In 2015, Shinji Kusachi, a 47-year-old teacher living in the Japanese prefecture of Okayama, was high-diving at a local pool — a passion he had developed in his 30s — when a tricky dive went awry. “I hit my head on the bottom,” Kusachi recalled of the incident that damaged his spinal cord and left him mostly paralysed. “They said I couldn’t use my arms and legs. I was really in despair.”
But Kusachi soon joined a clinical trial for a new treatment for spinal cord injuries called Stemirac. Researchers at Sapporo Medical University drew fluid from his bone marrow, isolated a type of stem cell found there, multiplied the cells in the lab, and infused them back into his bloodstream intravenously. The day after the treatment, Kusachi dramatically improved. “That was a real surprise to us,” said Toshihiko Yamashita, an orthopaedic surgeon at the university. “In the afternoon, he could rise up from his bed and sit. In the evening, he was getting around in a wheelchair.”
The improvement continued. Seven months after the injection, Kusachi left the hospital under his own power. Today, although control of his hands and feet is still clumsy, he cooks, drives, and teaches math online — all thanks, he says, to Stemirac.
The Japanese health ministry approved Stemirac last December, and the treatment is now available to the Japanese public, with most of the $140,000 cost covered by the country’s universal National Health Insurance. It’s arguably the world’s most ambitious approved stem cell treatment and should have been a cause for celebration: a long-awaited breakthrough for the field of regenerative medicine — using modern biological tools to repair the body — and a harbinger of more impressive medicines.
Instead, the therapy has been met with a heated debate. On one side, many experts have slammed Stemirac’s approval in uncommonly direct terms, saying there isn’t enough evidence to show it is effective or even safe. The treatment went through an expedited approval unique to Japan: After short, small clinical trials that suggest safety and efficacy, regulators can approve stem cell treatments on a conditional basis — allowing use of the treatments for seven years, while sponsors gather additional evidence to support a full approval.
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Critics also say Japan’s approach is far too soft — that early approvals allow patients to take experimental therapies that could be ineffective or dangerous, at a high cost to both patients and insurance providers. “This is essentially an unproven therapy,” said Arnold Kriegstein, a stem cell researcher at the University of California, San Francisco. “I’m very surprised this is happening in a country like Japan.” Doug Sipp, a policy researcher at the RIKEN Center for Biosystems Dynamics Research in Kobe, and a colleague at the University of Sussex argued in the August 16th issue of Science that the new approval system is the result of countries competing to approve therapies faster, which raises the risk of mistakes.
Meanwhile, proponents of the new approval system, especially libertarian critics of traditional drug regulation, say it points to the future of medical innovation not only in Japan but also in the United States and other technologically advanced countries.
On one level, the debate would seem to hinge on an empirical question: What is the fastest, surest way to identify the safest, most effective treatments and medicines? But critics of Japan’s approach suggest that the answers aren’t always so simple, and that health care systems, by definition, need to more carefully weigh the many tradeoffs between safety and innovation, as well as who gets to decide which matters more.
Japan’s conditional approval system traces a spiritual lineage to American libertarian thought, like the Nobel Prize-winning economist Milton Friedman’s 1979 book ”Free to Choose: A Personal Statement,” co-authored with his wife Rose. Friedman later summarised one of his more controversial arguments: “The [Food and Drug Administration (FDA)] has already done enormous harm to the health of the American public by greatly increasing the costs of pharmaceutical research, thereby reducing the supply of new and effective drugs, and by delaying the approval of such drugs as survive the tortuous FDA process.”
Subsequent libertarian writers put a finer point on Friedman’s argument. Daniel Klein, an economist at George Mason University, said the FDA erred by barring pharma companies from advertising aspirin to prevent heart attacks. “The FDA surely killed tens, and quite possibly hundreds, of thousands of Americans by this restriction alone,” he wrote in 2000.
A decade later, free market advocate Bartley Madden advanced a proposal for speeding the drug-approval process in a book called “Free to Choose Medicine,” published by the Heartland Institute, a libertarian think tank. The centrepiece: a system of expedited, conditional approvals based on small clinical trials hinting at safety and efficacy. Masaru Uchiyama, the president of the right-leaning advocacy group Japanese for Tax Reform, had the proposal translated into Japanese and sent 800 copies to government officials, health care professionals, researchers, and patient groups. Soon, the staff of Japan’s drug regulating agency were mentioning the idea in presentations, according to Sipp.
In Japan, “Free to Choose Medicine” found a welcome home: a country looking for a comeback. While remaining a prosperous country with the world’s third-largest economy, Japan is in something of an economic malaise that’s lasted for much of three decades. The population is the second-oldest in the world, behind Monaco, and it’s shrinking; the economy trundles through what Bank of Japan Governor Haruhiko Kuroda dubbed a “deflationary mindset” stemming from what are often referred to as the “lost decades” after the post-war boom; and after pacing the technology world in the 1980s, Japan was late to tech revolutions like the personal computer and smartphone.
But in 2007, an opportunity opened when Kyoto University researcher Shinya Yamanaka showed how to reprogram adult skin cells to potentially become almost any part of the body. His discovery of this capability in mice the previous year would go on to win Yamanaka a Nobel Prize.
This made-in-Japan discovery provided a technological edge. “Stem cells were relatively new, and the Japanese government was very excited to hear about iPS cells for humans,” said University of Tokyo medical sociologist Kaori Muto. Yamanaka’s “cells were the great hope for the Japanese government and scientists to become number one again.” When Shinzo Abe became prime minister in 2012, the government prioritised stem cell science, pledging to commit more than a billion dollars to relevant research. The treatments would be useful worldwide but especially so in ageing Japan; successful biotech businesses would help goose the economy; and a scientific triumph would help restore the nation’s technical reputation and confidence.
But creating and testing stem cell treatments promised to be long and expensive. So in 2014, the government adopted an accelerated approval system for regenerative medicines, much like the proposal in “Free to Choose Medicine.” The approach has already succeeded in one goal: drawing the attention of pharmaceutical and biotech companies with the promise to get drugs on the market quickly.
“Instead of having to go to the market, saying, ‘Hey investors, can you pony up an extra $50 million to fund our clinical trial?’, companies can get conditional approval far more easily,” said Colin Lee Novick, a regenerative medicine consultant at CJ Partners in Tokyo. “It’s an extremely attractive proposition to a small biotech.” Already, foreign companies, including Athersys, TiGenix, and Pluristem, are looking to debut new drugs in Japan and collaborating with companies there to create new regenerative medicines.
So far, only three treatments have earned conditional approval, but the government aims to add to the list. Japan’s economic development ministry has estimated that regenerative medicine will be a $10 billion market in the country by 2030.
As Japan opened the door wide for regenerative medicines, it also let in a flood of criticism. A news piece in Nature in January revealed the depth of the concerns, pulling together stunned reactions from 10 experts. The researchers criticised multiple aspects of the trial: its small sise (13 patients), its lack of blinding and placebos (everyone involved knew the subjects received an experimental treatment), its unconvincing explanation (one supposed mechanism was discounted by researchers years ago), and the fact that its results, while publicised in the media, were not published in a journal.
“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,” James Guest, a neurosurgeon at the University of Miami, told Nature.
What’s more, UCLA neurologist Bruce Dobkin told Undark, the results briefly reported in the media may suggest the treatment doesn’t even work. Dobkin pointed to previous trials testing other potential treatments for spinal cord injuries, and the Stemirac findings “are exactly the results we found in patients in randomised controlled trials — in the control groups,” he said. That is, patients injected with Stemirac seemed to do as well as patients who got placebos in these earlier trials. He says people who have recently suffered spinal cord injuries, like Kusachi, the injured high diver, and the others in the Stemirac trial, often have significant natural improvement over the next several months — exactly the period covered by the trial. It’s possible the patients were simply healing naturally, he says, but without a control group and double-blinding, it is hard to tell.
