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REGULATORY STATUS OF MEDICINAL PRODUCTS FOR HUMAN BEINGS IN THE EUROPEAN UNION. THE ROLE OF GENERIC PRODUCTS
Pharmacological Research, Vol. 34, No. 1/2, 1996
REGULATORY STATUS OF MEDICINAL PRODUCTS FOR HUMAN BEINGS IN THE EUROPEAN UNION. THE ROLE OF GENERIC PRODUCTS P. MINGHETTI Istituto di Chimica Farmaceuticae Tossicologica, viale Abruzzi, 42, 20131, Milano, Italy Accepted 1 July 1996 In this paper the definition and classification of medicinal products are discussed. Medicinal products from a regulatory and administrative point of view can be classified as: proprietary medicinal products (copy and new drugs), other medicinal products of industrial origin and, magistral and officinal formulas prepared by pharmacies (also called ‘generic products’). The term ’generic product’ becomes relevant only when the economic impact of medicinal products is considered. The formal characteristics of medicaments, as well as the different possible producers (industry or pharmacy) will be considered also in relation to the interchangeability of medicaments and the role of generic products. 1996 The Italian Pharmacological Society KEY WORDS: definition of medicinal product, medicinal administrative classification, generic products.
INTRODUCTION The notion of medicinal products is difficult to codify in the same way throughout the Community. Furthermore, the procedures required to guarantee quality, efficacy and safety of the product itself are different according to the definition given to the product. Because of the therapeutic use of medicaments and of their economic value, any law in the field of the public economy (e.g. interchangeability of medicines), must be carefully evaluated in the consideration of the therapeutic use of medicaments. In this paper the definition of medicinal products and the classification, even in relation to the procedures to put the products on the market, will be discussed. The formal characteristics of medicaments, as well as the different possible producers (industry or pharmacy) will also be considered in relation to the interchangeability of medicaments (Table I).
THE DEFINITION OF MEDICINAL PRODUCT Any substance (irrespective of its origin) with demonstrated pharmacological and clinical activities can not by itself be marketed as a medicinal product. In order to be qualified as a medicinal product the active substance has to be submitted to controls designed to guarantee its quality, efficacy and safety and has to be supported by specific information on its use in the treatment or preventinon of diseases. Since 1965, the European Union definition of medicinal product has been the following: ‘any substance or combination of substances presented for treating or 1043–6618/96/070003–05/$25.00/0
preventing disease in human beings or animals’. Moreover: ‘any substance or combination of substances which may be administered to human beings or animals with a view to making a medical diagnosis or to restoring, correcting or modifying physiological functions in human beings or in animals is likewise considered a medicinal product’ [1]. From an administrative point of view, the definition of a medicament is based on two different and independent parts, which is confirmed by jurisprudence stating that a substance may be considered a medicinal product according to either its essential function (objective, intrinsic characteristics) or its presentation (subjective, extrinsic characteristics). Essential aspects include the nature of the ingredients, the qualitative and quantitative composition, the pharmacological and/or therapeutical properties proven by proper use, the posology and the method of administration. As formal characteristics we consider indications, purposes, claimed properties, labels and package inserts (i.e. presentation) and advertising messages (when allowed). When the therapeutical activity is well known and the essential characteristics are evident, the product is classified without any doubt as a medicinal product, on the other hand, when the substance can be used for different purposes, the formal characteristics may become constitutive of the legal status of medicament. Specific products are not always defined as medicaments in every Member State. Many disputes have arisen in the Community as shown by the following examples. The Court of the Community has recently stated that a solution of eosin is not to be necessarily considered as a medicinal product if the label does not explicitly state that it has a therapeutic effect in the 1996 The Italian Pharmacological Society
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Pharmacological Research, Vol. 34, No. 1/2, 1996
treatment of cutaneous infections [2]. On the contrary, the therapeutical indications written in any kind of leaflet that the consumer may receive after buying any special food [3] may also contribute to classify the product as a medicament marketed without the prescribed authorisations [4]. In Italy, the superior Court has ruled that the information given orally to the consumer by the retailer is an integral part of the product presentation, and may be utilized to identify the product as a medicament, even if the label does not mention any therapeutic effect [5]. Another cause of difficulty in stating what is a medicinal product relates the non uniform definition of pathologies in the different Member States. Moreover, when the symptoms indicated in the label are not related to a specific pathology, but may also be caused by a transitory trouble, the National Health Authority has to decide if the product should be considered as a medicinal product or not according to its composition, unwanted effects and to the risks of a long term administration, as in the case of herbal remedies indicated for heaviness of legs, weariness, itching [6].
THE CLASSIFICATION OF MEDICINAL PRODUCTS Medicinal products can be classified from the regulatory and administrative point of view. In the pharmaceutical field the preventive evaluation of quality, efficacy and safety are nowadays consolidated and considered inviolable to safeguard public health. The same level of guarantee of public health can be obtained with various levels of technical and regulatory requirements. With this aim suitable measures can be put into effect according to the characteristics and the degree of knowledge of the active substances and
of the finished products, the pharmacological and therapeutic activity, the method and route of administration, the treated pathology and also the medical knowledge of the population. Medicinal products can be classified in several ways based on different aspects of the medicaments: administrative status, legal status of dispensing [7], reimbursability by the State, anatomical, therapeutical and chemical classification (ATC) [8].
