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JME Online First, published on September 26, 2012 as 10.1136/medethics-2011-100258
PAPEREthics and eplerenoneShruti Gupta,1 Adriane J Fugh-Berman,2 Anthony Scialli3 Although the putative question to be answered The use of a placebo arm in clinical trials is unethical if was whether any aldosterone antagonist would there is an active comparator that is acceptably safe and be beneficial, only eplerenone was compared with effective. We argue that reasonable evidence of a placebo as add-on therapy to standard heart effectiveness and safety of an inexpensive alternative to failure treatment. We argue that a spironolactone an expensive therapy is sufficient to require that the arm, either with or without an eplerenone arm, inexpensive therapy be included as a comparator when was ethically necessitated by the likelihood that the expensive therapy is tested, and that use of an spironolactone would be as effective and safe as inactive placebo comparator only is not ethical. For eplerenone and by the considerable cost benefit of example, studies of the expensive drug eplerenone for congestive heart failure have not included a spironolactone arm, although there is reasonable 1. A clinical trial is unethical if it fails to take evidence that spironolactone would be safe and effective, and spironolactone is inexpensive. The requirement to study inexpensive therapies is based on avoidance of 2. The comparable effectiveness and safety of unnecessary cost in medical care as an example of non- an inexpensive, widely available treatment is an maleficence. Several ethical actors in the design, important medical question for a study of an conduct, and publication of clinical trials and their results expensive treatment. This second argument views bear responsibility for the appropriate conduct of clinical costliness as an adverse effect of therapy and the trials. That responsibility includes protecting study avoidance of costliness as non-maleficence.
subjects from being asked to participate in clinical trials that serve primarily to promote the use of new and ALDOSTERONE ANTAGONISTSBoth eplerenone and spironolactone are aldosteroneantagonists. Spironolactone, approved in 1960 by the Food and Drug Administration, USA (FDA),4 Randomised controlled trials, recognised as the has been described as effective for the treatment of standard method of evaluating the effectiveness of hypertension,5 including resistant hypertension,6 therapeutic interventions, are considered to be as an adjunct therapy for NYHA classes III and IV based on a principle of equipoise, which holds that congestive heart failure,7 the treatment of cirrhotic none of the assigned treatments are known to be ascites,8 and as an antiandrogen for hirsutism9 and superior to the other treatments based on safety acne.10 Spironolactone is inexpensive, with a retail and effectiveness. Although equipoise has been cri- price of less than a penny per 100-mg dose.11 ticised as a criterion for justification of clinical By contrast, eplerenone, approved in 2002 for trials,1 it remains true that at the time most trials the treatment of hypertension,12 is expensive, are designed, any imbalance of benefits and with a retail price of more than $3 for a 50-mg burdens between the study groups is unknown.
dose of the generic product;13 the same dose of the Placebo-controlled trials are unethical if a safe and branded version, Inspra, retails for $4.73.14 effective treatment is available for a condition It is important, then, to understand whether under study.2 3 Under these circumstances, an eplerenone offers advantages over spironolactone experimental treatment may be compared with for the treatment of conditions that are believed to the known safe and effective treatment or may be be associated with mineralocorticoid receptor activ- studied as an add-on to the proven treatment.
ity. Although eplerenone is reputed to be a more Here, we raise an issue of appropriate compara- selective antagonist of the mineralocorticoid recep- tors in clinical trials. We ask whether, ethically, an tor than is spironolactone, no trials for congestive expensive novel treatment may be tested against a heart failure have compared these two drugs.
placebo alone if an inexpensive treatment can be Spironolactone has been shown to benefit reasonably expected to be effective. We specifically patients with NYHA classes III and IV heart ask whether the relative financial costs of the failure. In 1996, the Randomised Aldactone novel and existing treatment are properly factors Evaluation Study (RALES) randomised 214 patients in the determination of clinical equipoise. We use with symptomatic NYHA classes III or IV congest- as a case study a trial of eplerenone for New York ive heart failure and an ejection fraction of less than Heart Association (NYHA) class II congestive 35% to receive spironolactone or a placebo in add- heart failure. Spironolactone, an inexpensive generic ition to previous therapy for 12 weeks. This study drug, is used for classes III and IV congestive heart is not informative about NYHA class II heart failure, but no clinical trials have been reported on failure because fewer than 1% of subjects were spironolactone for class II congestive heart failure.
