FDA and Pharmaceutical Manufacturing Research Projects Jeffrey T. Macher Jackson A. Nickerson Co-Principal Investigators September 30, 2004

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FDA and Pharmaceutical Manufacturing Research
Projects Jeffrey T. Macher Jackson A.
NickersonCo-Principal Investigators September
30, 2004
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Presentation Overview

• FDA Research Project status report
• History
• Project Goals
• Approach and Expected Outcomes
• Current Status
• Pharmaceutical Manufacturing Research Project
  (PMRP) status report
• History
• Project Goals
• Approach and Expected Outcomes
• Current Status

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FDA Research Project
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FDA Research Project History

• Research 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.

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FDA Research Project Goals

• Risk-based assessment of FDA cGMP outcomes.
• Identify attributes (currently recorded by the
  FDA) that impact inspection outcomes.
• Transfer learning to FDA.

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FDA Project Approach

• Compile and link FDA databases.
• Estimate the likelihood of various outcomes
• NAI, VAI, OAI Warning Letters Field Alerts
  Product Recalls.
• based on
• compound/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.

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FDA Databases

• COMIS (Supplement filings)
• DQRS (Field alerts)
• EES (Outsourcing)
• FACTS (Inspections)
• Product Listing
• Product Recalls
• Product Shortages
• Registration
• Warning letters
• Training

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Some basic facts about the FDA data

• Years covered 1990-2003.
• Total number of facilities inspected 3753.
• Total number of Inspections 38,341.
• Total number of Facility visits 14,162.

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FDA-related Performance Outcomes

• Inspection outcomes
• NAI
• VAI
• OAI
• Warning letters
• Field reports
• Product recalls
• Product availability

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FDA-related Key Factors

• Product-level and Process-level variables
• NDA/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.

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FDA-related Key Factors

• Facility-level variables
• Age 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).

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FDA-related Key Factors

• Firm-level variables
• Age 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.

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FDA-related Key Factors

• FDA related variables
• FDA District Identifier and annual allocated
  inspection hours.
• Inspections
• Length 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)

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Expected Outcomes of Analysis

• Statistical 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.

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Status of FDA Research Project

• Phase 1 Exploratory pilot study.
• Completed Summer 2003.
• Phase 2 Data collection
• Complete for CDER and awaiting transfer.
• Incomplete for CBER.
• Phase 3 Data analysis
• Data received.
• Analysis underway (2-3 months for initial
  findings).

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Pharmaceutical Manufacturing Research Project
(PMRP)
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PMRP Project History

• Research 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.

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PMRP Goals

• Develop 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.

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PMRP Approach

• Develop 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.

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PMRP Database

• Secured 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.

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PMRP Performance Outcomes

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

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PMRP-related Key Factors

• Company / SBU
• Financial information.
• Demographic information.
• Manufacturing Facility
• Financial information.
• Demographic information (size, location, age,
  employees, etc.).
• Product information (number, type, etc.).
• Regulatory inspection information.
• Extent of Outsourcing (development,
  manufacturing, APIs, etc.).

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PMRP-related Key Factors

• Product and Process Development
• Location.
• Organization.
• Timing.
• Human Resource Management
• Appraisal, Promotion, Mobility, Demographics,
  Training, etc.
• Extent and use of teams.
• Deviation and Supplement Management
• Extent and use of information technology.
• Extent and use of Process Analytic Technology
  (PAT).
• Organization.

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Status of PMRP Project

• Phase 1 Exploratory pilot study
• Completed Summer, 2003.
• Phase 2 Data collection
• First round closed (but for a few stragglers).
• Phase 3 Data analysis
• Analysis will require 3-6 months.
• Statistical and econometric analysis of data.
• Final reports.