Will the First Administrative Measure on Clinical Stem Cell Research End the Wild East Scientific Feast?

Introduction

Biotechnology raises many controversies, particularly in human embryonic stem cell (HESC) research. As one of the most fascinating developments in the biomedical area over the past decade, HESC research holds great potential in tissue engineering, genetic engineering, and other regenerating technologies. ¹ With huge scientific innovations, medical benefits, and commercial interests implicated in this research, most countries have committed to securing a competitive position in HESC, transplantation, and the regeneration medicine industry. ² In stem cell science, China is showing the world that its research is top-notch. On one hand, with increasing international collaboration, China is determined to grasp the opportunity to develop promising HESC research. On the other hand, not only is Chinese HESC research stimulated and booming, but Chinese clinics and hospitals have also attracted many foreign patients coming in for stem cell therapies. ³

It has been argued that developing countries have profited from the legal and bioethical vacuum in this area. ⁴ Some scholars believe that unproven therapies—some not verified, some still under theoretical experiment—could yield negative consequences to patients. Although most researchers believe it is too early to transform HESC research into therapeutic applications, ⁵ stem cell therapy is performed in many regions of China. China practices high-quantity, but questionable, stem cell therapy, which has raised safety concerns for stem cell therapy used in patients before clinical trials. For example, online stem cell therapy advertisements, which are typically overly optimistic and inaccurate about therapy results, may mislead potential consumers. In addition, most stem cell therapies are not approved by the China Food and Drug Administration (CFDA). ⁶ Without close monitoring and proper guidance, the safety and efficacy of stem cell therapy cannot be guaranteed.

Critics have said that China turns a blind eye to these unauthorized stem cell therapies offered by hospitals and clinics. ⁷ On August 21, 2015, the National Health and Family Planning Commission of the People's Republic of China (NHFPC) and CFDA jointly launched the first Administrative Measure on Clinical Stem Cell Research (“the Administrative Measure”) in response. The main objectives of this normative document are monitoring clinical use of stem cells, protecting research subjects' rights, and promoting the development of stem cell research. The Administrative Measure, which is recognized as a regulation milestone in stem cell research, contains many breakthroughs, including in setting standards for the qualifications of stem cell research institutions, establishing a duty of responsibility for the authorities in the institutions conducting clinical stem cell research, and overseeing research using monitoring, documentation, and reporting mechanisms. These measures are taken for the protection of research subjects' rights. However, the effectiveness and efficiency of the Administrative Measure is questionable: will the first Administrative Measure stop people from travelling to China for unsafe and unguaranteed stem cell therapies? Will stem cell therapy be effectively regulated and monitored under the first Administrative Measure?

This article explores the key issues as well as inadequacies of the first Administrative Measure. This article starts with an examination of the current development of stem cell therapy in China. The article further outlines and discusses the regulatory supervision of clinical stem cell research—for example, the Ethical Guideline for HESC research in 2003, before the launch of the Administrative Measure. Then, the article illustrates the key developments the Administrative Measure has brought to the safety of clinical stem cell research. Finally, the article reveals some potential problems that may challenge the effectiveness of the Administrative Measure.

Stem Cell Therapy in China

It is not an exaggeration to say that China is entering stem cell therapy more quickly and easily than many other countries. Meeting the needs of foreign patients, clinics and hospitals are increasingly offering stem cell therapies. Many patients, who are deemed incurable in the U.S., may be healed in Chinese hospitals—at least according to their advertisements. ⁸ Additionally, medical tourists are not restricted by the regulatory regimes of their home and receiving countries. ⁹ Both stem cell technology and its related businesses are rapidly developing in China, which bodes well for future prosperity.

