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Clinical Research and the Physician–Patient Relationship FREE

Donna T. Chen, MD, MPH; Franklin G. Miller, PhD; and Donald L. Rosenstein, MD
[+] Article and Author Information

From the National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.


Disclaimer: The opinions expressed are those of the authors and do not necessarily reflect the opinions or policies of the National Institutes of Health, the Department of Health and Human Services, or the federal government.

Acknowledgments: The authors thank Bradford Worrall, MD; Maria Merritt, PhD; Davina Chen, JD; Marion Danis, MD; and Ezekiel Emanuel, MD, PhD, for their advice during the preparation of this manuscript.

Grant Support: This project was supported by National Institute of Mental Health Intramural Research Program funds as part of a Fellowship in Bioethics and Consultation–Liaison Psychiatry cosponsored by the Office of the Clinical Director, National Institute of Mental Health, and the Department of Clinical Bioethics, National Institutes of Health.

Potential Financial Conflicts of Interest: Honoraria: D.L. Rosenstein (Foundation for Advanced Education in the Sciences and College of Psychiatric and Neurologic Pharmacists).

Requests for Single Reprints: Donna T. Chen, MD, MPH, Department of Clinical Bioethics, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Room 10/1C118, Bethesda, MD 20892-1156; e-mail, dochen@cc.nih.gov.

Current Author Addresses: Dr. Chen: Department of Health Evaluation Sciences, PO Box 800717, Hospital West Complex, Multistory Building, 3rd Floor, Room 3181, Charlottesville, VA 22908-0717.

Dr. Miller: Department of Clinical Bioethics, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Room 10/1C118, Bethesda, MD 20892-1156.

Dr. Rosenstein: Office of the Clinical Director, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Room 10/3N242, Bethesda, MD 20892-1277.


Ann Intern Med. 2003;138(8):669-672. doi:10.7326/0003-4819-138-8-200304150-00015
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All practicing physicians should be prepared to respond to requests from patients for advice about participating in clinical trials research. Even physicians who choose not to conduct clinical trials but rather devote their practice to clinical care may have patients who consider volunteering for research. In advising patients about clinical research, physicians enhance the physicianpatient relationship and contribute to the overall goals of evidence-based medicine. We discuss several ethical and practical challenges facing physicians who wish to help their patients make decisions about volunteering for clinical trials. In addition, we suggest how preparation for advising patients about clinical research participation can be incorporated into the medical education process.

Over the past decade, clinical trials have grown enormously in number and are now more likely to be conducted in private practice settings than academic medical centers (13). They are commonly advertised in health sections of newspapers and on the Internet (4). Patients are increasingly seeking treatment through research participation instead of, or as an adjunct to, standard clinical care. Patient education guides recommend that patients consult with their own physicians when considering participating in a clinical trial (5). Accordingly, physicians are likely to be asked by their patients for advice about whether to enroll in clinical trials.

Physicians may be reluctant to discuss clinical research with their patients because of the uncertainty inherent in clinical research, lack of knowledge about the details of particular trials, and time pressures. Nevertheless, advising patients about research participation and considering referral to a clinical trial can be an important part of good clinical practice. The ethical challenges facing physicians who enroll their own patients in research or receive payment for referring patients to clinical research have received considerable attention (23, 68). However, the challenges facing physicians who are not recruiting patients for their own research or receiving referral incentives but rather helping patients make decisions about volunteering for clinical research have not been widely addressed.

Even without knowing the details about a clinical trial, physicians can help their patients understand some of the salient differences between clinical research and clinical practice. Importantly, patients should understand that although individuals may receive treatment in the context of both clinical practice and clinical research, the orientation of these activities is markedly different. Clinical practice is oriented toward providing patients with individualized care by physicians who are dedicated primarily to their patients' best interests. The risks of diagnostic procedures and treatment interventions are justified solely by anticipated medical benefits to the patient. The guiding ethos is referred to as “personal care” (9). In contrast, clinical research is oriented toward developing knowledge to help future patients.

