New journal policy regarding registration of clinical trials
When patients consent to participate in a clinical study, a principal motivation for many is to contribute to medical knowledge. From this foundation of trust, a sine qua non for clinical investigation, several questions arise: Do patients have a right to know that the results of the study in which they participate will eventually be available to medical researchers and the public at large? If a clinical trial is initiated but later canceled, how do physicians and patients learn why? When a trial fails to demonstrate efficacy and its results are never published, should that information be accessible, and to whom? Finally, if a trial demonstrates that a medication causes harm, who has the right to know, and when? These questions have driven much of the recent public debate about compulsory clinical trials registration.
The movement to register all clinical studies was the subject of a policy statement issued in September 2004 by members of the International Committee of Medical Journal Editors (ICMJE) (1), a committee of editors of 11 general medical journals (New England Journal of Medicine, Journal of the American Medical Association, Lancet, New Zealand Medical Journal, Norwegian Medical Journal, Canadian Medical Association Journal, Annals of Internal Medicine, Croatian Medical Journal, Nederlands Tijdschrift voor Geneeskunde, Journal of the Danish Medical Association, and Medical Journal of Australia). The ICMJE declared that, as of July 1, 2005, they will accept for publication only those reports of clinical trials that have been preregistered—before enrollment of the first patient—with one of several publicly accessible, free-of-charge Web sites. At approximately the same time, members of the Cochrane Collaboration met in Ottawa to develop a statement calling for even broader requirements in the area of clinical trials registration (2). Finally, clinical trials registration is the topic of bipartisan-sponsored legislation currently under debate on Capitol Hill. This legislation is known as the Fair Access to Clinical Trials (FACT) Act (3).
Proponents of clinical trials registration argue that this measure is essential not only to ensure accuracy in the publication of studies' results, but also to guarantee access (at appropriate times) to all interested parties: clinicians, institutional review boards (IRBs), sponsors, other investigators—and patients. Recent experiences with the selective serotonin release inhibitors in childhood depression (4, 5) and with cyclooxygenase 2 inhibitors (6, 7) demonstrate unequivocally that, under the status quo, information available to some parties—typically selected researchers and pharmaceutical houses—is not available to most physicians or patients. At best, this closed information loop leads to redundancy in the types of clinical trials undertaken and lack of access to data about promising therapies. At worst, undisclosed trial results have the potential to cause harm to patients that would be preventable in a more open structure for clinical trials reporting. At present, detailed information about the lifetime batting average of the most obscure major league baseball player is easier to access than are reliable data about even the very existence of some research conducted in the name of biomedical science. In the information age, medicine should do better.
Through the years, several attempts have been made to remedy the “secrecy” with which some trials are conducted. In 1997, the Food and Drug Administration (FDA) Modernization Act created a voluntary registry for clinical trials: www.clinicaltrials.gov. This registry, maintained by the National Library of Medicine, contains information related to trial design, eligibility criteria, investigators, and participating sites. Unfortunately, this Web site does not include information about the most important aspect of trials: their results. Moreover, because the law makes no provision for enforcement, www.clinicaltrials.gov registers only a fraction of all trials. Finally, because the statute that created the database applies only to trials conducted under Investigational New Drug licenses—required only for clinical trials conducted in the US—the database has a decided emphasis on American trials (although non-US studies are not excluded). European investigators often choose to register their trials at www.controlled-trials.com, an alternative that meets all of the criteria for a suitable registration site set forth by the ICMJE (Table 1). Other clinical trials registries also exist, some of which have been initiated by the pharmaceutical industry. In all cases, however, registries remain voluntary, somewhat haphazard, and dependent to a certain extent upon the institutional memory of the group initiating the effort.
Table 1. Criteria for appropriate clinical trial registries*
|Accessible to the public at no charge|
|Open to all prospective registrants and managed by a not-for-profit organization|
|Possesses a mechanism for ensuring data validity|
|Contains the minimum core of information and trial descriptors listed in |
Regardless of the success of the FACT Act in Congress, biomedical journals have a responsibility to encourage rigor in the conduct and publication of research. In this editorial, we outline the arguments in favor of clinical trials registration, discuss the potential downsides of this initiative, and state the policy of the American College of Rheumatology (ACR) journals that will take effect on January 1, 2007. We also elaborate the time line for the initiation of this new policy.
The basics of clinical trial registration
Three documents delineate the central concepts of the clinical trials registration movement: the ICMJE statement, the FACT Act, and the Ottawa Statement. Though similar in their fundamental philosophies, these documents differ from one another in some important details. The principles espoused in the ICMJE statement are shown in Table 2. The editors' statement defines “clinical trial” broadly. Specifically, the editors define 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” (1). The key words in this statement are “intervention” and “prospective.” The definition includes not only studies of drugs, biologic agents, and devices, but also research designed to address disease prevention, the promotion of health, screening tests, diagnostic algorithms, approaches to rehabilitation, the organization or financing of health care, and other interventions. Such a comprehensive registration would have a sizable impact on clinical research: on the manner in which funding proposals are evaluated, the ways in which research subjects are recruited, the mechanisms by which manuscripts are reviewed, and, ultimately, the way that clinical research is performed.
