Policy Interpretation of the Announcement on the Evaluation of the Quality and Efficacy Consistency of Generic Drugs

I What is the background and significance of the Announcement on the Evaluation of the Quality and Efficacy Consistency of Generic Drugs (2017 No. 100, hereinafter referred to as the Announcement)?
Since the issuance of the Opinions of the General Office of the State Council on Conducting the Evaluation of the Consistency of the Quality and Efficacy of Generic Drugs (GBF [2016] No. 8), the evaluation of the consistency of the quality and efficacy of generic drugs (hereinafter referred to as the consistency evaluation) has been steadily promoted. Some enterprises have completed part of the variety research and entered the application and evaluation stage. In order to further strengthen the guidance to enterprises and improve work efficiency, our bureau has summarized and analyzed the preliminary work, studied and formulated this Announcement, and optimized and adjusted all links of consistency evaluation, aiming to ensure smooth connection of acceptance, inspection, inspection and review, and ensure unified evaluation standards.
2、 What optimization measures are proposed in the Announcement for the determination and acquisition of reference preparations?
In order to facilitate enterprises to carry out research work, the State Administration has issued 8 batches of 610 varieties and specifications of reference preparations, Including 163 varieties (219 product specifications) in the Catalog of Varieties Subject to Conformity Evaluation of Generic Drugs by the End of 2018 (hereinafter referred to as the "289 Variety Catalog") published in the Announcement on the Implementation of Relevant Matters of the Opinions of the General Office of the State Council on Carrying out the Evaluation of the Quality and Efficacy Consistency of Generic Drugs (2016 No. 106). There are about 90 varieties in the catalog that have changed their specifications, dosage forms and bases, According to the technical guidelines such as General Considerations for the Evaluation of Modified Drugs (Oral Solid Preparations) in the Evaluation of the Consistency of the Quality and Efficacy of Generic Drugs, General Considerations for the Evaluation of Modified Drugs (Oral Solid Preparations) in the Evaluation of the Consistency of the Quality and Efficacy of Generic Drugs, and General Considerations for the Evaluation of Modified Base Drugs in the Evaluation of the Consistency of the Quality and Efficacy of Generic Drugs The basis for selecting reference preparations of about 90 varieties of modified base has also been clarified. So far, guidance has been given for the selection of reference preparations of most varieties in the 289 Variety Catalog. On the one hand, the Announcement further clarifies the selection order of reference preparations, on the other hand, it clarifies that our bureau will continue to select and confirm reference preparations filed by enterprises, and release the reference preparation catalogue if it meets the requirements of reference preparations.
With regard to obtaining reference preparations, enterprises can obtain reference preparations by applying for one-time import applications, import filing, customs clearance and other procedures. In addition, the Announcement specifies that enterprises can also obtain reference preparations by other means. When submitting conformance evaluation materials, they only need to provide purchase vouchers, product packaging, instructions and other materials in the materials, or use other appropriate methods to prove the authenticity of reference preparations.
3、 Is the responsibility of the enterprise clearly defined for the enterprise's independent behavior in selecting reference preparations? Article 3 of the Announcement puts forward that if an enterprise purchases reference preparation products from abroad on its own, and finds that the reference preparation products used are counterfeit products, the enterprise shall terminate the relevant work in a timely manner, and "exempt from liability as the case may be". What circumstances shall be exempted from liability? How to grasp the standards, and how to ensure the accurate implementation of accountability and exemption, without unintentional injury or connivance?
The enterprise is responsible for the selection, purchase and use of reference preparations and the whole process. If the reference preparation product is found to be a counterfeit product, the State Administration will conduct an investigation according to law. According to the investigation results, if there is evidence proving that the enterprise chooses a counterfeit product due to non subjective factors, it can be exempted from liability.
4、 What solutions are proposed in the Announcement to solve the problem of insufficient clinical institutions?
