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Analysis on the Influence of New Regulations of Chemical Generic Drugs on R & D and Registration

  • Author:Jane
  • Source:China New Drug Journal
  • Release on :2017-05-18
The Change of the Concept of Generic Medicine in China

Changes in the concept of generic drugs in China The concept of generic drugs from China in 2001 issued by the "People's Republic of China Drug Administration Law" and the 2002 issued by the "People's Republic of China Drug Administration Law Implementation Regulations", the management law and its implementation regulations There is a concept of national standard medicine. The State Food and Drug Administration issued in 2002 (abolished), and in 2007 revised the "Drug Registration Management Measures", clear drug registration applications, including new drug applications, generic drugs and other applications, including new drugs that have not been in China Listed drugs. Generic medicine refers to the production of the State Food and Drug Administration has approved the listing of existing national standards of drugs.

According to the above classification principle, whether the product is listed in the territory is to distinguish, determine the standard of generic drugs. Changes in the sale of salt drugs listed in the acid, base (or metal elements), to change the route of administration of the preparation, and change the domestic market has been listed on the sale of pharmaceutical formulations do not change the route of administration, are the scope of new drugs. In accordance with the State Council and the State Food and Drug Administration in 2015 to revise the classification of chemical registration, see Table 1

Under the old and new regulations, the scope of the concept of generic drugs, limited conditions, the following significant changes occurred:

① imitation of the object changes. The original laws and regulations are not explicitly imitation of the object, the new law that the original research drugs must be imitation of the object, that is, reference preparation.

② the scope of application of generic drug concept changes. The original laws and regulations will have been listed in foreign countries but not yet listed in the domestic drug is divided into three categories of new drugs. The new regulations will be divided into generic drugs in the first case, that is imitation of overseas listing but not listed in the original drug research drugs. Correspondingly, the new regulations extend the scope of the generic concept.

③ generic conditions are more stringent. The original laws and regulations of generic drugs specifications, indications, usage and other content is not clearly defined. New regulations, imitation of the dosage form, specifications, indications, route of administration and usage and dosage must be consistent with the original research drugs.

The new regulations expand the scope of the concept of generic drugs, basically the original three categories of drugs classified as generic drugs.

In accordance with the original registration management approach, domestic enterprises in the research and development abroad has been listed in the country has not yet listed drugs (subject to the compound), due to the lack of reference to both the common preparation, but also the lack of the original preparation of quality control information, resulting in different enterprises to develop, declare The same preparation of crystal form, dissolution behavior, other formulation characteristics (such as liposome particle size, surface potential, in vitro release, etc.) is not consistent with the phenomenon of different enterprises into the clinical trials and approved the listing of the sample quality is not entirely consistent, However, the clinical trial design of these products is basically the same, the product's generic name, manual, etc. are also completely consistent, can not reflect the individual differences in the product.

The original laws and regulations for the "same" and "improvement" can not distinguish between the new laws and regulations to declare the situation is divided into generic drugs and improved new drugs, for generic drugs, stressed the "same", strict requirements of its quality and efficacy should be consistent with the original research drugs, Reducing the possibility of different quality transmission of different enterprises in imitation of the same product.

In addition, for the original research on the basis of drugs, the structure, dosage forms, prescription process, route of administration, indications and other products optimized for "improved" type of new drugs, and requires a clear clinical advantages, that is, for different improvements Form, targeted design of clinical trials, therefore, for such declarations, need to fully reflect its "improvement" and "differences".

The Similarities and Differences of the Definition of Generic Drugs in Drug Departments at Home and Abroad

At present, the European and American drug regulatory departments of the generic drug definition, reporting procedures, evaluation requirements and other management methods there are some differences.

U. S. Code defines generic drugs as having the same pharmacologically active ingredients, dosage forms, specifications, route of administration, instructions, quality, indications and the like as reference drugs (RLD) Drug bioequivalence.

The European Medicines Administration (EMA) defines generic drugs as follows: has the same active ingredient as the reference formulation (regardless of the excipient used) and the dosage form, bioequivalence with the reference formulation by appropriate bioavailability Degree studies have been confirmed.

