The price of liberalism

The powerful effect of Japanese stem cell policy

The potent effects of Japan’s stem-cell policies David Cyranoski, Nature

Translation: InoSMI.RU

Stem cell clinics are popular in Japan. The state allowed them by law. And now the authorities around the world are being pressured by supporters of regenerative medicine, demanding easier certification. The author of the article is skeptical, he points to one fatal case and two tragic cases of vision loss.

Two floors above an expensive French pastry shop, next to nail salons and jewelry workshops, in the most fashionable area of Tokyo, the clinic "Helen" is hidden. They treat cardiovascular diseases with injections of stem cells. Fashionably dressed receptionists with large bows on their collars meet medical tourists from China and escort them past the aquarium to the examination rooms.

Treatment usually begins with doctors taking a biopsy of the skin behind the ear and extracting stem cells from adipose tissue. Then the cells are multiplied and injected intravenously. It is claimed that they repair damaged areas themselves – in this case, arteries hardened by atherosclerosis.

Posters on the wall promise promising results, they are echoed by large pharmaceutical companies and publications in leading scientific journals. They give solidity, although there is not a word about the treatment offered by the clinic in any of these magazines about what means the results are achieved. When one visitor (without introducing himself as a journalist) demanded details, the receptionist admitted that she did not have evidence of the effectiveness of this particular treatment, referring to the fact that everything is individual. As she explained, these procedures are done more for prevention. "It's to prevent aging," she explained.

There is no winner in the stem cell race

When a Nature correspondent later contacted the company, armed with a whole list of questions, its representative refused to provide both evidence of the effectiveness of treatment and basic information about the number of patients, noting that this information would soon be made public at the presentation. At the same time, he assured that the Helen clinic had passed all the necessary checks, that its procedures were approved by law, and not a single patient complained of side effects.

Clinics like this one offer untested stem cell therapies. This is not news, and the matter is not limited to Japan alone. A huge number of them have bred all over the world – from Mexico to Ukraine, India and Australia, and the supervisory authorities barely keep up with them. In the United States, the authorities are faced with a real influx of clinics that offer unapproved drugs that do more harm than good to patients. In Japan, however, the matter has taken a completely dangerous turn: stem cells are not only not banned, but are also promoted in every possible way in the highest echelons of power. And the reason for this is a couple of laws designed to stimulate business and bring Japan to the leaders of regenerative medicine.

The laws came into force five years ago, and now hundreds of clinics across the country offer more than 3,700 types of stem cell-based procedures. Foreign companies are also opening their branches. "Japan has become a hub for the development of innovative therapies," says Gil Van Bokkelen, executive director of the biotech company Athersys from Cleveland, Ohio. She is conducting clinical trials of a Japanese method of treating stroke and respiratory diseases with stem cells.

At the same time, many companies are looking for a loophole in the law in order to bring their methods and drugs to the market as soon as possible, bypassing thorough testing. Scientists suspect that patients in this case lose their chances of healing. Even methods of treating serious diseases receive a certificate, despite the paucity of evidence. Meanwhile, four cases of serious side effects have already been registered, as well as one death. Even scientists from state institutions and supporters of the existing legislation recognize that there is a need for changes in the laws.

The clinics say they fully comply with the law. And officials say that the Japanese system is still more reliable than others, because the results are closely monitored. But such an approach can inspire people with false hope for recovery.

Meanwhile, the bold experiment of liberalizing the market has found followers. Taiwan and India have already followed the Japanese example. The authorities around the world are increasingly under pressure from companies, patients and advocates of regenerative medicine to facilitate and speed up the certification procedure. "If different norms and standards arise around the world, this will be a really big problem," says Peter Marks, director of the Center for Biological Assessment and Research at the The U.S. Food and Drug Administration.

Cardiologist Yoshiki Yui from Kyoto University, an implacable opponent of the Japanese system, believes that the legislation, even if it gave an incentive to business, was a short-sighted step. "No one thought what would happen if something went wrong," Yui frowns.

Safety, but not efficiency

Barely taking office in December 2012, Japanese Prime Minister Shinzo Abe promised to invest 110 billion yen ($1 billion) in regenerative medicine over the next decade. A few months before this decisive step , Shinya Yamanaka from Kyoto University received the Nobel Prize in Physiology or Medicine for induced pluripotent stem cells. Abe boasted that Japan has become a world leader in the field of regenerative medicine, but complained about the slow pace of clinical trials. Hoping to reverse the situation, he soon announced two measures.

The first of them, the Regenerative Medicine Safety Act (ASRM), was adopted in November 2014. He allowed hospitals and clinics to treat patients with cell therapy that failed standard tests. It is only enough for the hospital cell processing center to receive a certificate from the Ministry of Health. In addition, the treatment method must be approved by an independent committee, also certified.

Clinic registration is not a guarantee

Previously, fraudulent clinics, where medical tourists were simply swindled, were not uncommon. The new law requires universal registration in order to avoid any surprises, explains ophthalmologist Masae Takahashi, a prominent member of the Japanese Society of Regenerative Medicine and a member of the advisory council to the government. "The idea was to include all applicants, and then gradually eliminate those who do not deserve it," she says.

Critics believe that the benefits of such a registry are deceptive. However, Doug Sipp, an expert on regulatory policy at the Institute of Physico-Chemical Research in Kobe, says that there is more clarity: even outright crooks had to pull up to the basic level. But there is a risk that in the eyes of patients, the registry will become "a kind of quality mark," he notes.

For example, the fashionable Tokyo clinic "Avenue" (Avenue) looks more like a spa than a medical center. The fact that her methods of treatment are listed in the register is reported immediately, in the most prominent place. At least ten of her patients received fat stem cell injections to treat the progressive neurodegenerative disorder, amyotrophic lateral sclerosis (ALS).

A representative of Avenue, in response to inquiries by phone, said that after therapy worth 1.5 million yen per session, the condition of 50-70% of patients improved. With a favorable outcome, repeated injections are recommended every two to three months. "Some can afford it," the representative said. In total, the clinic receives about a thousand patients a year.

There is simply no evidence of effectiveness

Five scientists involved in the treatment of ALS with the help of regenerative medicine admitted that there is no convincing evidence of the effectiveness of stem cells. Moreover, they reported, there are several reasons to think that they do not work in principle. Robert Baloh, from the Cedar-Sinai Institute of Regenerative Medicine in Los Angeles, California, stated bluntly: "Quackery has been sold to patients for hundreds of years, and this method is no different from them." The Avenue Clinic declined an official request for an interview from the Nature magazine, but noted in an email that its methods were included in the register. When we referred to the opinion of scientists on the treatment of ALS, we were informed that the medical staff of the clinic is busy with procedures and is currently unavailable.

In addition to the actual effectiveness of the methods, there are concerns about the qualifications and independence of the committees that approve the procedures before being included in the register. The Ministry of Health requires that these committees consist of five to eight specialists, including in cell biology, regenerative medicine, clinical research and cell cultures. The participation of lawyers, biological ethics specialists and statisticians is also required. The problem of conflict of interest, consider, is not regulated.

For example, the clinic "Helen" had its own committee, which successfully approved some of its methods, including the treatment of atherosclerosis. A representative of the company says that this therapy has never been prescribed to patients, and now the clinic is already turning to an independent third-party committee. The Ministry of Health says the internal committee was dissolved in March. In Avenue, the treatment of BOS and other procedures was approved by a committee, which includes a full-time doctor. The clinic did not answer our questions.

In April, the Ministry made sure that such conflicts stopped. But clinics are seeking permission even from completely independent committees. Yoji Sato, head of the cell therapy department at the Japanese National Institute of Medical Sciences in Kawasaki and himself a member of two committees, admits that many "jump from committee to committee." "Sometimes there is a conflict of interest, sometimes the procedures are ineffective, but at the moment this is all we can do," says Sato.

Nevertheless, he argues, the Japanese system is superior to the American one, where the supervisory authorities have lost their feet chasing scammers. Sato cites an example of a case where two people lost their sight after an unapproved stem cell treatment in Florida. It took the authorities four years of agonizing litigation to close the clinic. In Japan, those who work without the approval of the committee "will simply be taken to the police," says Sato.

Conditional approval

Another important practice that the Abe government established in 2014 is known as The Law on Pharmaceutical and Medical Devices. According to it, the company can get "conditional approval" for the sale of treatment throughout the country – not limited to one clinic or hospital – and the costs will be covered by the insurance system. In this case, the firm will have to provide performance harassment based on brief clinical trials. After that, the procedures can be prescribed for seven years, because it is believed that during this time the company collects new data on their effectiveness. So far, conditional approval is issued for three types of diseases: these are spinal cord injuries, cardiovascular diseases and ischemic limb disease. This extreme painful condition is characterized by a decrease in blood flow to the extremities.

But the shortened terms of clinical trials worry the scientific community. A 2016 report by the International Society for Stem Cell Research states that approval after brief trials threatens to undermine the rigor of the assessment and "undermine confidence in scientific standards."

Side effects

There is isolated evidence of side effects. One person, who asked not to be named, tried the HeartSheet method for the treatment of chronic heart disease. He learned about it from a news release in 2012. Moreover, this is not stem cell treatment in the strict sense of the word. A thin sheet of tissue is formed from the muscle cells extracted from the patient's thigh and placed on the damaged heart during chest surgery. Yoshiki Sava, a surgeon at Osaka University and co-author of the technique, assured the man that it would suit him perfectly.

At first, the man was doubtful, because for the treatment of his disease – it is called dilated cardiomyopathy – this method has not been used until now. In addition, he has never had heart surgery. But I decided to try.

According to him, the improvement has not come. Moreover, nine months later he began to suffer from shortness of breath, which had not happened before. A month later, he was admitted to the hospital with heart failure. And a month later, the attack was repeated.

As a result, about a year later he was informed that a heart transplant was required. "I was told that my condition was getting worse, but whether the procedure was to blame is unclear," he says.

Without additional information, it is impossible to say whether the HeartSheet procedure caused heart failure. In the end, this is only a special case, other explanations are possible. But uncertainty is only part of the problem. Only seven people participated in clinical trials for the certificate. Almost nothing is known about the frequency and severity of side effects.

Heated debates are simmering around random tests with placebo control. Actually, this is a generally accepted standard of clinical research, but the government has followed the regenerative medicine society in this matter. And there, in 2012, they said that in clinical tests of new treatments, it is not at all necessary to have a control group that receives a placebo or traditional treatment.

Sava stated that in natural conditions, the disease of the aforementioned patient is only progressing. Five out of seven people who received the HeartSheet did not have a worse condition, so it seemed that the treatment helped. However, a study of approximately 3,500 people showed that the condition of most people with similar cardiovascular diseases improves or stabilizes without radical intervention. Sava did not respond to a request for comment.

Placebo raises moral questions

However, with regard to placebo-controlled tests, the Japanese Ministry of Health stands its ground. After the method of treating spinal cord injuries, which was named STR01 and went on sale in May, was criticized, Shinji Miyamoto, a representative of the Ministry of Health, said that double-blind experiments were "structurally impossible" and that fictitious treatment or placebo would only "raise moral questions."

Biological ethicists have long discussed the potential harm of fictitious treatment in clinical trials and how fair it is to patients. Some procedures are too invasive, says Jonathan Kimmelman, a bioethicist from McGill University in Montreal, Canada. He advised the Japanese government on clinical trials. But doctors investigating the treatment of spinal cord injuries with stem cells say that placebo-controlled tests do not cause difficulties in this case.

Osamu Hongmou, a neurosurgeon at Sapporo Medical University who offers STR01 treatment, has previously defended the effectiveness of double-blind placebo-controlled tests to prove the effectiveness of treatment in people who have suffered a stroke. In a 2016 publication, he hoped that by now they would become common practice. However, he did not respond to Natcher's request to clarify their expediency for treating the consequences of a stroke, but not spinal injuries. A representative of the Ministry of Health says that in the latter case, a fictitious procedure is unethical, since treatment must be carried out within a certain period of time, and when the "window" closes, therapy will be less effective. From this, however, it follows that the treatment itself is beneficial.