Focusing on therapy, stem cell researchers in China are hastily transferring basic scientific research to commercializable diagnostic procedures. Shen Zhen Beike (Beike) is one company that has won world renown for the stem cell therapy it developed. From bench to bedside, Beike's highly reputed therapies are attracting patients from all over the world for treatment here in China. With the benefit of the first special economic zone of China, Beike has combined laboratories and hospitals to establish treatment centers. ¹⁰ As the president of Beike, Hu Xiang, said, “[i]nitially, we only build cooperation with laboratories and hospitals which [possess][high-standard] equipment, [high-standard] environment, and [high-level] team. In order to promote the interaction, Beike creatively launched stem cell public technical service platform and constructed [a] clinical stem cell research network.” ¹¹ So far, Beike has not only announced the largest clinical application security evaluation of allogeneic human umbilical cord blood-derived stem cells, but published research data of effective treatment in systemic lupus erythematosus, hereditary ataxia, and muscular dystrophy as well. ¹² Beike has also alleged that it treated over 6,000 patients. This should be a huge achievement. However, Beike has not published any papers related to these treatments in internationally recognized journals. ¹³

Not only tech companies, but city governments, too, would like to grasp the opportunities brought by stem cell technology. For example, the city of Tianjin set up China's first stem cell industry alliance, which includes 22 biotech companies and research institutions, like the National Industrial Base of Stem Cell Technology and the National Center of Stem Cell Engineering and Technology. The alliance aims to develop cures for complicated diseases, innovate stem cell technology, establish a public service platform, and accelerate the transfer from scientific results to clinical products. ¹⁴ The alliance, to some extent, accelerates the development of the stem cell industry; but, as some academics have pointed out, “[t]he issue[s] of healthcare system, physician-patient relationship, intellectual property [disputes], and other commercial conflicts of interest produce obstacles for translational medicine.” ¹⁵

Even in the capital market, we can find companies whose main business relies on the stem cell industry. Zhongyuan Union Stem Cell Bio-engineering Corporation is one of these companies. It is typical of its kind in the Shanghai and Shenzhen market. Zhongyuan Union is the deputy director of the National Strategic Alliance for Technical Innovation of Stem Cell and Regenerative Medicine Industry, and has carried the project in building the national stem cell and gene clinical translational base. ¹⁶ It successfully owns three famous stem cell enterprises: Union Stem Cell Genetic Co. Ltd, Union East China Stem Cell Gene Engineering Co. Ltd., and HeZe Biotechnology Co. Ltd. ¹⁷ The company holds some important stem cell technology patents, such as Umbilical Cord Tissue Derived Mesenchymal Seeded Separation Method, Human Umbilical Cord Mesenchymal Stem Cell, the Antifibrotic Injection and Its Preparation Method, Human Adipose Adult Stem Cell Acquisition Method, and Construction of the Stem Cell Bank, etc. ¹⁸ The main business of Zhongyuan Union covers stem cell drugs, tumor therapy, cell banking, and stem cell daily use for anti-aging and healthcare. ¹⁹ It is observed that Chinese companies have already entered the downstream market of the stem cell industry. ²⁰

Driven by the market pursuit of high-technology interventions, the number of clinics and hospitals in China offering stem cell therapy is rapidly increasing. ²¹ China seems to allow a liberal and HESC-favorable environment for research and application. But, we cannot ignore the fact that stem cell therapy does introduce safety problems. Usually, safety concerns regarding stem cells have only been demonstrated through drug evaluation experiments; therefore scientific evidence is insufficient and clinical testing is imperative. For example, a neural stem cell transplant performed on an ataxia telangiectasia patient provided data to the first report of the donor-derived brain tumor therapy. ²² According to this report, neural stem cells may induce gliomagenesis. Scientists then found that “tumor cells actually behave very much like stem cells—they divide indefinitely and they tend to be undifferentiated.” ²³ There are certain risks that stem cells would form tumors. Other risks (some potentially fatal) include stem cell failure, organ damage, infections, and cataracts. However, many stem cell therapies—which have only been tested on animals and not in human clinical trials—have already been performed on humans in some clinics, medical therapy companies, and hospitals in China, for commercial purposes. Since the human body is different, and more complex, than some animals' bodies, stem cell therapies effective on those animals may not be useful in humans, due to such differences. Thus, it is urgent that the safety of such therapies should be assessed. ²⁴

Before the First Administrative Measure: The Vague Ethical Guideline could not effectively monitor and supervise HESC Research

Despite the bright future of HESC research in conquering incurable diseases, its development faces many legal and ethical challenges. The complexity of HESC research creates most unusual and fraught situations for regulators in China. In order to supervise the stem cell industry, the Ministry of Science and Technology, jointly with the Ministry of Health, released the Ethical Guideline for HESC Research (“the Ethical Guideline”) in December 2003. ²⁵ The Ethical Guideline directly defined the justified source of HESC and regulated research conducts. Meanwhile, the Ethical Guideline banned all embryo sales and declared that it was illegal to perform any reproductive cloning research. ²⁶ This was the first time the government issued a guideline to clarify the illegitimate nature of reproductive cloning research. Undeniably, the Ethical Guideline has been of great significance to the rapid and healthy development of HESC research.

