THE FDA REGULATORY AND COMPLIANCE SYMPOSIUM Managing 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

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

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

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. 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. 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. 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. Outcome – Warning Letter cites company for failure to provide risk and warning information.

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.” 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 drug’s indication and benefits. DDMAC concluded it was a full product ad because the statement accompanied by the image made representations about the drug’s indication and benefits. The company was cited for failure to include risk, side-effect and contraindication information. The company was cited for failure to include risk, side-effect and contraindication information.

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 ….” 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. Omission of risks raises serious public health and safety concerns.

Omission or Inappropriate Display of Risk Information Companies were cited for: 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

Minimization of Risk Information Companies were cited for: 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

Unsubstantiated Efficacy Claims Companies were cited for: 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 – 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 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

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

Unsubstantiated Superiority Claims Companies were cited for: 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

Unsubstantiated Superiority Claims Companies were cited for: 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

Failure to Disclose or Misleading Communication of the Drug’s Indication Companies were cited for: 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 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

Less Frequently Cited Violations Failure to disclose or misstatement of ease of drug administration 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 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 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.

Example #1 Pfizer, Inc. NDA , , July 20, 2005

Example #2 Abbott Laboratories NPA July 15, 2005

Example #3 SuperGen Incorporated NDA August 18, 2005

Manufacturing Facility Inspections Frequently Cited Violations Improper Maintenance or Use of Equipment Improper Maintenance or Use of Equipment Failure to Follow or Have Written Procedures Failure to Follow or Have Written Procedures Inadequate Record Keeping and Documentation Inadequate Record Keeping and Documentation Understaffed or Under-qualified Quality Control Personnel Understaffed or Under-qualified Quality Control Personnel Manufacture of Unapproved Drugs Manufacture of Unapproved Drugs

Improper Maintenance or Use of Equipment Uncalibrated and Improperly used equipment does not provide reliable data Uncalibrated and Improperly used equipment does not provide reliable data Facilities were cited for: Facilities were cited for: –Uncalibrated Equipment used to test and manufacture product –Inadequate Equipment maintenance –Improper Equipment storage

Failure to Follow or Failure to Have Written Procedures Facilities must ensure procedures are followed by monitoring employees and verifying compliance Facilities must ensure procedures are followed by monitoring employees and verifying compliance Facilities were cited for: 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

Inadequate Record Keeping and Documentation Facilities were cited for: Facilities were cited for: –Missing data –Improperly changing data –Improperly documenting deviations –Improperly performing and documenting investigations into deviations

Understaffed or Under- Qualified Quality Control Personnel Facilities were cited for: 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 Example – Quality personnel were unable to answer the inspectors’ questions and did not have suitable academic training in chemistry or microbiology

Study Inspections Frequently Cited Violations Problems with the Integrity and Quality of the Studies Problems with the Integrity and Quality of the Studies Problems with Data Records and Documentation of Studies Problems with Data Records and Documentation of Studies Problems with the Analytical Methods used in the Studies Problems with the Analytical Methods used in the Studies

Quality and Integrity of Studies Companies were cited for: 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

Data Records and Documentation Companies were cited for: 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

Analytical Methods Companies were cited for: 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 When anomalous results are found the company must do a systematic evaluation of all the samples involved in the study

Further Development FDA Drug Safety Oversight Board FDA Drug Safety Oversight Board WLF – FDA Watch Group WLF – FDA Watch Group Manufacturer shutdowns ______ Manufacturer shutdowns ______

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

Preamble Increasing awareness about diseases; Increasing awareness about diseases; Educating patients about treatment options; Educating patients about treatment options; Motivating patients to contact their physicians and engage in a dialogue about health concerns; 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 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 Encouraging compliance with prescription drug treatment regimens

Guiding Principles The Principles are premised on the recognition that DTC advertising of prescription medicines can benefit the public health 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 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. 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.

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 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 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 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

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 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 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 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

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 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 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 All DTC advertising should respect the serious of the health conditions and the medicine being advertised

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 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 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 Companies are encouraged to include information in all DTC advertising, where feasible, about help of the uninsured and underinsured

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.

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.

Overarching Trend Safety

Health\ Health\