For other versions of this document, see http://wikileaks.org/wiki/CRS-RL32832 ------------------------------------------------------------------------------ Order Code RL32832 Clinical Trials Reporting and Publication Updated July 12, 2007 Erin D. Williams Specialist in Bioethical Policy Domestic Social Policy Division Clinical Trials Reporting and Publication Summary The central issue before Congress with respect to clinical trials reporting and publication is how to balance the potential beneficial public health effects of requiring that clinical trials data be made public with the burdens that such requirements may place on companies and their innovation. Clinical trials, which are conducted regularly to test the effects of new pharmaceuticals and medical devices, cost a significant amount of money, and by their nature may present some risk to the people who participate in them. Manufacturers as well as medical journal editors have been reluctant to publish clinical trial data indicating that products in development are harmful or ineffective. The availability of such information might save a duplication of effort and studies that harm or fail to help patients. While current federal regulations require the publication of some clinical trials data, and some private entities have taken steps to encourage publication, there is no requirement that the public have access to all standardized clinical trials data -- be it notice of trial launch or research results through a centralized system such as a registry. Food and Drug Administration (FDA) regulations require sponsors of trials that test the effectiveness of new drugs for serious or life-threatening conditions to register with the Department of Health and Human Services (HHS) at [http://clinicaltrials.gov/], although not all such trials are listed there. Clinical trial data from National Institutes of Health (NIH)-funded research may be made public through a Freedom of Information Act request only if the findings were used by the federal government in developing an agency action that has the force and effect of law. The International Committee of Medical Journal Editors (ICMJE) requires, for publication of clinical trial results, that a sponsor have posted its trial in a public registry before enrolling patients. A voluntary registry of recent controlled trials results was created in October 2004 by the Pharmaceutical Research and Manufacturers of America (PhRMA). Proposals for public access to all or most clinical trial data raise a variety of issues. These relate to the goals of providing public access, the appropriateness of the information and its presentation for the audience, the timing of a trial's inclusion, whether reporting should be mandatory, potential conflicts of interest, and whether medical device trials should be included. Nine relevant bills have been introduced during the 110th Congress, two of which also reauthorize key Food and Drug Administration programs. These bills are the Food and Drug Administration Revitalization Act (S. 1082), which the Senate passed on May 9, 2007, and the Food and Drug Administration Amendments Act of 2007 (H.R. 2900), which the House passed on July 11, 2007. Both bills would require the registration of clinical trials, some of which must currently be registered at [http://clinicaltrials.gov]. H.R. 2900 would also require the subsequent posting of clinical trial results. Differences between the two bills are expected to be addressed in conference. Seven other bills also contain relevant provisions: S. 467, S. 484/H.R. 1561, S. 468/H.R. 788, and S. 830/H.R. 1494. This report will be updated on a regular basis. Contents Introduction: Current Federal Regulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Clinical trials are the gold standard . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Federal regulations require the publication of certain clinical trial information and encourage the disclosure of some results . . . 3 Non-Federal Activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 World Health Organization (WHO) promotes trial registry standards, portal, and registration of all clinical trials . . . . . . . . . . 5 The International Committee of Medical Journal Editors (ICMJE) Clinical Trial Publication Policy requires registration . . . . . . . . . . 6 American Medical Association (AMA) recommends a comprehensive clinical trials registry . . . . . . . . . . . . . . . . . . . . . . . 7 The Association of American Medical Colleges (AAMC) develops principles for clinical trials reporting . . . . . . . . . . . . . . . 7 The Institute of Medicine (IOM) supports mandatory trial registration and results reporting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 The pharmaceutical industry favors limited, voluntary clinical trial registration and reporting . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Legislation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 FDA User Fee Reauthorization Legislation (S. 1082 and H.R. 2900) . . . . . 9 Other Clinical Trials Bills . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Registry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Results Database . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Goals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Appropriateness/Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Timing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Voluntary or Mandatory/Penalties . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Conflicts of Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Appendix A. World Health Organization, International Clinical Trials Registry Platform, Registration Data Set (Version 1.0) . . . . . . . . . . . . . . . . 35 List of Tables Table 1. Comparison of Proposals for Clinical Trials Reporting and Publication in the 110th Congress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Clinical Trials Reporting and Publication Introduction: Current Federal Regulations In 2004, Congress and others raised questions about the safety and effectiveness of several FDA-approved biomedical products on the market. These included certain antidepressants, Merck's pain relief drug, Vioxx, Boston Scientific's cardiac stents, and other drugs and medical devices. Discussion about ways to help ensure safety and effectiveness of biomedical products focused primarily on two questions: whether data from all clinical trials should be made publicly available, and whether FDA's processes for product approval and post-market surveillance and study are adequate. This report focuses on the first of these questions.1 The central issue before Congress with respect to clinical trials reporting and publication is how to balance the potential beneficial public health effects of requiring that clinical trials data be made public with the burdens that such requirements may place on companies and their innovation. On one hand, companies may lose a competitive advantage if their competitors are alerted to their clinical trials activities and failures. On the other hand, the public may be harmed if a particular type of clinical trial is repeated -- particularly if an earlier trial demonstrated that a product was ineffective or harmful. In addition, if clinical trial data are to be made public, the timing and contents of the disclosure may prove to be pivotal, both with respect to competitive innovation and public safety. Clinical trials reporting can mean public access to results after a trial's conclusion, to a proposed plan before a trial is begun, or both. There is no centralized system for either type of reporting; thus, different trials may have the same title, one trial may be reported in several places under different titles, and many trials are never reported. Researchers have traditionally reported pre- and post- market trial results in peer-reviewed medical journals, which have historically tended to favor publication of clinical trials demonstrating successful intervention; the results of negative or inconclusive trials often go unpublished.2 Other venues for the dissemination of research results are industry, government, or university press releases and presentations at medical conferences. Researchers -- who may be affiliated with a product's manufacturer, a university, the government, or an association established to find better treatments for a particular disease -- may have various motives for publishing or not publishing results. Some observers have 1 For further information about whether FDA's processes for product approval and post-market surveillance and study are adequate, see CRS Report RL32797, Drug Safety and Effectiveness: Issues and Action Options After FDA Approval, by Susan Thaul. 2 "Pressure Mounts for Clinical Trial Registry," Medicine & Health, vol. 58, no. 24 (June 21, 2004), pp. 2-3. CRS-2 expressed concern that a lack of transparency, particularly for negative data, could adversely affect medical decision-making.3 The lack of transparency may be amplified in part by sponsors' contractual requirements of their researchers. This concern was raised by two May 2005 medical journal articles, suggesting that contractual "gag" clauses might prohibit clinical trial investigators from examining data independently or submitting a manuscript for publication without first obtaining the consent of trial sponsors. According to one of the articles, sponsors with a financial interest in the outcomes of clinical research could thus suppress negative results and interfere with the publication of unfavorable data on safety.4 The other article, which described results from a survey of medical school research administrators responsible for negotiating clinical trial agreements with industry sponsors, reported that industry provides approximately 70% of funding for clinical drug trials in the United States.5 The survey results suggested that 85% of the administrators' offices would not approve provisions that gave industry sponsors the authority to revise manuscripts or to decide whether results should be published. Administrators' responses varied regarding whether contracts could contain provisions allowing sponsors to insert their own statistical analyses in manuscripts, draft manuscripts, or prohibit investigators from sharing data with their parties after the trial's conclusion. In order to fully understand the debate surrounding clinical trials reporting and publication, a basic understanding of clinical trials themselves and of the current federal requirements -- both of which are presented below -- is essential. The slate of issues that frequently arise during discussions of clinical trials reporting and publication, all of which are addressed below in the "Issues" section of this report, include questions related to the goals of publication, the materials' appropriateness and presentation, the timing the disclosures, whether disclosure should be voluntary or mandatory with penalties, overcoming potential conflicts of interest, and whether medical devices should be included in reporting requirements. Clinical trials are the gold standard. Clinical trials, which are the gold standard for assessing drug and device safety and effectiveness both before and after they are marketed in the United States, are scientific studies that systematically test interventions on human beings. They may include behavioral studies or other biomedical investigations, such as those that test drugs and medical devices. As described by FDA, clinical trials are generally conducted in four phases following successful animal testing.6 Phase I trials study a new drug or device in a small group 3 Robert Steinbrook, "Public Registration of Clinical Trials," JAMA, vol. 351, no. 4 (July 22, 2004), p. 315. 