Pharmaceutical Compliance Current Trends:

1. Pharmaceutical Compliance Current Trends: Hot Button Issues to Look at this Year in Sales, Marketing, Clinical, Medical Affairs and Government Pricing

2. Clinical & Medical Affairs: The Current Trends and Hot Issues Craig A. Metz, Ph.D. Vice President US Regulatory Affairs GlaxoSmithKline Mark A. DeWyngaert, MBA, Ph.D. Managing Director Huron Consulting Group

3. Clinical & Medical Affairs: The Current Trends and Hot Issues • Clinical Trial Transparency (CTR) • Post Marketing Clinical Trial Commitments • IRB Considerations • Investigator Initiated Trials • Fair Market value • Medical Liaisons Role Mark A. DeWyngaert, MBA, Ph.D. Managing Director Huron Consulting Group Craig A. Metz, Ph.D. Vice President Clinical Affairs GlaxoSmithKline

4. Clinical Research Transparency

5. Guiding Principles forClinical Research Transparency • Inform the medical and academic research community of ongoing research and the opportunity to participate • Prevent unnecessary study duplication • Promote collaboration with industry • Provide information on active studies to prospective study subjects • Provide a reference point for monitoring study result posting • Provide public access to study results (free)

6. Clinical Study Results DatabasesProgress to Date • PhRMA (clinicalstudyresults.org) – Nov 04 • 174 drugs posted by 33 companies (Sept. 05) • 252 drugs posted by XX companies (Jan 06) • Astra Zeneca (astrazenecaclinicaltrials.com) • 188 studies/29 products (Mar 06) • Roche (roche-trials.com) – April 2005 • 312 studies/39 products (Mar 06)

7. Clinical Study Results DatabasesProgress to Date • Novartis (novartisclinicaltrials.com) • 41 studies (Mar 06) • Lilly (lillytrials.com) – Dec 04 • Results from 126 studies posted (Jan 06) • GSK (ctr.gsk.co.uk) – Sept 04 • Results from >2600 studies/36 products (Jun 06)

8. Post Marketing Commitments

9. The FDA and Drug Safety:A Proposal for Sweeping Changes* “According to the most recent report, there were 1231 as yet unsatisfied commitments through September 2005.” • 2/3rds (797) were “pending” (ie. not initiated) • 21% were “ongoing” or “delayed” • Many pending study commitments lacked any deadline for completion *Furberg CD, Levin AA, Gross PA, et al. Arch Intern Med. 2006; 166: 1938-1942

10. Get your facts first…….. then you can distort them as much as you please. Mark Twain

11. Tracking Phase IV Commitments at the FDA • Annual reporting requirement (PDUFA 1997) • Feb 06 Final Guidance (April 2001 draft) • (www.fda.gov/cder/guidance/5569fnl.htm) • Public website (www.fda.gov/cder/pmc) • Annual status reports (506B) required for: • Studies that were a condition of Accelerated Approval • Studies in pediatric patients required under PREA • Studies the sponsor committed in writing to conduct • Annual reports required until FDA provides written notification that the commitment has been met or the study is no longer feasible or the study would no longer be useful

12. Tracking Phase IV Commitments at the FDA Processes • Develop/agree study schedule/completion dates • Communicate/agree timeline revisions • Original timeline remains in place for tracking • Final reports submitted as – Postmarketing Study Commitment – Final Study Report • FDA reviews and communicates whether commitment has been fulfilled • Reviews “generally” within 3 mo

13. Tracking Phase IV Commitments at the FDA Commitment Status Categories* • Pending – study has not been initiated, date for initiation of enrollment has not passed • Ongoing – study proceeding to original schedule • Delayed – study is behind original schedule • Terminated – study terminated before completion, study report not yet submitted • Submitted – study concluded/terminated, notification from FDA pending * Where multiple studies exist for a single commitment, tracking is driven by the least progressed study

14. IRB Considerations

19. Clinical Research in theDeveloping World

20. Key Focal Points • Data Generalizability • Ethics • Logistics • Monitoring • Metrics

21. Data Generalizability • Potential for unknown/poorly understood regional differences in medical practices/standard of care • Potential impact of culture/language on the effective deployment of PROs in developing countries • Placebo response rates may be higher at these sites for certain disease settings which could decrease study power and lead to failed trials • The more subjective the primary registration endpoint is the more regulatory risk is invoked with a VDA-based development program

22. Ethics • Potential regional differences in drivers for participation in clinical trials • Intent/ability to report adverse events • Adequacy of informed consent process • Need to adjust reading level/cultural content • Concerns of health/regulatory authorities • “Guinea pig syndrome” • Need to protect poor from exploitation • Obtaining truly informed consent from “unlettered” subjects • Are IRB/Ethics committees appropriately constituted/functioning at developing country sites?

