14. Laura Castanheira - Anvisa

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Wednesday, 20 November, 2013
Latin America Biotherapeutic Conference Day 2

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14. Laura Castanheira - Anvisa

  1. 1. Latin America Conference Biotherapeutic Medicines Biotherapeutic Medicines Regulation in Brazil Laura Gomes Castanheira ANVISA Agência Nacional de Vigilância Sanitária www.anvisa.gov.br
  2. 2. Development of Biological Products Regulation • Law 6360/1976 – general regulation about medicines, including biological products • RDC 80/2002 – first regulatory act, specific for biological products. Same approach for new products and copies 2
  3. 3. Development of Biological Products Regulation • RDC 315/2005 – second regulation regarding biological products. Same approach for new products and copies, with more detailed information • RDC 55/2010 – current regulation. Specific approach for copies of biologicals 3
  4. 4. Types of Biological Products 1.Vaccines; 2. Hiperimmune sera; 3. Blood products; 4. Biomedicines: - medicines obtained from biological fluids or animal tissues; - medicines from biotechonological procedures. 4
  5. 5. Types of Biological Products 5. Monoclonal antibodies; 6. Medicines containing live, attenuated or dead microorganisms; 7. Probiotics; 8. Allergens. 5
  6. 6. Regulatory acts concerning biological products Law 6360/76 RDC 47/09 RDC 60/12 Package insert RDC 71/09, RDC 168/02 RDC 61/12 Label RDC 81/08, RDC 234/05, RDC 38/10,RDC 58/12 Import General Regulation RDC 46/00 Blood products RDC 233/05 Allergenics RDC 55/10 Specific Guidelines REGISTRATION RDC 49/11 POST-APPROVAL RDC 323/03 Probiotics Portaria 174/96 Antivenom serums RDC 234/05 Quality Control RDC 17/10 Good Manufacturing Practices RDC 50/11 Stability 6
  7. 7. Classification of Biological Products I- New Biological Product: is the biological product containing molecule with known biological activity, still not registered in Brazil and that has undergone all stages of manufacturing RDC 55/2010 7
  8. 8. Classification of Biological Products II – Biological product: is the biological drug that is not new or is known, containing molecule with known biological activity, already registered in Brazil and that has undergone all stages of manufacturing RDC 55/2010 8
  9. 9. Regulatory Pathways Biological product New biological product Individual route of development Comparability development Individual route of development Complete dossier Comparability exercise Comparative Phase III Quality, Safety, Efficacy Complete dossier Non innovative biological product Biosimilar 9
  10. 10. Comparability Pathway • It is the regulatory route that can be used to register a biological product, in which the comparability exercise in terms of quality, efficacy and safety was used between the developed product and the comparer biological product • Detailed dossier containing full information of development, production, quality control and comparability exercise 10
  11. 11. Comparability Pathway • Non clinical and clinical data can be reduced • Extrapolation of safety and efficacy data for other therapeutic indications of the biological products registered through the comparability pathway will be established through specific guidelines 11
  12. 12. Non-clinical and clinical report for comparability pathway • Full report of non-clinical trials – it must be comparative. It has to be designed to detect meaningful differences between the biological product and the comparer • In vivo non-clinical trials reports: - PD studies for the indications requested; - Cumulative toxicity studies 12
  13. 13. Non-clinical and clinical report for comparability pathway • Clinical trials protocols and reports: PK and PD studies and a pivotal study to determine the clinical safety and efficacy • Comparative clinical trials – comparability of safety and efficacy profiles between biological product and comparer 13
  14. 14. Non-clinical and clinical report for comparability pathway • Clinical design and comparability ranges must be supported by statistical and clinical evidence • Equivalence or non-inferiority studies may be acceptable for the comparison of efficacy and safety • When available, phase IV studies must be presented 14
  15. 15. Comparator Biological Product • Comparator Biological Product: is the biological product already registered at Anvisa based on submission of a full dossier and that has already been sold in Brazil • The same biological comparator must be used in all stages of the comparability exercise 15
  16. 16. Individual Development Pathway • It is the regulatory route that can be used to register a biological product, in which there is need to present full data on the development, production, quality control and nonclinical & clinical data to demonstrate the quality, efficacy and safety of the product 16
  17. 17. Individual Development Pathway • Production and Quality Control data must meet the quality standards already established for the product to be registered 17
  18. 18. Individual Development Pathway • The extent of the nonclinical studies may be reduced, considering factors like molecule complexity, level of structure characterization, extent of characterization of the product’s level of impurity, mechanism of action of molecule, toxicity potential and therapeutic index 18
  19. 19. NC and clinical report individual development • Non-clinical trials can be reduced (molecule complexity, structure caracterization degree, extension of impurity caracterization, mechanism of action, toxicity potential) • Phase I and II clinical trials are not necessarily comparative 19