NYHA class II at the time of enrolment. These J Med Ethics 2012;0:1–5. doi:10.1136/medethics-2011-100258 Copyright Article author (or their employer) 2012. Produced by BMJ Publishing Group Ltd under licence. 1
subjects were eligible to enrol because they had been in NYHA and eplerenone in a clinical trial.20 In this trial, published class IV within 6 months prior to enrolment. At doses of only in abstract, 321 patients with stable NYHA classes II–IV 12.5–25 mg/day, spironolactone was considered to be acceptably heart failure were randomised to receive eplerenone at dose safe based largely on laboratory test results.15 A follow-up study levels from 25 mg to 100 mg daily, spironolactone 25 mg daily, followed 1663 patients randomised to receive spironolactone or a placebo for 12 weeks. The abstract concluded that eplere- 25 mg/day, or a placebo in addition to an ACE inhibitor, a loop none appeared pharmacologically similar to spironolactone.
diuretic, and in most cases digoxin for 3 years. The study was Eplerenone 50 mg and spironolactone 25 mg both produced sig- stopped at 24 months, because there was a 30% decrease in mor- nificant decreases in BNP and increases in urinary aldosterone tality attributable to a reduction in progressive heart failure and and renin in comparison with a placebo.21 The only apparent sudden cardiac death in spironolactone-treated patients with differences between the two drugs were that spironolactone NYHA classes III and IV heart failure.16 The frequency of hospi- increased serum testosterone and eplerenone was associated talisation due to worsening heart failure was also reduced by 35% in the spironolactone compared with the placebo group.
Our search of more recent literature from 2007 to 2011 iden- Eplerenone also benefits patients with heart failure. In 2001, tified only one other active comparator trial. In this study, the Eplerenone Post-Acute Myocardial Infarction Heart Failure 141 subjects with hypertension associated with hyperaldoster- Efficacy and Survival Study randomised 6642 patients with onism were randomised to receive either spironolactone NYHA classes III and IV heart failure to receive eplerenone 75 mg–225 mg daily, or eplerenone 100 mg–300 mg daily for 25 mg/day increasing to 50 mg/day, or a placebo, in addition to 16 weeks.22 Reductions in diastolic and systolic blood pressures previous regimens, which could include ACE inhibitors or were significantly greater in the spironolactone compared with angiotensin receptor blockers (ARB), β blockers, aspirin and the eplerenone group. More subjects taking eplerenone dropped diuretics. Compared with placebo, the addition of eplerenone out because of lack of efficacy. There were no significant differ- to an established regimen reduced hospitalisations for heart ences in treatment-emergent adverse events; however, there failure by 23%, and reduced the rate of death by 8%.17 In 2003, were significantly more cases of gynaecomastia in men and eplerenone was approved by the FDA for the indication of con- mastodynia in women in the spironolactone group.
gestive heart failure NYHA classes III and IV.12 Although published in 2011, the study comparing eplerenone Class II heart failure represents much milder disease than and spironolactone for hypertension appeared a decade earlier classes III or IV, and it was not clear that any antialdosterone in the New Drug Application (NDA) for eplerenone.23 The therapy would offer any benefit to patients with this milder NDA also included the report of a study in which 397 hyper- disease. Prior to 2011, no antialdosterone therapy was routinely tensive patients were randomised to receive eplerenone at recommended for class II heart failure. In early 2011, the 50 mg–400 mg daily in one or two doses, 50 mg of spironolac- Eplerenone in Mild Patients Hospitalisation and Survival Study tone twice daily, or a placebo twice daily. The highest dose in Heart Failure (EMPHASIS-HF) randomised 2737 NYHA level of eplerenone (400 mg daily or 200 mg twice daily) only class II congestive heart failure patients to receive either eplere- approximated the blood pressure effect of the twice-daily none 25 mg/day increasing to 50 mg/day, or a placebo in add- 50-mg dose of spironolactone, suggesting that eplerenone is less ition to treatment with an ARB, ACE inhibitor, or both, and potent than spironolactone in the treatment of hypertension.
with a β blocker.18 Only patients who had been hospitalised The FDA reviewer concluded that ‘Eplerenone was also com- for a cardiovascular indication within 6 months prior to the pared to spironolactone and appears to have fewer side effects.
screening visit and had a plasma B-type natriuretic peptide However, because spironolactone was more effective, the risk/ (BNP) of at least 250 pg/ml or a plasma N-terminal pro-BNP of benefit ratio of eplerenone to spironolactone is not adequately at least 500 pg/ml for men, or 750 pg/ml for women were eli- gible. Compared with placebo, eplerenone reduced hospitalisa- tions by 24% and hospitalisations for heart failure by 38%.
