- Email: [email protected]
Prospective Clinical Trial Registration
Prospective Clinical Trial Registration Hywel C. Williams and Robert S. Sternw
Centre of Evidence-Based Dermatology, Queen’s Medical Centre University Hospital NHS Trust, Nottingham, UK; wBeth Israel Deaconess Medical Center, Department of Dermatology, Harvard Medical School, Boston, Massachusetts, USA
lication is another way to emphasize the result of studies that sponsors find most to their liking. For example, one systematic review of 278 trials of atopic dermatitis treatments found eight duplicate publications (i.e., the same clinical trial data from one trial presented in two separate journals) and one triplicate publication (Hoare et al, 2000). Some sponsors have applied substantial pressures to suppress or delay the publication of meritorious studies, whose results were not favorable to their product (Rennie, 1997). A prospective register of trials would not guarantee that all trials are eventually published, but it would at least guide research users on what studies have been carried out so that questions can be asked if those studies have not been published. A further advantage of registering the basic details of a clinical trial beforehand is to minimize selective emphasis of positive post hoc subgroup analysis—in other words, the practice of emphasizing some minor secondary and statistically significant change in disease score in the abstract and conclusion, when in fact the primary outcome analysis was non-significant (Diepgen, 2002). For example, an article titled ‘‘A randomized investigator—blinded study comparing pimecrolimus 1% with tacrolimus ointment 0.03% in the treatment of pediatric patients with moderate atopic dermatitis’’ barely discussed relative efficacy, but instead emphasized ease of application (Kempers et al, 2004). Had this trial been registered, the editors (and hopefully the readers) could have determined whether the paper represented post hoc analysis or was merely titled in a somewhat peculiar manner for a study focused on which drug is nicer to apply. Some study results have broad appeal and sufficient merit for publication in high-impact general medical journals (Stern, 2003). Yet, one wonders whether the publication of two similar phase three trials of efalizumab for psoriasis within weeks of each other in JAMA and the NEJM by the same overall group funded by the same company without acknowledging each other came very close to the spirit of duplicate publication (Gordon et al, 2003; Lebwohl et al, 2003). A clinical trial registry would help address the problem if the sponsor of an intervention were required to reveal to the editors the status of any works conducted by the same study group submitted for publication for all clinical studies they sponsor. Another reason for registering all ongoing clinical trials is simply to avoid unnecessary duplication of efforts. Thus, it should be incumbent upon any trialist to check that their
What Exactly Have the ICMJE Proposed? The International Committee of Medical Journal Editors (ICMJE) is a group of the world’s leading medical journals whose participants meet annually to improve standards in manuscripts submitted to biomedical journals. In September 2004, the ICMJE announced a tough new stance on registering clinical trials. All trials that start enrolling participants after July 1, 2005 must register their trial in a suitable publicly accessible register before that date in order to be considered for subsequent publication in those journals. Those trials that have started enrolment before July 1, 2005 must register before September 13, 2005 to be considered for publication (De Angelis et al, 2004). The Journal of Investigative Dermatology subscribes to these standards.
Why Is Prospective Trial Registration Such a Big Issue? The ICMJE points out that researchers have an obligation to conduct themselves ethically and to report their results honestly. Honest reporting begins with revealing the existence of all clinical studies, even those that reflect unfavorably on a research sponsor’s product or hypothesis. Publication bias classically refers to selective publication of studies with favorable results. For example, in 2003, Melander et al (2003) traced the fate of 42 placebo-controlled studies of five selective serotonin reuptake inhibitors submitted to the Swedish drug regulatory authority as a basis for marketing approval for treating major depression, and compared these with the studies actually published between 1983 and 1999. The 42 trials are depicted in Fig 1, with the red circles representing studies showing ‘‘positive’’ results, and the blue circles representing studies with nonsignificant results. The Figure shows how the studies with ‘‘positive’’ results were published as stand-alone publications (shown as green diamonds in the figure) much more often than studies with non-significant results. The figure also shows that studies with positive results were included more often in meta-analyses (yellow squares) than the nonsignificant studies. What little research is available in the world of dermatological clinical trials suggests that it is not immune to such practices. For example, a UK Governmentfunded meta-analysis of evening primrose oil for atopic dermatitis included 20 trials, eight of which remain unpublished in the public domain (Williams, 2003). Duplicate pub-
Copyright r 2005 by The Society for Investigative Dermatology, Inc.
viii
124 : 5 MAY 2005
PROSPECTIVE CLINICAL TRIAL REGISTRATION
ix
The Journal of Investigative Dermatology recommendations for a suitable trial registry include: • • • •
Free public access Each trial has a unique identifier Registered information is checked Registered entry contains trial name, lead investigator, methodology, interventions, primary outcomes, sponsor and status • (Desirable) No charge to register trials and easy to complete
Figure 2 Traits of a suitable clinical trial registry.
