A session at DIA Europe 2021 explored the current implementation of the E17 guideline internationally, both from a regulatory authority and industry point of view discussing experiences from the Pharmaceuticals and Medical Devices Agency (PMDA) Japan, the European Medicines Agency (EMA), and industry on the use of the guideline in practice, as well as how to address barriers to implementation.

Key Takeaways

• Drug development now takes place on a global scale. The number of clinical trials has expanded rapidly over the last decade, and this increase is especially notable for Asia. In this context, the E17 guideline is an important tool in global drug development and registration.
• A European Federation of Pharmaceutical Industry Associations (EFPIA) survey on the implementation of the E17 guideline highlighted challenges, such as the use of the E17 training materials; and barriers to practical implementation of the guideline, such as the use of pooling strategies and the existence of local legislation and/or regulations.
• Japan, which was the ICH Rapporteur of the E17 Guideline, is in a transition phase to achieve complete implementation of the E17 guideline. Continuing experience gained from MRCT case studies will facilitate implementation in Japan.

Practical Experience

In the more than three years since the ICH E17 guideline was finalized, much experience has been gained by both regulatory authorities and industry in how to apply the guideline in practice.

As described in another article in this issue, industry experience in applying pooling strategies for Japan, South Korea, and China has been challenging. One potential strategy considers pooling patients from Japan, South Korea, and China into an East Asian region, provided that ethnic factors are adequately understood and comparable.

In this same survey, self-reported industry awareness and understanding of the E17 guideline is rated as high; however, use of the available E17 training materials is reported as low. It was recommended that the training materials should be further disseminated to increase their use and application, and possibly revised to include more case examples. Furthermore, local legislation and/or regulations that mandate local clinical data for registration are perceived as a barrier to implementation by industry. This is an area that may merit further exploration as adoption of the E17 guideline internationally continues to be relatively slow.

Dialogue and information sharing remain important. Investing in pre-trial discussion to ensure good trial design is particularly critical to successful MRCTs. Furthermore, sharing of pre-competitive information (e.g., case studies) has an important role in broadening the knowledge base that all stakeholders can then use to understand the critical factors for conducting successful MRCTs.

EMA has seen an increase in Asia-Pacific trial sites included in its applications as well as Chinese, Japanese, and South Korean patients participating in more and more trials, and a continuing need to consider intrinsic and extrinsic factors when designing MRCTs.

MRCTs do not exist in a vacuum. It is evident that the future role of real-world data (RWD) in MRCTs remains to be elucidated. Multiple sources of RWD, divergent quality of RWD, and the relative immaturity of real-world evidence (RWE) and RWD frameworks for international regulatory decision-making multiply the complexity involved in this area. One aspect that could potentially be considered for further thought is whether RWD can be used to evaluate ethnic differences between regions—for example, to support the concept of a pooled region or of subpopulations described in E17.

Based on ICH E17, the comparator(s) in a study should in principle be the same in all participating regions. Planning a study across regions is complex, not least because the standard of care may differ between regions. Moreover, use of a common comparator across regions in MRCTs is especially complex, as health technology assessment requirements must be considered on top of global regulatory requirements. This remains a very challenging issue on two topics that do not always align. However, an active comparator that is approved but not reimbursed may still be used and can add value to the trial’s robustness and ability to recruit patients.

Conclusion

Even with all the experience gained since the E17 guideline finalization in 2017, continued discussion among regulatory authorities, industry, and stakeholders is needed to promote greater use. Such dialogue may help identify and resolve common sponsor and regulatory challenges.