Standard Operating Procedure for Selecting Bioequivalence Study Design in BA/BE Studies

Department	BA-BE Studies
SOP No.	SOP/BA-BE/004/2025
Supersedes	SOP/BA-BE/004/2022
Page No.	Page 1 of 13
Issue Date	17/04/2025
Effective Date	20/04/2025
Review Date	17/04/2026

1. Purpose

To outline the procedure for selecting an appropriate study design—crossover, parallel, replicate, or alternative designs—for bioequivalence (BE) studies, ensuring the chosen approach is scientifically valid, regulatory compliant, and suited to the product’s characteristics.

2. Scope

This SOP applies to clinical pharmacologists, medical writers, statisticians, and regulatory affairs professionals involved in the design of BA/BE studies for both oral and non-oral formulations intended for global regulatory submissions.

3. Responsibilities

• Clinical Pharmacologist: Evaluates drug pharmacokinetics and recommends design options.
• Statistician: Assesses variability and determines appropriate statistical power and sample size for the design.
• Regulatory Affairs: Verifies design alignment with applicable regulatory guidance (USFDA, EMA, CDSCO).
• Medical Writer: Documents design justification in the protocol and synopsis.

4. Accountability

The Head of Clinical Research is accountable for ensuring that the selected BE study design is scientifically justified and meets all applicable regulatory standards.

5. Procedure

5.1 Evaluate Drug Characteristics

1. Review the pharmacokinetic profile of the reference drug:
   • Absorption rate and extent
   • Elimination half-life
   • Inter- and intra-subject variability
   • Therapeutic index (narrow or wide)
2. Determine whether single or multiple-dose BE study is needed.

5.2 Assess Regulatory Guidance

1. Consult relevant regional and product-specific regulatory guidance:
   • USFDA Product-Specific Guidance (PSG)
   • EMA Bioequivalence Guidelines
   • WHO TRS 1003 (2021) for global development
2. Check if replicate design is required (e.g., for highly variable drugs or NTI drugs).

5.3 Selection of Study Design

1. Choose the appropriate study design based on drug and regulatory parameters:
   • 2×2 Crossover: Standard for most immediate-release products.
   • Parallel Design: For long half-life drugs or when carryover is significant.
   • Replicate Design: For highly variable drugs (HVDs) or NTI drugs; e.g., 2×4 or 2x2x4 design.
   • Other Designs: Single-period for topical/oral inhalation/nasal studies (if applicable).
2. Document rationale in Annexure-1: Study Design Selection Form.

5.4 Sample Size Considerations

1. Calculate sample size using variability estimates and required power (≥80%).
2. Use software like WinNonlin, SAS, or PASS for simulations.
3. Provide sample size table as part of protocol annexures.

5.5 Food Effect Considerations

1. Determine if both fed and fasted studies are needed.
2. Refer to product labeling or SmPC to assess fed/fasted recommendations.
3. Include both studies if required for submission in US or EU.

5.6 Documentation and Review

1. Prepare a design justification memo including:
   • Selected design
   • Reasons for selection
   • Alternatives considered
   • Regulatory references
2. Review by medical, clinical, and regulatory team.
3. Finalize and archive in the eTMF “Design Justification” folder.

6. Abbreviations

• BE: Bioequivalence
• PK: Pharmacokinetics
• NTI: Narrow Therapeutic Index
• HVD: Highly Variable Drug
• PSG: Product Specific Guidance
• eTMF: Electronic Trial Master File

7. Documents

1. Study Design Selection Form – Annexure-1
2. Sample Size Simulation Output – Annexure-2
3. Design Justification Memo – Annexure-3

8. References

• USFDA Product-Specific Guidance
• EMA Guideline on Investigation of Bioequivalence
• ICH E6(R2) Good Clinical Practice
• WHO Technical Report Series No. 1003 (2021)

9. SOP Version

Version: 2.0

10. Approval Section

	Prepared By	Checked By	Approved By
Signature
Date
Name
Designation
Department

11. Annexures

Annexure-1: Study Design Selection Form

Drug	XYZ Tablet 50 mg
Design Selected	2×2 Crossover
Rationale	Short half-life, low variability
Regulatory Guidance	USFDA PSG – Feb 2023

Annexure-2: Sample Size Simulation Output

Design	Power (%)	CV (%)	Sample Size
2×2 Crossover	81.4	22	36
Replicate	92.7	38	48

Annexure-3: Design Justification Memo

Date	12/04/2025
Prepared By	Sunita Reddy
Reviewed By	Rajesh Kumar
Summary	Selected crossover design based on low intra-subject variability and standard regulatory expectation.

Revision History:

Revision Date	Revision No.	Details	Reason	Approved By
15/01/2022	1.0	Initial SOP Release	New SOP	QA Head
17/04/2025	2.0	Updated with replicate design considerations and new annexures	Regulatory Update	QA Head