Why you Should Care about Activities Related to Clinical Trials – Current Trends and Government Interest

1. Pharmaceutical Regulatory and Compliance Congress and Best Practices Forum Why you Should Care about Activities Related to Clinical Trials – Current Trends and Government Interest Craig Metz, PhD Vice President, Regulatory, GlaxoSmithKline Ned Kelly, MD Vice President, Global Pharmacovigilance, Quintiles Mark DeWyngaert, PhD MBA Managing Director, Huron Consulting Group November 8, 2007

2. Critical Considerations for Clinical Research in “Emerging Regions” (ERs) Craig A. Metz, PhD Vice President, Regulatory GlaxoSmithKline

3. Key Points to Consider • Data Integrity • Generalizability • Ethics

4. What’s Being Said AboutStudies in ERs

5. Notable Quotes In addition to manufacturing challenges, Dr. Woodcock explained that FDA has to interpret and extrapolate data from clinical trials conducted overseas. “We have to figure out how to deal with...intensified in recent years... extrapolating findings from one population, maybe a Third World-type of population, to our population and making sure the drug could still be safe and effective...under the conditions of the United States.”

6. Notable Quotes John Jenkins, who spoke on an audience-submitted question with CDER associate 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.”

7. Notable Quotes • Robert Temple stated, “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.” • “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 ...”

8. Notable QuotesSenator Grassley According to an FDA official interviewed by HHS OIG, about 20% to 25% of the trials for products that FDA oversees occur outside the U.S., and this number is growing. Because FDA’s regulations generally do not apply to trials conducted outside of the U.S., the agency’s oversight of foreign trials is limited. What steps, if any, is FDA taking to ensure the quality and integrity of data from foreign clinical trials, and what is FDA doing to improve its monitoring of such trials?

9. Notable QuotesEMEA Reflection Paper Clinical trials are now increasingly being conducted in countries outside the EU and the relevance of the data for EU patients is not always clear. In addition, there are now also examples of results of trials conducted globally, for which interpretation of the data for the EU was difficult.

10. Data Integrity • Each FDA Division may have a different philosophy regarding data from ERs • Are appropriate sensitivity analyses being conducted to evaluate the potential for regional effects? • How/when do you obtain regulatory authority concurrence with your analytical plan? • When are the regulatory authorities apprised of your enrollment balance across regions?

11. Data Generalizability Concerns • 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 ERs • Placebo response rates may be higher at ER 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 development program involving significant recruitment from ERs

12. Ultimate Goal APPROVAL NOT

13. Pharmaceutical Regulatory and Compliance Congress and Best Practices Forum Challenges in Outsourcing Clinical Trial Operations to the Developing World The CRO Perspective, with an Emphasis on Drug Safety Ned Kelly, MD VP Global Pharmacovigilance Quintiles

14. WHO Definition of “Developing Country” • “In the process of moving towards the economic and social model of the longer established industrialized countries.” • “Developing country” represents a concept that does not lend itself to a precise definition • Often reflects a value judgment • Refers to a large number of countries that are not homogenous • With respect to Pharmacovigilance, implies • Insufficient funds for public health • Insufficient access to medical care • Insufficient control of quality and distribution of medicines • Illiteracy or language problems in relation to medical and Healthcare communication • In clinical trials, sponsor must seek to avoid these circumstances, or implement strategies to minimize them. Lindquist M. The Need for Definitions in Pharmacovigilance. Drug Safety 2007; 30 (10): 825-830

15. Headlines • Clinical trials in India: ‘The wind is blowing’ (Outsourcing-Pharma.com 20 Sep 2007) • Staff remain core challenge for CROs in India (Outsourcing-Pharma.com 25 Sep 2007) • [In India] the pharmaceutical industry is growing at a rate of nearly 9 per cent annually(Outsourcing-Pharma.com 27 Sep 2007) • Population of China = 1.319 Billion(Chinability.com 2007-Sep-27) • Population of India = 1.136 Billion(Wikipedia, 01Sep2007 estimate)

