Over the past few years, the regulatory landscape for cell therapy development has grown increasingly complex. There are now accelerated pathways for advanced therapy medicinal products (ATMPs) in several countries worldwide, including the U.S., Japan, and South Korea. While the possibility for accelerated commercialization has resulted from these changes, substantial complexity has also been introduced, making it a more elaborate process to move cell therapy products from “bench to bedside.”
In the interview with Yaron Ramati, Director of Regulatory Affairs at Pluristem Therapeutics, we get an expert’s perspective on how the regulatory environment has changed and new opportunities that exist for bringing cell therapy products through the clinical trial process and into the global marketplace.
Cade Hildreth: What is your background and how did you get involved with regulatory oversight?
Yaron Ramati: I have 10 years of experience in regulatory affairs in biotechnology companies in Israel.
I have a PhD in Philosophy of Biology from the London School of Economics and an M.Sc. from the Technion in Neurobiology
Cade Hildreth: What countries in the world have accelerated pathways for cell therapy approvals and what years did these regulations take effect?
Yaron Ramati: The United States, Japan, and South Korea are countries that have accelerated pathways that are unique for cell and gene therapies. Legislation took effect in Japan in late 2014, in South Korea in 2016, and in the United States in 2017.
Additionally, the EU has a program for product acceleration – the Adaptive Pathways. Although it is not explicitly for cell and gene therapies, these have been given a lot of attention by the group.
Cade Hildreth: What types of pathways exist in these countries?
In the United States: Regenerative medicine advanced therapy (RMAT) designation.
Cell therapies that aim to treat serious medical conditions with high unmet need, and have preliminary favorable clinical data, can get the designation. It allows for accelerated approval (i.e., the use of biomarkers and intermediate endpoints for BLA, priority review).
In Japan: Conditional time-limited marketing authorization.
This program allows for regenerative therapies (cell, gene and tissue therapies) to receive conditional marketing authorization for up to 7 years, following confirmation of safety and an initial proof of efficacy in Japan in diseases that are serious and have a high unmet need.
In South Korea: Conditional marketing authorization for cell therapy.
As in Japan, this program allows for cell therapies to receive conditional marketing authorization for a limited time, following an initial proof of efficacy in serious diseases.
In EU: Adaptive Pathways pilot program.
This program is a pilot program established by the EMA to explore ways in which the EMA can assist the streamlining the development of new promising therapies for serious conditions with high unmet need. Although this program is not explicitly for cell or gene therapy, it is the main focus of the group.
Cade Hildreth: Are there differences in how each country defines advanced therapy medicinal products (ATMPs), cell therapies, and regenerative medicine products?
Yaron Ramati: All EU countries have a joint definition for ATMPs as set by EU regulation. Other countries have separate definitions that only partially overlap.
Cade Hildreth: Can these countries be used as “gateway” countries to seek approvals in other regions of the world?
Yaron Ramati: Only few countries in the world are willing to be the first to provide marketing authorization for novel therapies. For ATMPs, European regulation does not allow individual countries in the union to provide marketing authorization, and so the EMA is the only gateway for ATMPs in Europe.
The U.S. FDA, Japan PMDA, and South Korea KFDA are the only others that are willing to be first to approve ATMPs.
Cade Hildreth: What countries do you anticipate will see the most cell therapy approvals over the next 5 years?
Yaron Ramati: Currently, the EMA and PMDA are leading with four marketing approvals of cell and gene therapies each. RMAT designation procedure in the U.S. is expecting to give a boost to the products that are being developed for the U.S. market.
Cade Hildreth: What accelerated pathways has Pluristem Therapeutics chosen to pursue?
Yaron Ramati: Pluristem is very active in the field of accelerated development of its products. PLX-PAD of Pluristem has been accepted to the Japan conditional time-limited marketing authorization scheme by PMD, as well as to the adaptive pathways program of the EMA. It is active in both programs.
In addition, Pluristem intends to make use of the accelerated pathways offered for regenerative therapies in both the U.S. and in South Korea.
Cade Hildreth: What products is Pluristem moving through these pathways?
Yaron Ramati: The focus of Pluristem in these programs is the advancement of PLX-PAD. Pluristem had achieved understandings with EMA and PMDA regarding the accelerated approval of PLX-PAD for the treatment of critical limb ischemia (CLI).
It is the intention of Pluristem to achieve similar understandings with FDA, EMA, PMDA and KFDA regarding the development of PLX-PAD for the treatment of patients following hip fractures.
Cade Hildreth: How has Pluristem benefited from these pathways (shortened time to market, mitigated risk, added company value, etc.)?
Yaron Ramati: PLX-PAD was accepted into the EMA adaptive pathways pilot program in 2015. Since then, Pluristem has taken advantage of this program in coming to an understanding with the EMA on the desired regulatory path of PLX-PAD in CLI. In addition, Pluristem undertook parallel scientific advice with the EMA and leading health technology assessment (HTA) bodies in Europe.
In this meeting, Pluristem received valuable feedback on the expectations that these bodies have for purposes of reimbursement in Europe. Pluristem has designed the Phase 3 PACE study in CLI patients in view of the feedback received from both the EMA and the HTA bodies, with the purpose of addressing their respective expectations.