23. Logistics • Evaluating the infrastructure and understanding local expectations for infrastructure building/maintenance at sites • Developing and maintaining relationships with PIs and site staff • Use of electronic data transfer • Data security issues

24. Monitoring • Availability of funding/staffing to conduct increased full site audits in these regions • Understanding the Regulatory Authority view of data from these regions • Monitoring the approval metrics for NDA/MAAs with significant amounts of data from developing countries • Monitoring the RA audit patterns/results

25. Metrics • How are critical aspects of study performance other than recruitment and cost per patient (e.g. protocol compliance, dropout rates, cost/evaluable patient, data query rates) being evaluated? • What is known about regional differences in study contracting/approval rates?

26. A Word from the FDA • John Jenkins, MD (Director, Office of New Drugs, CDER): Jenkins, who spoke on the audience-submitted questions with CDER asssociate director for medical policy Robert Temple, said the trend has also caused FDA to have “concerns about the local standards of medical practice and how that may influence the ability to extrapolate and interpret the data that are brought back for consideration for the U.S. population. There are huge resource implications for us,” he continued, in sending inspectors to foreign clinical trial sites. “Those people also have to work for the State Department, so logistically it gets very difficult to start sending people to these foreign sites, yet at the same time we probably feel compelled more than ever to want to inspect those sites if we’re not familiar with trials coming from those locations.” • Robert Temple, MD (Director, Office of Medical Policy, Director (acting) Office of Drug Evaluation 1, CDER): Temple offered that the overseas outsourcing trend is making FDA “nervous.” The agency doesn’t “know entirely what’s reasonable,” he admitted. “We all know that subset differences can emerge. They may or may not be real. But when a study from Serbia drives the whole study, I have to tell you it provokes some nervousness — you don’t really know.” There are reassurances that come with U.S. studies, Temple pointed out. “The investigators in the U.S. sign [FDA Form] 1572 and if they do something disgraceful they will be barred from further service, they can even go to jail. We don’t have similar authority over people outside the U.S. and that lack makes me, at least, nervous. ... Where this comes up and is a real problem is where it’s an outcomes trial. How are you going to do a repeat survival study when it looks pretty good?” But, Temple acknowledged, “those are not the studies you most worry about. I’m more worried about depression studies. We’ve had some fairly stunning examples of at least one drug that looked pretty good in studies in South America and Eastern Europe, and we’re finding them not replicable in Western Europe and the U.S. We have no idea what that means. We have no reason to think anybody cheated. “There are some of those and they make me nervous. That said, it’s extremely common to accept data that’s collected from a wide variety of places in the world. Usually there’s fair consistency and it’s not a particular problem. I have to say we’ve not seen studies from India yet. We’ve seen a couple of giant Chinese studies that could very well figure in favorable actions — but not India yet, although we all know people who are moving there. When you talk to companies about what they encounter, they’re well aware that there are differences in delving through protocols that are different by region ...” In addition to the inspectional resources problem, he said, there’s a major language problem in many parts of the world — case report forms “in a language most of us can’t read. It’s inevitable, the current’s going there, there’s no doubt about it, but it’s not easy to know what to do. So we think it’s not a bad idea to have clearly U.S. data most of the time.”

27. Investigator Sponsored Trials

28. Belmont* Report “Practice refers to interventions that are designed solely to enhance the well-being of an individual patient or client and that have a reasonable expectation of success. “Research” is an activity designed to test an hypothesis, permit conclusions to be drawn and thereby to develop or contribute to generalizable knowledge. *Belmont Report – The National Commission for the Protection of Human Subjects of Biomedical Research and Behavioral Research (1979)

29. PhRMA Study Conduct Principles • Payment to clinical investigators or their institutions should be reasonable and based on work performed by the investigator and the investigator’s staff, not on any other considerations. • http://www.fast-track.com/products.php • A written contract or budgetary agreement should be in place, specifying the nature of the research services to be provided and the basis for payment for those services. • Payments or compensation of any sort should not be tied to the outcome of clinical trials. • Clinical investigators or their immediate family should not have a direct ownership interest in the specific pharmaceutical product being studied.