THE PROPRIETARY MEDICINAL PRODUCT (BRANDED MEDICINAL PRODUCT) The European definition of proprietary medicinal product is the following: ‘any ready-prepared medicinal product placed on the market under a special name and a special pack’ [9]. The special name may be the brand name as well as the common or scientific name together with a trade mark or the name of the manufacturer [10]. In the majority of countries the indication of a special pack presupposes that the label and the packaging have to be made by the manufacturer and that the pharmacist has to give patients the complete packaging. In the United Kingdom, pharmacists may divide up, or change packaging for retail supply without ‘manufacturer authorisation’ [11]. The authorisation to produce medicinal products is always necessary [12] and is given by the health authority following the verification of technical reliability [13] of the manufacturer. A marketing authorisation is also required for medicinal products. The procedure needed to obtain this authorisation is different for new drugs and non innovative products. In the case of new drugs the applicant shall supply complete documentation. The relevant parts of the dossier are the following: Part 1, Summary of the
Table I Administrative classification of medicinal products Administrative classification of medicinal products Proprietary (branded) a) New drug
Produced by
Industry
b) Copy Unbranded
Definition
Industry
Clinical trials Required by doctors Magistral formula
Industry Industry Pharmacy
Official formula
Pharmacy
(a) Any ready-prepared medicinal product placed on the market under a special name and a special pack. (b) Any ready-prepared medicinal product placed on the market under a special name and a special pack essentially similar to another. Medicinal product different from proprietary medicinal product (only from an administrative point of view). Medicinal product specifically produced to be used in clinical trials. Medicinal product prepared on the basis of a written request of a medical doctor. Any medicinal product prepared in a pharmacy in accordance with a prescription for an individual patient. Any medicinal product which is prepared in a pharmacy in accordance with the prescriptions of a Pharmacopoeia and is intended to be supplied directly to the patients served by the pharmacy in question.
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dossier; Part 2, Chemical, pharmaceutical and biological testing of medicinal products; Part 3, Toxicological and pharmacological tests; Part 4, Clinical documentation. For non innovative drugs the applicant is not required to provide the pharmacological, toxicological and clinical data (abridged application). Drugs are considered non innovative if: (a) the proprietary medicinal product is ‘essentially similar’ to a product authorized in the country concerned by the application and the person responsible for its marketing has consented to the pharmacological, toxicological or clinical references contained in the dossier on the original proprietary medicinal product being used for the purpose of examining the application in question; (b) it is possible to demonstrate, by detailed references to published scientific literature, that the constituents of the proprietary medicinal product have a well established medicinal use with recognized efficacy and an acceptable level of safety. These data have to be exhaustive enough to permit experts to fill in report tables; (a) the proprietary medicinal product is ‘essentially similar’ to a product which has already been authorized within the Community six or ten years before the launch of the new product, according to the rules established by the various Member States. The ten year period is always applicable in the case of high-technology medicinal products [14]. Many countries, for example the United Kingdom, Italy, The Netherlands, France, prefer the ten year period for all medicaments. For the purpose of the European abridged application, a medicinal product is ‘essentially similar’ to another product when it has the same qualitative and quantitative composition in terms of active principles, and the pharmaceutical form is the same; where necessary, bioequivalence with the first marketed product has to be demonstrated by appropriate bioavailability studies [15]. The definition and the characteristics of bioequivalence have been defined by the EEC [16] and in a draft guideline of WHO are the following: ‘two products are bioequivalent if they are pharmaceutically equivalent [17] and their bioavailabilities (rate and extent of absorption) after administration in the same molar dose are similar to such a degree that their effects, with respect to both efficacy and safety, will be essentially the same’ [18]. Two products are generally considered bioequivalent if, the 90% confidence interval of AUC-ratio lay within the accepted range (80–125%). This range may need to be reduced in the case of a drug with a particularly narrow therapeutical range. A larger acceptance range may be acceptable if inevitable and clinically acceptable [16]. The 90% confidence interval of the Cmax -ratio lay within a wider acceptance range (70–143%) and the range is justified taking into account safety and efficacy considerations. The non parametric 90% confi-
5
dence interval of the Tmax difference lay within a clinically determinated range. By extension the concept of ‘essentially similar’ may also be applied to different oral forms (tablets and capsules) with the same active substance if for immediate release [19]. The same extension could be appropriately provided for controlled release oral dosage forms. The ‘abridged application’ is excluded when drugs, even if copies of similar proprietary medicinal products, have different therapeutic indications, a different route of administration, have different dosages, or contain known constituents not hitherto used in combination [20]. A particular ‘abridged application’ (so called ‘hybrid’) is applicable when the product has been slightly modified, for example, there is a different dosing schedule, different strength, suprabioavailable products, different salt/ester/derivative of the same therapeutic moiety, different therapeutic use. Additional data is required which is consistent with the modifications [18].
