common ba/be inspection observations and scientific...
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Common BA/BE Inspection Observations and Scientific Evaluation
Ruben C. Ayala, Pharm.D.Lead Pharmacologist
Division of New Drug Bioequivalence EvaluationOffice of Study Integrity and Surveillance (OSIS)
Center for Drug Evaluation and ResearchU.S. Food and Drug Administration
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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.
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Agenda
• OSIS overview and activities• BA/BE studies• Inspection metrics• Common BA/BE inspection deficiencies• Scientific evaluations
www.fda.gov
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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.
www.fda.gov
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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 divisionswww.fda.gov
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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
www.fda.gov
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OSIS inspections and Applications Inspected*(CDER, FY 2014 ‐ FY 2017)
www.fda.gov *Based on inspection Start Date [Complis database as of December 29, 2017]. Includes only CDER numbers.
289
263
300289
290
328
431
488
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*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 .
Common BA/BE Inspection Deficiencies* (CDER, FY 2017)
www.fda.gov
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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
www.fda.gov
http://www.bgfermer.bg
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Deficiency and Scientific Evaluation: Validation
Observation • Quality controls (QCs) in serum didn’t represent subject sample concentrations
• FDA guidance recommends minimal number of QCs per analytical run.
FDA BMV Guidance
• If calibration standards in surrogate matrix are valid, then QCs in surrogate matrix are also valid
OSIS
Site/Sponsor • No additional data was provided. However, runs included two extra QCs in surrogate matrix. Those QCs bracketed subject sample concentrations
www.fda.gov
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Deficiency and Scientific Evaluation: Stability
Observation • Freeze‐thaw (FT) and short term (ST) stability assessments did not include freshly prepared comparators
• Concerns with data reliability without freshly prepared comparators
OSIS
• Long term (LT) stability assessment included freshly prepared calibrators. LT data may cover FT and ST frozen storage
OSIS
• Site disagreed with finding without providing additional stability data
Site/Sponsor
www.fda.gov
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Deficiency and Scientific Evaluation: Stability
Several Months @ ‐20◦CLT stability
FT Stability – 1 cycle Thaw @ RT Process AnalysisThaw @ RT Process AnalysisSeveral hours (24 hrs) @ ‐20◦C
ST Stability A few hours @ ‐20◦C
Frozen storage period Processing steps
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.
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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
• Post‐inspection IWRS audit trails and drug accountability logs confirmed treatment allocation and identity
OSIS
www.fda.gov
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Deficiency and Scientific Evaluation: Records
Inspectional findings
Randomized
Fasted
TestSubject 1
IWRSDispense
Bottle 123
Report submitted to FDA
Randomized
Fed
Placebo
Subject 1
DispenseBottle 123
Bottle 123 = placebo
PK
Uh?Bottle 123 = test
www.fda.gov
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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
www.fda.gov
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Deficiency and Scientific Evaluation: Reserves
Observation • Reserve samples were prelabeled and predesignated before shipping to clinical site
• Predesignated reserves don’t represent drug product used in the study
OSIS
• Products supplied to site for dosing directly represents material used in the study
OSIS
• Dosing materials supplied to site was still available for collection as representative reserve samples
Site/Sponsor
www.fda.gov
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Sponsor/Packager/Distributor Clinical Site FDA
Inspectional Finding
FDA Expectation
Deficiency and Scientific Evaluation: Reserves
Reserves
Dosing material
Dosing material
Reserves
√
Shipment Shipment
Reserves
Dosing material
√
www.fda.gov
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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
www.fda.gov
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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
www.fda.gov
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