Risk Benefit Implications for Pharmaceutical Marketing PMCQ Education Day

Risk/Benefit Implications for Pharmaceutical Marketing PMCQ Education Day - Emerging Trends in Pharmaceutical Marketing Montreal, October 20, 2005

Topics Covered v Recent Regulatory Decisions re Safety v Response in the Regulatory Arenas v Public Response v Implications for Marketing I would like to acknowledge IMS Canada and its publication, Provincial Reimbursement Advisor, in preparing this presentation.

Safety Letters Posted on Health Canada Website – 2000 -2005

Antidepressants and Suicide Potential Late 2003 - Public concern about possibility of antidepressants and suicide potential. v v February 2004 – Scientific Advisory Panel held v Recommended stronger warnings May 2004 – SSRIs updated to warn re potential of self-harm. v v Class warning – patients under the age of 16

VIOXX® v Market withdrawal of VIOXX on September 30, 2004 December 2004 – US Congressional Report criticized how Merck and the FDA had disseminated information related to safety of VIOXX. v June 2005 – Canadian Expert Advisory Panel recommends that VIOXX be returned to the Canadian market with updated labelling. v July 2005 – A US judge rules that a nationwide class action lawsuit could be brought by a labour union helaht plan on behalf of all 3 rd party payers. v

VIOXX® July 2005 – EU advises that compliance of VIOXX ADR reporting will be investigated. v August 2005 – Merck loses first case re VIOXX and must pay $253 million to family in Texas. v September 2005 – Ontario Superior Court hears arguments requesting class action be allowed. v

Adderall® XR v Feb 9, 2005 – marketing of ADDERALL XR suspended v Based on sudden deaths (20) reported in PMS. v v 14 in children Aug 26, 2005 – New Drug Committee Hearing held. Product can be remarketed with changes to Product Monograph. v

Long-Acting Beta-2 Agonists October 4, 2005 – possible increased of asthmarelated deaths v v SMART study v Began in 1996 at request of FDA. Study of approximately 30, 000 patients was prematurely halted in January 2003 v v FDA advisory committee in July 2005

Questions Being Asked How closely tied are the regulatory authorities to pharmaceutical companies? v How transparent are the decisions made by regulatory authorities? v How do pharmaceutical companies comply with disclosure regulations v Do pharmaceutical companies spin safety information to their own ends? v v How much does the public have a right to know? How much is really known about a drug when it is first marketed? v

Controversy re safety “Unless the Canadian public can be assured that Health Canada is adequately monitoring the safety of marketed drugs, then confidence in the use of therapeutic products will suffer, and so will the health of Canadians. ” Lexchin J. Drug withdrawals from the Canadian market for safety reasons, 1963 -2004. Canadian Med Assoc J 2005; 172: 765 -8.

Response in the Regulatory Arena

Transparency Canadian public want to know the basis on which decisions are made. v Provincial governments and other payers also want to know the basis on which these decisions are made v To address these concerns, Health Canada has taken a number of recent steps to disclose how decisions are made. v

Office of Public Ombudsman April 16, 2005 – Health Canada announced the creation of the Office of Public Ombudsman v Will receive complaints, concerns and feedback about how Health Canada fulfills its responsibilities. v v To date no Ombudsman has been appointed.

Public Expert Advisory Committee Meetings v June 9, 2005 – first public EAM held on COX-2 drugs Any interested parties could attend address the Panel. v Reort posted on Health Canada’s website, together with all documentation given to Panel to consider v Sept 2005 – second public advisory committee held on breast implants. v

Summary Basis of Decision In the past, when new drugs were approved, the basis on which the decision was made was not disclosed. v Health Canada have announced that they will provide a Summary Basis of Decision for all drugs approved after Jan 1, 2005. v To date, six have issued: Crestor®, Fabrazyme®, Lyrica®, Velcade®, Zemplar® and Macugen® v

Clinical Trial Information There is a belief that industry does not disclose negative results from clinical trials. v Several leading journals (including CMAJ) have announced that they will no longer publish articles on clinical trials unless the trials were registered in a public database, meeting certain minimum criteria. v v FDA has a database that meets requirements. July 7, 2005 – Health Canada announced that they would be setting up such a database in Canada. v

Public Listing of Recalls As of April 2005, all recalls are listed on Health Canada website. v Information available: product, lot numbers, reason for recall, hazard level and recalling firm. v

Public Disclosure of ADRs May 25, 2005 – new web-based database for ADRs launched by Health Canada v v Called Med. Effect Provides access to the latest advisories, warnings and recalls v v Promotes the reporting of adverse drug reactions v Patients can report directly v ADR Database also available Anyone can search ADRs and drugs for all data submitted to Health Canada since the early 60’s. v

Office of Pediatric Initiatives Concern that little is known about drugs in children and how to use them, specifically the dose. v This office has been set up to promote research in children. v Proposed legislation changes in Canada would allow some exclusivity related to companies doing research in children. v

Upgrading Pharmacovigilance In addition to transparency, Health Canada has focused on upgrading the collection and interpretation of pharmacovigilance data. v This includes providing money to Health Canada to upgrade Health Canada oversight of safety v v Feb 2005 - $170 million over 5 years provided.

