Guide to Researching Clinical Trials Registration and Results Reporting Requirements

Guide to Researching Clinical Trials Registration and Results Reporting Requirements Table of Contents I. Introduction II. III. IV. a. Statement of Purpose b. Clinical Trial Registration Holli Kubicki c. Other Sources of Registration and Reporting Requirements Primary Sources of Law a. Federal Law i. Statutes ii. Legislative History iii. Federal Regulations b. State Law c. Case Law i. Statutes and Regulations ii. Legislative History Secondary Sources of Law a. Looseleafs b. Journals and Law Reviews c. Books Current Awareness a. FDA Website b. Blogs c. Organizations d. BNA e. Westclip, Lexis Alerts V. Conclusion 2010 Holli A. Kubicki. All rights reserved. 1

I. Introduction a. Statement of Purpose Serious problems arise from misreporting or underreporting clinical trial results. In June 2004, New York Attorney General Eliot Spitzer sued GlaxoSmithKline (GSK) alleging the company purposefully withheld negative information concerning use of the antidepressant Paxil in teens. Shortly thereafter, Merck came under fire for similar misconduct. Though aware of increased cardiovascular risks associated with Vioxx, Merck continued seeking FDA approval and, once approved, marketing the drug, until September 2004 when Merck voluntarily withdrew the drug. In response to these and other drug company scandals, many states, industry organizations, and ultimately the federal government called for heightened clinical trial registration and results reporting requirements. This guide is intended to introduce attorneys and pharmaceutical industry regulatory officers to the applicable sources of law for clinical trial reporting requirements. This guide will point the reader to the federal laws controlling clinical trial registration, as well as introduce relevant statutory history resources to provide their context and background. In addition to federal requirements, some states have proposed additional legislation effectively increasing requirements. While the issue of preemption is undetermined, understanding state concerns and motivations for legislating may prove useful for determining whether a company wishes to disclose additional information beyond the federal requirements. As a result, this guide will also introduce resources for researching relevant state laws and regulations. Beyond background information, this guide will provide resources for following the upcoming expansion of federal laws and a variety of ways to stay current on the topic. Each section will provide a recommended path and featured methods for accessing the information, followed by alternative ways to access the information both in print and online. Applicable print resources include their Library of Congress call numbers for the Omer Poos Law Library at SLU. b. Clinical Trial Registration Clinical trials are research studies evaluating the safety and effectiveness of new drugs and devices on human participants. The Food and Drug Administration (FDA) bases approval decisions in part on the results of clinical trials. One of the largest databases for clinical trials is ClinicalTrials.gov, which currently lists 81,152 trials taking place in every state and 170 countries around the world. The public may search for clinical trials by location or specific disease or condition of interest if one wishes to enroll in a study. The public may also search clinical trial results if additional information is desired. Access to clinical trial information has been greatly expanded in the last decade and will continue to grow over the next two years as new regulations are likely to increase results reporting requirements. One of the main goals of Federal requirements and those in Maine require the use of ClinicalTrials.gov. Though beyond the scope of this pathfinder, it is important to recognize that other clinical trial reporting and registration requirements exist. For example, companies seeking to develop drugs for use and marketing in other countries may have additional requirements imposed by the respective countries (European Union, Japan). Further, the International Committee of Medical Journal 2010 Holli A. Kubicki. All rights reserved. 2

