Eur J Clin Pharmacol (1992) 42:395-399 EuropeanJ. . . . Io, ( ~ : ~ ( ~ : ~
@ Springer-Verlag 1992
FARMAGUIDAi a databank for the analysis of the italian drug market and drug utilization in general practice N. Montanaro, A. Vaccheri, N. Magrini, and M. Battilana Department of Pharmacology, Universityof Bologna, Italy Received: August 8, 1990/Acceptedin revised form: August 1, 1991
Summary. FARMAGUIDA,a databank of drugs marketed in Italy (2,596 pharmaceutical substances corresponding to 10,448 products), permits analysis of the nature and value of the drugs prescribed. It contains coded pharmaceutical and administrative information, an original classification, as well as indicators of the therapeutic status of each drug. The FARMAGUIDAclassification was built hierarchically according to a three-level pattern: the first level (42 categories) corresponds to major pharmacological groups; the second level (157 groups) gathers drugs having similar clinical indications and/or pharmacological actions; and the third level (246 subgroups) classifies drugs according to chemical structure and/or the mechanism of action. Drugs not falling into well-established pharmacotherapeutic criteria (e. g. neurotropics or liver protectants) are classified into separate subgroups. Two larger groupings were also formulated: THER (11 headings), a utilizationoriented arrangement in which each heading also contained the corresponding placebo-like drugs, and PHARM (14 headings), a rational pharmacological arrangement, in which all placebo-like drugs were relegated into a separate set. The following quality indicators were created: DOC, which defines five degrees of documentation of clinical efficacy according to major textbooks of pharmacology and therapeutics; CLASS,which groups DOC values for a more simple evaluation of prescription data; PREP,which distinguishes monocomponent preparations from fixed-dose combinations, and also provides coded information about the rationale for the combination; HOSP,which hallmarks drugs that should be reserved for in-patients, e.g. antipseudomonal antibiotics. The composition of the list of reimbursable drugs, the Italian National Formulary (NF; 5782 products in 1990) was analyzed according to the FARMAGUIDAclassification and indicators. Almost 20 % of NF products were classified as "Proposed as Coadjuvants" (placebo-like drugs) and about 40 % of products received a poor CLASSindicator.
The figures suggest that much work is required to achieve a more rational composition of the NE FARMAGUIDA should be a useful tool for monitoring the composition of the NF and for critically evaluating drug utilization patterns.
Key words: Databases; prescription data-collection, drugutilization, family practice, Italian National Formulary, drug market
The close prospect of a Europe without barriers in the drug market makes precise information on drug market and drug utilization patterns in different countries very important. Such information would aid the development of rational drug policy and possibly drug use. In the present paper, a databank (FARMAGUIDA)of drugs marketed in Italy is described, which permits analysis of the nature and value of the drugs prescribed. FARMAGUIDAis a databank containing coded pharmaceutical and administrative information about products on sale in Italy as documented by the Ministry of Health (e.g. manufacturer, price, ticket, etc.). FARMAGUIDAalso provides the possibility of evaluating drug prescription patterns according to the therapeutic status of each drug by using original indicators. In Italy, 2,596 pharmaceutical substances (1,340 monocomponent + 1,256 combinations of 2 to 9 substances) were available in July 1990, corresponding to 4,717 proprietary brands, marketed in 10,448 different pharmaceutical products. Almost half of the registered products, namely 5,782preparations (corresponding to 1,556 substances), comprised the reimbursement list, known as the National Formulary (NF). Although this vast formulary has been reduced in the past few years by several revisions, it remains inflated, containing groups of drugs or single substances of dubious clinical efficacy.
396
Table 1. Distribution of reimbursable products (Italian National Formulary, NF) and of total marketed products according to the scores of Doc, CLASS,PREP and HOSPindicators Code
Denomination
N. of NF products
N. of Total non-NF products
DOC
documentation of clinical effectiveness 1 2 3 4 5 9
Ample Acceptable a Insufficient Absent Unfavourable risk/benefit ratio To be classified b
3066 ~594 1450 479 37 156
2320 207 1013 657 54 415
5386 801 2463 1136 91 571
Total
5782
4666
10 448
a Also assigned to fixed-dose combinations of two agents, when the preparation corresponds to a rational therapeutic scheme or has the purpose of facilitating patients' compliance (e. g. diuretic-betablocking agents for the treatment of hypertension). b Most belonging to topical products
Italy with a population of 4 million, and it only comprised drugs of well-established therapeutic value. A few modifications of the classification were then introduced in order to deal with all the drugs on the market in Italy. This was necessary because there were products containing substances unlikely to be mentioned in the major textbooks of pharmacology and therapeutics, and which had no clear pharmacological or therapeutic profile, e.g. substances claiming to act as trophics, tonics, protectants. Groups and subgroups were created for these drugs defined as "proposed-as-coadjuvants-for-" a given disorder. A clear-cut distinction was also required between substances with differing degrees of evidence of clinical efficacy, even though they were classifiable in the same group on the basis of their mechanism of action, e.g. crataegus is poorly documented as cardiac inotropic agent, although it is classifiable under this heading [4]. To this end, coded quality indicators were given to each individual product, providing information on the therapeutic status of each drug according to authoritative sources of scientific information on therapeutic agents [1, 5-7]. Four indicators were adopted: DOC." the degree of documentation available in the above mentioned sources regarding the clinical efficacy of each product. A similar approach has previously been suggested by Laporte et al. [8]. Doc
