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Bioequivalence studies for anti-malarials in the prequalification project: Outcomes and frequently encountered deficien

Bioequivalence studies for anti-malarials in the prequalification project: Outcomes and frequently encountered deficiencies. Overview and Examples . Hans Kemmler Consultant to WHO White Sands, 23.Aug. 2006. Summary of Submissions for Anti-Malaria Drugs (May 2006). Mono

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Bioequivalence studies for anti-malarials in the prequalification project: Outcomes and frequently encountered deficien

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  1. Bioequivalence studies for anti-malarials in the prequalification project: Outcomes and frequently encountered deficiencies Overview and Examples Hans Kemmler Consultant to WHO White Sands, 23.Aug. 2006

  2. Summary of Submissions for Anti-Malaria Drugs (May 2006) • Mono • Artemether i.m. Inj. 11 • Artemether oral 5 • Artesunate oral 50mg 8 • Artesunate oral 100 mg 1 • Artesunate oral 200 mg 2 • Artesunate rectal 3 • Artesunate i.v. Inj. 1 • Dihydroartemisinin oral 1 • Amodiaquine 2 (N=34) Tanzania, 21.-25. August

  3. Summary of Submissions for Anti-Malaria Drugs (May 2006) • Artemisinin based combinations • Artesunate/ + Amodiaquine 8 • Artesunate/ + Mefloquine 3 • Artesunate + S/Pyrimethamin 2 • Artesunate/ + Sulfamethoxypyrazin/P 1 • Artemether/Lumefantrine 1 • DHA/ + Piperaquine 1 • N=16 • Mono+ Combi N=50 Tanzania, 21.-25. August

  4. Status of Submissions for Anti-Malaria Drugs (May 2006) • Mono+ Combi total submissions: N=50 • Prequalified: 5 • Cancelled: 19 • “Active” : 26 • (including rejected submissions with new data) • All five prequalified products are “innovators” (clinical Phase III trials (controlled) done with the product itself, showing the products efficacy/safety directly; pharmacokinetic studies also present) Tanzania, 21.-25. August

  5. Deficiencies in Submissions(Clinical part) • First product assessed July 2002(this one is not yet prequalified) • No submission without deficiencies • Not one submission for a generic product with a BE-study provided in the first dossier Tanzania, 21.-25. August

  6. Deficiencies in BE Studies Selected example: • Artesunate oral dosage forms: • 11 dossiers for mono, 14 for combination • For 2 products (relating to 8 dossiers, mono and combi) PK-studies submitted (originators) • For 4 products (relating to 7 dossiers) BE-Studies eventually provided • For 10 dossiers : Nothing Tanzania, 21.-25. August

  7. Results of Artesunate BE Studies Tanzania, 21.-25. August

  8. Results of Artesunate BE Studies Tanzania, 21.-25. August

  9. 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 Tanzania, 21.-25. August

  10. 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) Tanzania, 21.-25. August

  11. 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 Tanzania, 21.-25. August

  12. Thank you for your attention Tanzania, 21.-25. August

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