Sipp said this problem was preventable. The researchers “could have easily used a placebo,” he said. “Stemirac is an infusion” — simple to fake for a placebo group. “Why didn’t they? They said they didn’t need to do it to get conditional approval.”
Japan’s approval system also lacked transparency, which invited more criticism. “The most serious problem of the Sapporo Medical [University] group is that they have not published enough data about the spinal cord injury treatment,” said Norio Nakatsuji, a long-time stem cell researcher at Kyoto University. “In any case, treatment has been carried out only in one hospital by one group. The conditionally approved trial will be also at only the same hospital. Thus, lack of transparency and opportunity of critical examination and discussion of the medical data is worrying.”
The Sapporo researchers declined to publish their results at the request of the Japanese health ministry, reportedly because officials said doing so could constitute promotion of the treatment. Yet the Stemirac researchers and trial patients — including Kusachi — participated in a documentary on NHK, Japan’s public broadcaster, hailing the treatment as a wondrous medical revolution. The documentary closes with a narrator saying: “What was once lost has been recovered. The era of regenerative medicine is here.”
In 2015, researchers at Sapporo Medical University Hospital (shown here) removed fluid from Shinji Kusachi’s bone marrow as part of a new spinal cord injury treatment called Stemirac. Photo: Sapporo
Some experts were unimpressed or even alarmed by the documentary. For instance, Jun Takahashi, a stem cell researcher at Kyoto University, tweeted that “the treatment of the science-related content seems indulgent and overly optimistic,” before launching into a tweet thread criticising various parts of the Stemirac study. A Nature editorial published in January said that publicly promoting Stemirac while declining to publish the data in a journal was “Kafkaesque.”
Considering the lack of solid evidence in initial fast-track studies, their success may come down to how well drugs are studied after the conditional approval, when researchers are supposed to justify permanent approval. But this approach has a spotty track record. “Post-marketing study is a pain in the ass, and it’s rightly called PMS,” said Novick. Last year, an Undark investigation found that drugmakers frequently fail to perform the follow-up studies they promise to, while “the FDA seems to be paying scant attention.” The Japanese government has laid out some principles for studying regenerative medicines after conditional approval, but the process doesn’t seem to require large randomised controlled trials.
Historically, without those trials, it’s been difficult to resolve questions about whether a drug truly works. For instance, decades after the FDA’s initial opposition to advertising aspirin for heart health, a series of clinical studies finally bore out the agency’s position. The FDA’s ban on advertising aspirin didn’t, it seems, kill tens of thousands of people, as Klein argued in 2000. And in 2004, Merck had to pull the popular pain medication Vioxx off the market when a new randomised, controlled trialwith more than 2,500 subjects showed that it nearly doubled the likelihood of heart attacks and strokes. An official in the FDA’s Office of Drug Safety estimated that Vioxx killed up to 55,000 people.
If regenerative medicines like Stemirac don’t go through similar large, controlled studies, it’s possible that the public will never know whether they truly work or have any side effects.
Though the specifics of Japan’s fast-track system are unique, the country isn’t alone in relaxing drug regulations. Ever since Friedman questioned the need for the FDA in the 1970s, the agency has faced a rising drumbeat of calls to get out of the way. This reached a crescendo in the 1980s, when patients were desperate for any treatment that could slow the progression of AIDS. After sharp and public criticism, the FDA created Parallel Track, a scheme that let patients with AIDS take experimental drugs, and launched a similar program called Expanded Access — often referred to as compassionate use — for other terminal diseases.
