Pitfalls and Pathways in Prescription Drug Promotion:

Pitfalls and Pathways in Prescription Drug Promotion: Or what every healthcare auditor should know before she watches another drug ad! Paul Savidge Vice President Global Labeling & Promotion Compliance Bristol-Myers Squibb October 18, 2007

Let s be spontaneous Regulation of Drug Advertising My Welsh Terrier Thinks He s Mark Spitz Topic Select-o-Matic Why the Designated Hitter has Ruined Baseball 10 Reasons Philadelphia is Better Than New York I was Jane Austen in a Former Life

My Welsh Terrier Thinks He s Mark Spitz Paul Savidge Interesting and Spontaneous Person October 18, 2007

Disclaimer My opinions are my own and do not necessarily represent the views or practices of my employer. You are free to disagree with me. Most of my friends do.

What I will discuss today Fundamentals of FDA regulation of prescription drug promotion Hot enforcement trends and issues Auditing the promotion compliance function Recent amendments to the FFDCA* *Federal Food, Drug & Cosmetic Act of 1938

FDA s Powers FDA has broad authority to ensure that drugs are sufficiently safe and effective prior to their introduction into the marketplace. Since 1962, the FFDCA has given FDA responsibility to regulate the advertising of: Prescription human drugs Prescription veterinary drugs Biologics Restricted medical devices

Why? Why did Congress give FDA oversight of prescription drug advertising? Congress concluded that advertising can mislead health care professionals to the detriment of patient health. To encourage companies to submit clinical data to FDA to support new indications.

CDER has responsibility for drugs FDA s Center of Drug Evaluation and Research (CDER) has oversight for human prescription drugs and therapeutic biologics HUMAN CDER s Office of Medical Policy includes the Division of Drug Marketing, Advertising, and Communications (DDMAC) DDMAC oversees advertising and promotional activities for prescription drugs and therapeutic biologics

DDMAC DDMAC is headed by a Division Director, (Tom Abrams) with staff divided into Four Professional Review Groups Two Direct-to-Consumer (DTC) Review Groups A Training & Support Group DDMAC s mission is to protect the public health by ensuring that prescription drug/therapeutic biologic information is Truthful Balanced Accurately communicated

What does DDMAC do? DDMAC fulfills its mission through a variety of activities: Provides advice to the pharmaceutical industry, usually through Advisory Comments Performs surveillance of promotional activities Through sponsors submissions of promotional materials Through attendance at major scientific conferences Through complaints from industry, healthcare professionals, consumers Initiates enforcement actions Issues guidance documents for industry Conducts research on promotion topics, such as consumer behavior towards DTC advertising

An important limitation FDA has limited authority to require the review of advertising prior to its use* Sponsors may request DDMAC to provide advisory comments on promotional materials prior to their use DDMAC will not provide advisory comments on promotional claims that are already in the marketplace All promotional materials must be submitted to DDMAC before or at the time of initial use on Form 2253. *Recently expanded by Congress!

Relevant regulations Labeling Part 201 Prescription Drug Advertising Part 202 Prescription Drug Marketing Part 203 Investigational New Drug (IND) Application Part 312 New Drug Applications (NDA) Part 314 Post-Marketing Submission of Advertising Part 314.81 Accelerated Approval Part 314.550 Sub Part H Accelerated Approval for Biologics Part 601.45 Dissemination of Information on Unapproved/New Uses Part 99 Dear Healthcare Professional Letters Part 200.5 Information to Pharmacists Part 200.7

Drug labeling The regulations define labeling: Labeling is all labels and other written, printed, or graphic matter Upon product container or wrapper Accompanying such product Label is a subset of labeling and is defined as a display of written, printed, or graphic matter upon the immediate container of any article Each product approved in the United States has Prescribing Information (PI) that is the FDA approved product labeling Labeling also includes promotional labeling, which is distinct from advertising

Promotional labeling v. advertisements Regulations do not define advertising. Examples provided by FDA suggest that advertisements are forms of promotion that occupy a paid space such as broadcast, magazine and newspaper ads Promotional labeling is essentially all other types of promotion such as sales aids, patient pamphlets, company-owned internet sites and verbal communications Why should I care about the difference?