Figure 1 An illustration of publication bias. Selective publication of ‘‘positive’’ studies of five selective serotonin reuptake inhibitors submitted to the Swedish drug regulatory authority as a basis for marketing approval for treating major depression (Reproduced with the kind permission of the BMJ Publishing Group from Melander et al, 2003).
study is not being carried out elsewhere in the world before potentially wasting their time as well that of their patients and sponsors in carrying out the same work.
Where Should You Register Your Trial? The Journal of Investigative Dermatology does not wish to be too prescriptive with regard to which register its readers submit their trials to, providing the register fulfills the requirements set out in Fig 2. The ICMJE has suggested www.clinicaltrials.gov as its preferred register, a registry sponsored by the US National Library of Medicine. The register is free to use, and it contains comprehensive data on registered trials that are extracted from sponsors and lead investigators using a 12-page form. Although the register would be the automatic home for new investigational drug applications to the US Food and Drug Administration, it is unclear whether non-drug, non-NIH trials from low- to middle-income countries can be registered (Abbasi, 2004). Another registry worth considering is the International Standard Randomised Controlled Trial Number (ISRCTN)
registry (www.controlled-trials.com), managed by a commercial company called Controlled Clinical Trials. Although access to the registry is free, registration for trials that do not emanate from developing countries carries a $144 (h117) charge, which might be a disincentive to some. Other mechanisms to register trials that fulfill the JID registry criteria exist. One example unique to dermatology is the Cochrane Skin Group prospective trials register http://www. nottingham.ac.uk/ muzd/about/ongoingtrials. The Cochrane Skin Group editorial base is supported by public funds and supports an international and largely voluntary community dedicated to preparing and maintaining systematic reviews of interventions for skin diseases (Williams et al, 1998). The Cochrane Skin Group has been running its registry of prospective trials for the international dermatology community for the last 2 years and encourages the registration of completed but unpublished studies, as well as ongoing and planned clinical trials. Complete registration of trials will facilitate comprehensive systematic reviews by helping to identify all relevant trials. The one-page registration form for the Cochrane Skin Group trials register takes about 5 minutes to complete, and registration is free of charge. The emphasis on free registration and minimal paperwork might be important in order to avoid selective publication that might occur if those trials that lacked direct financial support were discouraged from registering.
What Type of Study Should Be Registered? The ICMJE defines a clinical trial as any research project that prospectively assigns human subjects to intervention or comparison groups to study the cause-and-effect relationship between a medical intervention and a health outcome. In other words, the register is not confined to drug studies and can include randomized controlled trials of medical devices, a new surgical technique, or even a new way of organizing care such as nurse-led clinics. Studies designed for other purposes, such as to study pharmacokinetics, cellular mechanisms in isolation or major toxicity (e.g., phase I trials), would be exempt.
The Bottom Line Many a stern word has been aired on the general poor reporting standards of dermatological trials (Bigby et al, 1985), but little seems to have changed over the last 20 years (Adetugbo and Williams, 2000; Naldi et al, 2003). It is easy to accept publication bias as ‘‘just the way things are’’;
x
WILLIAMS AND STERN
yet the effect of selective reporting of evidence is a major disservice to the trust and altruism at the heart of patients volunteering to participate in dermatological clinical trials. Selective reporting distorts the true effects of medical interventions, leading to a waste of doctors’ and patients’ time, a waste of public money, and possible serious harms (Chalmers, 2004). It is our vision that the data from all dermatological clinical trials conducted on volunteers belong to the people. Registering your clinical trial, searching the registries for other trials that evaluate similar interventions, and sharing this information with editors and readers bring us one step closer to such a vision. Conflict of interest: Hywel Williams is co-ordinating editor of the Cochrane Skin Group. DOI: 10.1111/j.0022-202X.2005.23665.x
References Abbasi K: Compulsory registration of clinical trials. BMJ 329:637–638, 2004 Adetugbo K, Williams H: How well are randomized controlled trials reported in the dermatology literature? Arch Dermatol 136:381–385, 2000 Bigby M, Stern RS, Bigby JA: An evaluation of method reporting and use in clinical trials in dermatology. Arch Dermatol 121:1394–1399, 1985