  20. 20. NC and clinical report individual development • Phase III studies will be always necessary and must be comparative to the new biological product • When available, phase IV studies must be presented 20
  21. 21. General Considerations • For both pathways is mandatory to present: - immunogenicity study report; - risk management plan; - pharmacovigillance plan. 21
  22. 22. General Considerations • Clinical trials must be conducted with biological product submitted to registration • Clinical trials must be approved by National Regulatory Authority in which country clinical trial was carried on 22
  23. 23. General Considerations • All clinical trials conducted in Brazil must have previous Anvisa’s authorization • The clinical trials reports must follow the document called “Guide for elaboration of clinical trials report to registration and postregistration changes of biological products” 23
  24. 24. General Considerations • All clinical trials conducted in Brazil must have previous Anvisa’s authorization • The clinical trials reports must follow the document called “Guide for elaboration of clinical trials report to registration and postregistration changes of biological products” 24
  25. 25. General Considerations • All clinical trials conducted in Brazil must have previous Anvisa’s authorization • The clinical trials reports must follow the document called “Guide for elaboration of clinical trials report to registration and postregistration changes of biological products” 25
  26. 26. Regulatory Approach COMPANY Molecule research and development phase Non-clinical Studies Phase I and II Clinical trials Pre-submission Meeting ANVISA Meeting to discuss clinical development program Phase III Clinical Trials Meeting to discuss phase I and II and to discuss phase III study design 26
  27. 27. Regulatory Approach Technical Regulatory Committees -NRA from country that is transfering the technology - NRA from country that is receiving the technology - Producers from country that is transfering the technology - Producer from country that is receiving the technology 27
  28. 28. Regulatory Approach Technical Regulatory Committees - -Working plan: - At least two general meetings each year -Specific meetings necessary (ex.: clinical Assess and Addres critical technology transfer process trials) issues if during 28
  29. 29. Regulatory Approach Example:Fusion Protein X CMC Part: Assay Result Eletrophoretic profile PFX similar to RBP Isoeletric focalization Non comparative test. SEC-HPLC and DLS PFX similar to RBP RP-HPLC PFX similar to RBP Circular dichroism PFX similar to RBP Nucelotide sequencing PFX similar to RBP Peptide maping PFX similar to RBP Sialic acid quantification Non comparative. PFX complies TNF receptor- ELISA PFX similar to RBP TNF receptor and human IgG portion- Western blot Non comparative. PFX complies Kinetic Assay TNF binding PFX similar to RBP Biologic assay- mice fibroblasts (ED50) PFX similar to RBP 29
  30. 30. Regulatory Approach Non clinical part: • 1 non comparative repeated toxicity studies using rats • 1 non comparative acute subcutaneous injection toxicity study using rats • 1 chronic subcutaneous injection toxicity study in monkeys • 1 PK study in monkeys 30
  31. 31. Regulatory Approach Clinical part: Phase I: • Single dose study: safety and tolerability- 36 health male volunteers • Single dose study: PK profile- 57 health volunteers. Non comparative to RBP • 6 weeks study:non comparative PK profile- 30 patients with rheumatoid arthritis. Immunogenicity 31
  32. 32. Regulatory Approach Clinical part: Phase II: • Dose-response, safety and efficacy: double blind – 24 weeks- 300 patients. Comparative to MTX • Phase III study: • Opened study- 560 patients • PFX X MTX • Primary endpoint: ACR 20. • Adverse events. Immunogenicity (6 months) 32
  33. 33. Regulatory Approach Clinical part: Phase III study: • Opened study- 560 patients • PFX X MTX • Primary endpoint: ACR 20. • Adverse events. Immunogenicity (6 months) Clinical indications claimed: Severe Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, Juvenile Idiopathic Arthritis 33
  34. 34. Regulatory Approach Studies in Brazil: • PK comparative study; 30 healthy male volunteers, comparative to RBP • Phase III safety and efficacy: double blind, noninferiority study – 1 year- 300 patients. Comparative to RBP • Primary endpoint: ACR 20. • Adverse events • Immunogenicity (1 year) 34
  35. 35. Regulatory Approach Clinical Clinical Non Clinical Non Clinical Quality Comparability exercise Comparability path Individual development path 35
  36. 36. Technical meetings • • • • • • etanercept rituximab trastuzumab bevacizumab interferon EPO filgrastin 36
  37. 37. Partnerships INCA- National Cancer Institute- Brazil - Brazilian Rheumatology Society - National Network of Clinical Studies - Technical Advisory Committee for Biologicals (CATEBIO) 37
  38. 38. Guidelines Comparability exercise Guideline http://s.anvisa.gov.br/wps/s/r/lg 38
  39. 39. Guidelines Heparin Guideline http://s.anvisa.gov.br/wps/s/r/lg 39
  40. 40. Guidelines Interferon Alpha Guideline http://s.anvisa.gov.br/wps/s/r/lg 40
  41. 41. Guidelines Guideline for elaboration of Clinical Study Reports http://s.anvisa.gov.br/wps/s/r/lg 41
  42. 42. Guidelines- Future Perspectives Etanercept Rituximab Non clinical guideline Establishment and evaluation of cell substrates used in production of biological 42
  43. 43. Agência Nacional de Vigilância Sanitária laura.castanheira@anvisa.gov.br produtos.biológicos@anvisa.gov.br www.anvisa.gov.br Agência Nacional de Vigilância Sanitária www.anvisa.gov.br

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