Mortality in the eplerenone group was reduced; 15.5% of The design of the eplerenone studies without a spironolactone patients in the placebo group died, compared with 12.5% in arm was not ethically sound. Ethical analysis includes the bal- the eplerenone group (HR 0.76; 95% CI, 0.62 to 0.93).
ancing of benefits and burdens. A treatment-controlled trial that compared eplerenone with spironolactone as well as with a placebo would have benefited patients with congestive heart An editorial accompanying the 2011 publication of failure, because it would have demonstrated which agent, if EMPHASIS-HF supported the incorporation of aldosterone either, was superior in effectiveness and safety. The inclusion of antagonism therapy into congestive heart failure regimens.19 a spironolactone arm would also have determined whether The editorialist suggested, however, that given its far lower there was a rationale for using the more expensive agent. The cost, spironolactone be considered for mineralocorticoid antag- fundamental question of whether adding any antialdosterone onism. We have, then, a conflict. Given what is known, it is therapy to existing therapies for NYHA class II congestive certainly reasonable to assume that spironolactone and eplere- heart failure would have been answered equally well by includ- none are similar in effectiveness, and spironolactone is far less ing either eplerenone or spironolactone or both; the ethical expensive than eplerenone. On the other hand, therapeutic question arises from the comparative financial costs and safety decisions should be based on randomised controlled trials when possible, and for NYHA class II congestive heart failure, only Study subjects are asked to undertake burdens of risks of eplerenone, not spironolactone, has been tested using this harm and inconvenience in the furtherance of scientific knowl- edge, and the quality of the study design is central to determin- This conflict would have been avoided had the eplerenone ing whether scientific knowledge can be optimally advanced by studies included a spironolactone arm as well as a placebo arm.
the study results. In the case of the eplerenone studies, subjects A review of early studies on aldosterone antagonist therapy undertook the burdens of participating in an experiment that identified only one direct comparison between spironolactone could not answer the question of whether the expensive new J Med Ethics 2012;0:1–5. doi:10.1136/medethics-2011-100258 treatment was better than, worse than, or equivalent to a scientific value of the study in which they were asked to par- ticipate, a duty to society, and a duty to its shareholders. Of Benefits and burdens to society, construed as public health, these duties, the responsibility to study subjects is paramount.
must also be considered in the ethical analysis of a clinical trial.
Study subjects are asked to accept inconvenience, discomforts, The potential benefits to society of improvements in the man- and risks of harm and should not be asked to do so in circum- agement of congestive heart failure include a decrease in suffer- stances where the trial design is ethically suboptimal. Between ing, an increase in productivity of affected persons, and a the duty to society and the duty to shareholders, duty decrease in healthcare costs. The potential burdens include an to society is superior, inasmuch as improving public health increase in healthcare costs of pharmacological therapy without trumps augmenting personal wealth. Shareholders too, are an offsetting decrease in costs of other components in the care members of society whose personal and financial health may be affected by therapies with unfavourable burden to benefit It is here that financial cost becomes a central issue. The pro- characteristics, including excessive cost.
motion of eplerenone instead of spironolactone for NYHA class It is possible to construe the responsibility of the manufac- II congestive heart failure was a foreseeable consequence of the turer as protecting the interest of its shareholders within the EMPHASIS-HF trial, a consequence with adverse effects on legal requirements of regulatory authorities and to consider that shareholders may value the worth of their shares more highly Corporations that market pharmaceutical and medical device than the possible benefits to society of less expensive therapies products have a legal responsibility to represent the best inter- for congestive heart failure. Such a construction assigns no ests of their shareholders, but they also have an ethical respon- responsibility to the manufacturer for improving public health; sibility to promote public health, as will be discussed in the however, pharmaceutical manufacturers have publicly asserted next section. Besides the risk of harm, cost is a burden of treat- their commitment to public health. In its guiding principles for ment in healthcare, and this burden has become increasingly the conduct of clinical trials, the Pharmaceutical Research and recognised by practitioners and payers as an important consid- eration in therapeutic decision making.
