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Wednesday, 20 November, 2013 Latin America Biotherapeutic Conference Day 2TRANSCRIPT
Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
Latin America Conference
Biotherapeutic Medicines
Biotherapeutic Medicines Regulation
in Brazil
Laura Gomes Castanheira
ANVISA
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
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
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.
5
Types of Biological Products
5. Monoclonal antibodies;
6. Medicines containing live, attenuated or dead microorganisms;
7. Probiotics;
8. Allergens.
6
Regulatory acts concerning
biological products
RDC 55/10
Specific Guidelines
REGISTRATION
RDC 49/11
POST-APPROVAL
RDC 46/00
Blood products
RDC 323/03
Probiotics
RDC 47/09
RDC 60/12
Package insert
RDC 71/09, RDC 168/02
RDC 61/12
Label
RDC 17/10
Good Manufacturing
Practices
RDC 233/05
Allergenics
RDC 50/11
Stability
RDC 81/08, RDC 234/05,
RDC 38/10,RDC 58/12
Import
Law 6360/76 General Regulation
RDC 234/05
Quality Control
Portaria 174/96
Antivenom serums
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
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
9
Regulatory Pathways
9
Biological product
Individual route
of development
Comparability
development
Complete
dossier
Comparative
Phase III
Comparability
exercise
Quality, Safety,
Efficacy
New biological
product
Individual route
of development
Complete
dossier Non innovative
biological product Biosimilar
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
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
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
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
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
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
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
17
Individual Development
Pathway • Production and Quality Control data must
meet the quality standards already established for the product to be registered
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
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
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
21
General Considerations
• For both pathways is mandatory to present:
- immunogenicity study report; - risk management plan;
- pharmacovigillance plan.
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
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 post-registration changes of biological products”
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 post-registration changes of biological products”
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 post-registration changes of biological products”
26
Regulatory Approach
ANVISA
Pre-submission Meeting Meeting to discuss
clinical development program
Meeting to discuss phase I and II and to discuss phase III study design
Molecule research and development phase
Non-clinical Studies
Phase I and II Clinical trials
Phase III Clinical Trials
COMPANY
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
28
Regulatory Approach
Technical Regulatory Committees
- -Working plan:
- At least two general meetings each year
-Specific meetings (ex.: clinical trials) if
necessary
Assess and Addres critical issues during
technology transfer process
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
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
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
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)
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
34
Regulatory Approach
Studies in Brazil:
• PK comparative study; 30 healthy male volunteers,
comparative to RBP
• Phase III safety and efficacy: double blind, non-
inferiority study – 1 year- 300 patients. Comparative to
RBP
• Primary endpoint: ACR 20.
• Adverse events
• Immunogenicity (1 year)
35
Regulatory Approach
Clinical
Non Clinical
Quality
Comparability path Individual
development path
Clinical
Non Clinical
Comparability exercise
36
Technical meetings
etanercept
• rituximab
• trastuzumab
• bevacizumab
• interferon
• EPO
• filgrastin
37
Partnerships
INCA- National Cancer Institute- Brazil
- Brazilian Rheumatology Society
- National Network of Clinical Studies
- Technical Advisory Committee for
Biologicals (CATEBIO)
38
Guidelines
Comparability exercise Guideline
http://s.anvisa.gov.br/wps/s/r/lg
39
Guidelines
Heparin Guideline
http://s.anvisa.gov.br/wps/s/r/lg
40
Guidelines
Interferon Alpha Guideline
http://s.anvisa.gov.br/wps/s/r/lg
41
Guidelines
Guideline for elaboration of Clinical Study Reports
http://s.anvisa.gov.br/wps/s/r/lg
42
Guidelines- Future Perspectives
Etanercept
Rituximab
Non clinical guideline
Establishment and evaluation of cell substrates used in production of biological
Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
produtos.bioló[email protected]
www.anvisa.gov.br
Agência Nacional
de Vigilância Sanitária