Chief among their worries is insufficient evidence that the therapy works.
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.
“This is an unprecedented revolution of science and medicine, which will open a new era of healthcare,” says oncologist Masanori Fukushima, head of the Translational Research Informatics Center, a Japanese government organization in Kobe that has been giving advice and support to the project for more than a decade.
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.
Path to approval
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.
One of the inventors of the treatment, neurosurgeon Osamu Honmou of Sapporo Medical University in Japan, says he is preparing to publish a scientific paper that will discuss the clinical-trial and safety issues. “I think it is very safe.” He says he did not do a double-blinded study because Japan’s regulations do not require it. “The most important point is that the efficacy is dramatic and definitive,” says Fukushima.
The unpublished results describe a trial of 13 people, who had experienced spinal-cord injuries in the past 40 days. The team found that infusions of stem cells extracted from the patients’ bone marrow helped them to regain some lost sensation and movement.
On the basis of these results, Japan’s health ministry last month gave conditional approval for the treatment, called Stemirac. It is made by extracting mesenchymal stem cells from a person and multiplying them in the lab. In the clinical trial, about 50 million to 200 million MSCs were intravenously infused back into patients 40 days after their injury to help repair the damage. 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. People could start paying for the treatment in the next few months.
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.
Mode of action
Honmou says that after 6 months, 12 of the 13 patients improved by at least one level on the American Spinal Injury Association impairment scale, an internationally recognized system that ranks people’s ability to contract muscles and sense touch on parts of the body.
The team thinks the stem cells might repair damage to the spinal cord through any of several mechanisms, including reducing inflammation and protecting existing neurons. They also say that some of the infused stem cells develop into neurons that can replace those damaged in the injury. Honmou says that he and others have demonstrated these mechanisms in animal studies1.
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 proteins2,3, 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.
Jeffery Kocsis, a neurologist at Yale University in New Haven, Connecticut, who has been collaborating with Honmou and others on the team for more than 20 years, calls the results “potentially interesting” . “While use of these cells may [have some] benefit,” he says, “continued work will be necessary to fully substantiate efficacy.”
Burden of proof
Some of the independent scientists also expressed concerns about the lack of double-blinding. This is the gold standard for assessing a treatment’s efficacy, because neither the physicians nor patients know who is receiving the experimental treatment. As a result, it reduces bias that could prevent scientists from discovering whether a treatment works, says Guest. 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.
Fukushima, however, says that the consistent improvement and high rate of success in their trial patients — even among those who were judged to have no hope of recovery — is “unprecedented”. This could not have been achieved by natural healing with rehabilitation, 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.
Nature 565, 544-545 (2019)