Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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Myopic view
- Eric Colman (11 August 2000)
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Re: Myopic view
- Kenneth J Rothman, Karin B Michels (12 August 2000)
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Placebo confusion
- Stephen Senn (15 August 2000)
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Sometimes it's unethical to prohibit placebo control
- Richard Anderson (15 August 2000)
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Is democratic or dictatorial research the goal of the WHO debate about the
- Hazel Thornton (15 August 2000)
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Re: Placebo confusion
- Kenneth J Rothman, Karin B Michels (15 August 2000)
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Re: Sometimes it's unethical to prohibit placebo control
- Kenneth J Rothman, Karin B Michels (15 August 2000)
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Declaration of Helsinki MUST be strengthened
- Roger M Goss (20 August 2000)
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Declaration of Helsinki - more honesty please
- Udo Schuklenk (23 August 2000)
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Standard treatment is compatible with use of placebo.
- Peter Allmark (24 August 2000)
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Equipoise as an essential principle of human experimentation
- R J Lilford, Benjamin Djulbegovic (25 August 2000)
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Equipoise: Analogies must have it.
- Adan Rios (9 July 2001)
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Eric Colman, Medical Officer FDA
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Rothman and Michels overestimate the influence of the FDA. Their view also neglects to acknowledge the reality that, in some circumstances, drug manufacturers favor placebo-controlled to active-controlled trials. The reasons for this are obvious. Furthermore, the FDA is not the only gatekeeper of trial participant safety. Indeed, this is the principal charge of IRBs. The design of clinical trials represents the amalgam of desires and beliefs of pharmaceutical companies, individual investigators, IRBs, and the FDA. These views are those of the author and do not necessarily reflect those of the FDA. |
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Kenneth J Rothman, Professor of Epidemiology Boston University, Karin B Michels
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Dr. Colman claims that our view is myopic because we neglect the reality that the FDA is not as powerful as we think. Who's kidding who? The global pharmaceutical industry jumps to the FDA tune, because the FDA controls drug approval in the world's biggest market. We do agree with Dr. Colman that the drug industry is happy to comply with FDA requirements, as it is easier to show superiority to placebo than to show equivalence with an existing drug. But what's his point? Many of those placebo-controlled studies that the FDA requires are unethical according to the Declaration of Helsinki. Institutional Review Boards, unfortunately, feel pressured by the FDA and manufacturers and often fail to fulfill their safekeeper role. Dr. Colman doesn't address the reasons why the FDA requires unethical studies. His argument boils down to this: the FDA is not alone and not as successful as you think in trying to get everyone to do unethical research. With all due respect, we would prefer to see the FDA commenting on the ethical issues directly, rather than shifting blame and denying responsibility. |
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Stephen Senn, Professor of Pharmaceutical and Heath Statistics UCL (University College London)
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The paper by Rothman and Michels1 will only serve to confuse the issues. A placebo is always specific to a given treatment. Its purpose is to blind that treatment, since for any other purpose it would be sufficient simply to have a control group in which the experimental treatment was withheld. The issue as to whether a placebo is given is logically independent of the decision as to whether a standard "effective" treatment is withheld. Placebo-controlled trials are frequently run as "add-on" trials. Indeed, when we consider that the list of effective treatments for all diseases includes, food, water, air and nursing care, all trials are (or should be!) add-on trials. The pure "no-treatment" group is a myth. The question is, how much of standard care to maintain when running a placebo controlled trial: frequently the answer has to be "all". In running a trial, the ethical issue is whether it is acceptable to withhold a standard available effective treatment. In the context of drug development, the experimental treatment is not generally available. Society has mandated the regulator