the fda regulatory and compliance symposium managing risks – from pipeline to patient
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THE FDA REGULATORY THE FDA REGULATORY AND COMPLIANCE AND COMPLIANCE SYMPOSIUMSYMPOSIUMManaging Risks – From Managing Risks – From Pipeline to PatientPipeline to Patient
Presented by:Presented by:Steven A. Johnson, Esq., Vice President and Steven A. Johnson, Esq., Vice President and Assistant General Counsel, Allergan, Irvine, CAAssistant General Counsel, Allergan, Irvine, CAKeith M. Korenchuk, J.D., M.P.H., Partner, Keith M. Korenchuk, J.D., M.P.H., Partner, McGuireWoods LLP, Washington, DC/Charlotte, McGuireWoods LLP, Washington, DC/Charlotte, NCNC
Categories of Warning Categories of Warning LettersLetters
Division of Drug Marketing, Division of Drug Marketing, Advertising and Communications Advertising and Communications (DDMAC) Warning Letters(DDMAC) Warning Letters
Pharmaceutical Manufacturing Pharmaceutical Manufacturing Facility Inspection Warning LettersFacility Inspection Warning Letters
Nonclinical and Bioequivalence Nonclinical and Bioequivalence Studies Inspection Warning LettersStudies Inspection Warning Letters
DDMAC Frequently DDMAC Frequently Cited ViolationsCited Violations
Minimization of Risk InformationMinimization of Risk Information Omission or Inappropriate Display of Risk Omission or Inappropriate Display of Risk
InformationInformation Unsubstantiated Efficacy ClaimsUnsubstantiated Efficacy Claims Unsubstantiated Superiority ClaimsUnsubstantiated Superiority Claims Failure to Disclose or Misleading Failure to Disclose or Misleading
Communication of Drug IndicationCommunication of Drug Indication Failure to Submit for ReviewFailure to Submit for Review
– Takes backseat to concerns over safety/ Takes backseat to concerns over safety/ accuracy of the information advertisedaccuracy of the information advertised
Full Product Versus Full Product Versus Reminder AdsReminder Ads
Full Product Ad must contain a true Full Product Ad must contain a true statement of risk and warning information statement of risk and warning information related to side effects, contraindications and related to side effects, contraindications and effectiveness.effectiveness.
Reminder Ad does not need to include risk or Reminder Ad does not need to include risk or warning information.warning information.
Problem – When the pharmaceutical company Problem – When the pharmaceutical company intends an ad to be a reminder ad, but the intends an ad to be a reminder ad, but the DDMAC concludes it is a full product ad.DDMAC concludes it is a full product ad.
Outcome – Warning Letter cites company for Outcome – Warning Letter cites company for failure to provide risk and warning failure to provide risk and warning information.information.
Full Product Versus Full Product Versus Reminder Ad ExampleReminder Ad Example
A Celebrex TV ad depicts a woman playing A Celebrex TV ad depicts a woman playing a guitar accompanied by the statement a guitar accompanied by the statement “With Celebrex, I will play the long version.”“With Celebrex, I will play the long version.”
DDMAC concluded it was a full product ad DDMAC concluded it was a full product ad because the statement accompanied by the because the statement accompanied by the image made representations about the image made representations about the drug’s indication and benefits. drug’s indication and benefits.
The company was cited for failure to include The company was cited for failure to include risk, side-effect and contraindication risk, side-effect and contraindication information. information.
Risk Information is a Risk Information is a Primary ConcernPrimary Concern
Ensuring thorough reporting of Ensuring thorough reporting of risk information is a primary risk information is a primary concern to the DDMAC because concern to the DDMAC because “failure to present this important “failure to present this important risk information may lead to risk information may lead to serious health risks ….” serious health risks ….”
Omission of risks raises serious Omission of risks raises serious public health and safety concerns.public health and safety concerns.
