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

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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.

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Types of Biological Products

5. Monoclonal antibodies;

6. Medicines containing live, attenuated or dead microorganisms;

7. Probiotics;

8. Allergens.

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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

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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

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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

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Regulatory Pathways

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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

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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

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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

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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

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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

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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

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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

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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

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Individual Development

Pathway • Production and Quality Control data must

meet the quality standards already established for the product to be registered

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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

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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

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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

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General Considerations

• For both pathways is mandatory to present:

- immunogenicity study report; - risk management plan;

- pharmacovigillance plan.

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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

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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”

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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”

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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”

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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

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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

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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

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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

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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

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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

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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)

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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

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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)

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Regulatory Approach

Clinical

Non Clinical

Quality

Comparability path Individual

development path

Clinical

Non Clinical

Comparability exercise

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Technical meetings

etanercept

• rituximab

• trastuzumab

• bevacizumab

• interferon

• EPO

• filgrastin

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Partnerships

INCA- National Cancer Institute- Brazil

- Brazilian Rheumatology Society

- National Network of Clinical Studies

- Technical Advisory Committee for

Biologicals (CATEBIO)

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Guidelines

Comparability exercise Guideline

http://s.anvisa.gov.br/wps/s/r/lg

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Guidelines

Heparin Guideline

http://s.anvisa.gov.br/wps/s/r/lg

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Guidelines

Interferon Alpha Guideline

http://s.anvisa.gov.br/wps/s/r/lg

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Guidelines

Guideline for elaboration of Clinical Study Reports

http://s.anvisa.gov.br/wps/s/r/lg

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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

laura.castanheira@anvisa.gov.br

produtos.biológicos@anvisa.gov.br

www.anvisa.gov.br

Agência Nacional

de Vigilância Sanitária