People's Daily: approval of generic drugs is too difficult!

Source: People's daily, August 17, 2015 interviewee: Li Weiping (former senior director of Xi'an YANGSEN pharmaceutical), Zhang Xianglin (Dean of Yihong Business School of Shenyang Pharmaceutical University), Guo yunpei (vice president of China Pharmaceutical Enterprise Management Association), song Ruilin (executive director of China pharmaceutical innovation promotion association), Li Ning (Senior Vice President of Sanofi Asia Pacific region)“ Compared with innovative drugs, generic drugs take longer to review " Recently, the reporter learned in the interview that the average clinical evaluation time of a generic drug is 3-4 years, and the approval for listing almost takes such a long time This means that it will take six or seven years, or even eight or nine years, for a generic drug to go on the market from its clinical application to its approval "We should pay attention to both innovative drugs and generic drugs." Experts pointed out that the problems caused by too long review time of generic drugs should not be underestimated According to the 2014 annual drug review report, the drug review center of the State Food and Drug Administration accepted 8868 new registration applications in 2014, an increase of 1258 over the previous year Although they completed the technical review of 5261 registration applications last year, an increase of 12.9% over the previous year, the backlog of tasks to be reviewed further increased as the number of tasks accepted increased by 16.5% over the previous year By the end of 2014, the total number of tasks to be reviewed had reached 18597, an increase of 4362 over the same period last year Among them, the task of generic drugs to be audited accounts for the vast majority "If we go on like this, the clinical trial tasks of generic drugs are like a mountain growing higher and higher, which makes people look scared." Li Ning said Experts point out that the consequences of too long approval of generic drugs are equally serious - they can't meet the needs of people in time Li Ning and Li Weiping pointed out that theoretically, if the review and approval are timely, foreign patent drugs will pass the patent protection period today, and China's generic drugs can be listed the next day This not only ensures the timely use of drugs by patients, but also greatly reduces the economic burden: after the first generic drug is listed, the price is only 1 / 3 of the patent drug; after the second and third generic drugs are listed, the price is only 1 / 4 and 1 / 5 of the patent drug respectively However, due to the long time of evaluation, some foreign patent drugs can not be marketed in China after expiration It causes great difficulties for the development of pharmaceutical enterprises Guo yunpei pointed out that although the R & D investment of generic drugs is less than that of innovative drugs, each of them will cost millions or even tens of millions of yuan The delay in the approval of generic drug clinical applications is tantamount to an extension of the time to market, resulting in the overstock of funds and idle production lines of many pharmaceutical plants As a result, more and more applications are filed, forming a vicious circle of "longer and longer reports" According to Li Weiping, due to the long waiting time, some enterprises hold the mentality of "occupying seats", declare and line up before the R & D is completed, which makes the already tense review resources even more tense According to experts, because of the long waiting time and too much investment in the early stage, some enterprises even try to fake in the R & D and clinical, in order to successfully pass the clinical and listing "The market share of generic drugs is 96%, which not only guarantees the basic drug demand of Chinese people, but also provides the basis for making innovative drugs." "In addition, there are so many review resources Generic drugs and innovative drugs are like grasshoppers tied to one rope The backlog of approval of the former is not solved, and the approval of the latter is difficult to get up quickly," Zhang said In order to fundamentally solve the problem of repeated declaration and solve the backlog problem, the State Food and drug administration has recently taken a number of measures, including adding people On the basis of 120 compilations, 70 new reviewers have been recruited this year Fee increase On May 27, the latest "drug and medical device product registration fee standard" and implementation rules were issued, and the fee standard was greatly increased Taking the registration fee of domestic new drugs as an example, the adjusted fee standard increased from 35000 yuan to 624000 yuan, 17.8 times of the previous one In this regard, experts believe that the above measures will help to improve the efficiency of review and limit the low level of repeated declaration, but it is difficult to fundamentally solve the problem In their view, the key is to find the root of the disease and prescribe the right medicine "In addition to the small number of reviewers and low registration fees, a large number of repeated applications and misappropriation of review resources are the important reasons for the backlog of review." Guo yunpei said that of the 2427 newly declared generic drug applications in 2013, 1039 had more than 20 approval numbers, accounting for 42.8% of the total number of applications; 932 had less than 10 approval numbers, accounting for 38.4% of the total number of applications "Repeat application of generic drugs can be said to be shocking If this problem is not solved, the efficiency of evaluation cannot be improved." "We also need to ask: what are the root causes behind the large number of repeated applications of generic drugs? Are the incoming review items necessary? What good systems should be implemented as soon as possible?" Zhang Xianglin pointed out that "to solve the problem of review backlog, we should consider fundamentally and start from the system In addition to the old and the new, we should cancel the ones that should be cancelled, and implement the ones that should be implemented." It is necessary to cancel the approval of bioequivalence test In addition to phase III clinical trials, there is another kind of bioequivalence test of generic drugs In short, the test is to let the subjects take the same amount of generic drug samples and the original research reference drug products at different times, then test their blood concentration, calculate and compare the absorption degree and speed of their active ingredients in the human body, so as to evaluate whether the generic drug samples meet the approval requirements For bioequivalence test, approval is not required internationally, and enterprises can do it by themselves However, in our country, before the test, the enterprise must be reviewed by the