日本干细胞医疗产品的宽松政策和对全球的影响

2020/7/28 10:49:54 本站原创 佚名 【字体:

廖联明   编译

 

出售以细胞为基础治疗方法的诊所不是日本独有的。它们在全球已经很普遍了。然而,在日本,干细胞诊所的增加却是不同的:它得到政府高层得到批准和推广,这得益于旨在促进企业发展和将日本定位为再生医学世界领导者的两项监管法

201212月上任后不久,日本首相安倍晋三许诺在未来十年内投资1100亿日元(10亿美元)用于再生医学。在京都大学的Shinya Yamanaka因诱导多能干细胞的研究而获得诺贝尔生理学或医学奖后几个月,就采取乐观的态度。安倍吹嘘日本是再生医学研究的世界领导者,但对临床应用的缓慢进程感到遗憾。他很快宣布了两项措施,希望能改变这种状况。

再生医学为期五年的放松政策已经推动了整个行业的发展。但病人可能要为此付出代价。

日本通过这些法规5年后,全国数百家诊所获批了3700多种治疗方法,其中包括许多基于干细胞的治疗方案,并有一批外国公司在那里开设了诊所。日本已成为创新疗法研发的中心。

但是,许多公司正利用这个监管法规,来避免对其疗法进行严格的临床验证,并将其快速推向市场。科学家说,使用这些方法的病人可能得不到有效的治疗。批准用于严重疾病的大多数疗法均缺乏证据支持。即使是支持这一法规的政府研究人员和学术科学家也表示,有必要进行修改。

诊所则他们是在依法经营的。政府官员也认为,日本的医疗系统比其他国家的更安全,因为它会密切关注所提供的治疗。但这些政策可能会让人们对这些疗法的有效性抱有错误的希望。

与此同时,日本在放松管制方面的大胆尝试开始影响其他国家。例如,台湾和印度已经开始效仿该国的做法,其他地方的监管机构正感受到来自企业、患者和其他倡导者的压力,要求它们加快审批程序。

最严厉的评论家之一,日本京都大学的心脏病专家Yoshiki Yui说,这些法案使商业发展方面取得了迅速的进展,但却是目光短浅的。

                  

放松管制的两项法案

 

2014年日本出台的两项法律为干细胞治疗和其他类型的再生医学进入市场提供了一条快速通道。

其中一项是201411月通过的《再生医学安全法》(ASRM),它允许医院和诊所无需经过常规试验证明药物有效的情况下推广细胞疗法。为了开始提供这种治疗,医院需要证明他们有一个经卫生、劳动和福利部认证的细胞生产设施,然后由独立的伦理委员会通过其治疗方法,该伦理委员会也必须经卫生、劳动和福利部认证。

《再生医学安全法》允许公司在三种风险类别中的一种注册治疗。

 

分类

要求

注册治疗的数量(20196月)

第一类(低风险)

使用患者的细胞进行治疗,其功能类似于它们最初提供的功能,如激活免疫细胞以对抗癌症。

3373

第二类(中风险)

使用患者细胞进行治疗,但可发挥不同功能,例如从脂肪中提取的干细胞用于治疗动脉粥样硬化或肌萎缩性侧索硬化。

337

第三类(高风险)

使用更危险来源的细胞的治疗,如胚胎干细胞、基因编辑细胞或来自他人的细胞。

0

 

 

在立法改革之前,钻空子的诊所不断涌现,并充分利用了医疗旅游业。

但批评人士说,ASRM的注册信息可能会产生误导。在神户里肯(RIKEN)从事监管政策研究的Doug Sipp表示,这给“行业带来了更大的透明度”。它迫使这些钻空子的诊所达到一些基本标准。他说,然而,患者将把登记册视为“疗效验证”,这是一种真正的风险。

例如,位在东京的一家时尚诊所“Avenue Cell Clinic”更像是一家水疗中心,而不是医疗中心。它在其网站上特别指出它的治疗方法在ASRM注册中心可以查到。至少有10名患者已将脂肪衍生的干细胞注射入血液中,以治疗或延缓神经退行性疾病肌萎缩侧索硬化(ALS)的进程。

