History, Policies, and Laws - ClinicalTrials.gov
`
`https://clinicaltrials.gov/ct2/about-site/history
`
`4/26/2021, 6:59 PM
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`This page provides information on selected events, policies, and laws related to the development and
`expansion of ClinicalTrials.gov. It is not intended to be comprehensive.
`
`Contents
`
`1997: Congress Passes Law (FDAMA) Requiring Trial Registration
`2000: NIH Releases ClinicalTrials.gov Web Site
`2000–2004: FDA Issues Guidance for Industry Documents
`2004: ClinicalTrials.gov Wins the Innovations in American Government Award
`2005: International Committee of Medical Journal Editors Requires Trial Registration
`2005: State of Maine Passes Clinical Studies Registration Law (Repealed in 2011)
`2006: World Health Organization Establishes Trial Registration Policy
`2007: Congress Passes Law (FDAAA) Expanding ClinicalTrials.gov Submission Requirements
`2008: ClinicalTrials.gov Releases Results Database
`2008: Declaration of Helsinki Revision Promotes Trial Registration and Results Dissemination
`2009: Public Meeting Held at the National Institutes of Health
`2013: European Medicines Agency Expands Clinical Trial Database to Include Summary Results
`2014: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 Issued for Public Comment
`2014: NIH Draft Policy on Registration and Results Submission of NIH-Funded Clinical Trials Issued
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`Mylan Exhibit 1086
`Mylan v. Regeneron, IPR2021-00881
`Page 1
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`Joining Petitioner: Apotex
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`History, Policies, and Laws - ClinicalTrials.gov
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`https://clinicaltrials.gov/ct2/about-site/history
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`4/26/2021, 6:59 PM
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`for Public Comment
`2015: National Cancer Institute Issues Clinical Trial Access Policy
`2016: Final Rule for FDAAA 801 Issued
`2016: Final NIH Policy on the Dissemination of NIH-Funded Clinical Trial Information Issued
`2017: Revised Common Rule (45 CFR 46) Issued
`2020: Federal Court Decision in Seife et al. v. HHS et al., 18-cv-11462 (NRB) (S.D.N.Y. Feb. 24, 2020)
`
`1997: Congress Passes Law (FDAMA) Requiring Trial Registration
`
`The first U.S. Federal law to require trial registration was the Food and Drug Administration
`Modernization Act of 1997 (FDAMA) (PDF). Section 113 of FDAMA (FDAMA 113) required the National
`Institutes of Health (NIH) to create a public information resource on certain clinical trials regulated by
`the Food and Drug Administration (FDA). Specifically, FDAMA 113 required that the registry include
`information about federally or privately funded clinical trials conducted under investigational new drug
`applications to test the effectiveness of experimental drugs for patients with serious or life-threatening
`diseases or conditions.
`
`The information in the registry was intended for a wide audience, including individuals with serious or
`life-threatening diseases or conditions, members of the public, health care providers, and researchers.
`
`TO TOP
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`2000: NIH Releases ClinicalTrials.gov Web Site
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`With input from FDA and others, the NIH National Library of Medicine (NLM) developed
`ClinicalTrials.gov. The first version of ClinicalTrials.gov was made available to the public on February
`29, 2000. At the time, ClinicalTrials.gov primarily included NIH-funded studies.
`
`NLM Press Release: National Institutes of Health Launches ClinicalTrials.gov (February 29, 2000)
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`TO TOP
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`2000–2004: FDA Issues Guidance for Industry Documents
`
`In 2000 FDA issued a draft Guidance for Industry document, which provided recommendations for
`researchers submitting information to ClinicalTrials.gov. A final guidance document that incorporated
`comments from the public was issued in 2002 and was withdrawn by FDA in September 2017.
`
`FDA Final Guidance, March 2002: Guidance for Industry: Information Program on Clinical Trials for
`Serious or Life-Threatening Diseases and Conditions (Withdrawn by FDA September 2017)
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`In January 2004 FDA proposed a revised draft Guidance for Industry document that included guidance
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`Mylan Exhibit 1086
`Mylan v. Regeneron, IPR2021-00881
`Page 2
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`Joining Petitioner: Apotex
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`History, Policies, and Laws - ClinicalTrials.gov
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`https://clinicaltrials.gov/ct2/about-site/history
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`4/26/2021, 6:59 PM
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`for researchers submitting information required by the Best Pharmaceuticals for Children Act of 2002.
`This draft guidance was withdrawn by FDA in September 2017.
