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A Other Elements of the Food and Drug Administration Amendments Act Chapter 1 discusses three sections of the Food and Drug Administration Amendments Act (FDAAA) of 20071 that are integral to the US Food and Drug Administration’s (FDA’s) ability to take a lifecycle approach to drug oversight: the authority to require postmarketing studies; the authority to require risk evalua- tion and mitigation strategies; and the requirement to develop a large-scale active surveillance system. This appendix discusses additional sections of FDAAA that improve FDA’s ability to oversee drugs in the postmarketing setting: increased authority to enforce submission of clinical-trial registry and database information; increased authority over the contents of direct-to-consumer advertising; increased authority to order labeling and warning changes in a timely manner; increased resources directed toward identifying and mitigating drug risks both premarketing and postmarketing; and increased requirements for agency transparency and risk communication. Those five elements are described briefly below. CONTENTS OF CLINICALTRIALS.GOV ClinicalTrials.gov is a clinical-trial registry and database website that is supported and housed by the National Institutes of Health (NIH) and provides public access to information regarding clinical trials. ClinicalTrials.gov was initially mandated by the FDA Modernization Act of 1997,2 and required that clinical trials for effectiveness conducted under an investigational new drug application (IND) for “serious or life threatening diseases” must be registered in 1 Food and Drug Administration Amendments Act of 2007, PL 110-85, 121 Stat. 823 (2007). 2 Food and Drug Administration Modernization Act of 1997, PL 105-115, 111 Stat. 2296 (1997). 227

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228 STUDYING THE SAFETY OF APPROVED DRUGS ClinicalTrials.gov; there was no enforcement capability to ensure that privately funded trials were included, and study results were not included in the database. 3 FDAAA expanded the requirements for registration of clinical trials to include all trials beyond Phase 1 that are parts of new drug applications, 4 required the reporting of results of those trials,5 and gave FDA the ability to enforce registra- tion by allowing penalties if drug sponsors failed to comply with submission of information to ClinicalTrials.gov.6 The statute directs NIH to ensure that the information submitted is truthful and not misleading.7 Sponsors must submit any changes in the information to NIH. FDAAA also increased FDA’s regulatory responsibility for the form of and methods for reporting serious adverse events in ClinicalTrials.gov.8 CONTENTS OF DIRECT-TO-CONSUMER ADVERTISING FDAAA provides FDA with the authority to require that direct-to-consumer radio and television advertisements include a “major statement relating to side effects and contraindications” of the drug and that the “major statement” be “presented in a clear, conspicuous, and neutral manner”.9 FDAAA stipulates that in the absence of such a statement, FDA can determine that the advertisement is “false or misleading”,10 and establishes civil penalties for dissemination of such advertisements.11 On March 29, 2010, FDA published in the Federal Register the following proposed standards for evaluating a “major statement”: • Information is presented in language that is readily understandable by consumers. • Audio information is understandable in terms of the volume, articulation, and pacing used. • Textual information is placed appropriately and is presented against a con- trasting background for sufficient duration and in a size and font style that can be read easily; and there are no distractions—such as statements, text, images or sounds—that detract from the communication of the major statement.12 3 42 USC § 282(i) (2010). 4 42 USC § 282(j)(1)(A) (2010). 5 42 USC § 282(j)(3) (2010). 6 42 USC § 282(j)(5)(E) (2010). 7 42 USC § 282(j)(5)(D) (2010). 8 42 USC § 282(j)(3)(I) (2010). 9 21 USC § 352(n) (2010). 10 21 USC § 352(q) (2010). 11 21 USC § 352(r) (2010). 12 Direct-to-Consumer Prescription Drug Advertisements; Presentation of the Major Statement in Television and Radio Advertisements in a Clear, Conspicuous, and Neutral Manner, 75 Fed. Reg. 15376-15387 (March 29, 2010) (amending 20 CFR § 202.1).

