THE FDA REGULATORY AND COMPLIANCE SYMPOSIUM Managing Risks

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THE FDA REGULATORY AND COMPLIANCE
SYMPOSIUMManaging Risks From Pipeline to
Patient

• Presented by
• Steven A. Johnson, Esq., Vice President and
  Assistant General Counsel, Allergan, Irvine, CA
• Keith M. Korenchuk, J.D., M.P.H., Partner,
  McGuireWoods LLP, Washington, DC/Charlotte, NC

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Categories of Warning Letters

• Division of Drug Marketing, Advertising and
  Communications (DDMAC) Warning Letters
• Pharmaceutical Manufacturing Facility Inspection
  Warning Letters
• Nonclinical and Bioequivalence Studies Inspection
  Warning Letters

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DDMAC Frequently Cited Violations

• Minimization of Risk Information
• Omission or Inappropriate Display of Risk
  Information
• Unsubstantiated Efficacy Claims
• Unsubstantiated Superiority Claims
• Failure to Disclose or Misleading Communication
  of Drug Indication
• Failure to Submit for Review
• Takes backseat to concerns over safety/ accuracy
  of the information advertised

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Full Product Versus Reminder Ads

• Full Product Ad must contain a true statement of
  risk and warning information related to side
  effects, contraindications and effectiveness.
• Reminder Ad does not need to include risk or
  warning information.
• Problem When the pharmaceutical company intends
  an ad to be a reminder ad, but the DDMAC
  concludes it is a full product ad.
• Outcome Warning Letter cites company for
  failure to provide risk and warning information.

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Full Product Versus Reminder Ad Example

• A Celebrex TV ad depicts a woman playing a guitar
  accompanied by the statement With Celebrex, I
  will play the long version.
• DDMAC concluded it was a full product ad because
  the statement accompanied by the image made
  representations about the drugs indication and
  benefits.
• The company was cited for failure to include
  risk, side-effect and contraindication
  information.

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Risk Information is a Primary Concern

• Ensuring thorough reporting of risk information
  is a primary concern to the DDMAC because
  failure to present this important risk
  information may lead to serious health risks .
• Omission of risks raises serious public health
  and safety concerns.

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Omission or Inappropriate Display of Risk
Information

• Companies were cited for
• Totally omitting risk information
• Mentioning some risks, but omitting others
• Advising the viewer to seek risk information at a
  separate source, but totally omitting risk
  information from the ad
• Linking to or accompanying the main ad with
  warning or prescribing information

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Minimization of Risk Information

• Companies were cited for
• Showing distracting imagery or voice-overs while
  displaying risk information
• Failing to flag or headline risk information as
  important
• Using broad or imprecise language to downplay
  risks
• Overstating safety by ignoring or misrepresenting
  data
• Providing incomplete or ambiguous
  contraindication lists

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Unsubstantiated Efficacy Claims

• Companies were cited for
• Suggesting a product can have certain effects
  without providing research to support the claims
• Example Claiming the product provides total
  relief without data to support the claim of
  total relief
• Example Stating results may vary or not
  everyone will respond is insufficient
• Suggesting the product can be used to treat
  patients for whom it is not recommended
• Relying on uncontrolled or retrospective analysis
  from failed studies

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Unsubstantiated Superiority Claims

• Superiority Claims must be supported by
  substantial evidence obtained from adequate and
  well-controlled head-to-head clinical trial(s).
• In order to claim superiority to all similar
  products, the company must have substantial
  comparative studies to support the claim.

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Unsubstantiated Superiority Claims

• Companies were cited for
• Comparative claims with no clinical support
• Comparative claims based on indirect comparisons
  or data from invalid studies
• Selectively advertising data from comparison
  studies to make it appear their product was
  superior when in fact one or more comparison
  product was superior

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Unsubstantiated Superiority Claims

• Companies were cited for
• Posing open-ended questions and not providing a
  complete comparison
• Calling product breakthrough or best without
  substantial evidence of superiority
• Implying other products are less effective by
  suggesting if the patient switches the advertised
  product will work
• Claiming superiority to all similar products
  based on research only comparing to two similar
  products

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Failure to Disclose or Misleading Communication
of the Drugs Indication

• Companies were cited for
• Not stating what illness the drug was indicated
  to treat
• Broadly characterizing the illness the drug was
  indicated to treat
• Example Depression medication ad was cited
  because the ad described depression symptoms so
  broadly that it did not communicate the
  difference between major depression and normal
  mood-swings
• Overstating the number of patients the drug could
  be used to treat by not stating risks or
  contraindications

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Less Frequently Cited Violations

• Failure to disclose or misstatement of ease of
  drug administration
• Suggesting a product was safe and effective for a
  use or dosage not FDA approved
• Failure to provide a brief summary or take
  adequate steps to make the PI available
• Must make PI available numerous ways website,
  healthcare provider, telephone, public places,
  etc.