to withhold treatments, until proved efficacious, except under the special circumstances of a clinical trial. This can be justified in terms of John Rawls's Theory of Justice2 as being a choice we would make in "the original position" regarding the sort of society we want to live in. Equipoise is an irrelevance3. Patients are entered onto the trial because the trialists believe that the experimental treatment is better. The control group treatment should be as good as that available outside the trial. Experimentation continues until either the trialists are convinced they are wrong (equipoise is reached) or they convince Society they are right. This is not to say that placebos are not sometimes used in ways in drug development that are unethical. One such use is in placebo run- ins3,4. These violate consent and should be abandoned. Declaration of interest: the author is a consultant to the pharmaceutical industry References 1 Rothman KJ, Michels, KB. Declaration of Helsinki should be strengthened: for. BMJ 2000;321:442-5 2 Rawls, JA Theory of Justice. Oxford: Oxford University Press, 1972 3 Senn SJ. Statistical Issues in Drug Development. Chichester: Wiley, 1997. 4 Senn SJ. (1997) Are placebo run ins justified? BMJ 2000; 314: 1191-3. |
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Richard Anderson, Associate professor of Psychology Bowling Green State University
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Sometimes it's unethical to prohibit placebo control. Scenario: A sub-population of depressed patients are best treated with antidepressant drugs, and a sub-population within that sub-population has forgone such treatment because they do not want to risk any "sexual side effects." A researcher would like to use patients from this "sub-sub- population" in a placebo controlled trial, comparing an aromatherapy treatment to a placebo treatment. An IRB, citing the Helsinki Agreement, prohibits use of the placebo group, even though subjects in that group have already made independent decisions not to subject themselves to any of the standard treatments for depression. -- RICHARD B. ANDERSON
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Hazel Thornton
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Editor - Richard Smith seeks questions. I have one: "Is a `for and against` presentation by health professionals an adequate format to present this issue in the 21st century?"[1] The involvement of non-health professionals as `participants* in research` now has two meanings: firstly, as invited trial participants; secondly, as participants in research teams and in the whole research process from choosing the question through to interpreting, publishing, disseminating and utilisation of resultant research data. (*Not "subjects" please, Robert Temple and Michael Baum!) [1] The second group of participants would query the implied homogenous passivity of patients [2] in need of "suggestions to strengthen protection of patients" and the "ethical choice of patients rights over the good of society". What about consideration of their responsibilities as citizens, hand-in-hand with their rights? [3] Inclusion of `patients` in trial steering committees and data monitoring committees provides lay members of society with a direct voice to balance researchers` aims with patients` desires and measures of outcome. This partly addresses their need for protection "from rogue investigators" by providing a stabilising component to redress the excesses of commercial and medical zeal and power over their "subjects". Achievement of democratic rather than dictatorial research should, I believe, be the perceived goal of those who are addressing the very difficult issues that revision of the Declaration of Helsinki exposes. I would agree with Professor Baum that flexibility is required, also a re- establishment and strengthening of trust, rather than going further down the road to absolutism and more stringent rules. The "tensions between the conduct of a trial and the autonomy of the individual" are better jointly considered within joint working groups of health professionals and `consumers`, such as the Consumers` Advisory Group for Clinical Trials (CAG-CT), jointly founded by Professor Michael Baum and the undersigned in September 1994. [4] Professor Baum has thus actively supported and encouraged consumer involvement in the research process. I believe he could have strengthened his argument by mentioning that the trial of clinical breast examination versus mammographic screening that he is proposing with Professor Indraneel Mittra has benefited from lay involvement and scrutiny by the undersigned; her contribution in the paper presenting a case for this [5]; and from the involvement and comment of the CAG-CT at an early stage of its consideration. It is hoped that he has retained his enthusiasm for lay involvement during his "transubstantiation" from "poacher to gamekeeper"! Hazel Thornton (Mrs.)
