Regulatory principles reflected in practice of WHO PQP

1. Regulatory principles reflected in practice of WHO PQP Milan Smid, M.D., Ph.D. Prequalification Programme: Priority Essential Medicines

2. Principle approaches to regulatory assessment of medicines • Innovative & generic medicines • Structure of the dossier of medicinal product • Product information

3. Life cycle of medicine Marketing and clinical use Post-registration follow-up and maintenance IP! Regulatory approval Proof of clinical efficacy and safety Accumulation of data Technological development Experimental and clinical concept verification IP! Experimental concept

4. Life cycle of medicine Established medicine WHO list of essential medicines Product follow-up and maintenance Marketing and clinical use Post-registration development, line extensions Generics Product calamity! Cost IP Product obsolete Patent expires

5. WHO list of essential medicines http://www.who.int/medicines/publications/TRS958June2010.pdf

6. Multisource pharmaceutical products need to conform to the same appropriate standards of quality, efficacy and safety as those required of the innovator’s (comparator) product. In addition, reasonable assurance must be provided that the multisource product is therapeutically equivalent and interchangeable with the comparator product. WHO Technical Report Series, No. 937, 2006, Annex 7

7. Multisource interchangeable pharmaceutical products • World Health Organization WHO Technical Report Series No. 937, 2006, Annex 7, Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability • Pharmaceutical products that are therapeutically equivalent. • Two pharmaceutical products are considered to be therapeutically equivalent if they are pharmaceutically equivalent or pharmaceutical alternatives and after administration in the same molar dose, their effects, with respect to both efficacy and safety, are essentially the same when administered to patients by the same route under the conditions specified in the labelling. • This can be demonstrated by appropriate bioequivalence studies, such as pharmacokinetic, pharmacodynamic, clinical or in vitro studies.

8. Generics and not generics • FDA requirements for generic drugs (www.fda.gov/cder/ogd) • Generic drugs must: • contain the same active ingredients as the innovator drug • be identical in strength, dosage form, and route of administration 3. have the same use indications 4. meet the same batch requirements for identity, strength, purity and quality 5. be manufactured under the same strict standards of GMP required for innovator products. 6. be bio-equivalent.

9. Generics and not generics • EU Directive 2001/83/EC Article 10 • “Generic medicinal product” shall mean a medicinal product which has the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference medicinal product, and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies.

10. Generics and not generics • EU Directive 2001/83/EC Article 10 • The various immediate-release oral pharmaceutical forms shall be considered to be one and the same pharmaceutical form. • Bioavailability studies need not be required of the applicant if he can demonstrate that the generic medicinal product meets the relevant criteria as defined in the appropriate detailed guidelines.

11. Regulation of innovatory products and generics • For innovator products proof of QUALITY, SAFETY and EFFICACY is needed. Newly also plan of prospective risk-management. • For multisource products (generics) safety and efficacy data is referred to the originator. QUALITY and THERAPEUTIC EQUIVALENCE must be demonstrated to allow bridging of data between originator and generic. • Different originators (comparators) may be required in different regulatory settings

12. Data required for regulatory approval Innovative medicine Experimental data/ Literature Clinical data Generic medicine Multisource interchangeable Preclinical data Proof of interchangeability Pharmaceutical data Pharmaceutical data Administrative and summarizing data, including GMP

14. Module 1 Regional Administrative Information Not Part of CTD Nonclinical Overview Clinical Overview Quality Overall Summary Nonclinical Summaries Clinical Summary CTD Module 3 Quality Module 4 Nonclinical Study Reports Module 5 Clinical Study Reports CTD triangle for innovator NDS Module 2

15. Module 1 Regional Administrative Information Not Part of CTD Nonclinical Overview Clinical Overview Quality Overall Summary Nonclinical Summaries Clinical Summary CTD Module 3 Quality Module 4 Nonclinical Study Reports Module 5 Clinical Study Reports CTD triangle for generic NDS Module 2 BE

17. Benefits of the CTD More “reviewable” applications Complete, well-organized submissions More predictable format More consistent reviews Easier analysis across applications Easier exchange of information Facilitates electronic submissions Common dossier for PQ and regulatory bodies adopting CTD

18. Prerequisites for regulatory approval of generic product • Data • about innovator are available and not protected by IP • literature data available and applicable for well established medicines, existing reference product • Pharmaceutically equivalent or alternative • Defined quality (Dossier) • Proven interchangeability (BE/BCS/waiver) • Defined and stable way of production (GMP) • Same way of clinical use as innovator (Product information)

19. Post-approval monitoring of innovatory and generic product • Variations to the dossier • Pharmacovigilance • Reinspections • Sampling and Testing • Reevaluation • Some medicines may require specific risk management and risk minimization programmes • Mechanisms must exist to deal with emergencies like quality or safety crisis

20. Conclusions on information • "Medicine = tablet + information" • Good quality drug information for healthcare professionals and patients is a shared responsibility of industry and regulators. • Regulators with limited resources could do more for public health by trusting scientific assessments by well resourced DRAs and concentrating more on ensuring the accuracy of drug information in national settings. • Not only accuracy of information but also its proper communication is important.

21. Correct information and its proper communication can reduce (preventable) ADRs • 27th Annual Meeting of Representatives of the National Centres participating in the WHO Programme for International Drug Monitoring Dublin, Ireland, 4 - 6 October 2004 • The summary of product characteristics (SPC) could be an effective tool in preventing ADRs. Accurate and recent information should be provided in the SPCs. The SPC should be appropriately worded and presented to help health professionals get the summary quickly and with the least effort. Doctors should be advised to read all package inserts and labels.

22. Product related regulatory information • Summary of Product Characteristics/ Data sheet • Package Information Leaflet / Patient Information Leaflet • Labelling / Text on the Packaging • Assessment / Evaluation Report • Public Assessment / Evaluation Report

23. WHO PQP • http://who.int/prequal (information for applicants, guidelines, generics) • Annex 5: Suggested structure of the Summary of Product Characteristics • Annex 6: Suggested structure of the Package Information Leaflet

24. WHO PQP • http://who.int/prequal (information for applicants, guidelines, WHO Public Assessment Reports - WHOPARs) • Guidance note to Applicants (Manufacturers) on the compilation of the WHO Public Assessment Report • Appendix 1: Characteristics of WHOPAR • Appendix 2: Documentation to submit together with the initial submission • Appendix 3: Guidance on Package Leaflet, Summary of Product Characteristics and Labelling • Appendix 4: Format of the Discussion

25. Thank you for attentionsmidm@who.int