Omission or Omission or Inappropriate Display of Inappropriate Display of
Risk InformationRisk Information Companies were cited for:Companies were cited for:
– Totally omitting risk informationTotally omitting risk information– Mentioning some risks, but omitting othersMentioning some risks, but omitting others– Advising the viewer to seek risk Advising the viewer to seek risk
information at a separate source, but information at a separate source, but totally omitting risk information from the totally omitting risk information from the adad
– Linking to or accompanying the main ad Linking to or accompanying the main ad with warning or prescribing informationwith warning or prescribing information
Minimization of Risk Minimization of Risk InformationInformation
Companies were cited for:Companies were cited for:– Showing distracting imagery or voice-overs Showing distracting imagery or voice-overs
while displaying risk informationwhile displaying risk information– Failing to flag or headline risk information as Failing to flag or headline risk information as
importantimportant– Using broad or imprecise language to downplay Using broad or imprecise language to downplay
risksrisks– Overstating safety by ignoring or Overstating safety by ignoring or
misrepresenting datamisrepresenting data– Providing incomplete or ambiguous Providing incomplete or ambiguous
contraindication listscontraindication lists
Unsubstantiated Unsubstantiated Efficacy ClaimsEfficacy Claims
Companies were cited for:Companies were cited for:– Suggesting a product can have certain effects Suggesting a product can have certain effects
without providing research to support the without providing research to support the claimsclaims
Example – Claiming the product provides “total relief” Example – Claiming the product provides “total relief” without data to support the claim of total reliefwithout data to support the claim of total relief
Example – Stating “results may vary” or “not Example – Stating “results may vary” or “not everyone will respond” is insufficienteveryone will respond” is insufficient
– Suggesting the product can be used to treat Suggesting the product can be used to treat patients for whom it is not recommendedpatients for whom it is not recommended
– Relying on uncontrolled or retrospective Relying on uncontrolled or retrospective analysis from failed studiesanalysis from failed studies
UnsubstantiatedUnsubstantiated SuperioritySuperiority ClaimsClaims
Superiority Claims must be supported Superiority Claims must be supported by “substantial evidence obtained by “substantial evidence obtained from adequate and well-controlled from adequate and well-controlled head-to-head clinical trial(s).” head-to-head clinical trial(s).”
In order to claim superiority to In order to claim superiority to allall similar products, the company must similar products, the company must have substantial comparative studies have substantial comparative studies to support the claim. to support the claim.
Unsubstantiated Unsubstantiated Superiority ClaimsSuperiority Claims
Companies were cited for:Companies were cited for:– Comparative claims with no clinical Comparative claims with no clinical
supportsupport– Comparative claims based on indirect Comparative claims based on indirect
comparisons or data from invalid studiescomparisons or data from invalid studies– Selectively advertising data from Selectively advertising data from
comparison studies to make it appear their comparison studies to make it appear their product was superior when in fact one or product was superior when in fact one or more comparison product was superiormore comparison product was superior
Unsubstantiated Unsubstantiated Superiority ClaimsSuperiority Claims
Companies were cited for:Companies were cited for:– Posing open-ended questions and not Posing open-ended questions and not
providing a complete comparisonproviding a complete comparison– Calling product “breakthrough” or “best” Calling product “breakthrough” or “best”
without substantial evidence of superioritywithout substantial evidence of superiority– Implying other products are less effective Implying other products are less effective
by suggesting if the patient switches the by suggesting if the patient switches the advertised product will workadvertised product will work
– Claiming superiority to Claiming superiority to allall similar products similar products based on research only comparing to two based on research only comparing to two similar productssimilar products
Failure to Disclose Failure to Disclose or Misleading Communication or Misleading Communication
of the Drug’s Indicationof the Drug’s Indication Companies were cited for:Companies were cited for:
– Not stating what illness the drug was Not stating what illness the drug was indicated to treatindicated to treat
– Broadly characterizing the illness the drug was Broadly characterizing the illness the drug was indicated to treatindicated to treat
Example – Depression medication ad was cited Example – Depression medication ad was cited because the ad described depression symptoms so because the ad described depression symptoms so broadly that it did not communicate the difference broadly that it did not communicate the difference between major depression and normal mood-swingsbetween major depression and normal mood-swings
– Overstating the number of patients the drug Overstating the number of patients the drug could be used to treat by not stating risks or could be used to treat by not stating risks or contraindications contraindications
Less Frequently Cited Less Frequently Cited ViolationsViolations
Failure to disclose or misstatement of Failure to disclose or misstatement of ease of drug administrationease of drug administration
Suggesting a product was safe and Suggesting a product was safe and effective for a use or dosage not FDA effective for a use or dosage not FDA approvedapproved
Failure to provide a brief summary or take Failure to provide a brief summary or take adequate steps to make the PI availableadequate steps to make the PI available– Must make PI available numerous ways: Must make PI available numerous ways:
website, healthcare provider, telephone, website, healthcare provider, telephone, public places, etc.public places, etc.
