On conditional approval of cell therapy products

by Alexey Bersenev on December 20, 2015 · 0 comments

in regulation

As you may know, about 2 years ago Japan has passed a new law for regulation of Regenerative Medicine. Under this law, the regulatory pathway for commercial cellular products is significantly accelerated by skipping of typical “Phase 3 trial” and allowance of marketing authorization after demonstration of safety and some (minimal) signs of efficacy (Phases 1/2). In this “accelerated scheme” the cell therapeutic candidate will be available to patients faster and company will able to generate profit and survive. It is important to keep in mind that this accelerated approval is conditional – in the next few years after market authorization, company-developer obligated to provide clinical data on efficacy. If there will be strong evidence for the efficacy, product will stay on the market. Professionals were watching this regulatory change in Japan with great interest and, most of us are very sympathetic of this approach.
Two years later, in September of 2015, the new Regenerative Medicine law yielded the first results – two cell products were approved on Japanese market. The first product is TemCell (by JCR Pharmaceuticals) – allogeneic mesenchymal stromal cells for GVHD. The second product is HeartSheet (by Terumo) – autologous skeletal muscle cells for heart failure. Two months after market authorization, both product have received price tag and reimbursement decision. TemCell is priced ~ $115,000 – $170,000 USD (depending on total number of doses infused) and HeartSheet is priced ~ $120,000 USD. Depending on insurance plans, Japanese patients will still pay out of pocket anything between 5% to 30% of the product price.

10 days ago, I was really surprised to see critical editorial in Nature journal about these milestones in new Japanese regenerative medicine regulation. The editorial called Japanese regulation as “unproven system to make patients pay for clinical trials“. Overall, tone of the article is negative:

Biotech companies in other countries are keen on the idea and have pushed their own regulatory bodies to follow Japan’s lead. This is a bad move. Regulatory agencies around the world should resist pressure to create such fast-track systems, at least until Japan has proved that its system works. That will take time. The country will have to demonstrate that its health-care system can withstand the costs of the new regenerative-medicine treatments, and that patients do not feel cheated.

First of all, I’d like to argue, that using term “clinical trial” after marketing authorization is not correct. It is not trial anymore. Patients do not pay for drugs that they received in clinical trial. And of course it is unproven at the moment, because the whole point of new legislation was to test whether system will prove itself to be effective and beneficial.

I don’t understand why patient may feel cheated, if they told about pricing/ reimbursement prior to therapy and were explained what conditional approval really means. I believe, patients able to make wise conscious decision, based on provided information. It is responsibility of product manufacturer to provide all necessary information.

I also don’t understand why if some other country would follow Japan’s path, “this is a bad move”? Aren’t governmental agencies of other countries competent and capable of making such decision? Who is Nature’s editorial author to judge? By the way, Japan did not invent a wheel here. There are few countries, which pioneered the system of conditional approvals long time before Japan. South Korean KFDA was the first to implement regulatory conditional approval system for cell products more than a decade ago (even thought, not exclusively for cellular products). Since 2001, S. Korea approved ~18 cell products on the market, most of them conditionally. Brazil, Canada and Europe have accelerated conditional approval systems in place. For example, dendritic cell-based cancer vaccine Hybricell was approved in Brazil in 2005 conditionally. Stem cell drug Prochymal was approved in Canada in 2012, conditionally. Finally, European EMA has a conditional market authorization option. All these conditional approval systems more or less similar. So, I’d argue that more likely Japan learned from other countries experience, and first of all, from South Korea.

It is not very clear right now how successful these conditional approval systems. I was trying to find any information about nearly 15-years old history of conditional approvals in S. Korea. There is almost zero publicly available information in English. However, I was able to find one failure on condition out of 18 approvals. Lymphokine activated killers product Inno-LAK (by Innomedisys) was approved conditionally by KFDA in 2007 for lung cancer. The company failed to provide additional clinical data and product was pulled off market in 2012. Based on what I’ve learned about S. Korean cell products approval, the system works quite well.

I’d also argue, that we don’t have very good example of efficient regulatory system in cell therapy/ regenerative medicine, from which both patients and product developers will benefit. So, why Nature’s editorial positions conventional FDA drug approval system as the best? FDA has a history of failures as well. Some FDA approved drugs were recalled from the market due to toxicity, some weren’t that efficacious as at point of approval. Weren’t those patients feeling cheated then by FDA’s system, which suppose to guarantee safety and efficacy? Also, I saw some articles, which argue that current (very lengthy and expensive) FDA regulatory system may not be sustainable for commercial cell therapy developers.

So, at this point, we do not know which regulatory system will work better for cell therapy/ regenerative medicine products. Neither Western (aka FDA) nor Asian (aka Korean/ Japanese) systems yet proved to be very efficient and beneficial for cell therapy field. Let’s wait one more decade to judge. As cell therapy trialist and developer I’m very happy about one thing here – right now we are witnessing unique experiment, where few countries simultaneously testing different regulatory frameworks for cell-based products. I’m eagerly awaiting results of this experiment. I’m very happy to see that Japan is moving fast. They will find out faster if the proposed law will work successfully. Other jurisdiction rather than go for “trial and error” may watch and adopt the most successful model.

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