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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary D Published Journal Editorials Clinical Trial Registration: A Statement from the International Committee of Medical Journal Editors Altruism and trust lie at the heart of research on human subjects. Altruistic individuals volunteer for research because they trust that their participation will contribute to improved health for others and that researchers will minimize risks to participants. In return for the altruism and trust that make clinical research possible, the research enterprise has an obligation to conduct research ethically and to report it honestly. Honest reporting begins with revealing the existence of all clinical studies, even those that reflect unfavorably on a research sponsor’s product. Unfortunately, selective reporting of trials does occur, and it distorts the body of evidence available for clinical decision making. Researchers (and journal editors) are generally most enthusiastic about the publication of trials that show either a large effect of a new treatment (positive trials) or equivalence of two approaches to treatment (noninferiority trials). Researchers (and journals) typically are less excited about trials that show that a new treatment is inferior to standard treatment (negative trials) and even less interested in trials that are neither clearly positive nor clearly negative, since inconclusive trials will not in themselves change practice. Irrespective of their scientific interest, trial results that place financial interests at risk are particularly likely to remain unpublished and hidden from public view. The interests of the sponsor or authors notwithstanding, anyone should be able to learn of any trial’s existence and its important characteristics. The case against selective reporting is particularly compelling for research that tests interventions that could enter mainstream clinical practice. Rather than a single trial, it is usually a body of evidence, consisting of many studies, that changes medical practice. When research sponsors or investigators conceal the presence of selected trials, these studies cannot influence the thinking of patients, clinicians, other researchers, and experts who write practice guidelines or decide on insurance-coverage policy. If all trials are registered in a public repository at their inception, every trial’s existence is part of the public record and the many stakeholders in clinical research can explore the full range of clinical evi-
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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary dence. We are far from this ideal at present, since trial registration is largely voluntary, registry data sets and public access to them vary, and registries contain only a small proportion of trials. In this editorial, published simultaneously in all member journals, the International Committee of Medical Journal Editors (ICMJE) proposes comprehensive trials registration as a solution to the problem of selective awareness and announces that all 11 ICMJE member journals will adopt a trials-registration policy to promote this goal. The ICMJE member journals will require, as a condition of consideration for publication, registration in a public trials registry. Trials must register at or before the onset of patient enrollment. This policy applies to any clinical trial starting enrollment after July 1, 2005. For trials that began enrollment prior to this date, the ICMJE member journals will require registration by September 13, 2005, before considering the trial for publication. We speak only for ourselves, but we encourage editors of other biomedical journals to adopt similar policies. For this purpose, 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. Studies designed for other purposes, such as to study pharmacokinetics or major toxicity (for example, phase I trials), would be exempt. The ICMJE does not advocate one particular registry, but its member journals will require authors to register their trial in a registry that meets several criteria. The registry must be accessible to the public at no charge. It must be open to all prospective registrants and managed by a not-for-profit organization. There must be a mechanism to ensure the validity of the registration data, and the registry should be electronically searchable. An acceptable registry must include at minimum the following information: a unique identifying number, a statement of the intervention (or interventions) and comparison (or comparisons) studied, a statement of the study hypothesis, definitions of the primary and secondary outcome measures, eligibility criteria, key trial dates (registration date, anticipated or actual start date, anticipated or actual date of last follow-up, planned or actual date of closure to data entry, and date trial data considered complete), target number of subjects, funding source, and contact information for the principal investigator. To our knowledge, at present, only www.clinicaltrials.gov, sponsored by the United States National Library of Medicine, meets these requirements; there may be other registries, now or in the future, that meet all these requirements.
