Is it really useless to compete for the first imitation?

In March 2016, the drug review center of the State Food and Drug Administration issued the 2015 drug review report In 2015, the number of chemical validation clinical approvals reached 2050 Such a high number of clinical approval documents confirmed the previous argument of the industry: "under centralized review, clinical approval documents are approved in batches, and it is useless to compete for the first copy" Is it really useless to compete for the first imitation? In the United States: the first example is to establish an effective balance between the incentive of drug innovation and the promotion of accessibility Let's review the situation in the United States As early as 1984, FDA put forward the concept of first imitation At that time, the United States passed the drug price competition and patent period recovery law, which said that under the condition that "the patent is invalid or the approval of the drug being applied will not infringe the patent", the first copy applicant will have 180 days of market monopoly The bill establishes an effective balance between the incentive and accessibility of drug innovation, that is, to establish an innovative drug data protection system, and to encourage the research and development of innovative drugs by giving it a five-year market monopoly; At the same time, the patent declaration mechanism is used to challenge the monopoly period of innovative drugs, so as to speed up the listing of generic drugs The priority review was proposed by FDA in 1992 In 1992, according to the prescription drug users act (PDUFA) and FDA approval, in order to speed up drug review, the two-level review time system (standard review and priority review) was established The priority review cycle was 6 months and the standard review cycle was 10 months The priority review determination aims to guide the overall attention and resources to the review of such applications FDA improves the speed of drug review by increasing the input of human and material resources The above two policies still exist The first simulation establishes an effective balance between the incentive of drug innovation and the promotion of accessibility The process of establishing the balance is also the process of the game between the original drug manufacturer and the generic drug manufacturer The early listing of generic drugs has brought consumers cheap drugs, but it has damaged the vested interests of the original drug manufacturers In order to reduce the economic losses caused by the listing of the first generic drugs, the original drug manufacturers have taken many legal measures in the practice process, among which "authorized generic drugs" is one of the means for the original drug manufacturers to deal with the competition of the first generic drug applicants Authorized generic drugs refers to the act that the holder of new drug application approval (usually also the holder of new drug patent) signs license production and sales authorization agreement with the third-party distributor to allow him to sell generic drugs Authorized generic drugs can only be marked with the generic name of the drug, but compared with ordinary generic drugs, its advantage lies in the convenience of registration and approval, that is, when applying to FDA for approval of authorized generic drugs, the authorized generic drug manufacturer does not need to challenge the original research drug manufacturer's patent, and only relies on the NDA application materials of the original research drug to obtain FDA approval The legal consequences of the authorized generic drugs after the approval of listing are equivalent to the brief new drug application In fact, in the oligopoly competition in which there are only two sales agencies in the 180 d exclusive period of the first generic drugs, the third-party competition units are added and the market monopoly effect of the first generic drugs manufacturers is reduced The first generic drug data protection system in the United States takes into account the interests of both innovators and first generic drug dealers On the one hand, it gives exclusive market incentives to the listing of first generic drugs, effectively reducing the drug price; on the other hand, it allows authorized generic drugs to be sold at the same time, which protects the interests of innovative drug manufacturers to the greatest extent, is an important supplement to the American drug innovation incentive system, and ensures the balance between drug innovation incentives and promoting accessibility In China, the concept of the first imitation is still unclear There are two opinions about the first imitation in China Some people think that the first imitation produced and sold in China is the "first imitation", mainly referring to Article 10 of the "drug price management measures" issued by the national development and Reform Commission in 2006 The price of the same kind of generic drugs that meet one of the following conditions is allowed to rise appropriately on the basis of unified pricing after being demonstrated by experts: (1) the quality, efficacy and safety of the drugs are obviously superior to that of the same kind; (2) the drugs that have won the national major technological progress or innovation awards; (3) the drugs that are first manufactured and marketed in China ; 6 (4) upgrading the original national standards and being determined as the new formal national standards Others believe that the first generic drug should be the first clinical generic drug After the 731 event last year (CFDA No 140, 2015), the State Council issued the opinions on reforming the review and approval system of medical devices (GF [2015] No 44), in which for the first time, the word "first generic drugs" was really mentioned （10） Implement the main responsibility of the applicant The registration application specification shall be formulated in accordance with the international general rules, and the applicant shall apply in strict accordance with the specified conditions and relevant technical requirements The drug registration applications accepted by the provincial food and Drug Administration and reviewed and approved by the food and drug administration shall be adjusted to the centralized online acceptance by the food and