THE JOURNAL OF INVESTIGATIVE DERMATOLOGY Chalmers I: In the dark: Drug companies should be forced to publish all the results of clinical trials. New Sci 181:19, 2004 De Angelis C, Drazen JM, Frizelle FA, et al: International Committee of Medical Journal Editors. Clinical trial registration: A statement from the International Committee of Medical Journal Editors. Lancet 364:911–912, 2004 Diepgen TL: Early Treatment of the Atopic Child Study Group. Long-term treatment with cetirizine of infants with atopic dermatitis: A multi-country, double-blind, randomized, placebo-controlled trial (the ETAC trial) over 18 months. Pediatr Allergy Immunol 13:278–286, 2002 Gordon KB, Papp KA, Hamilton TK, et al: Efalizumab for patients with moderate to severe plaque psoriasis: A randomized controlled trial. JAMA 290: 3073–3080, 2003 Hoare C, Li Wan Po A, Williams H: Systematic review of treatments for atopic eczema. Health Technol Assess 4:1–191, 2000 Kempers S, Boguniewicz M, Carter E, et al: A randomized investigator-blinded study comparing pimecrolimus cream 1% with tacrolimus ointment 0.03% in the treatment of pediatric patients with moderate atopic dermatitis. J Am Acad Dermatol 51:515–525, 2004 Lebwohl M, Tyring SK, Hamilton TK, et al: A novel targeted T-cell modulator, efalizumab, for plaque psoriasis. N Engl J Med 349:2004–2013, 2003 Melander H, Ahlqvist-Rastad J, Meijer G, Beermann B: Evidence b(i)ased medicine–selective reporting from studies sponsored by pharmaceutical industry: Review of studies in new drug applications. BMJ 326:1171–1173, 2003 Naldi L, Svensson A, Diepgen T, et al: European Dermato-Epidemiology Network. Randomized clinical trials for psoriasis 1977–2000: The EDEN survey. J Invest Dermatol 120:738–741, 2003 Rennie D: Thyroid storm. JAMA 277:1238–1243, 1997 Stern RS: A promising step forward in psoriasis therapy. JAMA 290:3133–3135, 2003 Williams H, Adetugbo K, Po AL, Naldi L, Diepgen T, Murrell D: The Cochrane Skin Group. Preparing, maintaining, and disseminating systematic reviews of clinical interventions in dermatology. Arch Dermatol 134:1620–1626, 1998 Williams HC: Evening primrose oil for atopic dermatitis. BMJ 327:1358–1359, 2003
Centre of Evidence-Based Dermatology, Queen’s Medical Centre University Hospital NHS Trust, Nottingham, UK; wBeth Israel Deaconess Medical Center, Department of Dermatology, Harvard Medical School, Boston, Massachusetts, USA
lication is another way to emphasize the result of studies that sponsors find most to their liking. For example, one systematic review of 278 trials of atopic dermatitis treatments found eight duplicate publications (i.e., the same clinical trial data from one trial presented in two separate journals) and one triplicate publication (Hoare et al, 2000). Some sponsors have applied substantial pressures to suppress or delay the publication of meritorious studies, whose results were not favorable to their product (Rennie, 1997). A prospective register of trials would not guarantee that all trials are eventually published, but it would at least guide research users on what studies have been carried out so that questions can be asked if those studies have not been published. A further advantage of registering the basic details of a clinical trial beforehand is to minimize selective emphasis of positive post hoc subgroup analysis—in other words, the practice of emphasizing some minor secondary and statistically significant change in disease score in the abstract and conclusion, when in fact the primary outcome analysis was non-significant (Diepgen, 2002). For example, an article titled ‘‘A randomized investigator—blinded study comparing pimecrolimus 1% with tacrolimus ointment 0.03% in the treatment of pediatric patients with moderate atopic dermatitis’’ barely discussed relative efficacy, but instead emphasized ease of application (Kempers et al, 2004). Had this trial been registered, the editors (and hopefully the readers) could have determined whether the paper represented post hoc analysis or was merely titled in a somewhat peculiar manner for a study focused on which drug is nicer to apply. Some study results have broad appeal and sufficient merit for publication in high-impact general medical journals (Stern, 2003). Yet, one wonders whether the publication of two similar phase three trials of efalizumab for psoriasis within weeks of each other in JAMA and the NEJM by the same overall group funded by the same company without acknowledging each other came very close to the spirit of duplicate publication (Gordon et al, 2003; Lebwohl et al, 2003). A clinical trial registry would help address the problem if the sponsor of an intervention were required to reveal to the editors the status of any works conducted by the same study group submitted for publication for all clinical studies they sponsor. Another reason for registering all ongoing clinical trials is simply to avoid unnecessary duplication of efforts. Thus, it should be incumbent upon any trialist to check that their
What Exactly Have the ICMJE Proposed? The International Committee of Medical Journal Editors (ICMJE) is a group of the world’s leading medical journals whose participants meet annually to improve standards in manuscripts submitted to biomedical journals. In September 2004, the ICMJE announced a tough new stance on registering clinical trials. All trials that start enrolling participants after July 1, 2005 must register their trial in a suitable publicly accessible register before that date in order to be considered for subsequent publication in those journals. Those trials that have started enrolment before July 1, 2005 must register before September 13, 2005 to be considered for publication (De Angelis et al, 2004). The Journal of Investigative Dermatology subscribes to these standards.