THE MEDICINAL PRODUCT DIFFERENT FROM THE PROPRIETARY MEDICINAL PRODUCT (UNBRANDED MEDICINAL PRODUCT) This category may include the following, (a) medicinal products different from the proprietary medicinal product. (b) Medicaments prepared by industrial manufacturers on the basis of a written request of a medical doctor. (The products have to be used under the medical doctor’s responsibility only to his/her patients [21]). (c) Medicaments prepared by industrial manufacturers for clinical trials. (d) Magistral and officinal formulas prepared by pharmacies (also called ‘galenic products’). In 1989, the European Council amended the Directives 65/65/EEC, 75/318/EEC and 75/319/EEC with the view of subjecting all the medicinal products of industrial origin to the same preventive and aftermarket controls. Thus, the term ‘proprietary medicinal product’ was substituted with the more general term ‘medicinal product’ which embraces both branded and unbranded products [22]. All countries where some industrial medicaments were marketed without ‘marketing authorisation’ changed their rules according to the previsions laid down by the European Union. Unbranded products can be authorized for the market following an ‘abridged application’ or ‘hybrid abridged application’ with the same rules and exemptions discussed in the case of proprietary medicinal products. The name is the distinctive element of the two classes of drugs (branded and unbranded). In fact, the definition of a proprietary medicinal product requires that the products are marketed with a special name,
6
while the unbranded product has to be marketed with the common or scientific name. This difference is important when physicians prescribe using the common name, in this case the pharmacist may dispense the unbranded medicinal product of his/her choice. The promotion of unbranded medicaments for the sake of medical doctors is not profitable, while industrial competition is played with the wholesalers and pharmacists. The medicaments prepared by industrial manufacturers on the basis of a written request of a medical doctor and the medicaments prepared by industrial manufacturers for clinical trials can be produced without the ‘marketing authorization’. In all cases, manufacturers shall possess the ‘manufacture authorization’ while pharmacies do not need any special authorisation to prepare generic products.
The medicinal product prepared by pharmacies The preparation and control of medicinal products in the community and hospital pharmacies are part of the activities permitted to pharmacists in the Community [23]. Products prepared in the pharmacy can be dispensed exclusively through the same pharmacy. As far as the quality is concerned, although not yet established by the European Union, a ‘good compounding practice’ is enforced by some Member States such as Italy [24], France [25] and Sweden [26] and now elaborated as draft in the USA [27]. The assurance of efficacy and safety appears more difficult. The consequence is that a source capable to legitimate the formula is required. Therefore, in a pharmacy the pharmacist can prepare the following. (a) A magistral formula: any medicinal product prepared in a pharmacy in accordance with a prescription for an individual patient. (b) An officinal formula: any medicinal product which is prepared in a pharmacy in accordance with the prescriptions of a Pharmacopoeia, and is intended to be supplied directly to the patients served by the pharmacy in question [28]. With regards to the magistral formula, the responsibility for the evaluation of the efficacy is assumed by the medical doctor who prescribes the medicament; as regards the officinal formula the public administration is responsible. The European Legislation considers the above mentioned products only to exclude them from the disposition enforced by the directives on medicinal products. In fact, these products are not prepared to be distributed in the common market, in this sense, possible disparities in the legislation of the different Member States are of no direct interest to the European Council. In Italy, any medical doctor can prescribe a magistral formula, only with few limitations, the most relevant of which is related to appetite suppresser medicaments [29]. The same limitations are also adopted in other countries: e.g. France [30].
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THE NOTION OF GENERIC PRODUCT AND THE INTERCHANGEABILITY OF MEDICAMENTS The term ‘generic product’ has a somewhat different meaning in different countries. Existing directives on the approximation of prevision relating to medicinal products never use this term. In fact, community regulations provide for the production and launching of medicinal products on the market with the primary purpose of safeguarding public health and establishing the common market, without hindering the development of pharmaceutical industries [31]. In these directives only the regulatory procedures have been considered without any interest for a costcontainment policy. The term ‘generic product’ becomes relevant when the economic impact of medicinal products is considered. Until now the European Union has not interfered with national policies except for the necessity of obtaining transparency on prices and social security schemes [32]. Therefore, the accepted definition of generics is given by the WHO. ‘Generic product’ means, ‘a pharmaceutical product, usually intended to be interchangeable with the innovator product, which is usually manufactured without a license from the innovator company and marketed after the expiration of the patent or other exclusivity rights’. ‘The innovator product’, on the other hand, ‘is that which was first authorized for marketing, as a patented drug, on the basis of documentation of safety, quality and efficacy (according to the contemporary requirement)’ [33]. The reference product could, in some cases, be different from the first innovator for many reasons, but it always has to be authorised for marketing after analysis of the complete documentation. Moreover, in order to be interchangeable with another drug, any medicament has to be bioequivalent. Furthermore it would be preferable that the packaging specifications, when critical to stability and shelflife, and the instructions for use are the same in order to obtain a uniformity of information given to patients [32, 34, 35, 36]. In terms of denomination, the generic product can be branded (branded generics) or unbranded (pure generics); while in terms of regulatory status the former are proprietary medicinal products essentially similar to other products, the latter are industrial products that, from an administrative point of view, are different from proprietary medicinal products. It should be noted that it is impossible to place the generics in one category in terms of administrative classification as defined by the EEC directive 65/65/EEC as amended by directive 89/341/EEC. In short, a medicinal product can be defined as generic when the following conditions are satisfied.