4 Robert Steinbrook, "Gag Clauses in Clinical-Trial Agreements," New England Journal of Medicine, vol. 352, no. 21 (May 26, 2005), p. 2160. 5 Michelle Mello, et al., "Academic Medical Centers' Standards for Clinical-Trial Agreements with Industry," New England Journal of Medicine, vol. 352, no. 21 (May 26, 2005), p. 2202. 6 For further information on the role of federal agencies in evaluating biomedical products, (continued...) CRS-3 of people (20-80) to evaluate its safety, determine a dosage range for drugs, and identify gross side effects. Phase II trials study the product in a larger group of people (100-300) to see whether it is effective for a specific purpose and to further evaluate its safety. Phase III trials investigate the product in a large group of people (1,000-3,000), to confirm the product's effectiveness, monitor side effects, and collect information that will allow the drug, treatment or device to be used safely. Phase IV trials are usually large-scale studies, conducted after the FDA approves a product for marketing in order to demonstrate effectiveness in a broader clinical context and to watch for rare side effects that may not be identified until significant numbers of people have used the product. Federal regulations require the publication of certain clinical trial information and encourage the disclosure of some results. The federal government has historically regulated certain aspects of some clinical trials by attaching conditions to those conducted with federal research funds, and/or by creating requirements that must be met before a drug or device can be marketed in the United States. Most federal funding occurs through the Department of Health and Human Services' (HHS) National Institutes of Health (NIH). According to NIH's regulations issued pursuant to a provision in the Omnibus Consolidated and Emergency Supplemental Appropriations Act, 1999 (P.L. 105-277), research data relating to published research findings produced under an award that were used by the federal government in developing an agency action that has the force and effect of law -- a limited number of research results if any -- must be released if a Freedom of Information Act request is made.7 Beginning in May 2005, the NIH has requested that investigators with manuscripts that are accepted for publication, and that are the result of research supported in whole or in part with direct costs from NIH, submit them voluntarily to the National Library of Medicine's (NLM's) PubMed Central.8 (The NLM, which is located on the NIH campus in Bethesda, Maryland, is the world's largest medical library.) This effort would enables free access to results published elsewhere and would not facilitate access to previously undisclosed results. The NIH announcement was preceded by a July 2004 House committee recommendation that NIH provide free public access to the complete text of articles and supplemental materials generated by NIH-funded research.9 6 (...continued) see CRS Report RS21962, From Bench to Bedside: The Role of Health and Human Services (HHS) Agencies in the Evaluation of New Medical Products, by Michele Schoonmaker. 7 Uniform Administrative Requirements for Grants and Agreements With Institutions of Higher Education, Hospitals, and Other Non-Profit Organizations; Final Rule (Office of Budget Management, Circular A 110), Federal Register, Vol. 65, No. 52, Page 14406 (March 16, 2000), at [http://grants2.nih.gov/grants/policy/a110_fed_reg_20000316.pdf]. 8 National Institutes of Health, "Policy on Enhancing Public Access to Archived Publications Resulting from NIH-Funded Research," NOT-OD-05-022, February 2, 2005, at [http://grants2.nih.gov/grants/guide/notice-files/NOT-OD-05-022.html]. 9 U.S. Congress, House Committee on Appropriations, Departments of Labor, Health and Human Services, and Education and Related Agencies Appropriations Bill, 2005, report to (continued...) CRS-4 Both pre-market approval and post-market monitoring of medical drugs and devices marketed in the U.S. are the responsibility of HHS's FDA. Each FDA center that reviews and approves biomedical products for human use -- the Center for Drug Evaluation and Research, the Center for Devices and Radiological Health, and the Center for Biologics Evaluation and Research -- posts summaries of safety and effectiveness data from clinical trials that support approved applications for new products, or new uses of approved products; FDA does not otherwise post clinical trials data. The FDA Modernization Act of 1997 (FDAMA, P.L. 105-115, Section 113) required the Secretary of HHS to establish a clinical trials registry, intending the availability of information to increase the access of individuals to cutting-edge medical care available only through research protocols. Sponsors of trials testing the effectiveness of life-threatening disease or condition treatments (drugs, but not devices) that are being conducted to obtain FDA approval for marketing,10 under an expanded use protocol11 of an investigational new drug application to FDA, or on Group C12 cancer drugs are required to register. In addition, any trial (drug, device, or other) that has been approved by a human subject review board (or equivalent) and conforms to the regulations of the appropriate national or international health authority may also be included. In response to FDAMA, the NLM established a clinical trials registry and made it available to the public in 2000 [http://clinicaltrials.gov]. It was later reported that an FDA analysis found that in 2002 only 48% of trials of cancer drugs had been registered, and a preliminary review indicated the listing rate for drugs for some other serious diseases is in the single digits. Some companies had reportedly listed no studies; some trials were listed without identifying the sponsoring company or the drug being tested.13 In March 2002, FDA issued a guidance document, instructing 9 (...continued) accompany H.R. 5006, 108th Cong., 2nd sess., H.Rept. 108-636 (Washington, GPO, 2004). 10 Pursuant to 21 U.S.C. § 355(i). 11 An expanded use protocol is one that allows for widespread patient access to an investigational new drug not yet approved for marketing, when the drug has shown promise for treating a serious or life-threatening condition, there is no comparable or satisfactory alternative therapy, and the sponsor is actively pursuing permission to market the drug (21 U.S.C. § 360bbb(c)). 12 Group C "was established by agreement between FDA and the National Cancer Institute (NCI). The Group C program is a means for the distribution of investigational agents to oncologists for the treatment of cancer under protocols outside the controlled clinical trial. Group C drugs are generally Phase 3 study drugs that have shown evidence of relative and reproducible efficacy in a specific tumor type. They can generally be administered by properly trained physicians without the need for specialized supportive care facilities. Group C drugs are distributed only by the National Institutes of Health under NCI protocols." Information Sheets: Guidance for Institutional Review Boards and Clinical Investigators,1998 Update, Drugs and Biologics, FDA, at [http://www.fda.gov/oc/ohrt/irbs/ drugsbiologics.html]. 13 Shankar Vedantam, "Drugmakers Prefer Silence on Test Data," Washington Post, July 6, (continued...) CRS-5 industry how and when to participate in the registry [http://www.fda.gov/cder/ guidance/4856fnl.htm]. A 2005 survey conducted by FDA's Office of Special Health Issues indicated that 67% of companies required to register their trials had done so.14 The 2005 survey results were not comparable to those of 2002 due to methodological differences. It was reported that FDA did not plan to continue to monitor whether companies registered beyond 2006.15 In a July 2004 announcement unrelated to [http://clinicaltrials.gov/], the FDA announced that clinical trial sponsors could use a standard format, the Study Data Tabulation Model (SDTM) developed by the nonprofit organization Clinical Data Interchange Standards Consortium (CDISC), to submit clinical trials data to the agency [http://www.cdisc.org/index.html]. While the data would not necessarily be made public, according to the FDA, providing a consistent framework and format for clinical trial information is expected to enhance data integration opportunities and thereby reduce data management barriers for sharing the latest clinical trial data.16 Non-Federal Activities A number of national and international groups recommended that clinical trial reporting be centralized, standardized, and/or include both positive and negative results, and have taken steps toward that goal. World Health Organization (WHO) promotes trial registry standards, portal, and registration of all clinical trials. In May 2006, the WHO, the United Nations specialized agency for health which supports and funds much of the international research on marginalized populations, began urging research institutions and companies to register all medical studies that test treatments on human beings, including the earliest studies, whether they involve patients or healthy volunteers.17 This dovetails with another WHO initiative: the International Clinical Trials Registry Platform (ICTRP), which aims to standardize the way information on medical studies is made available to the public. As a part of the ICTRP, WHO has 13 (...continued) 2004, p. A1. 14 "FDAMA Section 113: Status Report on Implementation," FDA Office of Special Health Issues, August 2005, at [http://www.fda.gov/oashi/clinicaltrials/section113/113report/ default.htm]. 15 "FDA to Stop Tracking Industry Compliance With Clinical Trial Registry," Inside Washington Publishers, September 26, 2006. 