Guideline for Clinical Evaluation of Antibacterial Drugs in Japan

1. Background and Purpose

The Guideline for Clinical Evaluation of Antibacterial Drugs was published via the PSEHB/PED Notification No. 1023-3 on October 23, 2017 and replaces the former 1998 version. It was developed to reflect contemporary scientific knowledge, the shift to global simultaneous drug development, and the need to converge data requirements among Japan, Europe, and the United States for antibacterial drug approval.

This guideline provides basic concepts for planning nonclinical and clinical studies necessary to support marketing approval applications for systemic antibacterial drugs. It emphasizes flexibility for applicants to propose alternative methods if properly rationalized based on scientific advancement.

2. Scope and Positioning

The guideline covers the clinical evaluation principles for investigational antibacterial drugs targeting ordinary bacterial pathogens, excluding mycobacteria, fungi, and viruses. It integrates microbiological evaluation with efficacy and safety assessments based on signs and symptoms of infectious diseases.

Clinical evaluation includes phase I–III studies; special population studies (e.g., hepatic/renal impairment, pediatric); methods for trial conduct; and considerations for utilizing foreign clinical data.

3. Nonclinical to Clinical Transition

The guideline highlights that bacteriological studies and pharmacological evaluations (such as in vitro activity, mode of action, resistance mechanisms, and in vivo infected animal models) should inform clinical trial design, helping determine target bacterial species, disease indications, and initial dosing. These nonclinical assessments provide critical context for subsequent clinical studies.

4. Clinical Trial Design Principles

4.1 Phase I Studies

Phase I studies aim to assess safety margins, pharmacokinetics (PK), and tolerability in humans. These may include single and repeated dosing to characterize blood drug concentrations relative to adverse events and microbiological targets, and to estimate dosing for later stages.

4.2 Phase II and Phase III Studies

Phase II studies estimate appropriate clinical doses based on PK/PD analyses and earlier results. Phase III studies are designed to demonstrate efficacy and safety in patients with specific infectious diseases, typically using randomized, double-blind, controlled trials to compare investigational drugs with appropriate controls (such as standard antibacterial therapy). Endpoints focus on clinical cure and microbiological eradication at the time of test-of-cure.

4.3 Special Populations

The guideline addresses clinical evaluation in special populations such as pregnant women, nursing women, pediatric patients, elderly patients, and those with hepatic or renal disorders, with tailored recommendations for inclusion/exclusion criteria, safety monitoring, and analysis plans.

5. Use of Foreign Clinical Data

Utilization of foreign clinical data is permitted if justified. When foreign trial results are used, intrinsic and extrinsic ethnic factors should be assessed to ensure relevance to the Japanese population. Strategies may involve demonstrating similar pharmacokinetics between Japanese and non-Japanese subjects, or including Japanese patients in global trials for key efficacy and safety confirmation.

6. Appendices and Disease-specific Guidance

The guideline includes appendices with disease-specific clinical evaluation considerations (e.g., sepsis, respiratory infections, urinary tract infections, skin/soft tissue infections, pediatric infections) which provide detailed guidance on clinical data packages for each infection type.

7. Flexible and Rational Design

The guideline emphasizes that developers are free to propose alternative study methods or designs so long as they are scientifically sound and justified based on current knowledge, enabling flexibility in the evolving landscape of antibacterial drug development.

Conclusion

The Guideline for Clinical Evaluation of Antibacterial Drugs outlines comprehensive and flexible principles for planning and conducting clinical studies of antibacterial drugs in Japan, aiming to ensure robust evidence for efficacy and safety while aligning with global development practices and regulatory expectations.