PREP
type of preparation $1 $2 $3 $4 T1 T2 99
Monocomponent Rational combination (a) Empirical combination (b) Unjustified combination (c) Monocomponent for topical use Combination for topical use To be classified
4199 85 409 221 579 251 38
2787 104 576 464 326 327 82
6986 189 985 685 905 578 120
Total
5782
4666
10 448
(a) e.g., sulphamethoxazole + trimethoprim; (b) e.g., thiazide diuretic + betablocker; (c) e.g., antibiotic + mucolytic. HOSP (now applied only to antiinfective agents) 1 2
R e c o m m e n d e d for hospital use R e c o m m e n d e d for general use
187 644
192 603
379 1247
Total
831
795
1626
Materials and m e t h o d Each pharmaceutical product on sale in Italy was classified in FARMAG~JII~A according to a classification modelled after the structure of G o o d m a n & Gilman's "The Pharmacological Basis of Therapeutics" [1]. This permits ready referal of actual prescription data to a well-established pharmaco-therapeutic framework. The need to prepare such a classification was due to the lack of a complete, official classification of drugs on sale in Italy. The only classification available for many years was that introduced by the non-official reference book of drug products [2], but it was unsatisfactory both in its general structure and in its allocation of individual products. The well-known A T C classification, much employed in other European countries, has not yet been adopted in Italy, apart from a version published by the above mentioned private source [2]. It is not supervised by the Italian Ministry of Health, so that any manufacturer could list a given product according to its claimed pharmacotherapeutic properties. Only very recently has the Italian Ministry of Health charged a working group with classifying all the pharmaceutical products on sale according to the 1991 version of ATC classification [3]. The new document will probably be released in the second half of 1991. The FARMAGUIDAclassification was initially prepared for the Regional Hospital Formulary of Emilia Romagna, a region in northern
Table 2. Distribution of reimbursable products (Italian National Formulary, NF) and of total market products according to the categories of FARMAGUIDAclassification Code Category name
1 2 3 4 5 6 7 8 9 10 ll 12 13 14 15 16 18 19 20 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 51 52 53 54 55 56 99
CNS drugs Local anesthetics Neuromuscular blocking agents Drugs for inflammation Antihistamines Autonomic nervous system drugs Anti-migraine agents Drugs for uterine motility Cardiovascular drugs Diuretics Antihyperlipoproteinemics Drugs of hemostasis Gastrointestinal agents Bronchopulmonary drugs Antigout agents Nutrient and hydrosaline solutions Plasma substitutes Blood and related products Antianemic agents Vitamins Drugs of endocrine system Antiinfective agents Antineoplastics and lmmunosupprcssives Vaccines Immune sera Human immunoglobulines Dermatological agents Otological agents Rinological agents Stomatological agents Gynaecological agents Ophthmnological agents Antidotes and chelating agents Diagnostic agents Contrast media Proposed as metabolic supplements Organ extracts Proposed for prostatic hypertrophy Proposed as immunostimulants Symptomatic antiinfluenzals Phytotherapeutics To be classified Total
N. ofNF N. of Total products non-NF products 344 3 0 499 64 237 14 11 689 61 95 106 454 438 13 39 7 75 101 188 320 831 105 19 5 82 370 10 29 20 156 183 29 0 0 64 0 5 35 38 1 42
403 55 9 281 31 104 9 5 272 36 35 79 562 217 4 49 9 38 34 238 149 795 29 99 11 94 255 18 78 75 47 96 21 16 92 63 80 0 3 29 68 78
747 58 9 780 95 341 23 16 961 97 130 185 1016 655 17 88 16 113 135 426 469 1626 134 118 16 176 625 28 107 95 203 279 50 16 92 127 80 5 38 67 69 120
5782
4666
10448
397 Table 3. Distribution of reimbursable products (Italian National Formulary, NF) and of total marketed products according to the PHARMset of the FARMAGUIDAclassification Pharm Pharm code denomination CA CH CV DV EM FL GI GN HR PL SN TP VT VV XX
N. ofNF N. of Total products non-NF products
Antineoplastics 105 Antiinfectivessera vaccines 937 Cardiovascular drugs 617 Diagnostics and others 73 Haematological drugs 131 Antiinflammatorydrugs 441 Gastrointestinal drugs 419 Gynaecological drugs 167 Hormones 320 Bronchopulmonary/antiallergics 575 Neurological drugs 260 Topical drugs 603 Vitamins 52 Proposed as coadjuvants 1040 To be classified 42 Total
5782
29 974 293 179 73 228 430 52 149 265 406 519 129 859 81
134 1911 910 252 204 669 849 219 469 840 666 1122 181 1899 123
4666
10 448
Table 5. Distribution of reimbursable products (Italian National Formulary, NF) and of total marketed products according to the groups/subgroups belonging to ~ER set "Infectious Diseases" Code
Group/subgroup denomination
2401 240101 240102 240103 240104
Penicillins Gram + active penicillins ~-lactamase resistant penicillins Broad spectrum penicillins Antipseudomonalpenicillins
N. of N. of Total NF non-NF products products 8 1 106 10
10 14 129 5
18 15 235 15
109
191
62
174
78
145
65
112
N. of NF N. of Total products non-NF products
Infectious diseases Cardiovascular system Gastrointestinal tract and metabolism Respiratory system Nervous system Locomotor system Antineoplastics and hormones Female genital apparatus Skin ORL and Ophthalmic disorders Miscellaneous disorders To be classified
1010 1001 890
1029 462 1010
2039 1463 1900
2403 Other B-lactam antibiotics 240301 Monobactams 240302 Carbapenems
4 0
4 11
8 11
Aminoglycosides
52
27
79
649 350 580 159 227 370 242 262 42
320 473 302 50 90 255 266 328 81
969 823 882 209 317 625 508 590 123
5 5
5 11
10 16
Total
5782
4666
10 448
Ther Ther code denomination
4 5 6 7 8 9 10 11 99
T h e FARMAGUIDA classification was built hierarchically with a six digit code: 1st level (first two digits): the category. This c o r r e s p o n d s to a m a j o r p h a r m a c o l o g i c a l g r o u p (e. g., 01-CNS Drugs, 06A u t o n o m i c N e r v o u s System Drugs, 0 9 - C a r d i o v a s c u l a r Drugs, etc.).
