AIDS TREATMENT ACTIVIST COALITION- ATAC DRUG DEVELOPMENT COMMITTEE- DDC

1. AIDS TREATMENT ACTIVIST COALITION- ATACDRUG DEVELOPMENT COMMITTEE- DDC FDA/DDC Meeting Lynda Dee July 28, 2008

2. PADUFA IV/FDAAA - NEW FDA LEGISLATION • Congress reauthorized the Prescription Drug User Fee Act (PADUFA) for another five years under the Food and Drug Administration Amendments Act of 2007 (FDAAA) . • Before FDAAA, a number of areas addressed by these amendments, including many pediatric laws, were found in many different statutes and were sometimes at odds.

3. FDAAA - NEW FDA LEGISLATION • The FDAAA titles I will be addressing are Titles VII, Conflicts of Interest, VIII, Clinical Trials Data Base and IX Enhanced Authorities Regarding Postmarket Safety of Drugs. • The new focus of FDAAA with respect to drug safety is to emphasize that it is equally important to ensure that drugs are used as safely and efficiently as possible as it is to ensure that drugs are getting drugs to market quickly and efficiently. It should be noted that this safety legislation was propelled by the Vioxx fiasco and by teen suicides after using anti-depressant drugs. The goal of some the new amendments is to maintain a systematic and scientific approach to evaluating the risk/benefit ratio throughout the life cycle of a drug, including post-approval, not just prior to approval.

4. Title VII - Conflicts of Interest • No person can participate in FDA Advisory Committees if they or their immediate family members have a financial interest that could be affected by their advice. • The Secretary of HHS may make exceptions and grant waivers if a person’s expertiseis essential to the Advisory Panel.

5. New Provisions: • The agency should only consider term appointments for Advisory Committees who will not need waivers. • Waivers are now limited and must be decreased annually by 5% from 2007 through 2012. • Not less than 15 days prior to the Advisory Committee meeting, the name of any participant who received a waiver must be posted on the FDA website and the type, nature and magnitude of the financial interest as well as the reason for the waiver must be provided.

6. Title VIII - Clinical Trials Databases • Clinialtrials.gov will be superceded by this new law. The NIH is chargedwith ensuring that the proscribed information is made publically available on the internet within 30 days of submission by the sponsor. $10,000,000 has been appropriated annually. New Provisions: • The FDA is responsible for supplying and linking adverse event (AE) information within 30 days of the information becoming public beginningno later than 18 months after enactment of FDAAA, including: • A table of serious anticipated and unanticipated AEs, grouped by organ system with the number and frequency of such events, and • A table of frequent anticipated and unanticipated AEs, grouped by organ system if they exceed 5% within any arm of the trial.

7. All clinical trials in Phase II and beyond will be included in the new databases. The database shall include the following: • A brief title and summary of the trial, • The primary purpose and type of study, • The study designand study phase, • The primary disease or condition being studied, • The intervention name and type. • The study start and anticipated completion date, • The target number of patients, • Outcomes, including primary and secondary outcome measures, • Recruitment information, including eligibility criteria, gender and age limits and recruitment statusand individual site status, • Location and contact information, • The name of the sponsor and responsible party, • Faculty contact, including name, address, toll-free number and facility name, • A protocol identification number as well as the FDA IND number.

8. Title VIII - Clinical Trials Databases Searchable categories shall include one or ore of the following: • The disease or condition, • The name of the drug or intervention, • The site location of the clinical trial, • The age group being studied, including pediatric studies, • The study phase, • The study sponsor, • The recruitment status; i.e., open or closed studies, • The National Clinical Trial number or other study number.

9. Timeline requirements for the above information: • 90days after FDAAA enactment. • 21days after the first patient is enrolled, • 1 year after FDAAA enactment if the clinical trial does not involve a serious or life-threatening disease or condition. No later than 1 year after FDAAA enactment, the database shall include the following: • Demographic and baseline patient characteristics, • Primary and secondary outcomes, • Point of Contact

10. Title VIII - Clinical Trials Databases Civil Monetary Penalties: • Not more than $10,000 for all violations adjudicated in a single proceeding, • Not more than $10,000 per day for violation untilviolation is corrected. Notice of Violations must be posted online, including: • The non-complying party or sponsor, • Whether no information or misleading information was provided, • The penalties proscribed, and • Whether the violation has been corrected

11. Title VIII - Clinical Trials Databases Other Provisions: • Informed Consent Documents shall be included. Preemption: • No state or other political subdivision may establish or continue in effect any requirements for registeringclinical trials or for the inclusion of information relating to clinical trials results.

12. Title IX - Enhanced Authorities Regarding Postmarket Safety of Drugs Prior to FDAAA, the FDA did not have the power to order sponsors to conduct postmarket trials. The conduct of these trials had to be negotiated with companies. Some companies were much better than others at complying with their agreements in this regard. New Provisions: The FDA may require postmarket studies or clinical trials to: • Assess known serious risks, • Assess signals of serious risks, • Identify unexpected serious risk when potential is identified. Sponsors must submit a timetable for completion and periodic status reports. Safety Labeling Changes: • Submit changes to the labeling that reflect new safety information, including boxed warnings, contraindications, warnings, precautions or adverse reactions.

