- Email: [email protected]
Placebo-controlled studies in rheumatoid arthritis: ethical issues
DEPARTMENT OF ETHICS
Department of ethics
Placebo-controlled studies in rheumatoid arthritis: ethical issues C Michael Stein, Theodore Pincus The double-blind, placebo-controlled, randomised clinical trial is the gold standard for the assessment of a new therapy.1 Such a study design balances known and unknown factors that may affect response in the study groups, and also quantifies the placebo response. This design allows the efficacy, or lack of efficacy, of a treatment to be measured directly relative to the placebo response, which may vary in different studies. The double-blind, placebo-controlled, randomised clinical trial—though not without limitations in the applicability of its findings to clinical practice2,3—is a powerful scientific tool that has become almost a prerequisite for demonstrating the efficacy of a new therapy, both to clinicians and to drug regulatory authorities. Various ethical guidelines have been proposed to govern the performance of clinical trials. The Declaration of Helsinki, drafted after the Nuremberg trials and subsequently updated,4 is the most widely cited ethical standard to guide institutional review boards and thus the performance of clinical trials.5 The declaration states: “In research on man, the interests of science and society should never take precedence over considerations related to the well-being of the subject”, and, “In any medical study, every patient—including those of control group, if any—should be assured of the best proven diagnostic and therapeutic method.” There are two key principles here: the well-being of the individual patient should be placed above societal needs, and participants enrolled into clinical trials should be assured of the best treatment. Application of these ethical guidelines to placebocontrolled studies is straightforward in many situations. The use of placebo-controlled studies is appropriate for most conditions for which no treatment has been effective, and such controlled studies may prevent the use of ineffective or dangerous treatments.6 However, there is general agreement that a placebo control is not appropriate in conditions for which an effective (or partly effective) treatment is known, and not treating the disease for the duration of the study might result in irreversible morbidity or premature death.7 Examples of clinical situations in which placebo-controlled trials are unethical include the treatment of many cancers, many infectious diseases, and myocardial infarction. A strict interpretation of the Declaration of Helsinki would be that if an effective treatment for any condition is known, however benign the condition is thought to be, the use of a placebo control is unethical.8 The argument that all placebo-controlled clinical trials are unethical if an Lancet 1999; 353: 400–03 Departments of Pharmacology (C M Stein MRCP) and Medicine ( T Pincus MD), Vanderbilt University, Nashville, Tennessee, USA Correspondence to: Dr C M Stein, Division of Rheumatology, T 3219 MCN, Vanderbilt School of Medicine, Nashville, TN 37232, USA (e-mail: [email protected])
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effective or partly effective treatment is known has occasionally been advanced8 but has not gained general acceptance. An interpretation of the ethical guidelines that has been accepted more generally is that use of placebo controls in conditions for which an effective treatment exists is ethical—provided that the use of placebo for the duration of the study does not place the patient at increased risk of irreversible harm or cause unacceptable discomfort. In some circumstances, a temporary increase in morbidity in patients randomly assigned placebo in a clinical trial may be ethically acceptable. For example, new treatments for symptomatic conditions resulting in minor pain, vomiting, or dyspepsia may often be assessed in placebo-controlled studies. However, at some point, the severity or potential consequences of these same symptoms—vomiting associated with cancer chemotherapy, for example, or pain control in children— raise ethical questions about the use of placebo controls in a particular setting.7 For most symptomatic illness there is a continuum of morbidity, so the line between ethical and unethical use of placebo is a matter of judgment and subject to change with medical advances. These issues become more complex when the treatment being assessed may modify the long-term course of a disease. In chronic diseases such as hypertension and rheumatoid arthritis (RA), a period of poor disease control may result in long-term, irreversible organ damage. Thus, short-term placebo-controlled trials assessing therapies for hypertension in patients with mild hypertension may be reasonable. However, short-term treatment of severe hypertension with placebo and long-term treatment of mild hypertension with placebo is unethical because untreated hypertension in these settings is associated with increased morbidity and mortality. With chronic conditions, therefore, ethical decisions about placebo controls should include consideration of the severity of the disease, the rate at which the disease causes irreversible damage, and the demonstrated capacity of treatment to alter the outcome of the disease. Some have suggested that placebo-controlled clinical trials in RA are unethical.9 At that time, RA was thought to be a fairly benign disease and the effectiveness of treatment was poorly documented.10,11 The inclusion of placebo controls was thus not generally seen as important. However, over the past decade, both these assumptions have been shown to be false. First, although many patients who meet the criteria for RA may have self-limited or mild disease, cumulative evidence has shown that the course of RA in most patients seen at treatment centres is not benign but is associated with functional declines, work disability, and premature death.12–15 Most patients with a self-limited process (type I RA) resolve within a few months. Patients seen over time in treatment settings and those who enter clinical trials have persistent inflammatory symmetrical arthritis (type III RA) and experience radiological
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DEPARTMENT OF ETHICS
