evaluation and registration process of allergen products in portugal

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Topics. - Introduction- Legislation Marketing authorization application and evaluation process Content of the application file on quality, nonclinical and clinical data: legislation and guidelines Allergen products registered in Portugal- Summary. Use of allergens in human medicine. Diagnosis, in vitro testsDiagnosis, in vivo testsSpecific immunotherapy .

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1. Evaluation and registration process of allergen products in Portugal Ana Cláudia Figueiredo Nonclinical Assessor Infarmed

2. Topics - Introduction - Legislation Marketing authorization application and evaluation process Content of the application file on quality, nonclinical and clinical data: legislation and guidelines Allergen products registered in Portugal - Summary

3. Use of allergens in human medicine Diagnosis, in vitro tests Diagnosis, in vivo tests Specific immunotherapy

4. Use of allergens in human medicine Diagnosis, in vitro tests medical devices Diagnosis, in vivo tests medicinal products Specific immunotherapy (allergen products)

5. Registration of allergen products in Portugal Law nr. 176/2006, from August 30 Transposes to the portuguese legislation - Directive 2001/83/EC, as amended by Directives 2002/98/EC, 2003/63/EC, 2004/24/EC and 2004/27/EC - and Directive 2003/94/EC

6. Law nr.176/2006 Article 3, on definitions: Medicinal product: Any substance or combination of substances presented as having properties for treating or preventing disease in human beings or of its symptoms or that can be used or administered to human beings either with a view of making a medical diagnosis or to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action

7. Law nr.176/2006 Article 3, on definitions: Immunological medicinal product: vaccines, toxins, and serums including, namely, any product which is administered to produce a specific active or passive immunity, as well as any product use to diagnose, induce or reduce a specific hypersensitivity in the immunological response to an allergen agent

8. Law nr.176/2006 Article 2, on the scope: It applies to medicinal products prepared industrially or by a method involving an industrial process

9. Procedures to Marketing authorization From the marketing authorization application to the decision: - Dossier validation (product managers) - Distribution to the assessors (internal and externals assessors) Assessment reports discussed at the drug evaluation board Decision by the Infarmed executive board

10. Content of the dossier:quality, nonclinical and clinical data Full application (article 15 of Law nr.176/2006; article 8(3) of Directive 2001/83/EC) The dossier should include results of — pharmaceutical tests, — pre-clinical tests, — clinical trials

11. Content of the dossier:quality, nonclinical and clinical data Well-established use application (article 20 of Law nr.176/2006; article 10a of Directive 2001/83/EC) Presentation of results from pre-clinical tests and clinical trials is not required These results can be replaced by appropriate scientific literature

12. Content of the dossier:quality, nonclinical and clinical data Immunological medicinal products (article 124 of Law nr.176/2006) The production processes are validated in order to ensure a continuous compliance of the batches. - The producers of immunological medicinal products provide the quality control reports signed by the qualified person

13. Content of the dossier:quality, nonclinical and clinical data Guidelines and monographs Quality aspects - European Pharmacopoeia monograph on Allergen products - Guideline on allergen products: production and quality issues (EMEA/CHMP/BWP/304831/2007) (coming into effect may 2009) (it has substituted another guidance approved in 1996)

14. Content of the dossier:quality, nonclinical and clinical data Guidelines and monographs Nonclinical aspects No specific guidance

15. Content of the dossier:quality, nonclinical and clinical data Guidelines and monographs Clinical aspects Guideline on the clinical development of products for specific immunotherapy for the treatment of allergic diseases (CHMP/EWP/18504/2006) (coming into effect on 1 june 2009) - Guideline on clinical evaluation of diagnostic agents (CPMP/EWP/1119/98/Rev 1) (coming into effect on 1 February 2010)

16. Allergen products registered in Portugal 8 marketing authorization applications 8 products authorized (one revoked)

17. Allergen products registered in Portugal Name Applicant Alergo-Merck Depot Polen Merck S.A. Alergo-Merck Formogoid Depot Merck S.A. Alergo-Merck Oral Merck S.A. Alergo-Merck Depot Ácaros Merck S.A. Prick-Teste Merck S.A. True Test Mekos Laboratories A/S Grazax ALK-Abelló A/S Phleum pratense Soluprick ALK-Abelló A/S

18. Allergen products registered in Portugal Name Date appl Type appl Alergo-Merck Depot Polen 2003 NAC Alergo-Merck Formogoid Depot 2003 NAC Alergo-Merck Oral 2003 NAC Alergo-Merck Depot Ácaros 2003 NAC Prick-Teste 2003 NAC True Test 2005 MR Grazax 2006 MR Phleum pratense Soluprick 2007 MR