Example #1Example #1
Pfizer, Inc. Pfizer, Inc.
NDA 21-130, 21-131, 21-132NDA 21-130, 21-131, 21-132
July 20, 2005July 20, 2005
Example #2Example #2
Abbott LaboratoriesAbbott Laboratories
NPA 20-032NPA 20-032
July 15, 2005July 15, 2005
Example #3Example #3
SuperGen IncorporatedSuperGen Incorporated
NDA 20-122NDA 20-122
August 18, 2005August 18, 2005
Manufacturing Facility Manufacturing Facility Inspections Frequently Inspections Frequently
Cited ViolationsCited Violations Improper Maintenance or Use of Improper Maintenance or Use of
EquipmentEquipment Failure to Follow or Have Written Failure to Follow or Have Written
ProceduresProcedures Inadequate Record Keeping and Inadequate Record Keeping and
DocumentationDocumentation Understaffed or Under-qualified Quality Understaffed or Under-qualified Quality
Control PersonnelControl Personnel Manufacture of Unapproved DrugsManufacture of Unapproved Drugs
Improper Maintenance Improper Maintenance or Use of Equipmentor Use of Equipment
Uncalibrated and Improperly used Uncalibrated and Improperly used equipment does not provide equipment does not provide reliable datareliable data
Facilities were cited for:Facilities were cited for:– Uncalibrated Equipment used to test Uncalibrated Equipment used to test
and manufacture productand manufacture product– Inadequate Equipment maintenanceInadequate Equipment maintenance– Improper Equipment storageImproper Equipment storage
Failure to Follow or Failure to Follow or Failure to Have Written Failure to Have Written
ProceduresProcedures Facilities must ensure procedures are Facilities must ensure procedures are
followed by monitoring employees and followed by monitoring employees and verifying complianceverifying compliance
Facilities were cited for:Facilities were cited for:– Not having written procedures for labeling Not having written procedures for labeling
materialsmaterials– Inadequate procedures for recovery of insolventsInadequate procedures for recovery of insolvents– Not testing incoming materialsNot testing incoming materials– Not testing each batch of product createdNot testing each batch of product created– Employees improperly following written Employees improperly following written
proceduresprocedures
Inadequate Record Inadequate Record Keeping and Keeping and
DocumentationDocumentation Facilities were cited for:Facilities were cited for:
– Missing dataMissing data– Improperly changing dataImproperly changing data– Improperly documenting deviationsImproperly documenting deviations– Improperly performing and Improperly performing and
documenting investigations into documenting investigations into deviationsdeviations
Understaffed or Under-Understaffed or Under-Qualified Quality Control Qualified Quality Control
PersonnelPersonnel Facilities were cited for:Facilities were cited for:
– Having only one person working in the Having only one person working in the quality control and quality assurance quality control and quality assurance departmentdepartment
– Having unqualified employees working Having unqualified employees working in the quality departmentin the quality department Example – Quality personnel were unable to Example – Quality personnel were unable to
answer the inspectors’ questions and did answer the inspectors’ questions and did not have suitable academic training in not have suitable academic training in chemistry or microbiologychemistry or microbiology
Study Inspections Study Inspections Frequently Cited Frequently Cited
ViolationsViolations Problems with the Integrity and Problems with the Integrity and
Quality of the StudiesQuality of the Studies Problems with Data Records and Problems with Data Records and
Documentation of StudiesDocumentation of Studies Problems with the Analytical Problems with the Analytical
Methods used in the Studies Methods used in the Studies
Quality and Integrity Quality and Integrity of Studiesof Studies
Companies were cited for:Companies were cited for:– Failure to conduct studies in accordance with Failure to conduct studies in accordance with
protocolprotocol– Failure to establish standard operating Failure to establish standard operating
proceduresprocedures– Failure to assure the protocol was approved by Failure to assure the protocol was approved by