In view of the "insufficient" problem of bioequivalence test institutions, the Announcement proposed that: first, bioequivalence test institutions should be subject to the filing system. The bioequivalence test in the consistency evaluation can be conducted in the existing recognized clinical trial institutions or other qualified institutions. In the early stage, our bureau, together with the Health and Family Planning Commission, has determined 619 clinical trial institutions. Our bureau is studying and formulating supporting regulations related to record management. Second, the relevant conditions and methods that meet the exemption conditions or can be exempted from evaluation are proposed in Articles 6, 7, 8 and 9 of the Announcement, and unnecessary bioequivalence tests are reduced according to scientific judgment.
V According to the Announcement, the initiator of bioequivalence test can hire a third party with evaluation capability to carry out the evaluation of bioequivalence test institutions according to GCP. How to clearly define the third-party evaluation capability?
The bioequivalence test in the consistency evaluation can be conducted in the existing recognized clinical trial institutions or other qualified institutions. If it is selected to be conducted in other qualified institutions, the sponsor of bioequivalence test can hire a third party with evaluation ability to evaluate the institutions conducting bioequivalence test according to the requirements of the Good Clinical Practice for Drugs (GCP). The third-party evaluation is an effective external improvement mechanism, which can make up for the deficiencies of some sponsors who cannot accurately and systematically evaluate the institutions to be selected due to their limited capacity. The third party assessment institution shall be responsible for the assessment results. It is necessary to give full play to the decisive role of the market in resource allocation. Through market-oriented competition, the sponsor can choose a third party with good foundation, rich experience and broad market recognition. Relevant industry organizations can improve the third-party evaluation mechanism by formulating self-discipline industry rules and technical specifications.
6、 For varieties that conform to the Guiding Principles for Exemption of Human Bioequivalence Test, and varieties that are not suitable for human research, enterprises can apply to the General Administration for exemption and explain the reasons. How about the exemption process? Are there any relevant regulations?
In the work of consistency evaluation, the bioequivalence research of some varieties exempted from human body should be treated scientifically and prudently. Relevant exemption requirements of enterprises can be proposed according to the following process:
(1) The applicant can submit an application to the Drug Evaluation Center of the State Administration of China, which includes the specific situation of the variety, the scientific basis for exemption from human bioequivalence test (hereinafter referred to as BE), etc., and send a document to the Drug Evaluation Center of the State Administration of China to apply for exemption from BE. The Drug Evaluation Center of the State Administration of China will give a reply after evaluating the specific situation of the variety.
(2) For the exempted varieties published by the State Administration, the applicant can indicate the exemption in the additional application items when applying for consistency evaluation, and submit the relevant basis for exemption in the application materials. The Drug Evaluation Center of the State Administration will conduct evaluation according to the specific conditions of the varieties.
VII The Announcement mentioned that when an enterprise submits an application for consistency evaluation, it needs to be rechecked and inspected by relevant institutions. Can it be inspected by a third party? What are the specific criteria for selecting a third-party organization? If there is cause based verification and sampling inspection in the review process, which institutions should be submitted for inspection?
When an enterprise submits an application for consistency evaluation, the application materials shall include the drug review and inspection report. The applicant may conduct the inspection by himself or entrust a statutory drug inspection agency or other third-party inspection agency. For the varieties that have been announced by the consistency evaluation office of the State Administration before the release of the Announcement and are subject to centralized review and inspection by relevant drug inspection institutions, the enterprise may conduct inspection in this inspection institution or other institutions. The organization issuing the inspection report shall pass the laboratory qualification certification and national laboratory recognition, meet the requirements of drug inspection in terms of organization, management system, inspection capacity, personnel, environment and facilities, equipment and reference materials, and have the ability to carry out drug inspection.
During the evaluation, the Drug Evaluation Center may propose to inspect the declared varieties, and the Center shall organize sampling and then submit it to the statutory drug inspection agency for inspection. For the varieties that have been announced to have a review and inspection agency, the designated agency will conduct inspection; For those not designated, the consistency evaluation office of the State Administration of Taxation shall designate them separately.
8、 With regard to the varieties of reference preparations that are not clear, how can the enterprise solve the consistency evaluation problem, whether to wait for the expert advisory committee to determine before carrying out the evaluation, or to propose other solutions to ensure that the enterprise completes the evaluation within the specified time limit?