drug Audit Center, and then it can be carried out after being approved; after the test, the enterprise shall submit relevant data and materials for listing review and approval As early as ten years ago, Li Weiping called for the approval of bioequivalence test to be cancelled, but it has not been adopted so far, one of the main reasons is the fear of safety problems "Bioequivalence testing generally does not raise safety concerns." Li Weiping said that the original research control drug used in the trial was approved for marketing long ago, and its safety has passed the clinical verification; the generic drug samples are developed by the enterprise with reference to the standard products, and the subjects take them according to the clinical specifications, so the risk is very low "Clinical approval should change with the development of pharmaceutical level." Zhang Xianglin said, "30 years ago, China's pharmaceutical level was not high as a whole I personally think the approval of this test is still necessary, otherwise there will be problems." But today, the production bases of all pharmaceutical factories in China have met the requirements of GMP (product production quality management standard), and the level of imitation has been generally improved The approval of bioequivalence test should be released " "Of course, after the opening up, the drug Audit Center will strictly audit the bioequivalence test data submitted by the enterprise." Li Ning said that it is necessary to go to the hospital to check the authenticity of clinical data, and also to the enterprise to check whether the samples used in the test are produced by themselves "If any fraud is found, they will not only veto the listing application, but also be severely punished, including the cancellation of the enterprise's Application qualification, production qualification and clinical qualification of the clinical hospital, which will make them lose more than gain." "The deregulation of bioequivalence test approval not only saves three or four years of waiting time and considerable review resources for enterprises, but also enhances the sense of responsibility and self-discipline of enterprises." Zhang Xianglin said that the original enterprise was "two reports and two batches" -- first clinical report and then listing, and the bioequivalence test was once closed by the drug Audit Center; after changing to "one report and one batch", the enterprise made its own bioequivalence test, and then listed together If the data is bad or fake, it will be rejected by one vote, and all the previous input will be wasted "The loss caused by" one report and one batch "is greater than that caused by" two reports and two batches " If you are an enterprise, which way is more serious? It must be" one report and one batch ", because your responsibility is greater and your investment is greater." "In the backlog of more than 18500 tasks to be reviewed, the bioequivalence test review of generic drugs accounts for nearly one third." Li Ning said that if this item is cancelled alone, the drug Audit Center will reduce the task volume by about 6000 The system of listing license should be implemented Many interviewees pointed out that the system of listing license should be implemented while the approval of bioequivalence test should be released The so-called listing license system refers to that the applicant of drug listing license can produce by himself or entrust qualified production enterprises with "OEM" The core of the system is to allow pharmaceutical enterprises to accept entrusted processing In China, the marketing license and the production license are tied together, and the drug approval number is only issued to the production enterprises with the drug production license, not to individuals and research and development institutions In other words, research institutions or scientists must invest in their own factories after developing new drugs, and cannot entrust enterprises to produce them On the other hand, enterprises can not accept commissioned production If they want to produce drugs, they have to develop and apply for registration "The" bundling "of listing license and production license has resulted in a large number of repeated declaration and construction." Zhang Xianglin said that there are now more than 4700 pharmaceutical enterprises in China If one enterprise applies for two products a year, it means more than 9000 Because it can't Commission production, the enterprise has to go on its own production line if it wants to get new products, and if it sells well, it will continue to expand Once the business is not good, the production equipment will be idle there, and the enterprise will have to find a new generic pharmaceutical newspaper - this is an annual increase of 1000 Important reasons for multiple clinical applications According to statistics, at present, the idle rate of equipment in Chinese pharmaceutical enterprises is more than 50%, resulting in serious false prosperity and a large number of capital precipitation As early as 2007, Li Weiping called for the implementation of the listing license system "After the implementation of this system, large enterprises do not have to build and expand production lines everywhere, and put their capital and energy on product research and development, quality control and brand maintenance Small enterprises can accept entrusted production, and do not have to work hard on their own research and development, self declaration - kill two birds with one stone, why not?" "the implementation of the Licensor system is the biggest incentive for new drug developers ”Song Ruilin pointed out that at present, there are many research institutions and R & D companies that do innovative drugs in China They have strong technical capabilities, but they lack funds and production bases If we implement the system of listing licensors and allow them to entrust production, they can spend their limited funds and energy on research and development "There are no legal obstacles to the implementation of the listing Licensor system." He said that Article 13 of the current drug administration law clearly stipulates that: with the approval of the drug regulatory department under the State Council or the drug regulatory department under the people's Government of the province, autonomous region or municipality directly under the central government authorized by the drug regulatory department under the State Council, drug manufacturing enterprises can accept the entrustment to produce drugs It is understood that the State Administration of food and drug will next prepare to launch pilot market licensors in innovative drugs To this end, Zhang Xianglin believes that the pilot should not be limited to innovative drugs - there are only a few innovative drugs in one year in China, and it is of little value to try and promote only in innovative drugs.