DRUG QUALITY SYSTEM FOR THE 21 ST CENTURY PQRI/FDA April 22-24

1. DRUG QUALITY SYSTEM FOR THE 21ST CENTURYPQRI/FDA April 22-24 CHANGES WITHOUT PRIOR APPROVAL AN FDA PERSPECTIVE Dennis M. Bensley, Jr., Ph.D. Center for Veterinary Medicine, FDA

2. OUTLINE • INTRODUCTION • BACKGROUND • CURRENT FDA ASSESSMENT • CURRENT RISK ANALYSIS • COMPARABILITY PROTOCOL • STRATEGIC GOALS • CONCLUSION

3. INTRODUCTION • Changes Without Prior Review working group established by FDA’s Drug GMP Steering Committee • Working Group members: -Ajaz Hussain, Co-chair (CDER) -Nancy Sager, Co-chair (CDER) -Kathy Jordan, Project Manager (CDER) -Nick Buhay (CDER) -Chris Joneckis (CBER) -John Finkbohner (CBER) -Dennis Bensley (CVM) -Nancy Rolli (ORA) -Patricia Alcock (ORA) -Marybet Lopez (ORA) -Janet Showalter (OC, OIP) -Lynn Whipkey (OC, OCC)

4. INTRODUCTION • Charge of Working Group: -examine current state of the supplemental change approval process, specifically those manufacturing changes requiring prior FDA approval.

5. INTRODUCTION • Charge of Working Group: -examine current state of the supplemental change approval process, specifically those manufacturing changes requiring prior FDA approval. -identify and recommend implementation of other means to reduce reporting requirements, for example the use of risk management tools, comparability protocols, product development information, and process control improvements (e.g., PAT).

6. INTRODUCTION • Purpose of Workshop -Present a summary of FDA’s current thinking and activities regarding the supplemental change approval process.

7. INTRODUCTION • Purpose of Workshop -Present a summary of FDA’s current thinking and activities regarding the supplemental change approval process. -Stimulate discussion and constructive feedback from stakeholders regarding the current and desired future state of the change approval process.

8. BACKGROUND • Legal Requirements - The applicant must notify FDA of each manufacturing change in accordance with section 506A of the Federal Food, Drug, and Cosmetic Act and, when finalized 21 CFR 314.70 (CDER) and 514.8(CVM).

9. BACKGROUND • Legal Requirements - The applicant must notify FDA of each manufacturing change in accordance with section 506A of the Federal Food, Drug, and Cosmetic Act and, when finalized 21 CFR 314.70 (CDER) and 514.8(CVM). • An applicant must inform the FDA about each change in the product, production process, quality controls, equipment, facilities, responsible personnel, or labeling established in the approved license application(s) (CBER 601.12).

10. BACKGROUND • Legal Requirements • The applicant must assess the effects of any change on the identity, strength, quality, purity, and potency of the drug as they may relate to the safety and effectiveness of the drug before distributing product made with the change (Section 506A of Act, Section 116 FDAMA). • Four legal reporting categories under FDAMA: prior-approval, CBE (immediate), CBE-30 and annual report.

11. BACKGROUND • Filing Categories: -Prior-approval (major change): Substantial potential to adversely affect the identity, strength, quality, purity, or potency of a product as they may relate to the safety or effectiveness of the product. Product made with change may not be distributed until approval.

12. BACKGROUND • Filing Categories: -Prior-approval (major change): Substantial potential to adversely affect the identity, strength, quality, purity, or potency of a product as they may relate to the safety or effectiveness of the product. Product made with change may not be distributed until approval. -CBE or CBE-30 (moderate change): Moderate potential….Product distribution upon receipt of application to FDA (CBE) or 30 days after receipt of application to FDA, if acceptable (CBE-30).

13. BACKGROUND • Filing Categories: -Prior-approval (major change): Substantial potential to adversely affect the identity, strength, quality, purity, or potency of a product as they may relate to the safety or effectiveness of the product. Product made with change may not be distributed until approval. -CBE or CBE-30 (moderate change): Moderate potential….Product distribution upon receipt of application to FDA (CBE) or 30 days after receipt of application to FDA, if acceptable (CBE-30). -Annual Report (minor change): Minimal potential….Annual reportable and immediate product distribution.

14. CURRENT FDA ASSESSMENT • Did Section 116 of FDAMA (506A of the Act) meet the expectation of: -providing regulatory relief by lessening the reporting requirements of manufacturing changes without compromising the drug’s “quality”, safety or effectiveness?