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Example 1

• Pfizer, Inc.
• NDA 21-130, 21-131, 21-132
• July 20, 2005

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Example 2

• Abbott Laboratories
• NPA 20-032
• July 15, 2005

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Example 3

• SuperGen Incorporated
• NDA 20-122
• August 18, 2005

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Manufacturing Facility Inspections Frequently
Cited Violations

• Improper Maintenance or Use of Equipment
• Failure to Follow or Have Written Procedures
• Inadequate Record Keeping and Documentation
• Understaffed or Under-qualified Quality Control
  Personnel
• Manufacture of Unapproved Drugs

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Improper Maintenance or Use of Equipment

• Uncalibrated and Improperly used equipment does
  not provide reliable data
• Facilities were cited for
• Uncalibrated Equipment used to test and
  manufacture product
• Inadequate Equipment maintenance
• Improper Equipment storage

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Failure to Follow or Failure to Have Written
Procedures

• Facilities must ensure procedures are followed by
  monitoring employees and verifying compliance
• Facilities were cited for
• Not having written procedures for labeling
  materials
• Inadequate procedures for recovery of insolvents
• Not testing incoming materials
• Not testing each batch of product created
• Employees improperly following written procedures

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Inadequate Record Keeping and Documentation

• Facilities were cited for
• Missing data
• Improperly changing data
• Improperly documenting deviations
• Improperly performing and documenting
  investigations into deviations

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Understaffed or Under-Qualified Quality Control
Personnel

• Facilities were cited for
• Having only one person working in the quality
  control and quality assurance department
• Having unqualified employees working in the
  quality department
• Example Quality personnel were unable to answer
  the inspectors questions and did not have
  suitable academic training in chemistry or
  microbiology

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Study Inspections Frequently Cited Violations

• Problems with the Integrity and Quality of the
  Studies
• Problems with Data Records and Documentation of
  Studies
• Problems with the Analytical Methods used in the
  Studies

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Quality and Integrity of Studies

• Companies were cited for
• Failure to conduct studies in accordance with
  protocol
• Failure to establish standard operating
  procedures
• Failure to assure the protocol was approved by
  the sponsor
• Failure to control and test mixtures for
  stability, strength and uniformity
• Inadequate policies to address contamination
  issues

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Data Records and Documentation

• Companies were cited for
• Failure to record data promptly and legibly
• Failure to include strength, purity and stability
  data in final reports
• Failure to describe all circumstances that may
  affect the quality or integrity of the data

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Analytical Methods

• Companies were cited for
• Being unable to accurately measure the actual
  concentration of active drug ingredient achieved
  in the body
• Being unable to account for anomalous results
• When anomalous results are found the company must
  do a systematic evaluation of all the samples
  involved in the study

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Further Development

• FDA Drug Safety Oversight Board
• WLF FDA Watch Group
• Manufacturer shutdowns ______

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• PhRMA Guiding Priniciples
• Direct to Consumer Advertisements
• About Prescription Medicines
• August 2005

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Preamble

• Increasing awareness about diseases
• Educating patients about treatment options
• Motivating patients to contact their physicians
  and engage in a dialogue about health concerns
• Increasing the likelihood that patients will
  receive appropriate care for conditions that are
  frequently under-diagnosed and under-treated and
• Encouraging compliance with prescription drug
  treatment regimens

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Guiding Principles

• The Principles are premised on the recognition
  that DTC advertising of prescription medicines
  can benefit the public health
• All DTC information should be accurate and not
  misleading, should make claims only when
  supported by substantial evidence, should reflect
  balance between risks and benefits, and should be
  consistent with FDA approved labeling
• DTC television and print advertising which is
  designed to market a prescription drug should
  also be designed to responsibly educate the
  consumer about that medicine and, where
  appropriate, the condition for which it may be
  prescribed.

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Guiding Principles (continued)

• DTC television and print advertising of
  prescription drugs should clearly indicate that
  the medicine is a prescription drug to
  distinguish such advertising from other
  advertising fro non-prescription products.
• DTC television and print advertising should
  foster responsible communications between
  patients and health care professionals to help
  patients achieve better health and a more
  complete appreciation of both the health benefits
  and the known risks associated with the medicine
  being advertised
• Companies should spend an appropriate amount of
  time to educate health professionals about a new
  medicine or a new therapeutic indication before
  commencing the first DTC advertising campaign

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Guiding Principles (continued)

• Working with the FDA, companies should continue
  to responsibly alter or discontinue a DTC
  advertising campaign should new and reliable
  information indicate a serious previously unknown
  safety risk
• Companies should submit all new DTC television
  advertisements to the FDA before releasing these
  advertisements for broadcast
• DTC television and print advertising should
  include information about the availability of
  other options such as diet and lifestyle changes
  where appropriate for the advertised condition

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Guiding Principles (continued)

• DTC television advertising that identifies a
  product by name should clearly state the health
  conditions for which the medicine is approved and
  the major risks associated with the medicine
  being advertised
• DTC television and print advertising should be
  designed to achieve a balanced presentation of
  both the benefits and the risks associated with
  the advertised prescription medicine
• All DTC advertising should respect the serious of
  the health conditions and the medicine being
  advertised

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Guiding Principles (continued)

• In terms of content and placement, DTC television
  and print advertisements should be targeted to
  avoid audiences that are not age appropriate for
  the messages involved
• Companies are encouraged to promote health and
  disease awareness as part of their DTC
  advertising
• Companies are encouraged to include information
  in all DTC advertising, where feasible, about
  help of the uninsured and underinsured

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Accountability for the Guiding Principles

• Companies commit to established internal process
  to ensure compliance with these guiding
  principles. Companies also commit to distributing
  these guidelines internally and to their
  advertising agencies.
• PhRMA will establish an office of accountability
  that will be responsible for receiving comments
  from the general public and from health care
  professionals regarding DTC advertising conducted
  by any signatory company to these principles.

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Accountability for the Guiding Principles
(continued)

• The PhRMA office of accountability will issue
  periodic reports to the public.
• One year after the effective date of the
  Principles, the PhRMA office of accountability
  will select an independent panel of credible
  individuals to review reports of that year, to
  track the overall trends in the industry as the
  relate to the Principles, and to make
  recommendations in accordance with the Principles.

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Overarching TrendSafety
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