Why the difference is important Print advertisements that make product claims must be accompanied by a brief summary A brief summary is a document that contains detailed information about a drug s safety profile based on information contained in approved product labeling. Promotional labeling that makes product claims must be accompanied by the approved Prescribing Information (the PI)

Advertising regulations 21 CFR Part 202 provides the requirements related to: The placement of the brand and generic name of the product Reminder advertisements Indication statement Presentation of information Must not be false or misleading Must have fair balance between efficacy and risk information Must be consistent with and not contrary to approved labeling Must not omit material facts

False, lacking in fair balance or otherwise misleading 21 CFR Part 202 provides a list of ways in advertisements (or promotional labeling) are or may be false, lacking in fair balance or otherwise misleading Fair balance is the requirement that information concerning the efficacy of a product must be adequately balanced by information concerning the product s safety Safety information should be communicated in a way that is reasonably comparable in prominence and readability to the communication of information regarding a product s efficacy Note: Although fair balance is a concept, the term is often used to refer to the safety information that is required to be communicated

What is false or misleading?? Promotional material is false or misleading if facts not in the labeling are stated or implied to support claims that the drug is: Better or more effective than indicated Useful for a broader range of patients than in the approved labeling Safer, or has fewer serious side effects or contraindications than indicated by then labeling

What is false or misleading? Examples of ways in which promotional material may be false or misleading: Presents a misleading comparison that suggests the product is safer or more effective than another drug, or otherwise unfairly compares two products Misrepresents a study or study results Uses graphics in a misleading way Misrepresents the drug s mechanism of action or its clinical impact Uses price information in a misleading fashion

Promotional claims must be adequately substantiated Most promotional and labeling claims must be supported by substantial evidence Substantial evidence typically is two or more adequate and well-controlled clinical investigations Limited instances where FDA has required fewer than two studies for safety and efficacy claims By statute, certain claims to managed care formulary committee members must be supported by competent and reliable scientific evidence

Promoting an unapproved drug as safe or effective is prohibited. A sponsor, investigator, or any person acting for or on behalf of a sponsor or investigator cannot represent that an investigational drug is safe or effective. Opportunities to publicize investigational compounds are very limited: Legitimate clinical recruitment activities Press releases concerning significant scientific events Required SEC disclosures (material events) Coming Soon advertisements under certain circumstances

Accelerated approval Accelerated approval is a process to speed to market drugs that promise significant benefit over existing therapy for serious or life-threatening illnesses or for which no therapy exists Because drugs approved under the accelerated approval provisions are approved based on incomplete information (and therefore their risk/benefit is less clear), FDA requires that all promotional materials for these drugs be submitted to DDMAC for comments prior to use.

The role of guidance documents FDA often communicates its current thinking on certain topics to the pharmaceutical industry through guidance documents FDA views these guidance documents as recommendations, unless specific regulatory or statutory requirements are cited Guidance documents do not create or confer any rights for or on any person and do not operate to bind FDA or the public (although this has been debated in the courts)

Guidance documents concerning drug promotion Final Guidance Documents Industry-Supported Scientific and Educational Activities Consumer-Directed Broadcast Advertisements Draft Guidance Documents Brief Summary: Disclosing Risk Information in Consumer-Directed Print Advertisements Help-Seeking and Other Disease Awareness Communications by or on Behalf of Drug or Device Firms Accelerated Approval Product Name Placement, Size, and Prominence in Advertising and Promotional Labeling

The flood gates are opened: Final guidance on Consumer-Directed Broadcast Advertisements (1999) Purpose: Provide guidance on advertising prescription drugs directly to consumers through broadcast media such as television, radio, or telephone Summary Adequate Provision for dissemination of the approved labeling must be made for prescription drug advertisements that are made through a broadcast media and cannot contain a brief summary Broadcast advertisements must disclose the product s major risks in either the audio or audio and visual parts of the presentation, commonly known as a Major Statement