16 "FDA Announces Standard Format That Drug Sponsors Can Use to Submit Human Drug Clinical Trial Data," FDA News, July 21, 2004, at [http://www.fda.gov/bbs/topics/ news/2004/NEW01095.html]. 17 "The World Health Organization announces new standards for registration of all human medical research," World Health Organization website, May 19, 2006, [http://www.who. int/mediacentre/news/releases/2006/pr25/en/index.html]. CRS-6 recommended that 20 key details -- such as title, funding source, research ethics review, and outcome measures -- be disclosed at the time studies are begun, that a Universal Trial Reference Number be assigned to each trial, and that minimum standards for the reporting of trial results be defined. (See Appendix A for a complete list of key details.) As the ICTRP progresses, WHO plans to launch a one-stop Search Portal for searching compatible registries worldwide.18 Some organizations have voiced opposition to the WHO efforts. The Pharmaceutical Research and Manufacturers of America (PhRMA) has reportedly opposed publicizing information early in the clinical trial, arguing that disclosing early research data does little to help doctors and patients, and may impede innovation by alerting competitors to companies' activities.19 For similar reasons, the Advanced Medical Device Medical Technology Association (AdvaMed) has reportedly attempted unsuccessfully to allow device firms to delay disclosure of some required data elements.20 AdvaMed argued that the issue was more pronounced for device than drug manufacturers because device development process is iterative, involving improvements over a period of time. Since April 2004, all clinical trials approved by the WHO ethics review board have been required to be registered at their outset and assigned a unique identification number.21 A London-based group of biomedical publishing companies agreed to maintain a no-charge, online register of these numbered trials at [http://www.controlled-trials.com] to identify and track them throughout their life cycle. The system was designed to avoid the problem of publication bias by posting information on trial starts and their results. The International Committee of Medical Journal Editors (ICMJE) Clinical Trial Publication Policy requires registration. The ICMJE consists of the editors of 12 major journals, including the New England Journal of Medicine, The Lancet, and the Journal of the American Medical Association. In order for a sponsor to have its clinical trial results published in one of the ICMJE journals, the ICMJE requires it to have posted its trial in a public registry before enrolling patients.22 The policy applies to any trial that started recruiting human subjects on or after July 1, 2005. The ICMJE did not advocate any particular registry, but cited 18 "International Clinical Trials Registry Platform" World Health Organization website, May 19, 2006, [http://www.who.int/ictrp/en/]. 19 "PhRMA Opposes UN Plan for Trial Data Disclosure," Inside Washington Publishers, May 30, 2006. 20 "AdvaMed, WHO at Odds Over Global Trial Registry Standards," Inside Washington Publishers, July 19, 2006. 21 Gerd Antes, "Registering clinical trials is necessary for ethical, scientific and economic reasons," Bulletin of the World Health Organization, May 2004, vol. 82, no. 5, at [http://www.who.int/bulletin/volumes/82/5/en/321.pdf]. 22 Catherine De Angelis et al., "Clinical Trial Registration: A Statement from the International Committee of Medical Journal Editors," New England Journal of Medicine, vol. 351, no. 12 (September 16, 2004), p. 1250, at [http://content.nejm.org/cgi/content/full/ 351/12/1250]. CRS-7 [http://clinicaltrials.gov/] as the only database currently meeting its requirements. In June 2005, the ICMJE specified the minimum set of data elements necessary for a trial to be considered fully registered, adopting the WHO list of 20 items.23 American Medical Association (AMA) recommends a comprehensive clinical trials registry. In an effort at dovetailing with the ICMJE requirements, in December 2004, the AMA House of Delegates committed the organization to take all appropriate action to protect the rights of physician researchers to present, publish, and disseminate data from clinical trials.24 In June 2004, the AMA recommended that HHS create a comprehensive, centralized clinical trials registry. The AMA further called on all institutional review boards to make registration in this database a condition of their approval of the bioethical aspects of clinical trials.25 Noting the AMA's position, Senators Tim Johnson and Christopher Dodd called for a national clinical drug trial registry in a July 8, 2004 letter to the heads of NIH and FDA.26 The Association of American Medical Colleges (AAMC) develops principles for clinical trials reporting. In January 2006, the AAMC Executive Committee approved a set of principles designed to promote standards for analyzing and reporting the results of sponsored clinical research.27 The principles include, among other things, that researchers have an ethical obligation to make their results public, that contracts with sponsors should require a good-faith effort to publish results, and that trials should be fully registered according to ICMJE standards within 21 days of their outset either in [http://clinicaltrials.gov/] or elsewhere. The Institute of Medicine (IOM) supports mandatory trial registration and results reporting. The IOM, a National Academies institute, conducted a workshop on developing a national clinical trials registry.28 Workshop participants presented a range of views on the need for registries, registry content, 23 Catherine DeAngelis et al., "Is This Clinical Trial Fully Registered?: A Statement from the International Committee of Medical Journal Editors," New England Journal of Medicine, vol. 352, no. 23 (June 9, 2005), p. 2436, and [http://www.icmje.org/ clin_trialup.htm]. 24 American Medical Association, "610. Physicians and Clinical Trials," December 2004 Resolutions, at [http://www.ama-assn.org/meetings/public/interim04/resolutions.pdf]. 25 Joseph M. Heyman, "AMA Encouraged by Early Signs of Industry Support for National Clinical Trials Registry," American Medical Association, press release, June 18, 2004, at [http://www.ama-assn.org/ama/pub/category/print/13909.html]. 26 "Senators Call for National Registry of Clinical Drug Trials," Senator Tim Johnson, press release, July 8, 2004, at [http://johnson.senate.gov/~johnson/releases/200407/2004708B20. html]. 27 Susan Ehringhaus and David Korn, "Principles for protecting Integrity in the Conduct and Reporting of Clinical Trials," Association ofAmerican Medical Colleges, January 6, 2007, at [http://www.aamc.org/research/clinicaltrialsreporting/clinicaltrialsreporting.pdf]. 28 Committee on Clinical Trials, Institute of Medicine of the National Academies, Developing a National Registry of Pharmacologic and Biologic Trials (Washington, DC: The National Academies Press, 2006), at [http://books.nap.edu/catalog/11561.html#toc]. CRS-8 implementation issues, and next steps. A separate draft publication published by IOM in 2006 recommended that Congress require industry drug sponsors to register phase 2-4 clinical trials at [http://clinicaltrials.gov/], and that initial postings be supplemented by a summary of safety and efficacy results.29 The pharmaceutical industry favors limited, voluntary clinical trial registration and reporting. The pharmaceutical industry's reaction to clinical trials reporting has been mixed, although as litigation and FDA and congressional interest have increased, some individual manufacturers and groups have volunteered to make some of their clinical trials data public. How the industry defines the types of trials to include (e.g., hypothesis-testing or late-phase only) could affect a registry's utility. Initially skeptical, PhRMA introduced its own clinical trials database in October 2004 at [http://www.clinicalstudyresults.org]. Companies that market drugs in the United States can voluntarily post the positive and negative results of controlled trials (mainly Phase III and IV studies) completed after October 2002 on the PhRMA database. As of April 16, 2007, 60 companies had posted results for 343 drugs. According to FDA, more than 10,000 drugs are approved for marketing in the United States. In January 2005, PhRMA additionally called for its members to voluntarily post all hypothesis-testing clinical trials on NLM's registry, clinicaltrials.gov. In January 2005, an international pharmaceutical federation of which PhRMA is a member, the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA), announced that its members would voluntarily disclose summary results of all industry-sponsored clinical trials.30 Trial results would be published in a standard, non-promotional summary that would include a description of trial design and methodology, results of primary and secondary outcome measures described in the protocol, and safety results. In October 2005, IFPMA announced that it had launched a search portal of clinical trial registries and databases worldwide.31 Legislation A number of bills related to clinical trials reporting and publication have been introduced in the 110th Congress. 29 Committee on the Assessment of the US Drug Safety System, Institute of Medicine of the National Academies, The Future of Drug Safety: Promoting and Protecting the Health of the Public, Advance Copy, Tuesday September 26, 2006, (Washington, DC: National Academies Press, 2006), at [http://books.nap.edu/books/0309103045/html]. 30 The announcement was made jointly with PhRMA, the European Federation of Pharmaceutical Industries and Associations (EFPIA), and the Japanese Pharmaceutical Manufacturers Association (JPMA). International Federation of Pharmaceutical Manufacturers and Associations (IFPMA), "Global Industry Position On Disclosure of Information About Clinical Trials," IFPMA Press Release, January 6, 2005, at [http://www.ifpma.org/News/NewsReleaseDetail.aspx?nID=2205]. 