It is widely held that in order to be ethical, clinical trials must satisfy the requirement known as “clinical equipoise”—that is, a genuine uncertainty and lack of consensus exists within the medical community about whether the investigational treatment evaluated in a clinical trial is as good as or better than standard treatment or placebo, when no effective treatment is available (1012). Clinical trials that comply with this ethical standard still have features that depart substantially from clinical practice. Treatment alternatives (or placebo) may be randomly assigned to patient–participants, patient–participants and physician–investigators are typically blind to which alternative is received, and protocol-driven limitations may be placed on the types and doses of interventions. In addition, clinical trials may include research procedures that impose discomforts or risks for harm to patient–participants that are not compensated by personal diagnostic or therapeutic benefits; instead, they are justified by the importance of the knowledge from the study (13). For example, participation in some trials may include medication washout periods, biopsies, overnight hospital stays, imaging studies, blood draws, and questionnaires—not because something will be learned that will benefit the patient–participant, but because they are needed to generate data necessary to test study hypotheses. Although patient–participants may benefit from research participation, that is not the primary purpose of research.

Physicians can help their patients by combating distorted assessments of the potential benefits and risks of participating in research. Patients may falsely believe that novel interventions, although experimental, are always better than standard available treatments. Patients may confuse invitations to participate in research with individualized recommendations for treatment. In addition, even patients who are fully informed and understand the purpose and procedures associated with research can believe that the treatment they receive as part of their participation has been individually determined to be the best option for them. This failure in appreciation has been termed the therapeutic misconception(1416). Physicians with whom patients already have trusting relationships are uniquely positioned to recognize when their patients misconstrue important aspects of research in such a way that their assessment of risks and potential benefits are distorted.

Emotions, such as hope and desperation, frequently motivate people to participate in a clinical trial. The motivation by small prospects for benefit has been noted in patients whose clinical situations are desperate (17). Desperation can predispose patients and their families to make decisions based on unrealistic hope. Although hope is an important component of healing, maintaining false hope in the research context may do more harm than good.

Physicians are not immune to desperation or frustration in their own decision making and may be influenced by either reaction to refer patients to experimental treatments (18). Physicians should be aware of their own emotions and motivations and how these may affect their actions (19). There are concerns that physicians may collude in their patients' misunderstanding of the likelihood of benefit in phase I oncology trials (18); however, such concerns are by no means restricted to phase I oncology trials.

To provide general advice about clinical research, physicians do not necessarily need to know the details of the trials their patients are considering. However, physicians should inform patients if they are advising them with limited knowledge about the studies. Physicians who want more information to provide more specific advice to their patients have several options, including reviewing the consent form; contacting the researchers for more information, such as a copy of the protocol, if desired; and reviewing the relevant literature.

Recommending that patients participate in clinical trials can contribute to the progress of medicine as a scientifically guided practice. However, if recommended inappropriately, it could constitute undue influence over a patient's decision making. If a physician recommends volunteering for a clinical trial to a patient, she must have a clear understanding of why she is making this recommendation and communicate her rationale to the patient and, if necessary, to the investigators. Professional standards for communication in the tripartite relationship between referring physician, consultant, and patient should also apply between referring physician, investigator, and patient–participant (2021). Ongoing communication will facilitate the resumption of clinical management after a patient's participation in the trial is over.

Volunteering for a clinical trial is, at least in part, an altruistic act done for the benefit of future patients. Whether a physician can justify a recommendation on the presumption that a clinical trial is the best option for an individual's care will depend on the circumstances. Some recent reviews suggest that patient–participant outcomes are better in either arm of a clinical trial than in standard available medical care (2223). The types of trial designs, medical conditions, and clinical settings in which this holds true remain unknown (24). Nevertheless, clinical trials are generally not designed to provide individualized treatment options for each participant. Accordingly, physicians should also discuss clinically available alternatives with patients, even if they believe that a clinical trial is the best available option.