Table 2. Summary of the International Committee of Medical Journal Editors (ICMJE) statement
|Includes prospective interventions of all kinds that involve human subjects, with the exception of phase I trials, pharmacokinetics studies, and studies without concurrent control groups|
|Registration must occur at or before the time the first patient is enrolled|
|Studies to be registered on publicly available, searchable, free-of-charge Web sites such as |
www.clinicaltrials.gov . Other Web sites may also be appropriate
|Information to include the following:|
| Unique identifying number|
| The intervention|
| Study hypothesis|
| Primary and secondary outcome measures|
| Eligibility criteria|
| Key trial dates (date of registration, start of enrollment, anticipated completion)|
| Target n|
| Funding source|
| Contact information for study sites|
|The ICMJE policy goes into effect July 1, 2005 for new studies. For studies that began before July 1, registration must occur by September 13, 2005|
Of note, the ICMJE statement excludes phase I trials of drugs, biologic agents, or devices, as well as studies designed merely to investigate the pharmacokinetics of a given agent. The ICMJE also does not require posting of the results of studies, only registration of their existence. Finally, in a recent clarification of their original statement, the ICMJE states that in order to trigger the requirement for registration, a trial must have at least one concurrent control or comparison group (8).
The FACT Act covers both the registration and the results of phase II–IV studies of drugs, biologic agents, and devices, to the exclusion of phase I studies. The FACT Act would also permit registration of other prospective studies of interventions on a purely voluntary basis, and is thereby less sweeping than the ICMJE statement. Under the FACT Act, however, all studies covered by the legislation would have to be registered on an approved Internet-based clinical trials registry in order to obtain approval from a US IRB. Moreover, the legislation would have teeth: sizable penalties would be invoked for failure by sponsors to comply with the new rules.
In contrast to both the ICMJE statement and the FACT Act, the Ottawa Statement calls for the registration of all prospective clinical studies, controlled or uncontrolled, thereby including phase I clinical trials as well.
Advantages of clinical trials registration
Arguments in favor of clinical trials registration are rooted in both bioethics and science. Much as the concept that poorly designed or sloppily conducted research is unethical, the conduct of human research without assurance that descriptions of the study and its findings will be available to the public is also unethical. Furthermore, although ethical concerns are paramount to these discussions and essential to maintaining the public's trust in biomedical research, it is also likely that the science of clinical investigation will benefit substantially from clinical trials registration, in the ways described below.
Reduction in potential for patient harm. Access to the results of all trials initiated (whether or not they are ever completed) may minimize known risks and potential harm arising from unnecessary exposure to interventions that have already been tested by others. Even trials that are discontinued for one reason or another would be identified by a unique identification number, updated according to a specified time line with an explanation of the trials' current status, and thus not “lost” to biomedical science.
Elimination of excessive redundancy. Clinical trials registration may also help identify (and therefore prevent) unnecessary duplication of research and publications.
Help in planning new studies. Access to information about all previous studies related to a given topic may enhance the planning of new studies.
Deterrence of negative reporting bias.Registration of all studies initiated will deter selective reporting of research results, thereby mitigating negative reporting bias. Similarly, the requirement for disclosure of research objectives in advance will discourage attempts to present retrospective experiences as prospective studies.
Improvement in the quality of clinical investigation. Finally, assuming that the ultimate intention of the researchers is to publish the results, the movement to require registration of clinical interventions as a precondition to publication (or even to the start of enrollment) will demand greater forethought in beginning research projects. This will raise the bar for investigators in a gentle but firm manner, thereby enhancing the quality of biomedical research.
Potential objections to clinical trials registration
Several potential objections to clinical trials registration are evident. One concern is the perception that compulsory clinical trials registration might be onerous to investigators. The responsibilities of clinical investigators vis-à-vis reporting to IRBs, data and safety monitoring boards, and the FDA already require considerable time. For investigators who have already invested the time necessary to design a worthwhile study, however, fear of yet another time-consuming hurdle to the initiation of studies is unfounded. The necessary information may be cut and pasted from a study protocol into the appropriate Internet-based registry within minutes.
Another potential objection to clinical trials registration is that information about clinical studies will be available for public consumption by anyone who wishes to access Internet registries, before all of the data have been subjected to peer review. This transparency, of course, is an inevitable result—and part of the appeal—of compulsory registration. Yet the concern also has at least partial merit, for this is a facet of compulsory trials registration for which the precise details remain unclear. The anxiety about widespread availability of unvetted information should be assuaged partly by provisions of both the Ottawa Statement and the FACT Act. Recognizing that the peer review process is the best safeguard for scientific accuracy, both the Ottawa Statement and the FACT Act provide time for researchers to publish their results. Under the provisions of the FACT Act, for example, before the release of results on a government-run registry, investigators would have up to 12 months after data collection to submit data for peer review, an additional 18 months for the peer review process, and a further 6 months for publication.