progression and functional declines.16,17 Second, evidence has evolved that, although not inducing remission in most patients, disease-modifying antirheumatic drugs (DMARDs) do have meaningful effects—both when used alone and in combination—that may modify short-term and long-term outcomes of RA.18–30 We therefore believe that the current ethical position with respect to placebocontrolled studies in RA should be reassessed. The continued use of placebo controls in RA clinical trials would be ethical if, first, there were no effective treatment for RA or, second, the use of placebo for 6–12 months in patients with active RA were not associated with unacceptable morbidity or irreversible damage. The first argument is no longer tenable because there is substantial evidence that drug treatment of RA with a DMARD has both short-term and long-term benefit; several drugs, particularly methotrexate, but also gold, hydroxychloroquine, sulfasalazine, and cyclosporin, have been shown to reduce pain and inflammation18,26–29 and to decrease radiological damage.19,20,30,31 In addition, there is growing evidence that treatment with a DMARD decreases not only radiological damage, but also long-term functional morbidity.32 The second argument, that delaying treatment with a DMARD for 6–12 months does not result in long-term morbidity or irreversible damage, is also becoming increasingly untenable. The increased short-term morbidity, as evidenced by pain and disability scores, in patients receiving placebo may be deemed ethically defensible since patients have access to “escape” analgesic medications, within most protocols, and are free to withdraw from the study at any time. However, of greater concern is that several studies, with several DMARDs, have now shown benefit, not only in short-term symptomatic clinical response measures, but also in the slowing of the radiological progression or erosions.19,20,30,31 Definitive data to document that efficacy in short-term clinical trials translates into long-term effectiveness in clinical outcomes is lacking because such a study has never been done—ironically, because it is generally accepted, even by advocates of the placebo-controlled trial in RA, that the long-term treatment of RA with placebo is unethical. However, it seems neither reasonable nor ethical that patients should be denied treatment that is (a) proven to be effective in the short term; (b) that is known to retard radiological progression; and (c) that is thought—albeit on the basis of incomplete data—to reduce, or even avoid, long-term damage. Furthermore, the long-term outcomes of a placebo-controlled study showed that patients with early RA who received placebo rather than a DMARD for an average of 8 months not only had a worse short-term outcome, but also, despite subsequent DMARD treatment, a worse radiological and clinical outcome 5 years later.23
Arguments in favour of continuing placebocontrolled trials in RA Rheumatoid arthritis has such a large and variable placebo response that the only way to assess whether new treatment is effective is to include a placebo arm We agree that the placebo response in RA is often large and variable and, if no harm came to patients, a placebocontrolled randomised trial would clearly be the ideal way of assessing the efficacy of a treatment. However, the ethical position that the greater good of society takes
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precedence over the wellbeing of the individual is not acceptable. To place patients at risk for the purpose of scientific rigour is not ethical. We believe that the wellbeing of the individual patient takes precedence over the potential wellbeing of future patients; and that ethical and scientific decisions are interlinked, but in debatable circumstances ethical considerations take precedence over scientific ones. Alternative study designs exist that allow comparison against an active control. Although the design and analysis of studies to compare active drugs are more complex and less clear-cut scientifically, this is not a valid reason for persisting with placebo-controlled studies. The end cannot justify the means in medical research.
Patients in clinical trials of DMARDs in RA are receiving other drugs that will control their symptoms In most studies of DMARDs in RA, patients usually receive a non-steroidal anti-inflammatory drug and often low-dose corticosteroids. Although such drugs may contribute usefully to the overall treatment of the patient with RA, it is on the background of such treatment that the inferiority of the placebo treatment—both in terms of control of disease activity and radiological progression— has been demonstrated. Coadministration of a suboptimum therapy with placebo does not justify use of placebo. DMARDs are highly toxic and may have unacceptably toxic effects on patients Historically, DMARDs such as gold and penicillamine have been highly toxic, and few patients have continued to receive them for long periods. The most effective current DMARD, methotrexate, when used in low weekly doses, may in fact cause fewer side-effects than the non-steroidal anti-inflammatory drugs that are often advocated as the safest treatment for RA.33 In our opinion, the risks of untreated RA—functional decline, deformity, and premature death—are substantially greater than the risks of standard drugs used to treat RA. Although a patient in the clinic is free, after weighing the options, to choose to receive aggressive treatment, no treatment, or ineffective treatment, it is unethical to allocate randomly a patient in a clinical trial to receive no treatment or ineffective treatment for an extended period when effective treatment exists. The ethical difference between a patient choosing no therapy and a patient being assigned none is crucial. Some have argued that many patients with RA have mild disease that does not warrant treatment with a DMARD and that placebo trials in RA are therefore acceptable. Relative to all patients with RA, it is true that a proportion have mild disease. However, patients eligible for clinical trials are not those with mild self-limited disease, but those who meet the diagnostic criteria for RA. The latter are candidates for DMARD treatment in the clinic. Patients who enter clinical trials do so freely and give informed consent The principle of informed consent, with individuals free to participate in research with full information about the potential risks and benefits, is important to medicine. The question of whether consent is ever truly informed has been debated,34 and informed consent may seldom exist in practice.35 For example, we have never seen a consent form for a RA-DMARD study that states: “There are treatments for RA that are effective in some patients. In this study, you may not receive effective treatment for your RA if you 401
DEPARTMENT OF ETHICS
are randomly allocated to placebo or if the experimental drug is not effective. There is a risk that, over the period of the study, if you are on placebo or if the new treatment is not effective, you may suffer some joint damage which may be irreversible”. Nevertheless, even in the ideal situation in which an intelligent patient fully understands the risks and benefits and is not influenced by other factors such as reimbursement of transport costs, free medication, free laboratory tests, and the contact with health-care providers, it is not acceptable to enroll patients into an unethical study, even if they consent to such enrolment.