Avenue Cell Clinic的一位客户服务代表在电话中告诉电话咨询者,50%-70%的患者在接受治疗后症状有所改善,每剂费用为150万日元。该诊所每年约有1000名病人接受其他适应症治疗。

研究ALS再生医学的科学家们表示,没有令人信服的证据表明这种干细胞疗法可以帮助ALS患者,并有几个理由认为这种疗法不起作用。在加利福尼亚州洛杉的Cedars-Sinai再生医学研究所研究ALSRobert Baloh坦率地说:“庸医和虚假治疗已经直接向患者推销了数百年,这没有什么不同。”

除了关于证据和效力的问题外,还对批准将此类治疗方法纳入注册表的伦理委员会的资格和独立性表示担忧。卫生部要求这些伦理委员会由58人组成,包括细胞生物学、再生医学、临床研究和细胞培养方面的专家。它还需要律师、生物伦理学家和生物统计学家的意见。但委员会关于利益冲突的规定一直很宽松。

例如,Helene诊所有一个内部委员会批准了某些治疗方法,包括动脉粥样硬化的治疗。根据卫生部的说法,内部委员会在3月份被解散。由Avenue Cell Clinic提供的ALS治疗和其他几种治疗方法得到了包括职员医师在内的委员会的批准。

该部门在4月份制定了防止此类冲突的政策。但即使有完全独立的委员会,诊所也可以四处寻找能够批准他们的项目的伦理委员会他们想要的答案。佐藤洋二(Yoji Sato)是位于川崎的日本国立卫生科学研究所(National Institute of Health Sciences)细胞治疗部的负责人,也是两个委员会的成员,他说“寻找有利的伦理委员会”是一个大问题。

政府正在考虑采取额外的措施,例如通过培训以改善委员会体系。佐藤(Sato)说:“委员会成员可能存在利益冲突,也许治疗效果不好,但这是我们目前的局限。”。

不过,他认为,该体系优于美国现有的体系,美国监管机构一直在追查钻空子的诊所。佐藤(Sato)援引了两名在佛罗里达接受未经证实和未经批准的干细胞治疗后失明的患者的例子。FDA花了四年时间和一场曲折的法律斗争才阻止该公司提供这种治疗。佐藤(Sato)说,在日本,对于那些缺乏委员会批准的人,“警察可以去抓人”。

 

有条件性批准

 

安倍政府2014年实施的另一项重要政策是《药品和医疗器械法》。根据该法案,一家公司可以获得“条件批准”在全国范围内销售一种疗法,而不仅仅是在一家诊所或医院销售,而且费用由保险系统支付。与ASRM不同的是,该公司需要提供表明一个小型临床试验疗效性的数据。。公司可以出售相关产品长达7年,条件是在7年期间必须收集疗效数据,证明疗效。到目前为止,只有三种治疗方法获得了条件批准:一种用于脊髓损伤,一种用于心脏病和一种用于严重肢体缺血的治疗。

《药品和医疗器械法》允许对已经通过某些临床试验的治疗有条件的批准。它使公司有机会在全国推广治疗方法并获得保险金,但公司必须在七年内收集有关疗效的额外数据。

 

 

 

治疗产品

适应症

心肌片层

来自骨骼肌的细胞被用来植入一层组织,以帮助修复受损的心肌。

骨髓间充质干细胞

使用骨髓干细胞治疗脊髓损伤。

CLBS12

使用造血干细胞治疗严重肢体缺血。

 

 

但简化临床试验所需的批准条件已激起了科学界的关注。国际干细胞研究学会(International Society for Stem Cell Research2016年的一份报告称,在小规模试验的基础上批准上市,可能会减缓对治疗方法的严格评估,并“削弱对该领域科学标准的信心”。

日本政策争论的核心是随机、安慰剂对照试验的价值。这些通常被认为是临床研究的黄金标准,但日本政府遵循了2012年日本再生医学学会(Japanese Society for resentative Medicine)提出的立场,该立场明确指出,证明疗效的试验设计不应总是要求对照组接受安慰剂或常规疗法。