drug administration For the registration application that does not meet the specified conditions and relevant technical requirements, the food and drug administration shall inform the applicant of the content to be supplemented at one time After entering the technical review procedure, except for the registration application of new drugs and first generic drugs, in principle, the applicant is no longer required to supplement information, and only makes the decision of approval or disapproval In the announcement of the State Council, it is clear that the first generic drug here refers to the first generic drug to declare clinical application No 19 document of 2016, i.e opinions of the General Administration on the implementation of priority review and approval for solving the backlog of drug registration applications, is once again clear about the scope of priority review by CFDA There are two pieces of information in the opinion draft related to the problem of first imitation "Application for clinical trials of drugs 3 years before the expiration of the patent and application for production of drugs 1 year before the expiration of the patent." Looking back at the patent issue that was widely discussed in Document No 140 in 2015, there was no relevant word in the document issued by the State Council, but it was mentioned again in this opinion draft Some people in the industry think that the introduction of this policy means that we don't need to rush for the first copy any more Anyway, three years before the patent expires, we can report together In fact, the enthusiasm of domestic enterprises to apply will not be extinguished because of this Firstly, patent infringement is not CFDA's responsibility In fact, CFDA's review and approval is rarely refused because of patent Instead, it is the original manufacturer's appeal after the approval of drug approval, and the approval will be cancelled only after the patent protection is effective In this case, if powerful enterprises can do a good job in patent system research, it is possible for them to launch the challenge of patent invalidity and strive for the position of first imitation, just like the production enterprises in the United States Secondly, the first copy in China seems to be more like the concept of time, and the first copy can be obtained if the acceptance number is reported first It's better to declare early than to queue late For example, drugs such as enzalutamide and irutinib, which will not expire until ten years later, expire in 2026 However, 10 enterprises of enzalutamide are applying for clinical application, and 8 enterprises of irutinib are also reporting If the enterprises want to do these two projects are still waiting for the patent to expire three years ago, they may be in line for Taiping Ocean "For the application of generic drugs urgently needed in clinic and short of market, from the date of publication of the product, the application for priority review and approval of new application varieties with the same active ingredients and administration route will not be accepted." That is to say, if a variety meets the requirements of the priority review and the first copy of the variety is recognized by the publicity to allow the priority review, the enterprises declared after the publicity date cannot obtain the qualification of the priority review This shows that in China, judging the qualification of priority review and approval attaches great importance to the time of administrative examination and approval, and encourages and guides enterprises to report first, get first, and establish a competitive environment that challenges the original research Of course, according to the documents of the conformity regulations, the quality of the project also needs to be taken into account Policy preferential treatment with the original research quality and patent system, R & D efficiency of high generic pharmaceutical enterprises To sum up, whether it is "priority review" or "first imitation" is a process of improving and developing CFDA review system Through the above laws and regulations, we can find that the "first imitation" still has some advantages As shown in the table below, the advantage of the first imitation is to allow a certain range of "trial and error" and preferential treatment on the time of entering the sales channel It is true that the pursuit of first imitation by pharmaceutical enterprises results in the waste of resources and wealth of the company After all, it can not immediately create profits if it is seized Early application before the expiration of patent will lead to the idle of a large number of clinical approvals of the variety, thus reducing the value of clinical approvals On the other hand, we should not put the existing R & D pipeline of the company on hold because of the introduction of priority review and excessive anxiety about the cost-effectiveness of the project As a balance mechanism of management, enterprises should fully evaluate their own competitive advantages, project returns and enterprise capital status before deciding whether to participate in the relevant competition   As for the clinical approval obtained under the relatively "loose" environment of clinical review and approval, the enterprise shall fully evaluate the existing registration environment, the value of the project, the change of product strategy of potential competitors and the possibility of clinical development, and the enterprise shall not be anxious about the centralized clinical approval After all, the new product is the future and fundamental of the manufacturing enterprise, and the enterprise can develop according to its own research and development The funding and priority of the project will be carried out within the validity period of the three-year approval As long as we try our best to improve the efficiency of R & D, improve pharmaceutical materials, and make the R & D process more compliant, we can cope with the changing policies in 2016 Author: Zhao Jiachen works in Nanjing Huawei Pharmaceutical Co., Ltd., focusing on new drug research and development information and international pharmaceutical market [this article is published by the author's authorized new drug collection, some contents have been modified, please indicate the source of Reprint: new drug collection]