The avoidance by clinicians and payers of unnecessarily costly Sponsors conduct clinical trials based on scientifically designed protocols, which balance potential risk to the research participant fils the ethical imperative of non-maleficence, the avoidance of doing harm, because unnecessarily costly treat- fit to the participant and to society.
Scientific, ethical and clinical judgments must guide and support ments consume funds that patients might otherwise spend on the design of the clinical trial, particularly those aspects directly shelter and food. Moreover, costly treatments decrease available affecting the research participants such as inclusion/exclusion cri- funds in private and government insurance pools for the provi- teria, endpoints, and choice of control, including active and/or The necessity of avoiding unnecessary healthcare costs is consistent with the first two ethical requirements for clinical research presented by Emanuel and colleagues.24 These require- ments are that the research has social or scientific value, and The investigators are responsible for understanding the drug that the research is scientifically valid. Part of the justification and disease they are studying, including a thorough under- for these principles is that valueless and scientifically invalid standing of existing treatments. Physician investigators have an studies waste scarce resources. Although Emanuel et al were interest in identifying the best therapies for their research sub- writing of research resources, we argue that the concept reason- jects and their patients and might reasonably have wanted to ably can be extended to healthcare resources.
know how spironolactone compares with eplerenone for the In the absence of a large discrepancy in the cost of therapy treatment of NYHA class II congestive heart failure. Indeed, with eplerenone and spironolactone, information from a spir- the EMPHASIS-HF investigators published a paper in 2010 onolactone arm in the eplerenone studies would be demoted titled, ‘Rationale and design of the Eplerenone in Mild Patients from an ethical imperative to simply nice-to-know. We argue Hospitalization and Survival Study in Heart Failure that the cost of therapy should be a mandatory part of the (EMPHASIS-HF)’ in which they demonstrated an excellent therapeutic decision-making process of every practitioner as we understanding of other aldosterone antagonists and their poten- struggle to make equitable the distribution of healthcare ser- tial for use in heart failure.26 In this paper, the failure to vices to all members of society. It follows that cost also must include a spironolactone arm was not explicitly addressed be a component of the burden versus benefit evaluation under- except for the statement, ‘Spironolactone, even at modest taken by clinical trialists, their regulators, and their sponsors.
doses, has undesirable side effects, particularly gynaecomastia’.
These authors did not cite an incidence for this side effect; in RALES, the incidence was 10%.15 Gynaecomastia may limit the Who bears the responsibility for ensuring that the performance acceptability of spironolactone therapy, but whether there are of studies meets ethical standards? There are several actors in offsetting advantages over eplerenone would have required a the performance and dissemination of clinical trials, and the responsibility for assuring compliance with ethical principles is The published EMPHASIS-HF paper indicates that the study joint. Each of these actors have interests that may come into was funded by the sponsor, that the lead author received speak- er’s fees from the sponsor, that one of the authors received travel reimbursements from the sponsor, and that two of the investigators were employees of the sponsor. If there were The manufacturer of eplerenone, which sponsored the studies, potential conflicts between the interests of study subjects and had the most to gain from the flawed design, and the most to the investigators, these conflicts should have been decided in lose from a properly designed study. The sponsor had conflict- favour of study subjects, as made clear by, among others, the ing duties: a duty to the study subjects to maximise the journal in which the EMPHASIS-HF trial was published.27 J Med Ethics 2012;0:1–5. doi:10.1136/medethics-2011-100258 information and, whether their editors intend it or not, in the Institutional review boards (IRB) and data safety monitoring marketing of pharmaceutical products. The placement of boards (DSMB) also have responsibility for ensuring that study papers in medical journals, and the use of those papers for the designs are ethical with an appropriate balance of possible marketing of pharmaceuticals has been documented,30 31 and it burdens and benefits. IRBs do not necessarily include indivi- would be naïve of journal editors not to be aware of the mar- duals with expertise in the specific area under study, and these keting implications of their publication of studies of new and boards rely to varying extents on information provided by study investigators. Although it is possible that IRBs might Indeed, the editors of major medical journals have enunciated claim that their approval of the impaired study designs was guidelines for authorship and sponsorship that recognise the due to incomplete information from the investigators, IRBs role of the medical journal in safeguarding the integrity of clin- should be asking investigators of all placebo-controlled trials ical trial research. The New England Journal of Medicine, which whether an active comparator would be more appropriate than an inactive placebo. The DSMB, if properly constituted, will Clinical trials are powerful tools; like all powerful tools, they must evaluation of the study design. The ability of the IRB and be used with care. They allow investigators to test biologic hypoth-eses in living patients, and they have the potential to change the DSMB to recognise ethical problems in studies will at least in standards of care. The secondary economic impact of such changes part depend on the knowledge possessed by the individuals can be substantial. Well-done trials, published in high-profile jour- who sit on these boards. Indeed, the relationship between nals, may be used to market drugs and medical devices, potentially knowledge and responsibility is an issue that confronts review resulting in substantial financial gain for the sponsor. But powerful boards on a regular basis. It is not customary, however, for tools must be used carefully. Patients participate in clinical trials IRBs or DSMBs to use cost considerations as the basis for largely for altruistic reasons—that is, to advance the standard of evaluating whether a study design is ethical. We believe that care. In the light of that truth, the use of clinical trials primarily for medical research that foreseeably will be used to promote marketing, in our view, makes a mockery of clinical investigation expensive therapies should be evaluated on just such grounds.