19. Allergen products registered in Portugal Name Legal basis Alergo-Merck Depot Polen Article 10a Alergo-Merck Formogoid Depot Article 10a Alergo-Merck Oral Article 10a Alergo-Merck Depot Ácaros Article 10a Prick-Teste Article 10a True Test Article 10a Grazax Article 8(3) Phleum pratense Soluprick Article 8(3)

20. Allergen products registered in Portugal Name Indication Alergo-Merck Depot Polen s.c. specific immunotherapy Alergo-Merck Formogoid Depot s.c specific immunotherapy Alergo-Merck Oral s.l. specific immunotherapy Alergo-Merck Depot Ácaros s.c. specific immunotherapy Prick-Teste Diagnosis IgE allergy (skin prick-test) True Test Diagnosis contact dermatitis (patch test) Grazax s.l. specific immunotherapy Phleum pratense Soluprick Diagnosis IgE allergy (skin prick-test)

21. Allergen products registered in Portugal Name dispensing classification Alergo-Merck Depot Polen subject to medical prescription Alergo-Merck Formogoid Depot subject to medical prescription Alergo-Merck Oral subject to medical prescription Alergo-Merck Depot Ácaros subject to medical prescription Prick-Teste subject to medical prescription True Test subject to medical prescription Grazax subject to medical prescription Phleum pratense Soluprick subject to medical prescription

22. Allergen products registered in Portugal Name reimbursement Alergo-Merck Depot Polen 0% Alergo-Merck Formogoid Depot 0% Alergo-Merck Oral 0% Alergo-Merck Depot Ácaros 0% Prick-Teste 0% True Test 0% Grazax 0% Phleum pratense Soluprick 0%

23. Allergen products registered in Portugal Alergo-Merck Depot Polen, Alergo-Merck Formogoid Depot, Alergo-Merck Depot Ácaros “Preparation for specific immunotherapy/hyposensitization. Allergic diseases (mediated by IgE), such as allergic rhinitis, allergic conjunctivitis, allergic bronchial asthma, etc, due to the unavoidable inhalation of allergens”

24. Allergen products registered in Portugal Alergo-Merck Depot Polen, Alergo-Merck Formogoid Depot, Alergo-Merck Depot Ácaros Subcutaneous route Recommended doses are variable and should be patient-based Use of increasing doses 1 to 6 weeks intervals between doses

25. Allergen products registered in Portugal Alergo-Merck Depot Polen Various allergens (extracted from pollens of grasses, herbs, cereals, and trees) Suspensions for injection with 20 different qualitative compositions For each composition, 4 strengths: - 5 TU/ml - 50 TU/ml - 500 TU/ml - 5000 TU/ml

26. Allergen products registered in Portugal Alergo-Merck Depot Polen Each qualitative composition supplied in the following packages: - 3 vials with concentrations 50, 500 and 5000 TU/ml - 4 vials with concentrations 5, 50, 500 and 5000 TU/ml - 1 vial with concentration 5000 TU/ml - 2 vials with concentration 5000 TU/ml Each package one registration number One single SPC and PL

27. Allergen products registered in Portugal Alergo-Merck Formogoid Depot Various allergoids (formaldehyde treated allergens) extracted from pollens of grasses, herbs, cereals, and trees Suspensions for injection with 22 different qualitative compositions For each composition, 2 strengths: - 1000 TU/ml - 10000 TU/ml

28. Allergen products registered in Portugal Alergo-Merck Formogoid Depot Each qualitative composition supplied in the following packages: 2 vials with concentrations 1000 and 10000 TU/ml 2 vials with concentration 10000 TU/ml - 1 vial with concentration 10000 TU/ml Each package one registration number One single SPC and PL

29. Allergen products registered in Portugal Alergo-Merck Depot Ácaros (house dust mites) Allergens extracted from house dust mites Suspensions for injection with 3 different qualitative compositions: - Dermatophagoides pteronissynus - Dermatophagoides farinae Dermatophagoides pteronissynus + Dermatophagoides farinae For each composition, 4 strengths: - 5 TU/ml - 50 TU/ml - 500 TU/ml - 5000 TU/ml

30. Allergen products registered in Portugal Alergo-Merck Depot Ácaros (House dust mites) Each qualitative composition supplied in the following packages: - 3 vials with concentrations 50, 500 and 5000 TU/ml - 4 vials with concentrations 5, 50, 500 and 5000 TU/ml - 1 vial with concentration 5000 TU/ml - 2 vials with concentration 5000 TU/ml Each package one registration number One single SPC and PL

31. Allergen products registered in Portugal Prick-Teste “The Prick-Teste suspensions are used in the diagnosis of diseases mediated by IgE antibodies (type I in the COOMB and GELL classification) by conducting a cutaneous test” Epicutaneous application

32. Allergen products registered in Portugal Prick-Teste Allergens extracted from pollens, moulds, foodstuffs, insects, mites, animal hair and skin, feathers, cereals flours Cutaneous suspensions with 168 different qualitative compositions, + positive and negative controls