31 IFPMA, "IFPMA Improves Biomedical Data Transparency with Launch of First Worldwide Clinical Trials Portal," IFPMA Press Release, September 21, 2005, at [http://www.ifpma.org/clinicaltrials.html]. CRS-9 FDA User Fee Reauthorization Legislation (S. 1082 and H.R. 2900) Two major pieces of legislation, which would reauthorize FDA drug and medical device user fee authorities, contain clinical trials databank titles or subtitles. Each bill has been passed by its respective chamber of Congress, leaving differences between the bills to be addressed in conference. The Food and Drug Administration Reauthorization Act (S. 1082), introduced by Senator Kennedy, passed the Senate on May 9, 2007. The bill is composed of titles on the topics of reauthorizing the Prescription Drug User Fee Act and the Medical Device User Fee Act, promoting drug safety, encouraging the development of pediatric medical drugs and devices, addressing drug importation, promoting food safety, and enabling domestic pet turtle market access. One subtitle of the drug safety provisions (Title II, Subtitle C) would create a clinical trial registry and could lead to the creation of a results database following rulemaking by the HHS Secretary. The Food and Drug Administration Amendments Act of 2007 (H.R. 2900), introduced by Representative Pallone on June 28, 2007, passed the House on July 11, 2007. H.R. 2900 is similar to S. 1082, but does not contain provisions related to drug importation, food safety, or domestic pet turtle market access. Its title on clinical trials databanks (Title VIII) would require both the registration of clinical trials and the posting of their results. One controversial provision that was dropped from H.R. 2900 (and was never present in S. 1082) specified that Act would not have had any legal effect on -- and thus would have allowed -- causes of action for damages under state law. Other Clinical Trials Bills One bill introduced in the 110th Congress is solely focused on clinical trials registration and reporting: S. 467, the Fair Access to Clinical Trials (FACT) Act, introduced by Senator Dodd. Similar legislation was introduced in the 109th Congress by Senator Dodd (S. 470) and Representative Waxman (H.R. 3196), and in the 108th Congress by Senator Dodd (S. 2933) and Representative Markey (H.R. 5252). Several other bills focused on promoting drug and device safety at the FDA contain clinical trials databank provisions as well. The Enhancing Drug Safety and Innovation Act of 2007 (S. 484/H.R. 1561), introduced by Senator Enzi and Representative Waxman, is composed of titles designed to address the following topics at FDA: risk evaluation and mitigation strategies, the Reagan-Udall Institute for Applied Biomedical Research, clinical trials, and conflicts of interest. The clinical trials title of each bill contains provisions that would create a clinical trial registry and results database. Although many provisions of S. 484 and H.R. 1561 are identical, those related to clinical trials reporting and publication are different. Two other pieces of legislation with provisions related to clinical trials reporting and publication are the identical companion bills S. 468 and H.R. 788, the Food and Drug Administration Safety Act of 2007, introduced by Senator Grassley and Representative Tierney. This measure would establish a Center for Postmarket CRS-10 Evaluation and Research for Drugs and Biologics at FDA. It would enable the Center Director to require certain pre- and postmarket studies, and would require the HHS Secretary to make information about those studies available to the public. The remaining two bills with provisions related to clinical trials reporting and publication are the pediatric Medical Device Safety and Improvement Act of 2007 (S. 830 / H.R. 1484) introduced by Senator Dodd and Representative Markey. The bills would expand tracking of FDA pediatric device approvals, modify and tighten the humanitarian device exemption (which waives user fees associated with the FDA's review of medical device applications), require the NIH Director to designate a point of contact to assist those seeking funding for pediatric device development, create demonstration grants for improving pediatric device availability, amend regulations governing the office of pediatric therapeutics and the pediatric advisory committee, and enable the Secretary to order certain postmarket studies as a condition of approval of pediatric medical devices. The bills would also require the HHS Secretary, acting through the FDA Commissioner, to establish a database of clinical trials on pediatric devices. The database would include trials conducted in conjunction with the aforementioned postmarket studies, or with FDA premarket device approval, clearance, or qualification as for the humanitarian device exemption. Details of five proposals for clinical trials reporting and publication contained in S. 1082, H.R. 2900, S. 467, S. 484 and H.R. 1561 are discussed in the text that follows, and compared with current law in Table 1. Due to the narrow scope of the proposal for clinical trial publication contained in S. 830/H.R. 1484, it is not incorporated into the text or table. For similar reasons, S. 468/H.R. 788 is not incorporated into the table. For purposes of this report, the repository of clinical trial information submitted at the outset of the trial is referred to as a registry, and the repository of the trial conclusions is referred to as a results database. Registry. Current law: Only trials that meet all three of the following criteria must be included in the registry, clinicaltrials.gov: (1) The trial is testing a drug; (2) The trial is being conducted to obtain FDA approval for marketing, is conducted pursuant to an expanded use protocol of investigational new drug application to FDA, or is conducted on a Group C cancer drug; and (3) The trial tests treatments of serious or life-threatening conditions. Other trials that have been approved by a human subject review board (or equivalent) and conform to the regulations of the appropriate national or international health authority may also be included. Each of the legislative proposals would expand the scope of the current law, which requires only the registration of certain drug trials, to include trials related to biologics as well. All but S. 484 would also require the inclusion of medical device trials. S. 467 would also allow for the results of other types of trials to be voluntarily submitted. All but S. 467 would also expand the registry to include trials beyond those for the treatment of life-threatening diseases or conditions. Results Database. Current law: there is no requirement that the results of clinical trials be made publically available, except those included as a portion of what FDA publishes upon its approval of an application. CRS-11 Most of the bills (all but S. 1082) would require public disclosure of study results. S. 1082 would require the NIH Director to issue a report and HHS Secretary to create a rule based on that report regarding the best way to make clinical study results available to the public. Issues Issues surrounding the possibility of clinical trials reporting and publication have focused on a range of topics. Those topics are discussed below, with an accompanying analysis of the clinical trials reporting and publication provisions contained in S. 1082, H.R. 2900, S. 467, S. 484, H.R. 1561, and S. 468/H.R. 788. Goals. Proponents of public access to clinical trials data cite the need to provide information to members of the general public, health care workers, and researchers, both to help inform treatment decisions and to help eliminate abuses. Industry advocates have also cited the potential benefits of public awareness of the resources necessary to get a drug approved, and the elimination of duplicated failed efforts. PhRMA cites making clinical trial results for U.S.-marketed pharmaceuticals more transparent, and providing information to practicing physicians and their patients. Each of the legislative proposals aims to make information available and understandable to members of the public. Appropriateness/Presentation. Some have questioned whether registration and publication of clinical trials and their results are the best mechanism for ensuring patient safety, both because the language may be too technical for lay audiences, and because numerous trials may need to be viewed together in order to draw meaningful conclusions -- an analysis that would be difficult for many doctors as well. (A single clinical trial may generate thousands of pages of documentation.) These questions have led some to focus on how information might be presented in an audience-appropriate way. PhRMA's registry contains a link to drug labels, a bibliography, and a summary of results in a format developed by industry consensus.32 All of the bills would contain information accessible to both the general public and professionals. Three bills, H.R. 2900, S. 484 and H.R. 1561, have the additional specific requirement that the results database contain both a technical and a nontechnical summary report, which might meet the differing requirements of professionals and lay persons. Timing. Some have argued that only clinical study results are important to judging effectiveness, so publication of a trial's inception is not necessary. Others have argued that some registration at inception is necessary to avoid abuse, and is helpful for connecting potential subjects with various trials. FDAMA requires that notice of a qualifying trial be submitted to [http://clinicaltrials.gov/] no later than 21 days after the trial is open for enrollment. PhRMA's database only accepts results from completed trials. S. 1082 and S. 467 would generally require registration within 21 days that a trial is opened for enrollment. H.R. 2900, S. 484, and H.R. 1561 would require enrollment within 14 days after the first patient is enrolled, except for 32 Structure and Content of Clinical Study Reports; Guideline Approved by the International Conference on Harmonization, July 1996, at [http://www.fda.gov/cder/guidance/iche3.pdf]. CRS-12 medical device clinical trials. H.R. 2900 would not allow the public release of the information until the device is approved or cleared by FDA. S. 467/H.R. 788 would require that information about the study be posted not less frequently than every 90 days. For clinical trial results, H.R. 2900, S. 467, and H.R. 1561 would require them to be submitted within one year of the earlier of the trial's actual or estimated completion date. S. 484 would require results submissions not later than one year after the last patient has his or her last medical visit, and S. 467 / H.R. 788 would require results to be submitted upon completion of the study. All the bills except for S. 467 / H.R. 788 would allow for extensions for results submission in certain circumstances, such as when publication in a peer-reviewed journal is pending. S. 467 / H.R. 788 may also allow for such extensions by nature of the fact that the Director of the act-created Center for Postmarket Evaluation and Research for Drugs and Biologics would determine the studies completion date, and might therefore be capable of delaying the date if presented with good cause. S. 1082 does not create a results databank and, therefore, does not specify when results would have to be released. Voluntary or Mandatory/Penalties. Concerns about the potential regulatory burden on smaller drug and device manufacturers, as well as about the potential