Medical network on April 7 - as early as 2016 on March 5, countries do hair [2016] no. 8 "the general office of the state council about to carry out the quality of generic drugs and curative effect evaluation of consistency opinions expressly pointed out:" the national list of essential medicines (2012 edition) on October 1, 2007 approved chemicals generics, oral solid preparations should be completed by the end of 2018 the consistency evaluation, which need to carry out clinical efficacy test and the variety of special circumstances, should be completed by the end of 2021 the consistency evaluation; exceed the time limit of unfinished, will not be registered again." Today, the consistency evaluation progress? What other problems? 

 

Published notice, opinions and guiding principles 

 

Since March 2015, according to the consistency evaluation, has published 10 policy documents, seven guiding principles, four guiding principles involving verification is for advice, the working train of thought of consistency evaluation gradually clear. 

 

 

 

Enterprise information reference preparations for the record 

 

As of April 1, 2017, announced the CFDA reference preparations for the record information for 4860, more than 1000 varieties, including different specifications) participation for the record, and consistency evaluation work as head of the engineering enterprise, enterprise attaches great importance to. 

 

 

 

Generic drug quality problems of consistency and curative effect evaluation 

 

1, evaluate varieties 

 

According to the current reference preparations for the record information table, some varieties appeared a "blowout" for the record, such as amoxicillin capsule for the record information 116, omeprazole enteric capsules for the record information 76, but there are also some directory 289 varieties have not yet had record for the record. Because of species has not yet been determined reference preparation or unable to get the reason such as the reference preparations, may need to choose consistency evaluation work by way of clinical efficacy. Single just for the record information provided by the data, it is not predict consistency varieties possible filing number, also depends on the government to release the relevant data, such as work plan according to the consistency of company submit evaluation, release excessive repetition of varieties and the shortage of varieties of possible directory, guide enterprises screening varieties for consistency. 

 

In the published reference preparations for the record information, can see a lot of varieties by the FDA warning (specifications), and there are better alternative varieties of drugs involved in the record. Pharmaceutical research should first because of its good clinical value, good safety and effectiveness, suggest that relevant departments for evaluation of consistency of varieties of initiation rationality give guidance. 

 

Released on April 5, 2017 CFDA generics quality consistency and efficacy evaluation variety classification guidance "pointed out:" the domestic special varieties. Choose by enterprises to carry out clinical trials to prove its effectiveness, safety and refer to the generic chemical medicine oral solid preparation quality and curative effect evaluation declaration data consistency requirements (try out) ", the filing of the subsequent audit after inspect through consistency evaluation; enterprise did not choose to carry out clinical trials, the state food and drug supervision and administration bureau announced its lack of effectiveness data, is not recommended ". Concept of "domestic special varieties" to further expand the scope consistency evaluation varieties, also shows the state drug quality improve further consideration. But what is a "domestic special varieties", has yet to have a clear concept of anecdotal think such varieties including the combination of Chinese and western, Chinese medicine extract preparations, etc., but consistency evaluation referred to as "generic quality consistency and efficacy evaluation variety", some "special" domestic varieties for domestic innovation varieties, even now provides exclusive varieties, such as varieties of generic quality consistency evaluation list, whether can enter remains unclear. 

 

2, in what way to carry out consistency evaluation 

 

At present to determine the reference preparations, can according to medicine contrast and BE consistency evaluation work study way, but there are many varieties in "see the left see right to see, I don't know what to do" period of hesitation. 

 

According to the reference preparations for the record information, large amounts of directory 289 varieties participated in the reference preparations for the record, in addition to the oral solid preparation, there are a large number of injection, oral liquid, inhalation preparation, dry suspension agent dosage forms, such as can be seen that enterprise in variety screening, evaluate the consistency of his main varieties to be highly valued. But because at present only released the generic chemical medicine oral solid preparation quality and curative effect evaluation declaration data consistency requirements (try out) ", the other guidelines is for oral solid preparation, the oral solid preparation should be how to develop the consistency evaluation, also need to further perfect guiding principles. 

 

In the record information, can see there are many varieties to declare as reference preparations, especially for directory 289 varieties, declare as reference information quantity of even far more than 289 varieties of directory. But declare as to which reference preparations, how to prepare for declaration data and submit the declaration data, as well as the reference preparation declare the review process is not yet clear. There is also a reference preparations to recommend a variety such problems. 