Patients referred to research by their physicians may pay less attention to assessing the risks and benefits for themselves out of trust that their physician considered their best interest in making the referral (15). Thus, it is particularly important to discuss the difference between receiving standard clinical care and volunteering for research. Physicians should emphasize that research participation is optional and that a decision not to participate in research should not affect the ability to get clinical care. Physicians should ascertain that their patients truly have an interest in considering research participation and are not just agreeing to do so to please the physician. If patients decline participation in research, physicians should provide the best available care or make an appropriate referral.

Physicians should not recommend participation in a clinical trial if they believe that participation would unduly compromise patient care or if they have unmanageable conflicts of interest (2). Dealing with one's real and perceived conflicts of interest is particularly important for physicians who are recommending that patients participate in research they are conducting as physician–investigators (23, 67). Considering whether to recommend patients to clinical trials can also be difficult when patients do not have access to medical care. In this case, clinical trials could provide needed treatment, albeit with real concerns about voluntariness and potential undue influence (25).

Ideally, if a physician believes that a patient should not participate in a research study, she will make her recommendation and reasoning clear to the patient and researchers. Despite reasonable inclusion and exclusion criteria, decisions regarding study enrollment are clinical in nature and there is always a role for second opinions. A patient and investigator may still decide that enrollment in research is acceptable despite another physician's recommendation against it. However, the researchers would be alerted that this individual may be at higher risk for a poorer outcome and may require closer monitoring. It may also be desirable in some such cases for referring physicians to continue to monitor their patients' clinical status as they proceed through the clinical trial and advocate withdrawal from research if necessary.

Fulfilling the fiduciary role of trusted advisor to patients may require consideration of the options presented by clinical trials. Therefore, all physicians should receive education in the fundamentals of clinical trials design and process. The implications of clinical trials research for the physician–patient relationship and guidance for physicians navigating through novel situations presented by clinical research should be incorporated into the medical education and residency training curricula and reinforced through continuing education. These issues are important to all physicians, whether or not they choose to become investigators; physicians who also conduct clinical research have more intensive educational needs (3, 6, 26). All medical students and residents learn to interpret the research literature in the practice of evidence-based medicine; such efforts could incorporate these general considerations. How to advise patients concerning research participation could also be included in courses on the patient–physician relationship.

Physicians have important roles as advisors and potential referral sources for their patients who are considering volunteering for clinical research. Investigators may consult with personal physicians about the appropriateness of particular patients as study participants, and human participant protection committees may require investigators to do this for some studies. It is expected that referring physicians will vary considerably regarding how much time and effort they will spend helping their patients consider options presented by clinical research participation. This time and effort should be reimbursed as part of standard medical consultation. Physicians will also vary in how supportive and encouraging of research participation they will be. Nevertheless, to advise patients optimally, it is desirable that all physicians appreciate the general aspects of how participation in a clinical trial differs from standard clinical practice. Accordingly, we recommend that these issues be incorporated into the standard and continuing medical education processes. The time has come for physicians to take a proactive stance in dealing with the various ways that clinical research affects the everyday practice of medicine. To neglect the challenges brought by these developments may result in physicians' being unprepared to serve as trusted advisors to their patients.

Rettig RA.  The industrialization of clinical research. Health Aff Millwood. 2000; 19:129-46. PubMed
CrossRef
 
Morin K, Rakatansky H, Riddick FA Jr, Morse LJ, O'Bannon JM 3rd, Goldrich MS, et al..  Managing conflicts of interest in the conduct of clinical trials. JAMA. 2002; 287:78-84. PubMed
 
Fleischman AR, Klein JE.  Clinical research in the private office setting—ethical issues. Trans Am Clin Climatol Assoc. 2002;113:126-35; discussion 135-6. [PMID: 12053705]
 
McCray AT.  Better access to information about clinical trials. Ann Intern Med. 2000; 133:609-14. PubMed
 
Emergency Care Research Institute. Should I Enter A Clinical Trial? A Patient Reference Guide for Adults with a Serious or Life-Threatening Illness. Accessed athttp://www.ecri.orgon 6 May 2002.
 