The different salts, esters, ethers, isomers, isomeric mixtures, complexes or derivatives of an active ingredient should be considered as the same active ingredient unless they are more relevant in terms of safety and / or efficacy Big difference. In the above case, the applicant shall provide additional information to prove the safety and / or efficacy of the various salts, esters or derivatives of an approved active ingredient. Various immediate release oral preparations should be considered as the same pharmaceutical dosage form. If the applicant can demonstrate that the generic drug meets the relevant criteria defined in the relevant detailed guidelines, no bioavailability studies are required.

By contrast, the definition of generic drugs in the United States is the most narrow, and even requires consistent with the appearance of reference drugs, for example, the requirements of tablet scoring. The definition of generic drugs in the EU is relatively broad, for a variety of immediate release oral preparations, are regarded as the same drug formulations for management. China's old and new laws and regulations on the scope of the scope of application of generic drugs, and Europe and the United States are some differences.

According to CFDA 2007 edition of "drug registration management approach", the scope of application of generic drugs similar to the United States, but the specifications and shape, etc. are not strictly limited to the rationality of the specification is in line with the use of clinical usage; compared with the EU is slightly narrow, For different varieties of modified formulations, as well as an active ingredient of different salts, esters, ethers, etc., are classified as new drug management.

The new regulations on the scope of new drugs and generic drugs have been a major adjustment, will change the dosage form, acid and salt-based products, still as a new drug management; will have been listed in foreign countries have not yet listed products, that is, New drugs, to generic drug management, compared with Europe and the United States, to expand the scope of the scope of generic drugs.

In addition, in 2007 edition of the registration management approach, based on the requirements of the generic drug specifications tightened with the original research drugs consistent with the requirements of the FDA.

The Similarities and Differences of Foreign Drug Administration Department 's Registration and Review Procedure of Generic Drugs

Foreign drug regulatory departments of the generic drug registration and review procedures similarities and differences in different stages of historical development, combined with the then drug research, management awareness of the development of generic drugs for the registration procedures, technical requirements, such as the development of different management regulations.

FDA before 1962, the application for generic drugs only requires the publication of published literature to prove drug safety, did not require the provision of appropriate research materials.

In 1962, after the "response to stop" incident, the proposed new drug application (ANDA), allowing the declaration of generic drugs, FDA can be used and published by the original drug safety and efficacy data, The implementation of the program review and approval of the information, without the need to submit a comprehensive clinical research data, just to prove that generic drugs and the original drug has a bioequivalence.

In 1984, the US Congress passed the "Hatch-Waxman Act", the Drug Price Competition and Patent Term Restoration Act. The amendment, on the basis of the US Federal Food, Drug and Cosmetic Act, adds 505 (j) to the management of generic drug registration applications, which relieves the generic drug preclinical animal toxicology test and human clinical research project.

At present, for generic drugs, according to ANDA procedures to declare. For example, changes in dosage form, specifications, route of administration, indications, usage, etc., compared to the reference drug; alteration of the salts, esters, and complexes, etc., in the same manner as in the active substance of the listed product; When the declared variety and the reference drug (RLD) are not bioequivalent, the application shall be declared in accordance with the new drug application procedure (NDA), that is, 505 (b) (2). The FDA has different policy settings for reporting procedures, technical requirements, etc., in accordance with the ANDA procedure and the 505 (b) (2) procedure.

At present, Europe and the United States and Japan for generic drugs registration process is basically similar. For generic drugs that require a BE test, the applicant must complete the pre-pharmacy study and the BE trial, and submit a registration application to the drug regulatory authority. The countries will treat the BE test as a pre-registration report. There are special management procedures.

For generic drugs that do not require a BE test, the applicant may submit a registration application directly after completing the pharmacy study. The FDA established a generic drug department in 1990, including a label and project assistance room, three pharmacy reviewrooms and two bioequivalence review rooms. Upon receipt of the generic application, the completeness and acceptability of the information will be confirmed by the re-examination, and the review of the pharmacy, bioequivalence and the labeling of the instructions will be initiated.

Also, the FDA will initiate the relevant cGMP assessment and examination. Figure 1 shows a brief flow chart of FDA's R & D and registration of generic drugs (with detailed procedures for supplementing and improving data). EMA is similar to that of R & D in Japan. Some of the details are slightly different.

Comparison of the New and Old Regulations on the Registration Process of Generic Drugs