What is adequate provision? To comply with the adequate provision requirement, the guidance recommends that broadcast ads include reference to the following sources of additional information: A toll-free telephone number A concurrently running DTC print ad A healthcare professional An Internet web page providing access to product information

Hot Enforcement Trends and Issues

DDMAC enforcement actions Most common enforcement actions (EAs) are: UNTITLED LETTER Typically addressed to the company s regulatory reviewer and signed by the DDMAC reviewer Requires immediate discontinuation of the violative materials and confirmation in writing within 2 weeks WARNING LETTER Titled and typically addressed to the CEO of the company and signed by the Division Director Requires immediate discontinuation of the violative materials and confirmation in writing within 2 weeks Includes request for corrective action Note: Warning letters usually concern serious safety issues or address a pattern of abuse by the sponsor

DDMAC Enforcement Trends: 1997-2007 Decreased Volume of EAs over the Past Decade 175 150 141 158 Total EAs Total Warning Letters Number of EAs 125 100 75 50 25 0 5 11 108 5 79 4 70 4 28 1 25 5 23 12 29 15 22 14 15* 7* 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007* Year http://www.fda.gov/cder/ddmac/lawsregs.htm#enforcement%20actions *through 9/30/07

DDMAC Enforcement Trends: 1997-2007 Increased Proportion of Warning Letters 100 Proportion of WL/EA, % 80 60 40 20 0 Proportion of WL/EA, % 64 52 52 47* 20 3.5 7.0 4.6 5.1 5.7 3.6 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007* Year *through 9/30/07

Trends in 2007 DDMAC Enforcement* Therapeutic Areas Ophthalmology 7% Rheumatology 7% Oncology 7% Neurology 26% Psychiatry 7% Allergy 13% Dermatology 13% Antiinfectives 20% http://www.fda.gov/cder/warn/warn2007.htm *through 9/30/07

Trends in 2007 DDMAC Enforcement* Material types 40% advertisements 40% sales aids Target audience Professional 87% (6 of 13 WL) Consumer 13% (1 of 2 WL) http://www.fda.gov/cder/warn/warn2007.htm *through 9/30/07

Top Issues in 2007 DDMAC Enforcement* Unsubstantiated claims 67% of EAs cite lack of substantial evidence Unsubstantiated efficacy or safety claims Overstatement of efficacy Unsubstantiated comparative claims Omission and/or minimization of risk information 60% of EAs cite lack of adequate presentation of safety information Promotion of off-label or unapproved uses 33% of EAs cite implied or overt off-label promotion *through 9/30/07.

Companies are responsible for their agents! Provigil (modafinil) [C-IV] WL Promotional material was presented by a physician consultant hired by Cephalon, Inc. to present to the Maryland Department of Health and Mental Hygiene s Pharmacy and Therapeutics Committee http://www.fda.gov/cder/warn/2007/provigil-wl.pdf

If its not good enough for the PI, it s probably not good enough for promotion Exelon (rivastigmine tartrate) Capsules and Oral Solution WL http://www.fda.gov/cder/warn/2007/exelon_wl.pdf

When the auditors came knocking

Audit methodology Objectives Evaluate department s compliance with FDA requirements and internal standards and procedures Assess the effectiveness of the review process Assess management and training Methods Review of standard operating procedures Review of sample of approved promotional materials against regulations, policies and standards Interviews of personnel

Pathways Audit was able to assess: Quality of review/approval/archival system Level of commitment to compliance Scope and depth of regulatory training Effectiveness of process (not just SOPs but level of implementation and enforcement) Quality of process training for all personnel involved Level of commitment to continuous improvement

Pitfalls Limited scope of this audit, which did not include: Interviews with or evaluation of other stakeholders and participants in the process In-depth review of promotional materials (inclusive of product history, previous communications with DDMAC, etc ) Review of other promotional and nonpromotional activities of the company (compliance activities, grant policies, public relations, advisory boards, market research)

Recent Amendments to the FFDCA related to drug promotion

FDAAA & PDUFA On September 27, 2007, President Bush signed into law the Food and Drug Administration Amendments Act (FDAAA) of 2007, which includes the reauthorization and expansion of the Prescription Drug User Fee Act (PDUFA) (effective in 180 days) The amendments and reauthorization of PDUFA will significantly broaden and upgrade the agency's drug safety program, increase resources for review of television drug advertising, and facilitate more efficient development of safe and effective new medications for the American public