REFERENCES: 1. Rothman KJ, Michels KB, Baum M. For and against. Declaration of Helsinki should be strengthened, BMJ 12 August 2000 321:442-445. 2. Thornton H. Today`s patient: passive or involved? Lancet 2000; siv/48 3. Thornton H. Patients` understanding of clinical trials. Lancet. 1998; 352:72 4. Baum M. The whole population must be mobilised in the war against cancer. BMJ 1997; 314: 1482 5. Mittra I, Baum B, Thornton H, Houghton J. Is Clinical Breast Examination an Acceptable Alternative to Mammographic Screening for Women and for the Health Service? BMJ 2000 In press. |
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Kenneth J Rothman, Professor of Epidemiology (Dr. Rothman) Boston University, Karin B Michels
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Placebos are used in trials both to facilitate blinding and to control for the psychosomatic effects of offering treatment. Dr. Senn is wrong to suggest that placebo is necessary for blinding. In most situations blinding can be achieved with an active control as well as with placebo, at least for outcome assessment. Dr. Senn has seriously misread our paper if he thinks we are advocating "no-treatment" as an alternative to placebo, and he seriously misunderstands modern medicine if he thinks that only newly developed treatments are effective. Furthermore, he is in sparse company in thinking that equipoise is irrelevant. What is his justification for deliberately denying effective treatment to a portion of his patients? –Kenneth J. Rothman and Karin B. Michels |
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Kenneth J Rothman, Professor of Epidemiology (Dr. Rothman) Boston University, Karin B Michels
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Dr. Anderson's example is fallacious: if side effects make a treatment unacceptable to some patients, for them the best treatment may be nothing. In that case a placebo control for them is completely ethical, and would not violate the Declaration of Helsinki. |
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Roger M Goss, Director Patient Concern
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Editor - Michael Baum’s attitude makes depressing reading. (1) He would have no problem with placebo controlled trials in some circumstances. He perceives nothing wrong with depriving patients of currently best available treatment for the benefit of medical research. This is a classic conflict of interest disguised by the profession’s mantra: everything is done “in the patient’s best interests”. Unfortunately medical advances depend on the use of patients as guinea pigs. Placebo controlled trials can easily lead to viewing experiments on people unable to give informed consent as ethically acceptable. “A disciplined search for an objective reality” is liable to mean sacrificing the interests of the already disadvantaged “in the service of mankind”. The Declaration of Helsinki aims to protect the vulnerable from attempts by over-enthusiastic seekers of new treatments to short cut ethical practice. Consumers for Ethical Research (CERES) has produced a comprehensive guide for patients contemplating participation in trials. It is sad to learn that the BMJ declined to publish this excellent document. In the new era of a patient-centred NHS, perhaps it should re-consider this decision as a public service to both doctors and patients. We must respect and cultivate the inherent altruism of many patients, rather than allow tunnel vision researchers to undermine it. Roger M. Goss
1 Rothman K, Michels K, and Baum M. Declaration of Helsinki should be strengthened BMJ 2000; 321: 442-445. (12 August) |
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Udo Schuklenk, Prof of Bioethics University of the Witwatersrand Faculty of Health Sciences
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The current debate over changes to the Declaration of Heklsinki is disappointing, because it has in many ways muddled the waters instead of clearing debris in order to improved international research ethics standards. What we see at the moment is a very clear faltline between the US and UK medical associations, for instance, both of which support lower standards of care for people living in developing countries and continental European, Latin American, but also some Asian medical associations who reject such a double standard. In the UK the private Wellcome Foundation sponsors currently a research project designed to bolster the case of the anglosaxon medical associations, while it saw itself unable to sponsor a project critical of this campaign. One of the crucial questions one has to face in this context is this: do we want to see more clinical research undertaken the primary objective of which are solutions to economic rather than medical problems. If the answer to this question is affirmative, it is only logical to demand lower standards of care, because they come cheaper. If, on the other hand, we are serious about tackling the health problems of people in developing countries, and this includes access to affordable medication, surely the point should be to question the economic frameworks that give rise to the purported necessity to develop 'cheaper drugs'. Anglosaxon pragmatism, in this case, readily accepts the economic frameworks and tries to make the best out of the situation. Is it really unreasonable then, to ask of them a bit more honesty in their campaign. They ought to state unequivocally, that they think it is ethically acceptable that Thai subjects (or soon African subjects) die as a consequence of an HIV infection acquired during preventive HIV vaccine trials. This is what the lower standards of care both associations deem ethically acceptable will mean practically for the impoverished and otherwise vulnerable subjects in these trials.[1]Reasons for this position can be found. They are not even unintelligent reasons. I find them unconvincing. A first step to improve the debate, could surely be to be frank about what one does and what one doesn't consider acceptable with regard to for instance standards of care in preventive vaccine trials. We should also be concerned about attempts to manufacture what is likely to be billed as an international 'consensus' on this matter. International research ethics meetings take place currently all over the world, but developing country based scholars and treatment access activists have more often than not only access if they know a generous Western sponsor who pays for their airfare, and accommodation. This itself renders these meetings, of course, unrepresentative in any meaning of the word. [1] U Schuklenk, R Ashcroft. International Research Ethics. BIOETHICS 2000; 14: 158-172. Competing interests: None |
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Peter Allmark, Nursing lecturer Sheffield University
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As I understand it placebos are usually given in addition to the
standard treatment. Thus patients are randomised into two groups:
This seems to offer no ethical problems unless the placebo is onerous
in some way (e.g. it involves injection). The problem would be where the
new treatment will be given instead of some aspect of standard treatment.