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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary Registration is only part of the means to an end; that end is full transparency with respect to performance and reporting of clinical trials. Research sponsors may argue that public registration of clinical trials will result in unnecessary bureaucratic delays and destroy their competitive edge by allowing competitors full access to their research plans. We argue that enhanced public confidence in the research enterprise will compensate for the costs of full disclosure. Patients who volunteer to participate in clinical trials deserve to know that their contribution to improving human health will be available to inform health care decisions. The knowledge made possible by their collective altruism must be accessible to everyone. Required trial registration will advance this goal. Catherine De Angelis, MD, MPH Editor-in-Chief, Journal of the American Medical Association Jeffrey M.Drazen, MD Editor-in-Chief, New England Journal of Medicine Frank A.Frizelle, MB, ChB, MMedSc, FRACS Editor, The New Zealand Medical Journal Charlotte Haug, MD, PhD, MSc Editor-in-Chief, Norwegian Medical Journal John Hoey, MD Editor, Canadian Medical Association Journal Richard Horton, FRCP Editor, The Lancet Sheldon Kotzin, MLS Executive Editor, MEDLINE, National Library of Medicine Christine Laine, MD, MPH Senior Deputy Editor, Annals of Internal Medicine Ana Marusic, MD, PhD Editor, Croatian Medical Journal A.John P.M. Overbeke, MD, PhD Executive Editor, Nederlands Tijdschrift voor Geneeskunde (Dutch Journal of Medicine) Torben V.Schroeder, MD, DMSc Editor, Journal of the Danish Medical Association Harold C.Sox, MD Editor, Annals of Internal Medicine Martin B.Van Der Weyden, MD Editor, The Medical Journal of Australia Original editorial available at www.ICMJE.com.
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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary Is This Clinical Trial Fully Registered?—A Statement from the International Committee of Medical Journal Editors Catherine D.De Angelis, M.D., M.P.H., Jeffrey M.Drazen, M.D., Frank A.Frizelle, M.B.,Ch.B., M.Med.Sc., F.R.A.C.S., Charlotte Haug, M.D., Ph.D., M.Sc., John Hoey, M.D., Richard Horton, F.R.C.P., Sheldon Kotzin, M.L.S., Christine Laine, M.D., M.P.H., Ana Marusic, M.D., Ph.D., A.John P.M. Overbeke, M.D., Ph.D., Torben V.Schroeder, M.D., D.M.Sc., Harold C.Sox, M.D., and Martin B.Van Der Weyden, M.D. In September 2004, the members of the International Committee of Medical Journal Editors (ICMJE) published a joint editorial aimed at promoting registration of all clinical trials (De Angelis et al., 2004). We stated that we will consider a trial for publication only if it has been registered before the enrollment of the first patient. This policy applies to trials that start recruiting on or after July 1, 2005. Because many ongoing trials were not registered at inception, we will consider for publication ongoing trials that are registered before September 13, 2005. Our goal then and now is to foster a comprehensive, publicly available database of clinical trials. A complete registry of trials would be a fitting way to thank the thousands of participants who have placed themselves at risk by volunteering for clinical trials. They deserve to know that the information that accrues from their altruism is part of the public record, where it is available to guide decisions about patient care, and deserve to know that decisions about their care rest on all of the evidence, not just the trials that authors decided to report and that journal editors decided to publish. We are not alone in pursuing this goal. The World Health Organization (WHO), through meetings in New York, Mexico City, and Geneva, has brought us close to the goal of a single worldwide standard for the information that trial authors must disclose. Around the world, governments are beginning to legislate mandatory disclosure of all trials. For example, among the bodies considering new legislation is the U.S. Congress, where the proposed Fair Access to Clinical Trials (FACT) Act would expand the current mandate for registration of clinical trials. Many other journals have adopted our policy of requiring trial registration. These initiatives show that trial registration has become a public issue. But, as our deadline for registration approaches, trial authors and spon-
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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary sors want to be sure that they understand our requirements, so that reports of their research will be eligible for editorial review. The purpose of this joint and simultaneously published editorial is to answer questions about the ICMJE initiative and to bring our position into harmony with that of others who are working toward the same end. Our definition of a clinical trial remains essentially the same as in our September 2004 editorial: “Any research project that prospectively assigns human subjects to intervention and comparison groups to study the cause-and-effect relationship between a medical intervention and a health outcome.” By “medical intervention” we mean any intervention used to modify a health outcome. This definition includes drugs, surgical procedures, devices, behavioral treatments, process-of-care changes, and the like. We update our 2004 editorial to state that a trial must have at least one prospectively assigned concurrent control or comparison group in order to trigger