Authorisation of medicinal products: selected challenges

1. Authorisation of medicinal products: selected challenges Rocío Salvador Roldán Pharmaceuticals Unit/DG SANCO This presentation only reflects the views of its author and does not necessarily reflect the opinion of the Commission

2. Overview I. High volume of procedures • Variations • Multiples • Increased complexities • Generics and divergent SmPCs • Reference product: • “hybrid” application • conditional MA/exceptional circumstances • not marketed • Combination of legal basis

3. I. High volume of procedures

4. 1. Variations: state of play • Very large number of variations applications received by EMA during 2010 (following entry into force of new Variations Regulation): • Type IA: over 1500 applications • Type IB: over 1000 applications • Type II: almost 1000 applications • In 2010 over 750 Commission decisions were adopted related to variations. • These figures are expected to increase in 2011 (277 Decisions have been adopted in Q1).

5. 1. Variations: challenges • Adoption deadlines: • Some variations are critical for public health reasons and must be implemented soonest. • Other variations are not so critical and the implementation thereof is not urgent. • However: • Non-critical variations may be submitted as Type II with a view to ensure earlier adoption date. • Safety warnings are often considered as Type IB. • Changes introduced through WS are often not critical from public health standpoint and yet they must be adopted within shortest deadlines.

6. 1. Variations: challenges (cont.) • Effect of changes to innovator product in generics: • General obligation for MAH (including generics) to submit information that may affect risk-benefit or affect the SmPC. • CA’s may also ask MAHs to submit data demonstrating that risk-benefit remains positive. • However: • No specific deadline within which generic companies must submit a variation application when the marketing authorisation of the reference medicinal product is amended. • Number of products involved may be very large: e.g. Clopidogrel. • Confusing messages to patients when there is different product information and possible risks to public health.

7. 2. Multiples: state of play • The regulatory framework: • Under the centralised procedure the general principle is only one marketing authorisation per product; unless public health or co-marketing. • Under Directive 2001/83, there are no specific restrictions on the number of marketing authorisations per company. • The note of duplicates published in 2010 aimed to bring transparency to the cases where multiple marketing authorisations are possible under the centralised procedure. • Companies (particularly in the generic sector) have expressed discontent.

8. 2. Multiples: challenges • Public health considerations: • Risk of different information being transmitted to consumers. • Risk of confusion due to similarity of names (e.g. in case where excipients are different). • Increasing workload for the authorities: • Multiplication of procedures in case of variations (e.g. clopidogrel). • Increasing number of submissions under pharmacovigilance. • Increasing resources needed to ensure compliance with conditions/obligations/risk management plan.

9. Increasing complexities

10. 1. Divergent SmPCs in reference product • General rule: • In case of divergences of the SmPCs of the reference product, MS should follow the SmPCs as approved/proposed by the RMS. • If disharmonisation between reference product and generic in a CMS may represent a risk to public health, a referral may be triggered.

11. 1. Divergent SmPCs in reference product • What if a generic application proposes SmPCs of the global MA not hitherto authorised (as such) in any MS?

12. 1. Divergent SmPCs in reference product Option 1: • Applicant must provide additional studies to “bridge” the data. • principle of global MA? Option 2 • MS must accept such applications • Is it a problem from a public health standpoint?

13. 2. Differences introduced in generic application A.Indications • The legislation envisages two situations: • The generic application has more indications than the reference product: • additional studies (clinical and preclinical) must be submitted by the generic. • The generic application has less indications than the reference product: • An indication of the reference product under patent protection needs not be included in the SmPCs of generic.

14. 2. Differences introduced in generic application • The legislation does not specifically address the issue whether it is possible for indication of the reference product not be included in the SmPCs of generic (outside of patent reasons). • Risk of disharmonisation and consequences for public health must be considered. • In addition, for veterinary medicinal products, the consequences in terms of environmental risk assessment should be carefully considered.

15. 2. Differences introduced in generic application B. Strengths/Pharmaceutical Forms • SmPC is specific per strength and pharmaceutical form. • Requiring the marketing of all pharmaceutical forms could reduce availability of generics.

16. 3. “Hybrid dossier” as reference product • Should there be bioequivalence to both the product used as reference by the hybrid application and the hybrid product itself?

17. 4. Reference product authorised under exceptional circumstances/conditional MA • The generic cannot have a different status than the reference product. • Conditional MA requires that there is an unmet medical need. • This criterion can hardly be met as the reference product is on the market. • Marketing authorisation under exceptional circumstances: • In principle, not excluded. However, generic would have to comply with the same obligations as the reference product.

18. 5. Reference product not marketed • Article 10(1) provides the possibility that the reference medicinal product is no longer authorised. • Public health concerns that may have led to the withdrawal of the reference product must be duly considered.

19. 6. Combination of legal basis • Applications under Article 10a in exceptional circumstances. • Results of clinical trials alone are not considered “extensive use” and therefore do not suffice to support an application under Article 10a. • Is it possible to allow such submissions if the marketing authorisation is granted under exceptional circumstances? • Consequences for innovation if the studies relied upon belong to a company that intends to apply for a marketing authorisation. • Consequences in terms of public health.