Research Corner（2）Clinical trials need to be registered prior to enrolling subjects

Michael R.PHILLIPS

Research Corner（2）Clinical trials need to be registered prior to enrolling subjects

Michael R.PHILLIPS

‘Registering’a clinical trial involves providing information about the design of the study on an approved,open-access website prior to enrolling subjects in the study［1］.The information the researcher provides on the registry usually includes the planned number and characteristics of enrolled subjects,the method of randomizing or assigning subjects to the experimental or control conditions, the specifics of the treatment provided in the experimental and control conditions,the method and timing of evaluating the outcome,the funding source for the project,and so forth.Study registration is only recommended for prospective trials in which two or more therapeutic or preventive interventions with human subjects are compared；in most cases these are randomized controlled trials.

The World Medical Association Declaration of Helsinki—Ethical Principles for Medical Research Involving Human Subjects—states that"Every clinical trial must be registered in a publicly accessible database before recruitment of the first subject"（http://www.wma.net/en/30publications/10policies/b3/index.htm l）.Based on this principle,the International Comm ittee of Medical Journal Editors（ICMJE）,the WHO,the Cochrane Collaboration, several national governments,and the Evidence Based Medicine Center at the Chinese M inistry of Health（http://www.chictr.org/Upload/6142006. pdf）strongly recommend that clinical controlled trials in medicine be registered prior to the enrollment of subjects in the study.Many leading medical journals now require prior registration of clinical control studies and publish the registration number（that reviewers and readers can use to check the original design of the study）as part of the abstract.The Shanghai Archives of Psychiatry also strongly recommends that clinical controlled trials be registered and p lans to make this a formal requirement for subm ission in the future.

There are several reasons international experts consider registration of clinical trials essential to improving the usefulness of medical research.The main reason is that the strong bias for reporting and publishing‘positive’studies—those that demonstrate the benefits of a new treatment—results in inaccurate information about the effectiveness and safety of new interventions.The promotion of ineffective and potentially unsafe treatments on the basis of biased scientific information is both unethical and deleterious to the health of the public.There are several exam ples in the literature w here the failure to report and publish negative studies has led to the introduction of new treatments of questionable benefit and safety or the continued use of a treatment long after it is clear it is useless or even harm ful.Journal editors are partly responsible for the preference of‘positive’studies but the major problem lies with the pharmaceutical companies that fund clinical research；they have a long history of selectively publishing papers on the benefits of the drugs they are trying to promote and suppressing the publication of studies that find the new drugs to be ineffective or potentially unsafe.

One way to address the problem is to encourage researchers to report negative studies and to encourage medical journal editors to publish welldesigned negative clinical studies,but this will only address part of the problem.Requiring registration of all clinical controlled trials prior to initiating patient enrollment will put the published positive studies into perspective；the number and result of registered but uncompleted or unpublished studies on the same treatment provides a crude measure of the potential degree of publication bias.And,more importantly,individuals who conduct meta-analyses and regulatory agencies that decide which treatments to approve or fund can conduct follow-up assessments with the principal investigators of the uncompleted and unpublished studies to arrive at a balanced assessment of the potential benefits and risks of a specific treatment for a specific type of patient.

There are several other benefits to registering controlled clinical trials:1）Potential ethical or methodological problem s in the design of a study can be recognized early and the principal investigators can be notified prior to starting their project［2］,2）Researchers planning a trial can determine whether or not other researchers have already initiated a similar study；this prevents unintentional duplication,allow s for necessary replication,and helps researchers identify areas that require further investigation,3）Researchers interested in expanding enrollment of subjects or in the conduct of parallel studies in multiple locations can use the registration of the main project to recruit other research sites as participating institutions in a multi-site study,and 4）Reviewers and editors can check the original design of the study to ensure that the authors of a submitted manuscript have followed the planned protocol and used the outcome measures originally specified；to avoid selective（biased）reporting of positive outcomes authors would need to explain any changes in the original methods or outcome measures.

The major concern expressed about the registration of controlled clinical trials,primarily voiced by pharmaceutical companies,is that registration of clinical trials will reveal proprietary secrets and, thus stifle innovation.Registration of trials does let one’s competitors know what you are doing and how you plan to do it,so it is not possible to conduct projects in complete secrecy.But registration of a study does BOT reveal the chemical characteristics of any new drugs or agents em ployed,so the proprietary interests of the com pany that funds the project are not seriously damaged.Conducting medical research projects in complete secrecy has the dual disadvantages of hiding highly unethical studies from evaluation by the scientific community（such as the failure to treat patients with syphilis in the Tuskegee syphilis study［3］）and of giving the funders of research the power to suppress the publication of studies that go against their economic interests.In recent years recognition of this problem has led regulatory agencies to force pharmaceutical companies to provide access to all studies they funded,not only those that had been published.For example,when assessing the likelihood that antidepressants increase the risk of suicide in adolescents,the Food and Drug Administration in the United States forced companies that sell antidepressants to provide data on ALL published and unpublished studies they funded［4］.

A much more systematic method of dealing with these problems is to require formal registration of all controlled clinical trials,regard less of where they are conducted and regard less of how they are funded.Despite more than 20 years of effort there in not yet a single,unified,worldwide method of registering clinical trials so hundreds of registries—some based on country of origin of the study,some on medical specialty,and some for specific diseases—have evolved.The major medical journals that subscribe to the principals of the International Committee of Medical Journal Editors（ICMJE）recognize registration of clinical trials in several highquality general registries.These include the registry run by the Bational Library of Medicine in the United States（clinicaltrials.gov.org）,the International Standard Random ized Controlled Trial Bum ber register（ICRCTB）in the United Kingdom（www.ISRCTB.org）and a variety of‘Primary’registries that are approved by the WHO International Clinical Trials Registry Platform（ICTRP）（www.who.int/ictrp）.One of the WHO-approved primary registries—the Chinese Clinical Trials Registry（ChiCTR）（www.chictr.org）—is managed by the Evidence-Based Medicine Center at W est China Medical University.

Prospective registration of trials is an ethical responsibility of clinical researchers because it is the best way to ensure that our treatments for patients are based on the most reliable evidence about effectiveness available.Authors do notneed to register on multiple registries；registry on any of the approved registries,which typically cost$100-$200（$US）,is sufficient to meet the requirements of the medical journals that support the ICMJE principles.It may take some time before a unified international system of trial registry is in place but the trend in this direction is clear.The Shanghai Archives of a Psychiatry strongly encourages Chinese psychiatric researchers to prospectively register their clinical trials on one of the many available registries.

1. D ickersin K,Rennie D.Registering clinical trials.JAMA,2003, 290（19）:516-523.

2. Antes G,Chalmers I.Under-reporting of clinical trials is unethical.The Lancet,2004,361（9362）:978.

3. Thomas SB,Quinn SC.The Tuskegee syphilis study,1932 to 1972:im p lications for HIV education and AIDS risk education programs in the black community.Am JPublic Health,1991,81（11）:1498-1505.doi:10.2105/AJPH.81.11.1498.

4. Bridge JA,Iyengar S,Salary CB,Barbe RP,Birmaher B,Pincus HA,et al.Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of random ized controlled trials.JAMA,2007, 297（15）:1683-1696.

（M ichael R.PH lLLlPS,MD,MPH,Professor of Psychiatry and Global Health,Emory University,USA and Shanghai Jiao Tong University School of Medicine,Shanghai,China.E-mail：phillipschina.archives@yahoo.com）

10.3969/j.issn.1002-0829.2011.02.013