Ursula Ptok and Christopher Ryan, Department of Psychiatry, Sydney West Area Health Service, Westmead Hospital, Westmead, Australia
10 February 2008
Ghaemi and Goodwin [1] set out “to assess the scientific and ethical basis for clinical innovation in psychopharmacology”, defining this as “the use of treatments in a clinical setting which have not been well-proven in a research setting”. Their abstract suggests that they will approach their task primarily by means of a literature review, but when their review strategy reveals “no studies in which the topic has been examined empirically” they fall back onto an historical and ethical analysis which we believe is significantly flawed in several respects.
The authors begin by setting up a straw man. They claim that “the bioethics community has sought to cleanly and completely separate clinical practice from research”. To support this claim, they quote from only one source – the 1979 Belmont Report [2], and do so only extremely selectively. In fact, the authors of the Belmont Report did not claim this neat separation but noted that “[t]he distinction between research and practice is blurred partly because both often occur together … and partly because notable departures from standard practice are often called ”experimental” when the terms ”experimental” and ”research” are not carefully defined”. The Belmont Report sets out to better define these terms, not to artificially separate them. No other source from the “bioethics community” is cited.
The authors seem at once surprised and indignant that their literature search reveals no empirical work on which to base their project. However much of the problem here is choice of search terms. Simply adding the term “off-label use” would have revealed several relevant articles which would have provided some of the empirical evidence the authors were seeking [3-8]. These papers provide considerable data on how frequently clinicians prescribe outside FDA indications, what conditions are treated in that setting and what medications used.
Having abandoned the literature review, the authors propose that the “ultimate rationale for clinical innovation” is “evidence from the history of psychopharmacology that such innovation is essential to the discovery of new knowledge”. Much of the paper is then consumed by a highly selective account of the history of psychopharmacology, focused solely on achievement and success. Most of their examples though owe more to careful clinical observation than “clinical innovation” as defined. There is certainly no acknowledgement that in the vast majority of cases, “clinical innovation” will yield no benefit to the patient or to practice, and no mention of the many tragedies that have resulted by the actions of doctors who felt sure that their idiosyncratic practices tapped into a well of truth that their colleagues could not see.
The paper is also a “challenge to traditional bioethics”. At odd intervals the authors embark on what might loosely be called ethical arguments designed to support their position. It would be tedious to attack each of these individually, so we will let one example stand for all. In the section entitled The history of psychopharmacology the authors espouse that:
“Since advancing knowledge is recognized as an ethically justified and important activity, and clinical innovation precedes and is the source of major advances in formal clinical research … then clinical innovation too is not only ethically justifiable, but is, indeed, ethically required.”
Even if one were to acknowledge the extremely dubious premise that clinical innovation might precede and be a source of major advances in formal clinical research, still this conclusion cannot follow logically. If “B” is ethically justified and can be brought about by “A”, it does not necessarily follow that “A” is ethically justified, let alone required. However this is the authors’ view, and ironically, this is exactly the sort of flawed logic that motivated the Tuskegee Syphilis Study [www.cdc.gov/tuskegee/timeline.htm ] that lead to the Belmont Report in the first place.
Off label use of psychotropic medications is common, concerning, and worthy of both scientific and ethical analysis. At least some of Ghaemi and Goodwin’s conclusions on the matter seem sensible and commonsensical. Overall, however, the paper contributes little to the debate.
References
1. Ghaemi SN, Goodwin FK. The ethics of clinical innovation in psychopharmacology: Challenging traditional bioethics. Philosophy, Ethics, and Humanities in Medicine 2[26]. 2007.
Ref Type: Journal (Full)
2. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. 1979. Office of Human Subjects Research, National Institutes of Health.
Ref Type: Report
3. Weiss E, Hummer M, Koller D, Ulmer H, Fleischhacker WW. Off-label use of antipsychotic drugs. Psychopharmacology 20[6], 695-698. 2000.
Ref Type: Journal (Full)
4. Martin-Latry K, Richard C, Verdoux H. A one-day survey of characteristics of off-label hospital prescription of psychotropic drugs. Pharmacopsychiatry 40[3], 116-120. 2007.
Ref Type: Journal (Full)
5. Haw C, Stubbs J. Off-label use of antipsychotics: Are we mad? Expert Opinion in Drug Saftey 6[5], 533-545. 2007.
Ref Type: Journal (Full)
6. Haw C, Stubbs J. A survey of off-label use of mood stabilisers in a large psychiatric hospital. Journal of Psychopharmacology 19[4], 402-407. 2005.