Patients may withdraw or be withdrawn from a study at any time if they are not doing well The worse radiological outcomes in patients receiving placebo20,23 suggest that the freedom to withdraw from a sudy does not adequately protect patients in the placebo group. Several factors other than control of disease can influence a patient’s decision to remain in a clinical trial. These factors include the provision of medication, increased medical attention that comes from participation in a clinical trial, reluctance to disappoint health-care providers, and the possibility that the active drug could be received. Moreover, pain, the symptom most likely to result in withdrawal from a study does not correlate with radiological damage.36 Although they may aspire to the highest ethical and clinical standards, participants in the clinical trial process, such as the industry sponsor and the contract research organisation, have a strong financial interest. Health-care providers, while remaining advocates for the patient, also have a clear financial conflict of interest to keep patients in industry-sponsored clinical trials if reinbursement is issued per visit. Current practice in many industry-sponsored clinical trials regarding payment is that study centres are reimbursed for each visit by a patient. If a patient withdraws, or is withdrawn from a study, no further payments are made for that patient; this places the investigators in a financial conflict of interest that encourages them to keep patients in a trial. Drug regulatory authorities demand placebo-controlled studies of drugs in RA Regulatory authorities appropriately require that a new drug is shown to be effective and safe in adequate and well controlled studies. The design of a study to support the approval of a new drug is often the result of discussion between a regulatory authority, such as the US Food and Drug Administration, and the industry sponsor. In the past, studies that have sought to show the efficacy of a new drug in RA have generally done so in placebo-controlled studies, a design that suits both the US Food and Drug Administration and the industry sponsor, because is the best way to demonstrate short-term efficacy. In the continuing evolution of the treatments for a disease, however, what is ethically acceptable and what is unacceptable—not only in clinical practice but also in clinical trials—requires re-examination. Ideas evolve as knowledge about the efficacy of treatment for a disease and about the consequences of not treating the disease emerges. Consequently, what may have been ethical in the past may no longer be so. A good example is the long-term treatment of mild hypertension with placebo—a design that was ethical in the 1970s but that is not ethical now. The point at which placebo-controlled trials for a disease are deemed no longer ethical is the point at which 402
alternative study designs become acceptable to regulatory authorities and to industry. In RA, the US Food and Drug Administration has indicated an increased flexibility in the acceptability of study designs other than the traditional design of placebo versus active drug.
Patients who enter clinical trials are protected by an institutional review board Institutional review boards provide an ethical review process that tries to ensure ethical research and to protect the interests of patients. However, the final responsibility for ethical research lies with the investigator responsible for the study, not with the board. With a disorder such as RA, the judgment of a board regarding the cut-off points between ethical and unethical studies is unlikely to be as informed as the judgment of an investigator working in the field. Bureaucratic decisions tend to be heavily influenced by the status quo and by precedent. Participants randomly allocated to placebo may have a better outcome that an intervention group No clinical study is free of risk—risk that affects both the placebo group and the intervention group. The placebo group runs the risk of no treatment and the intervention group runs the risks of increased toxic effects of the drug and potential inefficacy. In several cardiovascular studies, participants randomly assigned placebo have had a better outcome that those in the intervention group.6 One of the assumptions used to justify ethically the use of a clinical trial and placebo controls is that of equipoise. In other words, the outcome of the study is unknown and the probability of risk and benefit to patients in the placebo group and in the active-treatment groups is thought to be similar. Equipoise clearly does not exist when a treatment is available that is already known to be effective. The possibility that a new drug may increase toxic effects or be ineffective, or both, exists in any clinical trial, but is not a justification for the use of placebo for a condition for which effective (or partly effective) treatments have been identified. We believe a strong ethical argument exists for abandoning the continued use of placebo-control components in clinical trials of DMARDs for RA. This position is unlikely to gain immediate general acceptance. We therefore propose some modifications of current research designs that will increase the protection of patients. Minimisation of requirements for, and duration of, placebo treatment If placebo-controlled trials continue to be deemed ethical and necessary by investigators, the duration of such studies should be limited to a period that is not associated with irreversible structural damage—say, a maximum of 3 months on placebo treatment. How long placebo can be taken without an increased risk of radiological progression is unknown, but the risk is likely to be a continuum. In addition, the rate of radiological progression in RA is most rapid early on in the disease,37 so the deleterious effects of placebo treatment may vary with duration of RA. However, 6–12 months of placebo treatment may result in adverse long-term functional consequences,23 and differences between the abilities of various DMARDs to slow radiological progression have been detectable over as little as 24 weeks.19 The proposed 3-month maximum duration of placebo treatment could be reassessed as further data on joint damage over this time period become available.