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(a) Patent or other exclusivity rights have expired. (b) Bioequivalence and consequent interchangeability with the reference product. Generics can have a real market only if their prices are lower than those of the corresponding reference products. Pharmacists can generally dispense unbranded products without regard to their industrial origin if the doctor prescribes them using the common name of their active principle(s). On the other hand, in the majority of the European countries, medical doctors usually prescribe medicaments using their brand name. In this case, the possibility of substitution becomes the key of the market within the social security schemes. The European Union Commission believes that generics should be permitted to obtain reduction in terms of pharmaceutical expenditures, but it does not currently intend to prepare new legislation in this area [37], even though the Council calls on the Commission to draw up a report concerning policy on generic medicinal products in the Member States [38]. It should be stressed that the real impact on the market of generics depends on the political decision of the single Member State, as the final decision concerning generics is not a problem of public health but of public expenditure, if current technical regulations are fully respected.
REFERENCES 1. Article 1, n.2, Directive 65/65/EEC, January 26, 1965. 2. Conclusions of Legal Advisory Office, January 16, 1991, proceedings C-60/89. 3. Directive 89/398/EEC, May 3, 1989. 4. Court of Justice EU section V, judgement October 28, 1992, proceedings C-219/91, EU OJ n.C/310/2, November 27, 1991. 5. Supreme Court of Appeal, Section I, judgement no. 1597, April, 16, 1993. 6. Court of Justice EU, Section. V, judgement March 21, ¨ 108¨2 April 23, 1991, proceedings C-369/88. OJ n. C 1991. 7. Directive 92/26/EEC, March 31, 1992. 8. WHO Collaborating Center for Drug Statistics Methodology. 9. Article 1, n. 1 Directive 65/65/EEC. 10. Article 4, Directive 65/65/EEC. 11. Article 16(2), Directive 75/319/EEC, May 20, 1975.
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12. Article 16, Directive 75/319/EEC. 13. Article 3, Directive 89/341/EEC, May 3, 1989. 14. Part A and B in the Annex to Council regulation (EEC) No 2309/93 July 22, 1993. 15. Commission of the European Community, Notice to Applicant in: The Rules governing medicinal product in the European community, Volume II, III/118/87-EN 1989. 16. Note for Guidance of the EEC ’Investigation of bioavailability and bioequivalence’ III/54/89. 17. Two products are pharmaceutically equivalent if have: same amount of the same active substance(s) in the same dosage form that meets a comparable standard and are intended to be administered by the same route. 18. Interchangeable multi-source pharmaceutical products. WHO draft guideline on marketing authorisation. 19. Note for guidance of the EEC, Abridged Application III/3879/90-EN December 1991. 20. Article 4, n. 8, Directive 65/65/ECC amended by Article 1, n. 1, Directive 87/21/EEC, December 22, 1986. 21. Article 2 Directive 65/65/EEC amended by Article 2, point 3, Directive 89/341/EEC. 22. Directive 89/341/EEC. 23. Article 1(2) Directive 85/432/EEC of December 16, 1985. 24. National Formulary, third volume of the Italian Official National Pharmacopoeia, 1991. 25. ’Bonnes Pratiques de Pre´parations Officinales’, Bulletin official n.88/7 BIS, 1988. 26. Svensk La¨kemedelsstandard, SLS, 1989. Svenska farmakope´kommitte´n, sektion 4. 27. Pharmacopeial Previews, Pharmacopeial Forum, 21, pp. 258–266, 1995 General Chapters—General Information <1161> Pharmacy Compounding Practice. 28. Article 1, Directive 89/341/EEC amending Article 1, Directive 65/65/EEC. 29. Minister decree May 26 1987, April 13, 1993. 30. Decree no. 82–200 February 25, 1982. 31. Preamble Directive 65/65/EEC. 32. Directive 89/105/EEC December 21, 1988. 33. WHO Draft Guideline on Marketing Authorisation requirements—Interchangeable multi-source pharmaceutical products—December 6, 1993. 34. Montanari L, Minghetti P, Gazzaniga A, Santoro P. ‘European community procedures for the marketing authorisation of medicinal product: impact on presentation and distribution’ presented at the First European Congress of Pharmacology, Milan—June 16–19, 1995. 35. Economic and Social Committee, 278 Plenary session, April 7, 1990. 36. Dir 92/27/EEC, March 31, 1992. 37. Answer of Bangemann M. (Member of The Commission) to written question of Sotiris Kostopoulos, EU O.J. N.C.226/47 August 16, 1994. 38. Council Resolution of 20 December 1995 on generic medicinal products (95/C 350/06) O.J. no. C 350 30 December, 1995.
