Current Biologics Regulatory Scenario in Brazil

Carolina Damas Rocha Zarate Blades, PhDOffice of Biological ProductsBrazilian Health Regulatory Agency – ANVISA

Brazil, March/2019

LATAM CMC Strategy Forum 2019

Outline

Biological products

Regulatory framework

Regulatory updates

International Cooperation

Perspectives2

Biological Products

Vaccines;

Hyperimmune sera;

Blood products;

Biomedicines classified as:a) medicines obtained from biological fluids or animal‐originated tissue;b) medicines obtained through biotechnological procedures.

Monoclonal antibodies;

Medicines containing live, attenuated or dead microorganisms;

Probiotics;

Allergens. 3

Regulatory framework

RDC 55/2010Marketing Authorization

RDC 46/2000Blood products

RDC 323/2003Probiotics

RDC 50/2011Stability

RDC 47/2009RDC 60/2012 Package insert

RDC 71/2009RDC 61/2012

Labelling

RDC 17/2010GMP

RDC 194/2017Allergenics

RDC 187/2017Hyperimmune Sera

Law 6.360/1976Decree 8.077/2013

RDC 234/2005Quality control

RDC 49/2011Post-approval

changes

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Regulatory framework

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Resolution 55/2010 

Marketing authorization of Biological Products  in Brazil

Biosimilars

Regulatory framework

Stand alone approach

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Resolution 55/2010 Marketing authorization of Biological Products in Brazil

Regulatory requirements for the license of biological products in Brazil

New Biological Products

Biological Products (not new)

Comparability Stand Alone

CMC Needed Comparative Needed

Pre-clinical Needed Comparative May be reduced

Clinical 1 and 2 Needed Comparative When needed, may not be comparative

Clinical 3 Needed Comparative Comparative with exceptions

Immunogenicity Needed Comparative Needed

Same comparator Not applicable Yes Not applicable

Risk management plan Needed Needed Needed

Extrapolation Not applicable Possible Not possible

Regulatory framework

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Resolution 49/2011 Stablishes requirements and procedures for post‐approval changes of Biological Products

Resolution 50/2011Stablishes requirements and procedures for stability studies of Biological Products

Regulatory framework

Under review

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Regulatory updates

Law 13.411/2016

Establishes new deadlines for the conclusion of the drug applications.

Marketing authorization:

Ordinary category: 365 days* (487 days)

Priority category: 120 days* (160 days)

Post‐approval changes:

Ordinary category: 180 days* (240 days)

Priority category: 60 days* (80 days)* An extension of 1/3 of the time can be granted, under justification.

Categories will be defined according to technical complexity, clinical, social and economic relevance.

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Resolution 204/2017: 

Stablishes prioritization criteria for:

I. Marketing authorization

II. Post‐approval changes 

III. IND submission

Regulatory updates

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Prioritization criteria (Biological Products)Marketing authorization

• Drugs for neglected, rare or emerging diseases; public health emergencies; or serious debilitating

diseases, in situations where there is no therapeutic alternative available, or when there is a

significant improvement in the safety, efficacy;

• New drugs intended to pediatric population;

• Vaccines or hyperimmune sera to be incorporated into the National Immunization Program;

• Drugs that are part of the strategic product list, under the Brazilian National Health System (SUS) and

object of a Productive Development Partnership (PDP), e.g. biosimilars.

Regulatory updates

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Prioritization criteria (Biological Products)

Post‐approval changes• New indication or extended use for neglected, rare or emerging diseases; when there is a significant

improvement in the safety, efficacy; or for serious debilitating diseases, in situations where there is no

therapeutic alternative available;

• New indication or extended use for pediatric population;

• Vaccines or hyperimmune sera incorporated into the National Immunization Program;

• Applications related to the process of internalization of the production of drugs that are part of the strategic

product list, under the Brazilian National Health System (SUS) and object of a Productive Development

Partnership (PDP), e.g. biosimilars.

Regulatory updates

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Prioritization criteria (Biological Products)

• In addition to the previous criteria, Anvisa may classify as priority applications for

marketing authorization and post‐approval changes of drugs (under medical

prescription), when there is a risk of market shortage with public health impact.

Regulatory updates

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Resolution 205/2017: 

Establishes a special procedure for the consent of clinical trials,

certification for good manufacturing practices and registration of

new drugs for treatment, diagnosis or prevention of rare diseases*.