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Rigid inefficacy criteria must determine continued participation of a patient in a clinical trial Patients not responding to therapy in a clinical trial must be identified and withdrawn to protect them from the consequences of inadequate treatment. Just as rigid toxicity criteria exist for the withdrawal of many patients from clinical trials, rigid inefficacy criteria should also exist. Participants in a clinical trial not meeting a predefined improvement criterion at 12 weeks should be withdrawn for inefficacy. Such a protocol has been successful.25 The slow rate of radiological progression precludes its use as a practical study endpoint, though if a reliable measure of joint damage that changes over 3–6 months is identified, it could act as a study endpoint. Payment for clinical trials should not be issued per visit Participants who are withdrawn from trials early because of toxic reactions or inefficacy according to predetermined specified criteria have completed the study and provided valuable data. It is neither the investigator’s nor the patient’s fault if a treatment is toxic or ineffective, and payment for individuals withdrawn for these reasons should be full. To adjust payment for withdrawal of participants for protocol deviations is reasonable, but incentives to keep patients in long clinical trials without evidence of efficacy is unethical. Consent forms should include possible risk of irreversible radiological damage resulting from use of placebo or an ineffective investigational drug Radiological damage may be increased in participants who receive placebo or ineffective treatment for 6 months. In the spirit of informed consent, this information should be made available to participants. Clinical research guidelines should incorporate ethical guidelines specific to treatment of RA The interests of all concerned—patients, industry, investigators, and drug regulatory authorities—would be well served by the definition and justification of an ethical position specific to the treatment of RA by industry and drug regulatory authorities, who are the major decision makers in study design in clinical trials in RA. References 1
Ingelfinger FJ. The randomised clinical trial. N Engl J Med 1972; 287: 100–01. 2 Pincus T, Stein CM. What is the best source of useful data on the treatment of rheumatoid arthritis: clinical trials, clinical observations, or clinical protocols? J Rheumatol 1995; 22: 1611–17. 3 Feinstein AR. An additional basic science for clinical medicine: II. The limitations of randomized trials. Ann Intern Med 1983; 99: 544–50. 4 World Medical Association declaration of Helsinki. Recommendations guiding physicians in biomedical research involving human subjects. JAMA 1997; 277: 925–26. 5 Rennie D, Yank V. Disclosure to the reader of institutional review board approval and informed consent. JAMA 1997; 277: 922–23. 6 Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flexainide, or placebo: the Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991; 324: 781–88. 7 Clark PI, Leaverton PE. Scientific and ethical issues in the use of placebo controls in clinical trials. Annu Rev Public Health 1994; 15: 19–38. 8 Rothman KJ, Michels KB. The continuing unethical use of placebo controls. N Engl J Med 1994; 331: 394–98. 9 Haslock I. The ethics of placebo treatment in rheumatoid arthritis drug trials [letter]. Br J Rheumatol 1989; 28: 458. 10 Kirwan JR, Currey HL. Rheumatoid arthritis: disease-modifying antirheumatic drugs. Clin Rheum Dis 1983; 9: 581–99. 11 Iannuzzi L, Dawson N, Zein N, Kushner I. Does drug therapy slow radiographic deterioration in rheumatoid arthritis? N Engl Med 1983; 309: 1023–28.
