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Current Registry Activities

CLINICALTRIALS.GOV: CURRENT CLINICAL TRIAL DISCLOSURE REQUIREMENTS

All entities that conduct clinical trial research on drugs that may be marketed in the United States are required by law to disclose the clinical research data pertaining to the development of that product to the U.S. Food and Drug Administration (FDA) in order to file a New Drug Application or Biological License Application. Before any compound may be given to humans, several factors must be reviewed and approved by the FDA: the hypothesis being tested, details of the research protocol including primary and secondary endpoints, and the biologic and chemical properties of the compound. The FDA continues to review a drug’s development, authorize its continuation or not, and ultimately approve its use in humans—a process that takes an average of 10 years.

Since February 2000, all entities (whether federally or privately funded) conducting clinical trials of experimental treatments (drugs or biologics) for serious or life-threatening diseases and conditions have been required to submit certain information to the public clinical trial registry ClinicalTrials.gov. This registry was established by the Department of Health and Human Services’ (DHHS’s) National Library of Medicine as a result of Section 113 of the FDA Modernization Act of 1997 (see Appendix C). ClinicalTrials.gov was established to allow patients, health care providers, and researchers to explore options for or enroll in relevant clinical trials.

Table 3–1 shows the information as currently defined that must be submitted to ClinicalTrials.gov within 21 days of first patient enrollment for all clinical trials involving serious and life-threatening diseases and conditions.



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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary 3 Current Registry Activities CLINICALTRIALS.GOV: CURRENT CLINICAL TRIAL DISCLOSURE REQUIREMENTS All entities that conduct clinical trial research on drugs that may be marketed in the United States are required by law to disclose the clinical research data pertaining to the development of that product to the U.S. Food and Drug Administration (FDA) in order to file a New Drug Application or Biological License Application. Before any compound may be given to humans, several factors must be reviewed and approved by the FDA: the hypothesis being tested, details of the research protocol including primary and secondary endpoints, and the biologic and chemical properties of the compound. The FDA continues to review a drug’s development, authorize its continuation or not, and ultimately approve its use in humans—a process that takes an average of 10 years. Since February 2000, all entities (whether federally or privately funded) conducting clinical trials of experimental treatments (drugs or biologics) for serious or life-threatening diseases and conditions have been required to submit certain information to the public clinical trial registry ClinicalTrials.gov. This registry was established by the Department of Health and Human Services’ (DHHS’s) National Library of Medicine as a result of Section 113 of the FDA Modernization Act of 1997 (see Appendix C). ClinicalTrials.gov was established to allow patients, health care providers, and researchers to explore options for or enroll in relevant clinical trials. Table 3–1 shows the information as currently defined that must be submitted to ClinicalTrials.gov within 21 days of first patient enrollment for all clinical trials involving serious and life-threatening diseases and conditions.

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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary TABLE 3–1 Required Data Fields for the DHHS Clinical Trial Registry at ClinicalTrials.gov Unique Protocol ID Number Study Sponsor Verification Date Brief Title (in lay language) Brief Summary (in lay language) Study Design, Study Phase, Study Type Condition or Disease Intervention Study Status Eligibility Criteria/Gender/Age Location of Trial Contact Information Although ClinicalTrials.gov has been a valuable tool to enable patients and health care providers to understand the research occurring in various therapeutic areas and to locate clinical trials in which to enroll, it has certain limitations within its legislative mandate: It applies only to serious and life-threatening conditions. There is no mechanism to ensure compliance by all entities performing clinical trials. It does not include disclosure of study results. Required data fields are not always completed in an informative manner. For these reasons, several groups have called for the mandatory registration of additional clinical trials as well as the registration of more extensive clinical trial information and the posting of a summary of clinical trial results. In addition, a number of clinical trial registries have been created in the public sector and by several pharmaceutical companies. The most prominent, and probably influential, proposals for registry requirements—by the International Committee of Medical Journal Editors (ICMJE), the international pharmaceutical industry and, most recently, the World Health Organization (WHO)—were presented at the workshop and are described below.