Miller FG, Rosenstein DL, DeRenzo EG.  Professional integrity in clinical research. JAMA. 1998; 280:1449-54. PubMed
 
Wolf LE, Lo B.  Association of Professors of Medicine. Ethical issues in clinical research: an issue for all internists. Am J Med. 2000; 109:82-5. PubMed
 
Rao JN, Cassia LJ.  Ethics of undisclosed payments to doctors recruiting patients in clinical trials. BMJ. 2002; 325:36-7. PubMed
 
Fried C.  Medical Experimentation: Personal Integrity and Social Policy. Amsterdam: North-Holland; 1974; 47-104.
 
Freedman B.  Equipoise and the ethics of clinical research. N Engl J Med. 1987; 317:141-5. PubMed
 
Lilford RJ, Djulbegovic B.  Uncertainty about clinical equipoise. Equipose and uncertainty principle are not mutually exclusive [Letter]. BMJ. 2001; 322:795. PubMed
 
Emanuel EJ, Miller FG.  The ethics of placebo-controlled trials—a middle ground. N Engl J Med. 2001; 345:915-9. PubMed
 
Emanuel EJ, Wendler D, Grady C.  What makes clinical research ethical? JAMA. 2000; 283:2701-11. PubMed
 
Appelbaum PS, Roth LH, Lidz CW, Benson P, Winslade W.  False hopes and best data: consent to research and the therapeutic misconception. Hastings Cent Rep. 1987; 17:20-4. PubMed
 
Kass NE, Sugarman J, Faden R, Schoch-Spana M.  Trust, the fragile foundation of contemporary biomedical research. Hastings Cent Rep. 1996; 26:25-9. PubMed
 
Lidz CW, Appelbaum PS.  The therapeutic misconception: problems and solutions. Med Care. 2002; 40:V55-63. PubMed
 
Miller M.  Phase I cancer trials: a crucible of competing priorities. Int Anesthesiol Clin. 2001; 39:13-33. PubMed
 
Miller M.  Phase I cancer trials. A collusion of misunderstanding. Hastings Cent Rep. 2000; 30:34-43. PubMed
 
Novack DH, Suchman AL, Clark W, Epstein RM, Najberg E, Kaplan C.  Calibrating the physician. Personal awareness and effective patient care. Working Group on Promoting Physician Personal Awareness, American Academy on Physician and Patient. JAMA. 1997; 278:502-9. PubMed
 
Emanuel LL, Richter J.  The consultant and the patient–physician relationship. A trilateral deliberative model. Arch Intern Med. 1994; 154:1785-90. PubMed
 
Stoeckle JD, Ronan LJ, Emanuel LL, Ehrlich CM.  A manual on manners and courtesies for the shared care of patients. J Clin Ethics. 1997; 8:22-33. PubMed
 
Lantos JD.  The “inclusion benefit” in clinical trials [Editorial]. J Pediatr. 1999; 134:130-1. PubMed
 
Braunholtz DA, Edwards SJ, Lilford RJ.  Are randomized clinical trials good for us (in the short term)? Evidence for a “trial effect”. J Clin Epidemiol. 2001; 54:217-24. PubMed
 
Vist GE, Hagen KB, Devereaux PJ, Oxman AD.  Outcomes of patients who participate in randomized controlled trials versus those of similar patients who do not participate [Protocol].  The Cochrane Library. Oxford: Update Software; 2002.
 
Kolata G, Eichenwald K.  For the uninsured, drug trials are health care. The New York Times. 22 June 1999:A1, C12.
 
Chen DT.  Curricular approaches to research ethics training for psychiatric investigators. Psychopharmacology (Berl). [In press].
 

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Tables

References

Rettig RA.  The industrialization of clinical research. Health Aff Millwood. 2000; 19:129-46. PubMed
CrossRef
 
Morin K, Rakatansky H, Riddick FA Jr, Morse LJ, O'Bannon JM 3rd, Goldrich MS, et al..  Managing conflicts of interest in the conduct of clinical trials. JAMA. 2002; 287:78-84. PubMed
 
Fleischman AR, Klein JE.  Clinical research in the private office setting—ethical issues. Trans Am Clin Climatol Assoc. 2002;113:126-35; discussion 135-6. [PMID: 12053705]
 
McCray AT.  Better access to information about clinical trials. Ann Intern Med. 2000; 133:609-14. PubMed
 
Emergency Care Research Institute. Should I Enter A Clinical Trial? A Patient Reference Guide for Adults with a Serious or Life-Threatening Illness. Accessed athttp://www.ecri.orgon 6 May 2002.
 