REGULATORY STATUS OF MEDICINAL PRODUCTS FOR HUMAN BEINGS IN THE EUROPEAN UNION. THE ROLE OF GENERIC PRODUCTS P. MINGHETTI Istituto di Chimica Farmaceuticae Tossicologica, viale Abruzzi, 42, 20131, Milano, Italy Accepted 1 July 1996 In this paper the definition and classification of medicinal products are discussed. Medicinal products from a regulatory and administrative point of view can be classified as: proprietary medicinal products (copy and new drugs), other medicinal products of industrial origin and, magistral and officinal formulas prepared by pharmacies (also called ‘generic products’). The term ’generic product’ becomes relevant only when the economic impact of medicinal products is considered. The formal characteristics of medicaments, as well as the different possible producers (industry or pharmacy) will be considered also in relation to the interchangeability of medicaments and the role of generic products. 1996 The Italian Pharmacological Society KEY WORDS: definition of medicinal product, medicinal administrative classification, generic products.
INTRODUCTION The notion of medicinal products is difficult to codify in the same way throughout the Community. Furthermore, the procedures required to guarantee quality, efficacy and safety of the product itself are different according to the definition given to the product. Because of the therapeutic use of medicaments and of their economic value, any law in the field of the public economy (e.g. interchangeability of medicines), must be carefully evaluated in the consideration of the therapeutic use of medicaments. In this paper the definition of medicinal products and the classification, even in relation to the procedures to put the products on the market, will be discussed. The formal characteristics of medicaments, as well as the different possible producers (industry or pharmacy) will also be considered in relation to the interchangeability of medicaments (Table I).
THE DEFINITION OF MEDICINAL PRODUCT Any substance (irrespective of its origin) with demonstrated pharmacological and clinical activities can not by itself be marketed as a medicinal product. In order to be qualified as a medicinal product the active substance has to be submitted to controls designed to guarantee its quality, efficacy and safety and has to be supported by specific information on its use in the treatment or preventinon of diseases. Since 1965, the European Union definition of medicinal product has been the following: ‘any substance or combination of substances presented for treating or 1043–6618/96/070003–05/$25.00/0
preventing disease in human beings or animals’. Moreover: ‘any substance or combination of substances which may be administered to human beings or animals with a view to making a medical diagnosis or to restoring, correcting or modifying physiological functions in human beings or in animals is likewise considered a medicinal product’ [1]. From an administrative point of view, the definition of a medicament is based on two different and independent parts, which is confirmed by jurisprudence stating that a substance may be considered a medicinal product according to either its essential function (objective, intrinsic characteristics) or its presentation (subjective, extrinsic characteristics). Essential aspects include the nature of the ingredients, the qualitative and quantitative composition, the pharmacological and/or therapeutical properties proven by proper use, the posology and the method of administration. As formal characteristics we consider indications, purposes, claimed properties, labels and package inserts (i.e. presentation) and advertising messages (when allowed). When the therapeutical activity is well known and the essential characteristics are evident, the product is classified without any doubt as a medicinal product, on the other hand, when the substance can be used for different purposes, the formal characteristics may become constitutive of the legal status of medicament. Specific products are not always defined as medicaments in every Member State. Many disputes have arisen in the Community as shown by the following examples. The Court of the Community has recently stated that a solution of eosin is not to be necessarily considered as a medicinal product if the label does not explicitly state that it has a therapeutic effect in the 1996 The Italian Pharmacological Society
4
Pharmacological Research, Vol. 34, No. 1/2, 1996
treatment of cutaneous infections [2]. On the contrary, the therapeutical indications written in any kind of leaflet that the consumer may receive after buying any special food [3] may also contribute to classify the product as a medicament marketed without the prescribed authorisations [4]. In Italy, the superior Court has ruled that the information given orally to the consumer by the retailer is an integral part of the product presentation, and may be utilized to identify the product as a medicament, even if the label does not mention any therapeutic effect [5]. Another cause of difficulty in stating what is a medicinal product relates the non uniform definition of pathologies in the different Member States. Moreover, when the symptoms indicated in the label are not related to a specific pathology, but may also be caused by a transitory trouble, the National Health Authority has to decide if the product should be considered as a medicinal product or not according to its composition, unwanted effects and to the risks of a long term administration, as in the case of herbal remedies indicated for heaviness of legs, weariness, itching [6].
THE CLASSIFICATION OF MEDICINAL PRODUCTS Medicinal products can be classified from the regulatory and administrative point of view. In the pharmaceutical field the preventive evaluation of quality, efficacy and safety are nowadays consolidated and considered inviolable to safeguard public health. The same level of guarantee of public health can be obtained with various levels of technical and regulatory requirements. With this aim suitable measures can be put into effect according to the characteristics and the degree of knowledge of the active substances and
of the finished products, the pharmacological and therapeutic activity, the method and route of administration, the treated pathology and also the medical knowledge of the population. Medicinal products can be classified in several ways based on different aspects of the medicaments: administrative status, legal status of dispensing [7], reimbursability by the State, anatomical, therapeutical and chemical classification (ATC) [8].
