Guidelines on Cancer Immunotherapy Development in Japan

This guidance was issued under PSEHB/PED Notification No. 0308-1 and PSEHB/MDED Notification No. 0308-1 (dated March 8, 2019). It was developed as a regulatory-science reference to support marketing authorization applications for cancer immunotherapies and encourages developers to use PMDA consultations as needed.

Reference (PDF): Guidelines on Cancer Immunotherapy Development (PMDA).

1. What’s included in the English version (important scope note)

The PDF is an English translation (provisional translation as of March 2021) and explicitly notes that the Japanese original consists of four documents, while the English version includes only:

• “General principles on late-phase clinical studies”
• “Basic principles in quality, non-clinical and clinical studies of cellular products used for cancer immunotherapy”

2. Late-phase clinical studies: design principles tailored to immunotherapy

The guidance emphasizes that late-phase (pivotal/confirmatory) studies should be designed with a full understanding of the characteristics of cancer immunotherapies—such as delayed onset and durable effects—and should incorporate knowledge from early-phase studies and up-to-date external evidence.

2.1 Endpoint selection: why OS often becomes central

For efficacy, the guidance states that clinically meaningful endpoints should be specified and highlights overall survival (OS) as the most objectively measurable and clinically meaningful endpoint. It also warns that immunotherapies may show transient early progression and therefore PFS can underestimate treatment effect in some settings.

2.2 Tumor-response criteria: RECIST vs immune-related criteria

Because immune effects can take time and early radiologic patterns may differ, the guidance discusses immune-related response criteria such as irRC/irRECIST, while noting these criteria are not fully established and require further evidence accumulation.

2.3 Statistical analysis under non-proportional hazards

If survival curves overlap early and separate later, proportional hazards may not hold, affecting interim/final analysis planning. The guidance discusses options such as the Harrington–Fleming test (late-period weighting), milestone survival analysis considerations, and restricted mean survival time approaches—while cautioning that parameters must be planned reasonably in advance.

2.4 Biomarkers: exploratory early, confirmatory later

Given incomplete understanding of immune mechanisms, the guidance encourages identifying biomarkers for predicted effect, immune-related adverse events, and treatment response, recommending exploratory biomarker work in early phases with verification in late-phase studies.

2.5 Immune-related adverse events: detect, prevent, treat, communicate

For immune checkpoint inhibitors, the guidance notes reports of immune-related adverse events and stresses measures such as early detection of serious events, identifying markers involved in onset, establishing prevention and treatment methods, and providing safety information to healthcare professionals and patients.

3. Cellular products for cancer immunotherapy: quality and non-clinical/clinical fundamentals

The guidance also provides “basic principles” for human cellular products used in cancer immunotherapy, reflecting expanding use and the complexity of cell sources and manufacturing. It describes cellular products including:

• Effector cells (e.g., αβ-T cells, γδ-T cells, NK/NKT cells) that act directly, and
• Non-effector cells (e.g., dendritic cells as antigen-presenting “vaccine-like” products; mesenchymal stem cells for immune/local environment modulation), with sources ranging from autologous/allogeneic cells to iPS/ES cells, and manufacturing involving culture, genetic engineering, reprogramming/differentiation, etc.

3.1 Quality strategy: risk-based controls and infectious agent safety

The guidance highlights that for regenerative medical products, manufacturing methods and quality control should be based on reasonable rationales reflecting current knowledge, the intended use, scale, and risk. It also underscores a key challenge: because source cells may carry infectious contamination and sterilization/viral inactivation/removal like conventional drugs is often infeasible, safety against infectious agents should be evaluated through final-product testing plus in-process controls aligned to product properties and manufacturing.

3.2 Quality testing: common core attributes and potency/performance

Examples of commonly specified quality control tests include cell number/viability, identification, purity, process-related impurities, sterility, and mycoplasma. The guidance also notes that for some non-effector cell products, additional performance/potency testing (e.g., cytokine production–type assays) may be needed and should be designed reasonably.

3.3 Non-clinical safety topics: tumorigenicity and long observation where relevant

For products derived from ES/iPS cells, the guidance discusses evaluating the risk of malignant transformed cells in immunodeficient animal models with an observation period extended until engrafted cells are no longer detected (or until animals are not affected by aging/spontaneous lesions), highlighting the need for appropriately designed long-term assessment in relevant scenarios.

4. Practical takeaways for developers

• Confirm whether your program is primarily covered by the late-phase clinical principles, the cellular product principles, or additional Japanese documents not included in the English translation.
• Anticipate late-phase evidence needs shaped by immunotherapy’s delayed/durable effects: endpoint strategy, response criteria rationale, and analysis methods robust to non-proportional hazards.
• For cellular products, build a risk-based quality system with strong donor/material controls, in-process testing, and potency/performance strategies appropriate to mechanism and manufacturing variability.
• Engage PMDA consultation early to align development, evidence, and Japan-specific expectations.

Reference (PDF)

• Guidelines on Cancer Immunotherapy Development (PMDA).