`
`FDA Draft Guidance, January 2004: Guidance for Industry: Information Program on Clinical Trials for
`Serious or Life-Threatening Diseases and Conditions (Withdrawn by FDA September 2017)
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`TO TOP
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`2004: ClinicalTrials.gov Wins the Innovations in American Government Award
`
`In 2004 ClinicalTrials.gov was cited by the Ash Center for Democratic Governance and Innovation at the
`Harvard Kennedy School as "a successful model for the creation and maintenance of a system that
`processes and presents large amounts of specialized information to a wide range of users" and was
`selected as one of five award winners. The Innovations in American Government Awards is the Nation's
`preeminent program devoted to recognizing and promoting excellence and creativity in the public
`sector. The program highlights exemplary models of government innovation and advances efforts to
`address the Nation's most pressing public concerns.
`
`Ash Center: ClinicalTrials.gov award page
`NIH Press Release: National Institutes of Health's "ClinicalTrials.gov" Web Site Wins Prestigious
`Award
`
`TO TOP
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`2005: International Committee of Medical Journal Editors Requires Trial Registration
`
`In 2005 the International Committee of Medical Journal Editors (ICMJE) began requiring trial
`registration as a condition of publication.
`
`ICMJE Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Obligation to
`Register Clinical Trials
`ICMJE: Frequently Asked Questions About Clinical Trials Registration
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`TO TOP
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`2005: State of Maine Passes Clinical Studies Registration Law (Repealed in 2011)
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`In 2005 the State of Maine passed a law requiring prescription drug manufacturers or labelers to submit
`clinical study registration and results information to ClinicalTrials.gov. The law applied to FDA-
`approved prescription drugs that are dispensed, administered, delivered, or promoted in Maine. In
`2011 the law was repealed; it is no longer in effect.
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`Maine State Public Law, Chapter 461: An Act To Make Certain Prescription Drug Disclosure Laws
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`Mylan Exhibit 1086
`Mylan v. Regeneron, IPR2021-00881
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`Joining Petitioner: Apotex
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`History, Policies, and Laws - ClinicalTrials.gov
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`https://clinicaltrials.gov/ct2/about-site/history
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`Consistent with Federal Law (PDF) (Repealed on July 8, 2011)
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`TO TOP
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`2006: World Health Organization Establishes Trial Registration Policy
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`In 2006 the World Health Organization (WHO) stated that all clinical trials should be registered, and it
`identified a minimum trial registration dataset of 20 items. In 2007 WHO launched the International
`Clinical Trials Registry Platform (ICTRP), which includes a search portal providing a single point of
`access to studies registered in various international registries. The ICTRP Search Portal includes data
`available on ClinicalTrials.gov.
`
`WHO: International Clinical Trials Registry Platform
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`TO TOP
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`2007: Congress Passes Law (FDAAA) Expanding ClinicalTrials.gov Submission Requirements
`
`In 2007 the requirements for submission to ClinicalTrials.gov were expanded after Congress passed the
`Food and Drug Administration Amendments Act of 2007 (FDAAA) (PDF). Section 801 of FDAAA (FDAAA
`801) required more types of trials to be registered; additional trial registration information; and the
`submission of summary results, including adverse events, for certain trials. The law also included
`penalties for noncompliance, such as the withholding of NIH grant funding and civil monetary penalties
`of up to $10,000 a day.
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`FDAAA 801 and the Final Rule
`NIH Office of Extramural Research: Frequently Asked Questions: FDAAA - Further Resources for NIH
`Grantees
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`TO TOP
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`2008: ClinicalTrials.gov Releases Results Database
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`In September 2008, as required by FDAAA 801, ClinicalTrials.gov began allowing sponsors and principal
`investigators to submit the results of clinical studies. The submission of adverse event information was
`optional when the results database was released but was required beginning in September 2009.
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`NLM Technical Bulletin: ClinicalTrials.gov to Include Basic Results Data
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`TO TOP
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`2008: Declaration of Helsinki Revision Promotes Trial Registration and Results Dissemination
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`In October 2008 the 59th World Medical Association (WMA) General Assembly amended the Declaration
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`Mylan Exhibit 1086
`Mylan v. Regeneron, IPR2021-00881
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`Joining Petitioner: Apotex
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`History, Policies, and Laws - ClinicalTrials.gov
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`https://clinicaltrials.gov/ct2/about-site/history
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`4/26/2021, 6:59 PM
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`of Helsinki - Ethical Principles for Medical Research Involving Human Subjects. Two newly added
`principles (paragraphs 19 and 30) considered the prospective registration and the public disclosure of
`study results to be ethical obligations.
