Ethical Issues in Clinical Research on Fracture Prevention in Patients With Osteoporosis
2003; Oxford University Press; Volume: 18; Issue: 6 Linguagem: Inglês
10.1359/jbmr.2003.18.6.1110
ISSN1523-4681
Autores Tópico(s)Health Systems, Economic Evaluations, Quality of Life
ResumoJournal of Bone and Mineral ResearchVolume 18, Issue 6 p. 1110-1115 EditorialFree Access Ethical Issues in Clinical Research on Fracture Prevention in Patients With Osteoporosis† Norman Fost MD, MPH, Corresponding Author Norman Fost MD, MPH [email protected] Department of Pediatric and Bioethics, University of Wisconsin Medical School, Madison, Wisconsin, USADepartment of Pediatrics, University of Wisconsin Hospital, 600 Highland Avenue, Madison, WI 53792, USASearch for more papers by this author Norman Fost MD, MPH, Corresponding Author Norman Fost MD, MPH [email protected] Department of Pediatric and Bioethics, University of Wisconsin Medical School, Madison, Wisconsin, USADepartment of Pediatrics, University of Wisconsin Hospital, 600 Highland Avenue, Madison, WI 53792, USASearch for more papers by this author First published: 02 December 2009 https://doi.org/10.1359/jbmr.2003.18.6.1110Citations: 6 † The author has no conflict of interest AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL INTRODUCTION IN THIS ISSUE, MANY of the country's most knowledgeable and thoughtful individuals on the clinical aspects of osteoporosis, ethical issues in clinical research, and design of clinical trials present their views on how to ethically advance knowledge about treatment of this large and growing public health problem. A central question is whether placebo-controlled trials can be ethically justified. Suffice it to say there is disagreement over important questions. The disagreement is sufficiently clear and apparently intractable that a National Institutes of Health conference on the topic—typically called a "consensus conference"—did not attempt to produce a consensus. The conveners conceded that achieving a consensus was unlikely and decided to use the opportunity to present and publish the best opinions on the subject so that those who have to make decisions—including sponsors, investigators, institutional review boards (IRBs), and the Food and Drug Administration (FDA)—could be as informed as possible. When intelligent, informed, thoughtful, and respected individuals disagree, it is tempting to say that there is no right answer and that any of their views must be within an acceptable range. But that would be wrong. The modern history of research in the United States includes numerous examples of respected and admired physicians conducting human subjects research now universally considered to be egregiously unethical. One need only mention the infamous Tuskegee study, which continued to 1973, to make the point,1, 2 but there are numerous other examples.3, 4 It is important to note that most of the commonly cited examples of egregiously unethical research occurred before the creation of the "common rule,"5 the federal regulations on government sponsored research involving human subjects. They also occurred before the contemporary bioethics movement, beginning around 1970, which has produced agreement in practice on a range of core ethical issues in research. It is inconceivable that the Tuskegee study, or most of the studies cited by Beecher,2 would be approved by a sponsor or IRB today. Disagreements such as those expressed in this volume are therefore over a much narrower range of debate, a grayer zone, about which reasonable people may disagree. Reasonable people do not disagree about Tuskegee. Because consensus is not the goal of this volume, my purpose will be to identify issues about which there seems to be little disagreement, to suggest that some areas of apparent agreement may not be so clear, and to add some observations on the question of whether placebo-controlled trials are necessary to advance knowledge about prevention of fractures in patients with osteoporosis. RELATIVELY UNCONTESTED ISSUES The medical, economic, and social consequences of fractures secondary to osteoporosis is by anyone's account a public health problem of epidemic proportions. One-half of women and one-quarter of men over 50 years of age will experience a fragility fracture in industrialized countries.6 Nearly 140,000 nursing home admissions per year in the United States are attributable to hip fractures.7 The direct medical costs are estimated to exceed annual expenditures for breast and gynecological cancer combined, and most of these expenses are paid by public funds.6 The number of hip fractures are expected to rise by 3- to 8-fold by 2040. Thus, it is in the interest of the affected elderly population as well as the taxpaying public to develop cost-effective prevention. Drugs that improve bone density or bone structure are the major current strategy for accomplishing that. With regard to medical treatment, it is generally accepted that a regimen of supplemental calcium and vitamin D reduces the risk of fracture. The debate about placebo-controlled trials, therefore, is not whether a control group should receive placebo only—there is consensus that all patients in a trial should