日本卫生部坚持其对再生医学产品必须采用安慰剂对照临床试验的立场。继今年5月上市的一种脊髓损伤治疗方法STR01受到批评后,卫生部代表宫本伸二(Shinji Miyamoto)辩称,对该治疗方法进行双盲实验“在理论上是不可能的”,并表示假手术或安慰剂“会引起伦理问题”。

长期以来,生物伦理学家一直在争论临床试验中虚假治疗的潜在危害,以及它们是否对参与者公平。加拿大蒙特利尔麦吉尔大学(McGill University)的生物伦理学家乔纳森金梅尔曼(Jonathan Kimmelman)曾就临床试验政策向日本政府提供过建议,他说,有些的确过于创伤性。但研究脊髓损伤干细胞疗法的医生说,对这种疾病进行安慰剂对照试验相对容易。

日本札幌医科大学神经外科医生Osamu Honmou曾提出STR01治疗方案,他曾主张进行双盲、安慰剂对照试验,以证明该疗法对中风患者的疗效。卫生部代表说,在安慰剂对照试验中,假手术是不道德的,因为病人需要在一定的时间范围内接受治疗,之后证明该治疗效果不佳。然而,这类论点的前提是认为该疗效是有效的。

日本的几位著名科学家说,STR01,也被称为Stemirac,不应该被批准用于脊髓损伤。一位心脏病专家说:“安倍内阁急需一两个在科学上取得成功的例子。”。“安倍内阁太激进了。”

 

全球目标

 

尽管该体系存在漏洞,但日本正试图让其再生医学政策在其他地区得到采用,部分原因是为了确保其治疗的市场。根据卫生部药物管制司发布的一项五年计划,政府资助了旨在“传播日本再生医学产品监管模式,增强对日本监管机构的信任,并将日本监管模式引入其他国家”的推广计划。

佐藤(Sato)说,这些努力似乎正在产生影响。台湾根据日本立法起草了再生药品有条件审批法,韩国也在8月批准了类似日本的制度。印度在2015年首次有条件批准再生医学的审议中提到了日本的制度。其他几个国家也做出了类似的回应,将经济竞争力的扭曲愿景置于病人福利之上。

一些人希望在英国也能看到类似的体系,并说,随着英国退出欧盟的临近,这个时机是正确的。在20182月接受英国广播公司(BBC)采访时,英国埃文河畔斯特拉特福德(Stratford on Avon)的Celixir公司联合创始人兼首席执行官阿詹·雷金纳德(Ajan Reginald)表示,该公司生产一种名为Heartcel的用于心脏病的细胞疗法,英国脱欧可能给英国提供一个引入加速监管途径的机会。

英国利物浦大学(University of Liverpool)干细胞生物学家帕特里夏•默里(Patricia Murray)表示:“某些英国人对采用日本模式充满热情。她说,日本的这种放松管制,“将使企业能够直接向消费者出售他们伪造的疗法”。

而快速发展的步伐也给其他地方的监管机构带来了挑战。FDA一直面临来自企业和患者团体的越来越大的压力,包括加州再生医学研究所(California Institute for resentative Medicine)和保守派智囊团Heartland Institute,要求其采取类似于日本的方法。

加拿大温哥华再生医学公司RepliCel首席执行官李·巴克尔(Lee Buckler)认为,这种压力是有利因素。RepliCel2016年向东京化妆品公司资生堂(Shiseido)授权了其嫩肤产品。他说,那些希望快速获得药品的人看到了日本正在发生的事情,并“敦促在他们的国家获得类似的药品”。

对日本在干细胞生物学和再生医学方面取得的成就所产生的自豪感在推动该行业的发展上起了很大作用。Yamanaka一直是这些成就中最突出的面孔之一,但他在放松管制方问题上一直保持沉默。

与国内其他地区快速发展的潮流形成鲜明对比的是,Yamanaka的研究所致力于将干细胞疗法引入临床,似乎不愿意仓促完成临床试验。Yamanaka对《自然》杂志说:“只要有可能,就应该考虑双盲对照。”。尽管他知道这对某些细胞疗法来说是困难的,但即使在那些情况下,“科学家们应该尽最大努力使临床试验尽可能客观和科学”。

