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
Managing Risk with Third Parties and
Strategic Partners Track
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
Managing Risk with Third Parties and
Strategic Partners Track
What’s Being Said About
Studies in ERs
Managing Risk with Third Parties and
Strategic Partners Track
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.”
Managing Risk with Third Parties and
Strategic Partners Track
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.”
Managing Risk with Third Parties and
Strategic Partners Track
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 ...”
Managing Risk with Third Parties and
Strategic Partners Track
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 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?
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.
Managing Risk with Third Parties and
Strategic Partners Track
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?
Managing Risk with Third Parties and
Strategic Partners Track
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
Managing Risk with Third Parties and
Strategic Partners Track
Ultimate Goal
APPROVAL
NOT
Managing Risk with Third Parties and
Strategic Partners Track
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
Managing Risk with Third Parties and
Strategic Partners Track
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
Managing Risk with Third Parties and
Strategic Partners Track
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 2007Sep-27)
• Population of India = 1.136 Billion (Wikipedia, 01Sep2007
estimate)
Managing Risk with Third Parties and
Strategic Partners Track
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
Managing Risk with Third Parties and
Strategic Partners Track
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
Managing Risk with Third Parties and
Strategic Partners Track
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
Managing Risk with Third Parties and
Strategic Partners Track
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
Managing Risk with Third Parties and
Strategic Partners Track
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
Managing Risk with Third Parties and
Strategic Partners Track
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
Managing Risk with Third Parties and
Strategic Partners Track
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)
Managing Risk with Third Parties and
Strategic Partners Track
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
Managing Risk with Third Parties and
Strategic Partners Track
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
Managing Risk with Third Parties and
Strategic Partners Track
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
Managing Risk with Third Parties and
Strategic Partners Track
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….
Managing Risk with Third Parties and
Strategic Partners Track
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.
Managing Risk with Third Parties and
Strategic Partners Track
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
Managing Risk with Third Parties and
Strategic Partners Track
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
Compliance with regulatory
guidelines
Accuracy of billing
and invoices
Review of contract terms
against work performed
Investigator eligibility
and payments
Third Party Vendor
Assessments
Program management
Testing of selected
documentation
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.
Managing Risk with Third Parties and
Strategic Partners Track
Questions
Mark A DeWyngaert PhD MBA
Managing Director
Huron Consulting Group
Email: [email protected]
646-277-8817
Managing Risk with Third Parties and
Strategic Partners Track
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Challenges in Outsourcing Clinical Trial Operations to the