Miller FG, Rosenstein DL, DeRenzo EG.  Professional integrity in clinical research. JAMA. 1998; 280:1449-54. PubMed
 
Wolf LE, Lo B.  Association of Professors of Medicine. Ethical issues in clinical research: an issue for all internists. Am J Med. 2000; 109:82-5. PubMed
 
Rao JN, Cassia LJ.  Ethics of undisclosed payments to doctors recruiting patients in clinical trials. BMJ. 2002; 325:36-7. PubMed
 
Fried C.  Medical Experimentation: Personal Integrity and Social Policy. Amsterdam: North-Holland; 1974; 47-104.
 
Freedman B.  Equipoise and the ethics of clinical research. N Engl J Med. 1987; 317:141-5. PubMed
 
Lilford RJ, Djulbegovic B.  Uncertainty about clinical equipoise. Equipose and uncertainty principle are not mutually exclusive [Letter]. BMJ. 2001; 322:795. PubMed
 
Emanuel EJ, Miller FG.  The ethics of placebo-controlled trials—a middle ground. N Engl J Med. 2001; 345:915-9. PubMed
 
Emanuel EJ, Wendler D, Grady C.  What makes clinical research ethical? JAMA. 2000; 283:2701-11. PubMed
 
Appelbaum PS, Roth LH, Lidz CW, Benson P, Winslade W.  False hopes and best data: consent to research and the therapeutic misconception. Hastings Cent Rep. 1987; 17:20-4. PubMed
 
Kass NE, Sugarman J, Faden R, Schoch-Spana M.  Trust, the fragile foundation of contemporary biomedical research. Hastings Cent Rep. 1996; 26:25-9. PubMed
 
Lidz CW, Appelbaum PS.  The therapeutic misconception: problems and solutions. Med Care. 2002; 40:V55-63. PubMed
 
Miller M.  Phase I cancer trials: a crucible of competing priorities. Int Anesthesiol Clin. 2001; 39:13-33. PubMed
 
Miller M.  Phase I cancer trials. A collusion of misunderstanding. Hastings Cent Rep. 2000; 30:34-43. PubMed
 
Novack DH, Suchman AL, Clark W, Epstein RM, Najberg E, Kaplan C.  Calibrating the physician. Personal awareness and effective patient care. Working Group on Promoting Physician Personal Awareness, American Academy on Physician and Patient. JAMA. 1997; 278:502-9. PubMed
 
Emanuel LL, Richter J.  The consultant and the patient–physician relationship. A trilateral deliberative model. Arch Intern Med. 1994; 154:1785-90. PubMed
 
Stoeckle JD, Ronan LJ, Emanuel LL, Ehrlich CM.  A manual on manners and courtesies for the shared care of patients. J Clin Ethics. 1997; 8:22-33. PubMed
 
Lantos JD.  The “inclusion benefit” in clinical trials [Editorial]. J Pediatr. 1999; 134:130-1. PubMed
 
Braunholtz DA, Edwards SJ, Lilford RJ.  Are randomized clinical trials good for us (in the short term)? Evidence for a “trial effect”. J Clin Epidemiol. 2001; 54:217-24. PubMed
 
Vist GE, Hagen KB, Devereaux PJ, Oxman AD.  Outcomes of patients who participate in randomized controlled trials versus those of similar patients who do not participate [Protocol].  The Cochrane Library. Oxford: Update Software; 2002.
 
Kolata G, Eichenwald K.  For the uninsured, drug trials are health care. The New York Times. 22 June 1999:A1, C12.
 
Chen DT.  Curricular approaches to research ethics training for psychiatric investigators. Psychopharmacology (Berl). [In press].
 

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