- Email: [email protected]
Clinical Trial Registration
Pipeline GARY D. NOVACK, PHD, FEATURES EDITOR, PIPELINE
Clinical Trial Registration GARY D. NOVACK, PHD n 2004, the International Committee of Medical Journal Editors (ICMJE) made a proposal for public, a priori, comprehensive registration of controlled clinical trials. Their proposal addressed the selective reporting of trials and the distortion that this creates in the body of evidence in the literature. The ICMJE addressed the “publication bias” from both researchers and editors toward trials that showed either a large effect of a new treatment (positive trials) or equivalence of two treatments (noninferiority trials). The ICMJE proposal would require, as a condition of consideration for publication, registration in a public trials registry prior to the onset of patient enrollment. The most commonly used registry is www.ClinicalTrials.gov, which is hosted by the National Institutes of Health, although some firms have set up their own websites (eg, Glaxo SmithKline’s http://ctr. gsk.co.uk). There was an initial period for retroactive registration, but now, all studies must be registered up-front.1 Registration is required for “…human clinical research projects that prospectively assign subjects to intervention and concurrent control (comparison) groups in order to study the cause-and-effect relation between a medical intervention and a health outcome…This would encompass all phase 2 and 3 studies that test the efficacy of an intervention, but not, for example, case reports or small case series, retrospective
I
Dr. Novack consults with numerous pharmaceutical firms. He owns stock in King Pharmaceuticals and Inspire Pharmaceuticals. ©2007 Ethis Communications, Inc. The Ocular Surface ISSN: 1542-0124. Novack GD. Clinical trial registration. 2007;5(4):316-317.
316
studies, or any other exploratory clinical studies for which concurrent groups are not prospectively assigned.” Initially, journals requiring this up-front registration included the New England Journal of Medicine, Lancet, and the journals published by the American Medical Association (eg, JAMA, Archives of Ophthalmology). It is now required by most primary ophthalmology journals, including the American Journal of Ophthalmology, British Journal of Ophthalmology, Ophthalmology, and Investigative Ophthalmology and Visual Science.2 Clinical trial registration is also now required for presentation at the meeting of the Association for Research in Vision and Ophthalmology (ARVO). (The Ocular Surface does not have a statement regarding clinical trial registration, because the focus of this journal is review articles, rather than primary results of clinical trials.) Registration at ClinicalTrials.gov is a multi-step process. First, the Sponsor registers their firm or institution. Then, the Sponsor registers the trial, including the disease being studied, the intervention, the targeted enrollment size, the outcome measures, sites conducting the study, etc. Registration is not automatic. The entries are reviewed by ClinicalTrials.gov to assure that all fields are filled with meaningful information. They then respond to the Sponsor with either a registration number or requests for additional information. This registration can take some effort both in the on-line registration and the several days for the process to be complete. Registration is the responsibility of the sponsor, not the principal investigator at each site. However, for some academic studies, this may be the same person. Registration is yet another administrative responsibility of the clinical faculty.