2402 Cephalosporins 240201 13-1actamasesensitive cephalo82 sporins 240202 ]3-1actamaseresistant+ cephalo112 sporins 240203 [3-1actamaseresistant + + cephalo67 sporins 240204 Antipseudomonal cephalosporins 47
Table 4. Distribution of reimbursable products (Italian National Formulary, NF) and of total marketed products according to the aa4ERset of the VARMA~UmAclassification
1 2 3
Results
2404
values range from i to 5 (see Table 1). Doc does not simply apply to the substance but also considers the route of administration, dosage and indications as presented by the manufacturer. Therefore, two products containingthe same substance may have a different DOe according to the preparation being considered, e.g. heparin gel for topical use has been given a unfavourable DOC,owing to the lack of consistent clinical documentation of its efficacy, whereas preparations of heparin to be administered intravenouslyand subcutaneously as anticoagulants are well documented.
CLASS." a derived indicator which groups the DOCS as follows: A = 1 + 2; B = 3; C = 4 + 5. It was formed in order to have a simple way of drawing up tables and diagrams of prescription data. PREe: the type of preparation. It distinguishes monocomponent preparations from fixed-dose combinations, and in the latter case, provides information concerning the rationale for the combination (see Table 1). HOSe."marks those drugs whose usage is rarely justified outside the hospital and should be closely monitored. At present, it has been assigned only within the antiinfectives (e. g. ceftriaxone, piperacillin, tobramicin) (see Table 1).
2405 Amphenicols 240501 Chloramphenicol 240502 Thiamphenicol 2406
Tetracyclines
22
80
102
2407
Macrolide antibiotics
41
39
80
2408
Antituberculars
26
20
46
14 52
3 22
17 74
2409 Quinolones 240901 Systemic quinolones 240902 Urinary tract quinolones 2410
Sulfonamides
52
33
85
2411 241101 241102 241103
Various chemoantibiotics Antistaphylococcal agents Anti-anaerobicagents Various chemoantibiotics-others
4 6 65
1 1 32
5 7 97
2412
AntifungaI agents
15
3
18
2413
Antiprotozoal agents
15
4
19
2414
Antihelmintic agents
11
0
11
2415
Antiviralagents
9
4
13
0 0
20 3
20 3
19
99
118
5
11
16
2451 Antibiotics + other drugs 245101 Antibiotics + Bronchopulmonars 245102 Antibiotics + Enzymes 2601
Vaccines
2701
Immunesera
2801
Human immunoglobulines
82
92
174
5401
Proposed as immunostimulants
35
3
38
5501
Symptomatic antiinfIuenzals Total
38
29
67
1010
1029
2039
398 Table 6. Distribution of reimbursable products (Italian National Formulary, NF) and of total marketed products according to the groups/subgroups belonging to THERset "Cardiovascular System" Code
Group/subgroup denomination
N, of N. of Total NF non-NF products products
601 Sympathomimetics 60101 Catecholamines 0 60102 Alpha-beta stimulants 12 602 Adrenergic blocking agents 60602 Beta blocking agents 33 60203 Alpha-beta blocking agents 10 60501 Ganglionic blocking agents 0 901 Inotropic agents 90101 Digitalis 29 90102 Other inotropic agents 6 902 Antiarrhitmic drugs 28 903 AntianginaI agents 90301 Organic nitrates 37 90302 Other antianginal drugs 12 904 Antihypertensive agents 90401 Antihypertensives, plain 73 90402 Antihypertensives in combination 51 905 Calciumantagonists 53 951 Cardiovascularcoadjuvants 95101 Proposed for vascular diseases 226 95102 Circulatory analeptics 11 95103 Proposed as capillary protectants 45 95104 Proposed as heart tonics 84 95105 Topical vasculotropics 23 10 Diuretics 100201 Osmotic diuretics 3 100301 High-ceiling diuretics 15 100401 Thiazides and analogues 16 100501 Potassium-sparing diuretics 14 100601 Diuretics in combination 8 1101 Antihyperlipoproteinaemics 95 1201 Antihaemorrhagics 120101 Systemic haemostatics 9 120102 Topical haemostatics 1 120103 Antifibrinolytic agents 18 120151 Proposed as antihaemorrhagics 9 1202 Antithrombotics 120201 Direct anticoagulants 24 120202 Indirect anticoagulants 2 120203 Antiplatelet drugs 25 120204 Thrombolytics 16 120205 Other antithrombotics 2 Total 1001
6 1
6 13
20 13 1
53 23 1
18 1 12
47 7 40
8 18
45 30
29 16 12
102 67 65
114 0 27 16 12
340 11 72 100 35
1 4 15 12 3 35
4 19 31 26 11 130
6 12 19 9
15 13 37 18
21 0 4 8 0 462
45 2 29 24 2 1463
2nd level (second two digits): the group. This comprises drugs having similar clinical indications (0108-Antipsychotics) and/or pharmacological actions (0602-Adrenergic Blocking Agents). 3rd level (third two digits): the subgroup. This classifies drugs according to their chemical structure (010801phenothiazines, 010802-butyrophenones, etc.) and/or their mechanisms of action (060201-a-Adrenoceptor Blocking Agents, 060202-[3-Adrenoceptor Blocking Agents, ect.). The FARMAGUIDA classification is made up of 42 categories, 157groups and 246subgroups. The 42ca-
tegories, and the corresponding number of products on sale in Italy and those found in the NF are listed in Table 2. Two larger groupings have been formulated, rearranging the whole classification under 11 and 14 headings, respectively. The PHARM arrangement (Table 3) reorders the groups and subgroups of the classfication into 13 "true" pharmaco-therapeutic sets, and relegates those drugs called 'coadjuvants' to a fourteenth set, called "proposedas-coadjuvants". This permits a comprehensive listing of all the placebo-like drugs available in Italy. The THER arrangement (Table4) reorders the 246 groups and subgroups into 11 anatomico-therapeutic sets. In each of those sets the pertinent placebo-like groups have been placed on the basis of their therapeutic claims, e. g., myocardiotrophics within THER2-Cardiovascular Diseases. The various THERSbroadly reflect the main groups of the ATC classification. As examples of the FARMAGUIDAclassification rHEa 1Infectious Diseases (Table 5) and THER2-Cardiovascular Diseases (Table 6) have been set out in detail. In both tables, the first columns shows the number of products reimbursable, i. e. those present in the N E