However, the Ethical Guideline contained some serious flaws and has received much criticism. ²⁷ For example, Article 5 of the Ethical Guideline restricted HESC embryo source to four categories: “(1) embryos that are left unused after in vitro fertilization procedures; (2) foetus cells from spontaneous abortion or voluntary abortion; (3) embryos created by means of somatic cell nuclear transfer technique; (4) voluntarily donated germ cells.” ²⁸ Obviously, the creation of a human embryo utilizing sperm and egg is not allowed for research purposes. However, the Ethical Guideline ignored the main source of HESC—the already-existing embryonic stem cell lines. In Western countries (such as Germany, the UK, and the U.S.), the already-existing embryonic stem cell lines are very popular sources for HESC.

Another criticism focuses on Article 6: “In case the embryos from In Vitro Fertilization (IVF), somatic nuclear transfer, a single replication technology, or genetic modification blastocysts obtained in vitro, only embryos for a maximum of fourteen days could be used in research.” ²⁹ This article is similar to clause 4 of Article 36 of the Human Fertilization and Embryology Act of the UK. ³⁰ The 14-day restriction is also adopted in many other countries, such as Germany and Japan. ³¹ It seems the 14-day requirement in the Ethical Guideline is reasonable because China is adopting rules that were also popular in other countries. ³² The problem is that the restriction cannot be applied well in China. One important reason is that, unlike Western countries, abortion is widely considered legal in China. Human fetuses are legally killed under Chinese birth control policy. They do not have the legal status of human beings. On the premise that fetuses share no human dignity, embryos after 14 days surely cannot own human identity. Therefore, considering moral and culture difference between China and Western countries, it may be pragmatically meaningful for the regulators to rethink whether the 14-day restriction should be adopted in China. ³³ Moreover, the Ethical Guideline should justify the necessity for “transplanting” the regulations of Western countries.

In addition, another problem pointed out by the ethicists is that the Ethical Guideline lacks the relevant moral definition as well as the relevant moral objection. From Article 5 to Article 10, the regulation places its focus on the code of conduct instead of moral behavior. ³⁴ Thus, the Ethical Guideline is lacking moral connotation and appears monotonous and mechanical. In fact, it is necessary to express moral connotation and moral reasons in an appropriate form in order to let people deeply understand and accept the Ethical Guideline. Moreover, it is noticeable that Article 9 states that “the Ethical Committee should consist of the biologists, the doctors, the lawyers and the socialists. The responsibility of the committee is to examine, [to] supervise, and [to] provide consultation to HESC research.” ³⁵ The clause did not mention ethicists, who should play a critical role in the Ethical Committee.

The majority of ethical committee members are scientists, though they do include ethics advocates, patients, legal experts, doctors, and scientists. Apparently, researchers usually do not favor restrictions on stem cell researches and transfers. Therefore, some scientists on the ethical committee may not possess much ethical concern with regard to research subjects. Accordingly, the capacity or will of the ethical committee to restrict or limit research if appropriate could not be guaranteed. Furthermore, according to one report, “it is the scientist[s] themselves who have been the main initiators in setting up institutional review board[s], and who have personally facilitated or put efforts into the creation of written bioethics guidelines.” ³⁶

Generally, the Guideline delineates certain prohibited areas of research, including to “transfer a human embryo into the uterus after IVF, implant human blastocysts by Somatic Cell Nuclear Transfer (SCNT) into a human uterus, and so on.” ³⁷ However, there is no clause that relates to evaluating the qualification of research institutions; or licensing, monitoring, and supervising researchers. To make matter worse, despite the stipulation that HESC research must be examined and approved by the ethics committee, the 2003 Ethical Guideline introduced no additional implementation clauses. As a result, research freedom and supervision were not balanced. ³⁸ Chinese scientists are free to make their own decisions and consult their own consciences. ³⁹ In practice, there are two main arguments regarding whether the vague Guideline could be used to monitor and supervise HESC research and clinic use. Some scholars argue that the clinic data could contribute to stem cell therapy development, ⁴⁰ and to collect clinic data, HESC research policy requires flexibility. ⁴¹ But other ethical scholars believe that strict regulations should be adopted to protect patient interests. ⁴²

