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

What Exactly Have the ICMJE Proposed?

The International Committee of Medical Journal Editors(ICMJE) is a group of the world’s leading medical journalswhose participants meet annually to improve standards inmanuscripts submitted to biomedical journals. In Septem-ber 2004, the ICMJE announced a tough new stance onregistering clinical trials. All trials that start enrolling partic-ipants after July 1, 2005 must register their trial in a suitablepublicly accessible register before that date in order to beconsidered for subsequent publication in those journals.Those trials that have started enrolment before July 1, 2005must register before September 13, 2005 to be consideredfor publication (De Angelis et al, 2004). The Journal of In-vestigative Dermatology subscribes to these standards.

Why Is Prospective Trial RegistrationSuch a Big Issue?

The ICMJE points out that researchers have an obligationto conduct themselves ethically and to report their resultshonestly. Honest reporting begins with revealing the exist-ence of all clinical studies, even those that reflect unfavor-ably on a research sponsor’s product or hypothesis.Publication bias classically refers to selective publicationof studies with favorable results. For example, in 2003, Me-lander et al (2003) traced the fate of 42 placebo-controlledstudies of five selective serotonin reuptake inhibitors sub-mitted to the Swedish drug regulatory authority as a basisfor marketing approval for treating major depression, andcompared these with the studies actually published be-tween 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 non-significant results. The Figure shows how the studies with‘‘positive’’ results were published as stand-alone publica-tions (shown as green diamonds in the figure) much moreoften than studies with non-significant results. The figurealso shows that studies with positive results were includedmore often in meta-analyses (yellow squares) than the non-significant studies. What little research is available in theworld of dermatological clinical trials suggests that it is notimmune to such practices. For example, a UK Government-funded meta-analysis of evening primrose oil for atopicdermatitis included 20 trials, eight of which remain unpub-lished in the public domain (Williams, 2003). Duplicate pub-

lication is another way to emphasize the result of studiesthat sponsors find most to their liking. For example, onesystematic review of 278 trials of atopic dermatitis treat-ments found eight duplicate publications (i.e., the sameclinical trial data from one trial presented in two separatejournals) and one triplicate publication (Hoare et al, 2000).Some sponsors have applied substantial pressures to sup-press or delay the publication of meritorious studies, whoseresults were not favorable to their product (Rennie, 1997).A prospective register of trials would not guarantee that alltrials are eventually published, but it would at least guideresearch users on what studies have been carried outso that questions can be asked if those studies have notbeen published.

A further advantage of registering the basic details ofa clinical trial beforehand is to minimize selective emphasisof positive post hoc subgroup analysis—in other words,the practice of emphasizing some minor secondary andstatistically significant change in disease score in the ab-stract and conclusion, when in fact the primary outcomeanalysis was non-significant (Diepgen, 2002). For example,an article titled ‘‘A randomized investigator—blinded studycomparing pimecrolimus 1% with tacrolimus ointment0.03% in the treatment of pediatric patients with moderateatopic dermatitis’’ barely discussed relative efficacy, but in-stead emphasized ease of application (Kempers et al,2004). Had this trial been registered, the editors (and hope-fully the readers) could have determined whether the paperrepresented post hoc analysis or was merely titled in asomewhat peculiar manner for a study focused on whichdrug is nicer to apply.

Some study results have broad appeal and sufficientmerit for publication in high-impact general medical journals(Stern, 2003). Yet, one wonders whether the publication oftwo similar phase three trials of efalizumab for psoriasiswithin weeks of each other in JAMA and the NEJM by thesame overall group funded by the same company withoutacknowledging each other came very close to the spirit ofduplicate publication (Gordon et al, 2003; Lebwohl et al,2003). A clinical trial registry would help address the prob-lem if the sponsor of an intervention were required to revealto the editors the status of any works conducted by thesame study group submitted for publication for all clinicalstudies they sponsor.

Another reason for registering all ongoing clinical trials issimply to avoid unnecessary duplication of efforts. Thus, itshould be incumbent upon any trialist to check that their

Copyright r 2005 by The Society for Investigative Dermatology, Inc.

viii

study is not being carried out elsewhere in the world beforepotentially wasting their time as well that of their patientsand sponsors in carrying out the same work.

