The Approach to Applications for Established Active Ingredients - An Agency View

2. The Approach to Applications for Established Active Ingredients - An Agency View Kora Doorduyn-van der Stoep CMDh member Staff Member Policy, Governance and Regulatory affairs Medicines Evaluation Board in The Netherlands kh.doorduijn.@cbg-meb.nl www.cbg-meb.nl

3. Regulatory Intelligence The Approach to Applications for Established Active Ingredients An Agency View

4. Learning objectives (1/2) Possible legal bases for applications known active substances (validation) Reference medicinal product Environmental Risk Assessment (ERA) Risk Management/Minimisation Plan (RMP)

5. Learning objectives (2/2) Generic applications: bioequivalence study/biowaiver suitable reference product bioequivalence study Application new pharmaceutical form/indication of known active substance: which legal basis?

6. Possible legal bases for applications known active substances (validation)

7. Directive 2001/83/EC; article 8(3) application full dossier (Annex I Directive 2001/83) mixed dossier: modules 4 and 5 mix of own (pre-) clinical data and bibliographic data need for PIP (paediatric investigation plan) Examples: - new pharmaceutical form known active substance - combination packs/fixed combinations

8. Directive 2001/83/EC; article 10 abridged applications (1/3) Article 10(1): generic application Article 10(3): hybrid application Article 10(4): similar biologicals Abridged applications based on data (modules 4 and 5) of a reference medicinal product

9. Directive 2001/83/EC; article 10 abridged applications (2/3) Article 10(1);Generic product fully based on data reference medicinal product provided that: samequalitative and quantitative composition active substance as reference product samepharmaceutical form as reference product bioequivalence with reference product

10. Directive 2001/83/EC; article 10 abridged applications (3/3) Article 10(3);hybrid application rely partly on data Reference medicinal product + partly on additional data: where strict definition of generic product not met where bioavailability studies cannot be used (e.g. supra-bioavailable, locally acting products) Change in active substance, pharmaceutical form, therapeutic indication, strength, route of administration

11. Question • Active substance innovator product contains clopidogrel hydrogen sulphate • Abridged application for product containing clopidogrel besilate Article 10(1) or 10(3) application?

12. Answer Article 10(1) application The different salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives of an active substance shall be considered to be the same active substance • unless they differ significantly in properties with regard to safety and/or efficacy (Article 10.2(b))

13. Directive 2001/83/EC Article 10aWell established use (WEU) (1/2) Evidence for a systematic and documented use outside clinical trials, compassionate use and named patient supply to demonstrate WEU in the claimed indication in the EU. The period of time required for establishing well established use must not be less than one decade from the first systematic and documented use of the substance as a medicinal product in the EU (including Liechtenstein) in the claimed indication. Examples Paracetamol Glucosamine

14. Directive 2001/83/EC Article 10aWell established use (WEU) (2/2) Full dossier based on bibliographic data only (see Annex I Dir. 2001/83/EC) Modules 4 and 5 should cover all aspects of the safety and/or efficacy assessment, includinga review of the relevant literature, pre- and post-marketing studies and published scientific literature “Own” pharmacokinetic data as supportive data only Data exclusivity well established substance: literature dossier under data protection not allowed! When no reference medicinal product is available. See Commission Decision article 29 referral Ribavirin iQur (C(2008)6369 of 24/10/2008)

15. Directive2001/83/EC Article 10bFixed combinations Combination of active substances within a single pharmaceutical form All (pre-) clinical data concerning combination (in accordance with article 8(3)(i)) No need submission data/scientific references relating to each individual active substance Independent period (10 years) of data exclusivity and market protection from its first authorisation within the Community Examples: Antihypertensive products + diuretics NSAIDs + proton pump inhibitor

16. Combination packs Two or more medicinal products in one pack No definition of a combination package in Directive 2001/83/EC General article 8(3) application/different per MS MRP/DCP see Q&A 11 CMDh website (http://www.hma.eu/227.html) Example: Bonendro: tablets sodium alendronate + Effervescent Granules Calcium carbonate + colecalciferol

