Abstract
This paper describes the EEC regulatory requirements for the preparation and execution of a community concertation “High Tech” procedure and compares this “High Tech” procedure with the Multi-State procedure.
According to a decision of the European Commission enforced in July 1987, medicinal products, derived from high technology methods have been grouped in two categories: A. and B.
Category A. concerns biotechnology products made by R-DNA techniques and by manipulation of mammalian cells.
Category B. comprises all other products made by high ]technology.
Before applying for an EEC marketing licence (e.g. submission for registration) one must ascertain whether a product is most appropriate in Category A. or B. and one should contact a licencing authority at an early stage to discuss the planned submission. Various procedures for submission have to be followed:
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1.
for the so-called “High Tech” products and especially products derived from biotechnology with therapeutic applications (Category A.), it is mandatory that one of the Member States accepts the submission.
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2.
The “High Tech” procedure is derived from the so-called “2-country” (Multi-State) procedure, in which for the latter procedure a marketing licence in one of the Member States (except Portugal) is required before application in other Member States.
The Multi-State and “High Tech” (other products: Category B.) procedures are optional. When the procedures are started, all Member States concerned are involved in evaluation of full or abbreviated dossiers through mediation of the European Commission represented by the CPMP (Committee for Proprietary Medicinal Products), Brussels, Belgium. No application for a marketing licence of Category A. products is allowed without mediation of the CPMP. For Category B. products the applicant may opt for a national submission in one or more of the Member States without using the “High Tech” procedure. However, after consultation with the competent authority in one of the Member States, a “High Tech” procedure for Category B. products might still be advisable, but the applicant is not required to follow this procedure.
Both the “High Tech” and the Multi-State procedure are currently executed by the mediation of a rapporteur, who liaises with the applicant from the start of the “High Tech” procedure. Ideally, the applicant should contact a licencing authority some 6 to 9 months before an application is planned: to ensure that the near future submission is acceptable. The institution of a rapporteur (appointed by the licencing authority in the country from where the procedure has recently been established) is introduced for the Multi-State procedure. In the latter procedure the rapporteur only becomes active when objections are raised, though in the recent past this system already informally existed. Differences in the execution of both procedures will be outlined in the ensuing pages. The preparation and presentation for submissions requires, however, the same meticulous approach to ensure registration. The last issue of the “Notice to Applicants”, January 1989, describes in detail, how the submission should be prepared and presented.
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References and notes
Tryzelaar B, Regulatory affairs and biotechnology in Europe. 1. Introduction into good regulatory practices. Biotherapy 1988; 1: 59–69.
Schellekens H, Between clones and clinic, editorial. Biotherapy 1988; 1: 3–5.
Rules governing pharmaceuticals in the European Community; Commission of the European Communities, III/B/6 —Pharmaceuticals, Veterinary Medicines, January 1989.
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The rules governing medicaments for human use in the European Community. Commission of the European Communities, 11/182/87 (text completed in July 1987), covering COUNCIL Directives:- 65/65/EEC of 26.1.65 (O. J. no. L 22, 9.2.65)- 75/318/EEC of 20.5.75 (O. J. no. L 147, 9.6.75)- 75/319/EEC of 20.5.75 (O. J. no. L 147, 9.6.75)- 78/25/EEC of 12.12.77 (O. J. no. L 11, 14.1.78)- 83/189/EEC of 28.3.83 (O. J. no. L 109, 26.4.83)- 83/570/EEC of 26.10.83 (O. J. no. L 332, 28.11.83)- 86/609/EEC of 24.11.86 (O. J. no. L 358, 18.12.86)- 87/18/EEC of 18.12.86 (O. J. no. L 15, 17.1.87)- 87/19/EEC of 22.12.86 (O. J. no. L 15, 17.1.87)- 87/21/EEC of 22.12.86 (O. J. no. L 15, 17.1.87)- 87/22/EEC of 22.12.86 (O. J. no. L 15, 17.1.87)- 88/182/EEC of 22.03.88 (O. J. no. L 81, 26.3.88)- 88/320/EEC of 09.06.88 (O. J. no. L 145, 18.12.88)- 89... /EEC of 21.12.89 (O. J. no. L...,...) Council decisions- 75/320/EEC of 20.5.75 (O. J. no. L 147, 9.6.75) Council recommendations- 83/571/EEC of 26.10.83 (O. J. no. L 332, 28.11.83), Relates to 5 Notes for guidance: repeated dose toxicity, reproduction studies, carcinogenic potential, pharmacokinetics and metabolic studies in the safety evaluation of new drugs in animals, fixed combination products- 87/176/EEC of 9.2.87 (O. J. no. L 73, 16.3.87). Relates to 14 notes for guidance: single dose toxicity, mutagenicity, cardiac glycosides, clinical investigation of oral contraceptives, user information on oral contraceptives data sheets for antimicrobial drugs, clinical testing requirements for drugs for long term use, non-steroidal anti-inflammatory compounds for the treatment of chronic disorders, anti-epileptic/anticonvulsant drugs, investigation of bioavailability, clinical investigation of drugs for the treatment of chronic peripheral arterial diseases, pharmacokinetic studies in man, anti-anginal drugs, topical corticosteroids.
