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ABA Health eSource
May 2009 Volume 5 Number 9

FDA Issues Clarification of U.S. Clinical Trials Registry Requirements

By Carolyne Hathaway, J. Ben Haas and Cassie Scherer, Latham & Watkins LLP, Washington , D.C.

Introduction

The Food and Drug Administration Modernization Act of 1997 1 (FDAMA or Act) established a clinical trials registry (found at Clinicaltrials.gov) to provide a convenient source of public information regarding ongoing drug trials in human subjects. FDAMA required drug companies conducting clinical trials subject to the Act to submit information about their trials to the registry within the first 21 days of opening enrollment. The Act required that the information be made available to the public within five days of the sponsor's submission. The database, administered by the National Institutes of Health (NIH), provides transparency in the conduct of clinical trials, and is a resource for patients seeking to identify clinical trials in which they might participate. The Food and Drug Administration Amendments Act of 2007 (FDAAA) 2 expanded the scope and applicability of the clinical trials registry to include medical device trials. It also required sponsors to report information related to clinical trial results. 3 Among other things, FDAAA requires a company making regulatory submissions to the Food and Drug Administration (FDA) to certify that it has complied with all applicable clinical trial registry obligations. In many cases, the scope and applicability of these new requirements are ambiguous, particularly with respect to foreign sponsors and studies. Since the enactment of FDAAA, FDA has issued guidance documents to clarify the new requirements. This article focuses on FDA's interpretation of the new certification requirement and its clarification of FDAAA's potential impact on foreign clinical trial sponsors seeking to introduce a drug or device to the U.S. market.

A. Scope of Certification Requirement

The FDAAA requires regulatory submissions to FDA to be accompanied by a certification that "all applicable requirements [of the clinical trial registry] have been met." 4 Failure to provide this certification, knowingly submitting a false certification, or otherwise failing to comply with applicable requirements could lead to substantial civil penalties. 5 However, many regulatory submissions do not include information that needs to be posted on the registry, and other submissions may incorporate information provided in earlier submissions. 6 Thus, FDA recognized that imposing the certification requirement on all regulatory submissions would not serve the purpose of the clinical trials registry, and in January 2009 issued a final guidance document limiting the types of regulatory submissions subject to this requirement. 7 According to FDA's guidance, the following submissions need not include a certification:

Investigational Applications/Submissions

  • Chemistry and manufacturing amendments to investigational new drug applications(INDs) 8
  • Non-clinical pharmacology/toxicology amendments to INDs
  • IND Safety Reports
  • Single Patient INDs
  • Meeting requests
  • Investigational Device Exemption Applications 9 (IDEs)

Marketing and Post-Marketing Applications/Submissions

  • Chemistry and manufacturing amendments and supplements to Biologics License Applications 10 (BLAs) and New Drug Applications 11 (NDAs)
  • Non-clinical pharmacology/toxicology amendments and supplements to BLAs and NDAs
  • Humanitarian Device Exemptions 12 (HDEs) and Premarket Approval Application 13 (PMA) 30 Day Notices
  • Abbreviated New Drug Application 14 (ANDA) amendments and supplements that contain no in-vivo bioequivalence information
  • ANDA, BLA and NDA promotional materials
  • BLA and NDA Safety Reports
  • ANDA, BLA, NDA, HDE and PMA mandatory and voluntary adverse event or medical device reports
  • Meeting requests
  • 510(k)s 15 that contain no clinical data

FDA's guidance explains, however, that there may be times in which these submissions "do, in fact, contain information that refers to, relates to or includes information on an applicable clinical trial that the registry and results databases are intended to capture." 16 In these cases, FDA intends to require a certification of compliance to accompany an otherwise "exempt" submission on a case-by-case basis.

