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

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Critical Considerations for Clinical Research in Emerging Regions (ERs)

Craig A. Metz, PhD Vice President, Regulatory GlaxoSmithKline Managing Risk with Third Parties and Strategic Partners Track

Key Points to Consider

Data Integrity Generalizability Ethics

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Whats Being Said About Studies in ERs

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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.
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Notable Quotes
John Jenkins, who spoke on an audiencesubmitted 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.
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Notable Quotes
Robert Temple stated, Im more worried about depression studies. Weve had some fairly stunning examples of at least one drug that looked pretty good in studies in South America and Eastern Europe, and were 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. its extremely common to accept data thats collected from a wide variety of places in the world. Usually theres fair consistency and its not a particular problem. I have to say weve not seen studies from India yet. Weve 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, theyre well aware that there are differences in delving through protocols that are different by region ...

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Notable Quotes Senator 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 FDAs regulations generally do not apply to trials conducted outside of the U.S., the agencys 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? Managing Risk with Third Parties and Strategic Partners Track

Notable Quotes EMEA 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.

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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?
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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
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Ultimate Goal
APPROVAL

NOT

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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

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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

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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)

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Benefits of Outsourcing to Developing World

Access to patients:
Asia-Pacific India and China together have 33% of worlds 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

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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

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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

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India: Challenge of Training Investigators

As in the West, physicians in India are extremely busy Unlike physicians in the West, they cant afford Western CME costs Main motivation to become investigators is revenue No standard training curriculum for investigators in India Clinical-trial-nave Indian physicians see themselves as good at clinical practice, but dont 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

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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

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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

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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 youve 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)

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Sponsor Risk Mitigation

Are the chosen sites good? Review site selection process in audit of CRO Review CROs 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

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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

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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 FDAs 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

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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.

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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.

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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

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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 Third Party Vendor Assessments Compliance with regulatory guidelines

Review of contract terms against work performed

Testing of selected documentation Compliance with your companys policies, procedures, and practices

Investigator eligibility and payments

Program management

Assessment = Process and procedural review, transaction testing, and data analysis on a scope basis to provide an assessment of compliance for internal purposes.

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Questions

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

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