIANCE
The task of navigating through this regulatory maze can be daunting to any physician investigator considering whether or not to initiate or participate in a cancer clinical trial. The issues confronting the physician investigator will vary depending on the type of cancer clinical trial involved.
Those that arise as part of the complex and well-established "cooperative group" structure nurtured by the National Cancer Institute ("NCI") of the
U.S.National Institutes of Health ("NM") will be accompanied by a supporting network of resources, collaborators and coordinating centers to assist the physician investigator." Industry-sponsored clinical trials in which a drug company holds the IND and contracts with performance sites and investigators to conduct the clinical trial is also an example of a setting in which much of the regulatory compliance infrastructure is established and monitored by the company in its FDA-regulated role as the trial sponsor.12
It is when physician investigators elect to initiate a cancer clinical trial based on their own protocol and when they further elect to hold the IND that they must establish themselves and/or rely on their own institution's support system to address the regulatory compliance issues. It is important that physician investigators seek out the institutional support systems in place to assist them. To the extent these support systems are not in place or are not adequate, the physician investigator should urge institutional officials to take reasonable steps to establish and/or improve them, or to agree to have the institution hold the IND so the investigator is not as vulnerable in an
FDAaudit.
With the assistance of experienced institutional review board ("IRB") members and with the help of regulatory affairs managers and legal counsel, the physician investigator can succeed in the conduct of cancer clinical trials within this restrictive regulatory environment.
4. GENERAL ETHICAL AND LEGAL PRINCIPLES
The physician investigator conducting cancer clinical trials must be cognizant of the ethical and legal principles that form the basis for the regulatory environment described above. The general ethical principles applied in research involving human participants identified in The Belmont
~ e r 3 o r t ' ~ are summarized by Dr. Robert J. Levine in his important work
entitled Ethics and Regulation of Clinical ~ e s e a r c h . ' ~ These ethical
principles include respect for persons, beneficence and justice.
Ethical and legal issues in the conduct of cancer clinical trials 223
The "respect for persons" principle requires that the physician investigator embrace two interrelated ethical considerations. The first is that all potential trial participants in cancer clinical trials must be approached and treated as autonomous beings who are entitled to make independent decisions about whether they want to enroll in a clinical trial. The second is that extra care must be given to ensure that those individuals whose decision-making capacity is compromised by illness, condition, age or circumstance receive the assistance necessary to make an independent decision. This principle has contributed much of the basis for the requirement of a carefully constructed informed consent process.
The "beneficence" principle focuses on the critical need to ensure that any decision to conduct a cancer clinical trial at all or to enroll individuals into any cancer clinical trial is wholly supported by a finding that the benefits to the participant (and in some cases to society) outweigh the risks. This principle has provided the basis for the regulatory framework that requires that proposed clinical trials be independently reviewed to determine, among other things, whether the trial is well-designed and scientifically sound. The informed consent process requirements focus on a comprehensive risk and benefits explanation for the participant.
Additionally, the data and safety monitoring and continuing review requirements have been established to ensure that ongoing reconsideration of the risk-benefit ratio is ensured.
The "justice" principle emphasizes the importance of enrolling clinical trial participants in a fair manner that does not burden more vulnerable participants with greater exposure to risks of a cancer clinical trial. It also requires that the physician investigator make reasonable efforts to afford fair and equitable access to more vulnerable populations to extend the benefits of participation in the trial. This principle is embodied in the independent review by institutional review boards and ethical committees of the recruitment and outreach procedures to be used in the conduct of cancer clinical trials.
5. UNIQUE ETHICAL AND LEGAL CONSIDERATIONS
In addition to these general ethical and legal principles that are faced by all researchers involved in research involving human participants, the physician investigator involved in cancer clinical trials must also consider the unique ethical issues that arise in a setting in which the research participants are patients suffering from a disease for which the standard treatment available is not suitable to either effectively treat the patient's condition or to improve the patient's quality of life. Volumes have been and
will continue to be written about these unique ethical and legal considerations. This overview will simply highlight a few significant examples.
5.1 Physician as Researcher
Dr. Levine describes one of these unique ethical considerations in his discussion of the different standards that apply for clinical vs. research consent in his review of the informed consent process.'5 Cancer patients rely on the judgment of their treating physicians in making informed decisions about a course of treatment. When that same treating physician is also acting as the principle investigator or co-investigator of a cancer clinical trial, steps must be taken to ensure that the patient as a prospective clinical trial participant is exposed to and actively engages in a more complete and interactive informed consent process than might be typical in most clinical treatment settings. Prospective participants in cancer clinical trials are required to read and are encouraged to ask questions about all aspects of the cancer clinical trial described in lengthy and sometimes complicated informed consent forms. More documentation of the informed consent process is also required in the research context. In some cases, potential cancer clinical trial participants are offered an opportunity to ask questions of other physicians or health care professionals who are not involved in the conduct of the cancer clinical trial in order to ensure an enhanced degree of objectivity.
5.2 Therapeutic Misconception
A related ethical consideration that exists in the cancer clinical trial setting is a concept known as the "therapeutic misconception." The concept of "therapeutic misconception" was described by Dr. Paul Appelbaum and his colleagues in
198716as the belief that some patients as research participants hold that the research study or clinical trial in which they are invited to participate is primarily intended to benefit them individually.
Although some participants may benefit others may not. In fact, some participants may see their condition worsen or they may suffer side-effects that will threaten their very survival. Further in support of the conclusion that the belief of individual benefit is a misconception, Dr. Appelbaum, et al.
explained that "the unique aspects of clinical research include the goal of creating generalizable knowledge; the techniques of randomization; and the use of a study protocol, control groups and double-blind procedures."
l7One problem with the existence of a "therapeutic misconception" in
the cancer clinical trial setting is that the participants who hold this belief
Ethical and legal issues in the conduct of cancer clinical trials 225
may never fully and autonomously consider the "risks" associated with participation even if the informed consent process creates the ideal setting for that consideration. Another problem is that it exacerbates the already challenging task facing physician investigators of distinguishing between their roles as clinician and their roles as researchers in their interactions with the patient as a potential clinical trial participant. As summarized in related discussions in this book, the key solution to resolving the "therapeutic misconception" issue is to utilize an informed consent form and engage in an informed consent process that clearly describes to all potential cancer clinical trial participants the known and likely risks of participation and the non-research alternatives available to them.
Financial Conflicts of Interest
Finally, a critical ethical consideration that can pose serious legal risks for physician investigators and their institutions is the extent to which the cancer clinical trial is affected by financial conflicts of interest. These financial conflicts of interest can be either individual or institutional or both.
An individual conflict of interest is one in which the physician investigator (or a spouse or household member) has a financial interest that could be significantly affected by the outcome of the cancer clinical trial. An example would be a physician investigator's ownership of shares of stock issued by a pharmaceutical company who is sponsoring the physician investigator's cancer clinical trial. An example of an institutional conflict of interest is where a research institution or academic medical center that is approving and conducting the cancer clinical trial has a financial interest in a company whose cancer treatment drug is being tested in the same trial. The interest could be stock ownership or ownership of a patent interest the values of which could be significantly affected by the outcome of the cancer clinical trial.
The claims asserted by the family of Jesse Gelsinger in their widely publicized lawsuit against the University of Pennsylvania following Mr.
Gelsinger's death (while participating in a 1999 gene therapy trial) are illustrative of how ethical principles involving financial conflicts of interest can be transformed into a significant legal risk exposures for a physician investigators and their affiliate institutions under certain circumstances.
In the Gelsinger case, both the physician investigator and the University of Pennsylvania held financial interests in the company that financed the gene therapy trial being conducted by the University's Institute for Human Gene Therapy. It was alleged that these interests were intentionally not disclosed to Mr. Gelsinger. The Gelsinger lawsuit and U.S.