Journal editors must reject the publication of studies that are not ethically sound. Journals would be considered remiss if The FDA has the legal mandate to evaluate the safety and effect- they published clinical trials using prisoners or trials in develop- iveness of pharmaceutical products. The FDA has advanced ing countries that did not incorporate adequate protection of other reasons for its preference for, or in many cases, insistence human subjects. In the case of the eplerenone studies, the on placebo comparators in clinical trials;28 29 however, these journal editors might plead ignorance of the likely effectiveness reasons have been refuted on ethical and statistical grounds.2 3 of spironolactone in NYHA class II congestive heart failure, but However, the eplerenone studies examined therapy added on to they relied, or should have relied on, expert reviewers who existing standard therapies for heart failure. All subjects received would have been aware of the science. We do not know what standard therapy for heart failure and so there were no subjects the review comments were for the eplerenone studies, but who were denied proven therapies by virtue of being assigned to expert reviewers should have identified the failure to include a a placebo group. The studies were designed to evaluate whether spironolactone arm in these studies as a fatal flaw. Although add-on antialdosterone treatment would be beneficial, a ques- the rejection of the manuscript would have been too late to tion that represented ‘genuine medical uncertainty’.3 protect research subjects exposed to the burdens of a poorly At the time of the EMPHASIS-HF trial, eplerenone had designed study, a rejection would have served as a disincentive already been approved by the FDA for the treatment of NYHA to future similar errors in study design.
classes III and IV heart failure. Spironolactone had not been approved for these classes of congestive heart failure, although there was randomised clinical trial evidence that it was effect- The ethical dilemma for the practitioner now is whether in ive.16 The FDA could argue that an active comparator was not class II heart failure to recommend eplerenone, an expensive available, because spironolactone has not been approved by the medication for which there are randomised clinical trial data, or FDA for the treatment of heart failure. Such a stance would, spironolactone, an inexpensive medication for which there are however, require the FDA medical officers to act in ignorance of no clinical trial data. Based on the mechanism of action of spir- existing scientific evidence. Moreover, no reviewer of the eplere- onolactone, its effectiveness in classes III and IV heart failure, none data could plausibly argue that the studies would not and its cost, we would argue that spironolactone should be have been of more scientific value with a spironolactone arm.
recommended for NYHA class II patients who are considered Indeed, for the initial NDA submitted for a hypertension indi- candidates for aldosterone antagonist therapy. This recommen- cation, the sponsor provided an eplerenone study that con- dation prioritises the avoidance of unnecessarily costly therap- ies, which we have argued is required by the principle of There appears to be a conflict between the FDA’s legal mandate to evaluate medications for safety and effectiveness, ficence, over the general principal that randomised clinical trials, when available, should be used to guide therapy.