for intellectual property problems, have led some to call for voluntary registration and publication. The desire to protect public safety and to reduce abuse has led others to back mandatory reporting. PhRMA's registry is voluntary. The reporting proposed in all of the bills would be mandatory (with limited exceptions for trials not conducted on drugs, devices, or biological products and those completed before the bill's enactment) and would carry penalties for noncompliance. Conflicts of Interest. Some commentators have focused on the need for public disclosure of financial and other arrangements between researchers and sponsors in order to demonstrate potential conflicts of interest that may affect clinical trial design, interpretation of data, and presentation of results. The PhRMA database does not include information about funding relationships, though products there are identifiable by company, which may also be the trial funding source. All of the bills would require the disclosure of funding source(s), among other things. Devices. Some have questioned whether information about clinical trials related to medical devices should be included in the registry. The medical device advocacy group, Avamed, points out that FDA regulation of devices is different from its regulation of drugs. Devices are often approved based on analytical comparisons to existing products rather than on the conduct of new clinical trials. Devices as compared to drugs often tend to present a lower risk to patients, tend to be manufactured by smaller companies, tend to have a short market life due to frequent, incremental refinements rather than major breakthroughs, and tend to require more financial incentives to test. PhRMA's database contains only information related to drug trials; those proposed in all of the bills except S. 468 / H.R. 788 would include trials related to medical devices. S. 467 / H.R. 788 would require the HHS Secretary, in consultation with the FDA Commissioner, the Director of the Center for Postmarket Evaluation and Research for Drugs and Biologics, and the Director of the Center for Devices and Radiological Health, to submit to Congress a report that CRS-13 identifies gaps in the current process of postmarket surveillance of devices approved under the Federal Food, Drug, and Cosmetic Act, includes recommendations on ways to improve gaps in postmarket surveillance of devices, and identifies the changes in authority needed to make those improvements. CRS-14 Table 1. Comparison of Proposals for Clinical Trials Reporting and Publication in the 110th Congress Current Law S. 1082 H.R. 2900 S. 467 S. 484 H.R. 1561 Title Data bank of Food and Drug Food and Drug FACT Act Food and Drug Enhancing Drug information on Administration Administration Administration Safety and clinical trials for Revitalization Act Amendments Act Revitalization Act Innovation Act of drugs for serious or of 2007 2007 life-threatening diseases and conditions Sponsor Senator Kennedy Representative Senator Dodd Senator Enzi Representative Pallone Waxman Law Amended (Existing law) PHSA PHSA (42 U.S.C. PHSA Title IV (42 PHSA (42 U.S.C. Subsection (i) of Subsection (i) of (42 U.S.C. § 282 (j)) 282), as amended; U.S.C. 281, et seq.) 282), as amended section 402 of section 402 of and Section 492 by Public Law PHSA (42 USC PHSA (42 USC A(a) of the PHSA 109-482; and 282 as amended 282), as amended Section 492 A(a) by PL 109-482). by PL 109-482. of the PHSA Registry and/or Registry only Registry expanded, Both. Both Both Both Results (clinicaltrials.gov); and includes links Database with sponsor consent, to certain results. Required registry may also Results database to include information be created by HHS about the results of Secretary registered trials, rulemaking CRS-15 Current Law S. 1082 H.R. 2900 S. 467 S. 484 H.R. 1561 including potential following toxicities or adverse recommendations effects to be made in NIH Director's report about best, validated method of making trial results publically available. Product Trial REGISTRY: REGISTRY: BOTH: BOTH: BOTH: BOTH: Types Included Drugs Drugs, devices, Drugs, devices, Drugs, biologics, Drugs, biologics, Drugs, devices, biologics and biologics. devices. eventually biologics Information about possibly devices other trials may be voluntarily submitted. Public Access REGISTRY: REGISTRY: BOTH: BOTH: BOTH: BOTH: Yes, via information Yes, via Internet. Yes, via Internet. Yes, via Yes, via Internet. Yes, via Internet. systems, which are to Internet posting and FOIA request information Internet posting FOIA request include toll-free FOIA request disclosures not systems, which are and FOIA request disclosures not telephone disclosures limited available for results to include toll-free disclosures limited available for communications to terms of the act. for which the telephone to terms of the act. results for which Secretary principal communications. Secretary the principal promulgates investigator is Provisions related promulgates investigator is regulations that seeking to disclosure of regulations that seeking CRS-16 Current Law S. 1082 H.R. 2900 S. 467 S. 484 H.R. 1561 notice of posting be publication. FDA reviews notice of posting publication. part of informed Old versions of supersede FOIA. be part of consent. updated postings informed consent. remain available, with trackable changes the public can see. Location of REGISTRY: REGISTRY: BOTH: NLM and BOTH: BOTH: BOTH: Databases NLM at NIH is NLM at NIH NIH Not specified, but NIH. NIH. current location REGISTRY: bill amends the REGISTRY: REGISTRY: Either supplants or portion of the Either supplants or Either supplants or builds on USC related to the builds on builds on clinicaltrials.gov, current registry, clinicaltrials.gov, clinicaltrials.gov, whichever is more which is located at whichever is more whichever is more efficient. NLM at NIH. efficient. efficient. Links Between REGISTRY: REGISTRY: BOTH: Not specified, REGISTRY: BOTH: Registry, Not specified; except Entries link to Corresponding except that the Entries link to Corresponding Results that the activities of certain existing registry and results Secretary shall results entries. registry and Database the data bank are to results. database entries assign each results database be integrated and link to one another. clinical trial a entries link to one coordinated with unique identifier another. related activities of to be included in other agencies of the the registry and in DHHS, and, to the the database. extent practicable, CRS-17 Current Law S. 1082 H.R. 2900 S. 467 S. 484 H.R. 1561 coordinated with other data banks containing similar information. Who Submits REGISTRY: REGISTRY: BOTH: BOTH: BOTH: BOTH: Information Sponsor Responsible party Responsible party Responsible party Responsible party Responsible party (RP): sponsor; if no (RP): primary (RP): if such (RP): sponsor, or (RP): primary sponsor exists- sponsor as defined clinical trial is the principal sponsor as defined grantee, contractor by WHO, or subject of an investigator if by WHO, or or awardee of principal investigational designated by principal federal funding; if investigator (PI) if new drug sponsor investigator (PI) if designated by designated by application or an designated by sponsor, grantee, sponsor and if PI is application for an sponsor and if PI contractor or responsible for investigational is responsible for awardee - principal conducting the device exemption conducting the investigator. trial, has access to -- the sponsor; if trial, has access to and control over not -- the person and control over data, has the right that provides the data, has the right to publish trial largest share of to publish trial results, and has the monetary support, results, and has responsibility to but if that person the responsibility meet the RP is federal or state to meet the RP responsibilities. agency -- the responsibilities. principal investigator; if the main funder is a nonprofit -- the CRS-18 Current Law S. 1082 H.R. 2900 S. 467 S. 484 H.R. 1561 nonprofit alone or jointly with the principal investigator; if a request is made to the Secretary that another person be the RP, and that person provides monetary support for the trial is responsible for the conduct of the trial and will be responsible for submitting required trial information -- that person. CRS-19 Current Law S. 1082 H.R. 2900 S. 467 S. 484 H.R. 1561 Who Receives REGISTRY: REGISTRY: BOTH: BOTH: BOTH: BOTH: Information HHS Secretary, Director of NIH Director of NIH HHS Secretary, Director of NIH Director of NIH acting through the acting through the NIH Director NIH Director Timing of REGISTRY: REGISTRY: REGISTRY: REGISTRY: REGISTRY: REGISTRY: Submission Not later than 21 -Initially: not later -Initially: not later -Initially: not -Initially: not -Initially: not days after the than 21 days after than 14 days after later than 21 days later than 14 days later than 14 days approval of the the first patient is first patient is after the trial is after first patient after first patient protocol enrolled. enrolled opened for is enrolled is enrolled -Change in -Updates: not less enrollment. -Change in -Updates: not less enrollment status: than once every 6 RESULTS: Enrollment than once every 6 not later than 30 months -Initially: implied Status: not later months days after change. -Change in same date as for than 30 days after -Change in -Completion of Enrollment registry. (To the change Enrollment trial: not later than Status: not later extent practicable, -Final Status: not later 30 days after the than 30 days after the Secretary Submission: Not than 30 days after last patient enrolled change ensures that where later than 30 days change in the clinical trial -Notice of trial the same after last enrolled -Notice of trial has completed his completion: Not information is patient has last completion: Not or her last medical later than 30 days required for the medical visit later than 30 days visit, whether the after final registry and the RESULTS: after final clinical trial collection of data database (such as -Generally: Not collection of data conducted from subjects for initial information later than 1 year from subjects for according to the primary and required for the after last enrolled primary and prespecified secondary database), a patient has last secondary protocol or plan outcomes process exists to medical visit outcomes was terminated RESULTS: allow the RP to (extensions RESULTS: (extensions -Generally: Not make only one possible). -Generally: Not possible). later than 1 year submission. -Changes in later than 1 year CRS-20 Current Law S. 1082 H.R. 2900 S. 467 S. 484 H.R. 1561 after earlier of -Results: not later regulatory status: after earlier of estimated or actual than 1 year than