Why%20you%20Should%20Care%20about%20Activities%20Related%20to%20Clinical%20Trials%20

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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

3
Key Points to Consider

• Data Integrity
• Generalizability
• Ethics

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Whats Being Said AboutStudies 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 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.

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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 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 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?

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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.

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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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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-naïve 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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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 AssessmentsObjective 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
Compliance with your companys policies,
procedures, and practices
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_at_huronconsultin
ggroup.com 646-277-8817