Ref Type: Journal (Full)
7. Botvinik L, Ng C, Schweitzer I. Audit of antipsychotic prescribing in a private psychiatric hospital. Australasian Psychiatry 12[3], 277-233. 2004.
Ref Type: Journal (Full)
8. Radley DC, Finkelstein SN, Stafford RS. Off-label prescribing among office-based physicians. Archives of Internal Medicine 166, 1021-1026. 2006.
Ref Type: Journal (Full)
Competing interests
None
Response to Drs Ptok and Ryan
Nassir Ghaemi, Tufts Medical Center
13 September 2008
I thank Drs Ptok and Ryan for their comment and apologize for not responding sooner. While I appreciate that they took the time to read and comment on this article, we obviously do not agree.
We did not set up a straw man; the Belmont Report is in fact interpreted in practice as we claim. The fact that it has other language which is largely ignored does not change this reality, any more than the fact that the Bible can be interpreted in different ways does not alter the reality of its evangelical interpretation among one influential group.
Our literature search was complete. The commentators are discussing the research on “off-label” treatment, which is related to, but not the same as, our focus on clinical innovation as a source of research.
The “highly selective” history of psychopharmacology highlights successes to make the point that success can, and does, happen; as opposed to the Belmont Report extremist view, which the commentators seem to share, that the harm of clinical innovation is either complete or at least prominently outweighs any benefits.
The allusion to the Tuskegee Report is like claims of fascism in political dialogue: it is a bear that is meant to scare whenever interlocutors have run out of logical arguments. Of course we are not advocating a totalitarian consequentialism, but we are rejecting an almost medieval deontology, as formulated in the Belmont Report as practiced today, and again which the authors seem to accept. We are well aware that clinical innovation has its risks, that is why we set out to try to explain how it might be done ethically, with attention to its harms and risks. Otherwise, we would not have bothered writing the paper.
It is too bad that the bioethics community does not engage in more reasoned and serious debate, as opposed to challenging the motivations of those who do not unthinkingly accept the status quo.
Comment on Ghaemi and Goodwin
10 February 2008
Ghaemi and Goodwin [1] set out “to assess the scientific and ethical basis for clinical innovation in psychopharmacology”, defining this as “the use of treatments in a clinical setting which have not been well-proven in a research setting”. Their abstract suggests that they will approach their task primarily by means of a literature review, but when their review strategy reveals “no studies in which the topic has been examined empirically” they fall back onto an historical and ethical analysis which we believe is significantly flawed in several respects.
The authors begin by setting up a straw man. They claim that “the bioethics community has sought to cleanly and completely separate clinical practice from research”. To support this claim, they quote from only one source – the 1979 Belmont Report [2], and do so only extremely selectively. In fact, the authors of the Belmont Report did not claim this neat separation but noted that “[t]he distinction between research and practice is blurred partly because both often occur together … and partly because notable departures from standard practice are often called ”experimental” when the terms ”experimental” and ”research” are not carefully defined”. The Belmont Report sets out to better define these terms, not to artificially separate them. No other source from the “bioethics community” is cited.
The authors seem at once surprised and indignant that their literature search reveals no empirical work on which to base their project. However much of the problem here is choice of search terms. Simply adding the term “off-label use” would have revealed several relevant articles which would have provided some of the empirical evidence the authors were seeking [3-8]. These papers provide considerable data on how frequently clinicians prescribe outside FDA indications, what conditions are treated in that setting and what medications used.
Having abandoned the literature review, the authors propose that the “ultimate rationale for clinical innovation” is “evidence from the history of psychopharmacology that such innovation is essential to the discovery of new knowledge”. Much of the paper is then consumed by a highly selective account of the history of psychopharmacology, focused solely on achievement and success. Most of their examples though owe more to careful clinical observation than “clinical innovation” as defined. There is certainly no acknowledgement that in the vast majority of cases, “clinical innovation” will yield no benefit to the patient or to practice, and no mention of the many tragedies that have resulted by the actions of doctors who felt sure that their idiosyncratic practices tapped into a well of truth that their colleagues could not see.
