Compliance Considerations in Pharmaceutical Product Development

Transcription

1 Compliance Considerations in Pharmaceutical Product Development John C. (Jack) Garvey, Esq. THE WEINBERG GROUP INC. PRINCETON, NJ

2 Compliance in Drug Development The Drug Development Challenge A Sampling of Key Compliance Focus Areas Structuring Compliance for Sustainability Closing Thoughts

3 Business Climate Various sources estimate the current average drug approval costs between $900 million and $1.7 billion Estimates are that 1 FDAapproved drug results from 5-10,000 that enter the discovery phase PHRMA member companies increased R&D spending 53.5% between 2000 and 2005 to $40 billion Goldman Sachs estimates that pharma R&D spending will increase 7% per year from 2004 to 2009 Approval Cost

4 Snatched from the Headlines From CNNMoney.com, 16 August 2007 The The pharma The industry is The Food Food and and Drug Drug Administration is approved suffering a new new drugs drugs through July July of of this dearth dearth of of new this year, year, down down percent from from new approvals drug drug approvals during during the the same same period period in in 2006 thanks thanks to to an an increasingly stringent FDA FDA spokesperson Susan Susan Cruzan Cruzan FDA. denied FDA. denied that that her her agency agency was was getting getting [T]his tougher on on drug drug applications. "There [T]hisyear's "There approvals have have been been no no systematic changes in include include in only how how we we are are approaching the the approval only seven seven drugs drugs that standards for for new new applications," that can can be be considered wrote wrote Cruzan Cruzan in in an an to to completely CNNMoney.com, adding adding that that "each new, new, "each which application is is reviewed on on its its own which is is a own year merit." merit."... year low low for for the the. industry...

5 The TWO Main Goals of Drug Development Identifying a chemical entity / compound that has a specific, singular therapeutic impact on a broad population set with minimal adverse events. Then Developing a formulation and delivery system that consistently delivers the desired biological availability of the identified compound to the broadest possible population set.

6 The Drug Development Cycle (Simplified) DISCOVERY PRE- CLINICAL Phase 1 CLINICAL Phase 2 Phase 3 FDA REVIEW XFER TO MFG IND Filed NDA Filed

7 Drug Development Compliance Touchpoints DISCOVERY PRE- CLINICAL Phase 1 CLINICAL Phase 2 Phase 3 FDA REVIEW XFER TO MFG IND Filed NDA Filed

8 Sampling of Traditional and Evolving Compliance Considerations Phase I GMP Guidances Clinical Trials Risk Communication Access for Investigational Drugs Early CMS Involvement in Clinical Requirements Data Integrity -- Traditional Data Integrity Part 11 / CSV Considerations CMC Issues Pre-Approval Inspections Process Analytical Technology / Quality by Design Pharmacogenomic Data Submission Pediatric Studies Requirements Safety Reporting Requirements Third Party Services Current Hot-Button Areas New Guidances

9 The Changing Landscape of Development Compliance Guidance: Guidance: Using Using a Centralized Centralized IRB Draft IRB Draft Guidance: Guidance: Process Process in in Multicenter Exception Multicenter Exception from from Informed Informed Trials Trials (3/06) Consent (3/06) Consent Requirements Requirements for for Emergency Emergency Research Research (9/06) Guidance: (9/06) Guidance: Immunotoxicity ImmunotoxicityStudies for Guidance: Guidance: ICH ICH Q8 Q8 for Human Human Pharmaceuticals Pharmaceutical Pharmaceuticals (4/06) (4/06) Pharmaceutical Development Development (5/06) (5/06) Draft Draft Guidance: Guidance: Supervisory Supervisory Guidance: Guidance: Responsibilities Responsibilities of of Computerized Computerized Clinical Clinical Investigators Investigators (Out (Out Systems Systems Used Used in in for for Comment Comment 5/07) 5/07) Clinical Clinical Investigations Investigations (5/07) (5/07) Guidance: Guidance: Establishment Establishment and and Operation Operation of of Clinical Clinical Trial Trial Data Data Monitoring Monitoring Committees Committees (3/06) (3/06) Draft Draft Guidance: Guidance: Adverse Adverse Event Event Reporting Reporting Improving Improving Human Human Subject Subject Protection Protection (Out (Out for for Comment Comment 4/07) 4/07) Draft Draft Guidance: Guidance: Draft Draft Guidance: Guidance: Approaches Approaches to to ICH ICH Q10 Q10 Complying Complying with with Pharmaceutical Pharmaceutical CGMP CGMP During During Quality Quality System System Phase Phase I I (12/06) (12/06) (7/07) (7/07)

10 Phase I GMP Guidance Not a new requirement flows from original GMPs and heritage of 1991 Guidance Focus on Quality Control Well controlled procedures Adequately controlled equipment Accurate and consistently recorded data Agency Recommendations: Evaluate production environment for potential hazards Appropriate actions to minimize risks and safeguard quality In a phrase: Product Characterization And Risk Mitigation Specific Coverage: Personnel QC Function Facility & Equipment Control of Components Production & Documentation Laboratory controls Container closure and labeling Distribution Recordkeeping Other Coverage Screening Studies/Microdose Producers Multi-Product Facilities Biological and Biotechnological Products Sterile Products/Aseptically Processed Products