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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary INTERNATIONAL COMMITTEE OF MEDICAL JOURNAL EDITORS Harold Sox, Editor of Annals of Internal Medicine, gave a presentation on steps taken by the editors of 13 major international medical journals to promote clinical trial registration. In a joint statement entitled “Clinical Trial Registration: A Statement from the International Committee of Medical Journal Editors” that was published concurrently in their journals in September 2004 (see Appendix D), the editors announced that their journals would require registration of a clinical trial as a condition of consideration for publication beginning July 1, 2005. In an editorial (also in Appendix D) published on June 9, 2005, the ICMJE reiterated its position and endorsed the new proposal by WHO (see below), which has similar elements. Specifically, the editors called for the registration of trials at or before the onset of patient enrollment. The ICMJE defines a clinical trial as “any research project that prospectively assigns human subjects to intervention and has at least one prospectively assigned concurrent control or comparison group to study the cause-and-effect relationship between an intervention designed to modify a health outcome and the health outcome.” Studies designed for other purposes, such as to study pharmacokinetics or major toxicity (i.e., Phase I trials), would be exempt. The ICMJE policy does not require reporting of clinical trial results. Table 3–2 lists the specific data fields required by the ICMJE. TABLE 3–2 Data Fields Required by the ICMJE as a Condition of Publication 1. Unique Trial Number 11. Research Ethics Review 2. Trial Registration Date 12. Condition 3. Secondary IDs 13. Intervention(s) 4. Funding Source(s) 14. Key Inclusion and Exclusion Criteria 5. Primary Sponsor(s) 15. Study Type 6. Secondary Sponsor(s) 16. Anticipated Trial Start Date 7. Responsible Contact Person 17. Target Sample Size 8. Research Contact Person 18. Recruitment Status 9. Title of the Study 19. Primary Outcome 10. Official Scientific Title of the Study 20. Key Secondary Outcomes

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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary JOINT PHARMACEUTICAL INDUSTRY POSITION In describing the joint position published by the international pharmaceutical industry, Dr. Alan Breier, Vice President, Medical and Chief Medical Officer, Eli Lilly and Company, noted that the U.S. pharmaceutical industry had been considering guidelines for registries before the international position was adopted. In October 2002, the Pharmaceutical Research and Manufacturers of America (PhRMA) developed a voluntary set of principles to communicate the guidelines by which the pharmaceutical industry would conduct clinical trials and how results would be communicated. These principles were revised in June 2004. In January 2005, the international pharmaceutical industry, represented by the European Federation of Pharmaceutical Industries and Associations (EFPIA), the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA), the Japanese Pharmaceutical Manufacturers Association (JPMA), and PhRMA, released a consensus global policy entitled “Joint Position on the Disclosure of Clinical Trial Information via Clinical Trial Registries and Databases” (see Appendix E). This joint position was developed, in part, in response to the requirements set forth by the ICMJE. The Joint Position of the pharmaceutical industry calls for expansion of the existing DHHS clinical trial registry, ClinicalTrials.gov, to include the ICJME-required information (see Table 3–2) not just for serious and life-threatening conditions, but for all studies except exploratory studies, when a trial is initiated. Registration would occur within 21 days of the initiation of patient enrollment. To reduce occurrence of “the file drawer phenomenon,” the joint pharmaceutical industry position also committed to make the following outcomes information available on a public registry: The results of all clinical trials, other than exploratory trials, conducted on a drug that is approved for marketing and is commercially available in at least one country will be registered, regardless of outcome. If trial results for an investigational product that has failed in development have significant medical importance, sponsors will post if possible. If trial results are published in a peer-reviewed medical journal, the database will include a citation or link to the journal article and/or a summary of the results in a standard, nonpromotional