For example, standard treatment might include drug B instead of A. In
such a case, a placebo trial might result in standard treatment being
defined as everything normally given but absenting A. Then you would have
groups:
It seems that it is this type of trial which is of concern. My thought is that such trials would rarely be justified except where there was equipoise over whether A is effective or not. The key point is that it is not the fact of whether or not a placebo is used that makes a trial unethical, it is whether or not standard treatment is defined in such a way that patients as research participants/subjects are deprived of a treatment known to be effective. |
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R J Lilford , Benjamin Djulbegovic
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We would like to join the ongoing debate regarding the next revision of the Declaration of Helsinki, and address some "for and against "arguments eloquently put by Rohtman and Michels and by Baum in the recent issue of the BMJ1. We agree with Rothman and Michels that "equipoise" (or, "the uncertainty principle"2) is an essential ingredient of an ethical human experiment and that the declaration should be amended to say so. In fact, more recently, we argued that extraordinary care should be given to understand and protect this fundamental principle on which nearly the entire system of human experimentation stands3. However, Baum writes of "tensions between conduct of a trial and the autonomy of the individual"1. This involves the notion that patients who participate in trials are asked to make a sacrifice for the good of others 4. However, this concern is alleviated by explicitly invoking equipoise as the principle upon which randomized controlled trials (RCTs) are based. The uncertainty principle, or equipoise, states that the patient should be enrolled in a RCT only if uncertainty about which of the trial treatments would benefit a patient most is so substantial that they are in "equipoise" or "indifferent" between treatment options5 6. It follows that so long as we are substantially uncertain which treatment is superior, patients do not loose out prospectively and are not required to sacrifice themselves for the benefit of others5. Thus, ethically, RCTs should be acceptable to both utilitarians (who seek to bring the greatest good to the greatest number of patients by ensuring scientifically robust results) and Kantians (who seek to protect and preserve autonomy of individual patients)5. The same principle applies to any randomised trial, whether it is placebo- controlled or not. It is just that in the case of placebo-controlled trials we should be particularly vigilant about applying the uncertainty principle3. In our opinion, the ethical dilemma expressed in the BMJ article is false - it has already been resolved. The question is now a technical one - how do we improve communication so that patients can really find out whether or not they are indifferent between treatment options? Literature: 1. Rohtman KJ, Michels KB, Baum M. Declaration of Helsinki should be strengthened. For and against. BMJ 2000;321:442-5. 2. Peto R. Trials:the next 50 years. BMJ 1998;317:1170-1171. 3. Djulbegovic B, Lacevic M, Cantor A, Fields K, Bennett C, Adams J, et al. The uncertainty principle and industry-sponsored research. Lancet 2000;356:635-638. 4. Mathe G, Brienza S. From methodology to ethics and from ethics to methodology. Biomed & Pharmacother 1988;42:143-153. 5. Edwards SJL, Lilford RJ, Braunholtz DA, Jackson JC, Hewison J, Thornton J. Ethical issues in the design and conduct of randomized controlled trials. Health Technol Assessment 1998;2(15):1-130. 6. Lilford RJ, Jackson J. Equipoise and the ethics of randomization. J R Soc Med 1995;88:552-559. |
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Adan Rios, President Oncol Therapeutics,Houston, Texas
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Dear Sir: In arguing for randomized trials, Dr. Baum uses an attractive but flawed analogy. He states that there is an anlogy between demanding the best evidence to convict a criminal of a capital offense and the need to demand the absolute knowledge of the best treatment for a fatal illness. There is an ironic lack of correspondence(equipoise)in the manner that Dr. Baum uses this analogy. The correct use of this analogy should mantain a correspondence between the terms of comparison as follows: The best evidence to convict is the disease since it will result in the death of the accused. The remedy is the slightest doubt that the accused is guilty,since its use can lead to the survival of the accussed. In the case of the therapy of a fatal illness, the correspondence is that the illness is the equivalent of the best evidence to convict, since it will lead to the death of the patient. The evidence of therapeutic efficacy of a known remedy is the equivalent of doubt about the guilt of the accused,since its use can lead to the survival of the patient. Demanding the best evidence to convict has no correspondence with demanding to know the best treatment for a fatal illness, and thus invalidate the use of Dr. Baum analogy. Adan Rios M.D. |
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