Editors (ICMJE), in an attempt to protect the integrity of content published within its journals, may require certain information be disclosed as a condition of publishing articles reporting research. The ICMJE website (www.icmje.org/) contains a list of participating journals, including Journal of the American Medical Association, The Lancet, British Medical Journal, and New England Journal of Medicine, and information discussing the Uniform Requirements for Manuscripts (URM). II. Primary Sources of Law a. Federal Law The Food and Drug Administration Modernization Act (FDAMA) of 1997 (Pub. L. No. 105-115, 113, 111 Stat. 2296) mandated the creation of a website providing the public with expanded access to information regarding clinical trials for drugs developed to treat serious or life-threatening illnesses. In February 2000, ClinicalTrials.gov was launched to comply with the statute. FDAMA lacked enforcement provisions and penalties for non-compliance. As a result, few companies registered their clinical trials. In 2004, it was discovered that major pharmaceutical companies, including Pfizer, Merck, and GSK were underreporting clinical trial results. These events ultimately spurred a repurposing of ClinicalTrials.gov. The Food and Drug Administration Amendments Act (FDAAA) of 2007 (Pub. L. No. 110-85, 801, 121 Stat. 823) expanded registration and reporting requirements to include most clinical trials and results. In addition to the requirements under FDAMA, FDAAA requires all drug and device controlled trials beyond Phase I to be registered. In terms of reporting clinical trial results, the Act stipulates finalizing requirements in September 2010. Information on tracking forthcoming changes will be discussed in the Current Awareness section below. i. Statutes Recommended path: Read the Acts in their entirety as public laws (as they may be codified in scattered sections of the Code) and then use the tables in the United States Code (USC), United States Code Annotated (USCA), or United States Code Service (USCS) to locate applicable sections where the Acts have been codified. Feature: Public laws - Both FDAMA and FDAAA may be easily accessed online through GPO Access (www.gpoaccess.gov/). GPO Access is a free service of the U.S. Government Printing Office providing resources such as public and private laws, the Code of Federal Regulations (CFR), and The United States Code (USC) to name a few. From the GPO Access homepage, select Public and Private Laws and search the appropriate Congress by public law number. One can view the Acts in text or pdf format. Feature: United States Code Using the USCA-tables database on Westlaw, search the public law number to access a table linking the public law, by section and statutes at large page number, to the sections of the USC where codified (hyperlinked). Searching the Popular Names table by full name of the Act will provide links to the table. Public Laws 2010 Holli A. Kubicki. All rights reserved. 3

Print o Statutes at Large Access the Acts as published in the Statutes at Large by volume and page number (SLU Law KF50. A26). : o Hein Online Access the Acts in the Statutes at Large database; select the applicable volume and page to book browse a pdf version of the act. o THOMAS Browse the applicable Congress for either the public law number or the statute at large volume and page. o Lexis/Westlaw To access the FDAAA on Lexis, enter 110 P.L. 85 from Get a Document by citation. Search on Westlaw using the public law number in US- PL-OLD database; any public laws for the current congress may be located in the US-PL database. o Loislaw From Statutes and Acts, choose Public Laws of the United States and search by public law number, text, or history. o FDA Website Full text of the FDAAA of 2007 is available on the FDA website (www.fda.gov), along with an implementation chart discussed in the current awareness section, infra. Tables/Statutes Print o United States Code Official version of the USC. Use the tables to locate various, scattered sections of the Acts as codified (SLU Law KF62 2006.A2 2008). Lag time publishing the USC in print makes online options (discussed below) preferable to ensure finding the most current, up-to-date version of the Code. o United States Code Annotated and United States Code Service Both contain tables linking the Public Law sections to applicable USC sections and provide annotated cases and references to other primary and secondary sources. USCA (SLU Law KF62.W4) tends to provide more case law information while USCS (SLU Law KF62.L38) provides more references to regulatory materials. Due to the nature of this topic and relevant resources, it is preferable to use the USCS. o GPO Access and THOMAS also contain the USC free of charge. o Loislaw and Hein Online contain the USC for a subscription cost. o Lexis and Westlaw provide electronic versions of the USCS and USCA, respectively, along with tables; both are subject to contracted costs. The Westlaw tables are more user-friendly because the applicable sections of the USC are actually hyperlinked to the text of the USCA. Lexis USCS table references to USC sections must be copied and retrieved from another screen; however, once retrieved, may provide links to more useful additional resources. ii. Legislative History The legislative history of these Acts provides insight into lawmakers intent, help discern the meaning of the law, and help to explain why the laws were enacted. Additionally, it may be useful to retrieve information about related bills that were introduced but died before becoming law (e.g. the FACT Act, 109th Congress) and pending legislation. 2010 Holli A. Kubicki. All rights reserved. 4