Notice to applicants for the marketing for proprietary medicinal products in the member states of the European Community on the use of the new multi-state procedure created by council directive 83/570/EEC (III/158/85, final of April 1986).Now abandoned and replaced by: Notice to applicants for the marketing for proprietary medicinal products in the member states of the European Community (III/118/87, Rev. 11 of January 1989 — final).
Guidelines adopted by the CPMP (to be published in 1989):- Recommended basis for the conduct of clinical trials of medicinal products in the European Community, 111/411/87 —Rev. July 1987;- Production and quality control of monoclonal antibodies of murine origin intended for use in man (III/859/86, Rev. 7, Final, June 1987);- Production and quality control of medicinal products derived by recombinant DNA technology (III/860/86, Rev. 8, Final, June 1987);- Chemistry of the active ingredient (III/478/87, rev. 6);- Stability tests on active substances and finished products (III/66/87, Rev. 4);- Development pharmaceutics and analytical process validation (III/847/87);- Preclinical biological safety testing (11I/407/87, Rev. 5);- Antidepressant drugs (III/476/87, Rev. 7);- Testing medicinal products in the elderly (III/536/86, Rev. 7);- Clinical trials in children (III/535/86, Rev. 7);- Herbal remedies (III/74/87, Rev. 7);- Trials of medicinal products in the treatment of cardiac failure (III/1528/87, Rev. 5);- Anti-arrhytmic drugs (III/2106/86, Rev. 5). Drafts transmitted to interested groups for consultation:- Anticancer agents in man (III/699/88);- Studies of prolonged action forms in man (IIi/1962/87);- Production and quality control of cytokine products derived by modern biotechnology processes (III/3791/88)-* Anti-epileptic/anticonvulsant drugs (III/3128/88)- Analytical validation (III/844/87). Subjects under preparation within the working groups:- General pharmacodynamics (III/480/87);- Production and quality control of monoclonal antibodies derived from human lymphocytes intended for use in man (III/3975/88);- Good clinical practices (III/3976/88);- Local toxicity and skin/eye toxicity (III/3979/88);- Control tests in the finished product (III/3978/88);- Mental deficiency in the aged (III/3977/88).*Revision of existing guidelines (87/176/EEC):-*User information on oral contraceptives;-*Data sheets for antimicrobial drugs;-*Investigation of bioavailability; Future subjects:- Plastic containers;- Control of biological products derived from mammalian cell lines;- Cell substrates.
Extension of pharmaceutical directives to medicinal products not yet covered (to be enforced not later than 1-1-1991)- Proposal for a council directive amending directives 65/65/EEC, 75/318/EEC and 75/319/EEC on the approximation of provisions laid down by law, regulation or administrative action relating to proprietary medicinal products- Proposal for a council directive amending directives 65/65/EEC, and 75/319/EEC on the approximation of provisions laid down by law, regulation or administrative action relating to proprietary medicinal products and laying down additional provisions for: 1. Immunological medicinal products consisting of vaccines, toxins or serums and allergenes (III/.../87) 2. Medicinal products derived from human blood (III/2250/87) 3. Radiopharmaceuticals (III/.../87) 4. Homeopathic medicinal products (III/2175/87)
Further reading:
A brief Guide to the European Directives concerning Medicines, 3rd edition; F.A. Charlesworth, J.P. Griffin. To be ordered from: The Association of the British Pharmaceutical Industry, 12 Whitehall, London SWIA 2DY, U.K.
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Tryzelaar, B. Regulatory affairs and biotechnology in Europe II.. Biotherapy 1, 179–196 (1989). https://doi.org/10.1007/BF02170887
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DOI: https://doi.org/10.1007/BF02170887