receive calcium and vitamin D—but whether any other drugs have been proven to offer additional benefit when added to the calcium/vitamin D regimen, and if so, can they ethically be withheld from a control group. For this discussion, therefore, "placebo control" will be presumed to include calcium and vitamin D for all participants in a trial. That said, the debate about whether any other drug has been proven to have additional benefit is a temporary controversy that only postpones resolution of the debate about placebo-controlled trials for this disorder. Even if it were conceded that there is no other drug that provides additional benefit and that it is therefore ethically permissible to include a group which receives only placebo, this would be a temporary state of affairs, because there will inevitably be a drug (call it D1) that is shown to be safe and effective, and the question will then have to be confronted: can this new proven drug be withheld from anyone in a trial testing another drug (D2). APPARENTLY SETTLED ISSUES THAT REQUIRE RE-EXAMINATION Lurking behind the debate is apparent agreement about two matters that require further examination: first, that research involving human subjects should be consistent with the Declaration of Helsinki8; and second, that clinical trials should be in equipoise, meaning that there should be uncertainty in the scientific community about whether one arm of the trial is superior to the other. Limits to the Declaration of Helsinki The Declaration of Helsinki, an aspirational set of principles written and rewritten by the World Medical Association (WMA), has long included statements that are systematically and widely ignored, even by those who profess to be acting in accord with the Declaration. The U.S. FDA, for example, has long promoted and often required placebo-controlled trials while simultaneously endorsing the Declaration for foreign studies,9 although the Declaration, until recently, opposed placebo-controlled trials when there were known effective therapies. Another example is Article 5, which states, "In medical research on human subjects, considerations related to the well-being of the human subject should take precedence over the interests of science and society." This would prohibit all nontherapeutic research since such studies, by definition, offer no prospect to improve the well-being of the human subject. They always involve asking the subject to compromise his well being in the interests of science and society. Other problems with the Declaration have long been noted by Levine.10, 11 There are several implications to these observations. First, aspirational statements are not easily translated into operational regulations or guidelines. The latter are usually precise, and often interpreted and applied in an inflexible way that may not have been intended by the writer of the principles. The first "directive" of the hallowed Nuremberg Code, for example, states, "The voluntary consent of the human subject is absolutely essential."12 Few would disagree with the sentiment expressed, but few would accept it as a literal guideline, because it precludes any research with children or others incapable of consenting. Second, the aspirational principle itself may be poorly thought out, inconsistent with other important ethical principles, or may not withstand rigorous ethical analysis. Thus, the plausible principle that patient should not be asked to forego effective treatment in the name of advancing science conflicts with the principle underlying the requirement for informed consent, which is respect for an autonomous person's right to decide for himself whether he wants to be in a clinical trial. Many individuals may choose to forego effective treatment for reasons of altruism, money, or because they are averse to the side effects of the effective treatment.13 The fallibility of the Declaration has been implicitly acknowledged by the WMA through its serial revisions. None of these has been more controversial than its position on placebo-controlled trials. Through most of its history, the Declaration prohibited such trials when there is known effective treatment. While this prohibition had its supporters,14 it was widely ignored by U.S. and European investigators, sponsors, and regulatory agencies, with the support of numerous ethicists and others.15, 16 In 2000, in response to intensive and widespread criticism, the Declaration was revised to liberalize its previous opposition to placebo-controlled trials. This attempt to accommodate advocates for placebo-controlled trials was not successful and was followed by a clarifying statement in 2001 stating unequivocally that placebos "may be ethically acceptable, even if proven therapy is available… where for compelling and scientifically sound methodological reasons its use is necessary to determine the efficacy or safety of a prophylactic, diagnostic or therapeutic method."7 The word "necessary" is unavoidably ambiguous. As Jonas17 pointed out, research itself is never necessary; it is always an optional activity. Nor is it ever necessary to do a placebo-controlled trial to prove safety or efficacy. The first point is that there may be ethically