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Data Integrity and Fraud – Another Looming Crisis?

Edwin Rivera-Martinez, ChiefInvestigations and Preapproval Compliance Branch

Division of Manufacturing & Product QualityOffice of Compliance

Center for Drug Evaluation & ResearchU.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 personnel and activities

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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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• 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

Problems Found in Bioequivalence Studies Performed by MDS

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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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• Altering weights of samples and standards in analytical calculations

• Changing chromatogram processing parameters

Examples of Unreliable Data in Applicant Submissions

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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 NewsMarch 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 NewsMarch 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 NewsMarch 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 NewsMarch 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 NewsMarch 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 NewsMarch 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 NewsMarch 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) 827-9012E-MAIL: Edwin.RiveraMartinez@fda.hhs.gov