THE PROPRIETARY MEDICINAL PRODUCT (BRANDED MEDICINAL PRODUCT) The European definition of proprietary medicinal product is the following: ‘any ready-prepared medicinal product placed on the market under a special name and a special pack’ [9]. The special name may be the brand name as well as the common or scientific name together with a trade mark or the name of the manufacturer [10]. In the majority of countries the indication of a special pack presupposes that the label and the packaging have to be made by the manufacturer and that the pharmacist has to give patients the complete packaging. In the United Kingdom, pharmacists may divide up, or change packaging for retail supply without ‘manufacturer authorisation’ [11]. The authorisation to produce medicinal products is always necessary [12] and is given by the health authority following the verification of technical reliability [13] of the manufacturer. A marketing authorisation is also required for medicinal products. The procedure needed to obtain this authorisation is different for new drugs and non innovative products. In the case of new drugs the applicant shall supply complete documentation. The relevant parts of the dossier are the following: Part 1, Summary of the
Table I Administrative classification of medicinal products Administrative classification of medicinal products Proprietary (branded) a) New drug
Produced by
Industry
b) Copy Unbranded
Definition
Industry
Clinical trials Required by doctors Magistral formula
Industry Industry Pharmacy
Official formula
Pharmacy
(a) Any ready-prepared medicinal product placed on the market under a special name and a special pack. (b) Any ready-prepared medicinal product placed on the market under a special name and a special pack essentially similar to another. Medicinal product different from proprietary medicinal product (only from an administrative point of view). Medicinal product specifically produced to be used in clinical trials. Medicinal product prepared on the basis of a written request of a medical doctor. Any medicinal product prepared in a pharmacy in accordance with a prescription for an individual patient. Any medicinal product which is prepared in a pharmacy in accordance with the prescriptions of a Pharmacopoeia and is intended to be supplied directly to the patients served by the pharmacy in question.
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dossier; Part 2, Chemical, pharmaceutical and biological testing of medicinal products; Part 3, Toxicological and pharmacological tests; Part 4, Clinical documentation. For non innovative drugs the applicant is not required to provide the pharmacological, toxicological and clinical data (abridged application). Drugs are considered non innovative if: (a) the proprietary medicinal product is ‘essentially similar’ to a product authorized in the country concerned by the application and the person responsible for its marketing has consented to the pharmacological, toxicological or clinical references contained in the dossier on the original proprietary medicinal product being used for the purpose of examining the application in question; (b) it is possible to demonstrate, by detailed references to published scientific literature, that the constituents of the proprietary medicinal product have a well established medicinal use with recognized efficacy and an acceptable level of safety. These data have to be exhaustive enough to permit experts to fill in report tables; (a) the proprietary medicinal product is ‘essentially similar’ to a product which has already been authorized within the Community six or ten years before the launch of the new product, according to the rules established by the various Member States. The ten year period is always applicable in the case of high-technology medicinal products [14]. Many countries, for example the United Kingdom, Italy, The Netherlands, France, prefer the ten year period for all medicaments. For the purpose of the European abridged application, a medicinal product is ‘essentially similar’ to another product when it has the same qualitative and quantitative composition in terms of active principles, and the pharmaceutical form is the same; where necessary, bioequivalence with the first marketed product has to be demonstrated by appropriate bioavailability studies [15]. The definition and the characteristics of bioequivalence have been defined by the EEC [16] and in a draft guideline of WHO are the following: ‘two products are bioequivalent if they are pharmaceutically equivalent [17] and their bioavailabilities (rate and extent of absorption) after administration in the same molar dose are similar to such a degree that their effects, with respect to both efficacy and safety, will be essentially the same’ [18]. Two products are generally considered bioequivalent if, the 90% confidence interval of AUC-ratio lay within the accepted range (80–125%). This range may need to be reduced in the case of a drug with a particularly narrow therapeutical range. A larger acceptance range may be acceptable if inevitable and clinically acceptable [16]. The 90% confidence interval of the Cmax -ratio lay within a wider acceptance range (70–143%) and the range is justified taking into account safety and efficacy considerations. The non parametric 90% confi-
5
dence interval of the Tmax difference lay within a clinically determinated range. By extension the concept of ‘essentially similar’ may also be applied to different oral forms (tablets and capsules) with the same active substance if for immediate release [19]. The same extension could be appropriately provided for controlled release oral dosage forms. The ‘abridged application’ is excluded when drugs, even if copies of similar proprietary medicinal products, have different therapeutic indications, a different route of administration, have different dosages, or contain known constituents not hitherto used in combination [20]. A particular ‘abridged application’ (so called ‘hybrid’) is applicable when the product has been slightly modified, for example, there is a different dosing schedule, different strength, suprabioavailable products, different salt/ester/derivative of the same therapeutic moiety, different therapeutic use. Additional data is required which is consistent with the modifications [18].