Although it is not the intention to encourage the posting of interim or preliminary results on registries, this remains a possibility because not all studies initiated are submitted for publication and not all submissions lead to peer-reviewed publications. At some point after the completion of data collection, investigators would be required to supply updates on the status of their studies. Caveat emptor: Individuals choosing to access clinical trial registries must interpret the postings with appropriate caution, with the greatest trust placed in results that have undergone peer review. But provided that appropriate disclaimers are included in registry postings, the availability of more complete information about all clinical studies may enhance, rather than dilute, the process of evaluating biomedical research.
Pharmaceutical firms may worry that compliance with registration will result in a loss of their “edge” over competitors. This argument pertains particularly to the notion that phase I trials should be exempt from registration. Yet phase I trials are precisely the setting in which worrisome adverse effects may be observed for the first time (or when lack of efficacy may become evident). As outlined in Table 2 and below, the policy to be enacted by the ICMJE and the ACR journals currently excludes phase I trials; this point may be revisited in the future. Pharmaceutical companies benefit substantially from public largesse, be it basic research from universities and government-funded laboratories, access to patients through academic medical centers, or tax breaks for research and development. Rather than lobbying for the status quo, pharmaceutical companies should welcome a system in which their products are evaluated with greater scientific rigor and objectivity—and all of the data.
Finally, how will the new rules be enforced? If passed, the FACT Act would establish strong enforcement mechanisms. Grant funds may be withheld from investigators who fail to comply with registry deadlines. The civil monetary penalties may be up to $10,000/day for each day that the study sponsor is in arrears of posting data to the registry. In an ironic twist, funds collected from violators of the new regulations would be earmarked for Agency for Healthcare Research and Quality studies that compare 2 or more interventions for a given disease or condition. Whether or not the FACT Act is ratified by Congress, the strong stance taken by the ICMJE editors and by editors who become cosignatories to the statement may go a long way toward enforcing the policy of registration and ensuring fair access to information about clinical trials.
In summary, availability of information about a broader spectrum of all ongoing clinical studies may permit sponsors to allocate resources more wisely, enable regulators to evaluate proposals with greater insight, allow investigators to exchange ideas more freely, augment clinicians' ability to locate information about the safety and efficacy of treatments, and help patients to discover their potential eligibility for new clinical trials. The actions required of clinical trial sponsors during the development and performance of a prospective intervention study are summarized in Table 3.
Table 3. Clinical trial registration actions in the lifetime of a prospective intervention study
|Trial protocol drafted||Assigned unique identification (ID) number at either |
www.controlled-trials.com ; provide ID on consent forms and other trial documentation
|Trial protocol complete||Register and post minimum protocol items|
|Participant recruitment/data collection/ manuscript submission||Post protocol amendments; full protocol and data collection forms made publicly available|
|Publication of primary results||Post published results (if manuscript not published, results posted within 18 months of close of data collection); link publication citations to trials registry|
Policy of the ACR journals on clinical trials registration
Clinical trials registration is in the best interest of all parties involved in biomedical research: patients, clinicians, investigators, IRBs, medical journal editors, peer reviewers, and sponsors. Consequently, both Arthritis & Rheumatism and Arthritis Care & Research will join the signatories of the ICMJE statement and adopt a similar policy. To allow time for dissemination of this policy, this requirement will begin on January 1, 2007. Specific details of the new policy are as follows:
As of January 1, 2007, all prospective, interventional studies (be they initiated before or after that date) must be registered at either www.clinicaltrials.gov or www.controlled-trials.com in order to be considered for publication in either Arthritis & Rheumatism or Arthritis Care & Research. Phase I clinical trials, pharmacokinetic studies, and those that do not involve a concurrent control group are excluded from this policy at the present time. For studies initiated after January 1, 2007, registration must occur before the first patient is enrolled. In addition to prospective studies of drugs, biologic agents, and devices, this requirement will include prospective investigations of prevention strategies, screening procedures, diagnostic algorithms, health promotion approaches, behavioral interventions, and health care economics. Retrospective reviews, studies designed only to generate pharmacokinetic data, and observational studies that do not involve interventions are not included in this policy. The list of suitable Web sites will be updated from time to time, as new options emerge.
We anticipate that some manuscripts will not be easy to classify and will raise questions about whether the new policy does or does not apply. In such cases, subcommittees of either the editorial boards of the journals or the ACR Committee on Journal Publications will review and adjudicate the status of the manuscript in question.