The Drug Evaluation Center of the State Administration of Food and Drug Administration will organize research and discussion as soon as possible on issues related to unclear reference preparation varieties; The applicant can also provide consultation according to the variety situation and the Notice on Further Strengthening the Consultation Service Related to Consistency Evaluation issued by the Drug Evaluation Center of the State Administration, and the Drug Evaluation Center of the State Administration will reply after research.
9、 What incentive policies have been established for centralized drug procurement through consistency evaluation of varieties? How to ensure the implementation of these policies? What is the expected impact on market supply?
According to the Opinions of the General Office of the State Council on Carrying out the Evaluation of the Consistency of the Quality and Efficacy of Generic Drugs (GBF [2016] No. 8), the drug varieties that have passed the consistency evaluation should be properly supported in terms of medical insurance payment, and medical institutions should give priority to procurement and clinical use. If there are more than 3 manufacturers of drugs of the same variety that have passed the consistency evaluation, the varieties that have not passed the consistency evaluation will not be selected for centralized drug procurement. Through consistent evaluation of the technological transformation of drug manufacturers, they can apply for central infrastructure investment, industrial funds and other financial support if they meet the relevant conditions. The Opinions of the General Office of the State Council on Further Reforming and Improving the Drug Production, Circulation and Use Policy (GBF [2017] No. 13) further stipulates that for drugs that pass the consistency evaluation, relevant information should be released to the public in a timely manner and included in the list of alternative drugs with the original drugs. If there are more than 3 manufacturers of drugs of the same variety that have passed the consistency evaluation, the varieties that have not passed the consistency evaluation will not be selected for centralized drug procurement; If there are no more than 3 suppliers, the products that have passed the consistency evaluation shall be preferentially purchased and used. Relevant departments will speed up the formulation of payment standards for medical insurance drugs under common names, and form an incentive mechanism conducive to consistent evaluation of the use of generic drugs as soon as possible. In the later stage, our bureau will cooperate with relevant departments to refine and support the policies. The above will create a policy environment for supporting the fittest, improve the concentration of the pharmaceutical industry, guide advantageous enterprises to form scale effects, reduce costs, ensure market supply, and promote enterprises to form a large-scale and specialized production pattern.
X Article 16 of the Announcement mentions that the mark of "passing the consistency evaluation" is the mark of the drug label and instructions that are used to pass or deemed to pass the consistency evaluation. Does the enterprise need to apply for the change of drug instructions?
In the Announcement, it is proposed that our bureau will issue an announcement on the varieties that have passed the consistency evaluation. This work will be considered as a whole with the preparation of the "orange book" in the future, and a special class of announcement will be issued to clearly publish the drug catalog and related information that have passed the consistency evaluation, and on this basis, it will be continuously improved and developed to form the "orange book" in China. For the varieties that have passed the consistency evaluation, the domestic drugs shall be reported to the provincial food and drug regulatory authority for filing, and the imported drugs shall be reported to the State Food and Drug Administration for filing. After that, the label of "passed the consistency evaluation" can be used in the instructions and labels.
XI Does the Announcement adjust the content of the documents related to consistency evaluation previously issued?
The contents of this Announcement mainly adjust the working procedures for acceptance, review, verification and inspection of consistency evaluation, and supplement the unspecified matters in the previous documents, such as the Notice on Issuing Three Technical Guiding Principles for the Selection and Determination of Reference Preparations for Ordinary Oral Solid Preparations (Circular of the State Food and Drug Administration, 2016, No. 61) The relevant contents in the Announcement on the Implementation of the Relevant Issues of the Opinions of the General Office of the State Council on the Implementation of the Evaluation of the Quality and Efficacy Consistency of Generic Drugs (Announcement No. 106 of the State Food and Drug Administration in 2016), the Announcement on the Issuance of the Procedures for the Evaluation of the Quality and Efficacy Consistency of Generic Drugs (Announcement No. 105 of the State Food and Drug Administration in 2016) and other documents have been adjusted according to the implementation of the previous consistency evaluation.
