Ethnic Bridging Studies in Phase 1: When and Why They’re Needed

Table of Contents

Introduction

As drug development becomes increasingly global, regulatory authorities are placing greater emphasis on ensuring that clinical trial data are relevant across different ethnic populations. Ethnic bridging studies in Phase 1 help determine whether pharmacokinetic (PK), pharmacodynamic (PD), or safety profiles vary significantly between populations. These studies are essential to support drug approvals and dose recommendations in regions such as Asia, especially Japan, China, and India. This tutorial explores when bridging studies are required, how they’re designed, and how to interpret their outcomes.

What Is an Ethnic Bridging Study?

An ethnic bridging study is a clinical trial—typically in healthy volunteers—that evaluates whether the data obtained from a global population (often Western) can be extrapolated to another ethnic group without the need for full development programs.

The objective is to determine whether ethnic factors (genetic, physiological, cultural, or environmental) affect the drug’s safety, efficacy, or exposure.

ICH E5 Guideline: The Global Framework

The ICH E5(R1) guideline titled “Ethnic Factors in the Acceptability of Foreign Clinical Data” forms the regulatory backbone for bridging studies. It provides a structured approach to assess:

Intrinsic factors: Genetics, age, sex, body size, organ function
Extrinsic factors: Diet, medical practice, climate, adherence

ICH E5 emphasizes a bridging strategy that includes both foreign clinical data and local bridging data to support approval in new regions.

When Are Ethnic Bridging Studies Needed?

1. Global Data Comes Exclusively from One Region

If initial development was done only in the US or EU, countries like Japan or China often require bridging studies to assess relevance in their population.

2. Known Ethnic Variability

Drugs metabolized by polymorphic enzymes (e.g., CYP2D6, CYP2C19)
Sensitivity to certain adverse events (e.g., skin reactions, QT prolongation)

3. Drug Belongs to a Class With Ethnic Differences

Antihypertensives, antipsychotics, immunomodulators

4. Regulatory Requirement in Local Submission

Some countries mandate Phase 1 bridging as part of new drug approval, especially for first-in-class or high-risk drugs.

Typical Design of Ethnic Bridging Studies

Study Type

Generally, single-center, open-label, single-dose (or SAD/MAD) studies in healthy volunteers.

Population

Target ethnic group (e.g., Japanese, Chinese, Indian)
Typically 12–24 subjects per group

Comparator Arm

If possible, compare with a reference group from prior studies
Sometimes includes a parallel Caucasian or mixed-ethnicity arm

Dose Selection

Same dose and formulation as in foreign studies
Food effect and gender balance are considered

Endpoints

Primary: PK parameters (Cmax, Tmax, AUC, t½)
Secondary: Safety and tolerability, exploratory PD if applicable

Example Design: Japanese Bridging Study

Parameter	Design
Study Type	Open-label, crossover
Population	24 healthy Japanese males
Dose	100 mg oral tablet
Sampling	0 to 48 hours post-dose
Endpoints	Cmax, AUC_0–t, AUC_0–∞, t_½

PK Comparison and Statistical Analysis

Analysis includes comparing PK parameters with those from the original population.

Bioequivalence Ranges

Geometric mean ratios (GMR) and 90% confidence intervals (CI)
Acceptable range: 80–125% for AUC and Cmax

Interpretation

If within range → bridging successful
If outside range → further studies or dose adjustments may be required

Regulatory Perspective by Region

Japan (PMDA)

Highly structured requirement for ethnic bridging
Typically requires Japanese-specific PK and safety data
May be waived if exposure-matched studies in Japanese conducted overseas

China (NMPA)

Encourages local Phase 1 or bridging PK data for imported drugs
Promotes harmonization with ICH E5/E17 for multi-regional clinical trials (MRCTs)

India (CDSCO)

Requires bioequivalence or PK bridging studies for foreign clinical data
Schedule Y and NDCTR mandate local population data before marketing approval

Special Cases: When Bridging May Not Be Required

Topical or locally acting drugs with minimal systemic absorption
Drugs with wide therapeutic windows and low variability
Existing global PK/PD data includes subjects from the local ethnic group

Challenges in Ethnic Bridging Studies

Recruitment of homogeneous ethnic cohorts
Standardization of food, environment, and lifestyle factors
Assay validation for local labs
Interpreting PK variability due to genetics vs extrinsic factors

Best Practices

Plan bridging studies early in global development strategy
Use consistent analytical methods for comparison across studies
Engage local regulators during protocol design
Report ethnicity-based subgroup analysis in CSRs and global dossiers
Align with ICH E17 for Multi-Regional Clinical Trial (MRCT) strategy if applicable

Conclusion

Ethnic bridging studies ensure that drug development is inclusive, scientifically sound, and regulatory compliant across diverse populations. They protect patient safety, support dose precision, and facilitate global access to innovative therapies. By integrating these studies strategically into Phase 1, sponsors can reduce duplication, enhance approval success, and fulfill regulatory obligations with clinical confidence.