B. Applicability of Certification Requirements to Ex-US Trials

The clinical trial registration requirements apply only to "applicable clinical trials." 17 FDAAA defines "applicable clinical trials" to mean "applicable device clinical trials" or "applicable drug clinical trials." These include (i) post-Phase I clinical trials of drug or biologic products subject to FDA regulation 18 and (ii) clinical trials of devices subject to FDA regulation that investigate health outcomes, other than small feasibility studies, along with pediatric postmarket surveillance. 19 It is unclear whether this definition includes trials conducted outside the United States without an IND or an IDE, which are subsequently used to support U.S. marketing approval. Accordingly, the law leaves open the possibility that FDA may require the registration of such trials.

FDA proposed to clarify the definition of "applicable clinical trials," in a draft notice issued on December 8, 2008. 20 The notice attempts to resolve the confusion regarding application of the law to clinical trials conducted outside the United States. The notice explains that non-U.S. drug or device trials may be "subject to" FDA regulation and, thus, may be deemed "applicable clinical trials" if the drug or device under study is manufactured in the United States. In addition, FDA noted that the term "applicable drug clinical trial" includes non-U.S. drug trials conducted under an IND. 21 However, the notice does not address whether medical device trials conducted abroad under an IDE are similarly considered to be "applicable device clinical trials." It is not clear from the notice whether this distinction between non-U.S. drug and device trials is intentional.

The notice explicitly excludes from the term "applicable clinical trial" non-U.S. trials of products not manufactured in the United States or its territories and that are not being conducted under an IND. However, it does not address whether such trials might subsequently become "subject to" FDA regulations if they are used in support of a US marketing application. FDA may, therefore, conclude that ongoing or completed trials become "applicable clinical trials" when used to support such a submission and require responsible parties 22 to comply with the registration requirements at that time.

The ambiguity in the definition of "applicable clinical trials" creates considerable uncertainty regarding the application of the certification requirement to foreign applicants relying on non-U.S. studies to support marketing approval. The certification form 23 provides those making regulatory submissions with three options to indicate their compliance with the registration obligations of FDAAA. The submitter must certify that FDAAA's registration requirements either (A) do not apply because the submission has not referenced a clinical trial, (B) do not apply because the clinical trial referenced in the submission is not an applicable clinical trial, or (C) have been met because the trial referenced in the submission is an applicable clinical trial. Of course, without a clear understanding of whether (or when) a non-U.S. clinical trial is (or becomes) "applicable," the submitter may be unable to certify correctly and may subject itself to administrative penalties.

If FDA interprets the term "applicable clinical trial" to include non-U.S. trials submitted in a marketing application, the burden on overseas companies conducting clinical trials that are subsequently used to obtain U.S. marketing approval increases substantially. It is therefore important for companies undertaking such trials to keep abreast of the changing legal landscape and fully consider the need to register and certify their trials to ensure their U.S. marketing applications and regulatory submissions are compliant with FDA regulation.


1 Pub. L. No. 105-115, 111 Stat. 2296 (1997).
2 Pub. L. No. 110-85, 121 Stat. 823 (2007).
3 Id . § 801 (amending § 402 of the Public Health Service Act, 42 U.S.C. § 282).
4 42 USC. § 282(j)(5)(B). The certification form is available at http://www.fda.gov/opacom/morechoices/fdaforms/FDA-3674.pdf .
5 21 U.S.C. § 331(jj)(1)-(2).
6 US Food & Drug Admin., Draft Guidance for Sponsors, Industry, Researchers, Investigators, and Food and Drug Administration Staff—Certifications to Accompany Drug, Biological Product, and Device Applications/Submissions: Compliance with Section 402(j) of the Public Health Service Act, Added by Title VIII of the Food and Drug Administration Amendments Act of 2007 (2008), available at http://www.fda.gov/OHRMS/DOCKETS/98fr/FDA-2008-D-0224-GDL.pdf .
7 Id .
8 An IND is the mechanism through which clinical investigators are able to transport or distribute a drug across state lines for the purpose of clinical investigation prior to FDA's approval of a marketing application. See Center for Drug Evaluation and Research, US Food & Drug Admin., Investigational New Drug (IND) Application Process, http://www.fda.gov/cder/Regulatory/applications/ind_page_1.htm .
9 An IDE permits use of an unapproved medical device in clinical investigations to enable collection of sufficient data to support an application for marketing approval. See Center for Devices and Radiological Health, US Food & Drug Admin., Clinical Trials & Investigational Device Exemption (IDE), http://www.fda.gov/cdrh/devadvice/ide/index.shtml .
10 A BLA is the mechanism through which a biologic is approved for marketing in the United States. See James T. O'Reilly, Food and Drug Administration § 15.81 (3d ed. 2007).
11 A NDA is the mechanism through which a new drug is approved for marketing in the United States. See Center for Drug Evaluation and Research, US Food & Drug Admin., New Drug Application (NDA) Process, http://www.fda.gov/CDER/REGULATORY/APPLICATIONS/nda.htm .
12 A HDE is a mechanism through which a medical device may be distributed for humanitarian use in the United States. See Centers for Devices and Radiological Health, US Food & Drug Admin., Guidance for Industry and FDA Staff—Humanitarian Device Exemption (HDE) Regulation: Questions and Answers 2 (2001), available at http://www.fda.gov/cdrh/ode/guidance/1381.pdf .
13 A PMA is the mechanism through which higher risk devices are approved for marketing in the United States. See Center for Devices and Radiological Health, US Food & Drug Admin., Device Advice: Premarket Approval (PMA), http://www.fda.gov/cdrh/devadvice/pma/ .
14 An ANDA is the mechanism through which a generic drug is approved for marketing in the United States. See Center for Drug Evaluation and Research, US Food & Drug Admin., Abbreviated New Drug Application (ANDA) Process for Generic Drugs, http://www.fda.gov/cder/Regulatory/applications/ANDA.htm .

15

A 510(k) is the mechanism through which lower risk devices are cleared for marketing in the United States. See Center for Devices and Radiological Health, US Food & Drug Admin., Device Advice: Premarket Notification 510(k), http://www.fda.gov/CDRH/DEVADVICE/314.html .
16 US Food & Drug Admin., Draft Guidance for Sponsors, Industry, Researchers, Investigators, and Food and Drug Administration Staff—Certifications to Accompany Drug, Biological Product, and Device Applications/Submissions: Compliance with Section 402(j) of the Public Health Service Act, Added by Title VIII of the Food and Drug Administration Amendments Act of 2007, at 4 (2008), available at http://www.fda.gov/OHRMS/DOCKETS/98fr/FDA-2008-D-0224-GDL.pdf .
17 42 U.S.C. § 282(j)(1)(A)(i).
18 Id . § 282(j)(1)(A)(iii). Human clinical trials are typically conducted in three sequential phases (Phase I, II and III), which may overlap.
19 Id . § 282(j)(1)(A)(ii).
20 Draft Elaboration of Definitions , at 5-7 (2008), available at http://prsinfo.clinicaltrials.gov/ElaborationsOnDefinitions.pdf . This draft is posted on a webpage maintained by the National Library of Medicine at NIH, but it is unclear whether authorship is shared by FDA and NIH.
21 Id .
22 FDAAA defines the term "responsible party" as the sponsor of the trial, or the principal investigator if so designated by the sponsor, grantee, contractor or awardee, so long as the principal investigator is the individual responsible for conducting the trial and controlling the data, is authorized to publish the results, and can meet the requirements under FDAAA. 42 U.S.C. § 282(j)(1)(A)(ix). The December 8, 2008 Draft Elaboration of Definitions further clarifies the meaning of "responsible party" by indicating that the sponsor is the person initiating the trial, and the principal investigator is the person conducting the trial with full responsibility and accountability for the treatment of subjects and integrity of data and results. Draft Elaboration of Definitions, at 1-2 (2008), available at http://prsinfo.clinicaltrials.gov/ElaborationsOnDefinitions.pdf .
23 US Food & Drug Admin., Form FDA 3674: "Certification of Compliance, under 42 U.S.C. § 282(j)(5)(B), with Requirements of ClinicalTrials.gov Data Bank (42 U.S.C. § 282(j))," available at http://www.fda.gov/opacom/morechoices/fdaforms/FDA-3674_508.pdf .

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