compelling reasons to prefer such a design,18, 19 or at the least, no ethically compelling reason to prohibit such a trial if other conditions are met. The second point is that these questions cannot be settled by simply checking to see what the Declaration says, because the Declaration, as we have seen, has often been mistaken or misleading. Limits to the requirement for equipoise The requirement that the arms in a trial must be in equipoise was advocated in a detailed analysis by Fried,20 reaffirmed by Freedman21 and others, and has become a quasi-religious principle in discussions of the ethics of clinical trials. It is at the root of the Helsinki Declaration's Article 29, which states that "a new method should be tested against… the best current methods." It is based on the appealing notion that a physician should not ask his patient to forego known beneficial treatment in the name of science, because this violates a fiduciary duty to do what is best for the patient. This requires that an invitation to join a trial must be predicated on uncertainty whether the patient would be foregoing anything of known value by being assigned to any of the arms in the trial. There are several problems with requiring that this principle be applied in all trials. First, as discussed earlier, this conflicts with the oft-mentioned principle of "respect for persons," hallowed by the famous Belmont Report,22 widely cited as the Rosetta Stone of ethical principles that should guide human subjects research. Respect for an autonomous person, according to this catechism, is to allow him to decide how he will be treated (among the range of therapies considered to be acceptable to the physician) or whether he wants to be treated at all. It is virtually universally accepted in American law and bioethics that a competent person has a nearly absolute right to decide whether or not to accept medical treatment.23 This right extends even to refusal of a clearly life-saving transfusion if such treatment is not what the patient wants. It would be odd to hold the position that a competent informed patient may decide to forego any treatment at all for osteoporosis but should be prohibited from entering a trial where he has a 50% of receiving possibly effective treatment. As noted above, there are several plausible and common reasons why an informed patient may choose this path: he may be altruistic; he may seek financial benefits from being in the trial; he may be eager to avoid an especially dreaded side effect of the known effective treatment; and prefer taking a chance on a newer therapy that may be effective and less toxic. The word "effective" itself has a subjective and value-laden component.24 It may be used in a very narrow sense by scientists (e.g., shorthand for summarizing a well-designed study that showed a difference between two groups with a p value of <0.05). But this statistically significant difference may have been clinically less impressive. For example, only a small proportion of the group receiving the experimental treatment may have shown benefit, with unappealing side effects. A prospective subject, therefore, might be pleased to enter a trial with a more promising and less toxic drug, even if it involved a 50% chance of receiving a placebo. Receiving free drug might be a sufficient reason for many patients to enter a placebo-controlled trial. Several writers have urged that osteoporosis trials have extensive phase IV components, to gather as much data as possible on the actual incidence of fractures. Thus, it may be possible for patients to receive free drugs for an extended period. In most clinical trials, the research subjects are not offered that benefit. Second, there are instances in which there are clearly effective treatments, but they are unavailable to the patient, so that participating in a placebo-controlled trial—that is, a trial in which the two arms are almost certainly not in equipoise—offers him an opportunity to be better off than he would otherwise be. The principle of equipoise is intended to avoid situations in which a patient might be harmed, in the name of science, by being in a trial and thereby foregoing effective therapy. But if effective therapy is unavailable to the patient—for reasons that have not been created by the investigator—than the trial may be his only chance to obtain effective treatment. It is an odd kind of paternalism that would prevent a patient from entering a trial that offers him a 50% chance at effective treatment when the alternative is no treatment. The most celebrated example of this insistence on equipoise involved the so-called "short course" AZT trials in Africa, whose purpose was to find an inexpensive treatment regimen that would reduce maternal-fetal transmission of HIV. The proven effective treatment—the "076" regimen—had a cost that was 100-fold higher than the annual per capita health care expenditures of the countries most in need, and it required numerous prenatal and postnatal visits that were not consistent with the realities of the health care systems in which the treatment had to be delivered. The African trials compared a low-dose, short-course regimen—for which there were encouraging