Why Is Prospective Trial Registration Such a Big Issue? The ICMJE points out that researchers have an obligation to conduct themselves ethically and to report their results honestly. Honest reporting begins with revealing the existence of all clinical studies, even those that reflect unfavorably on a research sponsor’s product or hypothesis. Publication bias classically refers to selective publication of studies with favorable results. For example, in 2003, Melander et al (2003) traced the fate of 42 placebo-controlled studies of five selective serotonin reuptake inhibitors submitted to the Swedish drug regulatory authority as a basis for marketing approval for treating major depression, and compared these with the studies actually published between 1983 and 1999. The 42 trials are depicted in Fig 1, with the red circles representing studies showing ‘‘positive’’ results, and the blue circles representing studies with nonsignificant results. The Figure shows how the studies with ‘‘positive’’ results were published as stand-alone publications (shown as green diamonds in the figure) much more often than studies with non-significant results. The figure also shows that studies with positive results were included more often in meta-analyses (yellow squares) than the nonsignificant studies. What little research is available in the world of dermatological clinical trials suggests that it is not immune to such practices. For example, a UK Governmentfunded meta-analysis of evening primrose oil for atopic dermatitis included 20 trials, eight of which remain unpublished in the public domain (Williams, 2003). Duplicate pub-
Copyright r 2005 by The Society for Investigative Dermatology, Inc.
viii
124 : 5 MAY 2005
PROSPECTIVE CLINICAL TRIAL REGISTRATION
ix
The Journal of Investigative Dermatology recommendations for a suitable trial registry include: • • • •
Free public access Each trial has a unique identifier Registered information is checked Registered entry contains trial name, lead investigator, methodology, interventions, primary outcomes, sponsor and status • (Desirable) No charge to register trials and easy to complete
Figure 2 Traits of a suitable clinical trial registry.
Figure 1 An illustration of publication bias. Selective publication of ‘‘positive’’ studies of five selective serotonin reuptake inhibitors submitted to the Swedish drug regulatory authority as a basis for marketing approval for treating major depression (Reproduced with the kind permission of the BMJ Publishing Group from Melander et al, 2003).
study is not being carried out elsewhere in the world before potentially wasting their time as well that of their patients and sponsors in carrying out the same work.
Where Should You Register Your Trial? The Journal of Investigative Dermatology does not wish to be too prescriptive with regard to which register its readers submit their trials to, providing the register fulfills the requirements set out in Fig 2. The ICMJE has suggested www.clinicaltrials.gov as its preferred register, a registry sponsored by the US National Library of Medicine. The register is free to use, and it contains comprehensive data on registered trials that are extracted from sponsors and lead investigators using a 12-page form. Although the register would be the automatic home for new investigational drug applications to the US Food and Drug Administration, it is unclear whether non-drug, non-NIH trials from low- to middle-income countries can be registered (Abbasi, 2004). Another registry worth considering is the International Standard Randomised Controlled Trial Number (ISRCTN)
registry (www.controlled-trials.com), managed by a commercial company called Controlled Clinical Trials. Although access to the registry is free, registration for trials that do not emanate from developing countries carries a $144 (h117) charge, which might be a disincentive to some. Other mechanisms to register trials that fulfill the JID registry criteria exist. One example unique to dermatology is the Cochrane Skin Group prospective trials register http://www. nottingham.ac.uk/ muzd/about/ongoingtrials. The Cochrane Skin Group editorial base is supported by public funds and supports an international and largely voluntary community dedicated to preparing and maintaining systematic reviews of interventions for skin diseases (Williams et al, 1998). The Cochrane Skin Group has been running its registry of prospective trials for the international dermatology community for the last 2 years and encourages the registration of completed but unpublished studies, as well as ongoing and planned clinical trials. Complete registration of trials will facilitate comprehensive systematic reviews by helping to identify all relevant trials. The one-page registration form for the Cochrane Skin Group trials register takes about 5 minutes to complete, and registration is free of charge. The emphasis on free registration and minimal paperwork might be important in order to avoid selective publication that might occur if those trials that lacked direct financial support were discouraged from registering.