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12 Callahan LF, Pincus T. Mortality in the rheumatic diseases. Arthritis Care Res 1995; 8: 229–41. 13 Pincus T, Callahan LF. The ‘side effects’ of rheumatoid arthritis: joint destruction, disability and early mortality. Br J Rheumatol 1993; 32 (suppl 1): 28–37. 14 Wolfe F, Cathey MA. The assessment and prediction of functional disability in rheumatoid arthritis. J Rheumatol 1991; 18: 1298–306. 15 Reilly PA, Cosh JA, Maddison PJ, Rasker JJ, Silman A. Mortality and survival in rheumatoid arthritis: a 25 year prospective study of 100 patients. Ann Rheum Dis 1990; 49: 363–69. 16 Emery P. The Roche Rheumatology Prize Lecture: the optimal management of early rheumatoid disease: the key to preventing disability. Br J Rheumatol 1994; 33: 765–68. 17 Pincus T, Callahan LE. How many types of patients meet classification criteria for rheumatoid arthritis? Rheumatol 1994; 21: 1385–89. 18 Felson DT, Anderson JJ, Meenan RF. The comparative efficacy and toxicity of second-line drugs in rheumatoid arthritis: results of two metaanalyses. Arthritis Rheum 1990; 33: 1449–61. 19 Van Riel PL, van der Heijde DM, Nuver-Zwart IH, van de Putte LB. Radiographic progression in rheumatoid arthritis: results of 3 comparative trials. J Rheumatol 1995; 22: 1797–99. 20 Forre O. Radiologic evidence of disease modification in rheumatoid arthritis patients treated with cyclosporine: results of a 48-week multicenter study comparing low-dose cyclosporine with placebo: Norwegian Arthritis Study Group. Arthritis Rheum 1994; 37: 1506–12. 21 Boers M, Verhoeven AC, Markusse HM, et al. Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet 1997; 350: 309–18. 22 Fries JF, Williams CA, Morfeld D, Singh G, Sibley J. Reduction in long-term disability in patients with rheumatoid arthritis by diseasemodifying antirheumatic drug-based treatment strategies. Arthritis Rheum 1996; 39: 616–22. 23 Egsmose C, Lund B, Borg G, et al. Patients with rheumatoid arthritis benefit from early 2nd line therapy: 5 year follow-up of a prospective double-blind placebo-controlled study. J Rheumatol 1995; 22: 2208–13. 24 O’Dell JR, Haire CE, Palmer W, et al. Treatment of early rheumatoid arthritis with minocycline or placebo: results of a randomized, doubleblind, placebo-controlled trial. Arthritis Rheum 1997; 40: 842–48. 25 O’Dell JR, Haire CE, Palmer W, et al. Treatment of early rheumatoid arthritis with minocycline or placebo: results of a randomized, doubleblind, placebo-controlled trial. Arthritis Rheum 1997; 40: 842–48. 26 Kremer JM. Safety, efficacy, and mortality in a long-term cohort of patients with rheumatoid arthritis taking methotrexate: follow-up after a mean of 13·3 years. Arthritis Rheum 1997; 40: 984–85. 27 Hannonen P, Mottonen T, Hakola M, Oka M. Sulfasalazine in early rheumatoid arthritis: a 48-week double-blind, prospective, placebocontrolled study. Arthritis Rheum 1993; 36: 1501–09. 28 Borg G, Allander E, Berg E, Brodin U, From A, Trang L. Auranofin treatment in early rheumatoid arthritis may postpone early retirement: results from a 2-year double blind trial. J Rheumatol 1991; 18: 1015–20. 29 Tugwell P, Pincus T, Yocum D, et al. Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis: the Methotrexate-Cyclosporine Combination Study Group. N Engl J Med 1995; 333: 137–41. 30 Weinblatt ME, Polisson R, Blotner SD, et al. The effects of drug therapy on radiographic progression of rheumatoid arthritis: results of a 36-week randomized trial comparing methotrexate and auranofin. Arthritis Rheum 1993; 36: 613–19. 31 Pasero G, Priolo F, Marubini E, et al. Slow progression of joint damage in early rheumatoid arthritis treated with cyclosporin A. Arthritis Rheum 1996; 39: 1006–15. 32 Ward MM, Leigh JP, Fries JF. Progression of functional disability in patients with rheumatoid arthritis: associations with rheumatology subspecialty care. Arch Intern Med 1993; 153: 2229–37. 33 Fries JF, Williams CA, Ramey D, Bloch DA.The relative toxicity of disease-modifying antirheumatic drugs. Arthritis Rheum 1993; 36: 297–306. 34 Verheggen FW, van Wijmen FC. Myth and reality of informed consent in clinical trials. Med Law 1997; 16: 53–69. 35 Lynoe N, Sandlund M, Dahlqvist G, Jacobsson L. Informed consent: study of quality of information given to participants in a clinical trial. BMJ 1991; 303: 610–13. 36 Pincus T, Callahan LF, Fuchs HA, Larsen A, Kaye J. Quantitative analysis of hand radiographs in rheumatoid arthritis: time course of radiographic changes, relation to joint examination measures, and comparison of different scoring methods. J Rheumatol 1995; 22: 1983–89. 37 Fuchs HA, Pincus T. Radiographic damage in rheumatoid arthritis: description by nonlinear models. J Rheumatol 1992; 19: 1655–58.