preliminary data—with a placebo group. The obvious assumption and hope was that the short course would have some benefit in reducing transmission. No serious claim was made that the study was in equipoise. Angell25 and Lurie26 denounced the trial on this and other grounds. But others, also claiming to be advocates for the human subjects involved,27 argued that, notwithstanding the absence of equipoise, participants would not be deprived of effective treatment as a consequence of being in the trial. The purpose of equipoise—to minimize the risk of preventable harm that might result as a consequence of being in a trial—was not relevant in this case, because no one in the placebo group would experience this risk. As Levine has put it,9 for a patient who has no access to a known effective treatment, it is as if there is no effective treatment. A clinical trial in that setting, with a 50% chance of receiving effective treatment, constitutes an opportunity to be better off than the patient would be in the absence of the trial. The relevance of this to the osteoporosis debate is that there are many patients in the world, including the United States, for whom known effective treatment is unavailable. An invitation for such individuals to join a trial in which they have a 50% chance to receive possibly effective treatment is to give them a chance to be better off, not to expose them to a situation in which they might be worse off. To prohibit such a trial effectively ensures that such disadvantaged individuals will continue to be disadvantaged and suffer the consequences. Sometimes the criticism of conducting trials in underserved populations is reduced to the precept, "Don't do in another country what couldn't be done ethically in your own." A more plausible version of this admonition might be, "Use the same ethical principles everywhere." Assuming for the moment that there are universal principles that should guide human subjects research, proponents of international trials argue that the same principles can be followed, but that the facts of the matter support doing a trial in some populations that could not be ethically mounted in another population. For example, the principles that underlie careful trial design, independent review, favorable benefit/risk ratio for the subjects in the trial, and informed consent did not need to be compromised to conduct the AZT trials in Africa. It was the facts of the matter that were different and not the ethical principles. Inviting a patient who has access to proven effective treatment for osteoporosis into a placebo-controlled trial does have the problem of exposing that person to increased risk, but that concern would not exist in a population that had no prospect of access to any kind of treatment. If the control group in such an underserved population was to receive long-term vitamin D plus calcium supplementation, then everyone in the trial would have an excellent prospect of direct medical benefit. Presumably, there would be no objection to inviting patients who had failed all available treatments, or who were intolerant of existing therapies, to join a placebo-controlled trial. Such a study would be in equipoise because there was nothing of known efficacy that could benefit the patient; that is, it would be as if safe and effective treatment were unavailable. The difference between this situation and an underserved population is that in the latter example effective acceptable treatment does exist but is unavailable for financial reasons. Some would argue that a sponsor has a duty to provide such treatment to those in a trial, but it is not usually stated where this duty comes from or why the sponsor wouldn't also have a duty to everyone who was in need. Part of this may reflect a feeling that those who are in a trial are being "used" in some way and are owed something in return. As previously noted, such individuals have an opportunity to be better off; none are likely to be worse off, unless the new drug has undesirable adverse effects, but that is a risk that would be taken voluntarily in exchange for the potential benefit. Third, part of the commitment to equipoise derives from the concern that the investigator's interest in and concern for others (or science or society) will distract him from his primary and fiduciary obligation to the patient. This concern is well placed, as many of the most egregious examples of on unethical research involved apparently caring, compassionate physicians whose interest in advancing knowledge distracted them from their duty to their patients.28 This conflict of interest29 was at the root of many of these early scandals, and justifies the detailed oversight and independent review that characterized clinical research today. In many of the early scandals, the potential conflicts of interest became actualized as physician/investigators, with little oversight, external review, or commitment to consent, conducted studies that would not conceivably be approved today. But clinical research today is, by some accounts, over-regulated.30, 31 The same potential conflicts of interest exist, because the clinician and investigator are commonly the same person, but the vast majority