Research
The Ethics of Study Design
Overview of Departmental Initiatives: Clinical investigation begins with a research question that gives rise to the design of a scientific experiment involving human subjects. Many of the most challenging issues in the ethics of clinical research derive from the potential conflict between generating scientifically valid data to answer important research questions and protecting human subjects from harm or exploitation. The Department has undertaking wide-ranging conceptual and empirical initiatives on the ethics of study design in clinical research. The major areas of ethical inquiry include Phase I oncology trials, placebo-controlled trials, and the use of deception. Detailed descriptions of research initiatives in these three areas are presented below.
I. The Ethics of Phase I Oncology Research
Summary: This project aims to analyze the ethics of phase I oncology research and to provide data to assess the ethical concerns related to risks and benefits and the quality of informed consent. It also seeks to improve informed consent by developing a consent document template.
| Section: | Ethics of Human Subjects Research | ||||||||||||||
| Principal Investigators: | Christine Grady, Ph.D. Ezekiel J. Emanuel, M.D., Ph.D. |
||||||||||||||
| Collaborators: |
|
Background: For decades, Phase I oncology research has been highly controversial. Critics have attacked it for exposing desperately ill patients to unproven therapies with significant side effects — even risks of death — with remote chances of any substantive benefits. This very unfavorable risk-benefit ratio, they have argued, made the trials unethical. Furthermore, that thousands of patients enrolled in these trials provided prima facie evidence that there was something wrong with the informed consent process. Either prospective phase I research participants were not being accurately told the facts about Phase I oncology trials, or they did not understand them, or there was some form of coercion or compulsion. For instance, one bioethicist was quoted as having claimed that most phase I consent forms make phase I studies “sound like the cure for cancer.” Controversy has also emerged over the use of healthy volunteers in Phase I oncology trials to test the safety of novel biological agents that appear safe based on animal studies.
Departmental Research Initiative: The Department has undertaken a multi-pronged initiative. First, while there was much controversy about Phase I oncology research, the arguments were not well articulated and there had not been a synthesis of the arguments with the available empirical data to assess the validity of the claims, or to identify areas in need of additional research. In a 2003 JAMA article, Agrawal and Emanuel provided such a synthetic review. It showed that the available data on risks and benefits was old — dating mostly from the 1970s and early 1980s. It suggested that the issue of disclosure was not well studied, having been assessed in very small studies of recorded physician-patient interaction. The available data did not suggest poor disclosure of risks or benefits. It also showed that the empirical data on patient understanding was based on studies with about 700 research participants, but that many of these studies had methodological flaws, often interviewing patients weeks or months after consent, asking ambiguous questions about intent of Phase I research studies, and confusing understanding and motivations. The available data suggested participants did not seem to have systematic misunderstanding. Finally they disputed the claim that participants were coerced by both analyzing the notion of coercion and also examining the characteristics of those who enrolled in research.
Second, to examine the claims about faulty disclosure, the Department conducted a comprehensive survey of all phase I oncology informed consent documents used in the United States in one calendar year, 1999. This 2002 New England Journal study by Horng et al. indicated that these documents in general did an excellent job of disclosing that the participants were asked to enroll in a research study, contained on average 35 lines describing risks compared to only 4 lines describing benefits, usually mentioned death as a risk and almost never promised that the participants would definitely benefit. The study also noted that the documents were long — on average 6 pages — frequently used the term treatments and drugs not modified by “experimental” or “research” and very often failed to mention hospice as an alternative.
Third, the Department sought to update the available data on risks and benefits of Phase I studies by collaborating with the NCI's Cancer Therapy Evaluation Program. Using the NCI's databases on Phase I trials, the Department was able to provide a comprehensive analysis of the benefits and risks of 12 years of Phase I trials involving over 12,000 research participants. Published in the New England Journal in 2005, this study showed that most Phase I studies are no longer chemotherapy trials involving single agents never before tested in human beings but frequently involve multiple or FDA approved agents. It also showed that for single agent chemotherapy trials the risk benefit ratio has remained relatively unchanged — about 4 to 5 percent chance of CR or PR and 0.5 percent chance of death — but that overall the risks are lower but the benefits are much higher, especially when including the controversial outcome of stable disease (which seems relevant to many newer chemostatic agents such as kinase inhibitors). The study also provided data on grade III and IV toxicities to expand the understanding of risks beyond death.