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229 APPENDIX A Final standards for evaluating a major statement are not yet published. Under FDAAA, FDA also has the authority to require a company to disclose a drug’s approval date for up to 2 years after a drug is approved if it “determines that [an] advertisement would otherwise be false or misleading”.13 FDA has declined to require an indication that a drug is new out of concern that “new” will be wrongly interpreted by consumers to imply “new and improved” (FDA, 2009a). LABEL AND WARNING CHANGES Before the passage of FDAAA, FDA could not require a drug manufacturer to change a label even if FDA became aware of new safety information about a marketed drug. FDA negotiated with the manufacturer about the language of the label, and its recourse was to use a claim of “misbranding” to revoke, or threaten to revoke, approval if a company was not willing to change a drug’s label (Carpenter, 2010). Under FDAAA, FDA can require changes in the label of a drug to reflect new information about its benefit–risk profile. Those changes can include “boxed warnings, contraindications, warnings, precautions, or adverse reactions”.14 INCREASED RESOURCES FOR DRUG SAFETY In addition to increasing FDA’s postmarketing responsibility and authority, FDAAA specifies that user fees will be “dedicated toward expediting the drug development process and the process for the review of human drug applications, including postmarketing drug safety activities”.15 Much of the funding comes from a specific authorization of $225 million over 5 years for “drug safety”.16 The funds are being used by the Center for Drug Evaluation and Review (CDER) and others in FDA to increase the number of staff dedicated to the safety evaluation of marketed medications and to administer CDER’s new safety-related authority under FDAAA, including the implementation of REMSs, postmarketing require - ments (PMRs), safety-related labeling changes, and active postmarketing risk identification (such as Sentinel) (FDA, 2009b). TRANSPARENCY AND COMMUNICATION FDAAA requires FDA to improve the availability and transparency of infor- mation about the drug-approval process, approved drugs, and, in particular, drug 13 2 1USC § 353b(e) (2010). 14 21 USC § 355(o)(4)(B) (2010). 15 21 USC § 379g note (2010). 16 21 USC § 379h(b)(4)(B) (2010).

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230 STUDYING THE SAFETY OF APPROVED DRUGS safety. To that end, the website MedWatch: The FDA Safety Information and Adverse Event Reporting Program (http://www.fda.gov/Safety/MedWatch) now includes information on new package inserts and labels, recent safety informa - tion and alerts, quarterly reports on potential safety issues identified by using the Adverse Event Reporting System database, and links to other FDA-approved safety information. FDA has recently taken advantage of new technology by making electronic subscriptions available to MedWatch via e-newsletters, safety alerts, and Twitter (FDA, 2012). Under FDAAA, FDA is also required to include on its website the approval package, which contains FDA staff reviews of a drug with proprietary informa - tion redacted, for any new molecular entity. For drugs that are not new molecular entities, it is required to provide the same material upon request. That approval information is now posted for each drug on FDA’s website at Drugs@FDA. 17 As suggested in the 2007 Institute of Medicine report, FDAAA called for FDA to form an Advisory Committee on Risk Communication,18 which was established in 2008. The role of the advisory committee is to improve how infor- mation on drugs and drug safety is communicated to health care professionals and the public.19 REFERENCES Carpenter, D. 2010. The other side of the gate: Reputation, power, and post-market regulation. In Reputation and power. Organizational image and pharmaceutical regulation at the FDA . Cam- bridge, NY: Princeton University Press. FDA (US Food and Drug Administration). 2009a. IOM recommendations: FDA actions update. http:// www.fda.gov/Safety/SafetyofSpecificProducts/ucm184598.htm (accessed March 20, 2012). FDA. 2009b. FDAAA implementation—highlights two years after enactment. http://www.fda.gov/ RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/Significant AmendmentstotheFDCAct/FoodandDrugAdministrationAmendmentsActof2007/ucm184271. htm (accessed March 20, 2012). FDA. 2012. MedWatch: The FDA safety information and adverse event reporting program. http:// www.fda.gov/Safety/MedWatch (accessed August 17, 2011). 17 Drugs@FDA is located at http://www.accessdata.fda.gov/scripts/cder/drugsatfda (accessed on February 13, 2012). 18 21 USC § 360bbb–6 (2010). 19 21 USC § 355(r)(6) (2010).