11 IND 21 CFR 312 US Clinical Trial Regulatory Requirements Protection of Human Subjects CFR 50 Institutional Review Boards 21 CFR 56 Financial Disclosure by Clinical Investigators 21 CFR 54 FDA Guidance for Data Safety and Monitoring Boards NDA Regulations 21 CFR CFR 11

12 FDA GCP Concerns A strong IRB system Protection of vulnerable populations Data Quality and Integrity Advancing Technology (5/10 FDA guidance) Personalized Medicine / Pharmacogenomics International Research Subject Safety (AE reporting/ci Training) Two guidances in draft: AE reporting; Investigator Responsibilities

13 60% 50% 40% 30% 20% 10% 0% Protocol Record CDER Inspection Deficiencies 2006 Drug Acct VAI 46% Consent OAI 6% A Es Clinical Investigator Inspections 2006 Clinical Investigator Inspections 2006 (All Centers) NAI 48% NAI VAI OAI

14 Clinical Compliance Issues Investigator responsibilities critical to clinical compliance outcomes FDA Form 1572 Provides information regarding the investigator, protocols, research facilities / labs, responsible IRB, sub-investigator Commits investigator to responsibilities FDA s focus on Investigators Personal investigator involvement Focus on Informed Consent (21 CFR 50) and IRB responsibilities (21 CFR 56) Timely, accurate adverse event reporting Focus on financial disclosure compliance rules

15 Snatched from the Headlines From THE WALL STREET JOURNAL, 6 August 2007 Drug: Drug: Experimnetal Gene Gene Therapy Company: Targeted Genetics Subject: year year old old woman woman Issue: Issue: Informed consent process Outcomes: Patient Patient death; death; Negative media media exposure of of company What What happened: Trial Trial investigator introduced study study to to patient patient during during routine routine treatment Allegations of of mixed mixed signals signals with with warnings due due to to doctor doctor patient patient relationship If If a patient s doctor doctor is is an an investigator, there there should should be be additional counsel for for the the patient patient about about study study participation

16 Clinical Compliance Issues FDA Oversees Clinical Research through Agency central review primarily through safety reports and submissions Bioresearch Monitoring Program (BIMO) Site inspections A few FDA Challenges with Clinical Trials Large, multicenter studies Data integrity (ALCOA - Attributable, Legible, Contemporaneous, Organized, and Accurate) Ex-US studies Oversight with Limited Resources

17 Clinical Compliance Issues Other Compliance Issues Documentation practices appropriateness of delegations of responsibility, attribution, and accuracy Preparation of Regulatory Binder Product Compliance dispensing, accountability, reconciliation ICF accuracy proper versions Failure to maintain proper case histories Investigation not done pursuant to signed investigation plan or investigator statement Ensuring accurate AE reporting

18 Current FDA Hot-Button Areas Critical Path Initiative Risk management Quality Management GCP Inspecting Updating GCP Compliance Programs (Inspection SOPs) Standardized Inspection Reporting (Turbo EIR) Site selection criteria Streamlining Enforcement / Disqualification

19 Expanded Access for Investigational Drugs Abigail Alliance v. von Eschenbach Issues involve 21 CFR should terminally ill patients have access to purchase post-phase-i drugs?? Impacts on the sponsor liability, cost, etc. UPDATE: UPDATE: August August 7 7 th th U.S. U.S. Court Court of of Appeals, Appeals, DC DC Circuit, Circuit, reverses reverses District District Court Court and and denies denies right right to to expanded expanded access. access. Oral argument on 3/1/07 Decision Pending December 14, 06 FDA issues proposed rule on Expanded Access to Investigational Drugs for Treatment Use (71 FR 240, 75147)

20 CMS Draft Requirements for Clinical Research For drugs, biologics or devices that treat Medicare reimbursable diseases or injuries Provides what deemed studies are and outlines requirements and criteria Protocol Linkage of results in protocol to Medicare population Inclusion criteria and consideration of subpopulations Study results must be published

21 Compliance & Use of Third Party Services Continually increasing trend towards use of third parties for development activities CROs / CRAs AE Reporting Bioanalytical Services / Testing Services added all the time Some services being moved overseas, particularly those with IT components Complaint, AE, Pharmacovigilence handling / reporting Clinical studies Clinical trials data analysis When it s hard enough to keep operations in compliance with domestic oversight, how do we do this when operations are entrusted with another entity, halfway across the world?

