Common BA/BE Inspection Observations and Scientific Evaluation

Transcription

1 Common BA/BE Inspection Observations and Scientific Evaluation Ruben C. Ayala, Pharm.D. Lead Pharmacologist Division of New Drug Bioequivalence Evaluation Office of Study Integrity and Surveillance (OSIS) Center for Drug Evaluation and Research U.S. Food and Drug Administration

2 Disclaimer This presentation reflects the views of the author. It should not be construed to represent FDA s views or policies. The examples discussed in this presentation should not be used to avoid applicable FDA regulations. 2

3 Agenda OSIS overview and activities BA/BE studies Inspection metrics Common BA/BE inspection deficiencies Scientific evaluations 3

4 Office of Study Integrity and Surveillance Mission: To ensure data supporting regulatory decisions are reliable by conducting and directing inspections of bioavailability/bioequivalence (BA/BE) and nonclinical (GLP) studies. Staff: Scientists with different backgrounds including pharmacology, clinical pharmacology, toxicology, chemistry, biology, and other backgrounds. 4

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6 Organization 6

7 OSIS Activities Directs the inspection of clinical portion of BA/BE studies Inspects analytical portion of BA/BE studies and nonclinical safety (GLP) studies Upholds applicable Codes of Federal Regulations (CFR) 21 CFR 312, 21 CFR 320, and 21 CFR 58 Evaluates inspectional findings and their impact on data reliability Communicates findings and impact to CDER review divisions 7

8 Bioavailability and Bioequivalence Study Small (n <60 subjects), Phase 1 clinical study Compares two formulations of the same drug Evaluates clinical (safety/efficacy) and/or pharmacokinetic endpoints Includes two portions: Clinical Dosing, sample collection, safety/efficacy monitoring Typically audited by the Office of Regulatory Affairs (ORA) Analytical Bioanalytical method, sample analyses Typically audited by OSIS alone or jointly with ORA 8

9 OSIS inspections and Applications Inspected* (CDER, FY 2014 FY 2017) *Based on inspection Start Date [Complis database as of December 29, 2017]. Includes only CDER numbers. 9

10 Application Inspections per Fiscal Year 10

11 Common BA/BE Inspection Deficiencies* (CDER, FY 2017) *Based on Logout date and Final Classification, [Complis database as of April 10, 2018] Note that this does not denote number of inspections completed, but rather number of inspection reports evaluated and closed in the fiscal year. 11

12 OSIS Adds Value to Drug Development OSIS evaluates inspectional findings from regulatory and scientific perspectives Assesses the scientific merit of data and whether the data are reliable Encourages scientific discussions during and after inspections g 12

13 Deficiency and Scientific Evaluation: Validation Observation Quality controls (QCs) in serum didn t represent subject sample concentrations FDA BMV Guidance FDA guidance recommends minimal number of QCs per analytical run. Site/Sponsor No additional data was provided. However, runs included two extra QCs in surrogate matrix. Those QCs bracketed subject sample concentrations OSIS If calibration standards in surrogate matrix are valid, then QCs in surrogate matrix are also valid 13

14 Deficiency and Scientific Evaluation: Validation 14

15 Deficiency and Scientific Evaluation: Stability Observation Freeze thaw (FT) and short term (ST) stability assessments did not include freshly prepared comparators OSIS Site/Sponsor Concerns with data reliability without freshly prepared comparators Site disagreed with finding without providing additional stability data OSIS Long term (LT) stability assessment included freshly prepared calibrators. LT data may cover FT and ST frozen storage 15

16 Deficiency and Scientific Evaluation: Stability Frozen storage period Processing steps LT stability Several 20 C FT Stability 1 cycle Several hours (24 20 C RT Process Analysis ST Stability A few 20 C Rationale: Analyte is stable for several months (as determined with fresh CCs), then it should be stable after a few hours under same frozen conditions. 16

17 Deficiency and Scientific Evaluation: Records Observation Discrepancies with treatment allocation, treatment identity, and dietary conditions OSIS/FDA FDA must confirm treatment allocation and identity to assess data authenticity and reliability Site/Sponsor Mock randomization schedule was inadvertently submitted to FDA OSIS Post inspection IWRS audit trails and drug accountability logs confirmed treatment allocation and identity 17

18 Deficiency and Scientific Evaluation: Records Inspectional findings IWRS Randomized Fasted Dispense Bottle 123 Subject 1 Test Bottle 123 = test Uh? Report submitted to FDA Subject 1 Randomized Fed Placebo Dispense Bottle 123 PK Bottle 123 = placebo 18

19 Deficiency and Scientific Evaluation: Records IWRS vendor used a mock randomization schedule to design study platform Sponsor inadvertently submitted mock schedule to FDA Vendor IWRS audit trails confirmed the real randomization scheme was uploaded pre study Planning and Design Pre study FDA submission Mock Real Mock 19

20 Deficiency and Scientific Evaluation: Reserves Observation Reserve samples were prelabeled and predesignated before shipping to clinical site OSIS Predesignated reserves don t represent drug product used in the study Site/Sponsor OSIS Dosing materials supplied to site was still available for collection as representative reserve samples Products supplied to site for dosing directly represents material used in the study 20

21 Deficiency and Scientific Evaluation: Reserves Sponsor/Packager/Distributor Clinical Site FDA Reserves Reserves Inspectional Finding Dosing material Dosing material Reserves FDA Expectation Shipment Shipment Dosing material 21

22 Concluding Remarks OSIS directs and conducts inspections of clinical and analytical components of BA/BE studies and nonclinical safety studies Most inspectional findings involve method validation, stability, records, and reserve samples OSIS routinely evaluates findings based on the scientific merit of the data We encourage scientific discussions during and after inspections 22

23 Acknowledgements Arindam Dasgupta, Ph.D., OSIS Deputy Director Charles Bonapace, Pharm.D., OSIS Division Director Sally Choe, Ph.D., OSIS Office Deputy Sean Kassim, Ph.D., OSIS Office Director OSIS Staff 23

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