Guidance on Clinical Evaluation of Travelers’ Vaccines in Japan

Document overview

Japan’s Ministry of Health, Labour and Welfare (MHLW) issued PSEHB/ELD Notification No. 0407-1 dated April 7, 2016, attaching the Guidance on Clinical Evaluation of Travelers’ Vaccines, etc. The guidance provides basic principles based on current scientific knowledge and allows alternative methods if scientifically rationalized. Reference: PMDA PDF.

Why this guidance exists

Demand for vaccines for overseas travelers has increased, but some vaccines recommended for travelers internationally have not been launched in Japan. Japan also faces sporadic domestic cases due to importation of infections that are not endemic in Japan, increasing the need for preventive vaccines for diseases that are rare or absent domestically. A key challenge is that, for diseases that rarely occur in Japan, it is difficult to run Japanese clinical studies that directly evaluate preventive efficacy because events are too few. This guidance highlights that clinical evaluation principles may differ between vaccines for diseases prevalent in Japan and travelers’ vaccines. Reference: PMDA PDF.

Scope

This guidance applies to preventive vaccines against infectious diseases that pose an infection risk to overseas travelers. The same principles may also be applicable to vaccines for diseases that do not occur or are rare in Japan when administration is considered for people living in Japan (not only travelers). For vaccines developed as part of measures against novel influenza (pandemic preparedness), the separate prototype vaccine guidance should be referenced instead of this one. Reference: PMDA PDF.

Development principles: what differs (and what does not)

The guidance states that basic requirements and the types of data for an approval application are not fundamentally different from those described in the Guidelines for Clinical Studies of Preventive Vaccine for Infectious Diseases. What differs is how developers should obtain and interpret clinical evidence when Japan-based efficacy endpoint studies are impractical. It also notes that adult studies typically precede pediatric studies, but in endemic areas where infection occurs in childhood and adults may have acquired immunity, it may be appropriate to conduct clinical studies only in neonates and children in those areas. Reference: PMDA PDF.

Efficacy evaluation: the default expectation

1) Prefer efficacy endpoint trials in endemic areas

In principle, efficacy should be evaluated and verified via a randomized, double-blind comparative study with an appropriate control (such as placebo) using preventive effect as the endpoint in an endemic area of the target disease. The guidance notes that placebo-free designs may be considered depending on mortality and seriousness of the disease, and that challenge studies may be considered if they allow efficacy evaluation. Reference: PMDA PDF.

2) What Japan-based studies may need to do instead

If preventive efficacy has already been demonstrated in endemic areas, a confirmatory efficacy study in Japan is not required in principle. However, sponsors should consider confirming immunogenicity in Japan (for example, using antibody titers), and align the Japanese immunogenicity study design with the vaccination schedule, route, and immunogenicity endpoints used in the overseas efficacy-supporting study. The guidance also flags scenarios where immune response may differ between Japan and endemic regions due to pathogen distribution (strain/serotype/genotype), natural exposure levels, and other factors; in such cases, larger numbers of vaccinations may be useful to confirm immunogenicity in Japanese clinical studies. Reference: PMDA PDF.

3) If a similar vaccine is already approved in Japan

When a similar preventive vaccine is already approved in Japan and there is an alternative immunogenicity indicator with an established relationship to disease prevention, efficacy of the travelers’ vaccine may be explained by demonstrating non-inferiority to the Japan-approved similar vaccine using that alternative indicator in a Japanese clinical study (instead of evaluating preventive effect in endemic areas). Reference: PMDA PDF.

Post-marketing investigations: plan for real-world constraints

Travelers’ vaccines also require a risk management plan. The guidance notes that, when a product is primarily administered to overseas travelers, collecting information through routine post-marketing surveillance may be difficult; in such cases, developers should consider other methods that effectively collect post-marketing information from overseas travelers. Reference: PMDA PDF.

Other practical points highlighted

• Simultaneous vaccination: Japan clinical studies should ideally generate data reflecting actual practice, considering likely co-administered vaccines (routine vaccines in Japan and other travelers’ vaccines).
• Statistical considerations: for general statistical principles in clinical trials, refer to the Statistical Principles for Clinical Trials notification.
• Quality assurance: travelers’ vaccines must meet specification standards (monographs) in the Minimum Requirements for Biological Products to obtain marketing approval.

Key takeaways for developers

1. Assume efficacy evidence should be generated in endemic areas unless a justified alternative (such as established immune correlates with a Japan-approved comparator) is feasible.
2. Use Japan studies strategically for immunogenicity bridging when Japan-based efficacy endpoint trials are impractical.
3. Design post-marketing plans around the realities of traveler populations and data collection routes.

Reference: PMDA PDF.