FAST TRACK REGISTRATION OF COVID-19 VACCINES IN BRAZIL Global Regulatory Partners, Inc

EXECUTIVE SUMMARY

On 03/18/2020, Anvisa published a new regulation (RDC 348/2020), that defines the conditions of the priority review for the registration of covid-19 Vaccines .

According to this new regulation, Anvisa will approve new clinical trial applications for local clinical studies on new covid-19 vaccines within 72 hours after receiving a complete application from sponsors. Additionally, Anvisa will review and approve the complete registration dossiers for Covid-19 vaccines in 60 days after receiving an application from sponsors. REGULATORY AUTHORITIES INVOLVED IN CLINICAL TRIALS IN BRAZIL

In Brazil, under the supervision of Anvisa, there are three organizations involved in the review and approval of clinical trial applications, known also Dossier of Clinical Development of Medicines (DDCM). List of Documents for a DDCM are summarized in Table 1.

The regulatory organizations involved in Clinical Trials in Brazil are:

• CEPs and CONEP are responsible for evaluating the ethical aspects involving human subjects and for approving the protocols when applicable. Together, the CEPs and CONEP represent the ethical review system in Brazil, known as the CEP/CONEP System. • COPEC is responsible for conducting the review of the content of the clinical trial applications.

Before conducting any clinical trial involving human beings in Brazil, it is mandatory to receive approval from the Research Ethics Committees (CEPs) and / or the National Research Ethics Commission (CONEP) first. Receiving approval from Anvisa, applies only to clinical studies that are intended to support new products’ registration, including vaccines.

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Table 1: Content of DDCM

LIST OF DOCUMENTS

Global forwarding the dossier and being responsible for conducting clinical research (10754)

1. Petition form for consent in process of clinical drug development dossier (DDCM);

2. Proof of payment, or of exemption, from the Sanitary Surveillance Inspection Fee (TFVS), through a specific Union Collection Form (GRU);

3. Drug development plan;

4. Researcher's brochure;

5. Summary of safety aspects, if applicable;

6. Information regarding the interruption of the development or withdrawal of the experimental drug from the market, if applicable;

7. Description of the IFA (Experimental drug dossier);

8. Description of the Experimental Medicine (Dossier of the experimental medicine);

9. Description of the modified placebo or comparator drug, if applicable (Dossier of the experimental drug); 10. Document on the control of Transmissible Spongiform Encephalopathies (TSE) transmissibility (Experimental drug dossier);

11. Model of the label of the product(s) under investigation (Dossier of the experimental medicine);

12. Critical analysis of non-clinical pharmacological and toxicological studies (experimental drug dossier);

13. Critical analysis of clinical trials already conducted, if applicable

14. Authorization of the initial holder of the DDCM to use information from his dossier, if applicable (Dossier of the experimental drug); 15. Information regarding the registration process number of the experimental drug, if applicable (Dossier of the experimental drug); 16. CD-ROM containing the respective documentation. The electronic document must allow textual search. Responsible: Company hired by Global to conduct clinical trials in Brazil (10755) *The documents are the same as those (Global forwarding the dossier and being responsible for clinical research)

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Other consideration for DDCMs;

DD The whole application must be translated into Brazilian Portuguese. DD The only person allowed to submit the DDCM to Anvisa is the Principle Investigator (PI) responsible for Clinical Trial. DD Submission of the DDCM is done via the Anvisa online platform ( Plataforma Brasil). DD Foreign Sponsors must submit their applications to CONEP and CEP for an initial evaluation. DD It is mandatory for all applicants to register their clinical trials with the world health organization’s (WHO) ICTRP or other registry recognized by the ICMJE. REGISTRATION OF COVID-19 VACCINES IN BRAZIL

The list of documents required for the registration of a biologic products, such as vaccines, is provided in section IV of chapter III of Resolution of the Collegiate Board (RDC) 55/2010. Table 2 summarizes the List of Documents needed for a Biologic Product Registration in Brazil.

