Editorial policies on financial disclosure

CO R R E S P ON D E N C E

Editorial policies on financial disclosure To the editor: We applaud the clear policy of the Nature journals concerning disclosure of financial conflicts of interest1 among authors and editors. The Nature policy on this topic is consistent with that of other major journals2–4. Because the intent of your policy is clear, we call to your attention three instances of non-disclosure in a recent review article5 on the treatment of mood disorders by Charles B. Nemeroff and Michael J. Owens, which appeared in a Nature Neuroscience supplement in November 2002. This supplement aimed to highlight the potential practical benefits of neuroscience research. Developments featured in such commissioned reviews predictably attract favorable attention. First, the authors state, “Changing the pharmacokinetic profiles of existing drugs has also proven beneficial...and methods to deliver monoamine oxidase inhibitor and lithium via patch technology have been developed. (p.1069)” What Dr. Nemeroff did not indicate is that he holds U.S. Patent 6,375,990, issued 23 April 2002, on “Method and Devices for Transdermal Delivery of Lithium”. There is no published clinical evidence and no consensus about any clinical need for such a lithium delivery system. It thus would appear that Dr. Nemeroff stands potentially to profit by gratuitously promoting his patented lithium patch. Second, the authors state “...the marked hypercortisolemia observed in psychotic depression...has led to impressive studies indicating that...mifepristone (RU486) is very effective in the treatment of psychotic depression...clinical trials are currently being conducted by Corcept... (p.1069)” What Dr. Nemeroff also did not indicate in the article is that he is a member of the Scientific Advisory Board of Corcept Therapeutics and as such was given an option to purchase 72,000 shares of Corcept stock at $0.0003 per share (a total cost of $21.60)6. We presume Dr. Nemeroff exercised his option, because he has publicly acknowledged being a stockholder in Corcept. The “impressive studies” consist of two reports on small samples, neither of which demonstrated a statistically significant treatment effect7,8. Corcept Therapeutics has only one

product: mifepristone for psychiatric disorders. When the projected initial public offering of shares by Corcept occurs at the corporation’s estimated share price of $14–16, Dr. Nemeroff’s equity will be valued at more than $1,000,000. It again would appear that Dr. Nemeroff stands potentially to profit from the interest his positive assessment of mifepristone might generate for Corcept in advance of a public stock offering. Third, the authors state “Milnacipran, a dual 5-HT and NE reuptake inhibitor approved for the treatment of depression in France, Japan and other countries, is being developed in the U.S. market for the treatment of fibromyalgia as a collaboration between Pierre Fabre and Cypress Biosciences. (p.1069)” What Dr. Nemeroff again did not reveal is that he is both a director and chairman of the Psychopharmacology Advisory Board of Cypress Bioscience, for which he is paid $48,000 per year, plus stock options. He is the beneficial owner of over 18,000 company shares. He also has a performance incentive of $100,000 for materially contributing to the achievement of certain milestones in the development of milnacipran in the United States9. Cypress Bioscience, like Corcept Therapeutics, has only one product. Since milnacipran appeared in 1989, it has been on offer by Pierre Fabre but was rejected by major pharmaceutical corporations following due-diligence studies. The licensing of milnacipran by Cypress Bioscience is not a significant payoff of neuroscience research. Its inclusion in the review article thus would appear to further serve Dr. Nemeroff ’s potential personal financial interest. These are serious failures to disclose financial conflict by any author of a scientific article. We also call to your attention the fact that Dr. Nemeroff is editor-in-chief of Neuropsychopharmacology, the official journal of the American College of Neuropsychopharmacology and a journal published by the Nature Publishing Group. As the editor-in-chief of a scientific journal, Dr. Nemeroff has a responsibility to set standards of conduct, including disclosure

