A Regulator s Perspective on Risk Based and Phase Appropriate Comparability. Marjorie Shapiro, Ph.D. Division of Monoclonal Antibodies OBP, CDER,FDA

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1 A Regulator s Perspective on Risk Based and Phase Appropriate Comparability Marjorie Shapiro, Ph.D. Division of Monoclonal Antibodies OBP, CDER,FDA WCBP 2014

2 Outline Reasons for Changes Comparability ICH Q5E Comparability through product development Risk based approach Examples from post-marketing changes Case studies of inter-sponsor comparability Lessons learned 2

3 Why Make Manufacturing Changes? Improved process Improved yields Improved purity Improved quality Improved formulation Better stability profile Scale up Site transfer New technologies Change in product delivery system Meet new regulatory requirements Business decision 3

4 ICH Q5E: Comparable Identical The demonstration of comparability does not necessarily mean that the quality attributes of the prechange and postchange product are identical, but that they are highly similar and that the existing knowledge is sufficiently predictive to ensure that any differences in quality attributes have no adverse impact upon safety or efficacy of the drug product. 4

5 ICH Q5E: Comparability Outcomes No adverse impact on safety or efficacy profiles is foreseen. Quality attributes highly similar and considered comparable Quality attributes appear highly similar but some differences. No adverse impact on S&E justified with accumulated experience, relevant information and data Additional characterization, nonclincal and/or clinical studies Quality attributes appear highly similar, but the analytical procedures are not sufficient to discern relevant differences that can impact S&E. Additional testing needed (analytical, nonclinical and/or clinical) 5

6 ICH Q5E: Comparability Outcomes Additional nonclinical or clinical studies Quality attributes appear highly similar, some differences identified and a possible adverse impact on S&E profiles cannot be excluded. Nonclinical and/or clinical studies needed. Not comparable Differences in the quality attributes are significant 6

7 Categories of Testing Analytical Studies Physicochemical Tests Functional Assays (Bioassays) Animal Studies PK/PD/Biodistribution Toxicity Clinical Studies PK/PD S & E Higher Lower Sensitivity to Detect changes 7

8 Comparability During the Biotechnology Product Lifecycle Toxicology studies Short term Long term Development Decision IND Enabling Phase I II Phase III BLA Post Marketing Developmental lot(s) Tox studies Tox lot should be sufficiently similar to Phase 1 clinical lot Process Changes Scale up Site transfer Formulation Scale up Site transfer Full data set Design space Continuous improvement Changes outside of design space full data set QbD knowledge of design space will allow changes within space without need to demonstrate comparability Some products undergo 5 manufacturing changes during development! Tony Mire-Sluis 8

9 Comparability During the Biotechnology Product Lifecycle IND Enabling Phase I II Phase III BLA Post Marketing Increasing expectations from tox lot to FIH lot, from FIH to mid-stage lots, from mid-stage to pivotal lots and pivotal to commercial lots. Highest bar for post- marketing Expectations depend on: changes, but expectations are clearer. Phase of development; Extent of changes; Number and availability of development and pre-change clinical lots; Characterization of reference standard and pre-change lots; General product knowledge; Analytical tools (suitable for intended use) 9

10 Timing of Changes There is an expectation that improvements will be made in the process throughout the product lifecycle The amount of data needed to support manufacturing changes depends on the nature of the change and when in the product lifecycle the change is made For products still under clinical development, ideally the proposed commercial process would be implemented for phase 3 studies 10

11 Risk assessment approach (ICH Q9) Example S O D RRV 1. Prior to phase 2, new cell line, higher titer, data provided 2. Prior to phase 2, multiple changes: new clonal MCB, cell culture and purification, data provided 3. Similar extent of changes as in example 2, data not provided, acceptance criteria and viral safety risks not adequate in plan 4. During Phase 2, new sequence, new cell line, multiple other changes Patrick Swann 11

12 Meeting Specifications Potency units/ml Clinical lots Marketed Lots Manufacturing Change Post-Market: A product is not comparable just because it meets release specifications. Relevant tests may not be part of release testing. Pre-Market: Broad specifications, what is out of trend? What if Process 3 material looks more like Process 1 material? Barry Cherney 12

13 Cherry Picking Lots for PK Study Upper limit % tetra antennary Manufacturing Change Lots Lower limit Post Market: Are differences in CQAs addressed? Picking post-change lots most similar to pre-change lots is not useful Pre-Market: Are differences in CQAs addressed? What is the current clnical Phase? Not too late to do additional non-clinical or clinical. Depending on attribute, FDA may suggest/require additional studies Barry Cherney 13