Table 2: Documents needed for Biologic Registration

LIST OF DOCUMENTS Section I

I Registration petition forms - FP1 and FP2, duly filled in;

Original receipt of payment of the fee of health surveillance inspection, duly authenticated and/or stamped by II the bank, or proof of exemption when applicable;

III Declaration of the size (economic capacity) of the company;

IV Copy of the Company's Operating License and/or Sanitary Permit;

Copy of the Operating Authorization Certificate of the Company or its publication in the Official Journal of the V Union (DOU);

Copy of the updated Certificate of Technical Responsibility, issued by the Regional Pharmacy Council, proving VI that the requesting company and/or manufacturer has assistance from the responsible pharmacist qualified for that purpose;

VII Technical justification for product registration;

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Section I Copy of the Good Manufacturing Practices Certificate (GMPC) shipped by Anvisa to all manufacturers of the VIII active ingredient, the biological product in bulk, the biological product in its primary packaging, the finished biological product, the diluent and the adjuvant; Copy of GMPC, issued by the competent health authority of the country where the manufacturer of the active IX ingredient, the biological product in bulk, the biological product in its primary packaging, the finished biological product, the diluent and the adjuvant is located;

X History of the registration status of the biological product in other countries, when applicable;

Copy of the proof of registration in the country of origin of the biological product, issued by the respective XI competent Health Authority;

Copy of the model package insert approved by the authority competent health care of the country of origin, XII accompanied by a sworn translation;

XIII Models of package insert and packaging primary and secondary, in accordance with current legislation;

Updated pharmacovigilance data, according to with the sanitary legislation in force, obtained from clinical XIV studies and the commercialization of the product, when applicable;

Bar code (GTIN), for all presentation(s) or mechanisms of identification and security that allow the tracking of XV the product in accordance with current health legislation;

Copy of the national, international or internal compendium of the company with the determination of the XVI specifications of the biological product finished;

XVII Additional information according to the legislation current on EET control, when applicable;

XVIII Technical report;

XIX Therapeutic experimentation report; and

XX Pharmacovigilance report.

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Section II

I Name and address of the manufacturer and storage location of the cell bank;

Name and address of all manufacturers of the principle active, the biological product in bulk, II the biological product in its primary packaging, the finished biological product, the diluent and the adjuvant;

III Name and address of the issuer of the certificate of release of the finished product lots;

General data about the product:

a) pharmaceutical form and presentation; b) complete composition of the formulation, with all its components specified by their corresponding technical names and synonyms according to the Brazilian Common Denomination - DCB, if any, or International Nonproprietary Name - INN or, in its absence, the denomination Chemical Abstracts Service - CAS; indicating the units of measurement used; c) functions that each substance performs in the formula; d) route(s) of administration; e) instructions for use, when applicable; f) indications, purpose or use for which it is intended; g) contraindications; h) collateral effects; IV i) adverse reactions; j) restrictions or precautions that must be considered; k) precautions and warnings; l) drug and food interactions; m) changes in laboratory tests; n) signs, symptoms and conducts, in case of overdoses; o) expiration date; p) conservation care; q) conservation temperature; r) transport temperature; s) specifications of primary and secondary packaging material; e t) codes or conventions used by the company for identification of lots of active ingredient, biological product in bulk, biological product in its primary packaging and finished biological product;

Product development history, pointing to purpose of use of each batch produced (stability V study, pre-clinical and clinical studies);

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Section II Information on the manufacturing steps: a) summarized production protocol in the form of a flow chart, with identification of controls in process; b) list of the main equipment used in manufacturing; c) detailed description of all the manufacturing steps of the biological product, the diluent and the adjuvant; d) identification and justification for the selection of critical stages of the manufacturing process; VI e) description of in-process controls and justification for determination of the specifications; f) production scale in all manufacturing steps, pointing out the minimum and maximum sizes of the industrial batch to be produced for commercialization; g) description and justification for changes made in the production process, during the development of the finished biological product; h) report on the validation of the viral removal and/or disposal procedures used, where applicable; i) validation report of the critical steps of the manufacturing; and j) validation and justification for reprocesses; Quality control information: a) description of all quality control tests performed, from the active ingredient to the finished product; VII b) description of the reference standards used; c) validation of analytical methodologies according to the current health legislation; and d) reference and justification for each specification determined in quality control tests; Description of the storage care of the principle active, bulk biological product, biological VIII product intermediate, of the biological product in its primary packaging, of the finished biological product, the diluent and the adjuvant; Description of containers and forms of packaging for the active ingredient, bulk biological product, intermediate biological product, biological product in its primary packaging, finished IX biological product, diluent and adjuvant and conditions to be maintained to ensure product quality; Validation of the transport chain: a) operation qualification and performance of the boxes to be used for transport and validation of transport procedures the active ingredient, the bulk biological product, the X product biological intermediate, of the biological product in its packaging primary and finished biological product, diluent and adjuvant; b) operation qualification and performance of the boxes to be used for the transportation of the biological product finished in national territory; Description of solutions, components and culture media used in the manufacture of the XI biological product; Information about the excipients: a) description of physical-chemical, microbiological and other quality controls; b) specifications of the excipients; XII c) description of possible chemical interactions of the excipients with the active ingredient; d) study demonstrating the efficacy of the preservative used, for those products that contain some preservative in their final formulation;

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Section II

XIII Protocol and report of the stability studies of according to the sanitary legislation in force;

Contaminants and impurities: a) a) characterization of contaminants and impurities; b) b) description of the processes involved for the reduction/removal of impurities originated XIV by the product decomposition or manufacturing process; c) c) justifications for the specifications of impurities in the finished product; and d) d) safety evaluation for adventitious agents of starting materials of biological origin; and

XV Description and specifications of primary and secondary packaging.

