Changes Impacting Bioequivalence Inspections: What s New?

Transcription

1 Changes Impacting Bioequivalence Inspections: What s New? Sam H. Haidar, Ph.D., R.Ph. Division of Generic Drug Bioequivalence Evaluation Office of Study Integrity and Surveillance Center for Drug Evaluation and Research U.S. Food and Drug Administration 2nd MENA Regulatory Conference on BE, Biowaiver, Bioanalysis, Dissolution and Biomarkers Amman, Jordan, September 15,

2 Outline Organizational changes/new regulatory developments: Impact on BE inspections FDA s BE inspectional program, focus on bioanalytical inspections Selected topics for discussion 2

3 Organization Prior to January 11,

4 Center for Drug Evaluation and Research Office of the Center Director Janet Woodcock, MD, Director Office of Compliance Office of Scientific Investigations Office of Drug Security, Integrity & Recalls Office of Manufacturing & Product Quality Office of Unapproved Drugs and Labeling Compliance 4

5 Office of Scientific Investigations Director Immediate Office Policy & Communication Risk Science, Intelligence & Prioritization Program Management and Organizational Strategy Division of Bioequivalence & GLP Division of GCP Compliance Division of Safety Compliance 5

6 Organization Post January 11,

7 Center for Drug Evaluation and Research Office of the Center Director Janet Woodcock, MD, Director Office of Translational Science Office of Study Integrity and Surveillance Office of Clinical Pharmacology Office of Biostatistics Office of Computational Science 7

8 Office of Study Integrity and Surveillance (OSIS) Division of Generic Drug BE Evaluation Division of New Drug BE Evaluation BE BE BE BE BE GLP 8

9 Regulatory Developments Generic Drug User Fee Amendments of 2012 (GDUFA) Biologics Price Competition and Innovation Act of 2009 Section 351(k) Licensure of Biological Products as Biosimilar or Interchangeable. 9

10 Evolution of Procedures After Re-organization Inspectional data: Site specific vs. study specific Surveillance approach-parts of multiple studies Analytical inspections with and without ORA participation More large molecule PK assays, immunogenicity testing 10

11 Points to Remember Primary objective of any study should be to pursue good science, and good documentation Guidances do not and cannot address every aspect of every study Guidances provide best recommendations based on what we currently know (i.e., not regulations) By themselves, Guidances are not binding on FDA or industry 11

12 FDA s BE Inspection Program Type of studies: In vivo studies Bioavailability (BA), BE, pharmacokinetic (PK), pharmacodynamic (PD), clinical endpoint BE studies In vitro data Biowaiver permeability studies Nasal aerosols and sprays for local action Binding studies: Phosphate, calcium, bile acids 12

13 FDA s BE Inspection Program Biologics, Biosimilar Studies: Pharmacokinetic data (ELISA, ECL*, GyroLab) Immunogenicity data (anti-drug antibodies [ADA], neutralizing antibodies [NAb]) ELISA, ECL, RIP** Cell-based (neutralizing) *Electrochemiluminescense **Radioimmunoprecipitation 13

14 BE Inspections Inspection type: Routine, surveillance Studies pivotal to approval decisions (NDAs, ANDAs, BLAs); other studies submitted to FDA For Cause Concerns with study conduct or reported results Complaint follow-up 14

15 In Vivo BE Inspections Two components: 1. Clinical: Office of Regulatory Affairs (ORA) 2. Bioanalytical: ORA + Office of Study Integrity and Surveillance (OSIS); option: No ORA participation 15

16 Key Elements Clinical Inspections Subject safety Informed consent Reserve Samples-test and reference, per regulations Adherence to study protocol Adequate documentation 16

17 Bioanalytical Inspections Key Elements Facility Walk-Through Handling and storage of subject samples Assay validation 17

18 Bioanalytical Inspections Primary Objectives: Evaluate adherence to regulations, guidances, and scientific principles Ensure data quality and integrity Adequate documentation-paper and Electronic Allow reconstruction of the study 18

19 Bioanalytical Inspections Examples of Areas Covered Storage (freezers, appropriate temp), limited access, alarms Samples: chain of custody, storage, extractions, LC-MS/MS system, equilibration samples, audit trails, manual integration, carry-over effect, interference, reproducibility (ISR*) Light Sensitivity Archival area *Incurred sample reproducibility 19

20 Data Audit Assay Validation Comparison of data submitted by sponsor in application to source records on site Sample reanalysis: Justified? Well documented? 20

21 Data Quality QC samples-range covers observed subject concentrations? Standard curve-appropriate range Run acceptance Carryover effect/interference ISR 21

22 Data Integrity Audit trails-manual integration Electronic data management Contemporaneous documentation Correspondence File 22

23 Inspectional Outcomes No observations/nai Form FDA 483, Observations/VAI* Form FDA 483, Observations/OAI* NAI: No Action Indicated; VAI: Voluntary Action Indicated; OAI: Official Action Indicated *Site has 15 business days to respond 23

24 Inspectional Outcomes Recommendations are made to the review divisions (OGD, OND) to accept or reject data (partial or full) For OAI Classification, the Office of Compliance issues a regulatory letter to the inspected entity 24

25 Common/Serious Observations Reserve samples: In vivo, In vitro studies Rejection of data Assay Validation-Accuracy, precision, stability, sensitivity, selectivity Quality Controls-Inappropriate acceptance of analyzed run Documentation 25

26 References FDA Regulations 21 CFR 320 Bioavailability and Bioequivalence Requirements FDA Guidance document Bioanalytical Method Validation gulatoryinformation/guidances/ucm pdf Compliance Program Guidance Manual In Vivo Bioequivalence Program researchmonitoring/ucm pdf 26

27 Special Topics for Discussion Processed vs. Instrumental Batches Extract Stability Incurred Sample Stability (ISS) Long term stability for combination or coadministered drugs 27

28 Special Topics for Discussion Internal Standard Response Handling of Outliers 28

29 Questions 29