The need for further creating a competent Guideline for monitoring the stem cell industry was obvious in light of previous experience. Unlawful experiments have been conducted in renowned hospitals or research institutions over moral objections and safety concerns. ⁴³ For example, in Beike, many patients are treated by stem cell therapy, which has no clinical trial record. ⁴⁴ They are not told about the treatment procedure. One patient from Italy was not notified that he was injected with cortisones that might exacerbate his diabetes. ⁴⁵ Another patient from Italy wrote letters to Beike to complain about the failure to cure his disease, and he did not receive any response. ⁴⁶ Thus, the ethical committee and relevant issues should be further articulated in detail through specific legislation.

The Critical Issues of the First Administrative Measure on Clinical Stem Cell Research 2015

However, the authority seems not to turn a blind eye to stem cell therapy anymore. The Administrative Measure on Clinical Stem Cell research was launched, which is the first normative document related to stem cell therapy in China. The promulgation is of great significance to the promotion of the sound and orderly development of stem cell research, as well as the supervision of stem cell therapy. Generally, the regulatory requirements and procedures in the Administrative Measure are similar to those of other countries, such as stem cell clinical trials using Good Clinical Practice of Pharmaceutical Products (GCP), licensing of manufacturing using Good Manufacturing Practice (GMP), and the adverse event reporting system. ⁴⁷ The Administrative Measure states that the research must comply with the principles of science, standardization, openness, ethics, and sufficient protection of the rights of research subjects. ⁴⁸ Remarkably, the Administrative Measure specially stipulates the following three perspectives:

The First Administrative Measure cannot effectively control Stem Cell Therapy in China

In order to protect the health and safety of prospective patients, the Administrative Measure for Clinical Stem Cell Research aims to ensure safety, effectiveness, and quality of stem cell therapies. Some people think that the Administrative Measure seems to affirm the legitimacy of stem cell therapy from another perspective. ⁵⁶ Some people presume this Administrative Measure might accelerate the development of stem cell therapy. ⁵⁷ Currently, it is unclear to what extent the risk of stem cell therapy may be managed through this Administrative Measure. However, a failure to address the following issues may result in bad consequences.

Conclusion

Regulating clinical stem cell research, which might be the most ethically controversial technology of the present age, is an unenviable task for China. There are moves afoot—the first Administrative Measure has been launched. Upon promulgation of the Administrative Measure, the qualifications and duties of the research institutions, the review and record filing mechanism of the research projects, the regulatory measures for this research, and the protection of the rights of the research subjects are addressed. Some new developments are caught by this fresh Administrative Measure's underlying principles, such as the clarification of the qualifications of institutions conducting clinical stem cell research and the establishment of a reporting mechanism for unsafe events in clinical stem cell research. But this will not always be the case. The Administrative Measure does not, for example, cover liability clauses and a traceability system. The Administrative Measure does not bind military hospitals in China. And the Administrative Measure is not equipped with the expert responsible authority.

The ambit of the Administrative Measure is wide. However, as the first regulation addressing clinical stem cell research, the Administrative Measure faces effectiveness and efficiency challenges. The Administrative Measure is the normative document from the Ministry of Health, which has no binding force on some institutions, such as military hospitals. The absence of a liability clause and a traceability system might leave the door open for unsafe and unguaranteed stem cell therapy. To make matters worse, facing growing pressures and difficulties, the expert responsible authority has not been established. Therefore, it is argued the first Administrative Measure will not end the scientific feast of stem cell therapy in China. Contrarily, stem cell therapy might experience a sudden rapid growth under the Administrative Measure.

Acknowledgments

The author gratefully acknowledges the assistance of Keyi (Alvin) Xu, 2016 JD candidate, St. John's University School of Law.

This project was funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.