the sponsorthe sponsor– Failure to control and test mixtures for stability, Failure to control and test mixtures for stability,
strength and uniformitystrength and uniformity– Inadequate policies to address contamination Inadequate policies to address contamination
issuesissues
Data Records and Data Records and DocumentationDocumentation
Companies were cited for:Companies were cited for:– Failure to record data promptly and Failure to record data promptly and
legiblylegibly– Failure to include strength, purity Failure to include strength, purity
and stability data in final reportsand stability data in final reports– Failure to describe all circumstances Failure to describe all circumstances
that may affect the quality or that may affect the quality or integrity of the dataintegrity of the data
Analytical MethodsAnalytical Methods Companies were cited for:Companies were cited for:
– Being unable to accurately measure the Being unable to accurately measure the actual concentration of active drug actual concentration of active drug ingredient achieved in the bodyingredient achieved in the body
– Being unable to account for anomalous Being unable to account for anomalous resultsresults
When anomalous results are found the When anomalous results are found the company must do a systematic company must do a systematic evaluation of all the samples involved in evaluation of all the samples involved in the studythe study
Further DevelopmentFurther Development FDA Drug Safety Oversight BoardFDA Drug Safety Oversight Board WLF – FDA Watch GroupWLF – FDA Watch Group Manufacturer shutdowns ______Manufacturer shutdowns ______
PhRMA Guiding PriniciplesPhRMA Guiding PriniciplesDirect to Consumer Direct to Consumer
AdvertisementsAdvertisementsAbout Prescription MedicinesAbout Prescription Medicines
August 2005August 2005
PreamblePreamble Increasing awareness about diseases;Increasing awareness about diseases; Educating patients about treatment Educating patients about treatment
options;options; Motivating patients to contact their Motivating patients to contact their
physicians and engage in a dialogue physicians and engage in a dialogue about health concerns;about health concerns;
Increasing the likelihood that patients will Increasing the likelihood that patients will receive appropriate care for conditions receive appropriate care for conditions that are frequently under-diagnosed and that are frequently under-diagnosed and under-treated; andunder-treated; and
Encouraging compliance with prescription Encouraging compliance with prescription drug treatment regimensdrug treatment regimens
Guiding PrinciplesGuiding Principles The Principles are premised on the recognition The Principles are premised on the recognition
that DTC advertising of prescription medicines that DTC advertising of prescription medicines can benefit the public healthcan benefit the public health
All DTC information should be accurate and not All DTC information should be accurate and not misleading, should make claims only when misleading, should make claims only when supported by substantial evidence, should reflect supported by substantial evidence, should reflect balance between risks and benefits, and should balance between risks and benefits, and should be consistent with FDA approved labelingbe consistent with FDA approved labeling
DTC television and print advertising which is DTC television and print advertising which is designed to market a prescription drug should designed to market a prescription drug should also be designed to responsibly educate the also be designed to responsibly educate the consumer about that medicine and, where consumer about that medicine and, where appropriate, the condition for which it may be appropriate, the condition for which it may be prescribed.prescribed.
Guiding Principles Guiding Principles (continued)(continued)
DTC television and print advertising of prescription DTC television and print advertising of prescription drugs should clearly indicate that the medicine is a drugs should clearly indicate that the medicine is a prescription drug to distinguish such advertising prescription drug to distinguish such advertising from other advertising fro non-prescription products.from other advertising fro non-prescription products.