Discussion and conclusions The main purposes of the FARMAGUIDAclassification were a) to refer every product on sale to a known pharmacological and/or clinical framework, b) to devise a tool suitable for the analysis of drug prescription patterns, and c) to provide a stimulus for revising and updating other available classifications, mainly the ATC system. The FARMAGUIDA classification is not intended as a substitute for the ATC classification, which is internationally recognised, and is recommended by W H O for drug utilization studies. Rather, it may be used as an alternative way of examining prescription data. As an example of its value, the FARMAGUIDAclassification of antiinfective agents (Table 5) is more analytical and detailed than the ATC main group "J-General antiinfectives, systemic", in that such antibiotics as penicillins and cephalosporins are further subdivided according to their spectrum of activity. This permits the detection of problems in prescribing habits of GPs, such as possible misuse of antipseudomonal penicillins (e. g. mezlocillin, piperacillin), which should be reserved for hospital infections. On the other hand, the classification of drugs for cardiovascular diseases (Table 6) follows a simpler approach in comparison to the ATC main group "C-Cardiovascular system", which affords a clearer view of the therapeutic areas of cardiovascular products actually prescribed. As far as the NF is concerned, in certain categories of drugs, e.g. "CNS Drugs" and "Gastrointestinal Agents", less than half of the products are reimbursable by the National Health Service (see Table 1), owing to the exclusion of relevant groups, such as benzodiazepines and laxatives. On the other hand, drugs belonging to controversial groups, such as those classified as "Proposed for Prostatic Hypertrophy" and "Proposed as Immunostimulants", are almost all included in the NF. The large number of drugs
399 672
1798
3660
2/,63
6187
Fig.la, b. Number ofreimbursable products (a) (Italian National Formulary) and total number of products (b) on sale subdivided according to the values of the CLASSindicator. CLASSis a simplified version of the DO¢indicator (see Table 1): CLASS-A = [DOC-1 + Doe-2]; CLASS-B = DOC-3; CLASS-C = [DOC-4 + DOC-5]
a
b
" P r o p o s e d as C o a d j u v a n t s " shown in Table 2 (18% of both total and N F products) shows h o w distant are the goals of a m o r e rational a r r a n g e m e n t of the drug m a r k e t and of a m o r e rigorous composition of the N F [9]. A n even worse picture appears w h e n the CLASSindicator is applied to the Italian drug market: less than 60 % both of total and N F products achieved an A score (Fig. 1). It is true, however, that a slow trend t o w a r d a reduction and rationalization of the drug m a r k e t in Italy m a y be seen. T h e n u m b e r of p r o d u c t s of the N F was a b o u t 14,900 in 1959, 7900 in 1981, and 6900 in 1988 [10]. T h e p e r c e n t a g e of m o n o c o m p o n e n t products out of the total n u m b e r of products on the Italian m a r k e t s h o w e d the following trend: 37 % (of 26,700) in 1962, 6 9 % (of 12,900) in 1982 and 7 5 % (of 10,700) in 1988, with a sharp reduction in the n u m b e r of fixed-dose c o m b i n a t i o n p r o d u c t s [10]. T h e approval of new p r o d u c t s in Italy, too, n o w appears to follow stricter criteria, and a p r o g r a m of revision of the old medicines is n o w in place in Italy as in the other countries of the E u r o p e a n Community. Nevertheless, m u c h remains to be d o n e in o r d e r to achieve better p h a r m a c e u t i c a l habits in Italy and in E u r o p e . FARMAGUIDAallows a critical eye to be kept on this picture and its qualitative drug indicators will contribute to the m o n i t o r i n g and p r o m o t i o n of desirable changes.
CLASSindicator: [ ] A documentation present [ ] B documentation insufficient [ ] C documentation absent
References 1. Goodman Gilman A, Rall TW, Nies AS, Taylor P (1990) Goodman and Gilman's the pharmacological basis of therapeutics. Pergamon Press, New York 2. L'Informatore Farmaceutico (1990) Italian directory of drugs and manufacturers. Organizzazione Editoriale Medico Farmaceutica, Milano 3. ATC Index including DDDs for plain substances (1991) WHO Collaborating Centre for Drug Statistics Methodology, Oslo 4. Anonymous (1989) Cardiac inotropic agents. In: Reynolds JEF (ed) Martindale the extra pharmacopoeia. The Pharmaceutical Press, London 5. Reynolds JEF (1989) Martindale the extra pharmacopoeia. The Pharmaceutical Press, London 6. American Medical Association (1986) Drug evaluations. American Medical Association, Washington 7. Avery GS (1987) Drug treatment: principles and practice of clinical pharmacology and therapeutics. Livingstone, Edinburgh 8. Laporte JR, Porta M, Capellg D (1983) Drug utilization studies: a tool for determining the effectiveness of drug use. Br J Clin Pharmaco116: 301-304 9. Garattini S (1989) Public anger at health charges. Lancet I: 835 10. Italian Ministry of Health (1989) Ministero della Sanitfi - Direzione Generale del Servizio Farmaceutico. Esame della situazione farmaceutica Italiana anche con riferimento al contesto internazionale: risultati finora ottenuti e prospettive future. Official Report to the Italian Parliament
Acknowledgements. The project was supported by a grant from the Health Authority of Emilia Romagna Region (Assessorato alla Sanit~ della Regione Emilia Romagna). We thank the anonymous referees for helpful suggestions on a previous draft of this manuscript. We also thank Dr. D. P. Davis (Saint Bonaventure University, Saint Bonaventure, NY) for revising the English version.