13. Risk Evaluation and Mitigation Strategies: On a case by case basis, the Secretary shall determine what, if any, risk evaluation and mitigation strategy is necessary to ensure the benefits of the drug outweigh the risks associated with the drug. This includes drugs approved prior to enactment of FDAAA. Risk Evaluation and Mitigation Strategies (REMs) shall include: Timetable for submission, • An 18 month assessment, • A 3 month assessment, • A 7 year assessment. • Assessments may be increased or reduced as necessary or eliminated after 3 years if the Secretary determines that the serious risks have been adequately identified.  

14. Advisory Committees may be convened to review the safety of a drug, class of drugs or before an assessment of the risk evaluation and mitigation strategy or strategies is decided. • Medication Guide; Patient Package Insert: • The sponsor may be required to develop and distribute a medication guide or patient package insert to each patient when the drug is dispensed. • Communication Plan to Health Care Providers: • The sponsor may be required to provide a communication plan to health care providers by letters or, through professional societies.

15. Access to Drugs with Known Serious Risks That Would Otherwise Be Unavailable Examples of Elements to Assure Safe Use: • Required training or certification for health care providers, • Specially certified pharmacies, practitioners or health care settings, • Dispensed only in certain settings or hospitals, • Patient subjected to specific monitoring, • Patient enrolled in a registry. • Any system should not be unduly burdensome and to the extent possible, minimized the burdenon the health care delivery system.

16. Dispute Resolution at Initial Approval- Drug Oversight Board • Not later than 5 days after a dispute letter is received by the Secretary, notice shall be posted on the internet that the dispute will be reviewed by the Drug Oversight Board. • Review may be scheduled at next Drug Oversight Board Meeting or a special meeting may be convened. The proceedings are to be recorded and made public within 90 days of the meeting. Trade secrets, etc. are to be redacted. • Board makes a recommendation within 5 days. • Secretary makes the recommendation available to the public within 5 days. •  Secretary shall issue an action letter resolving the dispute no later than 7 days after receiving the recommendation of the Drug Safety Oversight Board which shall also be made public within 7 days. • Agreement between the FDA and the sponsor terminates the proceedings.

17. Composition of the Drug Oversight Safety Board: • One Scientist and one health care practitioner who are federal employees, • FDA employees, including postmarketing office employees, • One NIH employee and one HHS employee, not including FDA staff, • Other appropriate agencies as determined by the Secretary. • The Drug Safety Oversight Board shall meet monthly to provide oversight and advice on drug safety issues.

18. Prereview of TV Advertisements: • The Secretary may require prereviewof any drug TV advertisements. • The Secretary may require inclusion specific disclosures if it is determined that the ad is false or misleading. • Statements relating to side effects and contraindications shall be presented in a clear, conspicuous and neutral manner. • The Secretary may require disclosure of the approval date of any drug within 2 years of the approval date.

19. Civil Monetary Penalties: • A party may be fined not greater than $250,000 for disseminating false or misleading direct-to-consumer advertising for the first violation in any 3 year period, and not greater than $500,000 for each subsequent violation in any 3 year period. • The amount assessed may be deducted from any amount owed by the US to the person charged. • Misbranding penalties: $250,000 for the first 30-day period, doubled for every 30 dayperiod thereafter, not to exceed$1,000,000 for any 30-day period or $10,000,000 forall violations.

20. Benefit Risk Assessment: • No later than 1 year after enactment of FDAAA, the FDA Commissioner shall submit a report to Congress onhow best to communicate the risks and benefitsof new drugs and the role of the risk evaluation and mitigation strategy in assessing such risks and benefits. • As part of the study, the FDA Commissioner may consider the possibility of including aunique symbolin the labeling of a new drug and in any direct-to-consumeradvertisements promoting a new drug to indicate that it is newly approved or has a new indication.

21. A Statement to Be Included in Direct-to-Consumer (DTC) Advertisements: • In the case of published DTC ads, the following statement must be printed in conspicuous text: “You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.” • No later than 6 months after FDAAA enactment, the Secretary shall conduct a study in collaboration with the Risk and Communication Advisory Committee to determine whether the above statement is appropriate for TV ads or if it detracts from DTC risk information. If it is deemed appropriate, the Secretary shall promulgate regulationsrequiring such a statement.

22. Report on Direct-to-Consumer Advertising (DTC): • The Secretary of HHS shall make a report to Congress on DTC and its ability to communicate to subsets of the general population, including the elderly, children and racialand ethnic minorities. • The Risk Management Advisory Committee established under this Act shall be used toadvise the Secretary on this report. The committee shall includepatients, consumers and health professionals • No later than 1 year after enactment, the FDA shall submit to Congress a report on how to best communicate to the public the risks and benefits of new drugs and the role of riskand mitigation strategies in assessing risks and benefits.