16. Benefits of Outsourcing to Developing World • Access to patients: • Asia-Pacific • India and China together have 33% of world’s populations; each has significantly developed medical infrastructure and improving clinical trials infrastructure • Thailand, Singapore, Malaysia, Philippines • Latin America • South Africa • Eastern Europe • Especially for certain patient populations – e.g., oncology, HIV • Cost savings: labor costs are lower in developing world • Some investigators are often more diligent about ICH guidelines than are US and EU counterparts (e.g. Eastern Europe) • Some investigators in India have very high patient retention rates

17. Risks of Outsourcing to Developing World • Limited number of qualified investigators and study coordinators • Limited number of qualified CRO personnel • Competition among CROs result in high turnover rate • Is CRO quality adequate? • Regulatory environment approaching ICH standards, but not always at ICH standards • Concerns about intellectual property

18. Example Country: India • Larger sponsors typically audit CRO/sites more than once during study • Larger sponsors typically co-monitor at some site qualification visits • Regulatory change (abolishment of “Phase Gap”) in 2005 brought brisk increase in global clinical trials • Standard of care in urban population (approx 350 M) approaches that of West – prevalence of illness is approx 10%, or approximately 35 M patients in urban population • Most patients participating in Phase III global trials in India are educated, middle class in urban areas • Biggest constraint is paucity of trained investigators and coordinators • Increase in FDA inspections of investigative sites in 2007

19. India: Challenge of Training Investigators • As in the West, physicians in India are extremely busy • Unlike physicians in the West, they can’t afford Western CME costs • Main motivation to become investigators is revenue • No standard training curriculum for investigators in India • Clinical-trial-naïve Indian physicians see themselves as good at clinical practice, but don’t understand the regulatory term “Good Clinical Practice” • Important to initiate some type of training effort prior to Investigators’ Meeting – methods tend to be informal • Efforts underway to bring investigator training curriculum to India

20. Using CRO as Intermediary • CRO must have established local presence and access to best investigators • CRO must have well-trained, capable personnel • CRO must have SOPs in alignment with ICH – global SOPs preferable • CRO must have locally active QA Dept. • Benefits of CRO well-established in country of operations: • Knowledge of local languages and culture (important for site interactions) • Knowledge of qualified investigators with good coordinators • Knowledge of local medical culture and standards of practice • Knowledge of local regulatory environment

21. CRO Challenges in Pharmacovigilance • Very few trained and experienced personnel (e.g., Drug Safety Associates expert in processing safety cases) • Must be trained from within • Intense competition among CROs for qualified personnel • Operations must cover multiple countries, languages, cultures, and regulatory reporting requirements • New threat to CROs – BPOs (“Business Process Outsourcing” or “Business Process Optimization”) • Effective competitors at winning functional service provider work • Do not function as a local drug safety department, but as a commodity processor of safety cases from all markets • “BPO promise:” to learn and implement your business processes, then improve upon them – yet to be confirmed in PhV field • Risk in lack of domain knowledge of drug safety, a high-risk area of operations

22. Sponsor Risk Mitigation • Good feasibility – are you in the right countries for the patient population you need? • Compare feasibility analyses from more than one source • Is CRO capable in the developing country you’ve chosen? • If global CRO, how much in-country presence and history? • If local CRO, do you know them well enough to trust them? • Does CRO have training for investigators and coordinators? • Does CRO have good staff training programs, good mentoring programs, and high retention rate? • Audit of selected CRO(s) • For global study, one global CRO is best approach (some sponsors choose different CROs for different regions and/or functions)

