For Li Cheng, President of Sunshine Biotech, 28 April 2014 was an important day to remember.
That day, at the "Fourth International Conference on Molecular and Cell Biology" held in Dalian, Sunshine publicly released the world's first patented quality-controlled umbilical cord pluripotent stem cells.
In the stem cell field, setting a standard is a remarkable feat – even Nobel laureate Daniel Shechtman, who attended that day, had high praise for this achievement. Yet alongside Li Cheng's joy, there was always a tinge of regret.
Just one year before Sunshine released its quality-controlled stem cells, in February 2013, the International Organization for Standardization (ISO) announced the establishment of an International Biotechnology Committee responsible for formulating international standards for the quality control of stem cells, with its secretariat based in Germany.
Yet by that point, Sunshine's quality control standard for pluripotent stem cells – including its framework and content – had already been completed. The "preemption" by Germany was not just a loss for the company; it also meant that China could only participate as a member country in formulating the standard's content, regrettably losing the initiative and industry voice that come with leading the formulation of an international standard.
China still has the trump cards of an enormous market and rich resources, which may help China regain ground in the future on the clinical application of stem cells. But realizing all this depends on the prompt formulation and rollout of domestic regulations and standards for stem cells.
The reality, however, is precisely the opposite. Precisely because of the absence of industry and national standards, China's stem cell research and clinical application have long been in a state of disordered development, ultimately leading to a single notice from regulators in 2012 putting the brakes on the field. Since then, although national authorities have wanted to revive efforts to formulate stem cell industry regulations and technical standards, the timing has repeatedly slipped, and multiple initiatives have ended without result.
Today, with developed countries in Europe and North America treating stem cells as a strategic industry and providing strong support, formulating a unified set of stem cell management regulations and standards has become the most urgent hope of all sectors of China's stem cell academia, industry and research community.
Missing out on international standards
"This standard framework was originally proposed by Chinese companies, but now it has suddenly become Germany's achievement," Li Cheng said indignantly when discussing the German Institute for Standardization's "preemption".
"After ISO's announcement, we were stunned," Li Cheng said. "The content framework, terms and definitions of the international standard for stem cell quality control proposed by Germany are exactly the same as Sunshine's previously proposed enterprise standard."
In the standard framework of the International Biotechnology Committee, stem cells and stem cell storage are defined as "life resources" and "life banks" respectively. This is identical to the wording Sunshine had used in its public communications before 2013.
More importantly, in the international standard framework proposed by Germany, the breakdown of specific standard contents – such as analytical methods and bioprocesses – is also entirely consistent with the concepts originally proposed by Sunshine.
The source of the information leak can no longer be traced. Li Cheng told the reporter that Sunshine had previously described the definition and general framework of this standard on the company's website, which may have been one of the sources of information for industrial spies. In addition, as an investor herself, in order to expand business in Europe and North America, she had been in contact with many investment groups in Europe over the years, including investors with ties to German companies.
Even Sunshine's lab computers and hard drives at its Beijing headquarters had previously been the targets of theft.
By the time Li Cheng reacted and officially announced Sunshine's stem cell quality control standard, it was too late. "From the perspective of those abroad, all subsequent breakthroughs and achievements in stem cell quality control standards globally are just specific work done within the standard framework advocated by Germany."
And the German Institute for Standardization, two years on from its successful application in 2013, has not produced any actual content under the standard framework.
Li Cheng said that Sunshine had previously considered applying for national and international standards, but China's national standards for stem cells differ from those abroad.
For example, in Germany, enterprises propose enterprise standards. The German Institute for Standardization then formulates industry or national standards based on these enterprise standards, and on this basis applies for international standards from ISO.
The process in China is exactly the opposite. According to the "Standardization Law of the People's Republic of China", national standards must be formulated by "adopting standards" – that is, adopting international standards and using them as the basis for formulating Chinese national standards. For an enterprise, industry or national standard to become an international standard, the Standardization Administration of China and the relevant industry regulator must take the lead in organizing and applying for project approval from the international standards organization.
The whole process is not only time-consuming; it also requires overcoming disputes among various interest groups within the industry – on whose enterprise's or institution's standard should serve as the basis, who should take the lead, how to advance, and many other thorny issues. Conservative regulatory policies and a chaotic clinical market also make standard applications even more difficult.
Disputes over domestic standards
To this day, the absence of standards remains a sword hanging over China's stem cell industry.
Stem cell therapy products will ultimately be used in the human body, so quality control standards and a quality assurance system must be established and systematically implemented across the entire process – donor screening, tissue collection, cell isolation, culture, cryopreservation, thawing, release, transport and use – ensuring the safety, efficacy and stability of the product.
Wu Weihong, Vice Chair of the China Industry-University-Research Alliance for Translational Stem Cell Medicine Standards, said that, with no technical standards or regulations to constrain it, China's stem cell market had previously been chaotic, and the entire stem cell industry had suffered as a result. The prompt establishment of China's stem cell technology and clinical application regulations and the formulation of unified, systematic quality control standards have become an urgent demand from across academia, industry and research.