within 30 days estimated or actual completion date the earlier of the after change completion date (extensions trials' estimated or (extensions possible) actual completion possible) -Updates: every 6 date (extensions -Updates: every 6 months for 10 years possible). months for 10 from when initial BOTH: years from when posting was -Changes: initial posting was required within 30 days of required -Changes in the date on which -Changes in regulatory status: the RP or principal regulatory status: within 30 days after investigator within 30 days change became aware of after change the change Timing of REGISTRY: REGISTRY: REGISTRY: BOTH: REGISTRY: REGISTRY: Posting Not specified -Trials of drugs -Not specified In making -Not specified -Not specified and biological (NIH Director information about (NIH Director (NIH Director products: within ensures the registry clinical trials ensures the ensures the 30 days of information is publicly available, registry registry submission made publically the Secretary shall information is information is -Trials of devices: available via make information made publically made publically within 30 days of Internet) except available as soon available via available via clearance under that NIH Director as practicable after Internet) Internet) section 510(k) of may not make receiving the data, RESULTS: RESULTS: the FFDCA or registry and shall seek to (delays of up to 2 (delays of up to 2 approval under information about be as timely and years possible if years possible if sections 515 or device trials public transparent as seeking seeking 520(m) of the until the device is possible. publication) publication) CRS-21 Current Law S. 1082 H.R. 2900 S. 467 S. 484 H.R. 1561 FFDCA approved or cleared (Postponement -Pre-approval -Pre-approval -Links to trial by FDA. and extensions for studies: not later studies: not later results (from FDA RESULTS: (delays publication are than 30 days after than 30 days after and NIH of up to 2 years possible). approval or approval or information) that possible if seeking issuance of not issuance of not form the basis of publication) approvable letter approvable letter an efficacy claim -Pre-approval -Post-approval -Summaries of or are conducted studies: not later studies generally: medical, clinical after the drug or than 30 days after not later than 30 pharmacology biologic is approval or days after reviews of pre- approved or the issuance of not submission approval and device is cleared approvable letter -Post-approval new use studies: or approved: not -Summaries of studies of new within 90 days of earlier than 30 days medical, clinical uses in which the applicable date after the date of pharmacology manufacturer is a -Post-approval approval or reviews of pre- trial sponsor and studies generally: clearance, not later approval and new certifies it is within 30 days of than 30 days after use studies: within seeking or will submission the produce 90 days of seek approval -Post-approval becomes publically applicable date within 1 year: not studies of new available. -Post-approval later than 30 days uses in which studies generally: after approval, manufacturer is a within 30 days of issuance of not trial sponsor and submission approvable letter, certifies it is -Post-approval or application seeking or will studies of new withdrawal, or 2 seek approval uses in which years after within 1 year: not manufacturer is a certification. later than 30 days trial sponsor and after approval, certifies it is issuance of not CRS-22 Current Law S. 1082 H.R. 2900 S. 467 S. 484 H.R. 1561 seeking or will approvable letter, seek approval or application within 1 year: not withdrawal; or 2 later than 30 days years after after approval, certification. issuance of not approvable letter, or application withdrawal; or 2 years after certification. Searchable By REGISTRY: REGISTRY: REGISTRY: BOTH: REGISTRY: REGISTRY: Not specified (But -Indication, using -Trial enrollment Not specified (But -Enrollment status -Trial enrollment for a list of required Medical Subject status for a list of -Approval status status data elements, see Headers -Trial sponsor required data RESULTS: -Trial sponsor that entry below.) -Source of support RESULTS: elements, see that -Each financial RESULTS: -Study phase -Status of FDA entry below.) sponsor -Status of FDA -Treatment application -Clinical trial application -Recruitment status -Trial phase phase -Trial phase -Age group -Product name -Safety issue -Product name (including pediatric -Each financial -Drug name -Each financial subpopulations) sponsor BOTH: sponsor -Study location BOTH: -Indication, using BOTH: -National Clinical -Indication, using Medical Subject -Indication, using Trial number or Medical Subject Headers Medical Subject other identification Headers -Sponsor Headers number -Safety issue being -Safety issue studied being studied -Trial sponsor CRS-23 Current Law S. 1082 H.R. 2900 S. 467 S. 484 H.R. 1561 Trials Included REGISTRY: REGISTRY: BOTH: REGISTRY: REGISTRY: BOTH: -Investigational new -Device trials: -Drug, device, - Non-phase I -Premarket: -Drug, device, drug trials: trials prospective study biologic clinical clinical trials of Trials to verify biologic clinical (whether federally or of health outcomes trials: trials testing drugs, devices, efficacy and trials: Trials privately funded) of comparing an a products' safety biologics: trials establish doses testing a products' experimental intervention against or effectiveness if testing a treatment -Confirmatory: safety or treatments for serious a control in human conducted in the for a All effectiveness if or life- threatening subjects intended to U.S. or if the life-threatening RESULTS: conducted in the diseases and support an product has FDA disease or -Premarket: U.S. or if the conditions under application under approval or is the condition, that are Trials to verify product has FDA regulations section 520 (m) [re subject of an federally funded, efficacy and approval or is the promulgated pursuant humanitarian application for used in requesting establish doses if subject of an to section 21 USC devices] or 515 [re FDA approval. FDA approval, recommended by a application for 355(i) [re premarket approval and/or conducted required GAO FDA approval. investigational new of devices] or a in the United study and required drugs]. report under section States. by the HHS -Treatment use of 510(k) [re device RESULTS: Secretary through investigational new clearance] of the - Non-phase I rulemaking; drugs: FFDCA; pediatric Drug, device, or fast track product information postmarket biologic clinical trials if used as the pertaining to surveillance as trials, and those basis for efficacy. experimental required under required by the -Confirmatory: treatments for serious section 522 of the HHS Secretary in Premarket or life-threatening FFDCA (as the interest of confirmatory trials diseases and amended by the public health: if BOTH: conditions that may bill). federally funded, -Postmarket: all. be available - -Drug and biologic used in requesting -Pediatric (i) under a treatment trials: a controlled FDA approval, Pharmacokinetic: investigational new clinical and/or all drug application that investigation of a conducted in the has been submitted to product subject to United States. CRS-24 Current Law S. 1082 H.R. 2900 S. 467 S. 484 H.R. 1561 the Secretary under section 505 [re BOTH: 21 USC 360bbb(c); drug approval] or clinical trial or 351 [re approval of means a research (ii) as a Group C biological study in human cancer drug (as products] of the volunteers to defined by the FFDCA. answer specific National Cancer -Other trials: health questions, Institute). voluntary including submissions may treatment, be made. prevention, diagnostic, screening, and quality-of-life trials Exceptions REGISTRY: REGISTRY: BOTH: BOTH: BOTH: BOTH: (trials not Information relating -Device trials: -Pharmacokinetic -Phase I clinical -Exploratory -Pharmacokinetic included) to an investigation if limited studies to and toxicity trials conducted trials solely to and toxicity the sponsor has gather essential studies: a clinical solely to test the assess safety, studies: a clinical provided a detailed information used to trial to determine safety of an evaluate trial to determine certification to the refine the device or the safety of a use unapproved drug pharmacokinetics, the safety of a use Secretary that design a pivotal of a drug that is or unlicensed or verify efficacy of a drug that is disclosure would trial and that is not designed solely to biological product, -Observational designed solely to substantially interfere intended to detect major pilot or feasibility studies detect major with the timely determine safety toxicities in the studies conducted toxicities in the enrollment of and effectiveness of drug or to to confirm the drug or to subjects in the a device. investigate design and investigate investigation, unless -Drug and pharmacokinetics, operating pharmacokinetics, the Secretary, after Biologic Trials: unless the clinical specifications of unless the clinical the receipt of the Phase I trials. trial is designed to an unapproved or trial is designed to certification, provides investigate not yet cleared investigate CRS-25 Current Law S. 1082 H.R. 2900 S. 467 S. 484 H.R. 1561 the sponsor with a pharmacokinetics medical device pharmacokinetics detailed written in a special may be included in a special determination that population or with RP consent. population or such disclosure populations; and -Clinical trials of populations; and would not -Feasibility other health- -Feasibility substantially interfere studies: a small related studies: a small with such enrollment. clinical trial to interventions may clinical trial to determine the be included with determine the feasibility of a consent of RP. feasibility of a device, or a clinical device, or a trial to test clinical trial to test prototype devices prototype devices where the primary where the primary focus is feasibility. focus is feasibility. Registry Data -Purpose of each -WHO elements -WHO elements -Trial title -Sponsor -WHO elements Elements experimental drug (See Appendix A.) (See Appendix A.) -Unique identifier -Trial purpose (See Appendix -Eligibility criteria -City, state, zip -City, state, zip -Trial description -Patient A.) -Location of trial code of study code, toll free -Trial phase population -City, state, zip sites -Toll free number phone number of -Trial type description code of study -Point of contact for for study study -Trial purpose -General -Estimated enrollment -Whether there is -Estimated -Primary, description of completion date -Description of expanded access completion date secondary results, trial design -RP identity and whether and how the for unapproved -RP identity and outcome measures changes, and contact manufacturer or drugs and biologics contact information -Date outcome reasons for information sponsor will respond under FFDCA -Whether there is measures will be changes -Whether there is to requests for section 561 [re expanded access assessed -WHO elements expanded access protocol exception, emergency for unapproved -Dates and details (See Appendix for unapproved with appropriate situations, patient drugs and biologics of revisions to A.) drugs and safeguards, for access to under FFDCA outcomes -City, state, zip biologics under single- patient and treatments for section 561 [re -Eligibility and code of study FFDCA section CRS-26 Current Law S. 1082 H.R. 2900 S. 467 S. 484 H.R. 1561 expanded protocol serious diseases, emergency exclusion criteria -Whether 561 [re emergency use of the new drug, treatment uses] situations, patient -Whether and how compassionate use situations, patient particularly in -Other data access to requests for is available access to children elements as treatments for single-patient and -Elements treatments for -With sponsor appropriate serious diseases, expanded protocol specified by serious diseases, consent, may include -Links to results treatment uses] use (particularly in Secretary treatment uses] information about the from certain FDA -Restrictions on children) will be -Restrictions on results of included submissions, NIH non-employees' addressed non-employees' trials, including information discussion or -Trial and discussion or potential toxicities or (Medline cites and publication of enrollment status publication of adverse effects NLM database of results at individual sites results product labels), and -Elements specified -Estimated -Elements previously existing by Secretary completion date specified by databank entries -Trial location Secretary -RP identity and contact information -Sponsor -Funding source -Experimental treatments for serious or life- threatening conditions available under a treatment investigational new drug application or as a Group C cancer drug. CRS-27 Current Law S. 1082 H.R. 2900 S. 467 S. 484 H.R. 1561 Results Data None. None. -Registry data -Title -Indication studied -Indication studied Elements elements, plus: -Unique identifier -Safety issue -Safety issue TECHNICAL -Product tested -Status of FDA -Status of FDA SUMMARY: -Trial description application application -Each sponsor in lay language -Trial phase -Trial phase -Scientific point of -Trial phase, type TECHNICAL TECHNICAL contact -Trial purpose REPORT: REPORT: -Description of -Demographic -Each sponsor -Each sponsor patient population data -Scientific point of -Scientific point of -Summary data -Estimated contact contact describing completion date -Description of -Description of achievement of -Study sponsor patient population patient population primary and and funding -Summary of -Summary of secondary source aggregate data aggregate data endpoints, -Primary, assessing primary assessing primary assessment of secondary and secondary and secondary secondary outcome measures endpoints, safety endpoints, safety endpoints, safety -Date outcome information information information measures assessed -Information about -Information about -Information about -Dates, details of subjects quit trial subjects quit trial subjects who quit outcome revisions -Restrictions on -Restrictions on trial -Actual non-employees' non-employees' -Restrictions on completion date, discussion or discussion or non-employees' reason for publication of publication of discussion or difference from results. results. publication of estimate -Link to peer -Link to peer results -If terminated, reviewed reviewed -Link to peer reason for publications publications reviewed termination -completion date -completion date publications -Results summary -FDA adverse -FDA adverse -completion date with trial design, regulatory action regulatory action CRS-28 Current Law S. 1082 H.R. 2900 S. 467 S. 484 H.R. 1561 -FDA adverse methodology, NONTECHNICA NONTECHNI- regulatory action outcome L REPORT: CAL REPORT: NONTECHNI- measures, -Point of contact -Point of contact CAL SUMMARY: summary data -General -General -Point of contact tables, statistical description of description of -General significance of results, trial design results, trial design description of results changes, and changes, and results, trial design -Safety data, reasons for reasons for changes, and including adverse changes changes reasons for changes event information BOTH BOTH BOTH -Peer-reviewed REPORTS: REPORTS: REPORTS: publications -Trial purpose -Trial purpose -Trial purpose -Description of -Trial sponsor -Trial sponsor -Trial sponsor results review -General -General -General process, protocol description of description of description of -Status of FDA results, trial design results, trial design results, trial design application or changes, and changes, and changes, and reason trial not reasons for reasons for reasons for changes submitted to FDA changes changes [NIH Director to include links to Medline citations, NLM database product labels, prior databank entries.] Enforcement REGISTRY: REGISTRY: BOTH: BOTH: BOTH: BOTH: and Corrections None specified. -RP ensures -RP ensures -Sponsors of FDA -RP ensures -RP ensures General mechanisms submissions not submissions not new drug submissions not submissions not for enforcing false or misleading. false or misleading. applications false or false or CRS-29 Current Law S. 1082 H.R. 2900 S. 467 S. 484 H.R. 1561 compliance with -No federal agency -No federal agency submit to misleading. misleading. FDA requirements may release may release Secretary -No federal -No federal may be applicable, research grant research grant certification of agency may agency may but have not been funds to funds to compliance with release grant funds release research applied by FDA. noncompliant RPs. noncompliant RPs. FFDCA. If not, to noncompliant grant funds to -For applicable -Secretary consults after hearing, RPs. noncompliant RPs. trials funded by with other federal Secretary imposes -FDA -For applicable FDA, NIH, AHRQ, agencies to $10,000/day civil Commissioner trials funded by or VA, progress determine whether monetary penalty verifies required FDA, NIH, report forms studies funded by until certification submissions were AHRQ, or VA, include them and submitted. If made when progress report certification of conducted under 45 information is considering forms include compliance. CFR 46 [re federal inaccurate and applications for certification of Agency heads protections for sponsor knew or investigational compliance. verify compliance human subjects] are should have drug exemptions, Agency heads before releasing applicable clinical known, after new drug verify compliance grant funds to RPs. trials, and to notice and approvals, before releasing Secretary consults develop procedures hearing, Secretary biologics licences. grant funds to with other federal to ensure results orders sponsor to After notice to RP, RPs. Secretary agencies to submission. pay civil monetary opportunity to consults with determine whether -NIH Director penalty of correct, Secretary other federal studies funded by checks registry to $100,000 to refuses to file agencies to them and ensure $2,000,000 for any application. determine whether conducted under 45 corresponding 30-day period. -Secretary checks studies funded by CFR 46 [re federal results are filed. -To be eligible for registry to ensure them and protections for After notice to RP, a federal grant, corresponding conducted under human subjects] opportunity to contract, or results are filed. 45 CFR 46 [re merit similar correct, Director cooperative After notice to RP, federal protections procedures. reports agreement, opportunity to for human -Applications or noncompliance to principal correct, Secretary subjects] merit submissions under federal agencies investigator reports similar CRS-30 Current Law S. 1082 H.R. 2900 S. 467 S. 484 H.R. 1561 FFDCA sections and Office of certifies Act noncompliance to procedures. 505, 515, 520(m), Human Research compliance. federal agencies -NIH Director 351, or 510(k) [re Protections, posts Noncompliance, and Office of checks registry to new drugs, notice of after notice, leads Human Research ensure biologics and noncompliance in to ineligibility, Protections, posts corresponding devices], must have registry and posting of notice of results are filed. certifications of database. noncompliance noncompliance in After notice to RP, compliance. -FDA notice in database. registry and opportunity to -Secretary may Commissioner to database. correct, Director impose FFDCA verify submissions -In trial with -Secretary ensures reports penalties for are made for trials nonfederal content is not false noncompliance to noncompliance. in applications support, Act or misleading and federal agencies under FFDCA noncompliance non-promotional and Office of sections 505, 505(i) leads to notice, by checking a Human Research 515, 520(g), 351, or opportunity to representative Protections, posts 510(k) [re new or correct, hearing, sample. After notice of exempt drugs, $10,000/day notice to RP, noncompliance in biologics and penalty until opportunity to registry and devices]. After 30 compliant. correct, Secretary database. days after notice, may impose -Applications or failure to correct FFDCA penalties submissions under leads to Secretary's FFDCA sections refusal to file, 505, 515, 351, or approve, or clear 510(k) [re new application. drugs, biologics -Secretary to and devices], must review documents have certifications to ensure they are of compliance. non-promotional, -Secretary may not false or impose FFDCA misleading. 