15. CURRENT FDA ASSESSMENT • The reporting of many manufacturing changes has been provided through regulations and guidances: -Section 506A of FFD&C Act (CDER, CBER and CVM) -Regulations (being revised 314.70, 514.8, 601.12). -”Changes” Guidances: Changes to an Approved NDA or ANDA (CDER) Changes to an Approved Application: Biological Products (CBER) Changes to an Approved Application for Specified Biotechnology and Specified Synthetic Biological Products (CDER/CBER) Changes to an Approved NADA or ANADA (CVM) -Various PAC and SUPAC Guidances

16. CURRENT FDA ASSESSMENTImpact of FDAMA on Filing CVM • A significant number of CMC changes are currently being reported in CBE supplements or in annual reports.

17. CURRENT FDA ASSESSMENTImpact of FDAMA on Filing CDER Data (%Prior Approval/CBE Supplements) FY99 FY00 FY01 • NDAs • Prior Approval 62% 48% 39% • CBE 38% 52% 61% • ANDAs • Prior Approval 82% 26% 34% • CBE 18% 74% 66%

18. REPORTINGCBER CMC CHANGES IMPACT OF FDAMA/ GUIDANCE NON-PDUFA PRODUCTS PDUFA PRODUCTS

19. CURRENT FDA ASSESSMENT • FDAMA has significantly reduced the reporting requirements for manufacturing changes, however FDA recognizes that there could be additional improvements in the change reporting process.

20. CURRENT FDA ASSESSMENT • Concerns with current regulatory supplemental change process: -Though the relative percentage of prior-approval supplements as compared to other reporting categories have significantly decreased, the number of prior-approval supplements are starting to increase.

21. CURRENT FDA ASSESSMENT • Concerns with current regulatory supplemental change process: -Though significantly reduced overall from “pre-FDAMA” times, the number of reported prior approval changes remain high for certain product types/processes (e.g., sterile products).

22. CURRENT FDA ASSESSMENT • Concerns with current regulatory supplemental change process: -Recognize that any prior approval change could impact business planning and possibly impede innovation.

23. CURRENT FDA ASSESSMENT • Concerns with current regulatory supplemental change process: -No guarantee that the prior approval supplement will be approved during “first round.” CVM’s experience is that approximately 40% of “first round” prior approval supplements are found to be incomplete (data from 2000-2003).

24. CURRENT FDA ASSESSMENT • Concerns with current regulatory supplemental change process: -Regulatory compliance dilemma in finding unacceptable, i.e., inadequately assessed or documented, CMC changes in CBE or annual reports.

25. CURRENT FDA ASSESSMENT • Potential solutions identified by FDA to lessen reporting requirements: • Use of comparability protocols;

26. CURRENT FDA ASSESSMENT • Potential solutions identified by FDA to lessen reporting requirements: • Use of comparability protocols; • Drafting and publishing more PAC/SUPAC guidance documents;

27. CURRENT FDA ASSESSMENT • Potential solutions identified by FDA to lessen reporting requirements: • Use of comparability protocols; • Drafting and publishing more PAC/SUPAC guidance documents; • Identifying potential risk management tools;

28. CURRENT FDA ASSESSMENT • Potential solutions identified by FDA to lessen reporting requirements: • Use of comparability protocols; • Drafting and publishing more PAC/SUPAC guidance documents; • Identifying potential risk management tools; • Encouraging the use of product development information and process controlimprovements (e.g., Process Analytical Technologies).

29. CURRENT RISK ANALYSIS Potential for CMC Change To Adversely Affect Drug Prior Approval Supplement? Levels of Risk HIGH YES SIGNIFICANT SOME NO* MODERATE *CBE Supplements Required LOW NO MINIMAL

30. CURRENT RISK ANALYSIS • FDA’s determination of a CMC change as major or requiring prior approval: -What is the likely impact of the change on the identity, strength, quality, purity and/or potency of the drug product? If FDA believes there is a potential adverse affect, then major change.

31. CURRENT RISK ANALYSIS • FDA’s determination of a CMC change as major or requiring prior approval: -Will additional clinical or other “non-CMC” (e.g., toxicological) studies be required? If yes, then likely major change.

32. CURRENT RISK ANALYSIS • FDA’s determination of a CMC change as major or requiring prior approval: -Is the reported change either not well described, too complex or is the potential impact on the drug’s safety or effectiveness not certain? If yes, then likely major change.

33. CURRENT RISK ANALYSIS • FDA’s determination of a CMC change as major or requiring prior approval: -If applicable, what is the current GMP status? If unacceptable, then likely major change.