An example of instructions given by a University to their clinical researchers may be found at http://irb.ucsd.edu/Registry_Fact_Sheet.pdf. The ICMJE committed to an evaluation of this proposal 2 years after inception. In a recently published review, they stated that in spite of much angst among researchers and Sponsors, the response has been overwhelmingly positive.3 In the 6 months between May and October 2005, the number of registrations on ClinicalTrials.gov increased from 13,153 to 22,714. The entries also became more complete, although there still is room for substantial improvement.4 The World Health Organization is also involved, with maturation of their International Clinical Trial Registry Platform (http:// www.who.int/ictrp/en/). The ICMJE directive is expanding to include preliminary trials of pharmacokinetics and early safety evaluation. Also, the ICMJE has made a policy decision that brief publication of results (< 500 words) on the clinical trial registry does not constitute “publication” from a copyright perspective. We read frequently of Congressional hearings to manage public policy on the ying-yang of making drugs available while assuring their safety. I find the clinical trial registration proposal by ICMJE and its implementation to be an incredible example of how scientists, without any legislation, can improve the quality and credibility of their research. There has been some legislative activity around this issue. For example, the California State Senate passed in May 2007 SB 606 “The Pharmaceutical Drug Information and Safety Act,” which requires pharmaceutical firms to make public the results of their clinical trials. The implementation of this bill is not yet clear. One intent of the clinical trial registry was to allow prospective study
THE OCULAR SURFACE / OCTOBER 2007, VOL. 5, NO. 4 / www.theocularsurface.com
PIPELINE / Novack
subjects to find out about ongoing trials for which they might qualify. One lessintended consequence of registration is that scientists can see what clinical trials are ongoing by the competition. Starting a clinical trial, and its incumbent registration, is now essentially a press release from the Sponsor. What if I do not register my clinical trial? The ICMJE guidelines state that “...if a manuscript is submitted on a trial that is not registered, then a case will have to be made to the journal editor that the results of the trial are of such public health importance that the failure to register is superseded by the benefit to society.” I do not know of any examples where a manuscript has been submitted without having been registered or where editors waived the requirement. It used to be that journal articles did not have full disclosure of financial interests of authors and Sponsors. With disclosure policies by organizations such as ARVO,5 that situation has changed, and disclosure statements are nearly universal. In the same way, the ICMJE stated, “...Three years ago, registration was the exception, now it is the rule,”3 and we see clinical trial registry numbers on more and more papers. REFERENCES 1. DeAngelis CD, Drazen JM, Frizelle FA, et al. Clinical trial registration: a statement from the International Committee of Medical Journal Editors. JAMA 2004;292:1363-4 2. Levin LA, Gottlieb JL, Beck RW, et al. Registration of clinical trials. Arch Ophthalmol 2005;123:1263-4 3. Laine C, Horton R, DeAngelis CD, et al. Clinical trial registration: looking back and moving ahead. N Engl J Med 2007;356:2734-6 4. Zarin DA, Tse T, Ide NC. Trial registration at ClinicalTrials.gov between May and October 2005. N Engl J Med 2005;353:2779-87 5. Novack GD. ARVO Commercial relationships policy: Financial disclosure in ARVO presentations and publications. Invest Ophthalmol Vis Sci 1999;40:2765-6
NEWS FROM PHARMACEUTICAL AND MEDICAL DEVICE COMPANIES
Ophthalmic Products Related to the Ocular Surface
3 Akorn, Inc. has received U.S. Food and Drug Administration (FDA) approval for Ketotifen, its generic version of Novartis’ Zaditor eye solution, which is used to treat itchy eyes (July 2007). 3 Bausch & Lomb has acquired Soothe emollient (lubricant) eye drops from Alimera Sciences, a privately-held ophthalmic pharmaceutical company (August 2007). 3 ISTA announced positive results from the preliminary analysis of the Company’s Phase IIb clinical study of ecabet sodium, which is being developed as a treatment for dry eye syndrome (May 2007). 3 SARcode gave a note to Sunesis Pharmaceuticals as a milestone payment for a small molecule LFA1 inhibitor being developed by SARcode to treat T-cell mediated ophthalmic diseases (June 2007). Ophthalmic Products Not Related to the Ocular Surface
3 Acadia Pharmaceuticals announced that Allergan, Inc. will initiate an exploratory clinical study with a small molecule selective muscarinic compound for the treatment of glaucoma (July 2007). 3 Bausch & Lomb has withdrawn its European application for approval of Retisert®, an implant treatment for chronic, non-infectious uveitis, pending availability of additional information. wAkorn, Inc. announced the filing of a New Drug Application (NDA) for Akten® Ophthalmic Gel 3.5%, a unit-dose, preservative-free, topical, ocular anesthetic formulation (June 2007). wJerini Ophthalmics submitted an Investigational New Drug (IND) application for JSM 6427, a small molecule alpha5 beta1 integrin receptor antagonist for the treatment of age-related macular degeneration (July 2007). 3 Merck & Co. and SurModics, Inc. will collaborate on the development of medications to treat diseases of the retina (June 2007).