* one that affects up to sixty‐five people in every one hundred thousand individuals

Regulatory updates

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Resolution 205/2017: Art.18. The following procedures must be followed for the purpose of registration of newdrug for a rare disease:[….]IV ‐ assessment of the request for registration of drug by Anvisa within sixty days aftersubmission, with the emission of the notification requirement or conclusive opinion;[….]VI – Compliance of the requirements, by the interested party, within thirty days after readingthe notification; andVII ‐ assessment of requirements’ compliance, by Anvisa within forty‐five days after thesubmission at the agency.

Regulatory updates

Anvisa has up to 105 days to provide a conclusive opinion    (or ask for additional clarification) 

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OS n. 45, February of 2018 (Orientation of Service)

• Reliance Pilot Project (duration: 1,5 year – in progress);

• Establishes an optimized review pathway for the assessment of Biologics 

(for Marketing Authorization and Post‐approval changes applications);

• Eligibility Criteria: approved in the US FDA and EMA;

• Approval reports should be provided by the applicants.

Regulatory updates

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Marketing authorization: US FDA and EMA approval;

Detailed approval letters and/or assessment reports

Post‐approval changes:US FDA and/or EMA approval;

Detailed approval letters and/or assessment reports

• Complete information  required by Brazilian legislation must be presented;• Quality changes: same specifications, shelf‐life;• Efficacy and safety changes: same labelling content, including indications, dosage, 

warnings and precautions, ARs;• Any differences must be justified.

Regulatory updates

OS n. 45, February of 2018 (Orientation of Service)

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Resolution 219/2017For some post‐approval applications, if Anvisa has not started the assessment within 180 days, the post‐registration change shall be deemed acceptable.

• Demands that marketing authorization holders submit additional documents to the original application (risk assessment, statement);

• Does not apply for efficacy and safety changes and changes to the drug substance of biological products.

Regulatory updates

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Backlog Reduction New strategies which enable to considerably reduce the timelines for assessing the applications 

• Timelines were accomplished in most cases for biologics.

Approval before FDA and EMA in 2 cases and before EMA in 1 case (variations of new therapeutic indication).

• Two of the new indications (daratumumab – 1st L Multiple myeloma and pembrolizumab +chemotherapy – 1st L NSCLC) were approved by ANVISA before FDA and EMA in April/18 andJune/18. One indication was approved before EMA (nivolumab + ipilimumab for 1st L Renalcarcinoma cell in Oct/18).

Regulatory updates

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Backlog reduction

Regulatory updates

Marketing authorizaton

Year Average time (days)

2016 247

2017 157

2018 91

Post‐approval

Year Average time (days)

2016 372

2017 245

2018 108

Post‐approval (minor complexity)

Year Average time (days)

2016 1452017 1172018 82

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Marketing authorization ‐ Time for approval – 2018 (average time)

Regulatory updates

Status Backlog (days)

Assessment (days)

MAH (days) Backlog + Assessment 

(days)

Total Time for approval 

(days)

Priority 21 113 45 134 179

Ordinary 153 214 156 367 523

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Public Assessment Reports on website:http://www.anvisa.gov.br/datavisa/Fila_de_analise/index.asp

Technical basis for the approval or the refusal of marketing authorization of medicinal products 

Regulatory updates

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Note of clarification on procedural instruction :http:http://portal.anvisa.gov.br/documents/33836/4095801/Nota+de+esclarecimento+004+de+2017+‐+Medicamentos+Biol%C3%B3gicos/36e8ac57‐64e7‐4e7d‐86b5‐9d4e2f7ebeda 

Marketing authorization and Post‐approval changes for Biological Products;

Mandatory documents; Complementary applications. 

Regulatory updates

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Strengthen International Cooperation

MoU with Danish Health and Medicines Authority ‐ Workshop in November 2018:

• Brazilian Legislation X European Legislation;

• Quality, safety and efficacy requirements for Biological Products;

• Case studies (biosimilars). 

International Cooperation

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Perspectives

Anvisa CTD guideline;

Resolution on less complex Biologicals (draft concluded, available for PC soon);

Resolution on Stability (draft in progress);

Resolution on Post‐registration changes (draft in progress);

Implementation of Quality System for Biological Products in accordance with 

Good Revision Practices;

Improvement of the Biological Products webpage:• Hot site for biosimilars;• General information about vaccines. 25

Thank you!

Carolina Damas Rocha Zarate Bladesprodutos.biologicos@anvisa.gov.br

Agência Nacional de Vigilância Sanitária ‐ AnvisaSIA Trecho 5 ‐ Área especial 57 ‐ Lote 200

CEP: 71205‐050Brasília ‐ DF

www.anvisa.gov.brwww.twitter.com/anvisa_oficial

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