REGISTRATION OF MEDICINAL PRODUCTS: FOREIGN EXPERIENCE

Registration of medicinal products a basic element in the system of government control of pharmaceutical market on such indexes, as a nomenclature of sailed medications, their efficiency, safety and quality, information for doctors and users, terms of realization, in many countries is pricing.

The modern system of registration contain complex character and prophylactic orientation. Its purpose — on the basis of the presented materials to estimate correlation benefit/risk for every product with that to decide a question about his admitting for the sale. If to talk about quality of products, registration (as well as order of licensing of producers) is directed on determination of reliability of processes of their production, but not on quality of separate standards control. The last is a duty of producer. Exactly on this account the pharmaceutical analysis of the standards presented on registration is not strongly emphasized in the industrially developed countries. An exception is made by standards, selected during pre-registration verifications of producer.

Therefore it is necessary to remind that in world practice following state control of quality is examined not as independent work branch, but as form of verification of observance of terms which product was registered on the basis of.

The modern registration system is closely related to the rules of GMP. All of technological and control document on a production must correspond materials attached to the registration statements and by the approved registration organ.

In most countries basic elements of the system of registration are important component part of legislation about medications. The law determine aims and tasks of registration. This procedure, as a rule, is needed for placing a product to the market. Otherwise speaking, the state regulates trading in medicines, but not medical practice. A law sets the categories of medications registration of which is needed. In the industrially developed countries the object of registration are not «medications» as such, but prepared medications of concrete producer. The medicinal substances of registration are not subject accordingly.

In a law the name and plenary powers of registration organ, major requirements, is certain to registration materials, order of their consideration (terms, possibility of appeal) etc.

From reports, a first law, foreseeing the preliminary estimation of medications to their issue in a sale, was accepted in the USA in 1938. In other most industrially developed countries such laws appeared in 60th (in Japan — in 1961, in Great Britain — in 1968).

The important aspect of activity of registration organs is providing of confidentiality of the document presented producers. To that end employees give subscription about the nondisclosure of maintenance of materials to which they get access within the framework of implementation of official duties. Principle of confidentiality is observed so strictly, that to the process of registration usually even commissions and committees are not attracted , in spite of the fact that incoming in their composition specialists would participate in consideration of projects of specifications of quality. In order that to avoid the conflict of interests between persons, participating in registration, the employees of registration organs and independent experts conclude the special contracts.

Last years specialists are predisposed to opinion of necessity of introduction of the systems of quality for activity of organs of normative control of medications. The first step on this way is development of internal guidance in quality of work (Canada, Thailand and other). In some countries such systems of quality are certified independent organizations (Great Britain, some Scandinavian countries).

Product and consideration of registration materials is facilitated due to the compatible format of request and materials enclosed to it — so-called registration dossier, which usually consists of 4 basic sections, named: «Resume of dossier» (general product information and his producer); «Quality» (results of chemical, pharmaceutical and biological tests, information about a production and control); «Safety» (mainly results of experimental researches on animals) and «Efficiency» (results of clinical tests).

A concept «Registration dossier» unlike a concept «document» or «package of documents» has the followings features:

— product of the documents contained in him is carried out in accordance with the detailed instructional-methodical pointing;

— documents are structured, subdivide in accordance with the set sections and subsections, each of which is marked a certain index. For example, in the European system of registration subsection of dossier «Part 2 D» contains description of methods of production of intermediate goods control, and «Part 3, IIIA»  information about toxicness;

— if product is settled to the sale, major information from a section «Quality» (terms of production, specifications, shelf-lives and other) and from the section of general information (testimonies to application, contra-indications etc.) become firmly established automatically. In this connection a producer has no the authority to retreat from the positions expounded in a dossier without the consent of registration organ. The proper position is often brought in in the certificate of registration or analogical document. Possibility of exceptions makes a reservation the special instructions (see section «Procedure of consideration of request»).