the requirement for registration. Among the trials that meet this definition, which need to be registered? The ICMJE wants to ensure public access to all “clinically directive” trials—trials that test a clinical hypothesis about health outcomes (e.g., “Is drug X as effective as drug Y in treating heart failure?”). We have excluded trials from our registration requirement if their primary goal is to assess major unknown toxicity or determine pharmacokinetics (phase 1 trials). In contrast, we think the public deserves to know about trials that could shape the body of evidence about clinical effectiveness or adverse effects. Therefore, we require registration of all trials whose primary purpose is to affect clinical practice (phase 3 trials). Between these two extremes are some clinical trials whose prespecified goal is to investigate the biology of disease or to provide preliminary data that may lead to larger, clinically directive trials. We recognize that requiring public registration of trials whose prespecified goal is to investigate the biology of disease or to direct further research might slow the forces that drive innovation. Therefore, each journal editor will decide on a case-by-case basis about reviewing unregistered trials in this category. Authors whose trial is unregistered will have to convince the editor that they had a sound rationale when they decided not to register their trial. The ICMJE will maintain this policy for the next two years. We will then review our experience. Our September 2004 editorial specified the information that we would require for trial registration. Attendees at a recent meeting of the WHO registration advisory group identified a minimal registration data set of 20 items (Table D-1). The WHO-mandated items collectively ad-
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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary dress every key requirement that we established in our September 2004 editorial. The ICMJE supports the WHO minimal data set and has adopted it as the ICMJE’s requirement: we will consider a trial for publication if the authors register it at inception by completing all 20 fields in the WHO minimal data set. As individual editors, we will review the data in the registration fields when we decide whether to consider the trial for publication. We will consider a registration data set inadequate if it has missing fields or fields that contain uninformative terminology. If an investigator has already registered a clinical trial in a publicly owned, publicly accessible registry using the data fields that we specified in our 2004 editorial, we will consider that registration to be complete as long as each field contains useful information. TABLE D-1 Minimal Registration Data Set* Item Comment 1. Unique trial number The unique trial number will be established be the primary registering entity (the registry). 2. Trial registration date The date of registration will be established by the primary registering entity. 3. Secondary IDs May be assigned by sponsors or other interested parties (there may be none). 4. Funding source(s) Name of the organization(s) that provided funding for the study. 5. Primary sponsor The main entity responsible for performing the research. 6. Secondary sponsor(s) The secondary entities, if any, responsible for performing the research. 7. Responsible contact person Public contact person for the trial, for patients interested in participating. 8. Research contact person Person to contact for scientific inquiries about the trial.
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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary 9. Title of the study Brief title chosen by the research group (can be omitted if the researchers wish). 10. Official scientific title of the study This title must include the name of the intervention, the condition being studied, and the outcome (e.g., The International Study of Digoxin and Death from Congestive Heart Failure). 11. Research ethics review Has the study at the time of registration received appropriate ethics committee approval (yes/no)? (It is assumed that all registered trials will be approved by an ethics board before commencing.) 12. Condition The medical condition being studied (e.g., asthma, myocardial infarction, depression). 13. Intervention(s) A description of the study and comparison/control intervention(s) (for a drug or other product registered for public sale anywhere in the world, this is the generic name; for an unregistered drug the generic name or company serial number is acceptable). The duration of the intervention(s) must be specified. 14. Key inclusion and exclusion criteria Key patient characteristics that determine eligibility for participation in the study. 15. Study type Database should provide drop-down lists for selection. This would include choices for randomized vs. non-randomized, type of masking (e.g., double-blind, single-blind), type of controls (e.g., placebo, active), and group assignment, (e.g., parallel, crossover, factorial). 16. Anticipated trial start date Estimated enrollment date of the first participant. 17. Target sample size The total number of subjects the investigators plan to enroll before closing the trial to new participants. 18. Recruitment status Is this information available (yes/no) (if yes, link to information). 19. Primary outcome The primary outcome that the study was designed to evaluate. Description should include the time at which the outcome is measured (e.g., blood pressure at 12 months).
