regulation of allergen products - background and new developments dr. detlef bartel head of section 5

1. Regulation of Allergen Products - Background and New Developments

3. National and International Integration

4. PEI Allergology Division Structure

5. Allergenic Products Available in Germany

6. Allergens - Regulatory Facts I

7. Allergens – Immunotherapy Facts

8. Allergens – Regulatory Facts I

9. History No dosis finding studies for many products available Limited number of phase III studies Some combined phase II/III studies including two concentrations and placebo All studies are quite variant in regard of dosage, dosage schemes, study duration, inclusion and exclusion criteria, data analysis

10. Quality Regulation in Germany and Europe

18. Allergen Batch Release Procedure

19. Allergen Products Laboratory Test Procedures

20. Rejected Lots Jan-Aug 2010

29. Study Design for Therapy Allergens

30. No phase I studies with healthy subjects Main side effects of therapy allergens are allergic reactions Safety studies do make sense only with sensitized subjects Tolerability and dose schemes are to be dertermined In case if new adjuvants or other new additional contents , phase I studies are useful Dose finding studies should combine a number of product concentrations tolerable Short-time studies (2-4 months) are sufficient Primary end point for dose-finding studies can be provication tests and/or clinical endpoints Study Design for Therapy Allergens

31. Phase III Study Design Inhalative Allergens Double-blind, placebo-controlled randomized design Absolutely necessary due to variability in individual clinical responses, unpredictability and variability of allergenic exposure, and subjective nature of symptom assessments Insect Venom Allergens Because of its known efficacy of 80 – 95% it would be unethical to place allergic subjects at high risk by providing placebo in the control group An approved product would be suitable as comparator (double-dummy design) Special attention should be drawn to the assay sensitivity of the trial (scientific advice of competent authorities for auch study designs is recommended)

32. Co-Morbidity Rhinitis/Rhinoconjunctivitis and asthma are frequently occure in the same patient Patients with allergic asthma co-morbidity may be included in stidies investigating the effectivness on allergic rhinitis/rhinoconjunctivitis Asthma has to be well treated is such cases, analysis only on the basis of Rhinitis/Rhinoconjunctivitis possible Claim of efficacy in asthma separate trials should be conducted Allergen exposition Allergen exposition has to be determined during the study (seasonal allergens) which may vary from year to year Study duration Depending on study duration and indication different claims are possible Treatment of allergic symptoms: short term clinical trials Sustained clinical effect: 2-3 treatment years Long-term efficacy: 3 treatment years + 2 years post treatment Curing allergy: Sustained absence of allergic symptoms in post treatment years Children: PDCO accepts long-term studies only Phase III Study Design

33. Primary endpoint rhinitis/rhinoconjunctivitis Rescue medication needs to be specified and justified No validated medication score exists Generally accepted definition of a 4-point rating symptom scale: 0 = absent symptoms 1 = mild symptoms (minimal awareness of symptom) 2 = moderate symptoms (definite awareness of sign/symptom) 3 = severe symptoms (hard to tolerate) Symptom score and medication score can be combined but has to be pre-specified and justified Applicant has to provide a definition of a clinically meaningful effect in the primary efficacy endpoint and a basis for choosing this value Phase III Study Design

34. Secondary endpoints for rhinitis/rhinoconjunctivitis Total symptom score Total medication score Individual symptom score Symptom free days Physician or patient rated clinical golbal improvement Validated Questionnaires (health related quality of life) Provocation test Laboratory parameters Prevention of asthma Prevention on the occurrence of new sensitizations Phase III Study Design

39. Group Members

41. Thank you very much

42. Backup - Folien

47. Guidance on Allergen Products: Production and Quality Issues Scope Manufacturing and quality control of allergen preparations derived from natural sources of biological origin (e.g. allergen extracts) and recombinant DNA-technology - In-house reference preparations (IHRP) and sera pools for quality control and analysis of batch-to-batch consistency - Not included: Synthetic peptides RNA/DNA constructs Cell preparations Low molecular weight chemicals (epicutaneous tests)

49. General concepts Homologous groups Scientific criteria for the definition of a homologous group defined Limited extrapolation of data concerning safety and efficacy List of proposed homologous groups attached, new groups or new members may be introduced if data are provided Allergen extract mixtures Different source materials should not be mixed prior to extraction (active substance) Potency testing on individual drug substance level, total allergenic activity on finished product level Number and relative proportion of the individual active substances should be justified List of non-recommended mixtures

50. Active substance 4.2.1 General Information Stable preparation (allergen extract, as well as a purified natural or recombinant protein, all of which can be unmodified or modified (e.g. physically and/or chemically as allergoid orconjugate) Latest step before mixing or formulation (adsorption and addition of excipients are regarded as manufacturing of finished product) 4.2.2 Manufacture For validation data can be extrapolated from the representative species provided that the manufacturing processes are identical 4.2.3 Control of materials Including specific requirements for source material for allergen extracts (pollen, moulds, mites, animal allergens and hymenoptera venoms)

