Transcript Univ. of GA 2006 Compliance Update Presentation

Data Integrity and
Fraud – Another
Looming Crisis?
Edwin Rivera-Martinez, Chief
Investigations and Preapproval Compliance Branch
Division of Manufacturing & Product Quality
Office of Compliance
Center for Drug Evaluation & Research
U.S. Food and Drug Administration
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Agenda
• Headlines from the past
• Objectives of the Preapproval
Inspection Program
• Roles of reviewers, district office, OCI
and CDER’s Office of Compliance
• ORA Enforcement Report
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Agenda
• Examples of data integrity problems
• What is FDA doing?
• What can industry do?
• Summary
• Words to live by
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Objectives of Preapproval
Inspection Program Today
• Assure applications are not approved if the applicant has not
demonstrated ability to operate with integrity and in
compliance with CGMPs
• Assure adherence to application commitments (facilities,
equipment and controls)
• Assure the authenticity and accuracy of data submitted in
applications
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CDER Reviewer’s Role
• Reviews data submitted in
application
• Assists in establishing
specifications for
manufacture and control
based on submitted data
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District’s Role
• Conducts inspections of
manufacturing sites referenced in
applications to
– Assure CGMP compliance
– Verify authenticity/accuracy of data
in applications
– Report other data which may impact
approval of applications
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Office of Compliance’s Role
• Serves as liaison between field
offices and review offices
– Receives and processes inspection
requests
– Monitors status of inspections
– Reviews reports/recommendations
– Forwards final recommendations to
review offices
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Role of ORA’s Office of
Criminal Investigations
• Directs, plans, and develops criminal
investigation activities in
coordination with other Agency
components and with other Federal,
State, and local law enforcement
agencies
• Initiates and conducts criminal
investigations under all statutes
administered by the FDA
• Coordinates assignments involving
undercover and surveillance
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personnel and activities
Role of ORA’s Office of
Criminal Investigations
• Provides recommendations to the
Office of Chief Counsel on referrals
of criminal cases to the Department
of Justice for further investigation
and/or prosecution, or directly to the
U.S. Attorney when such direct
reference is authorized
• Participates in Grand Jury
investigations and serves as agents
of the Grand Jury
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ORA’s Enforcement Story
http://www.fda.gov/ora/about/enf_story/ch6/default.pdf
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Problems Found in Bioequivalence
Studies Performed by MDS
• Failure to conduct a systematic and thorough
evaluation to identify and correct sources of
contamination
• Failure to investigate anomalous results
• Lack of assay reproducibility between original
and repeat results
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Problems Found in Bioequivalence
Studies Performed by MDS
• Assay accuracy not assured under the conditions
of sample processing
• Biased manipulation of study data resulting in the
acceptance of failed runs
• Failure to demonstrate the accuracy of analytical
methods with appropriate validation experiments
and documentation
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Examples of Unreliable Data
in Applicant Submissions
• Intentional computer manipulation of chromatograms
by cutting and pasting chromatographic data so that
initial out-of-specification test results are brought into
specification
• Substitution of results from testing of aliquots from
vials samples that produced passing results to obtain
data for lots where initial samples failed specifications
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Examples of Unreliable Data
in Applicant Submissions
• Altering weights of samples and standards in
analytical calculations
• Changing chromatogram processing parameters
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Unreliable Data in GMP Records
• Manipulation of chromatograms by lab chemists
without justification and changing of calculations to
bring out-of-specification results within specification
• The chemists then placed the in-specification assay
results into the batch production and control record
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Unreliable Data in GMP Records at a
Contract Manufacturer and Laboratory
• Unreliable analytical results for degradants submitted
to FDA without notification/copy sent to the Sponsor
• Contractor failed to submit initial OOS results
obtained using original approved method filed with
FDA
• In-specification results reported to FDA were
obtained from an unapproved analytical method not
filed with the agency
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Data Integrity Audits Requested by CDER
Office of Compliance in Fiscal Year 2006
• Ten audits were assigned to ORA field offices and
completed
• Three of the ten audits revealed data of highly
questionable reliability that are currently under
review by CDER’s OC
• Second audit assignment to be issued shortly
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Breaking News
March 8, 2007 Press Release by US Dept. of
Justice, U.S. Attorney, District of New Jersey
• A former Vice President in charge of the Quality
Control Department and three supervisory chemists at
now-defunct New Jersey generic drug manufacturer
Able Laboratories pleaded guilt to a conspiracy
involving the rampant falsification and manipulation
of testing data of its drugs.
