Japan stem cell oversight system too lax?

The HeartSheet product shown here is advancing in the pipeline rapidly in part due to the Japan system of conditional approval of stem cells
The HeartSheet product shown here is advancing in the pipeline rapidly in part due to the Japan system of conditional approval of stem cells

The Japan stem cell and regenerative medicine oversight system has been designed to move investigational therapies forward fast, much faster than the systems in other countries such as the U.S. But how well is it working so far?

It’s an important question both for that country and more globally as the Japanese system was touted by some as a model and a reason why the U.S., to remain more competitive in this industry. Some of the same folks felt that the U.S. should also adopt a conditional approval approach and lobbied in past years for the REGROW Act. I felt REGROW was an extremely risky piece of legislation, especially in its initial incarnations. The regenerative medicine provisions in the 21st Century Cures Act, which became law, were more measured and balanced. We’ll see how it turns out now that it is being implemented in a practical sense in the real world. In the mean time, some of us have continuing concerns that the oversight system for stem cells and regenerative medicine in Japan may be too permissive.

Within the Japanese regenerative medicine oversight system, clinical studies involving induced pluripotent stem (IPS) cells such as the one I blogged about last week for heart disease involving the so-called HeartSheet led by Yoshiki Sawa can take steps forward with less pre-clinical and/or early clinical trial data than one might expect. The news about the heart IPS cell study has generated both buzz and some criticism that it is too risky.

The critics include Nature, which in an editorial this week called for better oversight in Japan and more preliminary data before stem cell therapies are sold to patients. The editorial was subtitled strongly, “Japan needs to demonstrate that a promising therapy for damaged hearts works as claimed.” Also, the editors wrote (emphasis mine), “The government needs to move quickly to make sure that evaluation of the HeartSheet therapy is as rigorous as promised. As more treatments emerge, officials should make sure that — fast track or not — they have a valid claim to efficacy before being sold to patients.

A NatureNews piece by David Cyranoski also highlighted some concerns about this situation:

“Yoshiki Yui, a cardiologist at Japan’s Kyoto University, says that, as well as meeting the requirements for safety, researchers should show that their treatment is effective, which would require testing it in larger numbers of people than are currently required. The evaluation process should also use randomized, controlled clinical trials, the gold standard for demonstrating efficacy in medical research, he says.

The iPS-cell therapy has potential, Yui adds, but under the current approval system, “we won’t know if it works or not” because it won’t have been tested in a controlled trial. “The biggest problem is there’s no adequate system of evaluation in Japan,” says Yui.”

The Japanese government contends the current system is fine. You can see more about Yui’s concerns including from a medical science level in a piece here.

It seems to me that it is only logical that stronger proof of efficacy including data from rigorously designed studies with proper control subjects is needed at the pre-market step. Less data equals higher risk for patients even if it also means speedier clinical science progression, but the question is where is the sweet “speed” spot of risk versus potential benefit? My own view is that Japan is still somewhat leaning too far to the speedy side at the moment. That could change.

Meanwhile, stem cell oversight is evolving in interesting ways elsewhere across the globe too. For instance, here in the U.S. we have the regenerative medicine advanced therapy (RMAT) designation program, which is also a regulatory experiment in accelerating stem cell oversight but does not allow selling incompletely tested stem cell therapies to patients, and also this week we have the new Right-To-Try law that may impact the stem cell field potentially interfering with some elements of oversight.

More will be coming on Right-To-Try and stem cells in future posts.

9 Comments


  1. @Paul

    “My own view is that Japan is still somewhat leaning too far to the speedy side at the moment. That could change”.

    What could change Paul, Japan regulations or your opinion of them?


      • @Paul, in this case I believe your perspective should change. IMHO, when you look at the big picture in Japan, the biggest change has been the availability of “conditional” approval where safety MUST be demonstrated. That fact alone should allay your most dire concern — commit no harm. The fact that the government is paying 80% of any conditionally approved cell therapy means they will not grant these approvals without a thorough look at all data. It also means that, unlike in the U.S., where thousands of unregulated and unverified therapies are still being offered to desperate patients, government insurance is picking up the bulk of the cost. Convinced, LOL?


        • @WST,
          As you expected I think, no I’m not convinced.

          If I understood correctly, firms that get on a certain track of oversight can start marketing stem cell products around the equivalent of a phase II trial and there doesn’t have to be data from a blinded RTT yet.

          Also, while it is true that the gov is picking up most of the tab, is that money well-spent and patients will have to pay some too.

          Thanks for weighing in.
          Paul


  2. It’s not that I disagree with you about the need for decent oversight of medications, stem cell based or not. But here’s the catch: we now know, for a fact, what patients will do if they don’t have any hope of effective treatments on the near horizons. They will go to stem cell clinics. They will pay their life savings for treatments which are ineffective at best and crippling at worst. This will happen is it does happen. We’re at this point with stem cell medicine because of a lot of factors that have fed into each other over a long period of time, many avoidable, some not. But however we got here, we are here now. This is exactly what I’ve been talking about for a long time, the point where desperate patients don’t have the luxury of waiting and will not wait. I think that a lot of the time, people know very well that treatments at stem cell clinics are extremely unlikely to work even in the best case scenario.