DTC television and print advertising should foster DTC television and print advertising should foster responsible communications between patients and responsible communications between patients and health care professionals to help patients achieve health care professionals to help patients achieve better health and a more complete appreciation of better health and a more complete appreciation of both the health benefits and the known risks both the health benefits and the known risks associated with the medicine being advertisedassociated with the medicine being advertised
Companies should spend an appropriate amount of Companies should spend an appropriate amount of time to educate health professionals about a new time to educate health professionals about a new medicine or a new therapeutic indication before medicine or a new therapeutic indication before commencing the first DTC advertising campaigncommencing the first DTC advertising campaign
Guiding Principles Guiding Principles (continued)(continued)
Working with the FDA, companies should Working with the FDA, companies should continue to responsibly alter or discontinue a continue to responsibly alter or discontinue a DTC advertising campaign should new and DTC advertising campaign should new and reliable information indicate a serious reliable information indicate a serious previously unknown safety riskpreviously unknown safety risk
Companies should submit all new DTC Companies should submit all new DTC television advertisements to the FDA before television advertisements to the FDA before releasing these advertisements for broadcastreleasing these advertisements for broadcast
DTC television and print advertising should DTC television and print advertising should include information about the availability of include information about the availability of other options such as diet and lifestyle other options such as diet and lifestyle changes where appropriate for the advertised changes where appropriate for the advertised conditioncondition
Guiding Principles Guiding Principles (continued)(continued)
DTC television advertising that identifies a DTC television advertising that identifies a product by name should clearly state the product by name should clearly state the health conditions for which the medicine is health conditions for which the medicine is approved and the major risks associated with approved and the major risks associated with the medicine being advertisedthe medicine being advertised
DTC television and print advertising should be DTC television and print advertising should be designed to achieve a balanced presentation designed to achieve a balanced presentation of both the benefits and the risks associated of both the benefits and the risks associated with the advertised prescription medicinewith the advertised prescription medicine
All DTC advertising should respect the serious All DTC advertising should respect the serious of the health conditions and the medicine of the health conditions and the medicine being advertisedbeing advertised
Guiding Principles Guiding Principles (continued)(continued)
In terms of content and placement, DTC In terms of content and placement, DTC television and print advertisements should television and print advertisements should be targeted to avoid audiences that are be targeted to avoid audiences that are not age appropriate for the messages not age appropriate for the messages involvedinvolved
Companies are encouraged to promote Companies are encouraged to promote health and disease awareness as part of health and disease awareness as part of their DTC advertisingtheir DTC advertising
Companies are encouraged to include Companies are encouraged to include information in all DTC advertising, where information in all DTC advertising, where feasible, about help of the uninsured and feasible, about help of the uninsured and underinsuredunderinsured
Accountability for the Accountability for the Guiding PrinciplesGuiding Principles
Companies commit to established internal Companies commit to established internal process to ensure compliance with these process to ensure compliance with these guiding principles. Companies also commit guiding principles. Companies also commit to distributing these guidelines internally to distributing these guidelines internally and to their advertising agencies.and to their advertising agencies.
PhRMA will establish an office of PhRMA will establish an office of accountability that will be responsible for accountability that will be responsible for receiving comments from the general receiving comments from the general public and from health care professionals public and from health care professionals regarding DTC advertising conducted by regarding DTC advertising conducted by any signatory company to these principles.any signatory company to these principles.
Accountability for the Accountability for the Guiding Principles Guiding Principles
(continued)(continued)The PhRMA office of accountability will The PhRMA office of accountability will issue periodic reports to the public.issue periodic reports to the public.
One year after the effective date of the One year after the effective date of the Principles, the PhRMA office of Principles, the PhRMA office of accountability will select an independent accountability will select an independent panel of credible individuals to review panel of credible individuals to review reports of that year, to track the overall reports of that year, to track the overall trends in the industry as the relate to the trends in the industry as the relate to the Principles, and to make Principles, and to make recommendations in accordance with recommendations in accordance with the Principles.the Principles.
Overarching TrendOverarching Trend
SafetySafety
Health\111468.3Health\111468.3
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