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Breaking News
March 8, 2007 Press Release by US Dept. of
Justice, U.S. Attorney, District of New Jersey
• The Information against one of the defendants
charges that the criminal conspiracy spanned 1999
through May 19, 2005, a period when the Company
and its leaders publicly touted Able’s enormous
growth and expansion.
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Breaking News
March 8, 2007 Press Release by US Dept. of
Justice, U.S. Attorney, District of New Jersey
• The defendants admitted to a broad-based fraud
scheme involving a series of drug products, and
conduct which ranged from improperly changing test
parameters to obtain satisfactory test results to a
secret project which included forging data in chemist
Laboratory Notebooks and Binders in order to obtain
the FDA’s approval to manufacture a new generic
drug product.
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Breaking News
March 8, 2007 Press Release by US Dept. of
Justice, U.S. Attorney, District of New Jersey
• The four outlined their supervisory roles and
participation with other chemists which resulted in
flouting, altering, and manipulating testing and
reporting requirements which were required to be
submitted to the FDA.
• All four face a statutory maximum penalty of five
years in federal prison and a $250,000 fine.
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What is FDA Doing?
• Specialized training of investigational staff on
uncovering data integrity, data manipulation and
fraud
• PAIs to focus more on data integrity and fraud
• Agency committed to follow-up on leads or
information regarding data manipulation and fraud
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What Can Industry Do?
• Train employees on proper data handling and
reporting
• Assure the reliability of data reported in
applications and manufacturing records
• Emphasize that everyone in the company is
responsible for data integrity
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Breaking News
March 8, 2007 Press Release by US Dept. of
Justice, U.S. Attorney, District of New Jersey
• “ The damage from the fraud at Able Labs was
devastatingly complete. ”
• “ Consumers were put at risk, a company that
employed 500 people was destroyed, and
shareholders were left with nothing in the end. This is
the legacy of the fraud perpetrated at Able Labs by
these defendants. ”
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Breaking News
March 8, 2007 Press Release by US Dept. of
Justice, U.S. Attorney, District of New Jersey
• “ Those who willfully falsify and manipulate the
various tests required during the manufacturing
process put the public health at risk, and do so at their
own peril, ” said Kim A. Rice, Special Agent in
Charge of the Food and Drug Administration in
Washington, which investigated the case.
• The investigation is continuing.
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Breaking News
March 8, 2007 Press Release by US Dept. of
Justice, U.S. Attorney, District of New Jersey
• Complete information is available at the website for
The United States Attorney’s Office – District of New
Jersey
http://www.usdoj.gov/usao/nj/press/2007releases.html
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Summary
• Data integrity, data manipulation and fraud appears
to be increasing
• It’s occuring in early stages of drug development
(i.e., clinical studies), during commercial
manufacturing and in various FDA regulated
products
• Quality by Integrity (QbI) is just as important as
QbD – the two go hand in hand to assure the safety
and efficacy of drug products
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Words to Live By
“Honesty and integrity are core values
that should be a part of our daily lives.
In the end, they are the only values that
truly identify us as individuals.”
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That’s All for Now Folks!
Thank you. See you next
time!
Gracias y hasta la proxima!
Merci et au revoir!
Danke schoon. Auf
Wiedersehen!
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For Additional Information
Edwin Rivera-Martinez, Chief
Investigations- and Preapproval Compliance
Branch, HFD-322
Division of Manufacturing & Product Quality
Office of Compliance
Center for Drug Evaluation and Research
11919 Rockville Pike
Rockville, MD 20858
TEL:
(301) 827-9012
E-MAIL: [email protected]
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