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of potential conflicts of interest, for his field editors, editorial board, manuscript reviewers and authors. For this the bar must be high; indeed, the Instructions to Authors for Neuropsychopharmacology state, “At the time of submission, each author must disclose any involvement, financial or otherwise, that might potentially bias their work. This information should be listed in the Acknowledgements that appear at the end of the manuscript and noted in the authors’ cover letter.” There are no exceptions. It is our position that an editor-in-chief who requires such explicit standards for his contributors should follow the same standards in his own publications in other scientific journals. The Uniform Requirements for Manuscripts Submitted to Biomedical Journals2 state that “conflict of interest exists when an author... reviewer, or editor has financial or personal relationships that inappropriately influence (bias) his or her actions... Disclosure of these relationships is particularly important in connection with editorials and review articles, because bias can be more difficult to detect in those publications than in reports of original research.” We therefore ask that the Nature journals expand their conflict-of-interest policy to cover all published writings. Bernard J Carroll Pacific Behavioral Research Foundation, Carmel, California 93922, USA. e-mail: [email protected] Robert T Rubin Professor of Neurosciences and Psychiatry, Drexel University College of Medicine, Allegheny General Hospital, Pittsburgh, Pennsylvania 15212, USA. e-mail: [email protected] 1. Editorial. Nat. Neurosci. 4, 961 (2001). 2. Davidoff, F., et al. N. Engl. J. Med. 345, 825–826 (2001). 3. Editorial. Lancet 359, 1167 (2002). 4. Alpert, J.S., Furman, S. & Smaha, L. Arch. Intern. Med. 162, 635–637 (2002). 5. Nemeroff, C.B. & Owens, M.J. Nat. Neurosci. 5 (Suppl.), 1068–1070 (2002). 6. SEC Amended Securities Registration Statement (http://www.sec.gov/Archives/edgar/data/1088856/000 101287002000273/ds1a.txt). 7. Belanoff, J.K., Flores, B.H., Kalezhan, M., Sund, B.

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CO R R E S P ON D E N C E & Schatzberg, A.F. J. Clin. Psychopharmacol. 21, 516–521 (2001). 8. Belanoff, J.K. et al. Biol. Psychiatry 52, 386–392 (2002). 9. SEC Form 10-K (http://www.sec.gov/Archives/edgar/ data/716054/000089843002001232/d10k405.txt).

Nemeroff and Owens reply: We appreciate the opportunity to respond to the issues raised by Drs. Carroll and Rubin, which were also featured in a recent New York Times article1. This is not the first time Drs. Carroll and Rubin have criticized our peer-reviewed publications and citation of our work in the popular press. Two journals, Biological Psychiatry2,3 and Neuropsychopharmacology4,5 have previously published their letters and our responses, and the interested reader may wish to refer to this scientific dialogue. These investigators have never contacted us directly regarding their concerns about our scientific publications. We were pleased to be invited to contribute a review to Nature Neuroscience on the treatment of mood disorders. The charge from the editor was to review the field in a very succinct manner. This is a broad research area and we wished to do it justice, both in terms of balance and scientific integrity. In order to review the field accurately, we needed to describe all the novel developments in the field, including compounds developed by companies we have consulted to and/or have provided one or both of us with grant support. In our review, we were less than enthusiastic about some compounds (e.g., gepirone), despite our ongoing consultation with their manufacturer, Organon. And conversely, we were quite enthusiastic about compounds developed by companies with which we have no commercial relationship (e.g., brain-derived neurotrophic factor or BDNF). After submission, we received detailed peer reviews from the journal, which resulted in revision of the manuscript, and thereafter, the editor made several further modifications to the manuscript. At the time of submission of our review, no request for any financial disclosure information was forthcoming from the journal, as it was simply not Nature Neuroscience’s policy. At no point in this process was any question raised with us about bias in our research review, nor was disclosure of financial information requested. We have always been forthcoming about financial relationships we have with any pharmaceutical or biotech companies. This is a matter of public record (for example, see ref. 6 or a variety of websites such as http://mts-npp.nature.com/letters/NPPcoi. pdf). We also exhibit financial disclosures