17. Reference Medicinal product

18. Reference Medicinal product (1/4) In application form “3 reference medicinal product”: 1)Reference medicinal product which is or has been authorised for not less than 6/10 years in the EEA Purpose: to define the reference medicinal product chosen for the purposes of establishing the expiry of the data protection period. 2)Reference medicinal product authorised in the Community/Member State→ Purpose to indicate to which reference product is referred for the (pre-) clinical data (historical/or European reference product) 3) Medicinal Product used for bioequivalence study (where applicable) All reference products should belong to the same Global Marketing Authorisation (GMA)

19. Reference Medicinal product (2/4) Reference medicinal product should have a MA on the basis of a complete dossier in accordance with Articles 8(3), 10a, 10b or 10c of Directive 2001/83 Reference medicinal product should have a MA for more than 6/10 (8 years after November 2013) and in compliance with Community acquis (date of submission generic application = date of expiration data exclusivity + 1) European reference product: no reference product in MS of generic application. Period of data exclusivity also expired in MS of reference product Historical reference product: reference product was authorisedin the MS in the past. → Combination of European/historical/”usual” reference product possible

20. Reference Medicinal product (3/4) Community Acquis (Q&A 6 CMDh website; http://www.hma.eu/210.html) Reference medicinal product should be (or have been) authorised in the European Union; i.e. for medicinal product authorised in countries prior to their accession to the European Union, the date of accession of the country concerned. It must be authorised in accordance with the Acquis Communautaire. This implies that the dossier of the medicinal product has been updated to comply with the Acquis Communautaire. And the relevant data exclusivity period has to be expired.

21. Reference Medicinal product (4/4) European reference product and 10(1)/10(3) applications Innovator A has MA in NL for product X tablets Innovator A has MA in FR for product X tablets and solution for injection Generic applicant wish to submit in NL generic tablets and solution for injection: 10(1) application based on European reference product X solution for injection authorised in FR, or 10(3) application based on reference product X tablets authorised in NL → Both routes are possible

22. Example/Question (1/3) Product X has been granted a MA in CZ in 2000 CZ acceded the EU in May 2004 In January 2003 the dossier of X was updated conform Community Acquis Date of start date exclusivity period? May 2004

23. Example/Question (2/3) Product Y has been granted a MA in CZ in 2000 CZ acceded the EU in May 2004 In January 2005 the dossier of Y was updated conform Community Acquis Date of start date exclusivity period? January 2005

24. Question/example (3/3) Reference product and start date data exclusivity In NL data exclusivity period 10 year In DK data exclusivity period 6 year Is it possible to submit in NL a generic application after 6 years by referring to European reference product (ERP) authorised in? No, data exclusivity period should be expired in both MSs

25. Environmental risk assessment (ERA)

26. Need for Evaluation ERA established active substances (1/2) Legal basis: Article 8(3)(ca) of Directive 2001/83/EC. CHMP Guideline on Environmental Risk Assessment of Medicinal Products for Human Use (EMEA/CHMP/SWP/4447/00 corr 1*). An ERA is required for all new marketing authorisation applications (MAA) for a medicinal product through a centralised, mutual recognition, decentralised and national procedure regardless of its legal basis.

27. Need for Evaluation ERA established active substances (2/2) Exemptions? Cross reference to ERA innovator not possible In general for 10.1 and 10.3 applications sufficient to provide an adequate justification for the absence of specific study data. The justification of the absence of significant increase of the environmental exposure, demonstrated by suitable information, can be accepted as a justification for the absence of a complete ERA Increase in patient population (e.g. new indication/new population/increase in maximum dose) → generally increase in environmental exposure.

28. Question Active substance X authorised as tablet. Application for new pharmaceutical form, i.e transdermal patch, via article 10(3) application/or extension application. Is there a need to submit an ERA?

29. Answer YES An extension application for the inclusion of new formulations such as a dermal patch may also constitute a significant increase in the environmental exposure if significant residual drug substance is present in the used patch

30. Risk Management/Minimisation Plan(RMP)

31. Need for RMP established active substances (1/3) EU-RMP should be submitted (volume 9 NtA) with the application for a new marketing authorisation for: any product containing a new active substance; a similar biological medicinal product; a generic/hybrid medicinal product where a safety concern requiring additional risk minimisation activities has been identified with the reference medicinal product. with an application for a paediatric use marketing authorisation (PUMA) Examples: some generics of centrally authorised innovator products: not full RMP but risk minimisation measures only

32. Need for RMP established active substances (2/3) EU-RMP should be submitted (continued): with an application involving a significant change in a marketing authorisation on request from a Competent Authority (both pre-and post-authorisation); on the initiative of an Applicant/Marketing Authorisation Holder when they identify a safety concern with a medicinal product at any stage of its life cycle.

