Presentation on theme: "Compliance Considerations in Pharmaceutical Product Development"— Presentation transcript:
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 ChallengeA Sampling of Key Compliance Focus AreasStructuring Compliance for SustainabilityClosing Thoughts
3 Business Climate Approval Cost 2007 2008 2009 2010 2011 Various sources estimate the current average drug approval costs between $900 million and $1.7 billionApproval CostEstimates are that 1 FDA-approved drug results from 5-10,000 that enter the discovery phasePHRMA member companies increased R&D spending 53.5% between 2000 and 2005 to $40 billionGoldman Sachs estimates that pharma R&D spending will increase 7% per year from 2004 to 2009
4 Snatched from the Headlines… From CNNMoney.com, 16 August 2007The pharma industry is suffering a dearth of new drug approvals thanks to an increasingly stringent FDA….The Food and Drug Administration approved 38 new drugs through July of this year, down 31 percent from 55 approvals during the same period in 2006 ….FDA spokesperson Susan Cruzan denied that her agency was getting tougher on drug applications. "There have been no systematic changes in how we are approaching the approval standards for new applications," wrote Cruzan in an to CNNMoney.com, adding that "each application is reviewed on its own merit." . ….[T]his year's approvals include only seven drugs that can be considered completely new, which is a 10-year low for 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.Developing a formulation and delivery system that consistently delivers the desired biological availability of the identified compound to the broadest possible population set.Then…
6 The Drug Development Cycle (Simplified) FDAREVIEWXFER TO MFGDISCOVERYPRE-CLINICALPhase 1Phase 2Phase 3IND FiledNDA Filed
7 Drug Development Compliance Touchpoints FDAREVIEWXFER TO MFGDISCOVERYPRE-CLINICALPhase 1Phase 2Phase 3IND FiledNDA Filed
8 Sampling of Traditional and Evolving Compliance Considerations Phase I GMP GuidancesClinical TrialsRisk CommunicationAccess for Investigational DrugsEarly CMS Involvement in Clinical RequirementsData Integrity -- TraditionalData Integrity – Part 11 / CSV ConsiderationsCMC IssuesPre-Approval InspectionsProcess Analytical Technology / Quality by DesignPharmacogenomic Data SubmissionPediatric Studies RequirementsSafety Reporting RequirementsThird Party ServicesCurrent “Hot-Button” AreasNew Guidances
9 The Changing Landscape of Development Compliance Guidance: Establishment and Operation of Clinical Trial Data Monitoring Committees (3/06)Guidance: Using a Centralized IRB Process in Multicenter Trials (3/06)Draft Guidance: Exception from Informed Consent Requirements for Emergency Research (9/06)Draft Guidance: Adverse Event Reporting – Improving Human Subject Protection (Out for Comment – 4/07)Guidance: Immunotoxicity Studies for Human Pharmaceuticals (4/06)Guidance: ICH Q8 – Pharmaceutical Development (5/06)Draft Guidance: Supervisory Responsibilities of Clinical Investigators (Out for Comment – 5/07)Draft Guidance: Approaches to Complying with CGMP During Phase I (12/06)Draft Guidance: ICH Q10 – Pharmaceutical Quality System (7/07)Guidance: Computerized Systems Used in Clinical Investigations (5/07)
10 Phase I GMP GuidanceNot a new requirement – flows from original GMPs and heritage of 1991 GuidanceFocus on “Quality Control”Well controlled proceduresAdequately controlled equipmentAccurate and consistently recorded dataAgency Recommendations:Evaluate production environment for potential hazardsAppropriate actions to minimize risks and safeguard qualityIn a phrase: Product Characterization And Risk MitigationSpecific Coverage:PersonnelQC FunctionFacility & EquipmentControl of Components Production & DocumentationLaboratory controlsContainer closure and labelingDistributionRecordkeepingOther CoverageScreening Studies/Microdose ProducersMulti-Product FacilitiesBiological and Biotechnological ProductsSterile Products/Aseptically Processed ProductsIn 1991, the Agency issued the Guideline on the Preparation of Investigational New Drug Products (Human and Animal). However, the 1991 document did not discuss all manufacturing situations, including, for example, small- or laboratory-scale production of investigational new drugs. In addition, the 1991 document did not address fully the Agency's expectation that an incremental approach to manufacturing controls would be taken during investigational drug development, which for most products includes a change in production scale.
11 US Clinical Trial Regulatory Requirements IND – 21 CFR 312Protection of Human Subjects CFR 50Institutional Review Boards – 21 CFR 56Financial Disclosure by Clinical Investigators – 21 CFR 54FDA Guidance for Data Safety and Monitoring BoardsNDA Regulations – 21 CFR 31421 CFR 11
12 FDA GCP Concerns A strong IRB system Protection of vulnerable populationsData Quality and IntegrityAdvancing Technology (5/10 FDA guidance)Personalized Medicine / PharmacogenomicsInternational ResearchSubject Safety (AE reporting/CI Training)Two guidances in draft: AE reporting; Investigator Responsibilities
14 Clinical Compliance Issues Investigator responsibilities – critical to clinical compliance outcomesFDA Form 1572 – Provides information regarding the investigator, protocols, research facilities / labs, responsible IRB, sub-investigator – Commits investigator to responsibilitiesFDA’s focus on InvestigatorsPersonal investigator involvementFocus on Informed Consent (21 CFR 50) and IRB responsibilities (21 CFR 56)Timely, accurate adverse event reportingFocus on financial disclosure compliance rules
15 Snatched from the Headlines… From THE WALL STREET JOURNAL, 6 August 2007Drug: Experimnetal Gene TherapyCompany: Targeted GeneticsSubject: 36 year old womanIssue: Informed consent processOutcomes: Patient death; Negative media exposure of companyWhat happened:Trial investigator introduced study to patient during routine treatmentAllegations of mixed signals with warnings due to doctor patient relationshipIf a patient’s doctor is an investigator, there should be additional counsel for the patient about study participation
16 Clinical Compliance Issues FDA Oversees Clinical Research throughAgency central review – primarily through safety reports and submissionsBioresearch Monitoring Program (BIMO)Site inspectionsA few FDA Challenges with Clinical TrialsLarge, multicenter studiesData integrity (ALCOA - Attributable, Legible, Contemporaneous, Organized, and Accurate)Ex-US studiesOversight with Limited Resources
17 Clinical Compliance Issues Other Compliance IssuesDocumentation practices – appropriateness of delegations of responsibility, attribution, and accuracy Preparation of Regulatory BinderProduct Compliance – dispensing, accountability, reconciliationICF accuracy – proper versionsFailure to maintain proper case historiesInvestigation not done pursuant to signed investigation plan or investigator statementEnsuring accurate AE reporting
18 Current FDA Hot-Button Areas Critical Path InitiativeRisk managementQuality ManagementGCP InspectingUpdating GCP Compliance Programs (Inspection SOPs)Standardized Inspection Reporting (Turbo EIR)Site selection criteriaStreamlining Enforcement / Disqualification
19 Expanded Access for Investigational Drugs Abigail Alliance v. von EschenbachIssues involve 21 CFR – should terminally ill patients have access to purchase post-phase-I drugs??Impacts on the sponsor – liability, cost, etc.Oral argument on 3/1/07 – Decision PendingDecember 14, 06 – FDA issues proposed rule on Expanded Access to Investigational Drugs for Treatment Use (71 FR 240, 75147)UPDATE: August 7th – U.S. Court of Appeals, DC Circuit, reverses District Court and denies right to expanded access.
20 CMS Draft Requirements for Clinical Research For drugs, biologics or devices that treat Medicare reimbursable diseases or injuriesProvides what “deemed” studies are and outlines requirements and criteriaProtocolLinkage of results in protocol to Medicare populationInclusion criteria and consideration of subpopulationsStudy results must be publishedApril 12, 2007CMS Issues Draft Clinical Research PolicyOn April 10, 2007, CMS issued a draft of its revised Clinical Trial Policy, renamed Clinical Research Policy. The draft policy was issued after CMS's consideration of public comments on the agency's July 10, 2006 coverage tracking sheet announcing the reconsideration of the September 19, 2000 Clinical Trial Policy. CMS also considered recommendations from the December 13, 2006 Medicare Evidence Development and Coverage Advisory Committee (MedCAC) after further consideration by a panel of federal agencies. There will be a 30 day public comment period on the draft Clinical Research Policy followed by issuance of a final policy 60 days later.Among other changes, the draft Clinical Research Policy:Renames the seven highly desirable characteristics of a clinical research study as "General Standards for a Scientifically Sound and Technically Sound Clinical Research Study;""Deems" FDA required and approved post-approval studies as meeting the general standards of a scientifically and technically sound clinical research study;"Deems" studies conducted under a National Coverage Determination requiring Coverage with Evidence Development (CED) as meeting the general standards of a scientifically and technically sound clinical research study;Expands "deemed" studies to those approved by any HHS agency, the Department of Veterans Affairs and the Department of Defense;Requires a written protocol for research studies;Revises the Medicare coverage requirements for a clinical study and renames the requirements as "Medicare -Specific Standards," which include, among other requirements:an explanation in the research protocol of how the results are generalizable to the Medicare population;a discussion in the research protocol of inclusion criteria and consideration of relevant subpopulations (as defined by age, gender, race/ethnicity, socioeconomic or other factors);study results, negative or positive, must be published;Clarifies and renames "routine clinical services" that will be covered under the policy;Clarifies and defines administrative services that Medicare will not cover;Defines investigational clinical services that may be covered for clinical research studies or through CED.Manufacturers conducting clinical trials on drugs, biologics or medical devices that treat Medicare covered diseases or injuries should review the draft policy carefully and consider commenting on the draft policy.By Kirk L. DobbinsPosted at 11:13 AM in Reimbursement | Permalink | Comments (0) | TrackBack (0
21 Compliance & Use of Third Party Services Continually increasing trend towards use of third parties for development activitiesCROs / CRAsAE ReportingBioanalytical Services / TestingServices added all the timeSome services being moved overseas, particularly those with IT componentsComplaint, AE, Pharmacovigilence handling / reportingClinical studiesClinical trials data analysisWhen 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 FDA Letter to Sponsors of Approved ANDAs (1/07): Case Study: MDS PharmaWarning Letter: 12/04“A systematic problem of inadequate analysis and investigation of anomalous results across multiple studies for multiple sponsors.”FDA Letter to Sponsors of Approved ANDAs (1/07):“[S]erious questions remain about the validity of bioequivalence data generated by MDS in studies during this time period that have not been inspected by FDA, including the studies you have submitted in support of your applications. In view of these findings, FDA is informing holders of approved ANDA(s) of these issues and would like to know what steps are being taken by you to assure the accuracy of data submitted in these applications and confirm the validity of MDS's analytical studies that were conducted from January 2000 through December 2004 and subsequently submitted to the FDA..”Warning Letter: 8/06“[F]ailure to demonstrate the accuracy of your analytical methods in more than thirty studies for six different drugs confirm that there are widespread problems at your facilities….”Warning Letter: 12/04“FDA has concerns about the validity of other bioequivalence data generated by MDS, including data submitted in support of currently-approved applications.”Inspection was
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 issuesRisk-based focuses are now the desired “end-state”Cannot do enough product and process characterizationessential product requirementscritical to quality attributesdesign 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 integrityJoint Center/District activity with Office of ComplianceFocus on:cGMP complianceAuthenticity, integrity of data in the applicationsAdherence to application commitmentsOther factors potentially impacting whether Agency should approve applicationCDER Reviewer: Reviews data submitted in application; Assists in establishing specifications for manufacture and control based on submitted dataDistricts Role: Conducts inpsections of manufacturing sites referenced in applications, assuring cGMP compliance and data integrityOffice of Compliance’s Role: Liaison between field offices and review offices: receives and processes inspection requests; monitors status of inspection; reviews reports and recommendations; forwards final recommendations to review offices
26 Focus on Data Integrity – Examples Cutting and pasting of chromatographic data to change OOS resultsManipulations of sample outcomes to force passing resultsModifying weights of samples in analytical calculationsSelective inclusion of raw data into final recordsDisconnect between results obtained and approved methods filed with Agency
27 Don’t mess with data integrity… What happened at Able:Fraud – Including improperly changing test parameters to obtain satisfactory results to a secret project which included forging data in chemist lab notebooks to obtain FDA approvalFour Supervisor involved in the conspiracy -- Each face five years in federal prison and $250K fine
28 Data Integrity – According to FDA… What they are seeing…What they are doing about it…Issues with data integrity and fraud appear to be increasingCuts across regulated product classes, and is occurring in clinical trials and elsewhere in the development processFDA is increasing staff focus on data integrity, data manipulation and fraudIncreasing focus on PAIs and on the data integrity issuesFocus on following up on tips or information provided regarding data integrity failures or fraud issuesGive credit to Edwin Rivera Martinez, CDER, Investigations and Preapproval Compliance Branch
29 Four Quadrant Compliance Program Framework GovernanceReporting & Management ReviewMetricsExecutive LinkageProcess ManagementProcess definitionProcess characterizationProcess executionCompliance SystemsPolicies, Procedures, Work Instructions, etc.Personnel and organizational structuresAudits, QA activities, etc.Knowledge & EnvironmentOrganizational CultureRegulatory IntelligenceTraining & Education
30 Application of the 4Q Compliance Model to Pharmaceutical Development Look at compliance end to end – should track to end-to-end quality considerationsEstablish an overall Pre-Marketing Compliance Leadership – Ensures executive involvementFocus on ensuring no substantive gaps across the development cycleApplication of substantive requirements to company business processes / development modelsLinkage 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 responsibilityDiscovery / pre-clinicalGCPData assuranceLate stage / product transferIncorporate 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 Research & DevelopmentStatutes, Regulations, Guidances, 483 / WL observations, Agency Statements, Case Law, etc.ApplicationSystemsProcesses&And remember…SystemsProcesses≠
33 Zones of Compliance Certainty Clearly above legal requirements andenforcement expectationsThe Rolling the Dice Zone –How much risk do you want to take?Clearly below legal requirements andenforcement expectations
34 Closing ThoughtsIs 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 John C. (Jack) Garvey, Esq. Thank you. Questions?For More Information, Contact:John C. (Jack) Garvey, Esq.THE WEINBERG GROUP INC.Office:Mobile: