The 13th ICDRA (16-19 September) Regulatory Approaches to proving Interchangeability. WHO Biowaiver Guideline in Regulatory Practice

Transcription

1 The 13th ICDRA (16-19 September) Regulatory Approaches to proving Interchangeability WHO Biowaiver Guideline in Regulatory Practice Dr Kamel IDDIR General Director Medicines and Pharmacy Directorate Berne 16th September 1

2 INTRODUCTION (1) In Tunisia and all over the world expenditures of health have not stopped growing for several decades constant and rapid increase 2

3 * Development of the generic market * local manufacturing (of generics ) * granting pharmacists the right of substitution (France -1998, Switzerland and Italy , Germany , Netherlands , Spain , Finland Tunisia ) 3

4 GENERICS MEDECINE 6 Definition WHO In Tunisia : : No harmonious generics : Interchangeable Product or multi-source Old Definition : «Copies or formulas considered to be equivalent to medical product having been used adequately on Man» Present Definition: (May 2008) «generic speciality are any medical product having the same pharmaceutical form and the same qualitative and quantitative composition in active ingredients as the reference speciality and its bioequivalence with the latter is shown by suitable studies of bioavailability» 4

5 Rgulation fixing the scientific criteria justifying the exemption of biowaiver studies A decree fixes the scientific criteria justifying the exemption of biowaiver studies on man. The criteria of the exemption of biowaiver studies on man are notably based on : Solubility, Permeability, Therapeutic margin. 5

6 The list of the molecules used in the manufacture of the exempted medical products of the studies of biowaiver at man, is fixed by the decision of the Minister of Public Health. the scientific criteria justifying the exemption of the studies of biowaiver at man not holding with the nature of the molecule used in the manufacturing of the medical products, are fixed by the decision of the Minister of Public Health 6

7 Therapeutic equivalence The Issue Direct demonstration of therapeutic equivalence requires clinical studies with a great number of patients These studies are financially heavy, often useless and sometimes not ethic For that reason the concept of biowaiver has been introduced for approximately 40 years 7

8 THERAPEUTIC EQUIVALENCE AND BIOWAIVER On the basis of the concept of bioequiuvalence two products are declared therapeutically equivalent if the blood pharmacokinetic parameters are primarily similar (Cmax, tmax, AUC) This step rests on an extrapolation of a blood concentration supposed to reproduce the concentration on the level of the site of action Recognized and admitted concept 8

9 THERAPEUTIC EQUIVALENCE AND BIOWAIVER Very variable position of the countries Systematic requirement in Europe List of exonerated products in the USA but not used No requirement in certain countries 9

10 COMPARAISON OF GENERICS AND PRINCEPS Speciality Generic - Active ingredient Princeps Identic - galenic Form Princeps Similar - Proportion per dosage unit Princeps Identic -Excipients - F (AUC ; Cmax ; Tmax) possibly different (excipients with notorious effect) Princeps Similar ± 10% (90% - 110%). 10

11 GENERAL CONSIDERATIONS (1) A/ studies of biowaiver are not required : 1- administred product by parenteral injection or by aqueous solution, 2- When the medicinal products are solutions for oral usage (ex: syrups, elixirs, dyeings) The excipients known as modifying the transit or the gastro-intestinal permeability or which affect the absorption or the stability of AP in the digestive tract must be studied in a critical way 11

12 GENERAL CONSIDERATIONS (2) Biowaver studies are not required : 3- Powders to be reconstituted in the form of solution 4- Pharmaceutical equivalents in the form of gas 5- Ocular or auricular preparations in the form of aqueous solution. 6- Products topics prepared in aqueous solution 12

13 GENERAL CONSIDERATIONS (3) Biowaver studies are not required : 7- Aqueous solutions: atomizers or nasal spray managed with primarily similar devices and containing same the AP with the same concentrations and of the excipients primarily similar to comparable concentrations. For the situations where a different excipient is added it is to the manufacturer that falls the responsibility to show the absence of consequence on the effectiveness and safety 13

14 GENERAL CONSIDERATIONS (4) «Non necessary Biowaiver do not apply to the biological products whose elements of interchangeability are more complex (safety or bio-similar) Associations Of.A.P : When several A.P are associated the exemption is based on the A.P having the most unfavourable situation 14

15 GENERAL CONSIDERATIONS (5) B/ Biowaver studies are not required : (when the differences in biodisponibility can affect equivalence therapeutic) 1- In vivo Studies (1) : a/ Administration by oral route of products with systemic action in the following cases (S) : * Drugs of critical use * Weak therapeutic margin * Problems of bioavailability * It was shown scientifically the problems with the polymorphic ones of the.a.p or processes 15

16 1- In vivo Studies (2) : b/ non-oral routes, non parenteral routes and with systemic action such as the transdermic patchs, gums with nicotine, the gel of testosterone and the contraceptive implants c/ Products with general action and modified release d/ Mixtures of A.P when one of them requires studies in vivo e/ The products with local action which should not pass in general circulation. 16

17 2/ In vitro Studies For certain drugs (and certain proportionings), in vitro studies can be suitable to dismount equivalence. The test of dissolution applies for the tablets or capsules. If the dissolution of the product to be evaluated and the reference product are sufficiently fast (> 80% in 15 min), their equivalence in vivo can be allowed. 17

18 THERAPEUTIC EQUIVALENCE Depending on active ingredient and formulation: dissolution (in vitro) bioequivalence studies (in vivo) pharmacodynamic studies (in vivo) clinical trials (in vivo) 18

19 Recording Of the Drugs / DPM The decree of the MSP, of September 10, 1996, stipulates that the demand for AM must be accompanied : an information sheet an administrative file a pharmaceutical, chemical and biological file a clinical, toxicological and pharmacological file. 19

20 NATIONAL STAKES Registration of the Drugs Reduced file warning the drifts (Raw materials, Validations of the methods) Interest of the internal or external laboratories of development (Ex: Faculty, Partnership, ) 11 20

21 CONCLUSIONS The generics are drug with whole share: have an AMM; it is authorized, inspected and controlled and thus granted the same guarantees of quality as a drug of reference. It is fundamental to standardize the physical characteristics of the active ingredients, especially when those are not very soluble, to have all the details on origin and the traceability of the raw materials used. 21

22 Because of its economic advantages, it seems a major tool in the control of the expenditure of health. To promote generic medicines and local manufacture With the project of the installation of the CNAM in Tunisia, the substitution of princeps by its generics became an obviousness substitution / Interchangeability Law voted by the House of Commons Tuesday May 6,