Feature: THOMAS is a free online resource of the Library of Congress. To access legislative history for FDAMA or FDAAA, use THOMAS (http://thomas.loc.gov/), select search multiple congresses, and search by the name of the Act. For each Act, any related bills, amendments, an overview of major congressional actions, links to the bills in the Congressional Record, and vote counts are available. Keyword searches of multiple congresses will also be useful to locate failed bills and pending legislation. For example, a keyword search for clinical trials in the 110 th and 111 th Congress yields 257 bills, including e.g. S.1674, introduced 9/15/2009. Print o Congressional Record Official record of the proceedings and debates of the United States Congress (SLU Law KF35). o GPO Access Provides legislative history, also free, in a slightly less userfriendly format. o LexisNexis Congressional (subscription cost) Easily locate legislative history by public law number. Results will provide a summary of the law, links to summaries of applicable reports, hearings, and committee prints. This information highlights the issues in contention before finalizing the law. o Lexis/Westlaw Lexis U.S. CIS Legislative Histories (1970 current) contains legislative history of key U.S. Public Laws from first consideration through presidential signature. Abstracts of the hearings, reports, prints and documents cited in the Legislative Histories are also included in the file. In contrast, the Westlaw database Legislative History (LH) contains similar materials for both enacted laws (1948 present) and bills that did not become laws (1990 present). iii. Federal Regulations The Federal Register contains proposed rules, final rules and regulations, hearing notices, and requests for comments. The Federal Register is published each federal working day. Once finalized, regulations are published in the Code of Federal Regulations (CFR), arranged by title. CFR is updated every year; however, specific titles are updated at certain times each year. In the case of clinical trial registries, the FDA may propose rules under delegated statutory authority, particularly FDAAA. Feature: GPO Access provides the most up-to-date free version of the CFR. It is arranged by title in a table format, making it easy to locate current regulations and the dates of their most recent revision, as well as the List of Sections Affected (LSA). The Federal Register (FR) is also available on GPO Access and contains notices, proposed rules, and executive orders. Feature: Regulations.gov is extremely useful for viewing public comments made in response to proposed rules in the FR. Search for clinical trial registry from the main page to locate relevant notices and public comments submitted in response. Results can be narrowed by agency, document type, or date. Browsing public submissions can introduce the various stakeholders in the legislation and their points of view; this information will be taken into consideration when the proposing agency finalizes the rule. Print: 2010 Holli A. Kubicki. All rights reserved. 5

o Federal Register Recent issues are available in the Law Library (SLU Law KF 70.A2); older issues are available in microfilm. o Code of Federal Regulations Volumes are located at SLU Law KF 70.A3. When using print resources, be sure to check the List of Sections Affected for each month after the CFR is published, as well as the Federal Register for any remaining days for applicable updates. o Hein Online Contains both the CFR and LSA. o Lexis/Westlaw From 1980 forward, contain the CFR. o FDA Website Title 21 is searchable from the FDA website and best used when seeking a particular section (need the section number or keywords). b. State Law States also responded to reporting misconduct by proposing legislation as early as 2005. While many states proposed legislation, very few bills actually became law. Maine is one state that passed legislation in 2005. In June 2009, despite an explicit preemption provision in FDAAA, Maine also proposed legislation mandating clinical trial requirements above and beyond federal law. Potential changes in Maine are expected within 150 days of the close of the comment period, which ended in July 2009. Comments are available by contacting the Maine Secretary of State and the final law, if enacted, will be available online. Recommended path: Information from secondary sources can help point to states considering legislation and substantially narrow a search. For example, searching the Westlaw legal periodicals database (described in Secondary sources All Journals and Law Reviews section below) for clinical trials and state require! will retrieve the July 2005 Guide to Good Clinical Practice Newsletter article States Continue to Consider Trial Registration, Result Disclosure (among other results). The article discusses proposed legislation in nine states, provides a brief description, and relevant bill numbers. i. Statutes and Legislative History Until the issue of federal preemption by FDAAA has been determined, states may establish their own clinical trial registration or results reporting requirements. While it seems a majority of the states proposing legislation did so in 2005, only a few enacted legislation. Print o MO Revised Statutes (official) (SLU Law KFM7830 2000.A25). o VAMS Vernon s Annotated Missouri Statutes (unofficial) (SLU Law KFM7830 1949.A413). o State Websites (free) Google [state name] statutes to locate relevant state websites. Many states have links to laws from the official state website or the secretary of state website. Availability of legislative history will vary by state. In Maine, a link from the Maine Legislature page allows one to search session laws (http://janus.state.me.us/legis/ros/meconlaw.htm). From secondary source 2010 Holli A. Kubicki. All rights reserved. 6

