- Email: [email protected]
Importance of disclosure of patent applications
Correspondence
Questions about SSRI antidepressant drug regulation
questions. Reflection about the answers could lead to further changes in practice, which might improve treatment for those with depression.
In your Editorial (June 12, p 1919),1 about the lawsuit against GlaxoSmithKline in New York, you argue the case for the company to be much more open about its clinical trial data. Perhaps your piece helped to persuade Glaxo, because news reports2 indicate that it is about to put clinical trial data on the company website. About time. I hope that other manufacturers of selective serotonin reuptake inhibitors (SSRIs) for depression will take heed and follow Glaxo’s apparent lead. The SSRIs are under scrutiny by regulatory authorities in many countries, and in the USA and Canada companies are being told to include a suicide-warning note with the products. Whether the same will be required in the UK will have to await the outcome of the review by the Medicines and Healthcare Regulatory Agency. The reviews, however, raise some disturbing questions. How have SSRIs managed to avoid having a suicide warning attached to them so far? These drugs have been reviewed before. Have the regulatory agencies been doing their job properly? Were previous reviewers not given the full information on the outcome of all clinical trials, as seems to have happened in the case of GlaxoSmithKline and paroxetine? If the outcomes of the reviews done in the USA and Canada are anything to go by, paroxetine is not the only SSRI that requires a suicide-warning label. So just what was handed over to the regulatory agencies, and in what form? And did all trials with adverse emotional responses group these responses under “Emotional lability”? This broad-ranging term covers anything from vague upset to suicidal thoughts. How could any drug company in all good conscience group these outcomes together? As someone who is still struggling to deal with the grief occasioned by the suicide of his wife 21 months ago, shortly after she had started a course of Prozac (Eli Lilly and Co, Indianapolis, IN, USA), it would help to have answers to these
Alastair Hay
www.thelancet.com Vol 364 August 14, 2004
[email protected] School of Medicine, Algernon Firth Building, University of Leeds, Leeds LS2 9JT, UK 1 2
The Lancet. Is GSK guilty of fraud? Lancet 2004; 363: 1919. Stewart H. Glaxo changes tack after Spitzer assault. http://www.guardian.co.uk/business/ story/0,,1242494,00.html (accessed July 27, 2004).
Importance of disclosure of patent applications For several reasons, including public enthusiasm for aggressive disease screening and physician concern about failure-to-prevent malpractice lawsuits, there is a real possibility of poor screening tests becoming part of routine medical care. For this reason, the scientific lapses surrounding news of a screening test for ovarian cancer are particularly troubling. A proteomic patterns screening test (OvaCheck) was announced to the public through the mass media in February, 2004. This test, developed by individuals at Correlogic Systems (Bethesda, MD, USA), working in conjunction with scientists from the Food and Drug Administration (FDA) and the National Cancer Institute (NCI), was first described in a fast-tracked article in The Lancet in February, 2002.1 Scientific and clinical-epidemiological limitations to the test were later discussed in the Correspondence section of the July 13, 2002, issue of The Lancet. After much initial positive announcement about the test, there has been subsequent quiet back-pedalling2 as additional scientific concerns have been raised.3,4 Neither the article in The Lancet1 nor a later one by the same authors in Gynecologic Oncology5 disclosed anything about the financial relations underlying development and promotion of the test. The Chief Executive Officer and chief scientist of Correlogic were co-authors on each article. Correlogic was founded in
2000, and by July, 2001, 8 months before publication of the Lancet article, two of the report’s authors, an NCI scientist (Liotta) and a scientist at a joint FDA/NCI agency (Petricoin), were listed along with Correlogic principals as coinventors on a patent application (number 20030004402, filed July 18, 2001) for an algorithm to detect hidden patterns in biological data. This algorithm was the foundation of the proteomics pattern test described in the articles. Neither the Lancet article nor the one in Gynecologic Oncology mentioned anything about the patent application by the authors. Furthermore, soon after publication in The Lancet, and well before publication in Gynecologic Oncology, Correlogic was awarded worldwide licensing rights to the OvaCheck screening test by the FDA and NCI (http:// www.correlogic.com). This event was not mentioned in Gynecologic Oncology. There was no way to discern, in either of the articles, that any of the authors had financial interests in the test they were enthusiastically describing. The Correlogic principals have obvious financial stakes in the promotion of their screening test. National Institutes of Health (NIH) employees are, now, similarly allowed to profit personally from scientific patents. An indication of the NIH’s new encouragement of commercial collaboration can be found at http://www. clinicalproteomics.steem.com. Whether this website is a commercial or a government website is unclear. On the home page, one is welcomed to the FDA-NCI Clinical Proteomics Program Databank and is informed that the joint interagency programme, co-directed by Petricoin and Liotta, is dedicated to the invention and development of proteomic technologies. The “Contact Us” listings on this website contain links to NCI, FDA, and Correlogic. This chronicle of overly-enthusiastic and premature promotion of scientific work by those in positions to profit, financially, from positive findings serves as yet another cautionary tale. The scientific community must increase its vigilance regarding full disclosure of conflicts of interest. If we are not attentive to this issue, scientific publishing is at risk of
e-mail submissions to [email protected]
See Department of Error page 582
577
Correspondence
becoming indistinguishable from commercial marketing.
