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