research, one may narrow keyword searches for clinical trials to the appropriate session (2005 laws). o Lexis/Westlaw/Loislaw (subscription) These resources will have relevant state statutory databases. Lexis and Westlaw include annotations and full text of bills. All three also enable keyword searching across all states. o Legislative History Westlaw - Westlaw State Legislative History Report database (STATE- LH-REP) contains amendments, bill analyses, bill histories, committee reports, and news releases; however the database does not include every state and is only for laws that were passed. Lexis Select the state of interest and look for legislative history materials. For example, in Illinois, Legislative Bill History database may be searched for clinical trials for potentially relevant information, including bills, analyses, governor s messages, committee reports, and summary amendments. ii. Regulations As with state statutes, searching for state rules and regulations will be significantly easier if secondary sources are used to point to particular states considering regulations. In June 2009, Maine proposed applicable regulations. Search for specific regulations (Maine) or look to see if states have proposed or finalized regulations on clinical trials (e.g. Missouri). o State websites (free) Google [state name] regulations to locate the secretary of state website. In Maine: (http://www.maine.gov/sos/cec/rules/). Browsing each June 2009 weekly rule-making notice will eventually lead to the proposed regulations of interest regarding clinical trials (2009-P136, proposed June 17th). The proposed rule-making notice provides a summary and information about and deadlines for submitting comments. o Lexis/Westlaw /Loislaw (subscription) These resources provide more userfriendly keyword searching in state-specific registries. Lexis and Westlaw provide annotations and links to other useful resources. All three enable keyword searching across all states codes and registries. These are ideal places to start state research without knowing which states have rules and regulations in effect. Print o State Registers Missouri (SLU Law KFM7834.A2 S4); locate notices of rulemaking and final rules, executive orders. o Code of State Regulations Missouri (SLU Law KFM7835 1988.A25); final regulations. Use the index to locate applicable regulations. c. Case Law While many related cases settle, it might still be instructive to browse relevant case law (federal and state) to spot potential issues with registering clinical trials and reporting results. 2010 Holli A. Kubicki. All rights reserved. 7

o NY Office of the Attorney General has both the Complaint and Consent and Order Judgment against GlaxoSmithKline. The documents can be accessed quickly and easily (and for free) by running a Google search. (e.g., see the Consent and Order Judgment at http://www.oag.state.ny.us/bureaus/health_care/pdfs/gsk_consent_and_order_j udgment.pdf). o Lexis run a Terms and Connectors search: clinical trial w/s regist! in the All Federal and State cases database. These terms will retrieve several variations of register (registration, registry, registries) in the same sentence as clinical trials (either before or after). o Westlaw to achieve similar results, select the All Cases database and run the following terms and connectors search: clinical trials /s regist! Quotes are necessary around clinical trials to search as a phrase instead of two separate words. III. Secondary Sources of Law Secondary sources are an excellent starting point for research, providing context and background information, as well as pointing the reader to applicable primary law. Sources range from brief news articles to extensive articles with in-depth analysis of particular issues. As previously mentioned, starting state law research with a quick look at the secondary sources can narrow the scope of the search considerably. a. Looseleafs Guide to Good Clinical Practice (Thompson Publishing Group) boasts one-stop shopping for clinical trial regulations and guidelines. Available in print and in Westlaw. This looseleaf covers federal and state reporting and registration requirements. o Guide to Good Clinical Practice subscribers will have access to a resource for tracking state requirements for clinical trials. Food Drug and Cosmetics Law Reporter (CCH) Full-text source covering federal and state laws and regulations and court decisions, along with pertinent regulations, proposals, rulings, decisions and other developments. Available online and in print (SLU Law KF3866.5.C65 1975) b. Journals and Law Reviews Feature: Food and Drug Law Journal is published four times a year by the Food and Drug Law Institute and features insight on and analysis of FDA actions, including FDAAA information. Articles from this journal are accessible online through Westlaw, Lexis and in print (SLU Law K6.O55). Featured article: Carolyne R. Hathaway et al., The Web of Clinical Trial Registration Obligations: Have Foreign Clinical Trials Been Caught?, 64 FOOD & DRUG L.J. 261 (2009). This article discusses the expansion of reporting and registration requirements under FDAAA and covers some of the additional sources of reporting requirements (industry and medical journal editors). 2010 Holli A. Kubicki. All rights reserved. 8