Highlights FDA can require pre-review of DTC advertisements under certain circumstances Direction on major safety statement in broadcast advertisements Toll free adverse experience reporting number in published advertisements Civil money penalties for DTC advertising violations Separate user fee program for review of DTC television ads

Pre-review of television ads The FDAAA grants FDA broad authority to require the submission of any television advertisement for a drug, 45 days prior to broadcast FDA may make recommendations on: Changes necessary to protect the consumer good and well-being Changes consistent with prescribing information for the product Statements to address the efficacy of the drug in specific population groups (e.g., elderly, children and racial and ethnic groups) FDA may require the sponsor to include a specific disclosure about a serious risk listed in the product labeling or the date of approval of the drug

Major statement in broadcast ads DTC broadcast ads (other than reminder ads) must present the major statement relating to side effects and contraindications in a clear, conspicuous, and neutral manner This requirement is designed to address concerns that background distractions undercut the communication of safety information in DTC broadcast ads FDA must issue regulations within 30 months of amendment s enactment establishing standards for determining whether a major statement meets this new standard

Toll-free AE reporting number in advertisements The amendment requires published DTC ads to include information, including a 1-800 number, about how consumers can report side effects to FDA Within 6 months of amendment s enactment, FDA must conduct a study to determine whether this information is appropriate for inclusion in DTC television ads "You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088."

New penalties for DTC ad violations FDA has new authority to impose money penalties against the NDA/BLA holder that disseminates any DTC ad (including print) that is false or misleading First violation $250,000 for any 3-year period Subsequent violation $500,000 in any 3-year period Repeated dissemination of the same or similar ad constitutes a single violation After written notice by FDA, however, each day constitutes a separate violation except that for print ads in publications that are published less frequently than daily, each issue date (e.g., weekly, monthly) is considered a single violation

User fees for DTC broadcast advertisements Separate user fee program for sponsors that submit DTC television ads for advisory review will pay fees Fees to be collected annually, adjusted for inflation and workload, will fund 27 DDMAC FTE for pre-market advisory review of TV advertisements Stable funding design: one-time participation fee in first year, and annual pre-payment for advisory reviews Five year phased-in performance FDA will commit to review specified number of ads submitted for advisory reviews in 45 days, and specified number of resubmissions in 30 days

Mechanism for collection 120 days before start of FY08 (or start of program if statute delayed), FDA will issue a Federal Register (FR) notice asking persons to identify number of TV ads they intend to submit for advisory review during FY08 Response will be a commitment to pay the advisory review fees for the identified submissions The ad shall be submitted in the FY for which the fee was assessed, except that A person can carry-over one paid fee to the next FY

Mechanism for collection Based on the number of submissions identified, 60 days before start of FY08 or program, FDA will issue another FR establishing the fees for FY08 Fees will be $6.25 million divided by the number of submissions identified e.g., if 150 submissions are identified, fee will be $6.25 million 150 = $42,000 Fee per submission may not exceed $83,000 in first year

Mechanism for collection FDA will invoice companies for fees Fees due and payable on or before October 1 of FY 50% Late fees For late payment of invoices For advisory reviews not identified before start of fiscal year

Mechanism of collection: participation fee One time only assessment, either before start of program in FY08, or when company decides to seek advisory reviews Designed to collect $6.25 million (one year of reserves) FDA will assess each participating sponsor for an amount equal to that assessed for the annual advisory review fees in the first year of program Payment is graduated based on number of advisory reviews

Late fees and end of program Late participants will be assessed at least as much as those who joined in FY08 Participation fee will capture all ads submitted for advisory review during first year of participation, even if identified late (and will be 50% more if late fees applied to advisory reviews) In FY12, or if program ends early, any money remaining, less expenses needed to close down the program, will be returned to sponsors

Next time we ll talk about baseball! Thank you very much paul.savidge@bms.com