of clinical trials are well vetted by sponsors, agencies, IRBs, and other committees. Numerous placebo-controlled trials have been approved at multiple levels, not just because they advance science, but because they may serve the interests of the potential subjects; that is, while the investigator may have a conflict of interests, the trial may constitute a congruence of interests which serve the subjects as well as society. Scandals epitomize studies in which the human subjects were victims. In the current situation, trials may be opportunities. Concerns about inclusion in clinical trials are now often replaced by concerns about exclusion. There is one other counter-argument to the claim that equipoise is important if the physician/investigator is to maintain his fiduciary duty to do what is in the patient's interest. In many cases, the investigator in a contemporary clinical trial is not conducted by the patient's physician but by someone who is a stranger to the patient. This is not to say that a physician/investigator has no duties to the welfare of potential subjects, but the relationship is not one of doctor/patient. Indeed, one advantage to this reality is that potential subjects may be less vulnerable to confusion about whether they are being offered treatment or an unproved drug, the so-called "therapeutic misconception."32 Critics of this analysis will correctly point out that there is a fault in a world, or a country, in which all individuals do not receive proven, effective health care; a world in which the only way some people can get needed health care is to join a research study; and that attention should be directed to correcting that basic fault. That complicated issue is beyond the scope of this paper and this volume. Suffice it to say it will be a long time before that blissful state is achieved, and during the wait, millions will suffer and die from the complications of osteoporosis, some of whom could benefit from the opportunity to be in a placebo controlled trial. At the heart of the equipoise debate is the concern that a patient who might otherwise receive effective treatment is diverted from that path by a physician/investigator who has goals other than the welfare of that patient. It was at the heart of the Tuskegee study, when men with untreated syphilis were systematically deterred from obtaining effective treatment, sometimes involving active lies.1, 2 It is common for critics of placebo-controlled trials to invoke the Tuskegee study when they disagree about the ethics of a clinical trial,25 but the differences between Tuskegee and proposed placebo-controlled trials for the treatment of osteoporosis are critical: proposals for osteoporosis trials would include high standards of informed consent, review by local IRBs, and need not divert any patient from effective treatment who would otherwise have received it. ARE PLACEBO-CONTROLLED TRIALS "NECESSARY?" The latest "note of clarification" on the Helsinki Declaration's position on placebo-controlled trials concedes that, in the opinion of the WMA, they may be justified if "necessary to determine the safety or efficacy" of a therapeutic method. But the undiscussed standard of "necessity" begs the question of whether such trials may be ethically permissible of even preferable for reasons other than necessity. It is never necessary to conduct a placebo-controlled trial. As noted earlier, it is not necessary to have any research, and when osteoporosis is the condition being studied, it will always be possible to conduct trials with an active control, either to show superiority or non-inferiority. But as Temple18 and Ellenberg19 point out, there are several reasons why such designs may be ethically problematic. First, such trials are likely to be considerably more expensive than placebo-controlled trials, sufficiently so that they may never be conducted at all. At the least, as Rosenblatt33 asserts, there will be fewer trials, a slower rate of progress. Kanis34 estimates that a typical superiority trial study might require 25,000–150,000 patients, concluding that "such studies are unrealistic." If improvements in the treatment of osteoporosis are in the interests of patients and society, then such a requirement works against such interests. Second, because such trials typically require much larger numbers of subjects, if fractures are the endpoint of interest, they will result in more fractures than placebo-controlled trials, even if the new agent is found to be effective. Because the trials will need to have more subjects to reach statistical significance, more individuals in the trial will be exposed to the risk of fractures. Kanis33 estimated that an equivalence study using an agent with 50% efficacy that reduced fracture frequency to 5% over 3 years would be associated with 3000 fractures, whereas a placebo-controlled trial would only have required 66 fractures to show a significant result. Third, for those in the larger population awaiting a demonstration of efficacy, more will suffer the consequences of inadequately treated osteoporosis if the trial takes more time. This point was illustrated dramatically in the African AZT transmission trials. Had the design advocated