Prof. Nicola Montanaro Department of Pharmacology Via Irnerio 48 1-40126 Bologna, Italy
@ Springer-Verlag 1992
FARMAGUIDAi a databank for the analysis of the italian drug market and drug utilization in general practice N. Montanaro, A. Vaccheri, N. Magrini, and M. Battilana Department of Pharmacology, Universityof Bologna, Italy Received: August 8, 1990/Acceptedin revised form: August 1, 1991
Summary. FARMAGUIDA,a databank of drugs marketed in Italy (2,596 pharmaceutical substances corresponding to 10,448 products), permits analysis of the nature and value of the drugs prescribed. It contains coded pharmaceutical and administrative information, an original classification, as well as indicators of the therapeutic status of each drug. The FARMAGUIDAclassification was built hierarchically according to a three-level pattern: the first level (42 categories) corresponds to major pharmacological groups; the second level (157 groups) gathers drugs having similar clinical indications and/or pharmacological actions; and the third level (246 subgroups) classifies drugs according to chemical structure and/or the mechanism of action. Drugs not falling into well-established pharmacotherapeutic criteria (e. g. neurotropics or liver protectants) are classified into separate subgroups. Two larger groupings were also formulated: THER (11 headings), a utilizationoriented arrangement in which each heading also contained the corresponding placebo-like drugs, and PHARM (14 headings), a rational pharmacological arrangement, in which all placebo-like drugs were relegated into a separate set. The following quality indicators were created: DOC, which defines five degrees of documentation of clinical efficacy according to major textbooks of pharmacology and therapeutics; CLASS,which groups DOC values for a more simple evaluation of prescription data; PREP,which distinguishes monocomponent preparations from fixed-dose combinations, and also provides coded information about the rationale for the combination; HOSP,which hallmarks drugs that should be reserved for in-patients, e.g. antipseudomonal antibiotics. The composition of the list of reimbursable drugs, the Italian National Formulary (NF; 5782 products in 1990) was analyzed according to the FARMAGUIDAclassification and indicators. Almost 20 % of NF products were classified as "Proposed as Coadjuvants" (placebo-like drugs) and about 40 % of products received a poor CLASSindicator.
The figures suggest that much work is required to achieve a more rational composition of the NE FARMAGUIDA should be a useful tool for monitoring the composition of the NF and for critically evaluating drug utilization patterns.
Key words: Databases; prescription data-collection, drugutilization, family practice, Italian National Formulary, drug market
The close prospect of a Europe without barriers in the drug market makes precise information on drug market and drug utilization patterns in different countries very important. Such information would aid the development of rational drug policy and possibly drug use. In the present paper, a databank (FARMAGUIDA)of drugs marketed in Italy is described, which permits analysis of the nature and value of the drugs prescribed. FARMAGUIDAis a databank containing coded pharmaceutical and administrative information about products on sale in Italy as documented by the Ministry of Health (e.g. manufacturer, price, ticket, etc.). FARMAGUIDAalso provides the possibility of evaluating drug prescription patterns according to the therapeutic status of each drug by using original indicators. In Italy, 2,596 pharmaceutical substances (1,340 monocomponent + 1,256 combinations of 2 to 9 substances) were available in July 1990, corresponding to 4,717 proprietary brands, marketed in 10,448 different pharmaceutical products. Almost half of the registered products, namely 5,782preparations (corresponding to 1,556 substances), comprised the reimbursement list, known as the National Formulary (NF). Although this vast formulary has been reduced in the past few years by several revisions, it remains inflated, containing groups of drugs or single substances of dubious clinical efficacy.
396
Table 1. Distribution of reimbursable products (Italian National Formulary, NF) and of total marketed products according to the scores of Doc, CLASS,PREP and HOSPindicators Code
Denomination
N. of NF products
N. of Total non-NF products
DOC
documentation of clinical effectiveness 1 2 3 4 5 9
Ample Acceptable a Insufficient Absent Unfavourable risk/benefit ratio To be classified b
3066 ~594 1450 479 37 156
2320 207 1013 657 54 415
5386 801 2463 1136 91 571
Total
5782
4666
10 448
a Also assigned to fixed-dose combinations of two agents, when the preparation corresponds to a rational therapeutic scheme or has the purpose of facilitating patients' compliance (e. g. diuretic-betablocking agents for the treatment of hypertension). b Most belonging to topical products
Italy with a population of 4 million, and it only comprised drugs of well-established therapeutic value. A few modifications of the classification were then introduced in order to deal with all the drugs on the market in Italy. This was necessary because there were products containing substances unlikely to be mentioned in the major textbooks of pharmacology and therapeutics, and which had no clear pharmacological or therapeutic profile, e.g. substances claiming to act as trophics, tonics, protectants. Groups and subgroups were created for these drugs defined as "proposed-as-coadjuvants-for-" a given disorder. A clear-cut distinction was also required between substances with differing degrees of evidence of clinical efficacy, even though they were classifiable in the same group on the basis of their mechanism of action, e.g. crataegus is poorly documented as cardiac inotropic agent, although it is classifiable under this heading [4]. To this end, coded quality indicators were given to each individual product, providing information on the therapeutic status of each drug according to authoritative sources of scientific information on therapeutic agents [1, 5-7]. Four indicators were adopted: DOC." the degree of documentation available in the above mentioned sources regarding the clinical efficacy of each product. A similar approach has previously been suggested by Laporte et al. [8]. Doc
PREP
type of preparation $1 $2 $3 $4 T1 T2 99
Monocomponent Rational combination (a) Empirical combination (b) Unjustified combination (c) Monocomponent for topical use Combination for topical use To be classified
4199 85 409 221 579 251 38
2787 104 576 464 326 327 82
6986 189 985 685 905 578 120
Total
5782
4666
10 448
(a) e.g., sulphamethoxazole + trimethoprim; (b) e.g., thiazide diuretic + betablocker; (c) e.g., antibiotic + mucolytic. HOSP (now applied only to antiinfective agents) 1 2
R e c o m m e n d e d for hospital use R e c o m m e n d e d for general use
187 644
192 603
379 1247
Total
831
795
1626
Materials and m e t h o d Each pharmaceutical product on sale in Italy was classified in FARMAG~JII~A according to a classification modelled after the structure of G o o d m a n & Gilman's "The Pharmacological Basis of Therapeutics" [1]. This permits ready referal of actual prescription data to a well-established pharmaco-therapeutic framework. The need to prepare such a classification was due to the lack of a complete, official classification of drugs on sale in Italy. The only classification available for many years was that introduced by the non-official reference book of drug products [2], but it was unsatisfactory both in its general structure and in its allocation of individual products. The well-known A T C classification, much employed in other European countries, has not yet been adopted in Italy, apart from a version published by the above mentioned private source [2]. It is not supervised by the Italian Ministry of Health, so that any manufacturer could list a given product according to its claimed pharmacotherapeutic properties. Only very recently has the Italian Ministry of Health charged a working group with classifying all the pharmaceutical products on sale according to the 1991 version of ATC classification [3]. The new document will probably be released in the second half of 1991. The FARMAGUIDAclassification was initially prepared for the Regional Hospital Formulary of Emilia Romagna, a region in northern
Table 2. Distribution of reimbursable products (Italian National Formulary, NF) and of total market products according to the categories of FARMAGUIDAclassification Code Category name
1 2 3 4 5 6 7 8 9 10 ll 12 13 14 15 16 18 19 20 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 51 52 53 54 55 56 99
CNS drugs Local anesthetics Neuromuscular blocking agents Drugs for inflammation Antihistamines Autonomic nervous system drugs Anti-migraine agents Drugs for uterine motility Cardiovascular drugs Diuretics Antihyperlipoproteinemics Drugs of hemostasis Gastrointestinal agents Bronchopulmonary drugs Antigout agents Nutrient and hydrosaline solutions Plasma substitutes Blood and related products Antianemic agents Vitamins Drugs of endocrine system Antiinfective agents Antineoplastics and lmmunosupprcssives Vaccines Immune sera Human immunoglobulines Dermatological agents Otological agents Rinological agents Stomatological agents Gynaecological agents Ophthmnological agents Antidotes and chelating agents Diagnostic agents Contrast media Proposed as metabolic supplements Organ extracts Proposed for prostatic hypertrophy Proposed as immunostimulants Symptomatic antiinfluenzals Phytotherapeutics To be classified Total
N. ofNF N. of Total products non-NF products 344 3 0 499 64 237 14 11 689 61 95 106 454 438 13 39 7 75 101 188 320 831 105 19 5 82 370 10 29 20 156 183 29 0 0 64 0 5 35 38 1 42
403 55 9 281 31 104 9 5 272 36 35 79 562 217 4 49 9 38 34 238 149 795 29 99 11 94 255 18 78 75 47 96 21 16 92 63 80 0 3 29 68 78
747 58 9 780 95 341 23 16 961 97 130 185 1016 655 17 88 16 113 135 426 469 1626 134 118 16 176 625 28 107 95 203 279 50 16 92 127 80 5 38 67 69 120
5782
4666
10448
397 Table 3. Distribution of reimbursable products (Italian National Formulary, NF) and of total marketed products according to the PHARMset of the FARMAGUIDAclassification Pharm Pharm code denomination CA CH CV DV EM FL GI GN HR PL SN TP VT VV XX
N. ofNF N. of Total products non-NF products
Antineoplastics 105 Antiinfectivessera vaccines 937 Cardiovascular drugs 617 Diagnostics and others 73 Haematological drugs 131 Antiinflammatorydrugs 441 Gastrointestinal drugs 419 Gynaecological drugs 167 Hormones 320 Bronchopulmonary/antiallergics 575 Neurological drugs 260 Topical drugs 603 Vitamins 52 Proposed as coadjuvants 1040 To be classified 42 Total
5782
29 974 293 179 73 228 430 52 149 265 406 519 129 859 81
134 1911 910 252 204 669 849 219 469 840 666 1122 181 1899 123
4666
10 448
Table 5. Distribution of reimbursable products (Italian National Formulary, NF) and of total marketed products according to the groups/subgroups belonging to ~ER set "Infectious Diseases" Code
Group/subgroup denomination
2401 240101 240102 240103 240104
Penicillins Gram + active penicillins ~-lactamase resistant penicillins Broad spectrum penicillins Antipseudomonalpenicillins
N. of N. of Total NF non-NF products products 8 1 106 10
10 14 129 5
18 15 235 15
109
191
62
174
78
145
65
112
N. of NF N. of Total products non-NF products
Infectious diseases Cardiovascular system Gastrointestinal tract and metabolism Respiratory system Nervous system Locomotor system Antineoplastics and hormones Female genital apparatus Skin ORL and Ophthalmic disorders Miscellaneous disorders To be classified
1010 1001 890
1029 462 1010
2039 1463 1900
2403 Other B-lactam antibiotics 240301 Monobactams 240302 Carbapenems
4 0
4 11
8 11
Aminoglycosides
52
27
79
649 350 580 159 227 370 242 262 42
320 473 302 50 90 255 266 328 81
969 823 882 209 317 625 508 590 123
5 5
5 11
10 16
Total
5782
4666
10 448
Ther Ther code denomination
4 5 6 7 8 9 10 11 99
T h e FARMAGUIDA classification was built hierarchically with a six digit code: 1st level (first two digits): the category. This c o r r e s p o n d s to a m a j o r p h a r m a c o l o g i c a l g r o u p (e. g., 01-CNS Drugs, 06A u t o n o m i c N e r v o u s System Drugs, 0 9 - C a r d i o v a s c u l a r Drugs, etc.).
