FDA and Pharmaceutical Manufacturing Research Projects

Jeffrey T. Macher Jackson A. Nickerson

Co-Principal Investigators

September 30, 2004

Presentation OverviewFDA Research Project status reportHistoryProject GoalsApproach and Expected OutcomesCurrent StatusPharmaceutical Manufacturing Research Project (PMRP) status reportHistoryProject GoalsApproach and Expected OutcomesCurrent Status

FDA Research Project

FDA Research Project HistoryResearch project idea emerged in Fall, 2001.Observed significant increases in both number and severity of cGMP violations.Approached FDA in Spring, 2002.Dozens of meetings with CBER, CDER, ORA and district offices.Formalized relationship with FDA in Fall, 2003.Signed Material Transfer Agreement (MTA) in October, 2003.Received data September, 2004.

FDA Research Project GoalsRisk-based assessment of FDA cGMP outcomes.

Identify attributes (currently recorded by the FDA) that impact inspection outcomes.

Transfer learning to FDA.

FDA Project ApproachCompile and link FDA databases. Estimate the likelihood of various outcomes:NAI, VAI, OAI; Warning Letters; Field Alerts; Product Recalls.based oncompound/product, facility, firm, FDA district, investigator and training derived factors.in order to evaluate the allocation of investigational resources.inform effectiveness of investigator training and management.

FDA DatabasesCOMIS (Supplement filings)DQRS (Field alerts)EES (Outsourcing)FACTS (Inspections) Product ListingProduct RecallsProduct ShortagesRegistrationWarning lettersTraining

Some basic facts about the FDA dataYears covered: 1990-2003.Total number of facilities inspected: 3753.Total number of Inspections: 38,341.Total number of Facility visits: 14,162.

FDA-related Performance OutcomesInspection outcomes:NAIVAIOAIWarning lettersField reportsProduct recallsProduct availability

FDA-related Key FactorsProduct-level and Process-level variablesNDA/ANDA.Prescription/non-prescription.Product class. Product subclass.Process indicator code.Supplement history.Extent of vertical integration.History of regulatory outcomes for the product.History of regulatory actions for related products.

FDA-related Key FactorsFacility-level variablesAge and Size.Number of products produced.Diversity of products produced:Prescription/non-prescription; Product class; Product subclass; Process indicator code. Increases/decreases in number of products and diversity of production n years prior.Time since last ownership change.Regulatory history (e.g., inspectional outcomes, warning letters and type).

FDA-related Key FactorsFirm-level variablesAge and Size.Number of manufacturing locations.Number of products produced.Diversity of products produced.Number of products introduced in past n years.Number of NAI, VAI, and OAI at non-focal facilities in the past n years.Number and type of warning letters at non-focal facilities in the past n years.

FDA-related Key FactorsFDA related variablesFDA District Identifier and annual allocated inspection hours.InspectionsLength of cGMP inspection; Number of investigators; Reason for inspection; Time since last inspection.Investigators Annual experience of Pharma versus non-Pharma inspections.Training: number and frequency of formal training classes.Policy shifts (e.g., SUPACs)

Expected Outcomes of AnalysisStatistical analysis will estimate the probability of various outcomes based on counterfactuals.Counterfactual analysis allows a risk-based assessment of changes in at least some FDA-related oversight policies.Results will improve understanding of certain inspection outcomes based on attributes examined.Risk assessments (in terms of increasing probability of occurrence) will be used to:Inform oversight choices of FDA.Identify underlying quality of manufacturers production and regulatory processes.

Status of FDA Research ProjectPhase 1: Exploratory pilot study.Completed Summer 2003.Phase 2: Data collectionComplete for CDER and awaiting transfer.Incomplete for CBER.Phase 3: Data analysisData received.Analysis underway (~2-3 months for initial findings).

Pharmaceutical Manufacturing Research Project

(PMRP)

PMRP Project HistoryResearch project idea emerged in Fall, 2001.Explore whether cGMP violations related to managerial, organizational and technical practices.Attempt to translate lessons learned from similar research study of manufacturing in semiconductor industry.Began interviewing manufacturers in Spring, 2002.Dozens of interviews with pharmaceutical, biotechnology, API, and contract manufacturers.Launched internet-based questionnaire in Fall, 2003.Went live in November, 2003.Ongoing marketing and participation solicitation since.First round closed but for a few firms finishing off the survey.

PMRP GoalsDevelop standard set of benchmarks for measuring manufacturing and regulatory performance.

Identify managerial, organizational, and technical practices underlying manufacturing and regulatory performance.

Provide confidential scorecard to manufacturing facilities on how they perform against anonymous others.

PMRP ApproachDevelop focused questionnaire of potential factors that influence manufacturing and regulatory performance.

Administer questionnaire over internet on secure-site.

Analyze data collected using a variety of econometric techniques.

Provide summary of findings and facility scorecard to participating manufacturers.

PMRP DatabaseSecured participation from cross section of U.S. and EU manufacturers.21 firms.58 manufacturing facilities.Online survey with each manufacturing facility providing detailed data on between 1 and 5 compounds.

PMRP Performance OutcomesManufacturing Performance Theoretical / Actual yield.Batches started / failed.Cycle time.Regulatory Performance.Field alerts/Biologic deviation reports.Warning letters.Consent decrees.Deviations.Supplement approval.

PMRP-related Key FactorsCompany / SBUFinancial information.Demographic information.Manufacturing FacilityFinancial information.Demographic information (size, location, age, employees, etc.).Product information (number, type, etc.).Regulatory inspection information.Extent of Outsourcing (development, manufacturing, APIs, etc.).

PMRP-related Key FactorsProduct and Process DevelopmentLocation.Organization.Timing.Human Resource ManagementAppraisal, Promotion, Mobility, Demographics, Training, etc.Extent and use of teams.Deviation and Supplement ManagementExtent and use of information technology.Extent and use of Process Analytic Technology (PAT).Organization.

Status of PMRP ProjectPhase 1: Exploratory pilot studyCompleted Summer, 2003.Phase 2: Data collectionFirst round closed (but for a few stragglers).Phase 3: Data analysisAnalysis will require 3-6 months. Statistical and econometric analysis of data.Final reports.