Fourth, to remedy many of the deficiencies of prior empirical studies of Phase I research participants, the Department undertook a 5 center study to assess the understanding of individuals who enrolled in Phase I oncology studies. The primary aim was to determine what participants understood and their decision-making process. This study, published in 2006 in the Journal of Clinical Oncology, is the second largest study of Phase I oncology patients and interviewed all patients on the day they consented to the trial. The data shows that, these research participants are not naïve, but have extensive prior experience with cancer therapies and have researched Phase I studies extensively visiting multiple physicians and cancer centers. Furthermore, despite limited disclosure in consent forms, the vast majority of participants knew about hospice and palliative care but do not seriously consider these options for themselves. It confirms that these participants are well aware of the risks of Phase I studies, but that they would not be dissuaded even from studies with serious and higher risks than those posed by current research, such as a 10% chance of death. In other words, it confirms that these participants are well informed “gamblers” wanting to try something with potential no matter the risks.
Finally, the Department undertook an evaluation of the controversial TGN 1412 Phase I trial in health volunteers, which administered a monoclonal antibody developed as a potential treatment for leukemia. Six research subjects became critically ill. The article presented an ethical framework for investigating the safety of novel agents in healthy volunteers and challenged the ethical relevance of the for-profit status of the research sponsor and the monetary payment of subjects — issues highlighted in ethical commentary on this tragic trial.
Impact of Research: These studies have re-focused the research on Phase I oncology studies. They have clarified the ethical issues and provided definitive data on two of the main issues: disclosure in informed consent documents and actual risks and benefits of phase I oncology trials. In addition, the Agrawal and Emanuel paper inspired a further analysis of the risks and benefits of Phase I studies published in articles by a research group at the Massachusetts General Hospital, published in 2005 in JAMA. The impact by citation number are:
Authors |
Publication Date |
Citation Number |
Horng et al. |
Dec. 2002 |
28 |
Agrawal and Emanuel |
Aug. 2003 |
26 |
Horstmann. et al. |
March 2005 |
20 |
Future Research Initiatives: There are four additional studies that will complete our research in this area. First, synthesizing the Department's experience with the informed consent documents and the processes of improving informed consent, we have developed a short template for Phase I oncology informed consent documents that is just 3 pages, a total of 814 words. This paper has been submitted for publication.
Second, we are examining the actual risks and benefits of pediatric phase I oncology studies — something that has never been done. This will be critical to understanding whether these studies can be considered of benefit to children or not.
Third, to delineate whether there is exploitation of vulnerable populations, such as poor minorities, we are analyzing the NCI database to delineate the socio-demographic and other characteristics of participants in Phase I oncology research.
Finally, using the 5-center study of participants in Phase I oncology research, specifically the TCI personality profile (Temperance and Character Inventory), we are testing the hypothesis that these participants have a different personality profile, they value control and are more often risk takers than average adults. This might explain the “gambling” approach to research participation and also suggest limited impact of disclosures of risks and alternatives.
Publications:
Horng S, Emanuel EJ, Wilfond B, Rackoff J, Martz K, Grady C. Descriptions of benefits and risks in consent forms for phase 1 oncology trials. New England Journal of Medicine. 2002;347:2134-2140.
Agrawal M, Emanuel EJ. Ethics of phase 1 oncology studies: re-examining the arguments and data. JAMA. 2003;290:1075-1082.
Horstmann E, McCabe MS, Growchow L, Yamamoto S, Rubinstein L, Budd T, Shoemaker D, Emanuel EJ, Grady C. New England Journal of Medicine. 2005;352:895-904.
Agrawal M, Grady C, Fairclough DL, Meropol N, Maynard K, Emanuel EJ. Patients' decision making process regarding participating in phase I oncology research. JCO. 2006;24:4479-84.
Joffe S, Miller FG. Rethinking risk-benefit assessment for phase I cancer trials. Journal of Clinical Oncology. 2006;24:2987-90.
Emanuel EJ, Miller FG. Money and distorted ethical judgments about research: Ethical assessment of the TeGenero TGN1412 trial. American Journal of Bioethics. (In Press).
II. The Ethics of Placebo-Controlled Trials
Summary: This project undertook conceptual research on ethical issues relating to placebo-controlled trials, focusing particularly on placebo controls that withhold proven effective treatment and sham invasive procedures. It also led to a systematic critique of “clinical equipoise,” the leading ethical guidance on the design and conduct of randomized controlled trial.
| Section: | Ethics of Human Subjects Research | ||||||||||||||
| Principal Investigator: | Franklin G. Miller, Ph.D. | ||||||||||||||
| Collaborators: |
|
Background: Since the inception of randomized controlled trials in the mid 20th century, ethical concern has been voiced about placebo controls that withhold established treatment. The prevailing bioethics position on placebo-controlled trials, articulated most prominently in the Declaration of Helsinki, has stipulated that they are unethical when proven effective treatments exist for the disorder under investigation. Nevertheless, such trials, routinely approved by Institutional Review Boards, have been employed to evaluate symptomatic treatments for a wide range of conditions, including pain, anxiety and mood disorders, neurological conditions, angina, hypertension, and asthma.
The ethical debate over placebo-controlled trials has been polarized. On the one hand, opponents of placebo-controlled trials that withhold proven effective treatment argue that they violate physicians' therapeutic obligations to offer patients optimal medical care. Moreover, they claim that such trials lack clinical value, since when one or more treatments have been proven effective for a given disorder, clinician are interested in how new treatments compare with established treatment. Proponents of placebo-controlled trials contend that they are often necessary to achieve scientific validity. They point to the methodological weaknesses of active-controlled equivalence or “non-inferiority” trials — the leading alternative to placebo-controlled trials. In addition to requiring larger sample sizes, active-controlled equivalence trials suffer from problems with internal validity. In chronic conditions with high rates of placebo response, findings that an investigational drug is not inferior to a standard drug are difficult to interpret. The results may mean that both drugs are effective and equivalent in efficacy; however, neither may be effective in the group of patients enrolled in the trial. A reliable test of efficacy, accordingly, requires demonstrating superiority either to placebo or standard treatment.
Controversy over competing considerations of scientific validity and protection of research participants also surrounded randomized trials employing sham surgery controls, initially provoked by two NIH-sponsored trials of fetal tissue transplantation for patients with refractory Parkinson’s disease. Critics argue that such trials violate duties of beneficence and nonmaleficence owed to trial participants. Proponents contend that sham surgery controls are methodologically necessary to produce unbiased results when randomized trials evaluate subjective symptomatic outcomes.
Departmental Research Initiative: The Department’s conceptual research on the ethics of placebo-controlled trials endeavored to move beyond the polarized debate over the use of placebo controls pitting “science versus ethics.” A two-pronged ethical approach to placebo-controlled trials was adopted. First, the tendency to view randomized controlled trials within the ethical framework of the therapeutic physician-patient relationship was challenged as inappropriate to the context of clinical research. As clinical research requires the use of procedures that pose risks to participants without a compensating prospect of medical benefit to them, the ethics of clinical research cannot be governed by the principles of therapeutic beneficence and nonmaleficence. Hence, the fact that placebo-controlled trials withhold proven effective treatment, or that sham surgery controls are “nontherapeutic” interventions that pose risks to trial participants, do not count as decisive ethical objections. They key issue is not whether therapeutic obligations of physicians are preserved in the context of clinical trials, but whether the placebo controls are methodologically necessary and their risks are reasonable.
Second, the tendency to view the debate as “science versus ethics” was challenged by pointing out that scientific validity is one of the basic ethical requirements of clinical research. Research is valueless and risks to subjects cannot be justified unless studies employ sufficiently rigorous methods to answer research questions. Nevertheless, when research procedures to promote scientific validity carry risks for trial participants, the risks need to be minimized and justified by the value of the knowledge to be gained from the research.
The Department's efforts to develop an ethical perspective on controversial placebo-controlled trials and an account of justificatory conditions for trials that withhold proven effective treatment and employ invasive sham controls were crystallized in two Sounding Board articles published in The New England Journal. Both articles emphasized the importance of a sound methodological rationale and contextualized risk-benefit assessment.
Research on the ethics of placebo-controlled trials led to a more general critique of the tendency to view clinical trials within the ethical framework of medical care. A series of papers by Miller and colleagues diagnosed “the therapeutic orientation to clinical trials” and challenged the doctrine of clinical equipoise. Clinical equipoise was proposed in 1987 to resolve the quandary of how physicians can maintain their therapeutic obligation to offer patients optimal medical care while inviting them to enroll in clinical trials that select treatments randomly. Clinical equipoise holds that randomization is ethically acceptable as long as the medical community is in a state of uncertainty about the best treatment for patients with a given disorder. When clinical equipoise obtains, no patient is randomized to a treatment known to be inferior. Accordingly, placebo-controlled trials that withhold proven effective treatment violate clinical equipoise.