Beverly Rockhill [email protected] Department of Epidemiology, CB 7435, University of North Carolina, Chapel Hill, NC 27599, USA 1
2
3
4
5
Petricoin E, Ardekani A, Hitt B, et al. Use of proteomic patterns in serum to identify ovarian cancer. Lancet 2002; 359: 572–77. Wagner L. A test before its time? FDA stalls distribution process of proteomic test. J Natl Cancer Inst 2004; 96: 500–01. Diamandis E. Analysis of serum proteomic patterns for early cancer diagnosis: drawing attention to potential problems. J Natl Cancer Inst 2004; 96: 353–56. Baggerly K, Morris J, Coombs K. Reproducibility of SELDI-TOF protein patterns in serum: comparing data sets from different experiments. Bioinformatics 2004; 20: 777–85. Liotta L, Petricoin E, Ardekani A, et al. General keynote: proteomic patterns in sera serve as biomarkers of ovarian cancer. Gynecologic Oncology 2003; 88: S25–28.
Authors’ reply As the letter from Beverly Rockhill shows, there has been much confusion about the NCI/FDA Clinical Proteomics Program and the newly marketed OvaCheck diagnostic. We welcome the opportunity to clear up this confusion. Although the research findings published in The Lancet in February, 2002, were derived with the same basic pattern recognition software developed by Correlogic Systems as the newly marketed OvaCheck diagnostic, the methods and instrumentation used in our initially reported pilot studies and subsequent research is distinct from those used in the OvaCheck diagnostic. Correlogic Systems has developed and promoted OvaCheck independently of both the NCI and the FDA. Rockhill claims that the relation— specifically the patenting and licensing of the technology among NCI, FDA, and Correlogic Systems—was not properly disclosed in The Lancet. This is clearly not the case. As required by The Lancet, each author and their respective organisation was properly designated on the publication. At the time of publication, collaboration existed among NCI, FDA, and Correlogic scientists. This collaboration resulted in joint discoveries independent of the later-developed Correlogic 578
Systems OvaCheck technology. At the time of the Lancet publication, only a provisional patent application (number 2003004402) had been filed and it had not been examined or issued on the joint research discoveries. At the time of submission, we did state that “any and all patent rights for which we are co-inventors associated with this work are assigned to the Department of Health and Human Services US Government”. Furthermore, with respect to disclosing the existence of a licence with Correlogic Systems, government inventors are prohibited from involvement in the negotiation of any such licences. Therefore, it was impossible for us to disclose or even predict the future issuance of a licence to the company, since the licence to Correlogic (a licence was awarded) in 2002. A second concern of Rockhill was the perceived appearance of government endorsement of the OvaCheck technology as a result of a company link found on the NCI/FDA Clinical Proteomics website. An earlier link has been removed that provided company contact information to individuals with inquiries specific to the Correlogic proprietary algorithm. Our sole intention was to identify the source of the proprietary software that we used to generate our data; it was never our intention to give the perception of commercial endorsement. We placed this identification on the website to acknowledge the source of the software. The NCI/FDA Clinical Proteomics website is part of our continuing effort to enlist the research community in the analysis of the research data that we generate, and to share such information openly and without restriction.1 Even before publication, we routinely place our research data in the public domain. Rockhill expresses further concern that “NIH employees . . . are allowed to profit personally from scientific patents” and speaks of the potential difficulties she perceives with financial incentive being tied to the successful marketing of a product. NIH’s policies and Federal law offer clear guidance in this area. Ownership of inventions made by government employees and include the assignment of intellectual property to