34. CURRENT RISK ANALYSIS • The question to address when a risk assessment is performed regarding a CMC change: What is the potential (risk) for the change to adversely affect the identity, strength, quality, purity, or potency of a product as they may relate to the safety or effectiveness of the product?

35. CURRENT RISK ANALYSIS • The potential risk for a CMC change increases when the knowledge regarding the potential impact of the change decreases.

36. CURRENT RISK ANALYSIS • The potential risk for a CMC change increases when the knowledge regarding the potential impact of the change decreases. • What is the purpose of prior approval supplements for specified CMC changes?

37. CURRENT RISK ANALYSIS • The potential risk for a CMC change increases when the knowledge regarding the potential impact of the change decreases. • What is the purpose of prior approval supplements for specified CMC changes? -Identified major changes are those changes that have a substantial potential to adversely affect the drug.

38. CURRENT RISK ANALYSIS • The potential risk for a CMC change increases when the knowledge regarding the potential impact of the change decreases. • What is the purpose of prior approval supplements for specified CMC changes? -Identified major changes are those changes that have a substantial potential to adversely affect the drug. -Allows FDA time to review and concur (or not concur) with the proposed major change and its assessment prior to product distribution.

39. CURRENT RISK ANALYSIS • FDA tends to be conservative in regard to accepting levels of risk, i.e., if we are not certain about the potential risk, then a higher filing category will likely be required.

40. CURRENT RISK ANALYSIS • FDA employees use risk analysis daily, for example: -Deciding whether a change is major or moderate (30-day CBE assessment) -Deciding whether the assessment of the change is satisfactory or not (review process) -Deciding whether a cGMP inspection is required (e.g., CBER’s SOPP 8410: Determining When Prelicense/Preapproval Inspections Are Necessary)

41. CURRENT RISK ANALYSIS • FDA employees use risk analysis daily, for example: -Deciding whether a change is major or moderate (30-day CBE assessment) -Deciding whether the assessment of the change is satisfactory or not (review process) -Deciding whether a cGMP inspection is required (e.g., CBER’s SOPP 8410: Determining When Prelicense/Preapproval Inspections Are Necessary) • However, risk assessments for CMC changes are neither formalized nor uniformly structured throughout FDA.

42. CURRENT RISK ANALYSIS • Possible ways to reduce the risk potential include the use of: 1. Comparability protocols Premise: FDA’s acceptance of proposed assessment of anticipated change will likely lessen risk for implementing the change and should lead to less burdensome reporting category

43. CURRENT RISK ANALYSIS • Possible ways to reduce the risk potential include the use of: 2. An applicant may establish their own filing criteria based on developmental information in original or supplemental applications (“Make your own SUPAC”). Premise:Increase in scientific understanding/knowledge of change’s impact may lessen risk for implementing change and could lead to less burdensome reporting category

44. CURRENT RISK ANALYSIS • Possible ways to reduce the risk potential include the use of: 3.incorporating significant process control improvements (e.g., PAT). Premise: Improvement in process controls, may lessen risk for producing poor product and could lead to less burdensome reporting category

45. CURRENT RISK ANALYSIS • Can other risk analysis models be used to identify the level of risk for implementing CMC changes? • For example, can we identify, through risk assessment, low-risk drugs, dosage forms, processes, etc. and significantly reduce the number of changes requiring prior approval before implementation?

46. COMPARABILITY PROTOCOL • What is a CP? A well-defined, detailed written plan that prospectively specifies the tests and studies that will be performed, analytical procedures that will be used, and acceptance criteria that will be achieved to assess the effect of specific CMC changes for specific products.

47. COMPARABILITY PROTOCOL • Draft Guidance for “small molecules” recently published (public comment by 6/25/03). • CP described in regulations (current and/or proposed 314.70, 514.8 and 601.12). • FDA believes that additional prior approval changes can be reported in CBEs or annual reports through the use of a CP.

48. COMPARABILITY PROTOCOL • Uses and benefits of CP: -Can allow for a reduced reporting category of CMC changes covered by the approved CP. -CP can describe single or multiple-related CMC changes including those that may occur sequentially over a period of time.

49. COMPARABILITY PROTOCOL • Uses and benefits of CP (cont.): -Earlier implementation of manufacturing changes. -Likely reduction in incomplete/deficiency letters issued by FDA (more “first-round” approvals), because the means of assessing the change has been approved in the CP.

50. COMPARABILITY PROTOCOL • Uses and benefits of CP (cont.): -Allows sponsors to design own “changes” filing and documentation criteria based on experiences with the drug product or similar drug product, e.g. developmental studies. “Make your own SUPAC” concept.