2402 Cephalosporins 240201 13-1actamasesensitive cephalo82 sporins 240202 ]3-1actamaseresistant+ cephalo112 sporins 240203 [3-1actamaseresistant + + cephalo67 sporins 240204 Antipseudomonal cephalosporins 47
Table 4. Distribution of reimbursable products (Italian National Formulary, NF) and of total marketed products according to the aa4ERset of the VARMA~UmAclassification
1 2 3
Results
2404
values range from i to 5 (see Table 1). Doc does not simply apply to the substance but also considers the route of administration, dosage and indications as presented by the manufacturer. Therefore, two products containingthe same substance may have a different DOe according to the preparation being considered, e.g. heparin gel for topical use has been given a unfavourable DOC,owing to the lack of consistent clinical documentation of its efficacy, whereas preparations of heparin to be administered intravenouslyand subcutaneously as anticoagulants are well documented.
CLASS." a derived indicator which groups the DOCS as follows: A = 1 + 2; B = 3; C = 4 + 5. It was formed in order to have a simple way of drawing up tables and diagrams of prescription data. PREe: the type of preparation. It distinguishes monocomponent preparations from fixed-dose combinations, and in the latter case, provides information concerning the rationale for the combination (see Table 1). HOSe."marks those drugs whose usage is rarely justified outside the hospital and should be closely monitored. At present, it has been assigned only within the antiinfectives (e. g. ceftriaxone, piperacillin, tobramicin) (see Table 1).
2405 Amphenicols 240501 Chloramphenicol 240502 Thiamphenicol 2406
Tetracyclines
22
80
102
2407
Macrolide antibiotics
41
39
80
2408
Antituberculars
26
20
46
14 52
3 22
17 74
2409 Quinolones 240901 Systemic quinolones 240902 Urinary tract quinolones 2410
Sulfonamides
52
33
85
2411 241101 241102 241103
Various chemoantibiotics Antistaphylococcal agents Anti-anaerobicagents Various chemoantibiotics-others
4 6 65
1 1 32
5 7 97
2412
AntifungaI agents
15
3
18
2413
Antiprotozoal agents
15
4
19
2414
Antihelmintic agents
11
0
11
2415
Antiviralagents
9
4
13
0 0
20 3
20 3
19
99
118
5
11
16
2451 Antibiotics + other drugs 245101 Antibiotics + Bronchopulmonars 245102 Antibiotics + Enzymes 2601
Vaccines
2701
Immunesera
2801
Human immunoglobulines
82
92
174
5401
Proposed as immunostimulants
35
3
38
5501
Symptomatic antiinfIuenzals Total
38
29
67
1010
1029
2039
398 Table 6. Distribution of reimbursable products (Italian National Formulary, NF) and of total marketed products according to the groups/subgroups belonging to THERset "Cardiovascular System" Code
Group/subgroup denomination
N, of N. of Total NF non-NF products products
601 Sympathomimetics 60101 Catecholamines 0 60102 Alpha-beta stimulants 12 602 Adrenergic blocking agents 60602 Beta blocking agents 33 60203 Alpha-beta blocking agents 10 60501 Ganglionic blocking agents 0 901 Inotropic agents 90101 Digitalis 29 90102 Other inotropic agents 6 902 Antiarrhitmic drugs 28 903 AntianginaI agents 90301 Organic nitrates 37 90302 Other antianginal drugs 12 904 Antihypertensive agents 90401 Antihypertensives, plain 73 90402 Antihypertensives in combination 51 905 Calciumantagonists 53 951 Cardiovascularcoadjuvants 95101 Proposed for vascular diseases 226 95102 Circulatory analeptics 11 95103 Proposed as capillary protectants 45 95104 Proposed as heart tonics 84 95105 Topical vasculotropics 23 10 Diuretics 100201 Osmotic diuretics 3 100301 High-ceiling diuretics 15 100401 Thiazides and analogues 16 100501 Potassium-sparing diuretics 14 100601 Diuretics in combination 8 1101 Antihyperlipoproteinaemics 95 1201 Antihaemorrhagics 120101 Systemic haemostatics 9 120102 Topical haemostatics 1 120103 Antifibrinolytic agents 18 120151 Proposed as antihaemorrhagics 9 1202 Antithrombotics 120201 Direct anticoagulants 24 120202 Indirect anticoagulants 2 120203 Antiplatelet drugs 25 120204 Thrombolytics 16 120205 Other antithrombotics 2 Total 1001
6 1
6 13
20 13 1
53 23 1
18 1 12
47 7 40
8 18
45 30
29 16 12
102 67 65
114 0 27 16 12
340 11 72 100 35
1 4 15 12 3 35
4 19 31 26 11 130
6 12 19 9
15 13 37 18
21 0 4 8 0 462
45 2 29 24 2 1463
2nd level (second two digits): the group. This comprises drugs having similar clinical indications (0108-Antipsychotics) and/or pharmacological actions (0602-Adrenergic Blocking Agents). 3rd level (third two digits): the subgroup. This classifies drugs according to their chemical structure (010801phenothiazines, 010802-butyrophenones, etc.) and/or their mechanisms of action (060201-a-Adrenoceptor Blocking Agents, 060202-[3-Adrenoceptor Blocking Agents, ect.). The FARMAGUIDA classification is made up of 42 categories, 157groups and 246subgroups. The 42ca-
tegories, and the corresponding number of products on sale in Italy and those found in the NF are listed in Table 2. Two larger groupings have been formulated, rearranging the whole classification under 11 and 14 headings, respectively. The PHARM arrangement (Table 3) reorders the groups and subgroups of the classfication into 13 "true" pharmaco-therapeutic sets, and relegates those drugs called 'coadjuvants' to a fourteenth set, called "proposedas-coadjuvants". This permits a comprehensive listing of all the placebo-like drugs available in Italy. The THER arrangement (Table4) reorders the 246 groups and subgroups into 11 anatomico-therapeutic sets. In each of those sets the pertinent placebo-like groups have been placed on the basis of their therapeutic claims, e. g., myocardiotrophics within THER2-Cardiovascular Diseases. The various THERSbroadly reflect the main groups of the ATC classification. As examples of the FARMAGUIDAclassification rHEa 1Infectious Diseases (Table 5) and THER2-Cardiovascular Diseases (Table 6) have been set out in detail. In both tables, the first columns shows the number of products reimbursable, i. e. those present in the N E