Several prominent Japanese scientists have told Natcher that the STR01 procedure, also known as Stemirac, is not suitable for the treatment of spinal cord injuries and does not deserve a certificate. "Abe's office urgently needed success in science, and not just one," explained one cardiologist who wished to remain anonymous. – They act too persistently there." The administration did not respond to a request for comment.

Global ambitions

Despite the flaws in the system, Japan is trying to ensure that its regenerative medicine regulations become a standard in other countries, in particular, in order to secure a market for its methods. According to the five-year plan published in March of this year by the Department of the Ministry of Health for the Regulation of medicines, the government finances information programs aimed at "spreading the Japanese model of regulation of regenerative medicine products, strengthening trust in Japanese supervisory authorities and the introduction of Japanese regulations in other countries."

Apparently, these efforts have already begun to bear fruit, says Sato. Taiwan formulated its law on conditional approval of regenerative drugs according to the Japanese model, and South Korea in August approved a system similar to the Japanese one. The Japanese system was also mentioned during discussions in India – after which the first conditional approval for regenerative procedures was granted in the country in 2015. Already this year, mainland China announced plans to give hospitals complete freedom in using stem cells as a medicine. "A number of countries have followed the example of Japan, sacrificing the welfare of patients for the sake of a misconception about economic competitiveness," Sipp believes.

Is leaving the EU a chance for such clinics in Britain?

Some expect to see a similar system in the UK, noting that now is the best time for this – in connection with the country's exit from the European Union. As stated in February 2018 in an interview with the BBC, Ajahn Reginald, co-founder and CEO of the company from Stratford-upon-Avon "Celixir" (Celixir), which deals with cell therapy "Heartcel" (Heartcel) for the treatment of heart diseases, Brexit is a chance for the UK to go its own way and significantly simplify the supervisory legislation.

"Many in the UK are excited to look at the Japanese model," says Patricia Murray, a specialist in stem cell biology at the University of Liverpool. According to her, the liberalization of the market on the Japanese model will allow companies to "sell their fake treatments directly to consumers."

Too hasty development has already become a headache for the supervisory authorities of other countries. The U.S. Food and Drug Administration is under increasing pressure from companies and consumer organizations to switch to the Japanese model. The same demands are made by the California Institute of Regenerative Medicine and the conservative analytical center Heartland Institute.

Marx foresees difficulties. People can always refer to Japan and complain: "Guys, you don't approve of anything at all." At a May conference on medical journalism in Baltimore, Maryland, he confirmed that his office is pushing for new treatments to become more accessible. "We just want to make sure they're safe and effective."

Advantages of Japanese pressure

Lee Buckler, Executive Director of RepliCel in Moscow Vancouver, Canada – in 2016, she licensed her skin rejuvenation product from the Tokyo cosmetics company Shiseido – she sees a lot of advantages in this pressure. People see what is happening in Japan, he says, and "make sure that everything is just as accessible in their country."

Pride in Japanese achievements in the field of stem cell biology and regenerative medicine predetermined the further development of the industry. But Yamanaka, one of the key figures in this area, looks at the policy of deregulation calmly.

Despite the rapid changes in other parts of the country, the Yamanaki Institute, which is engaged in the practical application of stem cells, does not seem to be in a hurry with clinical trials. "Double–blind control should be carried out whenever possible," Yamanaka believes. And although he admits that this may be difficult for some types of cell therapy, even then scientists should "do everything possible to achieve as much objectivity and scientific approach as possible."

Some stem cell researchers believe that it is difficult to figure out who to trust and who not without objective and strictly scientific measures. "It's a problem," Takahashi admits. "The law was invented for good people. But there are a lot of bad ones." Nevertheless, she is optimistic about the future. "In ten years, cell therapy will reach a decent level. In the meantime, we will tolerate criticism."

Portal "Eternal youth" http://vechnayamolodost.ru