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Deficiencies in Bioequivalence dossiers

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  1. Deficiencies in Bioequivalence dossiers Overview and Examples

  2. Summary of Submissions for Tuberculosis-Drugs • 2-FDC (R, H) 29 • Pyrazinamide (Z) 19 • Ethambutol (E) 18 • Isoniazid (H) 16 • 4-FDC (R,H,Z,E) 13 • Rifampicin (R) 12 • 3-FDC 8 Guilin, 9-13, January 2006

  3. Deficiencies in BE Studies Selected examples: Pyrazinamide: (19 submissions, 1 prequalified, 12 cancelled) • For 13 products no BE study submitted • For 3 , BES were submitted, but major deficiencies in all aspects (reporting, reference product) • Only 2 BE studies (for three products) acceptable -> one product prequalified • 18 of 19 submissions with quality documentation deficits Guilin, 9-13, January 2006

  4. Deficiencies in BE Studies Selected examples: 4-FDC (R,H,Z,E): (13 submitted, 3 prequalified, 4 cancelled, 6 with deficits) • For 3 products, no BES • For 7, major deficits, 6 studies with unacceptable reference products • 9 products with quality deficits Guilin, 9-13, January 2006

  5. Identified Deficiencies in BE studies Major deficiencies • No bioequivalence study performed and no adequate justification for not performing a study • Unacceptable reference product • Inadequate validation data of bioanalytical method Guilin, 9-13, January 2006

  6. Identified Deficiencies in BE studies Major deficiencies(cont.) • No verification that test product used in bioequivalence study is identical to product intended for marketing • 90 % Confidence Intervals for pharmacokinetic parameters not presented (or more generally, no adequate statistical analysis) Guilin, 9-13, January 2006

  7. Identified Deficiencies in BE studies Minor deficiencies (cont.) • No information on batch size of test product • Certificate of Analysis of test batch not submitted • In-vitro dissolution profiles not submitted • for test product • for reference product • for different strengths of the same product Guilin, 9-13, January 2006

  8. Advice: As the same problems arise again and again, from many applicants: Consider: • Note to Applicants on Choice of Comparator Products in the Prequalification Project • Template: Presentation of Bioequivalence trial information Guilin, 9-13, January 2006

  9. Note on Choice of Comparator Products: Current status • Note to Applicants on Choice of Comparator Products in the Prequalification Project: • First draft (Jan. 2005) was circulated among experienced assessors from several countries • Now published on the WHO website Guilin, 9-13, January 2006

  10. Note on Choice of Comparator • Objective: • This note is intended to provide to applicants some additional guidance and clarification on existing guidance documents how to select an appropriate comparator product for a bioequivalence study necessary for generic products submitted into the WHO prequalification project . Guilin, 9-13, January 2006

  11. Note on Choice of Comparator • The following information is already provided on the web site,see (http://mednet3. who.int/prequal/ , Documents and Materials, Bio-equivalence): • “What data and information needs to be submitted in a dossier for a generic product?” • “A set of bio-equivalence study data is required for all oral preparations” !!!!!! Guilin, 9-13, January 2006

  12. Note on Choice of Comparator • With regard to the choice of comparator products reference is made on the website to “International comparator products for bio-equivalence testing" • Annex 11 of Thirty-sixth Report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations. WHO Technical Report Series, No. 902, 2002: 161-180:Guidance on the selection of comparator pharmaceutical products for equivalence assessment of interchangeable multisource (generic) products. [Annex 11] Guilin, 9-13, January 2006

  13. Note on Choice of Comparators: General comments: • The innovator pharmaceutical product is usually the most logical comparator product for a multisource pharmaceutical product because its quality, safety and efficacy should have been well assessed and documented in premarketing studies and post-marketing monitoring schemes. Guilin, 9-13, January 2006

  14. Note on Choice of Comparators: General comments: • Whenever possible the innovator products should be obtained from a well regulated market with stringent regulatory authority (countries such as Australia, Canada, European Union Member States, Japan, USA, Switzerland) , and the Product Information (or Summary of Product Characteristics) of the respective country should be used for reference. Guilin, 9-13, January 2006

  15. Note on Choice of Comparators: General comments: • Never should a generic drug be used as comparator as long as an innovator drug is available, because this could lead to a “bio-creep” phenomenon, resulting in progressively less reliable similarity of future multisource products and to lack of interchangeability with the innovator. Guilin, 9-13, January 2006

  16. „Bio-Creep“ Interchangeable Not Interchangeable Guilin, 9-13, January 2006

  17. Note on Choice of Comparators: General comments, FDC: • Similar considerations apply to the use of fixed-dose-combinations, which were approved exclusively on the basis of bioequivalence studies comparing with the individual components, which were used as free combinations (i.e. individual products co-administered) in efficacy and safety studies. Guilin, 9-13, January 2006

  18. Note on Choice of Comparators: General comments, FDC: • Such FDC’s should normally not be used as comparators – even if approved by ICH countries – instead again the individual components should be used as comparators. • However, there are also some fixed-dose-combinations which were used as such extensively in clinical trials, thus direct, “own” evidence for their efficacy and safety is available. These can be used !!! Guilin, 9-13, January 2006

  19. Note on Choice of Comparators: Example for 4-FDC: • Bioequivalence study, 1999, accepted in EU, Switzerland and by WHO:   • Rimstar 4-FDC® versus • Rimactane ® + Isozid ® + Rolab Pyrazinamide ® + Myambutol® Guilin, 9-13, January 2006

  20. Note on Choice of Comparators: Example for 4-FDC: • Rimstar 4-FDC® (Rifampicin 150, Isoniazid 75, Pyrazinamide 400, Ethambutol 275mg) 4 tablets given in a single dose versus • Rimactane ® (Novartis, Switzerland*) 4 capsules each containing 150mg rifampicin • Isozid ® (Fatol, Germany) 3 tablets each containing 100 mg isoniazid • Rolab Pyrazinamide ® (Rolab, South Africa) 3 tablets each containing 500 mg Pyrazinamide • Myambutol® (Lederle Arzneimittel GmbH & Co) 2 tablets containing 400mg and 3 tablets containing 100mg ethambutol Guilin, 9-13, January 2006

  21. Thank you for your attention Guilin, 9-13, January 2006