and its ethical mandate as part of the Public Health service to The eplerenone studies are not unique; many studies have promote public health. We argue that the latter mandate failed to test an active comparator. Most new drugs in the USA requires considerations of cost, in spite of the FDA’s tradition of are approved based on comparisons with placebos. However, a study that is not designed to test the comparative effectiveness and safety of competing treatments is ethically impaired when there is scientific reason to believe that an inexpensive treatment The journal that published the study bears responsibility for its will compare favourably in safety and effectiveness with a content. Journals are actors in the dissemination of clinical trial new and costly treatment. We argue that the actors in the J Med Ethics 2012;0:1–5. doi:10.1136/medethics-2011-100258 development, conduct, approval and publication of clinical trials should recognise the importance of cost as an ethical consider- ation and should not condone asking research subjects to partici- pate in a study in which the principle benefits accrue to the The Rales Investigators. Effectiveness of spironolactone added to an manufacturer’s shareholders. IRBs, DSMBs, journal editors and angiotensin-converting enzyme inhibitor and a loop diuretic for severe chronic clinicians should be aware of the problem of placebo-controlled congestive heart failure (the Randomized Aldactone Evaluation Study (RALES)).
trials, and should decline to consider ethically impaired studies.
Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and Acknowledgements The authors thank Dr Edmund Pellegrino for helpful mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341:709–17.
Pitt B, Remme W, Zannad F, et al. Eplerenone Post-Acute Myocardial Infarction Contributors All authors contributed to this paper. SG, AS, and AJF-B planned the Heart Failure Efficacy Survival Study Investigators. Eplerenone, a selective project. SG did research and wrote the first draft. AS and AJF-B wrote revised drafts.
aldosterone blocker, in patients with left ventricular dysfunction after myocardial Competing interest All authors have completed the Uni infarction. N Engl J Med 2003;348:1309–21.
form (available on request from the corresponding author) and declare: no support Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart from any organisation for the submitted work, no failure and mild symptoms. N Engl J Med 2011;364:11–21.
organisations that might have an interest in the submitted work in the previous three Armstrong PW. Aldosterone antagonists—last man standing? N Engl J Med years, no other relationships or activities that could appear to have in Ezekowitz JA, McAlister FA. Aldosterone blockade and left ventricular dysfunction:a systematic review of randomized clinical trials. Eur Heart J 2009;30:469–77.
Provenance and peer review Not commissioned; externally peer reviewed.
Pitt B, Roniker B. Eplerenone, a novel selective aldosterone receptor antagonist(SARA): dose finding study in patients with heart failure. J Am Coll Cardiol 1999; Miller FG, Joffe S. Equipoise and the dilemma of randomized clinical trials. N Engl Parthasarathy HK, Ménard J, White WB, et al. A double-blind, randomized study comparing the antihypertensive effect of eplerenone and spironolactone in patients Freedman B, Weijer C, Glass KC. Placebo orthodoxy in clinical research. I: Empirical with hypertension and evidence of primary aldosteronism. J Hypertens and methodological myths. J Law Med Ethics 1996;24:243 Freedman B, Glass KC, Weijer C. Placebo orthodoxy in clinical research. II: Ethical, legal, and regulatory myths. J Law Med Ethics 1996;24:252 Spironolactone or Aldactone entered in Drugs at FDA, Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? JAMA Pharmaceutical Research and Manufacturers of America. Principles on Batterink J, Stabler SN, Tejani AM, et al. Spironolactone for hypertension.
Cochrane Database Syst Rev 2010;(8):CD008169.
Marrs JC. Spironolactone management of resistant hypertension. Ann Zannad F, McMurray JJ, Drexler H, et al. Rationale and design of the Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure (EMPHASIS-HF).
Soberman JE, Weber KT. Spironolactone in congestive heart failure. Curr Hypertens New England Journal of Medicine. Sponsorship, authorship, and responsibility.
Schouten J, Michielsen PP. Treatment of cirrhotic ascites. Acta Gastroenterol Belg Brown J, Farquhar C, Lee O, et al. Spironolactone versus placebo or in combination Temple R, Ellenberg SS. Placebo-controlled trials and active-control trials in the with steroids for hirsutism and/or acne. Cochrane Database Syst Rev 2009;(2): evaluation of new treatments. Part 1: ethical and scientific issues. Ann Intern Med Rathnayake D, Sinclair R. Use of spironolactone in dermatology. Skinmed 2010; Ellenberg SS, Temple R. Placebo-controlled trials and active-control trials in the evaluation of new treatments. Part 2: practical issues and speci Fugh-Berman A, Dodgson SJ. Ethical considerations of publication planning in the pharmaceutical industry. Open Med 2008;2:e121–4.
Fugh-Berman AJ. The haunting of medical journals: how ghostwriting sold "HRT".
J Med Ethics 2012;0:1–5. doi:10.1136/medethics-2011-100258 Ethics and eplerenone
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