33. Allergen products registered in Portugal Prick-Teste Each qualitative composition available in one single strength: - 10000 or 50000 SBU/ml - or 10000, 20000, 50000 or 100000 BU/ml - or 500, 1000, 2500, 5000, 10000 or 25000 PNU/ml Each composition supplied in single dropper containers Each composition one registration number One single SPC and PL

34. Allergen products registered in Portugal Truetest “Diagnosis of allergic contact dermatitis” Cutaneous application

35. Allergen products registered in Portugal Truetest Plaster for cutaneous testing 2 panels of surgical tape each containing 12 (chemical) allergen coated polyester patches Supplied in one package with 10 units (1 unit = 1 panel 1 and 1 panel 2) One registration number

36. Allergen products registered in Portugal Grazax “Treatment of rhinitis and conjuctivitis due to grass pollen in adult patients with clinically relevant symptoms and diagnosed by the Prick-test and/or IgE specific test for grass pollen” Sublingual administration Daily administration of the same dose

37. Allergen products registered in Portugal Grazax Oral lyophilisate with allergens extracted from timothy (Phleum pratense) pollen One single strength: 75,000 SQ-T Supplied in packages with blisters with 30 or 100 units Each package one registration number

38. Allergen products registered in Portugal Phleum pratense Soluprick “This medicinal product is for diagnosis use only. Phleum pratense Soluprick is used for skin prick tests in the diagnosis of allergy mediated by IgE specific for Phleum pratense and other cross-reactive grasses from the Pooideae family” Epicutaneous use

39. Allergen products registered in Portugal Phleum pratense Soluprick Skin-prick test solution with allergens extracted from timothy (Phleum pratense) pollen One single strength: 10 HEP/ml Supplied in one single vial One registration number

40. Medicinal products registered in Portugal: quality, nonclinical and clinical data Alergo-Merck Depot Polen Alergo-Merck Formogoid Depot Alergo-Merck Depot Ácaros Prick-Teste Grazax Phleum pratense Soluprick

41. Data on quality Units for strength/potency standardization TU/ml Alergo-Merck Depot Polen Alergo-Merck Formogoid Depot Alergo-Merck Depot Ácaros SBU/ml Prick-Teste BU/ml PNU/ml SQ-T Grazax HEP/ml Phleum pratense Soluprick

42. Data on quality Units for strength/potency standardization TU/ml (Alergo-Merck Depot Polen, Alergo-Merck Formogoid Depot Alergo-Merck Depot Ácaros) PNU and RAST inhibition

43. Data on quality Units for strength/potency standardization TU/ml (Alergo-Merck Depot Polen, Alergo-Merck Formogoid Depot Alergo-Merck Depot Ácaros) As described in the expert report for Alergo-Merck Depot Polen: “The baseline for standardization of strength 3 is a solution with 2500 PNU/ml (± 20%), with the exception of glasswort (1250 PNU/ml). When a precisely characterized RAST inhibition test system is available, with allergen reference, allergen discs and allergen-specific serum pool, a strength 3 solution of allergen in question is also standardized as follows (TU standardization”):…

44. Data on quality Units for strength/potency standardization TU/ml (Alergo-Merck Depot Polen, Alergo-Merck Formogoid Depot Alergo-Merck Depot Ácaros) As described in the expert report for Alergo-Merck Depot Polen: 1.The prel values of five freshly prepared batches, which have been adjusted to their PNU target value (± 20%), are measured in the RAST inhibition test and compared with the allergen reference 2.The prel value of all subsequent batches, measured in the same RAST inhibition system, should correspond to the baseline standardization of 2500 PNU/ml (± 20%), and differ from the mean prel value of the first 5 batches by less than ±40%. This figure of ± 40% of the prel value is derived from experience over many years

45. Data on quality Units for strength/potency standardization TU/ml (Alergo-Merck Depot Polen, Alergo-Merck Formogoid Depot Alergo-Merck Depot Ácaros) As described in the expert report for Alergo-Merck Depot Polen: 3. If the batches exceeds the ± 40% limit, then it is adjusted by appropriate dilution or concentration to the prescribed allergen activity. The agreement of the adjusted batch with the specifications is tested by a further prel value and PNU measurement. When the preparation is standardized in this way, strength 3 is defined as an active substance content of 5000 TU/ml. “

46. Data on quality Units for strength/potency standardization SBU/ml, BU/ml and PNU/ml (Prick-Teste) Groups of allergens and representative allergens With exception of food allergens, representative allergens of the groups were biologically standardized according to the suggestions of the Nordic Guidelines (1st edition) in clinical trials with 0.1% histamine as reference.

