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Putting the “c” in cGMP: How to Remain Current “ What Attorneys Need to Know” FDLI July 10, 2013 Washington D.C. Roy Sturgeon, Ph.D. President Lachman.

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Presentation on theme: "Putting the “c” in cGMP: How to Remain Current “ What Attorneys Need to Know” FDLI July 10, 2013 Washington D.C. Roy Sturgeon, Ph.D. President Lachman."— Presentation transcript:

1 Putting the “c” in cGMP: How to Remain Current “ What Attorneys Need to Know” FDLI July 10, 2013 Washington D.C. Roy Sturgeon, Ph.D. President Lachman Consultant Services Inc. 1

2 Topics  How to Get and Stay Current  What’s the Industry Perspective?  Aggressive GxP Enforcement Environment  Increased Data Integrity Focus  During PAIs and Other Inspections  Accountability and Prosecution 2

3 Industry Priorities/Strategies Uninterrupted Supply of High Quality Approved Products on Time at a Reasonable cost Quality Culture Compliance with Rules and Regulations Janet Woodcock, MD, USFDA Mission: To have a maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high quality drug products without extensive regulatory oversight. Lachman Consultant Services Inc. 3

4 Global Market Swamped in Product Recalls, Enforcement and Shortages  Regulatory Agencies assertive with companies about recalls. Global Regulatory Agencies (Except FDA) have mandatory recall authority.  Overall enforcement environment, focus on corporate and individuals, poster child criminal and civil actions - resulting in aggressive company decisions to recall  Many recalls based on GMP “lack of assurance” of quality versus actual/probable defects.  More aggressive recall classifications (I, II, III) and associated product removal strategies 4

5 When Do Attorneys Get Involved? Usually Late – “When the Sheriff is at the Door” After 483s, WLs, Recalls, Seizures, Data Integrity, Problem Resolution Ideal - In Strategy Development/Reviews at Senior Executive/Board Levels, Compliance Planning In Deploying Appropriate Controls 5

6 Advising on Corporate & Individual Liability and Responsibility for GMPs FDA deputy chief counsel for litigation Eric Blumberg calls for greater use of the Park Doctrine and jail terms in healthcare fraud prosecutions, holding executives personally responsible (strict liability) for regulatory infractions, even without personal knowledge or intent to defraud. Glaxo Settlement Adds New ‘Financial Recoupment Program’ (8-17-12) - This “puts at risk of forfeiture and recoupment an amount equivalent to up to three years of annual performance pay (i.e., annual bonus, plus long term incentives) for an executive who is discovered to have been involved in any significant misconduct”. 6

7 July 30, 2012 Court allows HHS to ban executives from industry GSK ex-Officials targeted? Appeals Court upheld a 12-year ban from government programs for former CEO Michael Friedman, general counsel Howard Udell and former CSO Paul D. Goldenheim in the government's case that was settled in 2007 for $634.5 million over marketing of OxyContin.OxyContin. 7

8 FDA - Focus on Risk  GMP & Product Quality  Risk Factors  Contamination Prevention  Sterility Assurance  Microbiological Quality  Cross Contamination  Intentional (melamine; OSCS)  Data Integrity  GxP Data and Records  Submissions  Global Sources  GMP  Quality  Safety  Counterfeits  Gray Market and Stolen Drugs  Drug Safety  REMS  Pharmacovigilance  Bioresearch Monitoring  GCP (Sponsors; Monitors; IRBs; Investigators)  GLP Studies  BA/BE Studies  Unapproved New Drugs  Internet  “Grandfathered” NEW Drugs  Improper Sales/Marketing  DTC  Control/Practice of Sales Team  Web Sites 8

9 Enforcement Priorities  Contamination Prevention – micro, chemical, intrinsic, extrinsic, particulates  Data Integrity  Response to Contamination Events  Investigations Program  Complaints  OOS/Rejections  CAPA Programs  Quality Systems/Quality Culture  OTC Drug Quality  High Risk Compounded Drugs  Internet Health Fraud  Unapproved Drugs  Adverse Event reporting  Supply Chain  Security  CMOs and Material Vendor Qualification  Field Alert Reporting  Prevention or Prompt Mitigation of Drug Shortages 9

10 Getting Ready for PAI What You Need to Know Knowledge of Laws, Regulations, Guidances, Policies Knowledge of FDA Processes Organized to Execute? Standards, SOPs and Enabling Documentation Right People in Right Positions Clear Roles, Responsibilities and Accountabilities Training (GMPs, Ethics, etc.) Good Documentation Data/ Record Keeping Capacity Infrastructure Metrics Evidence (raw data and records) Follow Up 10

11 Assessments for PAI Readiness for Commercial Manufacturing Investigations/Trends Materials Handling Contamination Procedures Process Feasibility Conformance to Application Data Integrity. 11

12 FDA Has Not Forgotten the Generic Drugs Scandal 12

13 What is a GMP Violation? What deems a drug adulterated? Distinguish from the facts of a drug “Most prosecuted cases turn on proof of failure to follow GMP practices – NOT the final quality of the drug” 13

14 Major Reasons for Failing PAIs  Not ready for inspection or lacks operational capability for responsibilities described in CMC  General GMP Status is Unacceptable (i.e., “OAI”)  GMP Deficiencies for Pivotal Clinical, Scale-Up, Stability and/or BE Batches  Data inconsistencies  Insufficient batch record detail to drive and document execution  Justification for critical process parameters and critical ingredient and product quality attributes 14

15 Top 10 FDA Domestic Inspection Citations October 2010 - October 2012 15

16 Prosecution DOJ makes GMP Regulations “Top Area of Focus” for 2013 95% of Park Doctrine Prosecutions have been in last 6 Years – Targets Board Members and Senior Executives 16