by Angell and Lurie been used—comparing short-course AZT against the proven 076 regimen—a larger, longer trial would have been necessary, delaying the discovery that the short course was sufficiently effective to warrant widescale distribution. Fourth, as Temple has long argued, placebo-controlled trials often are necessary to show efficacy because of the problems of "assay sensitivity" of an active control. Assume that Drug A was shown to be effective in Clinical Trial X. If an investigator purports to show in Clinical Trial Y that new Drug B is at least as effective as proven Drug A, it must be assumed that the patients in Y who receive Drug A have the same likelihood of fracture as those in Trial X. Suppose, for example, that patients receiving A in Trial Y were at much lower risk for fracture than those in Trial X, either for genetic reasons, less advanced disease, different diets, or different behaviors. If Drug A were shown to be associated with the same frequency of fractures as Drug B, the false conclusion would be drawn than Drug A had some effect in reducing fractures, whereas the truth might be that neither drug had any effect. In osteoporosis in particular, because the population is elderly, they will often have comorbidities or be on other drugs that may affect their risk of fractures or their responsiveness to drugs intended to improve osteoporosis. Prior phase III trials in osteoporosis have shown considerable heterogeneity in terms of fracture frequency. This is why historic controls are generally problematic for clinical trials. Assuming that a control group receiving an active drug will have the same incidence of fractures as the group in an earlier trial using the same drug requires the same leap of faith that is so problematic when historic controls are used as the comparison group. Because the concern about placebo-controlled trials is predicated on the concern that subjects in the control group might have a higher risk of fractures than they would have had they not been in the trial, some have suggested using surrogate endpoints—such as bone density—instead of fractures. The theory here is that efficacy could then be established without exposing any subjects to risk of harm. The central difficulty is whether these surrogate endpoints are sufficiently predictive of fractures to justify marketing a drug on that basis. Some claim that bone mineral density (BMD) is an "excellent predictor of fracture risk,"35 but others point to the a study of treatment with fluoride in which BMD did not reliably predict fracture incidence.13 WHY NOT JUST ASK? As in many discussions about profound medical-ethical issues that affect large numbers of patients, there is little in this volume to tell us what the patients would want. While there are empirical and philosophical limits to such information, it should be part of the discussion and in some instances can be influential in guiding policy.36-38 CONCLUSIONS Osteoporosis is an enormous and growing public health problem, associated with substantial costs. It is in the interests of patients and society to develop more effective measures for prevention and treatment than are currently available. Placebo-controlled trials are the most efficient way to test new candidate drugs. Objections have been based, in part, on principles articulated in the Declaration of Helsinki, and on the underlying principle of equipoise. Points of agreement about how to ethically advance knowledge about osteoporosis are identified. Some generally accepted positions—such as fidelity to the Declaration of Helsinki and the principle of equipoise—are examined, expanding on observations by other authors in this volume. REFERENCES 1 Brandt AM 1978 Racism and research: The case of the Tuskegee syphilis study. Hastings Cent Rep 8: 21– 29. 2 Jones James H 1993 Bad blood: The Tuskegee Syphilis Experiment. New and Expanded Edition. Free Press, New York, NY, USA. 3 Beecher HK 1966 Ethics and clinical research. N Engl J Med 274: 1354– 1360. 4 Advisory Committee on Human Radiation Experiments 1996 Research ethics and the medical profession: Report of advisory committee on human radiation experiments. JAMA 276: 403– 409. 5 45CFR46 Protection of Human Subjects, Revised Dec 2001. 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An industry perspective. J Bone Miner Res 18: 1142– 1145. 34 Kanis JA. Alexandre J-M, Bone HG, Abadie E, Brasseur D, Chassany O, Durrleman S, Lekkerkerker JFF, Caulin F 2003 Study design in osteoporosis: A European perspective. J Bone Miner Res 18: 1133– 1138. 35 Khosla S 2003 Surrogates for fracture endpoints in clinical trials. J Bone Miner Res 18: 1146– 1149. 36 Fost NC. 1975 A surrogate system for informed consent. JAMA 233: 800. 37 Fost NC and Farrell PM 1989 A prospective randomized trial of early diagnosis and treatment of cystic fibrosis: A unique ethical dilemma. Clin Res 37: 495– 500. 38 Love RR, Fost N 1997 Ethical and regulatory challenges in a randomized controlled trial of adjuvant treatment for breast cancer in Vietnam. J Invest Med 45: 423– 431. Citing Literature Volume18, Issue6June 2003Pages 1110-1115 ReferencesRelatedInformation
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