22 Case Study: MDS Pharma Warning Warning Letter: Letter: 12/04 12/04 A A systematic systematic problem problem of of inadequate inadequate analysis analysis and and investigation investigation of of anomalous anomalous results results across across multiple multiple studies studies for for multiple multiple sponsors. sponsors. Warning Warning Letter: Letter: 12/04 12/04 FDA FDA has has concerns concerns about about the the validity validity of of other other bioequivalence bioequivalence data data generated generated by by MDS, MDS, including including data data submitted submitted in in support support of of currently-approved currently-approved applications. applications. Warning Warning Letter: Letter: 8/06 8/06 [F]ailure [F]ailureto to demonstrate demonstrate the the accuracy accuracy of of your your analytical analytical methods methods in in more more than than thirty thirty studies studies for for six six different different drugs drugs confirm confirm that that there there are are widespread widespread problems problems at at your your facilities. facilities. FDA FDA Letter Letter to to Sponsors Sponsors of of Approved Approved ANDAs ANDAs (1/07): (1/07): [S]erious [S]erious questions questions remain remain about about the the validity validity of of bioequivalence bioequivalence data data generated generated by by MDS MDS in in studies studies during during this this time time period period that that have have not not been been inspected inspected by by FDA, FDA, including including the the studies studies you you have have submitted submitted in in support support of of your your applications. applications. In In view view of of these these findings, findings, FDA FDA is is informing informing holders holders of of approved approved ANDA(s) ANDA(s) of of these these issues issues and and would would like like to to know know what what steps steps are are being being taken taken by by you you to to assure assure the the accuracy accuracy of of data data submitted submitted in in these these applications applications and and confirm confirm the the validity validity of of MDS's MDS's analytical analytical studies studies that that were were conducted conducted from from January January through through December December and and subsequently subsequently submitted submitted to to the the FDA.. FDA..

23 Case Study: MDS Pharma (Contd.) Lesson 1: You don t want to have submissions or approved products at risk due to third-party compliance issues. Lesson 2: FDA expectations change. Are your service providers keeping up? How do you know? Lesson 3: Sponsors maintain responsibility for their products Responsibility is NOT able to be outsourced! Lesson 4: Continual oversight for 3-P services is essential.

24 Late Stage Development CMC Issues Q7, Q8, Q9 & Q10 are big drivers in late stage development issues Risk-based focuses are now the desired end-state Cannot do enough product and process characterization essential product requirements critical to quality attributes design space (multivariate analysis & modeling) critical control points (HACCP & like methodologies) Linearity and linkage from IND product through final formulation (including clinical impacts)

25 Preapproval Inspections Purpose: Insure application, data and sponsor operational integrity Joint Center/District activity with Office of Compliance Focus on: cgmp compliance Authenticity, integrity of data in the applications Adherence to application commitments Other factors potentially impacting whether Agency should approve application

26 Focus on Data Integrity Examples Cutting and pasting of chromatographic data to change OOS results Manipulations of sample outcomes to force passing results Modifying weights of samples in analytical calculations Selective inclusion of raw data into final records Disconnect between results obtained and approved methods filed with Agency

27 Don t mess with data integrity

28 Data Integrity According to FDA What they are seeing Issues with data integrity and fraud appear to be increasing Cuts across regulated product classes, and is occurring in clinical trials and elsewhere in the development process What they are doing about it FDA is increasing staff focus on data integrity, data manipulation and fraud Increasing focus on PAIs and on the data integrity issues Focus on following up on tips or information provided regarding data integrity failures or fraud issues

29 Four Four Quadrant Compliance Program Framework Governance Reporting & Management Review Review Metrics Executive Linkage Process Management Process definition Process characterization Process execution Compliance Systems Policies, Procedures, Work Work Instructions, etc. etc. Personnel and and organizational structures Audits, Audits, QA QA activities, etc. etc. Knowledge & Environment Organizational Culture Culture Regulatory Intelligence Training & Education

30 Application of the 4Q Compliance Model to Pharmaceutical Development Look at compliance end to end should track to end-to-end quality considerations Establish an overall Pre-Marketing Compliance Leadership Ensures executive involvement Focus on ensuring no substantive gaps across the development cycle Application of substantive requirements to company business processes / development models Linkage from requirements to infrastructure elements

31 Application of the 4Q Compliance Model to Pharmaceutical Development (Contd.) Break down development cycle or substantive requirements into areas of compliance responsibility Discovery / pre-clinical GCP Data assurance Late stage / product transfer Incorporate compliance metrics into development cycle metrics Create regular compliance Management Review Use third party (internal or external) compliance reviews for formal assessments -- No spin feedback is essential

32 Applied Regulatory Intelligence Statutes, Statutes, Regulations, Regulations, Guidances, Guidances, // WL WL observations, observations, Agency Agency Statements, Statements, Case Case Law, Law, etc. etc. Research & Development Application Systems & Processes And remember Systems Processes

33 Zones of Compliance Certainty Clearly above legal requirements and enforcement expectations The Rolling the Dice Zone How much risk do you want to take? Clearly below legal requirements and enforcement expectations

34 Closing Thoughts Is compliance a company s biggest challenge in pharmaceutical product development? Based on all this will drug development get less complex? Less Risky? How will you manage this? Do you know where in the Zone of Compliance Certainty your organization is? By system? By process? Does executive management understand this material? Are you proactive or reactive in your approach to compliance? Why? What will you do differently when you get back to your company?

35 Thank you. Questions? For For More More Information, Contact: Contact: John John C. C. (Jack) Garvey, Esq. Esq. THE WEINBERG GROUP INC. Office: Mobile: