Changes without Prior Approval Breakout Session Summary Rick Smith Aventis Pasteur, Inc.

Issues Discussed Risk Analysis for Post Approval Changes Comparability Protocols Development Reports Other Risk-Based Approaches and Next Steps

Risk Analysis Cost / market availability / approvability Team approach to risk assessment Change control True risk comes from an assessment of whether product has changed from the product used to generate clinical data Risk assessment capability is directly related to process knowledge and product experience

Concerns and Suggestions Industry wants a decision tree to assess risk (white paper from industry to FDA) Dilemma: can’t afford some changes, can’t afford not to change (keep up with cGMPs) Harmonization Develop a system to identify low risk changes that were successful to lessen the change category To bundle or not to bundle

Comparability Protocols Types of Comparability Protocols: General Comparability Protocols Product Specific Technology Specific Single Product

Experiences with Comparability Protocols Protein drugs – wide use Chemical drugs < 10 % use CVM, GphA – no use Application: Single change for multiple products Major changes to single product Planned changes Used during development

Advantages with Comparability Protocols Implementation timing can be immediate and consistent Early FDA input Greater assurance of acceptability and predictability Increased efficiency for Comparability Protocols covering multiple products Helps with changes not covered by SUPAC Most useful for complex molecules

Problems or Limitations with Comparability Protocols Time required is not always worth the effort Uncertainty regarding review time for non- PDUFA products Not useful for unplanned changes (due to timing) Draft guidance has too many exclusions Does require extra submissions unless in original NDA (Agency and Company)

Suggestions for Future One CP guidance for all types of products Utilize experiences from CPs to expand SUPACs Do not try to use CP for large numbers of changes most of which will not be executed

Development Reports Positive Feedback Development report needed to explain development strategy, data and why something was done. Easier to justify future changes Proactively identify critical parameters and impact of changes on those parameters. Gives FDA confidence that firms understand product and process

Development Reports Positive Feedback Helpful to maintain product history especially if employees leave the company Description of full story – failures and successes are valuable Helpful to have justification why certain tests are relevant and others not

Development Reports Negative Feedback May not be applicable for older products or generics Additional work or filing requirement with no obvious benefit Goes against goals of filing less or reducing burden Sharing failures is a concern All development data isn’t relevant to commercial product

Development Report Concerns How will FDA use the data? Which data should be submitted? Will development reports be reviewed by FDA and found to be deficient thereby holding up approval? Would not want to submit data because it may contain data generated in non GMP lab.

Other Risk-Based Approaches Develop system to permit less burdensome filing requirements based on company: Compliance history Robustness of quality system Quality of filings

Specific Recommendations for Opportunities for Less Burdensome Filing Requirements: SUPAC Guidances Analytical changes Packaging Sterile Products Common / repetitive changes Concurrent validation / stability Use of decision trees Comparability Protocol Templates

Other Systems European procedure for Type I and Type II Variations Re-registration every 5 years Canadian system Use as learning experience

Next Steps Need to be more global, not US centric Prioritize activities based on FDA and industry impact More dialogue with FDA / Industry on development data

Next Steps Guidances Have industry draft guidance for FDA Finalize draft guidances Draft more guidances Update existing guidances

Future Workshops Risk assessment of aseptic processing changes Development reports: value, what is needed, how used and benefit to industry Risk management systems and different approaches