一些干细胞研究人员说,在缺乏客观和科学的措施的情况下,很难知道该相信什么、相信谁。法律是为善良的人制定的,但也有许多人并不善良。

 

 

Nature 573, 482-485 (2019)

doi: 10.1038/d41586-019-02847-3

 

 原文:

The potent effects of Japan’s stem-cell policies

Clinics, which sell cell-based therapies, aren’t new and aren’t unique to Japan. They’ve become common globally. In Japan, however, the proliferation of stem-cell clinics is different: it is sanctioned and promoted at the top echelons of government, thanks to a pair of regulatory acts designed to stimulate business and position Japan as a world leader in regenerative medicine.

Shortly after taking office in December 2012, Japanese Prime Minister Shinzo Abe promised to invest ¥110 billion (US$1 billion) over the next decade into regenerative medicine. The bullish attitude came just months after Shinya Yamanaka at Kyoto University won the Nobel Prize in Physiology or Medicine for his work on induced pluripotent stem cells. Abe boasted that Japan is the world leader in regenerative-medicine research, but lamented the slow pace of clinical application. He soon announced two measures that he hoped would change that.

A five-year regulatory free-for-all in regenerative medicine has given the industry a boost. But patients might be paying the price.

Five years after Japan adopted these regulations, more than 3,700 treatments, including many based on stem cells, are on offer at hundreds of clinics across the country, and a wave of foreign companies has set up shop there. Japan has become a focal point for the development of innovative therapies.

Many companies, however, are taking advantage of the regulatory paths to avoid rigorous testing of their therapies and get them on the market fast. Scientists say that people who use them are probably not getting effective treatments. Most of the therapies approved for serious illnesses are supported by scant evidence. Even government researchers and academic scientists who support the regulations say that changes are necessary.

Clinics maintain that they are operating within the law. And government officials argue that Japan’s system is safer than those in other countries because it keeps tabs on the treatments being offered. But the policies might be giving people false hope about how effective these therapies are.

Meanwhile, Japan’s bold experiment in deregulation is beginning to influence others. Taiwan and India, for example, have started to follow the country’s lead, and regulators elsewhere are feeling pressure from companies, patients and other advocates to speed up the approval process.

One of the harshest critics, cardiologist Yoshiki Yui at Kyoto University in Japan, says that the acts made quick gains in terms of business development, but were short-sighted.

Deregulation in two acts

 

Two laws introduced in Japan in 2014 offer a fast track to the market for stem-cell-based treatments and other types of regenerative medicine.

One of these, the Act on the Safety of Regenerative Medicine (ASRM), adopted in November 2014, allows hospitals and clinics to market cellular therapies without going through the usual kinds of trials to prove that a medicine is effective. To start offering such treatments, hospitals need to show that they have a cell-processing facility that is certified by the Ministry of Health, Labour and Welfare and then pass their proposal by an independent review committee, which must also be certified by the ministry.

The Act on the Safety of Regenerative Medicine allows companies to register a therapy under one of three risk categories.

 

 

Classification

Requirements

Number of therapies registered (by June 2019)

Class III (low risk)

Treatments using cells from a patient and performing a function similar to the one they originally served, such as immune cells activated to fight cancer.

3,373

Class II (moderate risk)

Treatments using cells from a patient, but performing a different function, such as stem cells derived from fat used to treat atherosclerosis or amyotrophic lateral sclerosis.

337

Class I (high risk)

Treatments using cells from a riskier source such as embryonic stem cells, gene edited cells or cells from another person.

0

 

Before the legislative change, rogue clinics were springing up and taking advantage of medical tourism.

But the ASRM’s registry can be misleading, say critics. Doug Sipp, who researches regulatory policy at RIKEN in Kobe, says that it has brought “more transparency to the industry”. It has forced rogue clinics to meet some basic standards. There is a real risk, however, that patients will view the registry, “as a kind of validation”, he says.

For example, Avenue Cell Clinic, a sleek operation in Tokyo that looks more like a spa than a medical centre, features特别强调 the fact that its treatments are listed on the ASRM registry prominently on its website. At least ten patients have had fat-derived stem cells injected into their blood to cure or slow the progression of the neurodegenerative disorder amyotrophic lateral sclerosis (ALS).

