After 4 years of the MAH pilot program, the country will implement policy dividends with heavy responsibilities.

After 3 + 1 years of pilot, the market authorization holder (MAH) system, which is known as bringing a "timely rain" to innovative enterprises in China, will be fully implemented in December this year In the past four years, both the industry and regulators have hoped to break the ecological pattern of innovative drug R & D and production with MAH system Now, the pilot is over, how to judge the future development direction of innovative drugs in MAH pilot cases? What opportunities and challenges will it face in the future? Among the many innovative drugs in MAH pilot, fuquitinib is undoubtedly a typical representative This is not only a major and landmark success of Hutchison Whampoa pharmaceutical in its 16-year innovation and research, but also one of the first varieties in Shanghai pilot since the implementation of MAH pilot The new drug can go on the "green channel" and quickly bring good news to patients with advanced colon cancer in China, undoubtedly benefiting from this policy dividend For this reason, at the recent global conference on biomedical cutting edge technology, policies and regulations and Suzhou Conference on the 15th anniversary of freehand brushwork, Wu Zhenping, senior vice president of sina pharmaceutical, and Hutchison Whampoa pharmaceutical, deeply analyzed the current situation and practical problems of MAH in China What is mah? What is the meaning? Mah system refers to the management mode of separating listing license and production license Under this mechanism, marketing license and production license are independent of each other The holder of the marketing license may entrust the products to different manufacturers for production The safety, effectiveness and quality controllability of the drugs shall be the responsibility of the marketing license to the public In a word, in Dr Wu Zhenping's opinion, "the core of MAH system is to encourage new drug research and development, so that those skilled in research and development can focus on research and development, and producers can do well in production." In China, pharmaceutical enterprises are mainly divided into the above three categories Before 2016, China's drug registration system was a "bundling" mode of marketing license and production license If the R & D party wants to control the drug approval number in its own hands, it needs to build a production line and obtain the production license Therefore, many new drug R & D teams are deterred by the threshold of "investment and factory building" They only transfer the relevant drug technology to the manufacturer, which is commonly known as "painstaking selling of" green shoots "! According to Dr Wu Zhenping, the management mode of MAH project and production line is undoubtedly a "timely rain" for many innovative enterprises The main advantages are as follows: to stimulate the R & D enthusiasm and innovation vitality of all kinds of enterprises that do not have the production conditions temporarily; to reduce the investment threshold of production facilities attached to R & D investment, so that R & D enterprises can realize the rapid industrialization of innovative drugs through entrusted production, so that pharmaceutical enterprises can obtain innovative drugs through acquisition and other ways to achieve product listing Mah pilot 3 + 1 year to activate a pool of spring water  in November 2015, China began to pilot the listing license system (MAH);  on June 6, 2016, the pilot of drug listing license holder system was officially launched on the date of plan printing and issuing, and 10 provinces (cities) including Beijing, Tianjin, Hebei, Shanghai, Jiangsu, Zhejiang, Fujian, Shandong, Guangdong, Sichuan, etc rolled up their sleeves and dried up! On November 4, 2018, the original planned end date of MAH pilot project was extended for one year to November 4, 2019 On August 26, 2019, the new drug administration law announced that MAH will be officially promoted and implemented nationwide from December 1 In this pilot process, MAH pilot varieties have been approved one after another, which can be described as flowering all over the country As of the end of July 2019, the State Drug Administration announced that the database of drug listing license holders indicated that there were 3239 varieties of listed license holders (calculated by drug approval number) and 156 listing license holders According to the statistics of China Journal of new drugs earlier, by the end of September 2018, 1118 applicants for drug registration in 10 pilot provinces (cities) had applied for the holder, covering the administrative region, subject type and pilot drug scope specified in the pilot program In the coverage of pilot drugs, new drugs accounted for 42.6%; generic drugs developed according to the new standards consistent with the quality and efficacy of the original drugs accounted for 44.8%, while in terms of regional distribution, Jiangsu, Guangdong and Shandong accounted for more than half of the total It can be seen that MAH has brought multiple choices to major innovative pharmaceutical enterprises and further released the innovation vitality of China's pharmaceutical industry "At the beginning of the trial implementation of MAH system, we found in the communication with the regulatory authorities that under the new supervision mode, the most worry of the regulatory