1. The Food and Drug Administration Amendments Act of 2007: Implications of the Drug Safety Provisions Carolyn D. Jones, J.D., MPh Director, Regulatory Policy Biogen Idec Inc. November 30, 2007

2. 2 What is FDAAA? New legislation that –Was signed into law on September 27, 2007 –Made major changes to some of the provisions of the Federal Food Drug & Cosmetic Act (FFDCA) that were set to expire on September 30, 2007 –Added new provisions to the FFDCA

3. 3 What is FDAAA? Four provisions reauthorize existing law –Prescription Drug User Fee Act –Medical Device User Fee Act –Best Pharmaceutical for Children's Act –Pediatric Research Equity Act New provisions –Pediatric Medical Device Safety and Development Act –Reagan-Udall Foundation –Conflicts of Interest –Expanded Clinical Trial Registry Data Bank –Enhanced Authorities for Postmarket Safety of Drugs –Food Safety

4. 4 Title IX: Enhanced Authorities Regarding Postmarket Safety of Drugs Tools to Address Product-Specific Issues –Includes a new misbranding provision –Provides FDA specific authority to require post-market clinical studies or trials and labeling changes –Permits FDA to require a drug or biologics to submit a risk evaluation and mitigation strategy (REMS) with the application for approval –Adds a requirement for an “action package for approval” for new drugs –Provides for enhanced civil money penalties for compliance failures Tools for Systemic Drug Safety Monitoring –Creates an active postmarket risk identification & analysis system (goal of linking data on 100,000,000 patients by 2012) –Creates a drug safety web-site with comprehensive drug safety information for patients and providers –Requires referral of any NDA or BLA for a NME to an advisory committee (although this can be waived)

5. 5 Tools to Assess Product-Specific Issues Postmarket Studies and Surveillance –New misbranding provision that makes it a prohibited act to: Introduce or deliver for introduction into interstate commerce a new drug if the sponsor is in violation of a requirement regarding post-market clinical trials or studies or requested safety labeling changes –Imposes civil monetary penalties for violations of up to $250,000 per violation (doubles every 30 days up to $100,000,000; not to exceed $10,000,000 for all violations)

6. 6 Postmarket Studies and Surveillance –FDA can require a sponsor that holds an approved NDA or BLA for a drug to conduct a postmarket study or trial to assess a known risk assess signals of a serious risk identify an unexpected serious risk –To require a postmarket study of an approved drug, the FDA must first determine that the adverse event reporting and active postmarket surveillance would be inadequate and to require a clinical trial, postmarket studies would be insufficient –FDA’s request for postmarket studies must be based on appropriate scientific data or new safety information (already approved product) Tools to Assess Product-Specific Issues

7. 7 Labeling Changes –If there are new safety signals FDA can request a labeling change –FDA may issue an order requiring a labeling change –Includes a troubling rule of construction stating that complying with FDA required labeling does not exempt the sponsor from “maintaining its label in accordance with existing requirements” Tools to Assess Product-Specific Issues

8. 8 Risk Evaluation and Mitigation Strategy (REMS) –Required when FDA determines it is necessary to ensure the “benefits of the drug outweigh the risks” of the drug (pre or post-approval) Preapproval: FDA must consider the following factors : –size of the population likely to use the drug –seriousness of the disease or condition indicated for the drug –expected benefit of the drug –expected duration of treatment –seriousness of any known or potential adverse event –whether drug is a new molecular entity Postapproval: FDA decision based on new safety signals –Information about a serious risk or unexpected risk –Information from clinical trial data, adverse event reports, postmarket study, peer-reviewed literature, and the postmarket risk identification and analysis system Tools to Assess Product-Specific Issues

9. 9 REMS Content –REMS must include timetable for assessment of the strategy –REMS may include one or more additional elements medication guide or patient insert communications plan any elements needed to ensure safe use of the drug – when FDA determines that the drug is effective but is associated with a serious risk such that it would not be approved or would be withdrawn without the additional element(s) –restrictions must be commensurate with the risk –requires public notification –cannot be unduly burdensome on patient access or the healthcare system –element must be linked to a serious risk listed in the drug’s labeling Tools to Assess Product-Specific Issues

10. 10 REMS Distribution/Use Restrictions –A drug subject to distribution/use restrictions may be made available for an unapproved use to treat a life- threatening condition –Requires regulations to explain how a physician may provide a unapproved drug for this use –In a public health emergency the Secretary may waive any requirements related to restriction on distribution and use –Distribution/use restrictions cannot be used to block or delay approval of an ANDA Tools to Assess Product-Specific Issues

11. 11 Active Postmarket Risk Identification & Analysis System –Provision intended to improve FDA’s ability to detect problems with products already in commerce –FDA must develop an active system of postmarket risk surveillance and assessment utilizing Federal and private- sector electronic data FDA must ensure access to disparate data sources within 2 years –validated methods to link and analyze data from these sources –goal of including 100,000,000 by 2012 FDA must develop validated methods for risk identification and analysis within 1 year to allow the following: – risk analysis and identification based on electronic health data –active adverse event surveillance using public and private data –identification of safety trends and patterns Tools for Active Drug Safety Monitoring

12. 12 Tools for Active Drug Safety Monitoring Active Postmarket Risk Identification & Analysis System –Allows for public-private collaborations collaboration with public, academic and private entities to provide advance analysis of drug safety data –classifying and aggregating data –perform advance research on identified drug safety risks public process to identify priority drug safety questions and possible response (Risk Management Advisory Committee)

13. 13 Tools for Active Drug Safety Monitoring Action Package for Approval –Requires publication of an “action package for approval” upon approval of a new drug or biologic on the safety web-site summary within 48 hours full package within 30 days –Required element of action package for approval FDA generated document required for review documents pertaining to the content and format of the application labeling summary review of the drug FDA decision document name of each officer that participated in review –Protects trade secret, confidential commercial or financial information (FOIA protections)

14. 14 Tools for Active Drug Safety Monitoring Assuring Pharmaceutical Safety –This provision requires the Secretary to develop standards and to identify and validate effective technologies to secure the drug supply chain radio frequency identification technology nanotechnology encryption technologies other track-and-trace or authentication technologies –Requires a standard numerical identifier to be applied to a prescription drug at the point of manufacturing and repackaging (linked to the numerical identifier applied at the point of manufacturing) at the package or pallet level, sufficient to facilitate the identification, validation, authentication, and tracking and tracing of the prescription drug

15. 15 Tools for Active Drug Safety Monitoring Postmarket Drug Safety Information for Patients and Providers –Focus on improving the transparency of drug safety information –Creates a web-site with comprehensive safety information for approved prescription drugs patient labeling package inserts links to clinical trial databases –FDA must also provide access to reports and summaries from postmarket risk identification system prepare a summary analysis of all adverse events received or a drug within 18 months of approval post all approved labeling on web-site enable submission of adverse event reports via web-site –Requires the Advisory Committee on Risk Communication to perform a comprehensive review and evaluation of the information on the web-site

16. 16 Title VII: Conflicts of Interest Addresses concerns with financial conflicts of interest for those serving on FDA advisory committees –Establishes guidelines for recruitment and selection of advisory committee members –Requires disclosure of financial interest –Allows Secretary to grant waivers to provide necessary expertise –Requires disclosure on the FDA website, at least 15 days in advance of an advisory committee meeting, of any waiver granted (must also be noted in meeting transcript) Requires FDA, based on the number of waivers granted in 2007, to reduce the total number of waivers granted by 25% over 5 years

17. 17 QuestionsQuestions