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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary 20. Key secondary outcomes The secondary outcomes specified in the protocol. Description should include time of measurement (e.g., creatinine clearance at 6 months). *The data fields were specified at a meeting convened by the WHO in April 2004; the explanatory comments are largely from the ICMJE. Acceptable completion of data fields is an important concern. It shouldn’t be, but it is. Many entries in the publicly accessible clinicaltrials.gov database do not provide meaningful information in some key data fields. A search conducted on May 4, 2005 (ZarinD.: personal communication) indicates that certain pharmaceutical-company entries list a meaningless phrase (e.g., “investigational drug”) in place of the actual name of the drug, even though a U.S. law requires trial registrants to provide “intervention name” (www.fda.gov/cder/guidance/4856fnl.htm). Many companies and other entities are completing the data fields in a meaningful fashion. Data entries must include information that will be of value to patients and health professionals; the intervention name is needed if one is to search on that intervention. We recognize that clinical trial registries have many uses, but whatever the use, a worldwide uniform standard for a minimal database is necessary. We have participated in the WHO effort to establish a clinically meaningful trial registration process. The ICMJE supports this ongoing project. When it is complete we will evaluate the process, and if it meets our primary objectives, we will adopt it. We stated our requirements for an acceptable trial registry in the September 2004 editorial, and they remain the same. The registry must be electronically searchable and accessible to the public at no charge. It must be open to all registrants and not for profit. It must have a mechanism to ensure the validity of the registration data. The purpose of a clinical trials registry is to promote the public good by ensuring that everyone can find key information about every clinical trial whose principal aim is to shape medical decision making. We will do what we can to help reach this goal. We urge all parties to register new and ongoing clinical trials. If in doubt about whether a trial is “clinically directive,” register it. Don’t use meaningless phrases to describe key information. Every trial participant and every investigator should be asking, “Is this clinical trial fully registered?”
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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary Catherine D.De Angelis, M.D., M.P.H. Editor-in-Chief, Journal of the American Medical Association Jeffrey M.Drazen, M.D. Editor-in-Chief, New England Journal of Medicine Frank A.Frizelle, M.B., Ch.B., M.Med.Sc., F.R.A.C.S. Editor, The New Zealand Medical Journal Charlotte Haug, M.D., Ph.D., M.Sc. Editor-in-Chief, Norwegian Medical Journal John Hoey, M.D. Editor, Canadian Medical Association Journal Richard Horton, F.R.C.P. Editor, The Lancet Sheldon Kotzin, M.L.S. Executive Editor, MEDLINE, National Library of Medicine Christine Laine, M.D., M.P.H. Senior Deputy Editor, Annals of Internal Medicine Ana Marusic, M.D., Ph.D. Editor, Croatian Medical Journal A.John P.M. Overbeke, M.D., Ph.D. Executive Editor, Nederlands Tijdschrift voor Geneeskunde (Dutch Journal of Medicine) Torben V.Schroeder, M.D., D.M.Sc. Editor, Journal of the Danish Medical Association Harold C.Sox, M.D. Editor, Annals of Internal Medicine Martin B.Van Der Weyden, M.D. Editor, The Medical Journal of Australia
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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary REFERENCE De Angelis C, Drazen JM, Frizelle FA, et al. 2004. Clinical trial registration: A statement from the International Committee of Medical Journal Editors. New England Journal of Medicine 351:1250–1251. Original editorial available at www.ICMJE.com.
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