Department of Justice investigations were both resolved through an initial
settlement between and among the parties.18 There was no judicial determination as to whether any non-disclosure was intentional or whether the decision to enroll Mr. Gelsinger in the trial was improper or motivated by a profit incentive on the part of the physician investigator andlor the University of Pennsylvania. Nevertheless, the events leading up to the Gelsinger incident and others that followed at other institutions catapulted the topics of individual and institutional financial conflicts of interest in human subjects research into the spotlight.
Numerous scholarly reviews, articles, journal articles and guidelines have been published and recommendations ranging from outright prohibition to careful management of financial conflicts of interest have been debated and discussed in recent years.19 To improve the physician investigator's understanding of how to ethically resolve hidher potential for financial conflicts of interest in cancer clinical trials, it is helpful to understand how these financial conflicts may arise.
A variety of factors have produced an increasing level of cooperation between research institutions including academic medical centers and the pharmaceutical and biotechnology industries in the conduct of cancer clinical trials as well as the commercialization of technologies in the field of cancer diagnosis and treatment. One factor was the passage of the Bayh-Dole Act in 1980~' which encouraged research institutions to retain ownership of inventions from federally supported research. This development promoted the practice of technology transfer through which commercially viable products and technologies would be licensed by research institutions to pharmaceutical, biomedical and biotechnology companies. Another factor is the increased reliance by physician investigators and research institutions on private funding for the conduct of cancer clinical trials, most notably from pharmaceutical and biotechnology companies.
As summarized by the "Policy and Guidelines for the Oversight of Individual Financial Interests in Human Subjects Research" adopted by the American Association of American Medical Colleges ("AAMC") in 2001, opportunities to profit from research may affect - or appear to affect - a researcher's judgments about which subjects to enroll, the clinical care provided to subjects, even the proper use of subjects' confidential health information. Financial interests also threaten scientific integrity when they foster real or apparent biases in study design, data collection and analysis, adverse event reporting, or the presentation and publication of research findings." 21
Many research institutions and academic medical centers have elected to revise their individual financial conflict of interest policies that were established or refined in the mid 1990's in response to federal regulatory requirements.22 In general these modifications have imposed
Ethical and legal issues in the conduct of cancer clinical trials
22 7
stricter limitations on the financial interests that can be held by physician investigators when engaged in the conduct of human subjects research, including cancer clinical trials.
Some research institutions and academic medical centers have also established institutional conflict of interest policies that require careful review and consideration as to whether a clinical trial can be conducted at an institution that holds a potentially significant financial interest in the outcome. Those institutions who have established policies for institutional conflict of interest reviews have been guided by the 2002 AAMC Task Force Report
recommendation^^^
and the earlier work of the Association of American Universities ("AAU). 24The fundamental ethical and legal principle that serves as the foundation for individual and institutional financial conflict of interest polices is that of full disclosure. Full disclosure by physician investigators of the existence of current or future individual financial interests to their research institutions or academic medical centers is crucial. Depending on the policies and procedures in place at each research institution or academic medical center, the physician investigator may need to engage in a conflict management or mitigation process with institutional representatives.
Depending on the nature of the individual financial interest, it may also be necessary for the physician investigator to decide whether to simply eliminate the financial conflict of interest by electing to withdraw from participation in the cancer clinical trial or to dispose the interest. In most cases, physician investigators will be required to disclose to potential cancer clinical trial participants the existence of certain individual financial interests that are deemed by the institutional review board as significant. This participant disclosure process is usually incorporated into the informed consent process described earlier.
Since the policies and procedures at research institutions and academic medical centers vary widely, physician investigators interested in initiating or participating in a cancer clinical trial should thoroughly investigate the financial conflict of interest process at their own research institutions or academic medical centers. Diligent compliance with the financial conflict of interest policies and procedures is the best defense that a physician investigator can mount if faced with a legal challenge. In a high- visibility clinical trial, the investigator may want to eliminate any financial conflicts even if he or she is permitted by the institution to retain an interest, simply to avoid any appearance of a conflict.