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Department of ethics
Placebo-controlled studies in rheumatoid arthritis: ethical issues C Michael Stein, Theodore Pincus The double-blind, placebo-controlled, randomised clinical trial is the gold standard for the assessment of a new therapy.1 Such a study design balances known and unknown factors that may affect response in the study groups, and also quantifies the placebo response. This design allows the efficacy, or lack of efficacy, of a treatment to be measured directly relative to the placebo response, which may vary in different studies. The double-blind, placebo-controlled, randomised clinical trial—though not without limitations in the applicability of its findings to clinical practice2,3—is a powerful scientific tool that has become almost a prerequisite for demonstrating the efficacy of a new therapy, both to clinicians and to drug regulatory authorities. Various ethical guidelines have been proposed to govern the performance of clinical trials. The Declaration of Helsinki, drafted after the Nuremberg trials and subsequently updated,4 is the most widely cited ethical standard to guide institutional review boards and thus the performance of clinical trials.5 The declaration states: “In research on man, the interests of science and society should never take precedence over considerations related to the well-being of the subject”, and, “In any medical study, every patient—including those of control group, if any—should be assured of the best proven diagnostic and therapeutic method.” There are two key principles here: the well-being of the individual patient should be placed above societal needs, and participants enrolled into clinical trials should be assured of the best treatment. Application of these ethical guidelines to placebocontrolled studies is straightforward in many situations. The use of placebo-controlled studies is appropriate for most conditions for which no treatment has been effective, and such controlled studies may prevent the use of ineffective or dangerous treatments.6 However, there is general agreement that a placebo control is not appropriate in conditions for which an effective (or partly effective) treatment is known, and not treating the disease for the duration of the study might result in irreversible morbidity or premature death.7 Examples of clinical situations in which placebo-controlled trials are unethical include the treatment of many cancers, many infectious diseases, and myocardial infarction. A strict interpretation of the Declaration of Helsinki would be that if an effective treatment for any condition is known, however benign the condition is thought to be, the use of a placebo control is unethical.8 The argument that all placebo-controlled clinical trials are unethical if an Lancet 1999; 353: 400–03 Departments of Pharmacology (C M Stein MRCP) and Medicine ( T Pincus MD), Vanderbilt University, Nashville, Tennessee, USA Correspondence to: Dr C M Stein, Division of Rheumatology, T 3219 MCN, Vanderbilt School of Medicine, Nashville, TN 37232, USA (e-mail: [email protected])
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effective or partly effective treatment is known has occasionally been advanced8 but has not gained general acceptance. An interpretation of the ethical guidelines that has been accepted more generally is that use of placebo controls in conditions for which an effective treatment exists is ethical—provided that the use of placebo for the duration of the study does not place the patient at increased risk of irreversible harm or cause unacceptable discomfort. In some circumstances, a temporary increase in morbidity in patients randomly assigned placebo in a clinical trial may be ethically acceptable. For example, new treatments for symptomatic conditions resulting in minor pain, vomiting, or dyspepsia may often be assessed in placebo-controlled studies. However, at some point, the severity or potential consequences of these same symptoms—vomiting associated with cancer chemotherapy, for example, or pain control in children— raise ethical questions about the use of placebo controls in a particular setting.7 For most symptomatic illness there is a continuum of morbidity, so the line between ethical and unethical use of placebo is a matter of judgment and subject to change with medical advances. These issues become more complex when the treatment being assessed may modify the long-term course of a disease. In chronic diseases such as hypertension and rheumatoid arthritis (RA), a period of poor disease control may result in long-term, irreversible organ damage. Thus, short-term placebo-controlled trials assessing therapies for hypertension in patients with mild hypertension may be reasonable. However, short-term treatment of severe hypertension with placebo and long-term treatment of mild hypertension with placebo is unethical because untreated hypertension in these settings is associated with increased morbidity and mortality. With chronic conditions, therefore, ethical decisions about placebo controls should include consideration of the severity of the disease, the rate at which the disease causes irreversible damage, and the demonstrated capacity of treatment to alter the outcome of the disease. Some have suggested that placebo-controlled clinical trials in RA are unethical.9 At that time, RA was thought to be a fairly benign disease and the effectiveness of treatment was poorly documented.10,11 The inclusion of placebo controls was thus not generally seen as important. However, over the past decade, both these assumptions have been shown to be false. First, although many patients who meet the criteria for RA may have self-limited or mild disease, cumulative evidence has shown that the course of RA in most patients seen at treatment centres is not benign but is associated with functional declines, work disability, and premature death.12–15 Most patients with a self-limited process (type I RA) resolve within a few months. Patients seen over time in treatment settings and those who enter clinical trials have persistent inflammatory symmetrical arthritis (type III RA) and experience radiological
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progression and functional declines.16,17 Second, evidence has evolved that, although not inducing remission in most patients, disease-modifying antirheumatic drugs (DMARDs) do have meaningful effects—both when used alone and in combination—that may modify short-term and long-term outcomes of RA.18–30 We therefore believe that the current ethical position with respect to placebocontrolled studies in RA should be reassessed. The continued use of placebo controls in RA clinical trials would be ethical if, first, there were no effective treatment for RA or, second, the use of placebo for 6–12 months in patients with active RA were not associated with unacceptable morbidity or irreversible damage. The first argument is no longer tenable because there is substantial evidence that drug treatment of RA with a DMARD has both short-term and long-term benefit; several drugs, particularly methotrexate, but also gold, hydroxychloroquine, sulfasalazine, and cyclosporin, have been shown to reduce pain and inflammation18,26–29 and to decrease radiological damage.19,20,30,31 In addition, there is growing evidence that treatment with a DMARD decreases not only radiological damage, but also long-term functional morbidity.32 The second argument, that delaying treatment with a DMARD for 6–12 months does not result in long-term morbidity or irreversible damage, is also becoming increasingly untenable. The increased short-term morbidity, as evidenced by pain and disability scores, in patients receiving placebo may be deemed ethically defensible since patients have access to “escape” analgesic medications, within most protocols, and are free to withdraw from the study at any time. However, of greater concern is that several studies, with several DMARDs, have now shown benefit, not only in short-term symptomatic clinical response measures, but also in the slowing of the radiological progression or erosions.19,20,30,31 Definitive data to document that efficacy in short-term clinical trials translates into long-term effectiveness in clinical outcomes is lacking because such a study has never been done—ironically, because it is generally accepted, even by advocates of the placebo-controlled trial in RA, that the long-term treatment of RA with placebo is unethical. However, it seems neither reasonable nor ethical that patients should be denied treatment that is (a) proven to be effective in the short term; (b) that is known to retard radiological progression; and (c) that is thought—albeit on the basis of incomplete data—to reduce, or even avoid, long-term damage. Furthermore, the long-term outcomes of a placebo-controlled study showed that patients with early RA who received placebo rather than a DMARD for an average of 8 months not only had a worse short-term outcome, but also, despite subsequent DMARD treatment, a worse radiological and clinical outcome 5 years later.23
Arguments in favour of continuing placebocontrolled trials in RA Rheumatoid arthritis has such a large and variable placebo response that the only way to assess whether new treatment is effective is to include a placebo arm We agree that the placebo response in RA is often large and variable and, if no harm came to patients, a placebocontrolled randomised trial would clearly be the ideal way of assessing the efficacy of a treatment. However, the ethical position that the greater good of society takes
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precedence over the wellbeing of the individual is not acceptable. To place patients at risk for the purpose of scientific rigour is not ethical. We believe that the wellbeing of the individual patient takes precedence over the potential wellbeing of future patients; and that ethical and scientific decisions are interlinked, but in debatable circumstances ethical considerations take precedence over scientific ones. Alternative study designs exist that allow comparison against an active control. Although the design and analysis of studies to compare active drugs are more complex and less clear-cut scientifically, this is not a valid reason for persisting with placebo-controlled studies. The end cannot justify the means in medical research.