47. Data on quality Units for strength/potency standardization SBU/ml, BU/ml and PNU/ml (Prick-Teste) For the (non-food) representative allergens, the strength is expressed in SBU/ml (standardized biological units ) The other allergens of a group get a uniform protein content, with upper PNU-limits (PNU = protein nitrogen units). Strengths are expressed as BU/ml (biological units) Strengths for food allergens are expressed as PNU/ml

48. Data on quality Units for strength/potency standardization SQ-T (Grazax) Arbitary unit, SQ = Standardized Quality major allergen activity, by RID (radial immunodiffusion) total allergenic activity, by TATA (Total Allergen Centaur Assay)

49. Data on quality Units for strength/potency standardization SQ-T (Grazax) Arbitary unit, SQ = Standardized Quality As described in the expert report: “The determination of the relative major allergen activity by means of RID (radial immunodiffusion) gives the basis for standardization of the drug substance batch to ensure equivalent potency from batch to batch. “The relative determination of the total allergenic activity by means of TATA (Total Allergen Centaur Assay) ensures that the level of activity from all allergens is consistent from batch to batch.”

50. Data on quality Units for strength/potency standardization HEP/ml (Phleum pratense Soluprick) HEP = Histamine equivalent potency 10 HEP is equivalent to 10 mg/ml histamine dihydrochloride based on skin prick test

51. Nonclinical data Alergo-Merck Depot Polen, Alergo-Merck Formogoid Depot, Alergo-Merck Depot Ácaros, Prick-Teste Conventional studies not conducted Justifications based on: Relevance of animal models Dose levels Active ingredients Clinical experience

52. Nonclinical data Grazax Primary pharmacodynamics - Prophylactic and therapeutic mouse model

53. Nonclinical data Grazax Single dose toxicity - Mouse – sublingual - Mouse - intravenous (up to 1000000 SQ-T/mouse) Repeated dose toxicity - Mouse – sublingual – up to 26 weeks - Dog – sublingual – up to 52 weeks (up to 500000 SQ-T/animal/day)

54. Nonclinical data Grazax Genotoxicity - Ames test Reproductive toxicity - Combined fertility and embryo-fetal development – mouse – sublingual - Peri-post-natal development - mouse – sublingual (up to 500000 SQ-T/mouse/day)

55. Nonclinical data Phleum pratense Soluprick Single dose toxicity - Mouse – subcutaneous - Rat – subcutaneous Repeated dose toxicity - Mouse - subcutaneous – up to 28 days - Rat – subcutaneous – up to 28 days (studies performed in the 80s)

56. Nonclinical data Phleum pratense Soluprick “Owing to the vast clinical experience with pollen extracts, no further animal studies like mutagenicity, carcinogenicity, teratogenity and fertility have been considered necessary”

57. Clinical data Alergo-Merck Depot Polen, Alergo-Merck Formogoid Depot, Alergo-Merck Depot Ácaros, Prick-Teste Studies conducted: Clinical trials performed with a small number of the preparations

58. Clinical data Grazax Studies conducted: Three phase I safety trials One phase II safety and efficacy trial One dose-finding Phase II/III efficacy and safety trial One Phase III efficacy trial

59. Clinical data Phleum pratense Soluprick Studies conducted: Two clinical trials, referred to as key clinical trials Both phase IV

60. Issues raised on quality aspects National applications 1- The composition of the medicinal product in terms of excipients should be clearly expressed 2- The control and characterization of the material of the immediate container should be documented. 3- The control of the active ingredients should be documented with analytical data from representative batches demonstrating the compliance with the specifications 4- The stability of the active ingredients should be documented. 5- The shelf-life/stability of the medicinal product should be supported by consistent, appropriate and updated data

61. Issues raised on quality aspects Mutual recognition applications Issues brought to the CMD The definition of the strength of the product should be discussed and justified Need of an in use stability study representative of the real conditions of use of the medicinal product

62. Issues raised on nonclinical aspects National applications Content of point 5.3 of the SPC

63. Issues raised on nonclinical aspects Mutual recognition applications Discussion of an increased incidence and severity of arteritis/periartheritis observed in chronic toxicity study with dogs Content of the point 5.3 of the SPC

64. Issues raised on clinical aspects National applications - Translations

65. Issues raised on clinical aspects Mutual recognition applications Issues brought to the CMD Justification of the proposed indication on diagnosis of cross-reacting allergens as the sensibility in this indication has not been documented in the pivotal study. Discussion of the recommended quantification of the product to be administered in section 4.2 of the SPC.

66. Summary For the registration of allergen products to be placed on the portuguese market Law nr.176/2006 applies. Allergen products authorized in Portugal present a diversity of units to express strength a number of qualitative compositions submitted under a single marketing application that varies from 1 to 168 Presently, there are specific EMA guidelines on quality and clinical aspects of allergen products but not on nonclinical data

67. Thank you for your attention

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