23. Active Postmarket Risk Identification and Analysis: • Not later than 2 years after enactment, the Secretary shall develop postmarket risk andidentification and analysis methods to: • Develop methods to obtain disparate data sources, • Develop validated methods for the establishment of a postmarket risk identification analysis system to link and analyze safety data from 25,000,000patientsby July 1, 2010, and 100,000,000patientsby July 1, 2012. • Convene an expert committee to develop tools and methods for ethical andscientific uses for communicating postmarket data, including effective research methods in this regard.

24. Postmarket Risk Identification and Analysis System: • Not later than 1 year after the development of risk identification and anaylsis methods, the Secretary shall establish and maintain procedures for a risk identification and analysissystem: • For a risk and identification and analysis system based on electronic health data, • For the reporting of data in a standardized form all serious adverse drugexperiences, including events reported by patients, providers and sponsors, • To provide active electronic adverse event surveillance reports from Medicare and the VA. • To include approaches that would assess safety of drug use in underrepresentedpopulations, including the elderly, people with comorbidities, pregnant women and children.

25. Postmarket Risk Identification and Analysis System (cont): • The Secretary must establish government collaborations and contract with industry to establish this research, statistical, epidemiologic and/or clinical capability and expertise. • Congress has appropriated $25,000,000 for each fiscal year from 2008 through 2012 in this regard and directed the GAO to evaluate and ensure privacy, confidentiality and the security of this data within 18 months of FDAAA enactment. • Congress has also required the Secretary to report on the ways in which the risk identification and analysis system can been used to identify specific drug safety signals and better understand the outcomes associated with drugs marketed in the US.

26. Postmarket Drug Safety Information for Patients and Providers: • Within 1 year the Secretary must improve transparency of information about drugs and allow patients and providers better access to drug safety information by developing anInternet website that: • Provides links to drug safety information for approved drugs, • Improves communication of drug safety information to patients and providers. • The above shall be carried out by developing and maintaining an accessible consolidated website with easily searchable drug safety information forms sources such as US National Library ofMedicine and Medline Plus.

27. The web site shall include: • Patient labeling and patient packaging inserts, • Links to a list of each drug for which a Medication Guide is required, • Links to the registry and results data bank, • Most recent FDA safety information and alerts such as recalls, warning letters, import alerts, • Publically available information about implemented RiskMAPs and risk evaluation and mitigation strategies, • Guidance documents and drug safety regulations, • Surveillance summaries of known serious side effects, • Summary analyses of adverse events by either the later of 18 months after drug approval or use of the drug by 10,000 people, • Ability of patients and providers to report adverse events, • Educational materials on how to dispose of expired or unusable medications, • Drug labeling no later than 21 days after approval.

28. Database for Generic Drugs: • Not later than 9 months after enactment of FDAAA, the FDA shall publish on the web site a complete list of all authorized generic drugs, including: • The drug trade name, • Brand name and manufacturer, and • The date the generic drug entered the market.

29. Action Package: • The Secretary shall publish the action package for approval on the web site no later than 30 days after the approval date of a drug. • The action package shall include: • Related FDA generated documents. • Application documents generated, • Labelsubmitted by the applicant, • A summary review that documents conclusions from all reviewing disciplines about the drug, noting any critical issues, disagreements and resolutions, recommendations for action and an explanation of any non-concurrence with the review conclusions on the web site not later than 48 hours after drug approval, and (see next slide)

30. Action Package (Cont.) • Division Director and Office Director’s decision document which include: • Statement of concurrence with summary review, • Separate reviewif not in concurrence with the summary review, • Namesof each FDA employeeswho participated in the decisionif they consent to their names being included. • A scientific review of an application is considered the work of the reviewer and shall not be altered by management or the reviewer once final.

31. Response to the 2006 Institute of Medicine (IOM) Report: • No later than 1 year after enactment of FDAAA, the Secretary shall respond to the 2006IOM report titled: The Future of Drug Safety—Promoting and Protecting the Health of the Public. The report shall include an FDA update and assessment of the implemented recommendations as well as evidence that the office responsible for reviewing the drug and the office responsible for postapproval safety have worked togetherto assess, implement and ensure compliance with the requirements of FDAAA.

32. Adverse Drug Reaction Reports and Postmarket Safety: The Secretary shall: • Conduct regular, biweekly screening of the Adverse Event Reporting System database and post a quarterly report on the Adverse Event Reporting System website, including new safety information or potential serious risk signals identified within the last quarter. • Report to Congress no later than 2 years after enactment of FDAAA the FDA’s procedures and processes for addressing ongoing postmarket safety issues and how recommendations are handled within the agency. • Annually review the entire backlog of postmarket safety commitments to determine which commitments require revision or should be eliminated, report to Congress on these determinations, and assign start dates and estimated completion datesfor suchcommitments.