As the Department’s work on placebo-controlled trials was at loggerheads with clinical equipoise, a critique of this intuitively appealing and widely accepted ethical position was in order. The main thrust of the critique pointed to the failure to differentiate the ethics of clinical research from the ethics of medical care. Although clinical trials enroll patients and evaluate treatments, they are designed to develop generalizable knowledge, not to provide personalized medical care for participants. As a general rule, the ethics of medical care justifies risks to patients from medical interventions only when they are offset by the prospect of medical benefits. However, clinical research almost invariably includes procedures that carry risks to subjects without any compensating medical benefits to them. Hence, clinical research cannot be governed by the ethical framework of medical care, making it questionable why a therapeutically-oriented norm such as clinical equipoise should be considered ethically necessary. Placebo controls that withhold proven effective treatment are no different in principle than any non-beneficial research interventions that pose risks to research subjects. It was argued that the Department's ethical framework for clinical research, composed of 7 basic ethical requirements, is fully adequate to protect the rights and well-being of trial participants, without invoking clinical equipoise or other therapeutic norms.
Impact of research: The Department’s research has contributed to a more balanced ethical assessment of placebo-controlled trials that does justice to both methodological and risk-benefit considerations. It has also brought fresh, though controversial, thinking to the ethical foundation of clinical trials by challenging the prevailing therapeutic orientation and the doctrine of clinical equipoise.
Authors |
Publication Date |
Citation Number |
Emanuel and Miller |
Oct. 2001 |
82 |
Horng and Miller |
July 2002 |
45 |
Miller and Rosenstein |
April 2003 |
56 |
Miller and Brody |
May 2003 |
52 |
Publications:
Miller FG. Placebo-controlled trials in psychiatric research: an ethical perspective. Biological Psychiatry. 2000;47:707-16.
Emanuel EJ, Miller FG. The ethics of placebo-controlled trials — a middle ground. New England Journal of Medicine. 2001;345:915-9.
Miller FG, Shorr AF. Unnecessary use of placebo controls: the case of asthma clinical trials. Archives of Internal Medicine. 2002;162:1673-7.
Miller FG, Brody H. What makes placebo-controlled trials unethical? The American Journal of Bioethics. 2002;2(2):3-9.
Horng S, Miller FG. Is placebo surgery unethical? New England Journal of Medicine. 2002; 347:137-9.
Miller FG, Brody H. A critique of clinical equipoise: Therapeutic misconception in the ethics of clinical trials. Hastings Center Report. 2003;33(3):19-28.
Miller FG, Rosenstein DL. The therapeutic orientation to clinical trials. New England Journal of Medicine. 2003;348:1383-86.
Horng S, Miller FG. An ethical framework for the use of sham procedures in clinical trials. Critical Care Medicine. 2003;31(Suppl.):S126-S130.
Miller FG. Sham surgery: an ethical analysis. American Journal of Bioethics. 2003;3(4):41-8.
Miller FG, Kaptchuk TJ. Sham procedures and the ethics of clinical trials. Journal of the Royal Society of Medicine. 2004;97:576-78.
Buchanan D, Miller FG. Principles of early stopping of randomized trials for efficacy: a critique of equipoise and an alternative ethical framework. Kennedy Institute of Ethics Journal. 2005;15:161-78.
III. Deception in Clinical Research
Summary: This project aims to analyze systematically the ethical issues involved in the use of deception in clinical research and proposes a method of disclosure to research participants that harmonizes the use of deception with the principle of respect for autonomy and the ethical requirement of informed consent.
| Section: | Ethics of Human Subjects Research | ||
| Principal Investigator: | Wendler">David Wendler, Ph.D. Franklin G. Miller, Ph.D. |
||
| Collaborators: |
|
Background: Deception has been a common practice in research concerning human attitudes and behavior conducted by psychologists, social scientists, and neuroscientists. Deception in the form of withholding information from research subjects or deliberately misleading them about the purpose of the research and the nature of some research procedures has been thought necessary to obtain unbiased responses to experimental interventions. Deception has also been employed in clinical research. The ethics of deception has received extensive attention with respect to psychological research. However, there has been scant discussion of deception in clinical research, which poses additional ethical concerns, owing to the enrollment of patients in clinical settings.