3 Opko Health, Inc. announced the initiation of the Phase 3 COBALT (Combining Bevasiranib And Lucentis Therapy) clinical trial of bevasiranib for the treatment of wet age-related macular degeneration. Bevasiranib is a first-in-class small interfering RNA (siRNA) drug designed to silence the genes that produce vascular endothelial growth factor (July 2007). NEWS FROM THE FDA AND OTHER REGULATORY AGENCIES
3 The FDA called for the toughest safety warning on two diabetes drugs, Avandia® (rosiglitazone) and Actos® (pioglitazone). The manufacturers were asked to include a black box warning of its heart risks (June 2007). 3 The FDA rejected Arcoxia (etoricoxib), a new COX-2 inhibitor from Merck. Since 1962, the FDA has had a legislative mandate to assure substantive evidence of efficacy and safety. This has typically been judged to be relative to a placebo. However, some interpret this latest action to be an extension of FDA’s mandate that new drugs be more effective than existing drugs (April 2007). OTHER ITEMS OF INTEREST
3 Because of “numerous questions,” Osaka University’s Graduate School of Medicine has told one of its research groups to retract a 2004 Science paper on an insulin-mimicking protein secreted by fat tissue. The school’s dean, Masaya Tohyama, last week held a press conference to issue the unusual demand, which came after a year-long investigation. Iichiro Shimomura, one of the authors, says the issues raised by the investigation, such as ignoring data that complicated the paper’s conclusions, do not warrant retraction (Normile D. Scientific publishing. Osaka University researchers reject demand to retract Science paper. Science 2007;316:1681). 3 The U.S. Senate is discussing legislation to require a registry for pharmaceutical firms’ gifts to physicians (June 2007).
THE OCULAR SURFACE / OCTOBER 2007, VOL. 5, NO. 4 / www.theocularsurface.com
317
Clinical Trial Registration GARY D. NOVACK, PHD n 2004, the International Committee of Medical Journal Editors (ICMJE) made a proposal for public, a priori, comprehensive registration of controlled clinical trials. Their proposal addressed the selective reporting of trials and the distortion that this creates in the body of evidence in the literature. The ICMJE addressed the “publication bias” from both researchers and editors toward trials that showed either a large effect of a new treatment (positive trials) or equivalence of two treatments (noninferiority trials). The ICMJE proposal would require, as a condition of consideration for publication, registration in a public trials registry prior to the onset of patient enrollment. The most commonly used registry is www.ClinicalTrials.gov, which is hosted by the National Institutes of Health, although some firms have set up their own websites (eg, Glaxo SmithKline’s http://ctr. gsk.co.uk). There was an initial period for retroactive registration, but now, all studies must be registered up-front.1 Registration is required for “…human clinical research projects that prospectively assign subjects to intervention and concurrent control (comparison) groups in order to study the cause-and-effect relation between a medical intervention and a health outcome…This would encompass all phase 2 and 3 studies that test the efficacy of an intervention, but not, for example, case reports or small case series, retrospective
I
Dr. Novack consults with numerous pharmaceutical firms. He owns stock in King Pharmaceuticals and Inspire Pharmaceuticals. ©2007 Ethis Communications, Inc. The Ocular Surface ISSN: 1542-0124. Novack GD. Clinical trial registration. 2007;5(4):316-317.