MOU with US Rare ADRs – occur in less than one in 10, 000 patients. v Can only be detected post-marketing and by using large databases. v June 29, 2005 – Canada signed a MOU with the US Consumer Product Safety Commission to share data with the US. v Includes postmarketing surveillance and enforcement activities. v

Mandatory Reporting of ADRs Companies are required to report ADRs but physicians are encouraged to report them. v Some countries have mandatory reporting systems: France, Sweden, Norway, Austria, Italy v Canada has mandatory reporting of child abuse, chemical intoxication and some infectious diseases. v Health Canada has announced that they want to establish mandatory reporting and are currently setting consultation on what this would mean. v

Upgrade of Canada’s ADR System Program is underway to upgrade and modernize Health Canada’s systems v v Provide for greater on-line public query capacity v Integration of foreign safety v Automated signal detection v Electronic filing. Provincial governments could more easily monitor drugs. v Could assist limited reimbursement or delayed reimbursement. v

Establishment of New Regional Centers April 2005 – new centers opened in Alberta and Manitoba. v Now seven centers – Halifax, Montreal, Toronto, Winnipeg, Saskatoon, Edmonton, Vancouver. v

Need for Pharmacovigilance Plans in Submissions? v As of November 2005 – required in Europe v Post approval stability protocols required in Canada. Easy to make this a post approval pharmacovigilance protocol. v v I believe this will occur in the next year.

Federal/Provincial Conference on Drug Safety September 2005 – Federal Health Minister and BC Health Minister (leaders of the National Pharmaceuticals Strategy) held a meeting to discuss this issue. v Involved provincial representatives, health care providers, patient reps, industry and researchers v Press release indicated that Health Ministers were to evaluate how to strengthen real-world drug safety and effectiveness and to provide report by June 16, 2006. v

Response International - Regulatory

New Guidelines US has issued three new guidelines on how to document and assess adverse reaction data. v WHO organization has issued a new guideline on assessing ADRs in clinical trials (CIOMS). v Europe is requiring pharmacovigilance protocols in submissions. v v Expectation is that ICH will enter this arena.

Response in Academia

Conflict of Interest v April 2005 – The Drug Trial published A book focused on the drug trial at the Hospital for Sick Children and Dr. Olivieri v In Hamilton, the Spectator conducted a 3 -month investigation of Mc. Master’s Faculty of Health Sciences v Approximately 100 faculty members had financial relationships with industry v v Research funding, clinical trial contracts, honoraria, speaking fees, consultancies, stock options, sitting on Boards of Directors

Response of Public

Public Response v New publications v v Dangerous Doses v v The Drug Trial Xx Movies/TV v The Constant Gardener. Spring 2006 – new movie looking at the pharmaceutical industry. v v Law & Order episodes.

Public Response v Public Opinion Polls Show distrust of pharmaceutical industry at an all-time high. v Public response to perceived safety issues is that industry is holding back negative data and putting their health at risk. v

Implications for Marketing

Public Relations There has never been a time for a greater need for the industry to tell its side of the story. v Trade associations and individual companies need to get the benefits that this industry brings to the forefront. Otherwise, it will not be told. v Stories regarding these benefits need to be brought to the public media, e. g. , Law and Order. Counterfeit medications would be one way to do this. v

Litigation With the greater disclosure of ADR information and risk/benefit data that support decision making, there will be more data available for litigation purposes. v Companies should routinely be monitoring what is on this ADR website regarding their products. v

Time to Approval Given the concerns about safety, agencies are likely to make conservative decisions and to ask for more data. v Approval of non-life threatening drugs may be delayed or consensus requested from advisory committees. v

Post Approval Commitments We will see the Canadian system develop to require post-approval commitments, either through a change to the system, the use of more conditional NOCs or the use of postmarketing protocols v v Will focus on safety assessments in sub-populations. Monitoring ADRs in a small environment in real life, e. g. , a teaching hospital. v These post-marketing commitments will likely have an impact on listings for reimbursement. v

Use of Large Databases As regulatory agencies try to get at “rare” ADRs (<1/10, 000 patients), large databases will be the best place to get this information. v We will see large databases adapt themselves better to be able to provide this data. v We will see regulatory agencies requesting companies to use these databases more. v

Patient Access to Data v Patients will have far greater access to data. They will review the data and share it among themselves via the internet. v They will begin filling their own ADR forms, particularly the patient groups that are well-organized and can assist one another. v

Direct To Consumer Advertising v Ban on Direct to Consumer advertising will continue. v US DTC Advertising may well find itself restricted. US Trade organization has recently issued new guideline that it expects its members to abide by regarding DTC advertising. v

Risk Management in its broadest sense will become a strategic function within pharmaceutical companies. v Pharmacovigilance and safety is one component of risk management for a company. v v v Paramount in the assessment would be the risk to the patient. How that risk is explored and defined may need to be tightened – i. e. , move from art to science with predetermined numbers and probabilities.

Parting Message… As of October 31, 2005, the US have adapted SPL labelling for ALL drug product subject to an NDA. v Company submits in SPL. FDA provides SPL to National Library of Medicine (NLM). NLM maintains database of all approved labelling which HMOs and others can use to develop their patient labelling etc. v Approved labelling is transmitted to NLM within 10 minutes of approval. From there it is available throughout the country. v Compare this to the industry stance in Canada where we have no electronic database of Product Monographs. Nor do we want one because we can’t be sure that the English version is the same as the French version. v

Conclusions v We have entered a new environment focused on v The relationship that industry has with regulators. How transparent we are in sharing safety data on our products. v v How close we are to researchers. How much information our patients and customers have access to regarding our products. v The old environment will never come back. We need to learn to function in this new environment and address the concerns that are coming to us. v