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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary format, such as the ICH E3 summary format (see Appendix F), that includes a description of the trial design and methodology, results of the primary and secondary outcome measures, and safety results. Differences between the published positions of the ICMJE and the pharmaceutical industry (e.g., when to report primary and secondary outcome measures) offered further evidence of the need to reach some consensus or conciliation of expectations and wishes regarding clinical registries and clinical trial reporting. THE WORLD HEALTH ORGANIZATION PROJECT As the IOM was carrying out its discussions, WHO began work to set standards for a global clinical trial registry platform that would act as an umbrella for existing national registries. At the June 27 IOM workshop, a WHO representative presented the international position on clinical trial registration developed in April 2005 by global representatives of the medical journals, academia, public health, regulatory arena, the Cochrane Collaboration, and the pharmaceutical industry. The WHO registry position calls for registration of “any research project that prospectively assigns human participants or groups to one or more health-related interventions to evaluate the effects on health outcomes.” It excludes exploratory studies that are not designed to influence health practice and that serve only to set direction for future testing. The stakeholders convened by WHO agreed on a set of 20 data items that should be included with each registered trial. After soliciting public comments, WHO issued, in October 2005, a revised list of data items for what they call the International Clinical Trials Registry Platform. Both versions are shown in Table 3–3. According to the June 27 presentation by WHO scientist Metin Gulmezoglu, the registry project has five objectives: Provide standards for trial registration and results disclosure Launch a linked network of certified registers with global search capability and unique numbering system Advocate for compliance with registry requirements Advise and help build registry capacity Establish a self-funded business model by 2006

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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary TABLE 3–3 WHO Minimum Data Set Item # Original (April 2005) Version 2.2 (October 21, 2005) 1 Unique Trial Number Primary Register and Trial ID 2 Trial Registration Date Date of Registration in Primary Register 3 Secondary IDs Secondary IDs 4 Funding Source(s) Funding Source(s) 5 Primary Sponsor Primary Sponsor 6 Secondary Sponsor(s) Secondary Sponsor(s) 7 Responsible Contact Person Responsible Contact Person 8 Research Contact Person Research Contact Person 9 Title of the Study Public Title 10 Official Scientific Title of the Study Scientific Title 11 Research Ethics Review Research Ethics Review 12 Condition Disease or Condition Studied 13 Intervention(s) Intervention(s) 14 Key Inclusion and Exclusion Criteria Key Inclusion and Exclusion Criteria 15 Study Type Study Type 16 Anticipated Trial Start Date Date of First Enrollment 17 Target Sample Size Target Sample Size 18 Recruitment Status Recruitment Status at Time of UTRN [Universal Trial Reference Number] Request 19 Primary Outcome Primary Outcome(s) 20 Key Secondary Outcomes Secondary Outcomes *WHO identified Data Items 10, 13, 17, 19, and 20 as ones for which a sponsor might wish to delay release of the information. WHO plans to convene a group to develop a mechanism to advise on requests to delay release of one or more data items until a specified date. Local registries would be certified by a central office against certain specifications. Dr. Gulmezoglu expects that national registries, disease-based registries, and other certified registries would join. Local registries could be created in local languages, but the minimum data set information would be transmitted to the central registry in English. The registry would have a search function within a minimum data set. Results would be linked when a trial is completed. WHO plans to provide training and capacity building for national initiatives and for the pharmaceutical industry.

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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary FEDERAL AND STATE LEGISLATION The need for a publicly accessible clinical trial registry has become a legislative focus. At the federal level, three different Fair Access to Clinical Trial Information (FACT) Acts have been introduced in the House and Senate. At the state level, 55 bills have been introduced in 20 states calling for the registration of clinical trial information. However, state-by-state legislation on this topic would become a significant hurdle for drug development because many clinical trials involve patients in numerous states. Kate Reinhalter, Legislative Assistant in Rep. Edward Markey’s [D-MA] office, stated that federal legislation is necessary to ensure uniform standards and compliance. She described some points from a bill that Reps. Markey and Rep. Henry Waxman [D-CA] have since introduced as the most recent FACT Act (H.R. 3196) (see http://thomas.loc.gov/homr/gpoxmic109/h3196_ih.xml). The bill would create a database that expands on ClinicalTrials.gov. Sponsors of privately and publicly funded clinical trials would be required to provide public access to basic information on studies before they begin and to provide public access to the results of clinical studies, including primary and secondary outcomes and significant adverse events. It would also create penalties for noncompliance. SUMMARY OF FEATURES OF CURRENT AND PROPOSED REGISTRIES The narratives above show there are many similarities and few points of contention among the groups that have proposed or endorsed the establishment of a national clinical trial registry. Table 3–4 summarizes their positions on information posted at initiation of the trial, information posted when the trial is complete, and compliance.