30 penalties for CRS-31 Current Law S. 1082 H.R. 2900 S. 467 S. 484 H.R. 1561 days after notice of noncompliance, noncompliance, including civil penalties may monetary penalties apply. ($10,000/day for -Secretary may first violation, impose FFDCA $20,000/day for penalties for each subsequent noncompliance, violation) created including civil by Act. monetary penalties created by the Act (not more than $10,000/day, and not more than $15,000/ for all violations of an individual or nonprofit adjudicated in a single proceeding). Required None. RESULTS: BOTH: Not later BOTH: RESULTS: None required by Studies or The NIH Director than 1 year after Not later than 1 Not earlier than 2 clinical trials title. Reports conducts a study to enactment, year after years after results determine the best, Comptroller enactment, database validated methods General submits a Secretary submits established, of making trial report to Congress to appropriate Comptroller results public after on a study to committees of General initiates a the approval of a determine whether Congress a report GAO study of drug that is the information in the on the status of the inclusion of subject of an registry and implementation of certain premarket CRS-32 Current Law S. 1082 H.R. 2900 S. 467 S. 484 H.R. 1561 applicable drug database is Act requirements trials: burden to trial. Director considered including number sponsors and submits findings to promotional and to and types of trials agencies, benefit the HHS Secretary evaluate the submitted. to patients and within 18 months implementation of REGISTRY: health providers, of initiating the the database. Secretary recommendations. study. contracts with Makes report to IOM to conduct a HELP, Energy and study of the extent Commerce. to which data submitted to the registry and database have impacted the public health. Not later than 6 months after the contract date, IOM submits study to Secretary Authorized REGISTRY: BOTH: BOTH: BOTH: BOTH: BOTH: Appropriations Such sums as may be $10,000,000 each $10,000,000 each Such sums as may $10,000,000 each $10,000,000 each necessary; Fees FY FY be necessary FY FY collected under section 21 USC 379h [re FDA prescription drug user fees] may not be used for the registry. CRS-33 Current Law S. 1082 H.R. 2900 S. 467 S. 484 H.R. 1561 Preemption None. BOTH: BOTH: None. BOTH: BOTH: Yes. No state or Yes. No state or Yes. No state or Yes. No state or political political political political subdivision of a subdivision of a subdivision of a subdivision of a state may require or state may require or state may require state may require effect registration effect registration or effect or effect of trials or results. of trials or results. registration of registration of trials or results. trials or results. Safe Harbor None. BOTH: BOTH: None. BOTH: BOTH: Somewhat. Somewhat. Somewhat. Somewhat. Compliant Compliant Compliant Compliant submissions shall submissions shall submissions shall submissions shall not be considered not be considered not be considered not be considered (1) by Secretary as (1) by Secretary as (1) by Secretary as (1) by Secretary as evidence of a new evidence of a new evidence of a new evidence of a new intended use intended use intended use intended use different from different from different from different from labeling, or (2) as labeling, or (2) as labeling, or (2) as labeling, or (2) as FFDCA labeling, FFDCA labeling, FFDCA labeling, FFDCA labeling, adulteration, or adulteration, or adulteration, or adulteration, or misbranding. misbranding. misbranding. misbranding. Effective Dates REGISTRY: REGISTRY: BOTH: Not specified. BOTH: BOTH: Currently operational -Generally: -Databases Databases to be -Databases October 1, 2007 established not established not established not -Regulations later than 1 year later than 1 year later than 1 year become effective after enactment. after enactment. after enactment. 90 days after issuance of HHS Secretary's issuance of final CRS-34 Current Law S. 1082 H.R. 2900 S. 467 S. 484 H.R. 1561 rule. (Final rule issued pursuant to Act to be issued not later than 18 months after Act's enactment, and after notice and comment.) -Funding restrictions take effect 210 days after regulations' effective date. CRS-35 Appendix A. World Health Organization, International Clinical Trials Registry Platform, Registration Data Set (Version 1.0) ITEM DEFINITION / EXPLANATION Primary Name of Primary Register, and the unique ID number assigned by the Primary Register and Register to this trial. Trial ID # Date of Date when trial was officially registered in the Primary Register YYYY/MM/DD. Registration in Primary Register Secondary ID#s Other identifying numbers and issuing authorities besides the Primary Register, if any. Include the sponsor name and sponsor-issued trial number (e.g., protocol number) if available. Also include other trial registers that have issued an ID number to this trial. There is no limit on the number of Secondary ID numbers that can be provided. Source(s) of Major source(s) of monetary or material support for the trial (e.g., funding agency, Monetary or foundation, company). Material Support Primary The individual, organization, group or other legal person taking responsibility for Sponsor securing the arrangements to initiate and/or manage a study (including arrangements to ensure that the study design meets appropriate standards and to ensure appropriate conduct and reporting). In commercial trials, the primary sponsor is normally the main applicant for regulatory authorization to begin the study. It may or may not be the main funder. Secondary Additional individuals, organizations or other legal persons, if any, that have agreed Sponsor(s) with the primary sponsor to take on responsibilities of sponsorship. A secondary sponsor may have agreed -to take on all the responsibilities of sponsorship jointly with the primary sponsor; or -to form a group with the primary sponsor in which the responsibilities of sponsorship are allocated among the members of the group; or -to act as the sponsor's legal representative in relation to some or all of the trial sites; or -to take responsibility for the accuracy of trial registration information submitted. Contact for Email address, telephone number, or postal address of the contact who will respond Public Queries to general queries, including information about current recruitment status Contact for Email address, telephone number, or postal address, and affiliation of the person to Scientific contact for scientific queries about the trial (e.g., principal investigator, medical Queries director employed by the sponsor). For a multi-center study, enter the contact information for the lead Principal Investigator or overall scientific director. Public Title Email address, telephone number, or postal address, and affiliation of the person to contact for scientific queries about the trial (e.g., principal investigator, medical director employed by the sponsor). For a multi-center study, enter the contact information for the lead Principal Investigator or overall scientific director. CRS-36 Scientific Title Scientific title of the study as it appears in the protocol submitted for funding and ethical review. Include trial acronym if available. Countries of The countries from which participants will be, are intended to be, or have been Recruitment recruited. Health Primary health condition(s) or problem(s) studied (e.g., depression, breast cancer, Condition(s) or medication error). If the study is conducted on healthy human volunteers belonging Problem(s) to the target population of the intervention (e.g., preventative or screening Studied interventions), enter the particular health condition(s) or problem(s) being prevented. If the study is conducted using healthy human volunteers not belonging to the target population (e.g., a preliminary safety study), an appropriate keyword will be defined for users to select. Intervention(s) Enter the specific name of the intervention(s) and the comparator/control(s) being studied. Use the International Non-Proprietary Name if possible (not brand/trade names). For an unregistered drug, the generic name, chemical name, or company serial number is acceptable. If the intervention consists of several separate treatments, list them all in one line separated by commas (e.g., "low-fat diet, exercise"). The control intervention(s) is/are the interventions against which the study intervention is evaluated (e.g., placebo, no treatment, active control). If an active control is used, be sure to enter in the name(s) of that intervention, or enter "placebo" or "no treatment" as applicable. For each intervention, describe other intervention details as applicable (dose, duration, mode of administration, etc). Key Inclusion Inclusion and exclusion criteria for participant selection, including age and sex. and Exclusion Criteria Study Type A single arm study is one in which all participants are given the same intervention. Trials in which participants are assigned to receive one of two or more interventions are NOT single arm studies. Crossover trials are NOT single arm studies. A trial is "randomized" if participants are assigned to intervention groups using a method based on chance (e.g., random number table, random computer-generated sequence, minimization, adaptive randomization). Date of First Anticipated or actual date of enrollment of the first participant (YYYY/MM). Enrollment Target Sample Number of participants that this trial plans to enroll. Size Recruitment Recruitment status of this trial. Status -Pending: participants are not yet being recruited or enrolled at any site -Active: participants are currently being recruited and enrolled -Temporary halt: there is a temporary halt in recruitment and enrollment -Closed: participants are no longer being recruited or enrolled Primary Outcomes are events, variables, or experiences that are measured because it is Outcome(s) believed that they may be influenced by the intervention. The Primary Outcome should be the outcome used in sample size calculations, or the main outcome(s) used to determine the effects of the int[ervention(s). Enter the names of all primary outcomes in the trial as well as the pre-specified timepoint(s) of primary interest. Be as specific as possible with the metric used (e.g., "% with Beck Depression Score > 10" rather than just "depression"). Examples: Outcome Name: all-cause mortality, Timepoints: 5 years; or Outcome Name: Mean Beck Depression Score, Timepoint: 18 weeks CRS-37 Secondary Secondary outcomes are events, variables, or experiences that are of secondary Outcome(s) interest or that are measured at timepoints of secondary interest. A secondary outcome may involve the same event, variable, or experience as the primary outcome, but measured at timepoints other than those of primary interest (e.g., Primary outcome: all-cause mortality at 5 years; Secondary outcome: all-cause mortality at 1 year, 3 years), or may involve a different event, variable, or experience altogether (e.g., Primary outcome: all-cause mortality at 5 years; Secondary outcome: hospitalization rate at 5 years). Enter the name and timepoint(s) for all secondary outcomes of clinical and/or scientific importance. Be as specific as possible with the metric used (e.g., "% with Beck Depression Score > 10" rather than just "depression"). Examples: Outcome Name: all-cause mortality, Timepoints: 6 months, 1 year; or Outcome Name: Mean glycosylated hemoglobin A1C, Timepoints: 4 and 8 weeks Source: WHO, ICTRP, "Registration Data Set (version 1.0)," (March 16, 2007), at [http://www.who. int/ictrp/data_set/en/], visited Apr. 16, 2007. ------------------------------------------------------------------------------ For other versions of this document, see http://wikileaks.org/wiki/CRS-RL32832