`
`In October 2013 the 64th WMA General Assembly modified these two principles. In particular, paragraph
`35 (formerly 19) required prospective registration, as follows: "Every research study involving human
`subjects must be registered in a publicly accessible database before recruitment of the first subject."
`
`Paragraph 36 (formerly 30) promotes the public disclosure of study results as an ethical obligation and
`states, in part, "Researchers have a duty to make publicly available the results of their research on
`human subjects and are accountable for the completeness and accuracy of their reports. All parties
`[i.e., researchers, authors, sponsors, editors, and publishers] should adhere to accepted guidelines for
`ethical reporting. Negative and inconclusive as well as positive results should be published or
`otherwise made publicly available."
`
`WMA 2013 Declaration of Helsinki - Ethical Principles for Medical Research Involving Human
`Subjects
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`TO TOP
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`2009: Public Meeting Held at the National Institutes of Health
`
`In accordance with FDAAA 801, NIH held a public meeting in April 2009 to solicit input from interested
`individuals about future regulations that will expand the information on ClinicalTrials.gov.
`
`NIH gathered input on a range of issues, including the submission of adverse events information and
`the addition of narrative summaries to results submissions, for use in the development of draft
`regulations.
`
`NIH: Videocast and podcast of the public meeting
`Regulations.gov: Docket Folder Summary: Public Meeting on Expansion of the Clinical Trial Registry
`and Results Data Bank. Includes the meeting transcript, final meeting agenda, list of speakers for
`public statements, presentations, and public submissions.
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`TO TOP
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`2013: European Medicines Agency Expands Clinical Trial Database to Include Summary Results
`
`In October 2013 the European Medicines Agency (EMA) released a new version of the European Clinical
`Trials Database (EudraCT), marking "the initial step of a process through which summary clinical trial
`results will be made publicly available through the EU Clinical Trials Register (EU CTR)." Notably, the
`EudraCT summary results data requirements are "substantially aligned" with those of the
`ClinicalTrials.gov results database.
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`Mylan Exhibit 1086
`Mylan v. Regeneron, IPR2021-00881
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`Joining Petitioner: Apotex
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`History, Policies, and Laws - ClinicalTrials.gov
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`https://clinicaltrials.gov/ct2/about-site/history
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`EMA Press Release: European Medicines Agency launches a new version of EudraCT: Summary
`results of clinical trials soon to be available to the public
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`TO TOP
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`2014: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 Issued for Public Comment
`
`In November 2014 the U.S. Department of Health and Human Services issued a notice of proposed
`rulemaking (NPRM) describing the proposed requirements and procedures for registering and
`submitting the results, including adverse events, of clinical trials on ClinicalTrials.gov, in accordance
`with FDAAA 801. It also considers regulations intended to provide more complete results information
`and enhance patients' access to the results of clinical trials, by proposing to expand the requirement
`for submission of results information for Applicable Clinical Trials of unapproved products (i.e., drugs,
`biological products, or devices that have not been approved, licensed, or cleared by FDA). Public
`comments on the proposed rule were accepted until March 23, 2015. All substantive comments will be
`carefully reviewed and considered in drafting a final rule.
`
`NIH News Release: HHS and NIH take steps to enhance transparency of clinical trial results
`(November 19, 2014)
`
`Publication: Zarin DA, Tse T, Sheehan J. The proposed rule for U.S. clinical trial registration and
`results submission. N Engl J Med. 2015 Jan 8;372(2):174-80. [Full Text]
`Publication: Hudson KL, Collins FS. Sharing and reporting the results of clinical trials. JAMA.
`2015 Jan 27;313(4):355-6. [Full Text]
`Office of the Federal Register: Clinical Trials Registration and Results Submission Notice of
`Proposed Rulemaking (November 2014)
`
`NIH: What Changes From Current Practice Are Proposed in the NPRM? (PDF) (November 2014)
`NIH: NPRM at a Glance: Summary of Key Proposals (PDF) (November 2014)
`Reginfo.gov: U.S. Department of Health and Human Services Unified Agenda - Clinical Trials
`Registration and Results Submission (RIN:0925-AA55). Describes the public process for the
`expansion of ClinicalTrials.gov under FDAAA 801.
`
`OMB: EO 12866 Regulatory Review for Notice of Proposed Rulemaking (NPRM): OIRA received
`the NPRM on March 11, 2014, for regulatory review and concluded its review on August 29, 2014.