Departmental Research Initiative: The Department’s conceptual research on deception began with a systematic analysis of ethical issues involved in deceptive research, with particular attention to behavioral research. The prevailing ethical guidance has considered deception ethically acceptable, despite contravening informed consent, if four conditions are satisfied:
- Deception is necessary to answer the research questions;
- the anticipated value of the knowledge to be gained from the research justifies the use of deception;
- research subjects are not deceived about the risks of the research interventions or any other aspects that would affect their willingness to participate; and
- subjects are debriefed at the conclusion of their research participation about the nature of the deception and its scientific rationale.
In a 1996 article, published in Milbank Quarterly, Wendler argued that these conditions do not protect research subjects from the harms of deception itself. A method described as “second order consent” was advocated to permit the use of deception compatible with respect for the autonomy of research subjects. This method would allow prospective subjects to be informed that the research involves deception without disclosing the specific nature of the deception. Accordingly, it permits valid consent while preserving scientific validity of deceptive research.
A second article by Wendler and Miller adapted this ethical analysis to deception in clinical research. It was argued that the expectations of patients for truthful disclosure by clinicians and the centrality of trust to medical care and clinical research make deception in clinical research considerably more problematic than in the case of psychology research recruiting healthy subjects — typically psychology undergraduate students, who are likely to be familiar with the use of deceptive research methods. The method of second order consent, now described as "authorized deception," was proposed to permit prospective participants of clinical research to decide for themselves whether they are willing to enroll in studies employing deception, thus making deceptive research compatible with respect for participants’ autonomy and minimizing the chance that it will undermine trust. Potential methodological objections to authorized deception were examined critically and judged to be insufficient to call into question this key ethical safeguard.
The ethical approach to deceptive research was developed further and given a more contextualized analysis by examining the extensive use of deception in clinical research aimed at elucidating the placebo effect — a growing area of investigation. To shed light on whether the authorized deception approach might bias the responses of participants and thus impair the scientific validity of the research, it was recommended that the effects of authorized deception should be tested experimentally by randomizing research participants to consent disclosures with and without informing them that deception will be employed in the study.
A fourth examination of deception in clinical research criticized the prevailing practice of disclosure to participants in randomized, sham-controlled trials of acupuncture. In contrast to the standard practice of placebo-controlled trials, many of these acupuncture studies, including several recently published large-scale trials, inform subjects that they will receive two different methods of acupuncture, without mentioning that one of the interventions is a placebo or sham control. It was argued that this deceptive disclosure violates informed consent and is not necessary to achieve scientifically valid results.
Impact of Research: The Department’s published work has brought attention to the ethical issues involved in deception in clinical research. Anecdotal evidence indicates that this research is having an impact on some investigators and IRBs. Specifically, several protocols approved by the IRB for the NIMH Intramural Research Program have deployed an authorized deception disclosure in informed consent documents. The number of citations for two articles in this research initiative is the following:
Authors |
Publication Date |
Citation Number |
Wendler |
Jan. 1996 |
9 |
Wendler and Miller |
March 2004 |
10 |
Future Research Initiatives: Three future projects are under consideration: 1) an ethical analysis of debriefing in deceptive research as a tool of moral accountability aimed at mitigating the potential harms and the wrong of deception; 2) a conceptual inquiry aimed at clarifying the nature of deception in order to address unsettled issues, such as whether placebo-controlled trials involve an element of deception in addition to concealment of treatment assignment; and 3) collaboration with an investigator conducting research on the placebo effect, with an eye to undertaking a methodological test of the authorized deception approach.
Publications:
Wendler D. Deception in medical and behavioral research: Is it ever acceptable? Milbank Quarterly. 1996;74:87-114.
Wendler D, Miller FG. Deception in the pursuit of science. Archives of Internal Medicine. 2004;164:597-600.
Miller FG, Wendler D. Assessing the ethics of ethics research: a case study. IRB. 2004;26(2):9-12.
Miller FG, Wendler D, Swartzman L. Deception in research on the placebo effect. PLoS Medicine. 2005;2(9):e262.
Miller FG, Kaptchuk TJ. Acupuncture trials and informed consent. Journal of Medical Ethics. (In Press).