Section III

Report with data on the raw materials used, containing the following information: a) description of the strains used, with information on their origin, identification, processes for obtaining or building, mitigation processes and certificates of analysis, according to the type of vaccine; b) description of the master seed and working lots of the virus and cell lineage used, including identification, origin, characterization, stability, determination of foreign agents/ advertises, controls, methods used in its elaboration and frequency of tests; c) description of the system of master cell banks and work, including identification, analytical certificates, origin, characterization, stability, in-process controls, methods used in its elaboration, frequency of assays and definition of the number of passes; d) demonstration that the characteristics of the cells remain unchanged during the steps employed in production; e) description of the characteristics of the original donor, such as tissue or organ of origin, I ethnic and geographical origin, age, sex and general physiological condition, in the case of human cell lines; f) description of the conditions of the original donor and general characteristics such as species, lineage, tissue or organ of origin, geographical origin, age and sex, results of tests for pathogens and physiological condition for animal cell lines; g) description of the organism from which the cell substrate is derived and general characteristics such as species, strain, genotype, phenotype, pathogenicity, toxin production, antibiotic resistance and biosafety information for strains of microorganisms; h) description of the origin, identification and presentation of quality certificates for embryonated eggs; i) determination of the maximum cellular age in vitro; j) description of the manufacturing process and control of quality of the carrier protein; k) description of the process of conjugation and/or modification; l) description of the inactivation or detoxification process.

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REGISTRATION OF COVID-19 VACCINES IN BRAZIL: OTHER CONSIDERATIONS

It is important to emphasize that for COVID-19 vaccines, sponsors can request the evaluation of their registration dossier while their vaccine is still phase III studies. However, they should have enough data from phases I and phase II studies, that demonstrate the product preventive efficacy in COVID-19.

While conducting clinical studies on the vaccine product (phases I, II and III), sponsors should conduct stability studies to determine their shelf life and appropriate conditions of use and storage. In addition, sponsors must commit to conduct post-marketing surveillance studies to monitor the occurrence of any new adverse reactions not detected during the clinical studies. ANVISA TIMELINES AND REGISTRATION FEES

Anvisa Review Timelines Type of application Covid-19 vaccine Other vaccines

Clinical trial applications Up to 72 hours 180 days

Review of Registration Up to 60 days 120 to 365 days dossier for vaccines

ANVISA FEES

Anvisa Fee Type of application Covid-19 vaccine Other vaccines

Clinical trial applications R$ 19.677,00 R$ 19.677,00

Review of Registration R$ 157.416,00 R$ 157.416,00 dossier for vaccines

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REFERENCES:

• ANVISA. Resolution of the Collegiate Board (RDC) 55/2010. Registration of Biologic Product. • ANVISA . Resolution of the Collegiate Board (RDC) 204/2017. The framework in the priority category, petitions of registration, post- registration and prior consent in clinical research of drugs. • ANVISA. Resolution of the Collegiate Board (RDC) 348/2020. Alternative Procedures for Registration of Medicines, Biological Products and In Vitro Diagnostic Products Due to COVID-19 Epidemic

GRP REGULATORY SERVICES IN BRAZIL:

• In-country representation • Clinical Trial Application (DDCM) Dossier Compilation • Clinical Trial Application (DDCM) Submission • Anvisa Pre-submission Meetings • Vaccine Petition Submission • Vaccine Dossier Compilation • Company Registration Compliance (CBPF, AFE, ect.) • Vaccine Dossier Submission • Translation of Documents into Portuguese • Help answering Anvisa Queries

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ABOUT GLOBAL REGULATORY PARTNERS, INC

Global Regulatory Partners Inc, (GRP) provides regulatory affairs, clinical, quality and safety services to medical devices and pharmaceutical companies globally. As a qualified and licensed legal representative with offices in USA, China, Japan, Brazil, Mexico and Argentina, the company can represent life science companies in those countries and help them register their products in compliance with local regulations and in record time.

For additional information, please contact us at [email protected]

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