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prior to all of our scientific lectures and in all meeting proceedings. In terms of the specific allegations raised in the Carroll-Rubin letter, we would offer the following: First, we wish to reiterate that in contrast to their statement in the first paragraph, Nature Neuroscience had no established policy on financial conflicts of interest for review authors at the time of submission or publication of our report. Second, one of us (C.B.N.) and a colleague, C.D. Kilts, have been granted a patent for a novel method to deliver lithium by a transdermal patch. In contrast to Carroll and Rubin’s assertion that “there is no published clinical evidence and no consensus about any clinical need for such a lithium delivery system,” there is a vast literature7,8 documenting the high percentage of patients for whom lithium therapy is indicated and who are sensitive to its side effects (gastrointestinal and others) and cannot, therefore, achieve therapeutic lithium concentrations. The lithium transdermal system is an attempt to circumvent these problems associated with the use of oral lithium carbonate. Although we hold this patent, we have not engaged a partner to underwrite its development, and as such, it currently has no value. Moreover, patents have not traditionally been included in requests for financial disclosures. The criticisms concerning mifepristone and the relationship of one of us (C.B.N.) to Corcept Therapeutics bears discussion. The stated information in their letter is incorrect. No initial public offering of this stock has occurred, nor is any imminently planned, to the best of our knowledge. The articles in question appeared in peer-reviewed publications9,10. The latest article published in Biological Psychiatry was of sufficient interest that the Editor-in-Chief, Dennis S. Charney, Chief of the Mood and Anxiety Disorders Branch at the NIH, co-authored an accompanying editorial11. We stand by our enthusiasm for this novel approach of the treatment of psychotic depression. Finally, it is, indeed, true that one of us (C.B.N.) serves on the board of directors of Cypress Biosciences, the company developing milnacipran for the treatment of fibromyalgia, and the other (M.J.O.) was a grant recipient and consultant to Cypress. However, the statement covering “a performance incentive of $100,000” is wrong. Considering that the Cypress-sponsored trials in fibromyalgia have provided very promising results, that this devastating and common disorder has no FDA-approved treatment, and that several pharmaceutical companies have formally expressed their interest in partnering with Cypress, Carroll and Rubin’s claims that the “licensing of milnacipran by Cypress is not

a significant payoff of neuroscience research” and “Its inclusion...would appear to further serve Dr. Nemeroff ’s potential personal financial interest” is incorrect. In summary, we stand by the statements in our invited review article published in Nature Neuroscience. Lastly, Dr. Nemeroff’s role as editor-in-chief of Neuropsychopharmacology was cited in their letter as cause of concern because of his duty “to set standards of conduct, including disclosure of potential conflicts of interest, for his field editors, editorial board members, manuscript reviewers and authors.” We could not agree more—those are his duties for Neuropsychopharmacology, not, however, for Nature Neuroscience. After being named as editorin-chief of Neuropsychopharmacology, a position he was appointed to after a comprehensive national search conducted by the American College of Neuropsychopharmacology, Dr. Nemeroff immediately sought, together with input from the field editors, editorial board and staff of the Nature Publishing Group, to develop appropriate policies on a variety of issues for the journal, including financial disclosure. As recently as the field editors’ meeting held this past April, considerable discussion surrounding this topic occurred and a consensus was reached. We are proud of the policies that have been developed in this regard for Neuropsychopharmacology. Nevertheless, their relevance to our review publication in Nature Neuroscience, a journal neither of us serves in any editorial capacity, remains obscure. We applaud the recent increase in complete disclosure of potential financial conflicts of interest by professional organizations and journals. We have always and will continue to comply with all requests for such disclosures and prominently display this information on a variety of websites. Going forward, we intend to provide all financial disclosure information, even if it is not requested by the journal editor. We believe it unfortunate that Drs. Carroll and Rubin would attribute the views expressed in our Nature Neuroscience article to be motivated by personal avarice. That is not the case. Charles B Nemeroff Reunette W. Harris Professor and Chairman, Laboratory of Neuropsychopharmacology, Emory University School of Medicine, 1639 Pierce Drive, Atlanta, Georgia 30322, USA. e-mail: [email protected] Michael J Owens Associate Professor, Laboratory of Neuropsychopharmacology, Emory University School of Medicine, 1639 Pierce Drive, Atlanta, Georgia 30322, USA. e-mail: [email protected]