6. CONCLUSION AND RECOMMENDATIONS
In conclusion, physician investigators who elect to participate in cancer clinical trials must be vigilant in their monitoring of the ever- changing regulatory compliance environment. It is important that they avail themselves and their staff of all opportunities for education, training and professional development in the courses focused on the ethical and responsible conduct of research involving human participants. Particular attention should be directed to the unique ethical and legal issues involved in the conduct investigator-initiated clinical trials or those that could involve individual or institutional conflicts of interest. If the conduct of cancer clinical trials is encouraged and supported by the physician investigators' research institution or academic medical center, the senior leadership at those institutions must demonstrate their commitment to establish and adequately fund regulatory compliance resources to assist and support physician investigators in this important and noble work.
REFERENCES
1. 21 Code of Federal Regulations Part 3 12 2. 21 Code of Federal Regulations Part 812
3. The International Conference on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human Use, commonly referred to as the International Conference on Harmonisation or "ICH" was adopted as guidance by the U.S. Food and Drug Administration in 1997. (See Federal Register, Vol. 62, No. 90, May 9, 1997, pages 2569 1-25709)
4. For an up-to-date listing, see http://grants.nih.gov/grants/oer.htm 5. See www.cms.hhs.gov/manuals/OG cim/ci30.asr,
6.42 Code of Federal Regulations Part 50 7. 45 Code of Federal Regulations Part 164 8. 42 Code of Federal Regulations Part 93
9. See httu:Nwww.cmai.calcgi/contentlfull/l7 1/6/606 and http://www.icmie.org/clin trialup.htm
10. S.470 called the "Fair Access to Clinical Trials Act of 2005" or "FACT" was introduced into the Senate on 2/28/05. FACT would mandate the creation of a publicly accessible national data bank of clinical trial information comprised of a clinical trial registry and a clinical trial results database.
11, httr,:Nwww.cancer.gov/cancertor,icslfactshee~NCI/clinical-trials-coor,erative-grou~
12. See FDA regulations describing "sponsor" obligations at 21 Code of Federal Regulations Subpart D, as amended.
13. The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (1979) also known as the "Belmont Report."
Ethical and legal issues in the conduct of cancer clinical trials 229
14. Levine, Robert J., Ethics and Regulation of Clinical Research (2d ed. 1988) New Haven, CT: Yale University Press.
15. Levine. Robert J., Ethics and Regulation of Clinical Research (2d ed. 1988). Chavter 5.
16. Appelbaum, Paul S., "False Hopes and Best Data: Consent to Research and the Therapeutic Misconception, 17 Hastings Center Rep., April 1987.
17. Appelbaum, Paul S., "False Hopes and Best Data: Consent to Research and the Therapeutic Misconception, 17 Hastings Center Rep., April 1987, at 20.
18. httr,://~~~.irbforum.com/forum/read/2/95/95
19. See Coleman, Carl, et al., The Ethics and Regulation of Research with Human Subjects (Matthew Bender & Company 2005), especially Chapter 5 for a thought-provoking review of these debates and discussion.
20. 35 U.S.C. Q 200, Patents: Part 11. Patentability of Inventions and Grant of Patents Chapter 18, Patent Rights in Inventions Made with Federal Assistance.
21. "Policy and Guidelines for the Oversight of Individual Financial Interests in Human Subjects Research" by the AAMC Task Force on Financial Conflicts of Interest in Clinical Research (December 2001) at p. 3.
22. See: htt~:N~rants.nih.gov/grantsl~olicvlcoifa.hm for a discussion of investigator disclosure and institutional conflict of interest management requirements for institutions receiving funding support from the National Institutes of Health ("NIH) and the National Science Foundation ("NSF").
23. See: htt~:llwww.aamc.orglmcmbcrs/coitf/
24. httv://www.aau.edu/research/COI.O l .pdf