Discussion and conclusions The main purposes of the FARMAGUIDAclassification were a) to refer every product on sale to a known pharmacological and/or clinical framework, b) to devise a tool suitable for the analysis of drug prescription patterns, and c) to provide a stimulus for revising and updating other available classifications, mainly the ATC system. The FARMAGUIDA classification is not intended as a substitute for the ATC classification, which is internationally recognised, and is recommended by W H O for drug utilization studies. Rather, it may be used as an alternative way of examining prescription data. As an example of its value, the FARMAGUIDAclassification of antiinfective agents (Table 5) is more analytical and detailed than the ATC main group "J-General antiinfectives, systemic", in that such antibiotics as penicillins and cephalosporins are further subdivided according to their spectrum of activity. This permits the detection of problems in prescribing habits of GPs, such as possible misuse of antipseudomonal penicillins (e. g. mezlocillin, piperacillin), which should be reserved for hospital infections. On the other hand, the classification of drugs for cardiovascular diseases (Table 6) follows a simpler approach in comparison to the ATC main group "C-Cardiovascular system", which affords a clearer view of the therapeutic areas of cardiovascular products actually prescribed. As far as the NF is concerned, in certain categories of drugs, e.g. "CNS Drugs" and "Gastrointestinal Agents", less than half of the products are reimbursable by the National Health Service (see Table 1), owing to the exclusion of relevant groups, such as benzodiazepines and laxatives. On the other hand, drugs belonging to controversial groups, such as those classified as "Proposed for Prostatic Hypertrophy" and "Proposed as Immunostimulants", are almost all included in the NF. The large number of drugs
399 672
1798
3660
2/,63
6187
Fig.la, b. Number ofreimbursable products (a) (Italian National Formulary) and total number of products (b) on sale subdivided according to the values of the CLASSindicator. CLASSis a simplified version of the DO¢indicator (see Table 1): CLASS-A = [DOC-1 + Doe-2]; CLASS-B = DOC-3; CLASS-C = [DOC-4 + DOC-5]
a
b
" P r o p o s e d as C o a d j u v a n t s " shown in Table 2 (18% of both total and N F products) shows h o w distant are the goals of a m o r e rational a r r a n g e m e n t of the drug m a r k e t and of a m o r e rigorous composition of the N F [9]. A n even worse picture appears w h e n the CLASSindicator is applied to the Italian drug market: less than 60 % both of total and N F products achieved an A score (Fig. 1). It is true, however, that a slow trend t o w a r d a reduction and rationalization of the drug m a r k e t in Italy m a y be seen. T h e n u m b e r of p r o d u c t s of the N F was a b o u t 14,900 in 1959, 7900 in 1981, and 6900 in 1988 [10]. T h e p e r c e n t a g e of m o n o c o m p o n e n t products out of the total n u m b e r of products on the Italian m a r k e t s h o w e d the following trend: 37 % (of 26,700) in 1962, 6 9 % (of 12,900) in 1982 and 7 5 % (of 10,700) in 1988, with a sharp reduction in the n u m b e r of fixed-dose c o m b i n a t i o n p r o d u c t s [10]. T h e approval of new p r o d u c t s in Italy, too, n o w appears to follow stricter criteria, and a p r o g r a m of revision of the old medicines is n o w in place in Italy as in the other countries of the E u r o p e a n Community. Nevertheless, m u c h remains to be d o n e in o r d e r to achieve better p h a r m a c e u t i c a l habits in Italy and in E u r o p e . FARMAGUIDAallows a critical eye to be kept on this picture and its qualitative drug indicators will contribute to the m o n i t o r i n g and p r o m o t i o n of desirable changes.
CLASSindicator: [ ] A documentation present [ ] B documentation insufficient [ ] C documentation absent
References 1. Goodman Gilman A, Rall TW, Nies AS, Taylor P (1990) Goodman and Gilman's the pharmacological basis of therapeutics. Pergamon Press, New York 2. L'Informatore Farmaceutico (1990) Italian directory of drugs and manufacturers. Organizzazione Editoriale Medico Farmaceutica, Milano 3. ATC Index including DDDs for plain substances (1991) WHO Collaborating Centre for Drug Statistics Methodology, Oslo 4. Anonymous (1989) Cardiac inotropic agents. In: Reynolds JEF (ed) Martindale the extra pharmacopoeia. The Pharmaceutical Press, London 5. Reynolds JEF (1989) Martindale the extra pharmacopoeia. The Pharmaceutical Press, London 6. American Medical Association (1986) Drug evaluations. American Medical Association, Washington 7. Avery GS (1987) Drug treatment: principles and practice of clinical pharmacology and therapeutics. Livingstone, Edinburgh 8. Laporte JR, Porta M, Capellg D (1983) Drug utilization studies: a tool for determining the effectiveness of drug use. Br J Clin Pharmaco116: 301-304 9. Garattini S (1989) Public anger at health charges. Lancet I: 835 10. Italian Ministry of Health (1989) Ministero della Sanitfi - Direzione Generale del Servizio Farmaceutico. Esame della situazione farmaceutica Italiana anche con riferimento al contesto internazionale: risultati finora ottenuti e prospettive future. Official Report to the Italian Parliament
Acknowledgements. The project was supported by a grant from the Health Authority of Emilia Romagna Region (Assessorato alla Sanit~ della Regione Emilia Romagna). We thank the anonymous referees for helpful suggestions on a previous draft of this manuscript. We also thank Dr. D. P. Davis (Saint Bonaventure University, Saint Bonaventure, NY) for revising the English version.
Prof. Nicola Montanaro Department of Pharmacology Via Irnerio 48 1-40126 Bologna, Italy