the US Federal Government. There are provisions and statutes in place that require NIH to pay a portion of royalties then received from the licensing of such inventions to the inventors as monetary compensation for their achievement. At the time of publication of our research findings in The Lancet, there was neither a licence nor the possibility of financial gain. Finally, Rockhill evokes the “possibility of poor screening tests becoming part of routine medical care” based on the “overly-enthusiastic and premature promotion of scientific work by those in positions to profit, financially”. Our paper published in The Lancet in February, 2002, described only a research feasibility study and presented a new hypothesis. We placed our data from this research study in the public domain for examination, assessment, and comment by the scientific community. We stated in our article, and continue to maintain, that extensive validation through rigorously designed clinical trials is necessary to test and understand the practical limitations of our hypothesis. We are enthusiastic about the potential effect that our findings could have on future cancer diagnosis, and are proceeding to rigorously validate our research findings. Our latest research findings,2 applied to ovarian cancer study sets and employing higher resolution instrumentation, continue to support our original hypothesis. Although we are hopeful and optimistic that these proteomic approaches can provide new diagnostics that could help detect cancer earlier and save lives, we completely agree that the development and success of such technologies must be subjected to carefully controlled rigorous ethical and scientific scrutiny.
*Emanuel F Petricoin, Lance A Liotta [email protected] *OCTGT/CBER/FDA, 8800 Rockville Pike, Bethesda, MD 20892, USA (EFP); and Laboratory of Pathology, CCR/NCI/NIH, Bethesda, MD, USA (LAL) 1
Anon. Questions and answers: OvaCheck and NCI/FDA ovarian cancer clinical trials using proteomics technology. http://www.nci.nih. gov/newscenter/pressreleases/ ProteomicsOvarian (accessed July 13, 2004).
www.thelancet.com Vol 364 August 14, 2004
Questions about SSRI antidepressant drug regulation
questions. Reflection about the answers could lead to further changes in practice, which might improve treatment for those with depression.
In your Editorial (June 12, p 1919),1 about the lawsuit against GlaxoSmithKline in New York, you argue the case for the company to be much more open about its clinical trial data. Perhaps your piece helped to persuade Glaxo, because news reports2 indicate that it is about to put clinical trial data on the company website. About time. I hope that other manufacturers of selective serotonin reuptake inhibitors (SSRIs) for depression will take heed and follow Glaxo’s apparent lead. The SSRIs are under scrutiny by regulatory authorities in many countries, and in the USA and Canada companies are being told to include a suicide-warning note with the products. Whether the same will be required in the UK will have to await the outcome of the review by the Medicines and Healthcare Regulatory Agency. The reviews, however, raise some disturbing questions. How have SSRIs managed to avoid having a suicide warning attached to them so far? These drugs have been reviewed before. Have the regulatory agencies been doing their job properly? Were previous reviewers not given the full information on the outcome of all clinical trials, as seems to have happened in the case of GlaxoSmithKline and paroxetine? If the outcomes of the reviews done in the USA and Canada are anything to go by, paroxetine is not the only SSRI that requires a suicide-warning label. So just what was handed over to the regulatory agencies, and in what form? And did all trials with adverse emotional responses group these responses under “Emotional lability”? This broad-ranging term covers anything from vague upset to suicidal thoughts. How could any drug company in all good conscience group these outcomes together? As someone who is still struggling to deal with the grief occasioned by the suicide of his wife 21 months ago, shortly after she had started a course of Prozac (Eli Lilly and Co, Indianapolis, IN, USA), it would help to have answers to these
Alastair Hay
www.thelancet.com Vol 364 August 14, 2004
[email protected] School of Medicine, Algernon Firth Building, University of Leeds, Leeds LS2 9JT, UK 1 2
The Lancet. Is GSK guilty of fraud? Lancet 2004; 363: 1919. Stewart H. Glaxo changes tack after Spitzer assault. http://www.guardian.co.uk/business/ story/0,,1242494,00.html (accessed July 27, 2004).