THE MEDICINAL PRODUCT DIFFERENT FROM THE PROPRIETARY MEDICINAL PRODUCT (UNBRANDED MEDICINAL PRODUCT) This category may include the following, (a) medicinal products different from the proprietary medicinal product. (b) Medicaments prepared by industrial manufacturers on the basis of a written request of a medical doctor. (The products have to be used under the medical doctor’s responsibility only to his/her patients [21]). (c) Medicaments prepared by industrial manufacturers for clinical trials. (d) Magistral and officinal formulas prepared by pharmacies (also called ‘galenic products’). In 1989, the European Council amended the Directives 65/65/EEC, 75/318/EEC and 75/319/EEC with the view of subjecting all the medicinal products of industrial origin to the same preventive and aftermarket controls. Thus, the term ‘proprietary medicinal product’ was substituted with the more general term ‘medicinal product’ which embraces both branded and unbranded products [22]. All countries where some industrial medicaments were marketed without ‘marketing authorisation’ changed their rules according to the previsions laid down by the European Union. Unbranded products can be authorized for the market following an ‘abridged application’ or ‘hybrid abridged application’ with the same rules and exemptions discussed in the case of proprietary medicinal products. The name is the distinctive element of the two classes of drugs (branded and unbranded). In fact, the definition of a proprietary medicinal product requires that the products are marketed with a special name,
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while the unbranded product has to be marketed with the common or scientific name. This difference is important when physicians prescribe using the common name, in this case the pharmacist may dispense the unbranded medicinal product of his/her choice. The promotion of unbranded medicaments for the sake of medical doctors is not profitable, while industrial competition is played with the wholesalers and pharmacists. The medicaments prepared by industrial manufacturers on the basis of a written request of a medical doctor and the medicaments prepared by industrial manufacturers for clinical trials can be produced without the ‘marketing authorization’. In all cases, manufacturers shall possess the ‘manufacture authorization’ while pharmacies do not need any special authorisation to prepare generic products.
The medicinal product prepared by pharmacies The preparation and control of medicinal products in the community and hospital pharmacies are part of the activities permitted to pharmacists in the Community [23]. Products prepared in the pharmacy can be dispensed exclusively through the same pharmacy. As far as the quality is concerned, although not yet established by the European Union, a ‘good compounding practice’ is enforced by some Member States such as Italy [24], France [25] and Sweden [26] and now elaborated as draft in the USA [27]. The assurance of efficacy and safety appears more difficult. The consequence is that a source capable to legitimate the formula is required. Therefore, in a pharmacy the pharmacist can prepare the following. (a) A magistral formula: any medicinal product prepared in a pharmacy in accordance with a prescription for an individual patient. (b) An officinal formula: any medicinal product which is prepared in a pharmacy in accordance with the prescriptions of a Pharmacopoeia, and is intended to be supplied directly to the patients served by the pharmacy in question [28]. With regards to the magistral formula, the responsibility for the evaluation of the efficacy is assumed by the medical doctor who prescribes the medicament; as regards the officinal formula the public administration is responsible. The European Legislation considers the above mentioned products only to exclude them from the disposition enforced by the directives on medicinal products. In fact, these products are not prepared to be distributed in the common market, in this sense, possible disparities in the legislation of the different Member States are of no direct interest to the European Council. In Italy, any medical doctor can prescribe a magistral formula, only with few limitations, the most relevant of which is related to appetite suppresser medicaments [29]. The same limitations are also adopted in other countries: e.g. France [30].
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THE NOTION OF GENERIC PRODUCT AND THE INTERCHANGEABILITY OF MEDICAMENTS The term ‘generic product’ has a somewhat different meaning in different countries. Existing directives on the approximation of prevision relating to medicinal products never use this term. In fact, community regulations provide for the production and launching of medicinal products on the market with the primary purpose of safeguarding public health and establishing the common market, without hindering the development of pharmaceutical industries [31]. In these directives only the regulatory procedures have been considered without any interest for a costcontainment policy. The term ‘generic product’ becomes relevant when the economic impact of medicinal products is considered. Until now the European Union has not interfered with national policies except for the necessity of obtaining transparency on prices and social security schemes [32]. Therefore, the accepted definition of generics is given by the WHO. ‘Generic product’ means, ‘a pharmaceutical product, usually intended to be interchangeable with the innovator product, which is usually manufactured without a license from the innovator company and marketed after the expiration of the patent or other exclusivity rights’. ‘The innovator product’, on the other hand, ‘is that which was first authorized for marketing, as a patented drug, on the basis of documentation of safety, quality and efficacy (according to the contemporary requirement)’ [33]. The reference product could, in some cases, be different from the first innovator for many reasons, but it always has to be authorised for marketing after analysis of the complete documentation. Moreover, in order to be interchangeable with another drug, any medicament has to be bioequivalent. Furthermore it would be preferable that the packaging specifications, when critical to stability and shelflife, and the instructions for use are the same in order to obtain a uniformity of information given to patients [32, 34, 35, 36]. In terms of denomination, the generic product can be branded (branded generics) or unbranded (pure generics); while in terms of regulatory status the former are proprietary medicinal products essentially similar to other products, the latter are industrial products that, from an administrative point of view, are different from proprietary medicinal products. It should be noted that it is impossible to place the generics in one category in terms of administrative classification as defined by the EEC directive 65/65/EEC as amended by directive 89/341/EEC. In short, a medicinal product can be defined as generic when the following conditions are satisfied.
