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

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. 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. 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. 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. Types of Biological Products
5. Monoclonal antibodies;
6. Medicines containing live, attenuated or dead
microorganisms;
7. Probiotics;
8. Allergens.
5

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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. Individual Development
Pathway
• Production and Quality Control data must
meet the quality standards already
established for the product to be registered
17

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. 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. 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. General Considerations
• For both pathways is mandatory to present:
- immunogenicity study report;
- risk management plan;
- pharmacovigillance plan.
21

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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. Regulatory Approach
Clinical
Clinical
Non Clinical
Non Clinical
Quality
Comparability exercise
Comparability path
Individual
development path
35

36. Technical meetings
•
•
•
•
•
•
etanercept
rituximab
trastuzumab
bevacizumab
interferon
EPO
filgrastin
36

37. Partnerships
INCA- National Cancer Institute- Brazil
- Brazilian Rheumatology Society
- National Network of Clinical Studies
- Technical Advisory Committee for
Biologicals (CATEBIO)
37

38. Guidelines
Comparability exercise Guideline
http://s.anvisa.gov.br/wps/s/r/lg
38

39. Guidelines
Heparin Guideline
http://s.anvisa.gov.br/wps/s/r/lg
39

40. Guidelines
Interferon Alpha Guideline
http://s.anvisa.gov.br/wps/s/r/lg
40

41. Guidelines
Guideline for elaboration of Clinical
Study Reports
http://s.anvisa.gov.br/wps/s/r/lg
41

42. Guidelines- Future
Perspectives
Etanercept
Rituximab
Non clinical guideline
Establishment and evaluation of cell substrates used in
production of biological
42

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