Patients in clinical trials of DMARDs in RA are receiving other drugs that will control their symptoms In most studies of DMARDs in RA, patients usually receive a non-steroidal anti-inflammatory drug and often low-dose corticosteroids. Although such drugs may contribute usefully to the overall treatment of the patient with RA, it is on the background of such treatment that the inferiority of the placebo treatment—both in terms of control of disease activity and radiological progression— has been demonstrated. Coadministration of a suboptimum therapy with placebo does not justify use of placebo. DMARDs are highly toxic and may have unacceptably toxic effects on patients Historically, DMARDs such as gold and penicillamine have been highly toxic, and few patients have continued to receive them for long periods. The most effective current DMARD, methotrexate, when used in low weekly doses, may in fact cause fewer side-effects than the non-steroidal anti-inflammatory drugs that are often advocated as the safest treatment for RA.33 In our opinion, the risks of untreated RA—functional decline, deformity, and premature death—are substantially greater than the risks of standard drugs used to treat RA. Although a patient in the clinic is free, after weighing the options, to choose to receive aggressive treatment, no treatment, or ineffective treatment, it is unethical to allocate randomly a patient in a clinical trial to receive no treatment or ineffective treatment for an extended period when effective treatment exists. The ethical difference between a patient choosing no therapy and a patient being assigned none is crucial. Some have argued that many patients with RA have mild disease that does not warrant treatment with a DMARD and that placebo trials in RA are therefore acceptable. Relative to all patients with RA, it is true that a proportion have mild disease. However, patients eligible for clinical trials are not those with mild self-limited disease, but those who meet the diagnostic criteria for RA. The latter are candidates for DMARD treatment in the clinic. Patients who enter clinical trials do so freely and give informed consent The principle of informed consent, with individuals free to participate in research with full information about the potential risks and benefits, is important to medicine. The question of whether consent is ever truly informed has been debated,34 and informed consent may seldom exist in practice.35 For example, we have never seen a consent form for a RA-DMARD study that states: “There are treatments for RA that are effective in some patients. In this study, you may not receive effective treatment for your RA if you 401
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are randomly allocated to placebo or if the experimental drug is not effective. There is a risk that, over the period of the study, if you are on placebo or if the new treatment is not effective, you may suffer some joint damage which may be irreversible”. Nevertheless, even in the ideal situation in which an intelligent patient fully understands the risks and benefits and is not influenced by other factors such as reimbursement of transport costs, free medication, free laboratory tests, and the contact with health-care providers, it is not acceptable to enroll patients into an unethical study, even if they consent to such enrolment.
Patients may withdraw or be withdrawn from a study at any time if they are not doing well The worse radiological outcomes in patients receiving placebo20,23 suggest that the freedom to withdraw from a sudy does not adequately protect patients in the placebo group. Several factors other than control of disease can influence a patient’s decision to remain in a clinical trial. These factors include the provision of medication, increased medical attention that comes from participation in a clinical trial, reluctance to disappoint health-care providers, and the possibility that the active drug could be received. Moreover, pain, the symptom most likely to result in withdrawal from a study does not correlate with radiological damage.36 Although they may aspire to the highest ethical and clinical standards, participants in the clinical trial process, such as the industry sponsor and the contract research organisation, have a strong financial interest. Health-care providers, while remaining advocates for the patient, also have a clear financial conflict of interest to keep patients in industry-sponsored clinical trials if reinbursement is issued per visit. Current practice in many industry-sponsored clinical trials regarding payment is that study centres are reimbursed for each visit by a patient. If a patient withdraws, or is withdrawn from a study, no further payments are made for that patient; this places the investigators in a financial conflict of interest that encourages them to keep patients in a trial. Drug regulatory authorities demand placebo-controlled studies of drugs in RA Regulatory authorities appropriately require that a new drug is shown to be effective and safe in adequate and well controlled studies. The design of a study to support the approval of a new drug is often the result of discussion between a regulatory authority, such as the US Food and Drug Administration, and the industry sponsor. In the past, studies that have sought to show the efficacy of a new drug in RA have generally done so in placebo-controlled studies, a design that suits both the US Food and Drug Administration and the industry sponsor, because is the best way to demonstrate short-term efficacy. In the continuing evolution of the treatments for a disease, however, what is ethically acceptable and what is unacceptable—not only in clinical practice but also in clinical trials—requires re-examination. Ideas evolve as knowledge about the efficacy of treatment for a disease and about the consequences of not treating the disease emerges. Consequently, what may have been ethical in the past may no longer be so. A good example is the long-term treatment of mild hypertension with placebo—a design that was ethical in the 1970s but that is not ethical now. The point at which placebo-controlled trials for a disease are deemed no longer ethical is the point at which 402
alternative study designs become acceptable to regulatory authorities and to industry. In RA, the US Food and Drug Administration has indicated an increased flexibility in the acceptability of study designs other than the traditional design of placebo versus active drug.
