HISTORY OF DATA INTEGRITY - cbinet.com

1 CONFIDENTIAL 2016 PAREXEL INTERNATIONAL CORP. HISTORY OF data INTEGRITY August 16-17, 2017 Institute of Validation Technology 3rdAnnual data INTEGRITY ValidationJames Stumpff, RPh, Principal Consultant 2016 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL2 AGENDATHANK YOU FOR YOUR INTEREST Suggested Reading Industry Regulation Historical Events Current Trends Case Studies 2016 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL3 RECOMMENDED READING :Alicia(Pruett)LanghansBobMcDowallChrist ophJansenDavidStokesJeanneMoldenhauerJim StumpffJoeLiscouskiMagdalenaKurpierzRonT etzlaffSiegfriedSchmittYingyingLiu 2016 PAREXEL INTERNATIONAL CORP.

2 / CONFIDENTIAL4 RECOMMENDED READING PDA Publications Elements of a Code of Conduct for data INTEGRITY in Pharmaceutical Manufacturing PDA Points to Consider: Fundamental Concepts for data INTEGRITY PDA Technical Report: data INTEGRITY in Laboratory Systems Coming Soon! 2016 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL5 RECOMMENDED READING 2016 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL6 RECOMMENDED READING 2016 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL7 RECOMMENDED READING 2016 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL8 RECOMMENDED READING 2016 PAREXEL INTERNATIONAL CORP.

3 / CONFIDENTIAL9 RECOMMENDED READING 2016 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL10 RECOMMENDED READING 2016 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL11 RECOMMENDED READING Draft PIC/S Good Practices for data Management and INTEGRITY in Regulated GMP/GDP Environments 2016 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL12 INDUSTRY REGULATION In the United Kingdom, the Thalidomide incidents in the 1950s and 1960s led to the creation of the Committee on Safety of Drugs in 1963. In the United States, the Food, Drug and Cosmetic Act of 1938 required the safety of new drugs be shown prior to their marketing.

4 In Europe, the Council of the European Economic Community Directive765/65/EEC of January 1965 and subsequent amendments established the regulatory framework for European Member States. In Japan, the Fund for Adverse Drug Reactions Suffering Relief was established in October of 1979 and in 1993 became the Organization for Pharmaceutical Safety and Research to perform the generic drug reviews. 2016 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL13 data MANAGEMENT HAS CHANGED Historically, data was paper based and thus subject to the INTEGRITY of the individuals responsible for recording and checking the data entries.

5 The computer age has introduced electronic data which when properly managed increases the ability to assure the INTEGRITY of data . data may be generated from a variety of sources including toxicology studies, clinical studies, manufacturing operations and laboratory testing. The data may support regulatory submissions and/or required documentation for current Good Manufacturing Practice (cGMP) activities. 2016 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL14 data INTEGRITY MAJOR EVENTS In the 1970s the Searle Co. investigation revealed fraudulent animal data submitted in applications to the FDA.

6 If the INTEGRITY of that data is questioned, then the whole regulatory process is questioned. If the data are proved false and misleading, then the regulatory decisions may be tragically wrong. 2016 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL15 data INTEGRITY MAJOR EVENTS The Congressional Subcommittee hearings summed up the impact of the [FDA] investigation..Accurate science is the best protection the American people have from an unsafe and ineffective drug supply. Inaccurate science, sloppy science, fraudulent science these are the greatest threats to the health and safety of the American people.

7 Whether the science is wrong because of clerical error, or because of poor technique, or because of incompetence, or because of criminal negligence, is less important than the fact that it is wrong. For if it is wrong, and if, as in this case, the FDA did not indeed, under current practice, could not know it was wrong, then the protective regulatory barrier between a potentially dangerous drug and the patient is removed. Drug Regulation: HISTORY , Present and Future, World Health Organization (WHO) website Accessed 8/12/15. 2016 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL16 RESPONSE TO THE EVENT The FDA investigations into the toxicological animal data INTEGRITY issues led to the Good Laboratory Practices regulations which were put in place in 1979.

8 2016 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL17 data INTEGRITY MAJOR EVENTS In the late 1980s the Generic Drug Scandals were the headlines. Numerous generic drug manufacturers submitted fraudulent data to the FDA in support of their Abbreviated New Drug Application (ANDA) or other submissions. Bio-equivalency Testing ANDA Submission Batch Records Stability Summaries Manufacturing Site Retained Samples Inspection 2016 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL18 RESPONSE TO THE EVENTS Changes were implemented to improve data INTEGRITY compliance and strengthen the penalties for such egregious acts.

9 Updating the Pre-approval Inspection Program The Application INTEGRITY policy (AIP) compliance policy guide Sec. , Fraud, Untrue Statements of Material Facts, Bribery, and Illegal Gratuities The Generic Drug Enforcement Act of 1992 (GDEA). 2016 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL19 FDA PRE-APPROVAL PROGRAM In the 1990s the FDA update to the Pre-approval Program was made in part to put more emphasis on data INTEGRITY and this is clearly stated in the three objectives of the program: readiness for commercial manufacturing, conformance to application and data INTEGRITY audit.

10 2016 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL20 APPLICATION INTEGRITY PROGRAM (AIP) In September 1991, the FDA Application INTEGRITY policy (AIP), Fraud, Untrue Statements of Material Facts, Bribery, and Illegal Gratuities; Final policy was published. Review of applications suspended and/or withdrawing an approved application for reasons of fraud, untrue statements of material fact 2016 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL21 compliance policy guide In July 1991 the FDA issued compliance policy guide Sec. , Fraud, Untrue Statements of Material Facts, Bribery, and Illegal Gratuities.