316
studies, or any other exploratory clinical studies for which concurrent groups are not prospectively assigned.” Initially, journals requiring this up-front registration included the New England Journal of Medicine, Lancet, and the journals published by the American Medical Association (eg, JAMA, Archives of Ophthalmology). It is now required by most primary ophthalmology journals, including the American Journal of Ophthalmology, British Journal of Ophthalmology, Ophthalmology, and Investigative Ophthalmology and Visual Science.2 Clinical trial registration is also now required for presentation at the meeting of the Association for Research in Vision and Ophthalmology (ARVO). (The Ocular Surface does not have a statement regarding clinical trial registration, because the focus of this journal is review articles, rather than primary results of clinical trials.) Registration at ClinicalTrials.gov is a multi-step process. First, the Sponsor registers their firm or institution. Then, the Sponsor registers the trial, including the disease being studied, the intervention, the targeted enrollment size, the outcome measures, sites conducting the study, etc. Registration is not automatic. The entries are reviewed by ClinicalTrials.gov to assure that all fields are filled with meaningful information. They then respond to the Sponsor with either a registration number or requests for additional information. This registration can take some effort both in the on-line registration and the several days for the process to be complete. Registration is the responsibility of the sponsor, not the principal investigator at each site. However, for some academic studies, this may be the same person. Registration is yet another administrative responsibility of the clinical faculty.
An example of instructions given by a University to their clinical researchers may be found at http://irb.ucsd.edu/Registry_Fact_Sheet.pdf. The ICMJE committed to an evaluation of this proposal 2 years after inception. In a recently published review, they stated that in spite of much angst among researchers and Sponsors, the response has been overwhelmingly positive.3 In the 6 months between May and October 2005, the number of registrations on ClinicalTrials.gov increased from 13,153 to 22,714. The entries also became more complete, although there still is room for substantial improvement.4 The World Health Organization is also involved, with maturation of their International Clinical Trial Registry Platform (http:// www.who.int/ictrp/en/). The ICMJE directive is expanding to include preliminary trials of pharmacokinetics and early safety evaluation. Also, the ICMJE has made a policy decision that brief publication of results (< 500 words) on the clinical trial registry does not constitute “publication” from a copyright perspective. We read frequently of Congressional hearings to manage public policy on the ying-yang of making drugs available while assuring their safety. I find the clinical trial registration proposal by ICMJE and its implementation to be an incredible example of how scientists, without any legislation, can improve the quality and credibility of their research. There has been some legislative activity around this issue. For example, the California State Senate passed in May 2007 SB 606 “The Pharmaceutical Drug Information and Safety Act,” which requires pharmaceutical firms to make public the results of their clinical trials. The implementation of this bill is not yet clear. One intent of the clinical trial registry was to allow prospective study
THE OCULAR SURFACE / OCTOBER 2007, VOL. 5, NO. 4 / www.theocularsurface.com
PIPELINE / Novack
subjects to find out about ongoing trials for which they might qualify. One lessintended consequence of registration is that scientists can see what clinical trials are ongoing by the competition. Starting a clinical trial, and its incumbent registration, is now essentially a press release from the Sponsor. What if I do not register my clinical trial? The ICMJE guidelines state that “...if a manuscript is submitted on a trial that is not registered, then a case will have to be made to the journal editor that the results of the trial are of such public health importance that the failure to register is superseded by the benefit to society.” I do not know of any examples where a manuscript has been submitted without having been registered or where editors waived the requirement. It used to be that journal articles did not have full disclosure of financial interests of authors and Sponsors. With disclosure policies by organizations such as ARVO,5 that