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CO R R E S P ON D E N C E 1. Petersen, M. “Undisclosed Financial Ties Prompt Reproval of Doctor” New York Times, August 3, 2003. 2. Rubin, R.T. Biol. Psychiatry 48, 954 (2000). 3. Owens, M.J., Nemeroff, C.B. & Knight, D.L. Biol. Psychiatry 48, 955 (2000). 4. Carroll, B.J. Neuropsychopharmacology 26, 411–412 (2002).

5. Stout, S.C., Owens, M.J. & Nemeroff, C.B. Neuropsychopharmacology 26, 413–414 (2002). 6. Hollander, E. et al. Neuropsychopharmacology 28, 1186–1197 (2003). 7. Lenox, R.H. & Manji, H.K. in Textbook of Psychopharmacology 2nd edn. (eds. Schatzberg, A.F. & Nemeroff, C.B.) 379–429 (American Psychiatric Press, Washington, DC, 1998).

8. Stoudemire, A. et al. Gen. Hosp. Psychiatry 20, 85–90 (1998). 9. Belanoff, J.K. et al. J. Clin. Psychopharmacol. 21, 516–521 (2001). 10. Belanoff, J.K. et al. Biol. Psychiatry 52, 386–392 (2002). 11. Gold, P.W., Drevets, W.C. & Charney, D.S. Biol. Psychiatry 52, 381–385 (2002).

To the editor: We read with interest the recent article1 in the New York Times reporting on undisclosed financial ties in a Nature Neuroscience review article on treatments for mood disorders2. According to the Times article, Nature’s policy permitted the author of the review to remain silent about his patent and other significant financial interests in treatments praised in his review. In February 2002, the Center for Science in the Public Interest and two dozen prominent scientists wrote a letter urging the Nature journals to strengthen their policies and procedures regarding conflicts of interest. A lengthy story3 about the issues raised in that letter was published in the March 28, 2002 issue of Nature. Among other things, that article pointed out that Nature’s policy was weaker than a number of its peer publications. You will be interested to know that despite the fact that it was cited as having one of the strongest policies, The Proceedings of the National Academy of Sciences has taken additional steps to improve its policy4, by explicitly expanding the disclosure requirement to “all authors, members, referees, and editors”— be they authors of letters, review articles, or editorials. Particularly in light of the New York Times article, the undersigned urge you to revisit our recommendations and establish a more robust policy that requires (i) mandatory disclosure of conflicts of interest for all authors, referees, and editors, (ii) mandatory disclosure of all information regarding the specific contributions of authors, (iii) publication of those disclosures, and (iv) rejection of submissions where authors’ conflicts are incompatible with integrity in science. Such a policy is a necessary safeguard against potential bias and would ensure that your readers have sufficient information to evaluate the studies, commentary, reviews, letters, and other statements made in the pages of the Nature journals.

Michael F Jacobson Executive Director, Center for Science in the Public Interest, 1875 Connecticut Avenue NW #300, Washington, DC 20009, USA. e-mail: [email protected]

Sheldon Krimsky, Professor, Department of Urban & Environmental Policy & Planning, Tufts University

1. Petersen, M. “Undisclosed Financial Ties Prompt Reproval of Doctor” New York Times, August 3, 2003. 2. Nemeroff, C.B. & Owens, M.J. Nat. Neurosci. 5 (Suppl.), 1068–1070 (2002). 3. van Kolfschooten, F. Nature 416, 360–363 (2002). 4. PNAS Online Information for Authors (http://www. pnas.org/misc/iforc.shtml#Editorial%20Policies).