Patients who enter clinical trials are protected by an institutional review board Institutional review boards provide an ethical review process that tries to ensure ethical research and to protect the interests of patients. However, the final responsibility for ethical research lies with the investigator responsible for the study, not with the board. With a disorder such as RA, the judgment of a board regarding the cut-off points between ethical and unethical studies is unlikely to be as informed as the judgment of an investigator working in the field. Bureaucratic decisions tend to be heavily influenced by the status quo and by precedent. Participants randomly allocated to placebo may have a better outcome that an intervention group No clinical study is free of risk—risk that affects both the placebo group and the intervention group. The placebo group runs the risk of no treatment and the intervention group runs the risks of increased toxic effects of the drug and potential inefficacy. In several cardiovascular studies, participants randomly assigned placebo have had a better outcome that those in the intervention group.6 One of the assumptions used to justify ethically the use of a clinical trial and placebo controls is that of equipoise. In other words, the outcome of the study is unknown and the probability of risk and benefit to patients in the placebo group and in the active-treatment groups is thought to be similar. Equipoise clearly does not exist when a treatment is available that is already known to be effective. The possibility that a new drug may increase toxic effects or be ineffective, or both, exists in any clinical trial, but is not a justification for the use of placebo for a condition for which effective (or partly effective) treatments have been identified. We believe a strong ethical argument exists for abandoning the continued use of placebo-control components in clinical trials of DMARDs for RA. This position is unlikely to gain immediate general acceptance. We therefore propose some modifications of current research designs that will increase the protection of patients. Minimisation of requirements for, and duration of, placebo treatment If placebo-controlled trials continue to be deemed ethical and necessary by investigators, the duration of such studies should be limited to a period that is not associated with irreversible structural damage—say, a maximum of 3 months on placebo treatment. How long placebo can be taken without an increased risk of radiological progression is unknown, but the risk is likely to be a continuum. In addition, the rate of radiological progression in RA is most rapid early on in the disease,37 so the deleterious effects of placebo treatment may vary with duration of RA. However, 6–12 months of placebo treatment may result in adverse long-term functional consequences,23 and differences between the abilities of various DMARDs to slow radiological progression have been detectable over as little as 24 weeks.19 The proposed 3-month maximum duration of placebo treatment could be reassessed as further data on joint damage over this time period become available.
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Rigid inefficacy criteria must determine continued participation of a patient in a clinical trial Patients not responding to therapy in a clinical trial must be identified and withdrawn to protect them from the consequences of inadequate treatment. Just as rigid toxicity criteria exist for the withdrawal of many patients from clinical trials, rigid inefficacy criteria should also exist. Participants in a clinical trial not meeting a predefined improvement criterion at 12 weeks should be withdrawn for inefficacy. Such a protocol has been successful.25 The slow rate of radiological progression precludes its use as a practical study endpoint, though if a reliable measure of joint damage that changes over 3–6 months is identified, it could act as a study endpoint. Payment for clinical trials should not be issued per visit Participants who are withdrawn from trials early because of toxic reactions or inefficacy according to predetermined specified criteria have completed the study and provided valuable data. It is neither the investigator’s nor the patient’s fault if a treatment is toxic or ineffective, and payment for individuals withdrawn for these reasons should be full. To adjust payment for withdrawal of participants for protocol deviations is reasonable, but incentives to keep patients in long clinical trials without evidence of efficacy is unethical. Consent forms should include possible risk of irreversible radiological damage resulting from use of placebo or an ineffective investigational drug Radiological damage may be increased in participants who receive placebo or ineffective treatment for 6 months. In the spirit of informed consent, this information should be made available to participants. Clinical research guidelines should incorporate ethical guidelines specific to treatment of RA The interests of all concerned—patients, industry, investigators, and drug regulatory authorities—would be well served by the definition and justification of an ethical position specific to the treatment of RA by industry and drug regulatory authorities, who are the major decision makers in study design in clinical trials in RA. References 1
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