situation has changed, and disclosure statements are nearly universal. In the same way, the ICMJE stated, “...Three years ago, registration was the exception, now it is the rule,”3 and we see clinical trial registry numbers on more and more papers. REFERENCES 1. DeAngelis CD, Drazen JM, Frizelle FA, et al. Clinical trial registration: a statement from the International Committee of Medical Journal Editors. JAMA 2004;292:1363-4 2. Levin LA, Gottlieb JL, Beck RW, et al. Registration of clinical trials. Arch Ophthalmol 2005;123:1263-4 3. Laine C, Horton R, DeAngelis CD, et al. Clinical trial registration: looking back and moving ahead. N Engl J Med 2007;356:2734-6 4. Zarin DA, Tse T, Ide NC. Trial registration at ClinicalTrials.gov between May and October 2005. N Engl J Med 2005;353:2779-87 5. Novack GD. ARVO Commercial relationships policy: Financial disclosure in ARVO presentations and publications. Invest Ophthalmol Vis Sci 1999;40:2765-6
NEWS FROM PHARMACEUTICAL AND MEDICAL DEVICE COMPANIES
Ophthalmic Products Related to the Ocular Surface
3 Akorn, Inc. has received U.S. Food and Drug Administration (FDA) approval for Ketotifen, its generic version of Novartis’ Zaditor eye solution, which is used to treat itchy eyes (July 2007). 3 Bausch & Lomb has acquired Soothe emollient (lubricant) eye drops from Alimera Sciences, a privately-held ophthalmic pharmaceutical company (August 2007). 3 ISTA announced positive results from the preliminary analysis of the Company’s Phase IIb clinical study of ecabet sodium, which is being developed as a treatment for dry eye syndrome (May 2007). 3 SARcode gave a note to Sunesis Pharmaceuticals as a milestone payment for a small molecule LFA1 inhibitor being developed by SARcode to treat T-cell mediated ophthalmic diseases (June 2007). Ophthalmic Products Not Related to the Ocular Surface
3 Acadia Pharmaceuticals announced that Allergan, Inc. will initiate an exploratory clinical study with a small molecule selective muscarinic compound for the treatment of glaucoma (July 2007). 3 Bausch & Lomb has withdrawn its European application for approval of Retisert®, an implant treatment for chronic, non-infectious uveitis, pending availability of additional information. wAkorn, Inc. announced the filing of a New Drug Application (NDA) for Akten® Ophthalmic Gel 3.5%, a unit-dose, preservative-free, topical, ocular anesthetic formulation (June 2007). wJerini Ophthalmics submitted an Investigational New Drug (IND) application for JSM 6427, a small molecule alpha5 beta1 integrin receptor antagonist for the treatment of age-related macular degeneration (July 2007). 3 Merck & Co. and SurModics, Inc. will collaborate on the development of medications to treat diseases of the retina (June 2007).
3 Opko Health, Inc. announced the initiation of the Phase 3 COBALT (Combining Bevasiranib And Lucentis Therapy) clinical trial of bevasiranib for the treatment of wet age-related macular degeneration. Bevasiranib is a first-in-class small interfering RNA (siRNA) drug designed to silence the genes that produce vascular endothelial growth factor (July 2007). NEWS FROM THE FDA AND OTHER REGULATORY AGENCIES
3 The FDA called for the toughest safety warning on two diabetes drugs, Avandia® (rosiglitazone) and Actos® (pioglitazone). The manufacturers were asked to include a black box warning of its heart risks (June 2007). 3 The FDA rejected Arcoxia (etoricoxib), a new COX-2 inhibitor from Merck. Since 1962, the FDA has had a legislative mandate to assure substantive evidence of efficacy and safety. This has typically been judged to be relative to a placebo. However, some interpret this latest action to be an extension of FDA’s mandate that new drugs be more effective than existing drugs (April 2007). OTHER ITEMS OF INTEREST
3 Because of “numerous questions,” Osaka University’s Graduate School of Medicine has told one of its research groups to retract a 2004 Science paper on an insulin-mimicking protein secreted by fat tissue. The school’s dean, Masaya Tohyama, last week held a press conference to issue the unusual demand, which came after a year-long investigation. Iichiro Shimomura, one of the authors, says the issues raised by the investigation, such as ignoring data that complicated the paper’s conclusions, do not warrant retraction (Normile D. Scientific publishing. Osaka University researchers reject demand to retract Science paper. Science 2007;316:1681). 3 The U.S. Senate is discussing legislation to require a registry for pharmaceutical firms’ gifts to physicians (June 2007).
THE OCULAR SURFACE / OCTOBER 2007, VOL. 5, NO. 4 / www.theocularsurface.com
317