What Type of Study Should Be Registered? The ICMJE defines a clinical trial as any research project that prospectively assigns human subjects to intervention or comparison groups to study the cause-and-effect relationship between a medical intervention and a health outcome. In other words, the register is not confined to drug studies and can include randomized controlled trials of medical devices, a new surgical technique, or even a new way of organizing care such as nurse-led clinics. Studies designed for other purposes, such as to study pharmacokinetics, cellular mechanisms in isolation or major toxicity (e.g., phase I trials), would be exempt.
The Bottom Line Many a stern word has been aired on the general poor reporting standards of dermatological trials (Bigby et al, 1985), but little seems to have changed over the last 20 years (Adetugbo and Williams, 2000; Naldi et al, 2003). It is easy to accept publication bias as ‘‘just the way things are’’;
x
WILLIAMS AND STERN
yet the effect of selective reporting of evidence is a major disservice to the trust and altruism at the heart of patients volunteering to participate in dermatological clinical trials. Selective reporting distorts the true effects of medical interventions, leading to a waste of doctors’ and patients’ time, a waste of public money, and possible serious harms (Chalmers, 2004). It is our vision that the data from all dermatological clinical trials conducted on volunteers belong to the people. Registering your clinical trial, searching the registries for other trials that evaluate similar interventions, and sharing this information with editors and readers bring us one step closer to such a vision. Conflict of interest: Hywel Williams is co-ordinating editor of the Cochrane Skin Group. DOI: 10.1111/j.0022-202X.2005.23665.x
References Abbasi K: Compulsory registration of clinical trials. BMJ 329:637–638, 2004 Adetugbo K, Williams H: How well are randomized controlled trials reported in the dermatology literature? Arch Dermatol 136:381–385, 2000 Bigby M, Stern RS, Bigby JA: An evaluation of method reporting and use in clinical trials in dermatology. Arch Dermatol 121:1394–1399, 1985
THE JOURNAL OF INVESTIGATIVE DERMATOLOGY Chalmers I: In the dark: Drug companies should be forced to publish all the results of clinical trials. New Sci 181:19, 2004 De Angelis C, Drazen JM, Frizelle FA, et al: International Committee of Medical Journal Editors. Clinical trial registration: A statement from the International Committee of Medical Journal Editors. Lancet 364:911–912, 2004 Diepgen TL: Early Treatment of the Atopic Child Study Group. Long-term treatment with cetirizine of infants with atopic dermatitis: A multi-country, double-blind, randomized, placebo-controlled trial (the ETAC trial) over 18 months. Pediatr Allergy Immunol 13:278–286, 2002 Gordon KB, Papp KA, Hamilton TK, et al: Efalizumab for patients with moderate to severe plaque psoriasis: A randomized controlled trial. JAMA 290: 3073–3080, 2003 Hoare C, Li Wan Po A, Williams H: Systematic review of treatments for atopic eczema. Health Technol Assess 4:1–191, 2000 Kempers S, Boguniewicz M, Carter E, et al: A randomized investigator-blinded study comparing pimecrolimus cream 1% with tacrolimus ointment 0.03% in the treatment of pediatric patients with moderate atopic dermatitis. J Am Acad Dermatol 51:515–525, 2004 Lebwohl M, Tyring SK, Hamilton TK, et al: A novel targeted T-cell modulator, efalizumab, for plaque psoriasis. N Engl J Med 349:2004–2013, 2003 Melander H, Ahlqvist-Rastad J, Meijer G, Beermann B: Evidence b(i)ased medicine–selective reporting from studies sponsored by pharmaceutical industry: Review of studies in new drug applications. BMJ 326:1171–1173, 2003 Naldi L, Svensson A, Diepgen T, et al: European Dermato-Epidemiology Network. Randomized clinical trials for psoriasis 1977–2000: The EDEN survey. J Invest Dermatol 120:738–741, 2003 Rennie D: Thyroid storm. JAMA 277:1238–1243, 1997 Stern RS: A promising step forward in psoriasis therapy. JAMA 290:3133–3135, 2003 Williams H, Adetugbo K, Po AL, Naldi L, Diepgen T, Murrell D: The Cochrane Skin Group. Preparing, maintaining, and disseminating systematic reviews of clinical interventions in dermatology. Arch Dermatol 134:1620–1626, 1998 Williams HC: Evening primrose oil for atopic dermatitis. BMJ 327:1358–1359, 2003