A narrative review on drug development for the management of antimicrobial- resistant infection crisis in Japan: the past, present, and future

Figures & data

Table 1. Regulatory guidance and guidelines for clinical development of antimicrobial agents.

	US FDA	EMA	Japanese MHLW/PMDA
Guidance/guidelines for clinical development of antimicrobial agents	Guidance for industry: Antibacterial therapies for patients with an unmet medical need for the treatment of serious bacterial diseases	Addendum to the guideline on the evaluation of medicinal products indicated for treatment of bacterial infections	Guideline for clinical evaluation of antibacterial drugs	Guideline for PK/PD evaluation of antibacterial agents
Published year	Draft version in 2013, final version in 2017	Draft version in 2012, final version in 2014	First version in 1998, revised version in 2017	2015
Aim of the guidance/guidelines	To assist sponsors in the clinical development of new antibacterial drugs for serious bacterial diseases in patients with unmet medical needs through possible streamlined development programs and clinical trial designs	To suggest possible clinical development programs for new antibacterial agents with very narrow spectra of antibacterial activity and/or with activity against multi-resistant pathogens that have very limited treatment options	To resolve challenges in the clinical development of antibacterial agents and provide recommendations on clinical evaluation of systemic antimicrobial agents	To facilitate active use of PK/PD evaluation in the development of antibacterial agents
References	[21]	[22]	[23,24]	[25]

EMA, European Medicines Agency; MHLW, Ministry of Health, Labour and Welfare; PD, pharmacodynamics; PK, pharmacokinetics; PMDA, Pharmaceuticals and Medical Devices Agency; US FDA, United States Food and Drug Administration

Table 2. National and regulatory actions in Japan to promote clinical development of novel anti-infective agents.

Actions	Details	References
National strategy and action plan for infectious disease crisis management	Japanese AMR National Action Plan (2016–2020)	[36]
Drug discovery and research programs hosted by a national agency	AMED initiatives (e.g. J-PRIDE, CiCLE, Research Program on Emerging and Re-emerging Infectious Diseases, R&D support for COVID-19–related projects, and participation in JPIAMR)	[39,43,47–49]
Initiatives for globally aligned and streamlined clinical development	Joint initiative by the US FDA, EMA, and Japan PMDA for achieving regulatory alignment for anti-infective clinical trials	[28]
Expedited regulatory pathways	Sakigake Designation System Conditional Early Approval System Special Approval for Emergency System	[50,51,53]

AMED, Japan Agency for Medical Research and Development; AMR, antimicrobial resistance; CiCLE, Cyclic Innovation for Clinical Empowerment; COVID-19, coronavirus disease 2019; EMA, European Medicines Agency; J-PRIDE, Japanese Initiative for Progress of Research on Infectious Disease for global Epidemic; JPIAMR, Joint Programming Initiative on Antimicrobial Resistance; PMDA, Pharmaceuticals and Medical Devices Agency; R&D, research and development; US FDA, United States Food and Drug Administration

Table 3. Key scientific proposals from the PMDA Science Board AMR subcommittee to facilitate clinical development of novel antimicrobial agents.

Proposal	Key points
1. Facilitation of global clinical trials	Primary endpoint harmonization among regulatory authorities Global information sharing regarding drug safety and efficacy Use of data obtained from non-Japanese populations
2. Exploration of alternative evaluation methods	Modeling and simulation Dose estimation using PK/PD models Monte Carlo simulation Pediatric dose determination using adult data Hollow-fiber simulation
3. Establishment of clinical trial networks	Establishment of domestic networks between advanced medical institutions experienced in clinical trials and local hospitals Establishment of core medical institution networks across the nation and collaboration with networks outside Japan
4. Exploration of development strategies involving new tactics	Implementation of novel study designs (e.g. single master protocol) Full use of data obtained from a limited number of patients
5. Establishment of pediatric development strategies	Extrapolation of adult clinical trial data Pediatric PK/PD analysis and PPK

The proposals and details listed are based on section 2 of the report published by the AMR Subcommittee of the PMDA Science Board [26].

AMR, antimicrobial resistance; PD, pharmacodynamics; PK, pharmacokinetics; PMDA, Pharmaceuticals and Medical Devices Agency; PPK, population pharmacokinetics

Table 4. What do we need to establish during the interpandemic period for the development of novel agents against antimicrobial-resistant bacteria?

Key factors	Details
1. International collaboration and funding	Research using international clinical trial platforms Academia-industry collaboration Funding through international platforms
2. Continued investment in novel drug development	Funding by the national government Incentive programs (push, pull, or hybrid strategies) National strategy for novel antimicrobial agent development
3. Independent pandemic command center and risk management plan for infectious disease pandemics	Independent function authorized to perform infection control and guideline development

Table 5. Push, pull, and hybrid incentive strategies for antimicrobial drug research and development.

	Push strategy	Pull strategy	Hybrid strategy
Definition	Lowering cost of research and development for new drugs by distributing the expenditures across multiple parties	Rewarding successful drug development by increasing or ensuring future revenue	Combination of multiple push and pull strategies
Examples	Increased access to research, research grants, tax incentives, and public-private partnerships	Monetary prizes, advanced market commitments, patent buyouts, accelerated market approval process, extended market exclusivity rights, increased reimbursement prices, and market entry rewards	OMA model
Incentives applied outside Japan	ND4BB, CARB-X, and BARDA	The GAIN Act
References	[78–80]	[17]	[81]

The details of the push, pull, and hybrid incentive strategies are based on publications by Renwick MJ, et al. (2016) [77] and Cama J, et al. (2021) [10].

BARDA, Biomedical Advanced Research and Development Authority; CARB-X, Combating Antibiotic-Resistant Bacteria; GAIN, Generating Antibiotic Incentives Now; ND4BB, New Drugs for Bad Bugs; OMA, Options Market for Antibiotics

Figure 1. What do we need to cope with future AMR pandemics?

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Data availability statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.