12、 For example, before the end of 2018, some varieties of oral solid preparations of essential drugs could not complete the consistency evaluation. What are the considerations of the Food and Drug Administration?
The enterprise shall, in accordance with the requirements of the Opinions of the General Office of the State Council on the Evaluation of the Consistency of the Quality and Efficacy of Generic Drugs (GBF [2016] No. 8), complete the evaluation of the consistency of the varieties of oral solid preparations of essential drugs on time. The State Administration will continue to strengthen its guidance to enterprises, scientifically organize the review and pay close attention to the progress of varieties. For the varieties that affect the market supply due to the small number of manufacturers passing the consistency evaluation, the General Administration, together with relevant ministries and commissions, will issue a list to encourage enterprises to research and develop generic drugs to ensure the market supply.
13、 If it is listed in the EU, the United States or Japan but not in China, and there is no racial difference after clinical research, it can use the bioequivalence research, pharmaceutical research data and other technical materials declared for overseas listing to apply to the State Food and Drug Administration for listing; If there may be racial differences, corresponding clinical trials should be carried out. Those passing the review shall be deemed to have passed the consistency evaluation. Why consider racial differences?
For generic drugs that have been listed in Europe, the United States and Japan, they can use the bioequivalence research, pharmaceutical research data and other technical materials declared for overseas listing to apply for listing, proving the consistency of their quality and efficacy with the original research. However, since this product has not been marketed in China, there may be racial differences. Therefore, whether its usage and dosage are applicable to Chinese people needs further experimental research.
14、 What kind of policies will the State Administration introduce to guide the originally developed varieties?
The Announcement has specified the path for the original research enterprises to apply for reference preparations of varieties produced and listed in China, and the State Administration will subsequently issue detailed data requirements. If there is no major change after the listing, or if there is a major change after the listing but it does not affect the quality and efficacy after the review, it can be included in the reference preparation list after the review and verification of the General Administration, and it will be uniformly released during the release of the reference preparation list.
In case of major changes after the listing and differences in the quality and efficacy of the same products from the country of origin, the enterprise shall issue a statement on its own, explain the differences and reasons, and conduct consistency evaluation as required.
15、 Does the enterprise have a channel for feedback when it encounters problems in carrying out consistency work?
For specific problems encountered in the research, enterprises can consult the Center in accordance with the Notice on Further Strengthening Consultation Services Related to Consistency Evaluation issued by the Center. The Drug Approval Center will study the problems raised by the enterprise.
XVI In the second paragraph of Article 8 of the Announcement, for the generic drug registration application that is being reviewed and accepted according to the original chemical drug registration classification, the applicant applies to the Drug Evaluation Center of the Food and Drug Administration for review according to the standards consistent with the quality and efficacy of the original drug. What channels can be used to apply?
In the case of Paragraph 2 of Article 8 of the Proclamation, the applicant may submit a written application to the Center for review according to the standards consistent with the quality and efficacy of the original drug, and pay the additional fees according to the relevant provisions.
17、 As the deadline for the end of 2018 approaches, there is not much time left for enterprises. What measures will the State Administration take to promote the consistency evaluation, such as how to consider the original developed varieties, how to guide enterprises to obtain reference preparations, how to apply for BE exemption, whether the regulatory department can classify drugs according to the actual situation (such as whether the accessibility of reference preparations, clinical efficacy and other indicators are clear), evaluate the consistency in batches and stages, and appropriately extend the time for some special varieties?
The Announcement has specified the path for the original research enterprises to apply for reference preparations of varieties produced and listed in China, and will issue detailed data requirements later.
In order to facilitate enterprises to carry out research, the State Administration has issued 8 batches of reference preparations with 610 varieties and specifications, including 163 varieties in the 289 Variety Catalogue. About 90 varieties in the catalog are those with modified specifications, modified dosage forms and modified bases. According to the technical guidelines related to the consistency evaluation of the modified specifications, modified dosage forms and modified bases of generic drugs, about 90 varieties with modified specifications, modified dosage forms and modified bases are listed above