17 What is a GMP Violation? What deems a drug adulterated? Distinguish from the facts of a drug “Most prosecuted cases turn on proof of failure to follow GMP practices – NOT the final quality of the drug” Lachman Consultant Services Inc. 17

18 Major FDC Act Violations Unchanged  Submitting false and/or misleading information to the agency  Falsification of GXP records, regardless of whether submitted to agency  Distributing a drug product in violation of investigational or approved requirements  False/misleading use, promotion or advertising  Drug safety monitoring and reporting violations  Adulteration of drug substance or finished drug product  Commercial or clinical use  Not meeting appropriate, established specifications  Contamination  Manufactured in violation of GMP requirements, regardless of whether analytical specs met  Unlawful distribution of clinical materials or physician samples 18

19 Significant Post-Approval Findings Post approval inspections often triggered when PAIs are waived and when there are > average # of FARs and Recalls. Significant findings:  Lack of justification for critical process parameters, operating ranges and control strategies.  Scale-up to commercial process not adequately validated prior to distribution  Stability testing commitments not met; unreported stability test failures; expiry dates unsupported  Unreported/unapproved changes to material/component suppliers, contractors, specifications, facilities, equipment, process, test methods, etc.  Discrepancies suggesting fraud or deception  Unfulfilled application commitments  Inadequate Pharmacovigilance programs Lachman Consultant Services Inc. 19

20 How to Fix Significant GMP Deficiencies 20

21 Data Integrity Issues - How They Happen Non-Deliberate › Raw data misplaced – lack of clarity/training in procedures to require retention of all data › Data misfiled, can’t be located › Errors in transcription › Lack of adequate review of final records › Rushing to meet deadlines causes errors to be overlooked Deliberate › Fear of discovery of failure or error by management or regulators – desire to “avoid pain” › Desire to achieve objectives resulting in covering up errors › Rare if a systemic effort to falsify records by management 21

22 Fraudulent Practices Creating passing test results without performing the test Substituting test results from one sample/batch to another Backdating records/reports Falsifying GxP documents – submitted or not Reporting only acceptable results (running “practice injections” and deleting any unacceptable results) Reporting unrealistic results Data that looks “too perfect” or same Forging signatures, sharing passwords, software that allows for deletion of results/data by all analysts/employees 22

23 What to Do For alleged or suspected wrong doing, obtain assistance from qualified/experienced third party expert: Consultant(s) with experience in fraud Investigations Attorney/Law Firm - internal and/or external Establish the scope and breadth of the problem Bracket dates when alleged wrong doing occurred Determine if product(s), applications effected Develop internal investigation plan Identify / isolate suspect documents Locate raw data Compare raw data to summaries Tabulate data and sort by each variable Identify / resolve inconsistencies 23

24 What to Do (cont’d) Examine firm’s organization Examine roles, responsibilities and accountabilities Identify personnel alleged/suspected of involvement Determine scope of involvement of each employee Consider higher ups - managers, directors, etc. Conduct Interviews (by third party and attorney (s)) Investigate all work of suspected personnel Determine root cause of problem: Poorly defined procedures, roles, responsibilities, training gaps, incompetence, deliberate wrongful acts, financial gain/incentives, others Involve legal counsel in all decisions Consult FDA’s “Points to Consider for Internal Reviews and Corrective Action Operating Plans” Take personnel action where justified by facts Lachman Consultant Services Inc. 24

25 Ethics and GMP Training Importance of preserving raw data and reporting all data including failing data in addition to passing data Creating accurate data summaries and verifying raw data to support the summaries (electronic and paper records) Business ethics – adopt the elements of the HHS OIG seven point compliance program for pharmaceutical companies Include whistleblower protection and a telephone/email “hot line” for reporting alleged wrongdoings 25

26 Fix the Problem NEVER alter / destroy original data, documents Enter correct data or prepare addendum Justify / explain errors Preserve as part of formal record Determine root cause Correct and prevent root cause of errors Re-audit following corrections (by independent third party and internal auditors) Assess the specific and system matters Document and resolve any additional findings 26

27 Conclusions Firms must have strong quality and ethics programs and maintain management oversight procedures and clear personnel policies that prevent data integrity matters, be able to detect them if they do occur, and deal with them effectively Data integrity - focus and concern during any FDA inspection Not all data integrity matters are “fraud”, isolated instances of data integrity matter where not deliberate are easily remediated A pattern or practice of data integrity matters, or the commission of deliberate wrongful acts, are extremely serious and must be dealt with timely and adequately FDA has administrative and legal remedies it can apply when companies fail to have the above in place and adequately in use 27

28 Advice to Attorneys from Dr. Mom “It’s easier to keep firms out of trouble than to get them out of trouble” AND a lot less expensive. 28

29 Thank You! Roy Sturgeon, PhD President Lachman Consultants Westbury, NY 11590 516-222-6222 Email: Website: Lachman Consultant Services Inc. 29

30 2011 Enforcement Seizures – 8 Injunctions – 18 Convictions – 375 Warning Letters - >1700 (1200 Tobacco, 159 – Drugs & Devices for 6 months) Recalls – Drugs – 1616 Import Refusals - >27,000 Fines - > $4.5 Billion 30

31 Corrective Actions by Company Will depend on facts from investigation Actions should include: Communicate effectively with FDA and other law enforcement agencies Take actions and/or remove all personnel (employees, contractors and others) who were or may have been involved in wrongful acts A credible investigation using a competent third parties (consultants/attorneys) 31

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