authorities is whether the holders have the ability and determination to implement the main responsibility." According to Dr Wu Zhenping, the process of drug research and development is complex, involving many professional fields, as well as barrier filled patent application, drug application and other work, which not only bears unexpected drug quality risks but also bears significant liability for compensation, so the threshold is high and the liability is heavy The third chapter "drug marketing license holder" is specially set up in the new drug administration law, which makes comprehensive and systematic provisions on the conditions, rights, obligations and responsibilities of the holder It is clearly pointed out that MAH refers to "the enterprise or drug development institution that has obtained the drug registration certificate" In short, all drugs have holders, and the holders are not allowed to be individuals The accountability is accurate to people In his view, proving the strength of enterprises may be a problem that every enterprise that wants to go through MAH channel will encounter The requirements of the new deal for the ability of the holders mainly include: the management ability of the whole life cycle of drugs: the R & D management ability, the production management ability, the risk control ability of post marketing drug vigilance and the ability of compensation for damages The holder of the marketing license shall be responsible for the whole process from drug research and development to mass production, and also for the final release of the drug before marketing In addition, in addition to the major responsibility accident, with MAH to be launched nationwide, a series of troubling phenomena have also emerged in the pilot process, which need to be concerned: 1 The whole life cycle: for example, MAH certified drug quality assurance system has not yet had a model for reference Under the MAH system, the product quality problem is actually closely related to each link of the industrial chain, but if only MAH takes the main responsibility, is it appropriate? 2 Regional differences: with the increasing situation of cross provincial entrusted production, but the different understanding of MAH in each province leads to different policies in each province, and the cross regional supervision problems are gradually spread out At the same time, due to the differences in development level and attraction policies in each region, the inclined distribution of scientific researchers may also aggravate the imbalance in the development of pharmaceutical industry between regions 3 Drug distribution: in the previous MAH system pilot scheme and subsequent policy interpretation documents, the words were used carefully to stipulate that the holder could entrust the sale of drugs, and then the policy was relaxed to the extent that the holder could sell the varieties held by himself Later, through further policy interpretation, drug "sales" is not the narrow sense "sales" of "hand in money and hand in delivery" in the process of commodity exchange in the usual sense Its original meaning refers to drug business behavior, not only including logistics, ticket flow, capital flow, information flow and other processes, but also a series of activities of drug business quality management From the legal point of view, the pilot scheme not only gives the holder the right to produce drugs, but also naturally gives the holder the right to sell drugs and obtain profits Its production and operation rights should be jointly owned, but if the holder does not have the content of drug production and sales in his business or business scope, he will not be able to issue an invoice to the drug buyer through the tax control system, and he will not be able to complete the actual sales This is the drug sales problem encountered by a few pure R & D institutional holders in the pilot 4 "Two vote system" conflict: due to the need to implement "two vote system" when drugs are sold to public medical institutions, in the pilot, some holders can only bill and sell to a drug handling enterprise as the general agent, and then sell to the downstream because they do not have the ability of drug handling or market operation However, the general agent often does not have the national distribution capacity, and must open one more ticket to sell to the regional distributors, and then sell and distribute to the public medical institutions, which violates the "two ticket system", which is also a problem "It's all crossing the river by feeling the stones, and the road will come out." Although there are some perplexing phenomena in the experimental process of MAH, these problems do not affect the enthusiasm of enterprises for MAH system It is reported that in addition to furquitinib, Hutchison Whampoa has another seven new drugs in clinical trials, and they plan to continue to use MAH to promote the marketing of follow-up products With reference to the successful listing experience of fuquitinib, we can see that with Mah The implementation of the policy will also give some new insurance companies, third-party evaluation, professional evaluation of entrustment contracts and other service-oriented organizations room to grow As long as all parties better run in and adapt, improve the MAH market mechanism, they can really do a good job in opening up green channels for more innovative drugs, and create more Chinese patients as soon as possible.