All Journals and Law Reviews Index to Legal Periodicals (ILP) enables users to keyword search across periodicals. Once identified, articles may be viewed online or located in print where applicable. ILP is available online (from Law Library homepage), on Westlaw or Lexis, and in print (SLU Law K33.I5). Lexis and Westlaw both have databases covering journals and law reviews. The Lexis Legal Periodicals database includes Law Reviews, Bar Journals, ABA Journals, Legal Newspapers, Legal Newsletters, Specialty Legal Publications, and CLE Materials. The Westlaw counterpart includes law reviews, journals, CLE material, ALR, Texts and other periodicals. Lexis and Westlaw also have smaller databases limited to journals and law reviews which may be a cheaper alternative to searching a more expansive database. Feature: Christine D. Galbraith, Dying to Know: A Demand for Genuine Public Access to Clinical Trial Results Data, 78 MISS. L.J. 705 (2009). This article provides background information on events leading up to FDAAA, analyzes FDAAA provisions, and discusses weaknesses of the Act. Available online (Hein Online, Lexis, Westlaw) and in print (SLU Law K13.I65). c. Books Feature: CLINICAL TRIAL REGISTRIES: A PRACTICAL GUIDE FOR SPONSORS AND RESEARCHERS OF MEDICINAL PRODUCTS (2006) provides articles written from the perspective of major stakeholders in clinical trials, including pharmaceutical companies, industry organizations, patients, and medical journal editors. Though published before FDAAA of 2007, the book is an invaluable resource for getting up to speed pre-fdaaa and contains a useful annotated bibliography referencing primary and secondary sources of law. While not in SLU Library holdings, the book may be requested using MOBIUS. IV. Current Awareness Once up to speed on relevant background information, there are a number of ways to stay current. This section highlights some of the more useful options. a. FDA Website The Clinical Trials section of the FDA website (www.fda.gov/scienceresearch/specialtopics/runningclinicaltrials/default.htm) provides a wealth of useful information for free. Interested parties can sign up for good clinical practice/human subjects protection email updates, browse for upcoming workshops and conferences, and view relevant FDA guidance documents issued. Feature: The FDA website contains a FDAAA Implementation Chart (http://www.fda.gov/regulatoryinformation/legislation/federalfooddrugandcosmeticactfdc Act/SignificantAmendmentstotheFDCAct/FoodandDrugAdministrationAmendmentsActof2007/ FDAAAImplementationChart/default.htm) which clearly shows the latest actions with respect to 2010 Holli A. Kubicki. All rights reserved. 9

the sections of the Act which were left open for subsequent regulation. Scroll to see section 801, the relevant clinical trial registry section. b. Blogs Feature: FDA Law Blog (http://www.fdalawblog.net/) is maintained by attorneys at Hyman, Phelps & McNamara, P.C. and generally tracks news from the FDA. Since the FDA oversees FDAAA, the blog will tip readers off to relevant updates and links to primary sources of law. The blog is typically updated daily. FDA Law Update (http://www.fdalawblog.com) is published by attorneys at Sheppard Mullin. The clinical trials topic link provides recent relevant information. c. Organizations Food and Drug Law Institute (http://www.fdli.org/) publishes the Food and Drug Law Journal, hosts conferences and workshops and has a mailing list to keep professionals up to date on relevant food and drug law topics. FDLI currently has over 10,000 members, including industry manufacturers and suppliers, consultants, law firms, associations, and individuals. d. BNA Life Sciences Law & Industry Report provides information geared toward the pharmaceutical industry regarding research. Users may search by keywords or browse recent topics by subject, arranged alphabetically (suggested topics: Clinical Trials, pharmaceutical research). Articles can also be sorted by state or agency. Medical Research Law & Policy Report provides frequent updates on topics, including clinical trials. e. Westclip, Lexis Alerts After running any of the searches previously discussed in either Westlaw or Lexis, setting up a Westclip or Alert, respectively, will rerun the searches and deliver results in print or email. It is easy to eliminate duplicate results so that only new information is included. V. Conclusion This guide has provided an overview of resources available covering federal and state requirements for registration and results reporting in clinical trials. It is important to note that other stakeholders (industry, medical journal editors, patient organizations, and international agencies) may require broader considerations or stricter disclosure requirements. 2010 Holli A. Kubicki. All rights reserved. 10