THE FDA REGULATORY THE FDA REGULATORY AND COMPLIANCE AND COMPLIANCE SYMPOSIUMSYMPOSIUMManaging Risks Managing Risks –– From From Pipeline to PatientPipeline to Patient

Presented by:Presented by:Steven A. Johnson, Esq., Vice President and Assistant Steven A. Johnson, Esq., Vice President and Assistant General Counsel, Allergan, Irvine, CAGeneral 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, NCMcGuireWoods LLP, Washington, DC/Charlotte, NC

Categories of Warning Categories of Warning LettersLetters

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

DDMAC Frequently Cited DDMAC Frequently Cited ViolationsViolations

Minimization of Risk InformationMinimization of Risk InformationOmission or Inappropriate Display of Risk Omission or Inappropriate Display of Risk InformationInformationUnsubstantiated Efficacy ClaimsUnsubstantiated Efficacy ClaimsUnsubstantiated Superiority ClaimsUnsubstantiated Superiority ClaimsFailure to Disclose or Misleading Failure to Disclose or Misleading Communication of Drug IndicationCommunication of Drug IndicationFailure 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 Reminder Ad does not need to include risk or warning information.or warning information.Problem Problem –– When the pharmaceutical When the pharmaceutical company intends an ad to be a reminder ad, company intends an ad to be a reminder ad, but the DDMAC concludes it is a full product but the DDMAC concludes it is a full product ad.ad.Outcome Outcome –– Warning Letter cites company Warning Letter cites company for failure to provide risk and warning for 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 A Celebrex TV ad depicts a woman playing a guitar accompanied by the statement “With guitar accompanied by the statement “With Celebrex, I will play the long version.”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, siderisk, side--effect and contraindication effect and contraindication information. information.

Risk Information is a Risk Information is a Primary ConcernPrimary Concern

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

Omission or Inappropriate Omission or Inappropriate Display of Risk InformationDisplay of Risk Information

Companies were cited for:Companies were cited for:–– Totally omitting risk informationTotally omitting risk information–– Mentioning some risks, but omitting Mentioning some risks, but omitting

othersothers–– 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 voiceShowing distracting imagery or voice--overs while overs while

displaying risk informationdisplaying 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 Efficacy Unsubstantiated Efficacy ClaimsClaims

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 claimswithout providing research to support the claimsExample Example –– Claiming the product provides “total relief” Claiming the product provides “total relief” without data to support the claim of total reliefwithout data to support the claim of total reliefExample Example –– Stating “results may vary” or “not everyone Stating “results may vary” or “not everyone will respond” is insufficientwill 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 analysis Relying on uncontrolled or retrospective analysis from failed studiesfrom failed studies

UnsubstantiatedUnsubstantiatedSuperioritySuperiority ClaimsClaims

Superiority Claims must be supported Superiority Claims must be supported by “substantial evidence obtained from by “substantial evidence obtained from adequate and welladequate and well--controlled headcontrolled head--toto--head clinical trial(s).” head clinical trial(s).” In order to claim superiority to In order to claim superiority to allallsimilar 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 comparison studies to make it appear their product was superior when in fact their product was superior when in fact one or more comparison product was one or more comparison product was superiorsuperior

Unsubstantiated Unsubstantiated Superiority ClaimsSuperiority Claims

Companies were cited for:Companies were cited for:–– Posing openPosing open--ended questions and not providing ended questions and not providing

a complete comparisona complete comparison–– Calling product “breakthrough” or “best” without Calling product “breakthrough” or “best” without

substantial evidence of superioritysubstantial evidence of superiority–– Implying other products are less effective by Implying other products are less effective by

suggesting if the patient switches the advertised suggesting if the patient switches the advertised product will workproduct will work

–– Claiming superiority to Claiming superiority to allall similar products based similar products based on research only comparing to two similar on research only comparing to two similar productsproducts

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 indicated Not stating what illness the drug was indicated

to treatto treat–– Broadly characterizing the illness the drug was Broadly characterizing the illness the drug was

indicated to treatindicated to treatExample Example –– Depression medication ad was cited 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 moodbetween major depression and normal mood--swingsswings

–– 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 ease Failure to disclose or misstatement of ease of drug administrationof drug administrationSuggesting a product was safe and effective Suggesting a product was safe and effective for a use or dosage not FDA approvedfor a use or dosage not FDA approvedFailure 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, public website, healthcare provider, telephone, public places, etc.places, etc.

Example #1Example #1

Pfizer, Inc. Pfizer, Inc.

NDA 21NDA 21--130, 21130, 21--131, 21131, 21--132132

July 20, 2005July 20, 2005

Example #2Example #2

Abbott LaboratoriesAbbott Laboratories

NPA 20NPA 20--032032

July 15, 2005July 15, 2005

Example #3Example #3

SuperGenSuperGen IncorporatedIncorporated

NDA 20NDA 20--122122

August 18, 2005August 18, 2005

Manufacturing Facility Manufacturing Facility Inspections Frequently Cited Inspections Frequently Cited

ViolationsViolationsImproper Maintenance or Use of Improper Maintenance or Use of EquipmentEquipmentFailure to Follow or Have Written Failure to Follow or Have Written ProceduresProceduresInadequate Record Keeping and Inadequate Record Keeping and DocumentationDocumentationUnderstaffed or UnderUnderstaffed or Under--qualified qualified Quality Control PersonnelQuality Control PersonnelManufacture of Unapproved DrugsManufacture of Unapproved Drugs

