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Author Topic: Japan’s approval of stem-cell treatment for spinal-cord injury concerns scientis  (Read 266 times)


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Nature 565(7741):544-5 (Jan 31, 2019)

Japan’s approval of stem-cell treatment for spinal-cord injury concerns scientists
Chief among their worries is insufficient evidence that the therapy works.

David Cyranoski

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"Japan has approved a stem-cell treatment for spinal-cord injuries. The event marks the first such therapy for this kind of injury to receive government approval for sale to patients."

"But independent researchers warn that the approval is premature. Ten specialists in stem-cell science or spinal-cord injuries, who were approached for comment by Nature and were not involved in the work or its commercialization, say that evidence that the treatment works is insufficient. Many of them say that the approval for the therapy, which is injected intravenously, was based on a small, poorly designed clinical trial.

"They say that the trial’s flaws — including that it was not double-blinded — make it difficult to assess the treatment’s long-term efficacy, because it is hard to rule out whether patients might have recovered naturally. And, although the cells used — known as mesenchymal stem cells (MSCs) — are thought to be safe, the infusion of stem cells into the blood has been connected with dangerous blood clots in the lungs. And all medical procedures carry risks, which makes them hard to justify unless they are proven to offer a benefit."

"That the treatment won approval to be sold to patients is concerning, says James Guest, a neurosurgeon at the Miami Project to Cure Paralysis at the University of Miami in Florida. 'This approval is an unfortunate step away from everything researchers have learned over the past 70 years about how to conduct a valid clinical trial,' he says."

"The team can market and sell the therapy as long as they collect data from the participants over the next seven years, to show that it works."

"Whereas many governments require new treatments to undergo rigorous clinical trials with hundreds of patients before the therapies can be sold, Japan has a programme to fast track the development of regenerative medicines, which approves therapies that show only hints of efficacy, on the condition that the researchers collect follow-up data."

"The claim that MSCs can become neurons, in particular, concerns some of the independent scientists Nature consulted. Studies in the early to mid 2000s found that MSCs could take on certain features of neurons, such as expressing some of the same proteins, but the idea that they can function as neurons has been widely discarded.

"So it is very unlikely that the MSCs converted to neurons in the trial, says Bruce Dobkin, a neurologist at the University of California, Los Angeles. Other studies in animals and people have found that MSCs infused intravenously tend to get stuck in the lungs. 'The fact that the cells are trapped in the lungs makes it difficult to see how they can be effective in the spinal cord,' says Pamela Robey, a stem-cell researcher at the US National Institutes of Health in Bethesda, Maryland."

"Some of the independent scientists also expressed concerns about the lack of double-blinding...Double-blinded studies can be difficult to achieve. In this case, Guest says, it would have been easy.

"Instead, the results could be explained by natural healing and physical rehabilitation in the months after an injury, says Dobkin. 'This trial, as designed, cannot reveal efficacy,' he says."

"But once the treatment is sold to patients, it will be even harder for the team to gather evidence that it is effective, says Arnold Kriegstein, a stem-cell researcher at the University of California, San Francisco. Paying for treatments can increase the likelihood that the patient will experience a placebo effect, and makes it impossible to perform a blinded trial, because people cannot be charged for a placebo procedure.

"Kriegstein worries that the product could remain on the market without ever providing evidence that it works. 'I do not think it is morally justified to charge patients for an unproven therapy that has risks,' he says."


Related editorial, pp. 535-6:

Japan should put the brakes on stem-cell sales
Unproven therapies should not be marketed to patients.

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"Meanwhile, in Japan, a more worrisome approach is unfolding. Last month, researchers at Sapporo Medical University leapfrogged all other spinal-cord injury treatments that use stem cells — including the one being investigated by Asterias — and received market approval for injections of a type of cell called a mesenchymal stem cell. There are reasons to be sceptical, or at least to delay the sale of this procedure to patients.

"The very nature of these cells — in particular, whether they function as stem cells and do turn into neurons as suggested by the Japanese group — is subject to fierce debate (D. Sipp et al. Nature 561, 455–457; 2018). The clinical trials that demonstrated efficacy were based on only 13 participants. There was no control group and the trial data remain unpublished."

"A better way would have been to run a randomized controlled clinical trial, with both participants and physicians unaware of who received the cells and who received a placebo. But under Japan’s fast-track system, researchers at the university didn’t have to do this. The researchers also should have published the clinical data already collected, but in Japan they are discouraged from doing so.

"This seems surprising. Some companies might not want to publish clinical results to protect their trade secrets. But in this case, it is Japan’s health ministry that seems to be telling researchers not to publish data."

"Japan has set up a bizarre situation. The university has made promises about the treatment in an advertisement unencumbered by data, but the inclusion of scientific evidence, in a form that the world’s experts can evaluate, is considered too potentially misleading to publish. The Kafkaesque logic at play here seems to be that promoting a medicine without data is better than promoting it with.

"The Japanese team has promised results so dramatically convincing that controlled trials would be unnecessary. Let’s hope that is the case. But it is more likely that ambiguous results from the uncontrolled trial will allow the treatment to continue in use indefinitely."
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