23. Sponsor Risk Mitigation • Are the chosen sites good? • Review site selection process in audit of CRO • Review CRO’s audit plan • Have your CRA accompany one or more randomly selected CRAs from CRO on randomly selected site qualification visits • Audit study, including audit a few sites already audited by CRO, and a few not audited by CRO • Stay in collaborative partnership with chosen CRO(s) • Remain aware of and sensitive to cross-cultural issues • For example, most of the world has more “high context” culture than does the US • For example, many countries have more than one culture, based on multiple ethnicities and/or “modern business” vs. “traditional” cultural differences

24. Pharmaceutical Regulatory and Compliance Congress and Best Practices Forum Monitoring Audit Practices to Assure Data Validity and Trial Integrity An Independent Perspective Mark DeWyngaert PhD, MBA Managing Director Huron Consulting Group

25. Third Party Vendor Assessments: • Pharmaceutical companies have a growing need to examine their relationships with third party vendors as a result of increased international, federal and state regulations. There is also a continued focus on the bottom line and a rising number of contracted responsibilities. • Third party vendors are used in a number of capacities. Companies routinely employ the services of Clinical Research Organizations (CROs), medical education vendors, healthcare technology firms, and data management. • Areas of concern for many pharmaceutical companies center around vendor efficiency, quality, security, contract fulfillment, and compliance with the ICH and FDA’s GXPs • Across all vendor relationships, pharmaceutical companies should be interested in : • The sufficiency of contracts and vendor policies currently in place • Whether current operating controls adequately regulate vendor activities • The extent to which potential vulnerabilities are identified by current monitoring • Sufficiency in the degree of oversight by sponsor

26. Assessments/Audits - CROs Using other reviewers provides assurance that compliance and ethical requirements are met and that there is high degree of independence from both Sponsor and Vendor • Prior to CRO selection (optimal) • Assess qualifications of key personnel • Assess SOPs: comparability with internal SOPs and change control processes • Review systems and processes for contracted services management • Audits/Assessments at other times • Routine, on-going basis • Prior to any interim and/or final analysis • Third party vendor contract terms • For cause….

27. Identify Business Gaps and Risks • Identify the regulations, guidelines, standards that apply to the respective process both local and in major markets • Identify existing process from a-z, ie: how are adverse events reported. Include all business functions that relate to the activity • Once the “current state” process is outlined, identify controls that are missing in the process, ie: clearly defined roles, objective policies, systems which have controls validated throughout the process, IT/manual systems for collecting data, duplications etc. • Policies, i.e.: investigator Training, payments to trial participants, data collection and validation, site selection, trial drug control • Audit and monitoring plans • Systems, ie: data integrity, function, checks and balances • Define “to be” process and identify action steps to address the gaps in the “as is” process • Monitoring plan should be designed with the Compliance Program goals in mind.

28. Practical Considerations Related to Auditing and Monitoring Strategy • Developing your Auditing and Monitoring Plan • Deciding what to monitor • Prioritize Risk Areas • Internal Factors, i.e. any system changes, people changes, etc. • External Factors, i.e. new regulation, national and local enforcement etc. • Compliance Program Identify controls that make the process work : • Determine overall purpose to be effective • Resources available to execute plan • Consider integration with Internal Audit Plan • Identify timeframes for audits and monitoring • Communication and Commitment to Plan to Vendors and Internal

29. Third Party Vendor Assessments:Objective and Scope The assessment should evaluate the comprehensive performance of a third party vendors by closely examining their adherence to contractual obligations and the effectiveness of their processes and controls. On-site audits* of vendors • Accuracy of billing • and invoices Compliance with regulatory guidelines Third Party Vendor Assessments • Review of contract terms against work performed Testing of selected documentation Investigator eligibility and payments Program management Compliance with your company’s policies, procedures, and practices “Assessment” = Process and procedural review, transaction testing, and data analysis on a scope basis to provide an assessment of compliance for internal purposes.

30. Questions Mark A DeWyngaert PhD MBA Managing Director Huron Consulting Group Email: mdewyngaert@huronconsultinggroup.com 646-277-8817