Improper Maintenance or Improper Maintenance or Use of EquipmentUse of Equipment

Uncalibrated and Improperly used Uncalibrated and Improperly used equipment does not provide reliable equipment does not provide reliable datadataFacilities were cited for:Facilities were cited for:–– Uncalibrated Equipment used to test and Uncalibrated Equipment used to test and

manufacture productmanufacture product–– Inadequate Equipment maintenanceInadequate Equipment maintenance–– Improper Equipment storageImproper Equipment storage

Failure to Follow or Failure Failure to Follow or Failure to Have Written Proceduresto Have Written Procedures

Facilities must ensure procedures are Facilities must ensure procedures are followed by monitoring employees and followed by monitoring employees and verifying complianceverifying complianceFacilities 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 Keeping Inadequate Record Keeping and Documentationand Documentation

Facilities were cited for:Facilities were cited for:–– Missing dataMissing data–– Improperly changing dataImproperly changing data–– Improperly documenting deviationsImproperly documenting deviations–– Improperly performing and documenting Improperly performing and documenting

investigations into deviationsinvestigations into deviations

Understaffed or UnderUnderstaffed or Under--Qualified Quality Control Qualified Quality Control

PersonnelPersonnelFacilities 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 in Having unqualified employees working in the quality departmentthe quality department

Example Example –– Quality personnel were unable to Quality personnel were unable to answer the inspectors’ questions and did not answer the inspectors’ questions and did not have suitable academic training in chemistry have suitable academic training in chemistry or microbiologyor microbiology

Study Inspections Study Inspections Frequently Cited ViolationsFrequently Cited Violations

Problems with the Integrity and Problems with the Integrity and Quality of the StudiesQuality of the StudiesProblems with Data Records and Problems with Data Records and Documentation of StudiesDocumentation of StudiesProblems with the Analytical Methods Problems with the Analytical Methods used in the Studies used in the Studies

Quality and Integrity of Quality and Integrity of StudiesStudies

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 and Failure to include strength, purity and

stability data in final reportsstability data in final reports–– Failure to describe all circumstances that Failure to describe all circumstances that

may affect the quality or integrity of the may affect the quality or integrity of the datadata

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 evaluation of all the samples involved in the studyin the study

Further DevelopmentFurther Development

FDA Drug Safety Oversight BoardFDA Drug Safety Oversight BoardWLF WLF –– FDA Watch GroupFDA Watch GroupManufacturer shutdowns ______Manufacturer shutdowns ______

PhRMAPhRMA Guiding Guiding PriniciplesPriniciplesDirect to Consumer AdvertisementsDirect to Consumer Advertisements

About Prescription MedicinesAbout Prescription Medicines

August 2005August 2005

PreamblePreamble

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

Guiding PrinciplesGuiding Principles

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

Guiding Principles Guiding Principles (continued)(continued)

DTC television and print advertising of prescription drugs DTC television and print advertising of prescription drugs should clearly indicate that the medicine is a prescription should clearly indicate that the medicine is a prescription drug to distinguish such advertising from other drug to distinguish such advertising from other advertising fro nonadvertising fro non--prescription products.prescription products.DTC television and print advertising should foster DTC television and print advertising should foster responsible communications between patients and health responsible communications between patients and health care professionals to help patients achieve better health care professionals to help patients achieve better health and a more complete appreciation of both the health and a more complete appreciation of both the health benefits and the known risks associated with the benefits and the known risks associated with the medicine being advertisedmedicine being advertisedCompanies should spend an appropriate amount of time Companies should spend an appropriate amount of time to educate health professionals about a new medicine or to educate health professionals about a new medicine or a new therapeutic indication before commencing the first a new therapeutic indication before commencing the first DTC advertising campaignDTC 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 previously reliable information indicate a serious previously unknown safety riskunknown safety riskCompanies should submit all new DTC television Companies should submit all new DTC television advertisements to the FDA before releasing these advertisements to the FDA before releasing these advertisements for broadcastadvertisements for broadcastDTC television and print advertising should DTC television and print advertising should include information about the availability of other include information about the availability of other options such as diet and lifestyle changes where options such as diet and lifestyle changes where appropriate for the advertised conditionappropriate for the advertised condition

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

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 be television and print advertisements should be targeted to avoid audiences that are not age targeted to avoid audiences that are not age appropriate for the messages involvedappropriate for the messages involvedCompanies are encouraged to promote health Companies are encouraged to promote health and disease awareness as part of their DTC and disease awareness as part of their DTC advertisingadvertisingCompanies 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 to guiding principles. Companies also commit to distributing these guidelines internally and to distributing these guidelines internally and to their advertising agencies.their advertising agencies.

PhRMAPhRMA will establish an office of accountability will establish an office of accountability that will be responsible for receiving that will be responsible for receiving comments from the general public and from comments from the general public and from health care professionals regarding DTC health care professionals regarding DTC advertising conducted by any signatory advertising conducted by any signatory company to these principles.company to these principles.

Accountability for the Accountability for the Guiding Principles Guiding Principles

(continued)(continued)The The PhRMAPhRMA office of accountability will issue office of accountability will issue periodic reports to the periodic reports to the public.public.

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

Overarching TrendOverarching Trend

SafetySafety

HealthHealth\\111468.3111468.3