    But it’s a measure of this desperation that they will put down their money anyway, because there is no other choice. People will support questionable Right to Try laws because there is no other choice. People will basically do anything when their backs are against the wall and they see no other choice. And the regulatory climate in the U.S. is weakening by the day, so there’s less and less that is keeping the bad choices from being dangled in front of people’s faces. We’ll be lucky if we even have an FDA in anything but name in ten years.

    So science and medicine have got to offer desperate people other choices that at least have research backing them up, even if the process of doing so is not perfect. Otherwise, the worst choice will win out.


    • It seems I’m just the polar opposite of you, Cathy, in terms of your take on patients, the existing regenerative medicine clinics as well as the Food and Drug Administration. I believe in patients and their decisions, not in a financially conflicted government agency that in words (rather than deeds) seems only to say that it is acting in our best interests. If patients decide to seek out alternative medical practices, then that should be respected for what it is without resorting to name calling or labeling their actions as “desperate”. Most patients are intelligent enough and can decide for themselves which protocols serve their best interests versus those that serve only people or industries already in positions of power. After all, patients are in the majority. This is not so with government agencies or even the experts who run blogs like this one and work in academic or corporate laboratories .
      I believe that you are painting with too broad a brush in your characterization of those who seek out regenerative therapies. From a personal perspective my decision to go outside the mainstream of medical practice was well researched and thought out. Despite the costs, my treatments have not broken the bank, they’ve been effective and allowed me greater mobility to get around and exercise more often. The regenerative procedures have not crippled me either. By your words, it seems to me you’ve never sought out regenerative therapies. Therefore, you do not speak for me. Hopefully you will remain healthy enough and free of arthritis in your knees and other areas never to need regenerative treatments or worse, traditionally more invasive therapies like replacement surgery. Other words in your post like “ineffective” and “crippling” seem to me very inflammatory and just not very well researched on your part particularly when describing what you call “stem cell clinics”. The clinic that I’ve frequented offers a variety of services including physical therapy, anti inflammatory or steroid injections as well as platelet rich plasma into joints. For those services involving stem cells, this clinic works with other specialists like plastic surgeons and laboratory technicians for the removal and harvesting of stem cells. However, this is only one small part of the many services they offer. Additionally, this clinic limits itself solely to orthopedic procedures and employs on its’ staff a surgeon from that specialty. To characterize them all as just “stem cell clinics” is again (to me) very shortsighted and not well researched on your part.


      • Here’s the part I didn’t say. In 2011, I had a terrifying, sudden, inexplicable attack of idiopathic macular degeneration. Eight doctors in a row said they’d never seen anything exactly like it before– including top level specialists at the retinal clinic at Oregon Health and Science University. I remember walking around in a daze, suddenly unable to see anything, nobody knowing what was going on. There seemed to be no hope. If somebody had talked to me about stem cell clinics then, I would probably have jumped at the chance. I would have tried anything.

        The doctors at the Casey Retinal Institute decided to try Avastin injections. I’m sure they didn’t expect it to work.

        But it did. I had a totally unexpected remission, and to this day, nobody knows why. I have permanent damage. I did not emerge unscarred. It’s minor compared to a lot of people with AMD, so a lot of the time, I’m able to think about how lucky I am. But I do not know what will happen next. I have to live one day at a time. My ultimate hope, and the only one I have for a real cure, is that at least one of the trials for AMD will work out and lead to a treatment.

        So I know very well indeed what the lure of unproven treatments can be. I would give ANYTHING to have only had arthritis to deal with. Sorry, and I know that doesn’t sound good at all, but it is the honest truth. If you had gone through what I did, the nightmare, the terror– believe me– you would understand. I have been there, done that, and gotten the t-shirt. I do not talk about what I do not know.

        And I ended up with a point of view that doesn’t really please anybody. I do not support experimental stem clinics. But I also can’t support moving too slowly on treatments. And I think that’s what has happened with at least one of the AMD therapies. Obviously, cases where people just weren’t helped at all are different (one of the most recent posts on this blog actually is about an AMD study where people didn’t get any positive results.) But there are studies where half of the participants had improvements and all but one at least didn’t get worse. In my opinion, that treatment should be available on a compassionate use basis right now. For a whole variety of reasons, it isn’t.

        You would likely agree with me on that, but not on my opposition to stem cell clinics. Others would agree with me on that opposition, but then they’d disagree about the compassionate use of the treatment in that AMD study. (And for people who have been following this for years… I think you know the one I’m talking about!)

        So basically, I’m not going to please anybody. But from my personal experience, I have the right to this unpopular opinion. As Martin Luther once said: I cannot and will not recant anything, for to go against conscience is neither right nor safe. Here I stand, I can do no other.


        • Hi Cathy,
          Thanks for sharing your story. You’ve been through a lot!
          I think a lot of us are looking for some kind of “sweet spot” on oversight and regulations. I have some hope for the “new” FDA under Dr. Gottlieb, but we’ll see.
          Paul


  3. I read the Nature article. It is mentioned that the transplanted cells will not integrate in the patient heart but will only provide a trophic support based on animal studies they have done. But mesenchymal cells are best to provide trophic support ! Why transplant allogeneic iPS cells derived cardiac cells?

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