 

On March 17, 2017 and released on March 20, the reference preparation directory, released 84 varieties of the reference preparation (including different specifications), currently has more than 1000 varieties compared to submit the reference preparations for the record information, reference preparation to confirm the work done only about 8.4%, compared to the early stage of the enterprise to submit reference preparations for the record information and reference for the final preparations, major differences do exist in the previous companies and regulators, the choice of the reference preparation at present is still the bottleneck of restrict consistency evaluation schedule. 

 

Released on April 5, 2017 CFDA generics quality consistency and efficacy evaluation variety classification guidance ", according to the original property varieties, in order to "audit determined by the state food and drug administration is released, can be selected as the reference preparation" a word, in the draft, the original property varieties in the "pre-ipo whether according to the consistency with the original drug quality and curative effect evaluation of application and review of the principle of" there are two types of evaluation; In network version of the guidelines, the original property varieties in the "production process is changed" since going public is divided into two types of evaluation, the official draft statement makes the original property of varieties of uncertain future. If real estate varieties approved, will be the reference preparations, so whether generics firms need to wait for real estate varieties of audit result to carry out consistency evaluation? If property change varieties is not approved, this kind of variety and will go? The guidelines also pointed out that "the domestic variety" unique "to carry out clinical trials to prove its safety effectiveness". CFDA "about the implementation of" the state council general office on the opinions of the consistency to carry out the quality of generic drugs and curative effect evaluation > announcement of relevant matters of no. 106 (2016), to find, or unable to determine the reference preparations, effectiveness by the pharmaceutical producing enterprises to carry out the clinical trial, was not called for safety evaluation, on February 7, 2017 CFDA released "generic quality consistency and curative effect evaluation of clinical efficacy test generally consider", only to illustrate the effectiveness of experiment, how to carry out the safety evaluation of this kind of variety, has yet to be further discussed enterprise, guiding principle to further improve. 

 

3, financial support 

 

With consistency evaluation work, enterprises gradually realized that single consistency evaluation may far exceed the cost of the original is expected to 5 million yuan, is only a reference preparations, purchase cost around $20000 on average, entecavir and adefovir varieties such as reference preparation purchases is up to an astonishing $150000. With the understanding of the pharmaceutical research, many enterprises realize that one of the difficult points of consistency evaluation of pharmaceutical research shift in pilot - production link, the need for more batches or even dozens of batch production research, to ensure the controllability of listed after the production process and product quality control. Enterprises will face a large amount of raw materials costs, in the case of amoxicillin capsules, complete the three batch production research, raw material cost is about 900000 yuan. BE (bioequivalence) cost is the most big spending, consistency evaluation at the beginning of 2016, 5 million yuan of the cost of BE regarded as the day price, but as we know to BE test constantly, single BE cost gradually in 3 million - 5 million is regarded as reasonable. According to the known conditions, however, BE a through case does not see more, former senior American FDA review officer Wei Xiaoxiong pointed out: the international BE average passing rate is only 48%, still only 50% pass rate after improvement, even if again or there will BE some not through a third time. Many times BE trials will greatly increase the consistency evaluation of spending on research and development, most needs to BE consistency evaluation of the experiment is complete varieties, the individual will reach more than 10 million varieties of cost budget. 

 

To encourage enterprises to carry out the consistency evaluation work, some methods to local governments issued a series of financial support, varieties of complete consistency evaluation, 100000-4 million or so, but compared to the required consistency evaluation of high development costs, the government's financial support is not enough to the emergencies. In addition to Daniel company self-raised funds to carry out many kinds of consistency evaluation, some small and medium-sized enterprises may need to introduce technology of vc, CRO stake in such ways as consistency evaluation work. 

 

4, time limit problem 

 

Time limit has been everybody worry and hot issues. 2018 and 2021 deadline to a great extent, arouse the enthusiasm of the consistency evaluation personnel, and greatly improve the efficiency of the consistency evaluation. But given the job of a variety of difficulty, consistency evaluation of time limit also produced some negative effects, such as the present stage, as the record information of the public, 289 directory appeared some varieties have not yet registered varieties, some companies are considering whether to start this kind of variety research, tend to hold only more than 20 months from the end of 2018, to complete the whole project research is almost an impossible task. Have introduced varieties of consistency evaluation, at the same time, if cannot one-time pass BE, before the end of 2018 is likely to BE also unable to complete consistency evaluation work. 

 

summary 

 

Generic drugs in our country quality and curative effect evaluation is a consistency in many companies and many varieties of mega project, its difficult and complex degree is unprecedented, r&d knowledge is weak and lack of research and development environment and so on has made the work difficult. The good news is, we see consistency evaluation has been steadily advancing, exist many problems in the work, subject to enterprise actively working together to solve.