30. Fair Market Value

31. The Regulatory Environment • Regulatory bodies are increasingly scrutinizing payments made by Medical Device, Pharmaceutical and Biotechnology Companies to healthcare professionals: • Centers for Medicare and Medicaid Services; • HHS Office of Inspector General; • Department of Justice; • State Attorneys General. • Key risk areas: • Are these payments potential inducements for product selection? • Could these payments be construed as a “kickback” or part of a “quid pro quo” arrangement? • Did these payments potentially initiate use of the product inappropriately? • Risk management for Pharmaceutical Companies: • Demonstrate that the payments are for “bona fide purposes”. • Demonstrate that the payments represent “fair market value”.

32. PPNPS – 5 Critical Elements to Documentation • Process • Is there a formal process through which payment levels are determined through pre-specified criteria? • Are the payments pre-set and defined or can they be variable? • Purpose • Why is the payment necessary? • What is the underlying purpose? • Is the payment potentially duplicative? • Is there a potential for fraud, waste, and abuse? • Need • Why is the service necessary from this individual or company? • How does it relate to the company’s commercial or clinical strategy? • Payment • Was there a determination process to derive a “fair market value” range for the payment? • Is there a process to track the “totality of spend” on a particular healthcare professional? • Service • Was the service actually performed? • Was there a demonstrable outcome that resulted from the payment?

33. Medical Science Liaisons

34. MSL Basics • The role of a medical science liaison is to provide scientific and educational information to health care professionals (“HCPs”) • MSLs occupy a middle ground between two groups: • Sales and marketing • Medical communications / Medical affairs • The Food & Drug Administration (“FDA”) does not recognize MSLs as a special class • If MSLs sell or promote products, they are subject to the same rules as sales representatives • DOJ and OIG monitor the role of MSLs in terms of both healthcare compliance and off-label sales Enforcement is based on the message, not the messenger

35. Current MSL Issues • “Proactive versus Reactive” behaviors • Definition of Key Opinion Leader (KOL) • IIS process- criteria for selection and role of MSLs • Interactions with sales and marketing employees • Consistency in off-label medical information communication processes and message • Standards for the preparation, review and approval of written medical information • Qualifications of MSLs, job descriptions and how they are supervised • Verification and centralized documentation of all requests and responses • Metrics and reward system for MSLs • Monitoring/Auditing process and follow-up

36. Recent Focus on Off-Label Promotion • Federal prosecutors are increasingly focusing on off-label promotion • Red flags include: • Using MSLs as a means to promote off-label • Targeting physicians who, because of their specialty, are unlikely to prescribe a drug for its approved use • Paying KOLs high fees to speak on off-label uses or act as consultants • Corporate Integrity Agreements • Often required as part of the settlement of federal investigations arising under the False Claims Act • Increased emphasis on MSLs and Medical Communications

37. Enforcement: Clinical Trial Results • Federal Government has expressed interest in this area as well • “I think the focus, from our perspective is not just what is the impact on reimbursement but what is the impact on patients.”—Associate U.S. Attorney James Sheehan, Eastern District of Pennsylvania (Rx Compliance Report, April 10, 2006) • “If I had to forecast an area that I think is going to be a growth area it is that area of the research that supports the clinical trials.”—Sheehan, id.

38. Questions?

39. A Word from the FDA • John Jenkins, MD (Director, Office of New Drugs, CDER): Jenkins, who spoke on the audience-submitted questions with CDER asssociate director for medical policy Robert Temple, said the trend has also caused FDA to have “concerns about the local standards of medical practice and how that may influence the ability to extrapolate and interpret the data that are brought back for consideration for the U.S. population. There are huge resource implications for us,” he continued, in sending inspectors to foreign clinical trial sites. “Those people also have to work for the State Department, so logistically it gets very difficult to start sending people to these foreign sites, yet at the same time we probably feel compelled more than ever to want to inspect those sites if we’re not familiar with trials coming from those locations.” • Robert Temple, MD (Director, Office of Medical Policy, Director (acting) Office of Drug Evaluation 1, CDER): Temple offered that the overseas outsourcing trend is making FDA “nervous.” The agency doesn’t “know entirely what’s reasonable,” he admitted. “We all know that subset differences can emerge. They may or may not be real. But when a study from Serbia drives the whole study, I have to tell you it provokes some nervousness — you don’t really know.” But, Temple acknowledged, “those are not the studies you most worry about. I’m more worried about depression studies. We’ve had some fairly stunning examples of at least one drug that looked pretty good in studies in South America and Eastern Europe, and we’re finding them not replicable in Western Europe and the U.S. We have no idea what that means. We have no reason to think anybody cheated. In addition to the inspectional resources problem, he said, there’s a major language problem in many parts of the world — case report forms “in a language most of us can’t read. It’s inevitable, the current’s going there, there’s no doubt about it, but it’s not easy to know what to do. So we think it’s not a bad idea to have clearly U.S. data most of the time.”