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(a) Patent or other exclusivity rights have expired. (b) Bioequivalence and consequent interchangeability with the reference product. Generics can have a real market only if their prices are lower than those of the corresponding reference products. Pharmacists can generally dispense unbranded products without regard to their industrial origin if the doctor prescribes them using the common name of their active principle(s). On the other hand, in the majority of the European countries, medical doctors usually prescribe medicaments using their brand name. In this case, the possibility of substitution becomes the key of the market within the social security schemes. The European Union Commission believes that generics should be permitted to obtain reduction in terms of pharmaceutical expenditures, but it does not currently intend to prepare new legislation in this area [37], even though the Council calls on the Commission to draw up a report concerning policy on generic medicinal products in the Member States [38]. It should be stressed that the real impact on the market of generics depends on the political decision of the single Member State, as the final decision concerning generics is not a problem of public health but of public expenditure, if current technical regulations are fully respected.
REFERENCES 1. Article 1, n.2, Directive 65/65/EEC, January 26, 1965. 2. Conclusions of Legal Advisory Office, January 16, 1991, proceedings C-60/89. 3. Directive 89/398/EEC, May 3, 1989. 4. Court of Justice EU section V, judgement October 28, 1992, proceedings C-219/91, EU OJ n.C/310/2, November 27, 1991. 5. Supreme Court of Appeal, Section I, judgement no. 1597, April, 16, 1993. 6. Court of Justice EU, Section. V, judgement March 21, ¨ 108¨2 April 23, 1991, proceedings C-369/88. OJ n. C 1991. 7. Directive 92/26/EEC, March 31, 1992. 8. WHO Collaborating Center for Drug Statistics Methodology. 9. Article 1, n. 1 Directive 65/65/EEC. 10. Article 4, Directive 65/65/EEC. 11. Article 16(2), Directive 75/319/EEC, May 20, 1975.
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12. Article 16, Directive 75/319/EEC. 13. Article 3, Directive 89/341/EEC, May 3, 1989. 14. Part A and B in the Annex to Council regulation (EEC) No 2309/93 July 22, 1993. 15. Commission of the European Community, Notice to Applicant in: The Rules governing medicinal product in the European community, Volume II, III/118/87-EN 1989. 16. Note for Guidance of the EEC ’Investigation of bioavailability and bioequivalence’ III/54/89. 17. Two products are pharmaceutically equivalent if have: same amount of the same active substance(s) in the same dosage form that meets a comparable standard and are intended to be administered by the same route. 18. Interchangeable multi-source pharmaceutical products. WHO draft guideline on marketing authorisation. 19. Note for guidance of the EEC, Abridged Application III/3879/90-EN December 1991. 20. Article 4, n. 8, Directive 65/65/ECC amended by Article 1, n. 1, Directive 87/21/EEC, December 22, 1986. 21. Article 2 Directive 65/65/EEC amended by Article 2, point 3, Directive 89/341/EEC. 22. Directive 89/341/EEC. 23. Article 1(2) Directive 85/432/EEC of December 16, 1985. 24. National Formulary, third volume of the Italian Official National Pharmacopoeia, 1991. 25. ’Bonnes Pratiques de Pre´parations Officinales’, Bulletin official n.88/7 BIS, 1988. 26. Svensk La¨kemedelsstandard, SLS, 1989. Svenska farmakope´kommitte´n, sektion 4. 27. Pharmacopeial Previews, Pharmacopeial Forum, 21, pp. 258–266, 1995 General Chapters—General Information <1161> Pharmacy Compounding Practice. 28. Article 1, Directive 89/341/EEC amending Article 1, Directive 65/65/EEC. 29. Minister decree May 26 1987, April 13, 1993. 30. Decree no. 82–200 February 25, 1982. 31. Preamble Directive 65/65/EEC. 32. Directive 89/105/EEC December 21, 1988. 33. WHO Draft Guideline on Marketing Authorisation requirements—Interchangeable multi-source pharmaceutical products—December 6, 1993. 34. Montanari L, Minghetti P, Gazzaniga A, Santoro P. ‘European community procedures for the marketing authorisation of medicinal product: impact on presentation and distribution’ presented at the First European Congress of Pharmacology, Milan—June 16–19, 1995. 35. Economic and Social Committee, 278 Plenary session, April 7, 1990. 36. Dir 92/27/EEC, March 31, 1992. 37. Answer of Bangemann M. (Member of The Commission) to written question of Sotiris Kostopoulos, EU O.J. N.C.226/47 August 16, 1994. 38. Council Resolution of 20 December 1995 on generic medicinal products (95/C 350/06) O.J. no. C 350 30 December, 1995.