postcards from the edge: regulatory reflections€¦ · postcards from the edge: regulatory...
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Postcards from the Edge: Regulatory Reflections
“There is no point at which you can say, 'Well, I'm successful now. I might as well take a nap.'” Carrie Fischer
Susan Kirshner Ph.D.Review ChiefDivision of Biotechnology Review and ResearchOffice of Biotechnology ProductMay 7, 2019
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Outline
• Postcard 1: Potency reference material qualification
• Postcard 2: Measuring things that change
• Postcard 3: Do you know what you are measuring
• Postcard 4: Staying in control
• Postcard 5: PMCs
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3www.fda.gov
Postcard 1:In for the long haul – potency reference material qualification.
Colorado
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Reference Material Potency Qualification in Development: Example 1
• Reference material (RM) potency for multiple RMs initially established using 3 replicates
• FDA communicated that would not be sufficient to maintain a link between the potency of material used in clinical and analytical studies and the commercial RM
• Conclusion: The Sponsor shifted to qualifying RM using 15 replicates thereby maintaining a link between development data and commercial RM
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Reference Material Potency Qualification in Development: Example 1
RRM1 RRM2 RRMx
PRMIRM
RRS – research reference materialIRM – interim reference materialPRM – primary reference material for commercial product
n = 3 replicates
n = 3 replicates
n > 15 replicates
n > 15 replicates
n = 3 replicates
Weak links
Strong links
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Reference Material Potency Qualification in Development: Example 2
• Potency qualified for 2 clinical RM and the proposed commercial RM using a single independent dilution of RM tested on 4 plates
• RM1=104% relative potency; RM2=112% relative potency; RM3=80% relative potency
• Is the potency of the 3 reference materials the same or different?
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Reference Material Potency Qualification in Development: Example 2
• During the BLA review cycle the Sponsor was asked to requalify the reference materials and then recalculate the potency of the clinical lots
• RM1, RM2, and RM3 were each tested a minimum of 9 times.
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Reference Material Potency Qualification in Development: Example 2
• RM1 activity was designated to be 100% because it was used in the clinical trials.
• RM3 (commercial) had a relative potency of 112% against RM1.
• RM2 (clinical not used) had a relative potency of 124% against RM1.
• Conclusion: The Sponsor updated their RM qualification program to include at least 9 independent assessments of potency and the potency of RM3 was established as 112%
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Postcard 2: A trip down the river – measuring things that change
Great Falls National Park, MD
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Change by Design
• Prodrug – protein chemically conjugated to 4 – 8 small molecule inhibitors
• Inhibitors are designed to be released non-enzymatically in the blood over time, T1/2 = 20 h
• Prodrug is inactive
• Complexity – the inhibitors are released over time during the potency assay. Therefore, product potency is constantly changing during the assay.
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Change by Design
Starve cellsAdd TA or RM to
cells
Measure proliferation after
24 h
Phase 1 Assay
Prior to phase 3 the Sponsor proposed a new assay because they found the phase 1 assay lacked robustness and had high inter-assay variability
TA = Test articleRM = Reference material
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Change by Design
Starve cellsAdd pre-treated TA,
RM, or intermediate
Measure proliferation after
24 h
Proposed Phase 3 Assay
Chemically remove inhibitor
• Test in assay• Pretreated
• Intermediate (never conjugated protein)• Reference material• Test article
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Change by Design
• Sponsor optimized the pretreatment process and characterized the extent of inhibitor removal by RP-HPLC, SDS-PAGE, peptide mapping, LC/MS, bioassay
• FDA questioned the relevance of this assay since the molecule was designed to lose the inhibitor over time and asked how the consistent release of inhibitor would be controlled
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Change by Design
• Most recent communication from the Sponsor is that they further optimized the phase 1 assay and now have acceptable robustness and precision
• FDA hasn’t seen the data yet
• To be continued….
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Postcard 3: Do you know what you are measuring?
Mount Rainier, Washington
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Do You Know What You Are Measuring?
• Drug is a biologic that is chemically conjugated to a payload.
• The biologic binds to a marker expressed on cancer cells
• The drug is designed to release the payload non-enzymatically both in the serum and in the cell for both targeted and by-stander killing
• Potency assay is a cytotoxicity assay using a cell line that expresses the marker
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Do You Know What You Are Measuring?
• Oxidation of the protein significantly reduced binding to the marker in a binding assay but potency was not reduced in the cytotoxicity assay
• FDA expressed concerns that the cytotoxicity assay does not distinguish between targeted and bystander killing
• The Sponsor is developing a multi-assay control strategy
• To be continued…
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Postcard 4: Staying in control
Hoover Dam, Nevada
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Staying In Control• Reference material unexpectedly failed EC50 acceptance
criteria of 15 – 35 ng/ml during requalification• EC50 acceptance criteria were set using EC50 data from
multiple batches rather than multiple replicates of a single batch
• EC50 acceptance criteria were recalculated to be 14 - 25 ng/ml using data from hundreds of runs with the RM
• Results from 9 independent runs are sufficient for reference material requalification.
• Conclusion 1: RM EC50 acceptance criteria were not set correctly. RM potency acceptance criteria should not include manufacturing variability.
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Staying In Control
• Reference material EC50 was 13 ng/ml at next requalification time point
• During routine assay performance EC50 is calculated from a single run and acceptance criteria range is 5 – 35 ng/ml
• After extensive investigation the Sponsor determined that the assay had changed but the reference material was acceptable
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Staying In Control
• The Sponsor introduced an independent quality control to help ensure assay suitability
• Conclusion 2: The assay initially lacked a critical control
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Postcard 5: Post marketingcommitments
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Post Marketing Commitments
• Reviewed PMCs for 29 BLAs approved between January 1, 2018 and April 30 2019
• Potency assay related PMCs:– Develop a control strategy for effector function (2
applications)• Assays to monitor effector function should be included in the
product control strategy when effector function cannot be eliminated as a mechanism of efficacy for the drug
– Confirm the suitability of the assay or acceptance criteria (2 applications)
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Post Marketing Commitments
• Potency assay related PMCs continued:
– Implement an independent quality control (1 application)
– Explore alternative assays (3 applications)
• Develop a non-animal based assay
• Further evaluate structure function relationships to ensure all MOA were identified
• Add a potency assay to monitor a secondary MOA
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Conclusions• Reference material potency should be established using a
sufficient number of independent replicates to ensure accurate potency assessment
• RM potency acceptance criteria should not include manufacturing variability
• Potency assays should evaluate the mechanism of action of the drug
• Multiple assays may be needed when there are multiple mechanisms of action
• System suitability controls are critical for identifying changes to assay performance
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Thanks to:Tere Gutierrez-Lugo Joanna Zhou Merry ChristieCecilia Tami
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