Virginia A Sharpe Director, Project on Integrity in Science, Center for Science in the Public Interest, 1875 Connecticut Avenue NW #300, Washington, DC 20009, USA. On behalf of: Marcia Angell, Senior Lecturer in Social Medicine, Harvard Medical School; Former Editor-in-Chief, New England Journal of Medicine Nicholas A Ashford, Professor of Technology and Policy, Massachusetts Institute of Technology Alan Blum, Professor and Endowed Chair in Family Medicine and Director, The University of Alabama Center for the Study of Tobacco and Society, University of Alabama; Former Editor-in-Chief, Medical Journal of Australia and New York State Journal of Medicine Lin Kaatz Chary, Great Lakes Center for Occupational and Environmental Safety and Health, School of Public

Joseph LaDou, Department of Medicine, University of California School of Medicine, San Francisco Charles Levenstein, Professor of Work Environment, University of Massachusetts, Lowell Steven Miles, Professor of Medicine, Center for Bioethics, University of Minnesota Herbert Needleman, Professor of Psychiatry and Pediatrics, University of Pittsburgh School of Medicine Edmund D Pellegrino, Professor Emeritus of Medicine and Medical Ethics, Georgetown University Medical Center Bill Ravanesi, Boston Campaign Director, Health Care Without Harm Jennifer Sass, Senior Scientist, Natural Resources Defense Council Arnold Schecter, Professor of Environmental Sciences, University of Texas School of Public Health Jill S Schneiderman, Professor of Geology, Vassar College David Schubert, Professor, Salk Institute for Biological Studies

Health, University of Illinois at Chicago Mildred Cho, Senior Research Scholar and Acting Co-Director, Stanford Center for Biomedical Ethics,

Morando Soffritti, Scientific Director, European Ramazzini Foundation of Oncology and Environmental Sciences, Bologna, Italy

Stanford University Bruce C Coull, Carolina Distinguished Professor and Dean, School of the Environment,

David Suzuki, Professor Emeritus, Sustainable Development Research Institute, University of British Columbia

University of South Carolina Devra Davis, Visiting Professor, Heinz School of Public Policy and Management, Carnegie Mellon University; Senior Advisor to the World Health Organization Russell F Doolittle, Center for Molecular Genetics, University of California, San Diego David Egilman, Clinical Associate Professor, Department of Community Health, Brown University Samuel S Epstein, Professor Emeritus, Environmental & Occupational Medicine, School of Public Health, University of Illinois at Chicago; Chairman, Cancer

Tim K Takaro, Occupational and Environmental Medicine, University of Washington Norman J Temple, Associate Professor of Nutrition, Centre for Science, Athabasca (Alberta) University Benedetto Terracini, Professor of Biostatistics (retired), University of Torino, Italy Andrew Thompson, Associate Professor (retired), University Counseling Center and Department of Counseling Psychology, University of Oregon David Wallinga, Antibiotic Resistance Project Director, Institute for Agriculture and Trade Policy

Prevention Coalition Morris Greenberg, London, England Kim Hooper, Hazardous Materials Laboratory,

Steven Wing, Associate Professor, Department of Epidemiology, School of Public Health, University of North Carolina

Department of Toxic Substances Control, Cal/EPA James Huff, Senior Investigator, National Institute of Environmental Health Sciences Tushar K Joshi, Head, Centre for Occupational and Environmental Health, Lok Nayak Hospital, New Delhi, India

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Editor’s Footnote: Drs. Nemeroff and Owens are correct in stating that Nature Neuroscience’s policy for review articles (in contrast to primary research) did not require them to make a financial disclosure and that we did not ask them to do so. We are now changing our policy, for reasons that are discussed in the editorial on page 997.

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