`HHS.gov: HHS Regulations Toolkit - Information about the rulemaking process
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`TO TOP
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`2014: NIH Draft Policy on Registration and Results Submission of NIH-Funded Clinical Trials Issued for
`Public Comment
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`In November 2014 NIH proposed a policy to ensure that every clinical trial (see the Revised NIH
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`Mylan Exhibit 1086
`Mylan v. Regeneron, IPR2021-00881
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`Joining Petitioner: Apotex
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`History, Policies, and Laws - ClinicalTrials.gov
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`https://clinicaltrials.gov/ct2/about-site/history
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`Definition of "Clinical Trial") that receives NIH funding is registered on ClinicalTrials.gov and has
`summary results submitted and posted in a timely manner, whether subject to FDAAA 801 or not.
`Public comments on the proposed rule were accepted until March 23, 2015. All substantive comments
`will be carefully reviewed and considered in drafting a final policy.
`
`NIH News Release: HHS and NIH take steps to enhance transparency of clinical trial results
`(November 19, 2014)
`
`Publication: Hudson KL, Collins FS. Sharing and reporting the results of clinical trials. JAMA.
`2015 Jan 27;313(4):355-6. [Full Text]
`NIH: Request for Public Comments on the Draft NIH Policy on the Dissemination of NIH-Funded
`Clinical Trial Information (November 2014)
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`TO TOP
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`2015: National Cancer Institute Issues Clinical Trial Access Policy
`
`In January 2015 the NIH National Cancer Institute (NCI) issued its Policy Ensuring Public Availability of
`Results from NCI-supported Clinical Trials. Generally, for "all initiated or commenced NCI-Supported
`Interventional Clinical Trials whether extramural or intramural" (i.e., Covered Trials), "Final Trial Results
`are expected to be reported in a publicly accessible manner within twelve (12) months of the Trial's
`Primary Completion Date regardless of whether the clinical trial was completed as planned or
`terminated earlier." This policy will be incorporated as a term and condition of any award supporting a
`Covered Trial.
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`TO TOP
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`2016: Final Rule for FDAAA 801 Issued
`
`In September 2016, the U.S. Department of Health and Human Services issued a Final Rule for Clinical
`Trials Registration and Results Information Submission (42 CFR Part 11) that clarifies and expands the
`regulatory requirements and procedures for submitting registration and summary results information
`of clinical trials on ClinicalTrials.gov, in accordance with FDAAA 801. The final rule is intended to make it
`clear to sponsors, investigators, and the public which trials must be submitted, when they must be
`submitted, and whether compliance has been achieved. For example, the final rule clarifies the
`definition of an Applicable Clinical Trial and provides structured criteria for determining which studies
`are considered to meet the definition. The final rule also expands the FDAAA 801 requirements by
`requiring the submission of results information for trials of unapproved products. The regulation is
`effective on January 18, 2017 and responsible parties are expected to be in compliance as of April 18,
`2017.
`
`NIH News Release: HHS takes steps to provide more information about clinical trials to the public
`(September 16, 2016)
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`Mylan Exhibit 1086
`Mylan v. Regeneron, IPR2021-00881
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`Joining Petitioner: Apotex
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`History, Policies, and Laws - ClinicalTrials.gov
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`https://clinicaltrials.gov/ct2/about-site/history
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`Publication: Zarin DA, Tse T, Williams RJ, Carr S. Trial reporting in ClinicalTrials.gov - the final
`rule. N Engl J Med. 2016 Nov 17;375(20):1998-2004. [Full Text]
`Publication: Hudson KL, Lauer MS, Collins FS. Toward a new era of trust and transparency in
`clinical trials. JAMA; 2016 Oct4;316(13):1353-1354. [Full Text]
`Office of the Federal Register: Final Rule for Clinical Trials Registration and Results Information
`Submission (September 2016)
`
`NIH: Changes from Current Practice Described in the Final Rule
`Office of Management and Budget (OMB): EO 12866 Regulatory Review for Final Rule: OMB's
`Office of Information and Regulatory Affairs (OIRA) received the final rule on August 1, 2016, and
`concluded its review on September 15, 2016.