Since then, the FDA has created a patchwork of alternative pathways to speed up drug approval: Fast Track, Priority Review, Breakthrough Therapy, and Accelerated Approval, the last of which shares features with Japan’s conditional approval structure. Congress has also picked up the deregulatory banner. In 2016, for instance, it passed the 21st Century Cures Act, which created a new category for promising regenerative medicines and may accelerate commercialisation. And last year, President Trump signed the Right to Try Act, which, like compassionate use, aims to provide experimental medicines to people with hard-to-treat diseases.
These changes are part of a broader shift away from regulation, as the FDA has dramatically loosened rules on dietary supplements, drug advertising, and stem cell clinics, the latter of which have spread across the country with barely any regulatory oversight. The treatments have little research backing and most experts think they’re wholly ineffective.
“What breaks my heart is that people who are hard-working are doing crowdfunding, asking their neighbours, their families and friends for money to go down to the mall, to clinics where stem cells are advertised in the newspaper, and get their osteoarthritis treated, or indeed their migraines, or their kid’s autism, or cerebral palsy,” University of Sydney stem cell researcher John Rasko told Medscape in February. “They’re treated at $5,000, $10,000, $20,000 a pop.” By absorbing those health care dollars, bunk treatments can crowd out effective ones. “If you’re spending it on futile therapeutics that have never been proven, then you ain’t spending it on things that I would suggest are going to do better,” Rasko said.
Deregulation has also changed people’s relationships to medicine. Patients are now health care consumers and have more say over their medical decisions than at any other time in the modern era, giving the freedom to pursue pointless treatments and a powerful voice to demand them. “Recently I’ve gotten many emails that reflect almost entitlement. ‘Why do I have to go to Mexico? Why can’t I do this in the US?” said Kriegstein. “Patients feel they have a right to these treatments even before they’ve been shown to be effective. I think that kind of attitude can actually change policy on a federal level, and I see this as a very alarming trend.”
The freedom to choose medicine also comes with the freedom of providers to market specious drugs, which “engenders false hope in miracle cures and leads to cynicism about the value of research,” wrote Sipp, Rasko, and another colleague in a comment in Nature in 2017.
The freedom to choose medicine also comes with the freedom of providers to market specious drugs. Photo: Srdjan Zivulovic via Reuters.
Considering the trends toward individual choice, the move toward deregulation won’t likely abate anytime soon. Yoshihide Esaki, a senior member of the Japanese economic development ministry who helped create the expedited system, says the government is looking to expand it to all medicines. “This time we focused on regenerative medicine, but this was only a first step to changing the medical field,” he said in an interview at an industry conference in 2015. “Our next target is changing the total system for clinical trials.”
Free market advocates are using Japan’s example to try to open up the American system even more. “The US can continue to pass occasional legislation that does not encounter much political opposition and makes small incremental improvements. If so, we can get ready for worldwide leadership in biopharmaceutical research to begin shifting to Japan,” wrote Madden, the author of “Free to Choose Medicine,” and Nobel-winning economist Vernon Smith in a 2015 Forbes column.
The free market advocacy is gaining traction. In a Heartland Institute policy brief published in March, Edward Hudgins called on the FDA to enact Free to Choose Medicine, which would, among other things, effectively expand the AIDS Parallel Track and get experimental drugs to patients with “debilitating diseases” like “Alzheimer’s, ALS, Parkinson’s, cancers of various kinds.” Soon after, Ted Cruz and three other US Senators wrote a letter to the FDA calling on it to expand the AIDS Parallel Track to get experimental drugs to patients with “devastating diseases” like “Alzheimer’s disease, cancer, and amyotrophic lateral sclerosis (ALS).”
It’s hard to say how far this change will go in Japan or in the US, but it’s clear the balance is tipping from scepticism and a focus on patients toward boosterism and a focus on consumers. “If the US ramps up approvals, Japan might respond with more,” said Sipp. “A race to the bottom would be serious and very bad; we could go back to the days when most medical products didn’t work.”
Amos Zeeberg is a freelance journalist based in Phnom Penh, Cambodia, whose work has appeared in publications including The New Yorker, The Atlantic, and Discover.