The paper is also a “challenge to traditional bioethics”. At odd intervals the authors embark on what might loosely be called ethical arguments designed to support their position. It would be tedious to attack each of these individually, so we will let one example stand for all. In the section entitled The history of psychopharmacology the authors espouse that:
“Since advancing knowledge is recognized as an ethically justified and important activity, and clinical innovation precedes and is the source of major advances in formal clinical research … then clinical innovation too is not only ethically justifiable, but is, indeed, ethically required.”
Even if one were to acknowledge the extremely dubious premise that clinical innovation might precede and be a source of major advances in formal clinical research, still this conclusion cannot follow logically. If “B” is ethically justified and can be brought about by “A”, it does not necessarily follow that “A” is ethically justified, let alone required. However this is the authors’ view, and ironically, this is exactly the sort of flawed logic that motivated the Tuskegee Syphilis Study [www.cdc.gov/tuskegee/timeline.htm ] that lead to the Belmont Report in the first place.
Off label use of psychotropic medications is common, concerning, and worthy of both scientific and ethical analysis. At least some of Ghaemi and Goodwin’s conclusions on the matter seem sensible and commonsensical. Overall, however, the paper contributes little to the debate.
References
1. Ghaemi SN, Goodwin FK. The ethics of clinical innovation in psychopharmacology: Challenging traditional bioethics. Philosophy, Ethics, and Humanities in Medicine 2[26]. 2007.
Ref Type: Journal (Full)
2. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. 1979. Office of Human Subjects Research, National Institutes of Health.
Ref Type: Report
3. Weiss E, Hummer M, Koller D, Ulmer H, Fleischhacker WW. Off-label use of antipsychotic drugs. Psychopharmacology 20[6], 695-698. 2000.
Ref Type: Journal (Full)
4. Martin-Latry K, Richard C, Verdoux H. A one-day survey of characteristics of off-label hospital prescription of psychotropic drugs. Pharmacopsychiatry 40[3], 116-120. 2007.
Ref Type: Journal (Full)
5. Haw C, Stubbs J. Off-label use of antipsychotics: Are we mad? Expert Opinion in Drug Saftey 6[5], 533-545. 2007.
Ref Type: Journal (Full)
6. Haw C, Stubbs J. A survey of off-label use of mood stabilisers in a large psychiatric hospital. Journal of Psychopharmacology 19[4], 402-407. 2005.
Ref Type: Journal (Full)
7. Botvinik L, Ng C, Schweitzer I. Audit of antipsychotic prescribing in a private psychiatric hospital. Australasian Psychiatry 12[3], 277-233. 2004.
Ref Type: Journal (Full)
8. Radley DC, Finkelstein SN, Stafford RS. Off-label prescribing among office-based physicians. Archives of Internal Medicine 166, 1021-1026. 2006.
Ref Type: Journal (Full)
Competing interests
None
Response to Drs Ptok and Ryan
13 September 2008
I thank Drs Ptok and Ryan for their comment and apologize for not responding sooner. While I appreciate that they took the time to read and comment on this article, we obviously do not agree.
We did not set up a straw man; the Belmont Report is in fact interpreted in practice as we claim. The fact that it has other language which is largely ignored does not change this reality, any more than the fact that the Bible can be interpreted in different ways does not alter the reality of its evangelical interpretation among one influential group.
Our literature search was complete. The commentators are discussing the research on “off-label” treatment, which is related to, but not the same as, our focus on clinical innovation as a source of research.
The “highly selective” history of psychopharmacology highlights successes to make the point that success can, and does, happen; as opposed to the Belmont Report extremist view, which the commentators seem to share, that the harm of clinical innovation is either complete or at least prominently outweighs any benefits.
The allusion to the Tuskegee Report is like claims of fascism in political dialogue: it is a bear that is meant to scare whenever interlocutors have run out of logical arguments. Of course we are not advocating a totalitarian consequentialism, but we are rejecting an almost medieval deontology, as formulated in the Belmont Report as practiced today, and again which the authors seem to accept. We are well aware that clinical innovation has its risks, that is why we set out to try to explain how it might be done ethically, with attention to its harms and risks. Otherwise, we would not have bothered writing the paper.
It is too bad that the bioethics community does not engage in more reasoned and serious debate, as opposed to challenging the motivations of those who do not unthinkingly accept the status quo.
Competing interests
Research grants: Pfizer
Speakers' Bureaus: Pfizer and Astra Zeneca
Honoraria: Bristol Myers Squibb