An Avenue Cell Clinic customer service representative said on the phone to someone calling for information that the symptoms of 50–70% of patients improved after the therapy, which costs ¥1.5 million per dose. The clinic has about 1,000 patients per year for other indications.

Scientists working on regenerative medicine for ALS said that there was no convincing evidence that this kind of stem-cell treatment would help people with the disease, and there are several reasons to think that it wouldn’t work. Robert Baloh, who studies ALS at the Cedars-Sinai Regenerative Medicine Institute in Los Angeles, California, put it bluntly: “Quackery and false treatments have been marketed directly to patients for hundreds of years, and this is no different.”

In addition to the questions about evidence and efficacy, there are also concerns about the qualifications and independence of the committees that approve such treatments for inclusion in the registry. The health ministry requires that these committees comprise five to eight people, and include specialists in cell biology, regenerative medicine, clinical research and cell culture. It also requires input from lawyers, bioethicists and biostatisticians. But rules about conflicts of interest on the committee have been lax.

Helene Clinic, for example, had an in-house committee that approved some of its therapies, including a treatment for atherosclerosis. The in-house committee was disbanded in March, according to the health ministry. The ALS treatment and several other therapies offered by Avenue Cell Clinic were approved by a committee that includes a staff physician.

The ministry instituted policies in April to prevent such conflicts. But even with fully independent committees, clinics can shop around for the answer they want. Yoji Sato, who heads the cellular therapeutics unit of Japan’s National Institute of Health Sciences in Kawasaki and who sits on two committees himself, says that “committee surfing” is a big problem.

The government is considering extra fixes, such as requiring training to make the committee system better. “Maybe there is a conflict of interest in the committees, maybe the treatments are not effective, but that’s our limit right now,” Sato says.

He nevertheless argues that the system is superior to what exists in the United States, where regulators are continually chasing rogue clinics. Sato cites the case of two people who lost their sight after receiving an unproven and unapproved stem-cell treatment in Florida. It took the FDA four years and a tortuous legal battle to stop the company from offering the treatment. In Japan, for those lacking committee approval, “the police can go and arrest people”, Sato says.

Conditional approval

The other important policy that Abe’s government implemented in 2014 is known as the Pharmaceutical and Medical Devices Act. Under it, a company can earn ‘conditional approval’ to sell a treatment nationwide — not just at a single clinic or hospital — and have the costs covered by the insurance system. Unlike with the ASRM, the firm needs to present data that suggest efficacy from a small clinical trial. It can then sell the treatment for up to seven years, as it ostensibly collects better efficacy data. So far, only three treatments have earned conditional approval: one for spinal-cord injury, one for heart disease and one for critical limb ischaemia.

The Pharmaceutical and Medical Devices Act allows for conditional approval of treatments that have gone through some clinical testing. It gives companies the opportunity to market a treatment nationally and to receive insurance payments, but companies must collect extra data on efficacy over a seven-year period.

 

Treatment

Purpose

HeartSheet

Cells from skeletal muscle are used to seed a sheet of tissue designed to help heal damaged heart muscle.

Stemirac

Uses stem cells derived from bone marrow to try to treat spinal-cord injury.

CLBS12

Uses blood-forming stem cells to treat critical limb ischaemia.

 

 

But the pared-down clinical trials necessary for conditional approval have stoked concern in the scientific community. A 2016 report from the International Society for Stem Cell Research said that giving marketing approval on the basis of small-scale trials could slow down rigorous evaluations of the treatments and “erode confidence in the scientific standards of the field”.

 

Central to the debate over Japan’s policy is the value of randomized, placebo-controlled trials. These are conventionally considered to be the gold standard for clinical research, but Japan’s government followed a position floated by the Japanese Society for Regenerative Medicine in 2012, which specifies that trial designs to prove efficacy should not always require control groups receiving a placebo or conventional therapies.