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`TO TOP
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`2016: Final NIH Policy on the Dissemination of NIH-funded Clinical Trial Information Issued
`
`In September 2016, NIH issued a final policy to promote broad and responsible dissemination of
`information from NIH-funded clinical trials through ClinicalTrials.gov. Under this policy, every clinical
`trial funded in whole or in part by NIH is expected to be registered on ClinicalTrials.gov and have
`summary results information submitted and posted in a timely manner, whether subject to FDAAA 801
`or not. This policy is effective for applications for funding, including grants, other transactions, and
`contracts submitted on or after January 18, 2017. For the NIH intramural program, the policy applies to
`clinical trials initiated on or after January 18, 2017.
`
`NIH News Release: HHS takes steps to provide more information about clinical trials to the public
`(September 16, 2016)
`
`Publication: Hudson KL, Lauer MS, Collins FS. Toward a new era of trust and transparency in
`clinical trials. JAMA; 2016 Oct4;316(13):1353-1354. [Full Text]
`NIH Policy on the Dissemination of NIH-Funded Clinical Trial Information (September 2016)
`NIH OER: Continued Extension of Certain Flexibilities for Prospective Basic Experimental Studies
`With Human Participants (March 2021)
`
`TO TOP
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`2017: Revised Common Rule (45 CFR 46) Issued
`
`In January 2017, nearly 20 Federal department and agencies issued a revised Federal Policy for the
`Protection of Human Subjects (also known as subpart A of 45 CFR part 46, or the "Common Rule"). The
`revisions were designed to modernize, strengthen, and make more effective the Common Rule
`originally promulgated in 1991. The revised Common Rule is intended to better protect human subjects
`involved in research, while facilitating valuable research and reducing burden, delay, and ambiguity for
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`Mylan v. Regeneron, IPR2021-00881
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`History, Policies, and Laws - ClinicalTrials.gov
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`https://clinicaltrials.gov/ct2/about-site/history
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`investigators. It became effective on July 19, 2018, as amended.
`
`The revised Common Rule (45 CFR 46.116(h)) requires that for any clinical trial conducted or supported
`by a Common Rule department or agency, one consent form used in enrolling participants be posted
`on a publicly available Federal website within a specific time frame. In an August 2018 announcement,
`ClinicalTrials.gov and Regulations.gov were identified as the publicly available federal websites that
`will satisfy the consent form posting requirement.
`
`Office of Human Research Protections (OHRP): Announcement: Federal websites that will satisfy
`the revised Common Rule's requirement to post clinical trial consent forms (45 CFR 46.116(h))
`(August 2018) (PDF)
`
`TO TOP
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`2020: Federal Court Decision in Seife et al. v. HHS et al., 18-cv-11462 (NRB) (S.D.N.Y. Feb. 24, 2020)
`
`On February 24, 2020, a Federal court held that Section 801 of the Food and Drug Administration
`Amendments Act of 2007 (FDAAA 801) (PDF) requires submission of results information for an
`"applicable clinical trial" ("ACT") that was initiated after September 27, 2007, or that was ongoing as of
`December 26, 2007, if the ACT studies a product that is approved, licensed, or cleared by the Food and
`Drug Administration (FDA) at any time, including after the ACT's primary completion date.
`
`On September 21, 2016, the Department of Health and Human Services ("HHS") published the Final
`Rule for Clinical Trials Registration and Results Information Submission (81 FR 64981). The preamble to
`the Final Rule states that a responsible party is not required to submit to the ClinicalTrials.gov data
`bank results information under sections 402(j)(3)(C) and 402(j)(3)(I) of the Public Health Service (PHS)
`Act for an ACT that was completed before January 18, 2017, the effective date of the Final Rule, if the
`ACT studied a product that was not approved, licensed, or cleared for any use until after the ACT's
`primary completion date (81 FR 65067).
`
`On February 24, 2020, a Federal court rejected this interpretation, holding that FDAAA 801 requires
`responsible parties to submit to the ClinicalTrials.gov data bank results information required under
`section 402(j)(3)(C) of the PHS Act, which includes information required under section 402(j)(3)(I) of the
`PHS Act, for ACTs subject to the registration requirements and with a primary completion date before
`January 18, 2017, if the ACT studies a product that is approved, licensed, or cleared after the ACT's
`primary completion date. The Court set aside HHS's contrary interpretation in the preamble to the Final
`Rule but did not change the regulations promulgated in 2016. Seife et al. v. HHS, et al., No. 18-cv-11462-
`NRB, 2020 WL 883478 (S.D.N.Y. February 24, 2020).
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`This page last reviewed in March 2021
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`Mylan Exhibit 1086
`Mylan v. Regeneron, IPR2021-00881
`Page 9
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`Joining Petitioner: Apotex
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