In most countries of requirement to maintenance and volume of registration materials, and also the methodical pointing on their product is set by laws. Package of the instructional-methodical pointing about the order of product, registration and presentation of materials, enclosed to the request, is, perhaps, by the major element of the system of registration, as his maintenance determines the «face» of pharmaceutical market of country in a great deal. The detailed and carefully developed requirements to character and volume of the documents (to the registration dossier) presented on registration, from one side, facilitate and accelerate procedure of registration, and from other — considerably limit administrative tyranny at consideration of requests.

It is as an example possible to bring the instructional-methodical pointing over of European Union. They are expounded in a few volumes a general volume about 900 pages and contain more than 60  documents, touching the order of leadthrough and registration of results of pharmacological, toxicological and clinical researches of new products, and also providing of their quality and preproduction. This package is constantly filled up and brushes up. Analogical requirements exist in the USA, Japan, Canada, Australia.

Speaking about the rules of GLP and GCP, it should be noted that in countries with the developed regulator system clinical researches of new productbegin to complete completion of toxicological researches: II phase of clinical tests — to completion of the I phase, III phase — to completion II.

The important feature of the European system is presentation of conclusions of independent experts on the sections of dossier together with a registration statement. Such order allows substantially to shorten the volume of work of registration organs in part of examination of materials of requests.

For development and modernization of the system of registration of medications in the industrially developed countries are widely used results of international cooperation, foremost on multilateral basis. In the states of European Union of requirement to registration maximally conniving. The concordance of these requirements is actively conducted with the USA and Japan within the framework of the International conference on harmonization of technical requirements to registration of medicinal product for a man (ICH). About 40 conciliatory documents geared-up presently, development of compatible electronic format of request is closed.

In a global scale a collaboration is carried out through mechanisms WHO. In this plan it would be desirable especially to select going out in 1999 Guidance on registration. On meaningfulness this document can be put in one row with the rules of GMP, GCP, GLP etc.

Procedure of consideration of request includes an order and terms of consideration of the presented materials, speed-up procedure of registration, brief request, possibility of bringing of post-registration changes, presence of official mechanism of appeal, size of registration payments and row of other elements. We will consider some of them.

One of most stumpers of order of registration is limitation of terms of consideration of requests. Attempts to set a single control term, for example 6  months, in most countries did not result in success, as in swingeing majority of cases a registration organ is forced to inquire for a declarant additional materials and to expect their receipt. Therefore the carefully developed regulation of consideration of materials of request is certain in the European system of registration. It is possible to consider the step chart of consideration and establishment of terms his most essential elements for the separate stages of this procedure besides the general term of examination (210 days). The periods of expectation of the inquired failings materials are eliminated from a general term (principle of «stop of clock»).

Concordantly to widely widespread practice, the reproduced product(генерики) are registered on the basis of the so-called brief request without presentation of materials on sections «Safety» and «Efficiency». From a «brief request» it is necessary to distinguish speed-up procedure of registration (so-called rapid path), applied in regard to some new products. In respect of medications, the quickest appearance on sale of which appears important from the medical or social point of view (for example, facilities, intended for application on vital testimonies), that reduction of checkin can be attained next methods. At first, in this case on all of the stages delays are eliminated «in expectant of turn», secondly, their sale can be settled to complete completion of the III  phase of clinical researches.

The order of post-registration changes includes classification of changes the sample of writing, technology and packing on the degree of meaningfulness (in European Union distinguish 2  categories, in the USA — 3), and also determination right duties of producer on every category. Insignificant changes are brought in with notification of registration organ, while for bringing of substantial changes the preliminary consent of this organ is needed. In addition, instructions are determined by character and volume of experimental works, necessary for confirmation of accordance of new terms of production before ratified.

Under a term «registration policy» imply general principles of selection of medicinal productfor admittance to the market. A registration policy of ES is liberal; admittance of medicines to the market is carried out only coming from their efficiency, safety and quality without the account of prices and other factors. In the Scandinavian countries, especially in Norway, opposite, products, considered necessary, are registered only. In this connection the incurrence of medications, presented on the markets of the states of North Europe, is calculated thousands, but not in tens thousands, as in many other countries. In a number of developing countries an accent is done on registration of the reproduced products.