Where Should You Register Your Trial?

The Journal of Investigative Dermatology does not wish tobe too prescriptive with regard to which register its readerssubmit their trials to, providing the register fulfills the re-quirements set out in Fig 2. The ICMJE has suggestedwww.clinicaltrials.gov as its preferred register, a registrysponsored by the US National Library of Medicine. Theregister is free to use, and it contains comprehensive dataon registered trials that are extracted from sponsors andlead investigators using a 12-page form. Although the reg-ister would be the automatic home for new investigationaldrug applications to the US Food and Drug Administration,it is unclear whether non-drug, non-NIH trials from low- tomiddle-income countries can be registered (Abbasi, 2004).Another registry worth considering is the InternationalStandard Randomised Controlled Trial Number (ISRCTN)

registry (www.controlled-trials.com), managed by a com-mercial company called Controlled Clinical Trials. Althoughaccess to the registry is free, registration for trials that donot emanate from developing countries carries a $144(h117) charge, which might be a disincentive to some. Othermechanisms to register trials that fulfill the JID registry cri-teria exist. One example unique to dermatology is the Co-chrane Skin Group prospective trials register http://www.nottingham.ac.uk/�muzd/about/ongoingtrials. The Coch-rane Skin Group editorial base is supported by public fundsand supports an international and largely voluntary com-munity dedicated to preparing and maintaining systematicreviews of interventions for skin diseases (Williams et al,1998). The Cochrane Skin Group has been running its reg-istry of prospective trials for the international dermatologycommunity for the last 2 years and encourages the regis-tration of completed but unpublished studies, as well asongoing and planned clinical trials. Complete registration oftrials will facilitate comprehensive systematic reviews byhelping to identify all relevant trials. The one-page registra-tion form for the Cochrane Skin Group trials register takesabout 5 minutes to complete, and registration is free ofcharge. The emphasis on free registration and minimal pa-perwork might be important in order to avoid selectivepublication that might occur if those trials that lacked directfinancial support were discouraged from registering.

What Type of Study Should Be Registered?

The ICMJE defines a clinical trial as any research projectthat prospectively assigns human subjects to intervention orcomparison groups to study the cause-and-effect relation-ship between a medical intervention and a health outcome.In other words, the register is not confined to drug studiesand can include randomized controlled trials of medicaldevices, a new surgical technique, or even a new way oforganizing care such as nurse-led clinics. Studies designedfor 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 poorreporting standards of dermatological trials (Bigby et al,1985), but little seems to have changed over the last 20years (Adetugbo and Williams, 2000; Naldi et al, 2003). It iseasy to accept publication bias as ‘‘just the way things are’’;

Figure 1An illustration of publication bias. Selective publication of ‘‘positive’’studies of five selective serotonin reuptake inhibitors submitted to theSwedish drug regulatory authority as a basis for marketing approval fortreating major depression (Reproduced with the kind permission of theBMJ Publishing Group from Melander et al, 2003).

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

Figure2Traits of a suitable clinical trial registry.

PROSPECTIVE CLINICAL TRIAL REGISTRATION ix124 : 5 MAY 2005

yet the effect of selective reporting of evidence is a majordisservice to the trust and altruism at the heart of patientsvolunteering to participate in dermatological clinical trials.Selective reporting distorts the true effects of medical in-terventions, 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 der-matological clinical trials conducted on volunteers belong tothe people. Registering your clinical trial, searching the reg-istries for other trials that evaluate similar interventions, andsharing this information with editors and readers bring usone step closer to such a vision.

Conflict of interest:Hywel Williams is co-ordinating editor of the Cochrane SkinGroup.

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

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 Interna-

tional Committee of Medical Journal Editors. Lancet 364:911–912, 2004

Diepgen TL: Early Treatment of the Atopic Child Study Group. Long-term treat-

ment 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 der-

matitis. 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 med-

icine–selective reporting from studies sponsored by pharmaceutical indus-

try: 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

x WILLIAMS AND STERN THE JOURNAL OF INVESTIGATIVE DERMATOLOGY