In fact, national industry regulators have not failed to consider formulating stem cell technology regulations and standards in China.
Xi Tingfei, Director of the Center for Biomedical Materials and Tissue Engineering at Peking University, said that as early as 2008, after the former Ministry of Health's Department of Science, Technology and Education took over stem cell oversight responsibilities, it had organized the China Medicinal Biotech Association, the Chinese Medical Association, the Chinese Medical Doctor Association and other entities to draft management measures related to stem cells.
However, the expert teams responsible for clinical project review consisted mostly of professors from research institutions and universities and were too transient. The Department of Science, Technology and Education also lacked law-enforcement and supervisory authority. The whole management measure lacked an actionable implementation plan, could not be enforced and ultimately fizzled out.
Later, in March 2013, the former Ministry of Health and the China Food and Drug Administration jointly issued three "drafts for comment": "Administrative Measures for Stem Cell Clinical Trial Research", "Administrative Measures for Stem Cell Clinical Trial Research Bases" and "Guiding Principles for Quality Control and Preclinical Research of Stem Cell Preparations".
However, as soon as the drafts came out, controversy erupted. Most commentary considered that the drafts brought favorable news for stem cells and that the industrialization of China's stem cells was accelerating into the fast lane. The system would manage stem cell clinical application research in line with the framework for Class I new drugs and could fill the gap in domestic regulation of the stem cell industry.
But some experts argued that the lack of clarity in some specific contents and standards in the drafts would create confusion for the stem cell industry.
On the question of standards, while the "Guiding Principles for Quality Control and Preclinical Research of Stem Cell Preparations" did set out norms for some stem cell preparation and inspection processes, it did not give specific indicators for preparation processes and quality control, nor did it clearly differentiate technical standards across different types of stem cells.
In addition, Zhang Lei, a director of the Chinese Society of Biotechnology, noted that the drafts did not clarify the specific division of labor, review procedures and supervisory authority between the Ministry of Health and the China Food and Drug Administration in accepting filings for stem cell clinical trial research, which could easily lead to inter-agency buck-passing. The measures did not even clarify the purpose of stem cell clinical trial research; even after completing clinical research, stem cell products would still have no registration channel, providing no exit for industrialization of stem cells.
Real-world challenges
In theory, the problem is not unsolvable, Li Cheng said. By normal logic, as long as national regulators take the lead and organize relevant enterprises and institutions to apply for the enterprise's technical standard to become an international standard, this would not only lay the foundation for national standards but also make up for the regret of having had the standard framework "preempted".
Wang Zongling, Party Secretary and Vice President of the China National Institute of Standardization, told the China Economic Weekly reporter that the institute had now signed an agreement with Sunshine commissioning Sunshine to draft the umbilical cord pluripotent stem cell quality control standard, in order to apply for an ISO international standard.
The early-stage drafting work is not the difficult part – after all, Sunshine's mature enterprise standard is already available as a reference. The follow-on application work is the real challenge.
Wang Zongling told the reporter that, under the normal procedure, from completing drafting through organizing the project application to passing review by the International Biotechnology Committee, the entire process takes at least 10 months even at its fastest. But this is just the ideal scenario; under the rules of the game set by developed Western countries, it has always been difficult for Chinese standards to "go global".
In fact, this issue is not unique to China; the same is true of countries other than the United States and the European Union. Before the German Institute for Standardization "preempted" the international standard's definition and framework, South Korea and other countries had also applied to ISO for quality control standards but were quickly rejected; only the German Institute for Standardization's application was rapidly approved.
Wang Zongling believes that, against today's backdrop of intensifying global competition in stem cell technology research and industry, the resistance China's stem cell quality control standard would encounter on its way to becoming a global international standard is not difficult to imagine. To win this battle for standards, in addition to its existing mature, high-level enterprise standards, China's trump cards – in the view of Zhao Chunhua, Director of the Tissue Engineering Research Center at the Chinese Academy of Medical Sciences – also include the large body of data and case examples accumulated from stem cell clinical research before 2012, as well as China's massive market and stem cell resource potential.
In addition, in early 2015, media reported that the National Health and Family Planning Commission and the China Food and Drug Administration were intensifying work on the formal versions of the three drafts and were close to completion, with the prospect of finishing the process and officially releasing them publicly in the near future.
The problem is that the buffer time China has to make good use of these trump cards is running short. Guo Lei said that the United States is currently in the lead in global stem cell clinical research; while the United States too lacks the corresponding technical standards and clinical data support, once it completes its standards research and technology reserves, given a more favorable clinical-application policy environment than China's, short-term efficacy in disease treatment could be seen in as little as two years or so.
By then, the advantages China has accumulated in clinical research and application will no longer exist, and the gap between China and other countries in the clinical application and industrialization of stem cell technology will widen further.
