Clinical effectiveness evaluation is a necessary supplementary course for generic pharmaceutical enterprises

[news] recently, CFDA organized the drafting of "general considerations for clinical effectiveness test of conformity evaluation of quality and efficacy of generic drugs (Draft for comments)", and asked for comments from the public before October 15 This document is a supplement to the previous guiding principles, such as technical guidelines for bioequivalence research of chemical drug generic human body with pharmacokinetic parameters as the end point evaluation index Since the opinions of the State Council on the reform of the review and approval system for pharmaceutical and medical devices (GF [2015] No 44) in August 2015 and the opinions of the general office of the State Council on the evaluation of the quality and efficacy of generic drugs (GF [2016] No 8) in early 2016, the State Food and drug regulatory authorities have made it clear that generic drugs must be divided into batches / points Step to evaluate the consistency of quality and efficacy In the technical route, the bioequivalence test with the reference drugs (preparations) is the main method The dissolution behavior of high dissolution and high permeability generic drugs (refer to BCS-1 classification) under different conditions is consistent, and the comprehensive clinical evaluation is combined to promote Subsequently, the competent authorities successively issued the general principles for the selection and identification of reference preparations, and the enterprise level successively recommended and filed the reference preparations Judging from the promotion of the evaluation of the consistency of quality and efficacy of generic drugs, there are still a considerable number of generic drugs that are difficult to find or determine the reference preparation due to various reasons For the consistency evaluation of quality and efficacy of this kind of generic drugs, the draft of this consultation made it clear that clinical effectiveness test must be carried out for evaluation The opinion draft once again explains the principle that the clinical value of generic drugs should be the highest standard for the consistency evaluation of quality and efficacy of generic drugs For many years, there has been a dispute between "dissolving group" and "be group" for the technical route of conformity evaluation of generic drugs The former is based on the practice of promoting the quality improvement of generic drugs in Japan in recent years, and according to the reality of low-level repeated development of China's industry, it should be said that it has a certain industrial public opinion basis However, there is still a statistical basis of "false negative" and "false positive" in the logic of the method of evaluating the consistency between the quality and efficacy of generic drugs by fitting multiple dissolution curves and the dissolution curves of reference preparations under different conditions: the former corresponds to the risk of drug quality of patients, while the latter corresponds to the risk of false evaluation of enterprises At the same time, it should be objectively recognized that while Japanese drug regulatory authorities promote the consistency evaluation of dissolution behavior, the basis of their work is still the consistency of be evaluation conclusions of generic drugs Therefore, when deciding the technical route of the conformity assessment of quality and efficacy of generic drugs, the competent authorities in China finally chose the general criterion under the ICH regulatory framework, that is, the biological evaluation of generic drugs as the basic principle of the conformity assessment This technical route is also consistent with the "five step strategy" of mainstream drug regulatory system to evaluate the consistency of quality and efficacy of generic drugs: consistent pharmaceutical basis; production under cGMP specification; bioequivalence; consistent label (instruction); and clinical equivalence After the above technical route is determined, for the pharmaceutical industry system dominated by generic drugs in China, the technical pressure, economic pressure, policy pressure and market risk brought by the consistency evaluation of quality and efficacy of generic drugs are self-evident For most enterprises, in order to meet the requirements of quality and efficacy evaluation of generic drugs, they need to make great determination and make great efforts to promote the relevant work In this document release, the evaluation requirements for the consistency evaluation of generic drugs with unclear evaluation technology and lack of reference preparation are specified, which must be finally carried out in the way of clinical efficacy verification The design, implementation, summary and report of the experimental scheme invested by generic pharmaceutical enterprises must be put on the agenda In view of the time phased objectives of the quality and efficacy evaluation of generic drugs have been clear, the generic drugs that can not pass the consistency evaluation will face the fate of access and exit at that time, the relevant enterprises should take the situation into consideration and make rational decisions Of course, it should also be noted that even if the clinical effectiveness test is required to evaluate the consistency of the generic drugs that cannot be found and the reference preparation cannot be determined, in the technical principle of this opinion draft, only the evaluation standard of "placebo-controlled or positive control for the superiority or non inferiority test" is proposed, which is what the generic drugs should have in clinical The most basic requirement of curative effect is not unattainable This requirement is only the minimum legal requirement for "drugs" If even this standard can not be met, the relevant varieties should not be qualified to exist as "drugs", and should be resolutely removed from the market In this sense, like the requirements of pharmaceutical equivalence and bioequivalence of drugs, the clinical effectiveness evaluation of generic drugs is only a required course that our country's generic drug industry has to fill up the historical deficiencies There is no doubt that the opinion draft is an important implementation step of GBF [2016] No 8 document Human bioequivalence test is the main clinical basis to support the listing of generic drugs For chemical generic drugs that cannot be found and can not be confirmed as reference preparations, manufacturers carry out the clinical effectiveness test of generic drugs to ensure that patients can use drugs with good efficacy, which will bring new impact on the application of Chinese generic drugs 1 The requirement of reducing low-level duplication for generic drugs has been raised, which will certainly increase some R & D costs, which will urge pharmaceutical companies to evaluate whether they are in urgent need of clinic and market return rate when choosing generic drugs without reference preparation, and reduce repeated application 2 The opinion draft on tracking the development progress of similar drugs stipulates that the "effectiveness" of experimental drugs shall be compared in clinical trials, and the preliminary judgment shall be made according to the background information and evidence-based medicine evidence first, which will urge pharmaceutical enterprises to conduct feasibility analysis and evaluation on the same type of drugs and track the progress of similar drugs before investing in the research and development of generic drugs 3 In-depth study of relevant policy opinions, it is pointed out that the opinions and other relevant documents of clinical trials should be referred to, and pharmaceutical enterprises must conduct in-depth study of relevant documents and regulations Due to the particularity of the clinical trial process, based on these documents, if the competent department can guide according to different research and development fields and different types of drugs, it will be more conducive to the implementation of the new generic drug policy 4 It is worth noting that it is more difficult to evaluate the efficacy of generic drugs if only placebo is used There is no reference preparation in the market and it is urgently needed in clinical practice, which shows that the lack of the same type of drugs in the market means that there is no reference scheme for clinical trials, and there is a need for corresponding guiding principles of clinical research, so as to reduce the detour, the cost of R & D funds and time, and make the cheap generic drugs come into the market as soon as possible In addition, the judgment of clinical end point, the choice of alternative end point and markers are also the key to the success of clinical trials for drugs that are urgently needed and have no reference preparations Before the determination, increasing the interaction between drug companies and review experts is conducive to improving the probability of success of clinical urgently needed generic trials Whether to invest or not depends on the clinical value As a supplementary document to the guiding principles such as the technical guidelines for bioequivalence research of chemical drug generic human body with pharmacokinetic parameters as the end point evaluation index, and the circular on the issuance of Biostatistics guiding principles for clinical trials of drugs, this exposure draft puts forward the technical operation level of "clinical effectiveness test for consistency evaluation of quality and efficacy of generic drugs" More specific principles and requirements The opinion repeatedly emphasizes the clinical value of generic drugs in the existing treatment Personal understanding is that it repeatedly reminds researchers that not only the clinical value of new generic drugs should be considered first, but also the clinical value of existing generic drugs should be paid attention to first if the clinical effectiveness test needs to be carried out in the consistency evaluation study Based on its background information and evidence-based medical evidence, if the results of preliminary judgment of clinical effectiveness can not withstand scrutiny, there is no need to make meaningless investment (Chen zhouquan)