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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, 2015

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Outline

● Organizational changes/New regulatory developments: Impact on BE inspections

● FDA’s BE inspectional program, focus on

bioanalytical inspections

● Selected topics for discussion

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Organization Prior to January 11, 2015

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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

Office of the Center Director Janet Woodcock, MD, Director

Center for Drug Evaluation and Research

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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

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Organization Post January 11, 2015

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Office of Translational Science

Office of Study Integrity and Surveillance Office of Clinical Pharmacology

Office of Biostatistics Office of Computational Science

Office of the Center Director Janet Woodcock, MD, Director

Center for Drug Evaluation and Research

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Division of Generic Drug BE Evaluation

Division of New Drug BE Evaluation

Office of Study Integrity and Surveillance (OSIS)

BE BE BE BE BE GLP

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.”

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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

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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

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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

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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

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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

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Two components:

1. Clinical: Office of Regulatory Affairs (ORA)

2. Bioanalytical: ORA + Office of Study Integrity and Surveillance (OSIS); option: No ORA participation

In Vivo BE Inspections

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Clinical Inspections

Key Elements Subject safety Informed consent Reserve Samples-test and reference,

per regulations Adherence to study protocol Adequate documentation

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Bioanalytical Inspections

Key Elements

Facility Walk-Through

Handling and storage of subject samples

Assay validation

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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

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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

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Data Audit

• Assay Validation

• Comparison of data submitted by sponsor in application to source records on site

• Sample reanalysis: Justified? Well documented?

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Data Quality

• QC samples-range covers observed subject concentrations?

• Standard curve-appropriate range

• Run acceptance

• Carryover effect/interference

• ISR

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Data Integrity

• Audit trails-manual integration – Electronic data management

• Contemporaneous documentation

• Correspondence File

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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

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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

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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

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References • FDA Regulations – 21 CFR 320

– Bioavailability and Bioequivalence Requirements

• FDA Guidance document – “Bioanalytical Method Validation”

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070107.pdf

• Compliance Program Guidance Manual

– In Vivo Bioequivalence Program 7348.001 http://www.fda.gov/downloads/ICECI/EnforcementActions/BioresearchMonitoring/UCM133760.pdf

Special Topics for Discussion

• Processed vs. Instrumental Batches

• Extract Stability

• Incurred Sample Stability (ISS)

• Long term stability for combination or co-administered drugs

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Special Topics for Discussion

• Internal Standard Response

• Handling of Outliers

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Questions