AIDS TREATMENT ACTIVIST COALITION ATAC DRUG DEVELOPMENT COMMITTEE DDC

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AIDS TREATMENT ACTIVIST COALITION- ATACDRUG
DEVELOPMENT COMMITTEE- DDC

• FDA/DDC Meeting
• Lynda Dee
• July 28, 2008

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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.
•  

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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.

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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 persons expertise is
  essential to the Advisory Panel.
•  

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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.

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Title VIII - Clinical Trials Databases

• Clinialtrials.gov will be superceded by this new
  law. The NIH is charged with 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 beginning no
  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.

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• 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 design and 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
  status and 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.
•  

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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.
•  

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• Timeline requirements for the above information
•  
• 90 days after FDAAA enactment.
• 21 days 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

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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 until
  violation 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

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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 registering clinical trials or for the
  inclusion of information relating to clinical
  trials results.

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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.

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  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.  

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• 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.
•  

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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 burden on the
  health care delivery system.

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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.
•  

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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.
•  

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Prereview of TV Advertisements

• The Secretary may require prereview of 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.

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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 day period
  thereafter, not to exceed 1,000,000 for any
  30-day period or 10,000,000 for all violations.

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Benefit Risk Assessment

• No later than 1 year after enactment of FDAAA,
  the FDA Commissioner shall submit a report to
  Congress on how best to communicate the risks and
  benefits of 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 a unique
  symbol in the labeling of a new drug and in any
  direct-to-consumer advertisements promoting a new
  drug to indicate that it is newly approved or has
  a new indication.

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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 regulations requiring such a statement.

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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 racial and ethnic
  minorities.
• The Risk Management Advisory Committee
  established under this Act shall be used to
  advise the Secretary on this report. The
  committee shall include patients, 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 risk and mitigation
  strategies in assessing risks and benefits.

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Active Postmarket Risk Identification and
Analysis

• Not later than 2 years after enactment, the
  Secretary shall develop postmarket risk and
  identification 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
  25,000,000 patients by July 1, 2010, and
  100,000,000 patients by July 1, 2012.
• Convene an expert committee to develop tools and
  methods for ethical and scientific uses for
  communicating postmarket data, including
  effective research methods in this regard.

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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 analysis system
• 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 drug experiences, 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 underrepresented populations,
  including the elderly, people with comorbidities,
  pregnant women and children.

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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.

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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 an Internet web
  site 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 web site
  with easily searchable drug safety information
  forms sources such as US National Library of
  Medicine and Medline Plus.

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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.

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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.

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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,
• Label submitted 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)

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Action Package (Cont.)

• Division Director and Office Directors decision
  document which include
• Statement of concurrence with summary review,
• Separate review if not in concurrence with the
  summary review,
• Names of each FDA employees who participated in
  the decision if 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.

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Response to the 2006 Institute of Medicine (IOM)
Report

• No later than 1 year after enactment of FDAAA,
  the Secretary shall respond to the 2006 IOM
  report titled The Future of Drug
  SafetyPromoting 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 together to
  assess, implement and ensure compliance with the
  requirements of FDAAA.

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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 web site, 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 FDAs 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 dates for
  such commitments.