51. 4.2 Active substance (ff.) 4.2.4 Characterisation and control of the active substance Characterisation may be performed on intermediates if not possible on active substance level (e.g. allergoides), but have to be included into the release specifications Allergens relevant for the product have to be defined by the applicant. Their presence and their content has to be determined Modified allergen preparations (e.g. allergoides or conjungates) the relevant allergens have to be identified in the modified form and the consistency of the modification process has to be demonstrated

52. 4.2 Active substance (ff.) 4.2.4.4 Potency Tests Allergen extracts and purified proteins without structural modifications Total allergenic activity: competitive IgE-binding test If defined by relevant allergens: correlation to total allergenic activity Allergoides Test to distinguish between native and modified molecules discriminatory test combination of immunological tests: (e.g. ELISA) or mediator release assay Other tests to demonstrate the presence of relevant allergens (e.g. MS) Test to determine lack of IgE reactivity

53. 4.2 Active substance (ff.) 4.2.5 Stability Reference to ICH guidelines Homologues groups “representative” allergen: Full set of data for “non-representative” allergen: Ongoing stability studies after authorisation are acceptable Extrapolation of some stability data from representative allergen is possible if justified

54. 4.3 Standards and reference materials In-House reference preparation (IHRP) IHRP is derived from a production run as described in the dossier Detailed characterisation of the IHRP: - biochemical and structural characterisation (including carbohydrate composition) - concentration of individual allergens - allergenic properties (e.g. immunoblot with patient sera) - potency (competitive IgE binding test, cellular mediator release, T-cell proliferation) - in vivo standardisation (e.g. skin test reactivity) - pre-defined program for establishment of new IHRP Sera pools - problem of geographic sensitisation - pool should contain 10 – 15 individuals - not included: previous SIT with cross reactive allergens sera recognising carbohydrate epitopes IgE against certain proteins (BSA, milk proteins, gelatine)

55. 4.4 Finished product 4.4.1 Description and Composition of the Finished Product 4.4.2 Manufacture For homologous groups a reduced validation program may be applied, if - Manufacturing process for the representative allergen is fully validated - Manufacturing processes are identical - Critical steps and key parameters are integrated in the reduced program 4.4.3 Control of Finished Product If any control test cannot be performed on the finished product, quality specifications for the intermediate at the latest step prior modification should be defined Different proceedings for the individual preparations Non-Modified Allergen Preparations Allergen Mixtures Adsorbed Products Recombinant Allergens Non-Standardised Allergen Extracts

56. 4.4 Finished product (ff.) 4.4.4 Container Closure System 4.4.5 Stability Full set of data for representative species. These studies may be performed as ongoing studies In mixtures stability studies should be performed considering each individual drug substance. If this is not possible due to cross-reactivity, a determination of the overall potency is appropriate Stability studies of drug products manufactured with drug substance at the end of its shelf-life should be considered on an ongoing basis after marketing approval. For adsorbed and/or modified products the stability of the adsorption and/or modification has to be shown at the end of the shelf-life by e.g. testing of soluble protein, mediator release assay or in vivo immunogenicity test If it is not possible to perform potency tests, in vivo immunogenicity or other in vitro test should be performed at beginning and end of shelf life

57. Definitions Relevant allergens are allergens causing a clinically relevant effect in a significant proportion of the allergic patients. Potency as defined in ICH Q6B guideline is the “quantitative measure of the biological activity based on the attribute of the product which is linked to the relevant biological properties”, using a suitable quantitative biological assay (also called potency assay or bioassay). Total allergenic activity is defined as the capacity to bind specific IgE antibodies from allergic subjects measured by a competitive IgE-binding test. Competitive IgE-binding test: IgE-inhibition assays with human IgE being inhibited from binding to reference allergens at the solid phase by the allergen sample (dilution series) in the liquid phase. Assays with a constant amount of labelled allergens and the allergen sample (dilution series) competing for specific binding to IgE-antibodies bound to a solid phase.

58. Situation: SIT was used for decades based on expert opinions derived from retrospective evaluation of individual patients´s treatment For MA dossiers, quite often only 3 dosis schemes are described (actual, very low and very high dosis), no substancial determination of effective dosis Tolerability studies or combined studies using more extensive dosis schemes are required In principle, effectiveness can be monitored by determination of IgE serology, T cell rections, cytokine release, provocation tests Guideline CHMP/EWP/18405/2006 basically does not accept any arbitrarily defines scoring system but requests a justified and validated scoring system

61. Germany: Prevalence of Asthma and Allergies

62. Regulatory Environment in Germany and Europe Germany German Drug Law (AMG) Regulations eg Good Clinical Practice Administrative Regulations eg call-back System Guidelines reflecting current status of science and technology eg for therapy of allergies Europe Directive 2001/83/EC on the community code relating to medicimal products for human use Regulation of Marketing Authorization procedures eg mutual recognition procedure EU Commission Regulation eg variation of market authorization EMA Guidelines reflecting current status of science and technology

63. Allergen Products Laboratory Test Procedures

64. What are Modified Allergens?

65. Allergen Products Laboratory Test Procedures

66. Batch Release Procedures

67. Batch Release Procedures

68. New test systems for batch release

69. PEI Allergen Laboratory QA System