Japan’s health ministry has stuck by its stance on placebo-controlled clinical trials for regenerative medicine. Following the criticism of a treatment for spinal-cord injury called STR01 that went on sale in May, Shinji Miyamoto, a health-ministry representative, argued that double-blinded experiments with the therapy were “structurally impossible” and said that a sham procedure or placebo “would raise ethical issues”.

Bioethicists have long debated the potential harms caused by sham treatments in clinical trials and whether they are fair to participants. Some are certainly too invasive, says Jonathan Kimmelman, a bioethicist at McGill University in Montreal, Canada, who has advised the Japanese government on clinical-trial policy. But doctors researching stem-cell therapies for spinal-cord injury say that a placebo-controlled trial for this condition would be relatively easy.

Osamu Honmou, a neurosurgeon at Sapporo Medical University in Japan who offers STR01, had previously advocated for double-blinded, placebo-controlled trials to prove the treatment’s efficacy in people who have had a stroke. A health-ministry representative says that a sham procedure would be unethical in the latter case because patients need treatment within a certain window of time, after which therapy might prove less effective. Such arguments, however, assume that the procedure is effective.

Several prominent scientists in Japan said that STR01, also known as Stemirac, shouldn’t have been approved for spinal-cord injury. “Abe’s cabinet needs one or two successful examples of success in science urgently,” says one cardiologist. “Abe’s cabinet is being too aggressive.”

Global ambitions

Despite holes in the system, Japan is trying to get its regenerative-medicine policies adopted elsewhere, in part to secure markets for its treatments. According to a five-year plan released by the health ministry’s drug-regulating division, the government funds outreach programmes aimed at “disseminating Japan’s model for regulating regenerative-medicine products, and fostering trust towards Japanese regulatory agencies and get Japan’s regulatory model introduced in other countries”.

The efforts seem to be making an impact, says Sato. Taiwan has drafted a conditional-approval law for regenerative medicines based on Japan’s legislation, and South Korea approved a system similar to Japan’s in August. India mentioned Japan’s system in deliberations leading to its first regenerative-medicine conditional approval in 2015. Several other countries have responded in kind, prioritizing a skewed vision of economic competitiveness over patient welfare.

Some hope to see a similar system in the United Kingdom, and say that the timing — with the country’s exit from the European Union looming — is right. In a February 2018 interview with the BBC, Ajan Reginald, co-founder and chief executive of Celixir, a company in Stratford-upon-Avon, UK, that makes a cellular therapy called Heartcel for heart disease, said that Brexit could offer the United Kingdom a chance to introduce its own accelerated regulatory pathway.

 “There is a lot of enthusiasm amongst certain people in the UK to adopt the Japanese model,” says Patricia Murray, a stem-cell biologist at the University of Liverpool, UK. The kind of deregulation done in Japan, she says, “will enable companies to sell their bogus therapies direct to consumers”.

And the rapid pace of development has presented a challenge for regulators elsewhere. The FDA has been under increasing pressure from businesses and patient groups — including the California Institute for Regenerative Medicine and conservative thinktank The Heartland Institute — to take an approach more like Japan’s.

Lee Buckler, the chief executive of regenerative-medicine company RepliCel in Vancouver, Canada, which licensed its skin-rejuvenation product to the Tokyo-based cosmetics company Shiseido in 2016, sees this pressure as a plus. He says people who desire fast access to medicines see what’s happening in Japan and “press for similar access in their country”.

Pride over Japan’s achievements in stem-cell biology and regenerative medicine have played a large part in the efforts to grow the industry. But Yamanaka, who has been one of the most prominent faces of those achievements, has remained relatively quiet on matters of deregulation.

In contrast to the quickly moving currents elsewhere in the country, Yamanaka’s institute, which is dedicated to bringing stem-cell treatments to the clinic, seems unwilling to rush through a clinical trial. “Double-blinding control should be considered whenever possible,” Yamanaka told Nature. And although he understands that this can be difficult for some cell therapies, even in those cases, “scientists should do their best to make clinical trials as objective and scientific as possible”.

In the absence of objective and scientific measures, it becomes difficult to know what and who to trust, say some stem-cell researchers. The law was made for men of good nature, but there are many that are not good.

 

Nature 573, 482-485 (2019)

doi: 10.1038/d41586-019-02847-3

 

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