14 Inter-sponsor comparability examples 14

15 Case 1: Commercial to Commercial Sponsor - Phase 3 Comparability Old material, limited lots available More DP lots stored at 2-8 o C than frozen DS lots Still meeting original release criteria, but degradation present Available data from older methods Comparability study thoughtful and thorough, updated methods Accounted for changes due to age Additional studies to understand predicted differences Related to age, freeze/thaw process etc. Additional effector function assays Forced degradation study Tissue cross reactivity study After comparability data assessed, performed human PK study 15

16 Case 2: Academic to Commercial Sponsor - Post Phase 3 Comparability Successful Phase 3 trial, then identified commercial sponsor Met with FDA to discuss manufacturing plans Had preliminary data from lab scale lots; data were encouraging Agreed that if new process resulted in comparable lots, only a bridging human PK study would be needed 16

17 Case 2: Academic to Commercial Sponsor - Post Phase 3 Comparability Commercial Sponsor Methods thorough and current Additional methods to assess MOA Manufactured 3 clinical lots, compared with several lots from academic sponsor manufactured between Noted several differences, but associated with oldest lots. Newer lots from academic sponsor and lots from commercial sponsor were found comparable Forced degradation study Tissue Cross Reactivity study 17

18 Case 3: Commercial to Commercial Sponsor Phase 2b/3 Comparability Old material, limited lots available Old lots stored at 2-8 o C (6 and 7 years old at time of study) Sample constraints; limited testing on one lot Compared interim reference standard (development lot) and reference standard (GMP lot) with two old lots Methods could have been more comprehensive but included those most likely to detect important differences Differences noted, likely due to age (not considered) Differences favored new product (HMWS and LMWS species) Bioassay not reliable, added binding assay for potency Conflicting data related to glycan structure Product designed for no effector function Animal PK comparability to address potential concerns related to observed glycan differences 18

19 Case 4: Academic* to Commercial Sponsor Phase 1 Comparability Old material, limited lots available Old lots stored at 2-8 o C, Reference standard available Still meeting original release criteria, but degradation present Commercial Sponsor Compared 1 new lot with 1 old lot and old reference standard Methods sufficient for early stage development, could have been more comprehensive Noted several differences likely related to age of original lots These particular differences may not matter for the MOA of this product Age not considered in study nor discussed in IND submission No accelerated stress stability Could not conclude materials were comparable, but starting at phase 1 Sponsor put on hold for other reasons 19

20 Case 5 : Academic* to Commercial Sponsor Phase 1 Comparability 1 lot of frozen DS available(manufactured in 2007) Manufactured into clinical DP lot Minimal characterization Did new release testing, reasonable methods and acceptance criteria Starting with Phase 1 clinical trial Will need to do comparability study when make next lot(s) Manufacturer and manufacturing process not yet identified Safe-to-proceed letter had comments on our expectations for future lots 20

21 Case 6 : Commercial to Commercial* Sponsor Phase 1/2 Comparability Phase 1 and 2a trials completed by commercial sponsor (Ex- US) Business decision to drop development Academic formed company to develop product Proposed Phase 2b trial (pind) Only a single clinical batch manufactured in 2006 is available New manufacturer and manufacturing process identified New sponsor does not intend to perform comparability studies Plans to rely on historical release and minimal characterization data Not clear how much reference standard is available or if non-clinical lots are available Told sponsor that we would not be able to make a meaningful assessment, gave many suggestions and requested follow-up tcon. 21

22 Lessons Learned Product and clinical development should be parallel May be complicated for breakthrough therapy Consider risk of changes according to nature of changes and clinical development phase Upstream process changes (i.e., impacting fermentation) have a greater risk to product quality Do not ignore limitations of comparability study Limited number of lots Age of lots Old methods Do not ignore observed changes across multiple processes Perform additional characterization, as appropriate, to address concerns We are likely to notice or 22

23 Lessons Learned If there are special concerns, communicate with FDA prior to implementing changes Physicochemical/biological characterizations are not a reliable predictor of immunological properties of a product Do not ignore any differences that may potentially impact clinical performance (PK/PD, safety and efficacy). Provide a discussion and if appropriate, a risk assessment Believe in every product! You never know how many lives it will have! Save samples of every lot manufactured, ever! development and clinical 23