Principles for the Evaluation of Vaccines Against the Novel Coronavirus SARS-CoV-2 in Japan

Document overview

PMDA’s Principles for the Evaluation of Vaccines Against the Novel Coronavirus SARS-CoV-2 was issued on September 2, 2020 by the Office of Vaccines and Blood Products. It summarizes basic principles for efficacy and safety evaluation of SARS-CoV-2 vaccines in Japan, based on the situation as of August 2020, and notes the principles may change as scientific knowledge and development status evolve. Reference: PMDA PDF.

Vaccine modalities in scope

The document recognizes multiple vaccine platforms under development, including inactivated virus, recombinant protein, LNP-mRNA, DNA, and recombinant viral-vector vaccines.

Nonclinical evaluation

Pharmacology (immunogenicity and protective effect)

Nonclinical pharmacology assessments are generally expected to support clinical trials, including:

• Confirming antigen-specific antibodies and neutralizing antibodies
• Characterizing immune responses (e.g., IgG subclass, cytokines)
• Confirming induction of cell-mediated immunity
• Assessing anti-infective or disease-preventive effects in relevant animal infection models and exploring correlations between immune markers and protection Reference: PMDA PDF.

Nonclinical safety

The principles describe nonclinical safety expectations (e.g., GLP-based studies) and note that, for certain modalities (e.g., LNP-mRNA, DNA, recombinant viral vectors), conducting nonclinical safety studies in parallel with clinical trials may be acceptable when safety can be explained using existing nonclinical/clinical data for related platform components/vectors.

Disease enhancement risk (ADE/ERD)

The document highlights potential risks of disease enhancement (e.g., antibody-dependent enhancement (ADE) or enhanced respiratory disease (ERD)) and emphasizes characterizing immune responses prior to initiating clinical trials to help estimate such risks.

Clinical evaluation

Immunogenicity

The document discusses collecting immunoreactivity results (e.g., antigen-specific and neutralizing antibody titers) and indicates that, once standards/correlates are established from completed trials, immunogenicity can support evaluation. It also notes that incidence of COVID-19 during observation should be collected appropriately to allow exploratory evaluation of efficacy/safety where possible.

Efficacy: primary endpoints and alternatives

• In principle, vaccine efficacy should be evaluated using disease-preventive effect as the primary endpoint, because (at the time of issuance) no surrogate marker for prevention against COVID-19 was known.
• Other possible key endpoints may include confirmed SARS-CoV-2 infection (virological/serological) and severity-related outcomes (e.g., SpO2, oxygen therapy, ventilator/ECMO management, death).
• If a vaccine with demonstrated disease-preventive effect becomes available in Japan, subsequent candidates may be evaluated in controlled trials using such an efficacy-demonstrated vaccine as a comparator, with endpoints determined based on the evolving scientific understanding of protection mechanisms.
• The document anticipates that if immune markers associated with protection are confirmed in the future, immunogenicity could be used as reference in evaluating candidates (with nonclinical protection plus Japanese immunogenicity as an example approach).

Safety: what to collect and for how long

The principles specify collecting:

• Solicited local and systemic reactions for at least the first 7 days after administration
• All adverse events for at least the first 28 days after administration (longer may be needed depending on vaccine characteristics) They also describe practical methods for AE capture (e.g., diaries and follow-up calls) and emphasize planning to ensure proper collection beyond Day 8.

Japanese development strategy when overseas confirmatory efficacy exists

When a large-scale confirmatory efficacy trial is conducted overseas using disease-preventive effect as the primary endpoint, the document states it may be sufficient in Japan to conduct a clinical trial to confirm immunogenicity and safety in Japanese subjects without running a Japan-based confirmatory efficacy trial; alternatively, Japan may participate in a multi-regional program to evaluate efficacy.

Practical takeaways for sponsors

• Build the nonclinical package to demonstrate both immunogenicity and protective activity in animal models early, while proactively evaluating enhancement risks (ADE/ERD).
• Design clinical programs around prevention endpoints unless/ until validated correlates are available; plan for comparator-controlled designs as vaccines become established.
• Implement a safety data collection system that reliably captures solicited reactions (≥7 days) and all AEs (≥28 days), with scalable follow-up methods.
• If robust overseas efficacy data exist, use Japan trials strategically for immunogenicity and safety bridging, or join multi-regional efficacy programs.

Reference: PMDA PDF.