Importance of disclosure of patent applications For several reasons, including public enthusiasm for aggressive disease screening and physician concern about failure-to-prevent malpractice lawsuits, there is a real possibility of poor screening tests becoming part of routine medical care. For this reason, the scientific lapses surrounding news of a screening test for ovarian cancer are particularly troubling. A proteomic patterns screening test (OvaCheck) was announced to the public through the mass media in February, 2004. This test, developed by individuals at Correlogic Systems (Bethesda, MD, USA), working in conjunction with scientists from the Food and Drug Administration (FDA) and the National Cancer Institute (NCI), was first described in a fast-tracked article in The Lancet in February, 2002.1 Scientific and clinical-epidemiological limitations to the test were later discussed in the Correspondence section of the July 13, 2002, issue of The Lancet. After much initial positive announcement about the test, there has been subsequent quiet back-pedalling2 as additional scientific concerns have been raised.3,4 Neither the article in The Lancet1 nor a later one by the same authors in Gynecologic Oncology5 disclosed anything about the financial relations underlying development and promotion of the test. The Chief Executive Officer and chief scientist of Correlogic were co-authors on each article. Correlogic was founded in
2000, and by July, 2001, 8 months before publication of the Lancet article, two of the report’s authors, an NCI scientist (Liotta) and a scientist at a joint FDA/NCI agency (Petricoin), were listed along with Correlogic principals as coinventors on a patent application (number 20030004402, filed July 18, 2001) for an algorithm to detect hidden patterns in biological data. This algorithm was the foundation of the proteomics pattern test described in the articles. Neither the Lancet article nor the one in Gynecologic Oncology mentioned anything about the patent application by the authors. Furthermore, soon after publication in The Lancet, and well before publication in Gynecologic Oncology, Correlogic was awarded worldwide licensing rights to the OvaCheck screening test by the FDA and NCI (http:// www.correlogic.com). This event was not mentioned in Gynecologic Oncology. There was no way to discern, in either of the articles, that any of the authors had financial interests in the test they were enthusiastically describing. The Correlogic principals have obvious financial stakes in the promotion of their screening test. National Institutes of Health (NIH) employees are, now, similarly allowed to profit personally from scientific patents. An indication of the NIH’s new encouragement of commercial collaboration can be found at http://www. clinicalproteomics.steem.com. Whether this website is a commercial or a government website is unclear. On the home page, one is welcomed to the FDA-NCI Clinical Proteomics Program Databank and is informed that the joint interagency programme, co-directed by Petricoin and Liotta, is dedicated to the invention and development of proteomic technologies. The “Contact Us” listings on this website contain links to NCI, FDA, and Correlogic. This chronicle of overly-enthusiastic and premature promotion of scientific work by those in positions to profit, financially, from positive findings serves as yet another cautionary tale. The scientific community must increase its vigilance regarding full disclosure of conflicts of interest. If we are not attentive to this issue, scientific publishing is at risk of
e-mail submissions to [email protected]
See Department of Error page 582
577
Correspondence
becoming indistinguishable from commercial marketing.
Beverly Rockhill [email protected] Department of Epidemiology, CB 7435, University of North Carolina, Chapel Hill, NC 27599, USA 1
2
3
4
5
Petricoin E, Ardekani A, Hitt B, et al. Use of proteomic patterns in serum to identify ovarian cancer. Lancet 2002; 359: 572–77. Wagner L. A test before its time? FDA stalls distribution process of proteomic test. J Natl Cancer Inst 2004; 96: 500–01. Diamandis E. Analysis of serum proteomic patterns for early cancer diagnosis: drawing attention to potential problems. J Natl Cancer Inst 2004; 96: 353–56. Baggerly K, Morris J, Coombs K. Reproducibility of SELDI-TOF protein patterns in serum: comparing data sets from different experiments. Bioinformatics 2004; 20: 777–85. Liotta L, Petricoin E, Ardekani A, et al. General keynote: proteomic patterns in sera serve as biomarkers of ovarian cancer. Gynecologic Oncology 2003; 88: S25–28.