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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary TABLE 3–4 Comparison of Registry/Disclosure Policies Organization/Sponsor Registry: Trials Posted When Initiated Results Database: Information Posted When Trial Completed How Compliance Is Verified Trial Phase Information Posted Trial Phase Format Product Scope ICMJE Clinical trials testing cause and effect. Excludes Phase I. Some Phase II determined case by case by journal editor. Same as the WHO minimal data set of 20 items (see below). N/A N/A Any product for which publication is desired. Will consider a trial for publication only if it is registered before enrollment of first patient, or by 9/13/05. PhRMA All hypotheses-testing clinical trials will be posted at initiation to the registry, www.ClinicalTrials.gov. Provide information consistent with www.ClinicalTrials.gov: Brief title, trial description, trial phase, trial type, trial status, trial purpose, intervention type, condition or disease, key eligibility criteria, location of trial, and contact information. Hypothesis-testing clinical trial results posted to www.ClinicalStudyResults.org. Reference citation unless results on marketed product have not been published; then provide a clinical trial summary. Product marketed or intended for marketing in United States. Posting is voluntary. Registry policy states, “Members will establish a process of verification and make public how they adhere to these standards.” Joint Position of the Pharmaceutical Industry All clinical trials except exploratory to www.ClinicalTrials.gov. Provide information consistent with www.ClinicalTrials.gov: Brief title, trial description, trial phase, trial type, trial status, trial purpose, intervention type, condition or disease, key eligibility criteria, location of trial, and contact information. All clinical trials except exploratory posted to a publicly accessible database. Clinical trial summary AND/OR reference citation. Product marketed anywhere in the world. Companies will establish a process of verification and make public how they adhere to these standards.

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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary Fair Access to Clinical Trials Act Rep. Waxman with 36 cosponsors—H.R. 3196 Excludes trials designed to detect major toxicity and pharmacokinetics (except in special populations). Primary and secondary endpoints, eligibility criteria, trial dates, number of subjects, and Principal Investigator information. Medical condition; scientific title with name of intervention, condition, and outcome under study; ethics review; start date; purpose; eligibility criteria; funding source; statement that product is unapproved or approved but investigated for what use; completion date; primary and secondary outcomes; hypothesis being tested; total subjects; contact information; study design; methods; phase; type; note of any restrictions on results discussion; periodic updates. All clinical trials except those designed to detect major toxicity and pharmacokinetics (except in special populations). Structured abstract determined by (Q: DHHS?) Secretary. Results will include: primary and secondary outcomes presented as quantitative data, AE data, demographic data, and trial dates. All products, approved or unapproved. Secretary will audit; posting at initiation required for IRB approval. Civil monetary penalties, public notification of noncompliance. World Health Organization (from WHO website, http://www.who.int/ictrp/results/en/, accessed 10/21/05) Excludes exploratory studies. Trial ID number, date of registration, secondary ID numbers, funding sources, primary sponsor, secondary sponsor, contact persons, public title, scientific title,* research ethics review, condition studied, intervention(s),* inclusion/exclusion criteria, study type, date of first enrollment, target sample size,* recruitment status at time of Universal Trial Reference Number request, primary* and secondary* outcomes. Registers are encouraged but not required to provide links to trial results. “Results reporting remains a top concern of the Registry Platform and will be addressed in more detail starting in mid-2006.” At least as much detail as ICH-E3 format. Products marketed anywhere in the world as well as products in development. WHO will advocate for compliance. * Delayed reporting may be considered for these items.

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