33. Need for RMP established active substances (3/3) In some circumstances need for EU-RMP in case of: Known active substances Hybrid medicinal products where the changes compared with the reference medicinal product suggest different risks Bibliographical applications Fixed combination applications

34. Generic applications Biowaiver/bioequivalence study

35. Biowaiver (1/2) Biowaiver between test and reference product (pharmaceutically equivalent immediate release, solid pharmaceutical forms for oral administration and systemic action) between additional strengths of generic product Not applicable for sublingual, buccal, orodispersible, and modifiedrelease formulations. Guideline on the investigation of bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1) Claim of biowaivernot a validation issue but assessment

36. Biowaiver (2/2) Approach MEB: Claim of biowaiver not a validation issue but assessment MEB website: is it possible to obtain an exemption for the bioequivalence study? Yes list of active substances published for which no bioequivalence study may be necessary HOWEVER National policy not (always) European “Old” list

37. Problems raised with claims of biowaiver Problems with comparability of excipients generic/reference product as some excipients (e.g. sorbitol) may affect the dissolution, stability and absorption processes. Dissolution data often not performed at all pH’s requested in bio equivalence guideline/published Q&A’s Expiration test/bio batches Enteric coated formulations: monolytic formulations: coating often dose proportional and not based on surface area

38. Examples acceptable biowaiver Paracetamol (see e.g. PAR Paracetamol Genmed 500 mg, tablets NL/H/1479/001/DC and RVG 103106) Betahistine dihydrochloride (see Commission Decision Betavert C(2009)4399 of 2/06/2009): In conclusion, considering the absorption correlated with high permeability, the allocation of betahistine dihydrochloride to BCS Class I is considered justified by the CHMP. Consequently the drug product is eligible for BCS based biowaiver approach.

39. Suitable Reference product in bioequivalence study Innovator product to which essential similarity is claimed Reference product should have a MA on the basis of a complete dossier in accordance with Articles 8(3), 10a, 10b or 10c of Directive 2001/83 (see earlier) Reference product biostudy should be part of GMA of reference medicinal product (module 1.2) Innovator product authorised in an EU MS + justification why applicable to MS where application in made In case no reference product is available → no generic application possible

40. Application new pharmaceutical form/indication of known active substance: which legal basis?

41. Application new pharmaceutical form/indication - legal basis Applicant is different from MAH of other already authorised product containing same active substance Article 8(3) = full application/mixed dossier: (pre-)clinical data regarding new pharmaceutical form/indication Bibliographic data on active substance already known Article 10.3 hybrid application (pre-)clinical data regarding new pharmaceutical form/indication Bridging data (biostudy) to product already authorised Examples: Paracetamolorodispersible tablets/ effervescent tablets

42. Learning outcomes (1/2) • Possible legal bases for applications known active substances (validation) • Reference medicinal product • Environmental Risk Assessment (ERA) • Risk Management/Minimisation Plan (RMP)

43. Learning outcomes (2/2) • Generic applications: • bioequivalence study/biowaiver • suitable reference product bioequivalence study • Application new pharmaceutical form/indication of known active substance: which legal basis?

44. Useful documents/websites • Eudralex • Volume 1 Pharmaceutical legislation (http://ec.europa.eu/health/documents/eudralex/vol-1/index_en.htm) • Volume 2 Notice to Applicants Chapter 1 (http://ec.europa.eu/health/documents/eudralex/vol-2/index_en.htm) • Volume 9 Pharmacovigilance (http://ec.europa.eu/health/documents/eudralex/vol-9/index_en.htm) • CMDh website (Q&As applications for MA/procedural guidance) • CHMP Guideline on the investigation of bioequivalence • CHMP Guideline on Environmental Risk Assessment of Medicinal Products for Human Use

45. THANK YOUQUESTIONS?