Authors’ reply As the letter from Beverly Rockhill shows, there has been much confusion about the NCI/FDA Clinical Proteomics Program and the newly marketed OvaCheck diagnostic. We welcome the opportunity to clear up this confusion. Although the research findings published in The Lancet in February, 2002, were derived with the same basic pattern recognition software developed by Correlogic Systems as the newly marketed OvaCheck diagnostic, the methods and instrumentation used in our initially reported pilot studies and subsequent research is distinct from those used in the OvaCheck diagnostic. Correlogic Systems has developed and promoted OvaCheck independently of both the NCI and the FDA. Rockhill claims that the relation— specifically the patenting and licensing of the technology among NCI, FDA, and Correlogic Systems—was not properly disclosed in The Lancet. This is clearly not the case. As required by The Lancet, each author and their respective organisation was properly designated on the publication. At the time of publication, collaboration existed among NCI, FDA, and Correlogic scientists. This collaboration resulted in joint discoveries independent of the later-developed Correlogic 578
Systems OvaCheck technology. At the time of the Lancet publication, only a provisional patent application (number 2003004402) had been filed and it had not been examined or issued on the joint research discoveries. At the time of submission, we did state that “any and all patent rights for which we are co-inventors associated with this work are assigned to the Department of Health and Human Services US Government”. Furthermore, with respect to disclosing the existence of a licence with Correlogic Systems, government inventors are prohibited from involvement in the negotiation of any such licences. Therefore, it was impossible for us to disclose or even predict the future issuance of a licence to the company, since the licence to Correlogic (a licence was awarded) in 2002. A second concern of Rockhill was the perceived appearance of government endorsement of the OvaCheck technology as a result of a company link found on the NCI/FDA Clinical Proteomics website. An earlier link has been removed that provided company contact information to individuals with inquiries specific to the Correlogic proprietary algorithm. Our sole intention was to identify the source of the proprietary software that we used to generate our data; it was never our intention to give the perception of commercial endorsement. We placed this identification on the website to acknowledge the source of the software. The NCI/FDA Clinical Proteomics website is part of our continuing effort to enlist the research community in the analysis of the research data that we generate, and to share such information openly and without restriction.1 Even before publication, we routinely place our research data in the public domain. Rockhill expresses further concern that “NIH employees . . . are allowed to profit personally from scientific patents” and speaks of the potential difficulties she perceives with financial incentive being tied to the successful marketing of a product. NIH’s policies and Federal law offer clear guidance in this area. Ownership of inventions made by government employees and include the assignment of intellectual property to
the US Federal Government. There are provisions and statutes in place that require NIH to pay a portion of royalties then received from the licensing of such inventions to the inventors as monetary compensation for their achievement. At the time of publication of our research findings in The Lancet, there was neither a licence nor the possibility of financial gain. Finally, Rockhill evokes the “possibility of poor screening tests becoming part of routine medical care” based on the “overly-enthusiastic and premature promotion of scientific work by those in positions to profit, financially”. Our paper published in The Lancet in February, 2002, described only a research feasibility study and presented a new hypothesis. We placed our data from this research study in the public domain for examination, assessment, and comment by the scientific community. We stated in our article, and continue to maintain, that extensive validation through rigorously designed clinical trials is necessary to test and understand the practical limitations of our hypothesis. We are enthusiastic about the potential effect that our findings could have on future cancer diagnosis, and are proceeding to rigorously validate our research findings. Our latest research findings,2 applied to ovarian cancer study sets and employing higher resolution instrumentation, continue to support our original hypothesis. Although we are hopeful and optimistic that these proteomic approaches can provide new diagnostics that could help detect cancer earlier and save lives, we completely agree that the development and success of such technologies must be subjected to carefully controlled rigorous ethical and scientific scrutiny.
*Emanuel F Petricoin, Lance A Liotta [email protected] *OCTGT/CBER/FDA, 8800 Rockville Pike, Bethesda, MD 20892, USA (EFP); and Laboratory of Pathology, CCR/NCI/NIH, Bethesda, MD, USA (LAL) 1
Anon. Questions and answers: OvaCheck and NCI/FDA ovarian cancer clinical trials using proteomics technology. http://www.nci.nih. gov/newscenter/pressreleases/ ProteomicsOvarian (accessed July 13, 2004).
www.thelancet.com Vol 364 August 14, 2004