5. Investigator and Investigational Product

5.1 Does local regulation require PI/CI to be approved/registered by any health authority (e.g., RA/EC)?

The investigator is the professional responsible for conducting a clinical trial. If the clinical trial is conducted by a group of people, the investigator is the leader of the group and shall be called the “main investigator”.

The investigator is responsible for:

1. Conducting the clinical trial according to the protocol agreed upon with the sponsor, the Good Clinical Practices, and the regulatory and ethical requirements.
2. Personally supervising the clinical trial.
3. Allowing the occurrence of monitoring, audits, and inspections.
4. Ensuring medical assistance for the research participants relating to adverse events from the clinical trial.
5. Promptly informing the research participants when the clinical trial finishes prematurely or is suspended for any reason.
6. Ensuring proper therapy and assistance for the participants.
7. Using the investigational products solely in the context of the clinical trial and storing such products according to the sponsor’s specifications.

Further, the investigator has the following additional responsibilities:

1. Presenting the protocol properly instructed to the CEP or to CONEP and awaiting a decision on ethical approval before initiating the clinical trial.
2. Preparing the informed consent form.
3. Developing the project as outlined.
4. Preparing and presenting partial and final reports.
5. Presenting data requested by the CEP or CONEP at any moment.
6. Maintaining clinical trial data in a physical or digital file under its custody and responsibility for a five-year period after the end of the trial.
7. Forwarding the results of the clinical trial for publishing, with proper credit to the researchers and technical personnel that are part of the project.
8. Properly justifying before the CEP or CONEP the interruption of the project or the non-publishing of the results.

There must be evidence that the principal investigator fulfills the responsibilities described in the Good Clinical Practices and that he/she is aware that the study product may be checked in the clinical trial inspection.

5.2 Does local regulation require any specific documents if PI/CI is based outside the country?

The PI needs to be based in Brazil. For those trials, lead from outside of Brazil but with participation from Brazilian sites requires CONEP approval.

5.3 Does local authority allow electronic ICF administration, including electronic signatures?

Both electronic ICF and electronic signatures are legal in Brazil. Therefore, ICF being completed with electronic signatures is accepted. 

5.4 Does local regulation require ICF to be administered as audio/visual and do these need to be recorded?

The regulations state that the participant and/or the participant’s legal representative(s) or guardian(s), and the investigator(s) must sign and date the ICF. If the participant and/or his/her legal representative(s) or guardian(s) is illiterate, an impartial witness should be present throughout the consent process. At this time, the participant and/or his/her legal representative(s) or guardian(s) will give verbal, and, if possible, written consent, and the witness should sign and date the form, certifying that the written information was explained accurately and understood.

Therefore, there is no requirement for recordings.

5.5 Is there any specific information/requirement on data capture/management (e.g., privacy regulations, etc.)?

The General Data Protection Law came into Federal Law in Brazil in 2020. This includes regulation of personal health information.

It forbids physicians to reveal the content of a medical record without the patient’s consent. Even in cases of compulsory notification of diseases, the physician’s duty is restricted exclusively to communicating this fact to the competent authority, and they are prohibited from sending the patient's medical record.

5.6 If a clinical study involves the study product as OTC and this is provided via pharmacy/amazon, etc., are there any specific regulations for IP management that need to be followed?

There are no specific guidelines on this matter.

5.7 For a marketed study product/OTC, can a participant be compensated after confirmation of the purchased study product, or upfront prior to product acquisition? Does compensation in any way impact how the study is viewed (i.e., RWE vs. Interventional Study)?

http://conselho.saude.gov.br/resolucoes/2012/Reso466.pdf

Resolution No. 466 states that compensation to participants may only be provided for transportation costs and meals for the participants and/or their legal representative(s) or guardian(s) during the trial.

Participants may also be compensated for travel expenses incurred while participating in the trial. In addition, at the end of the study, the sponsor must ensure free and indefinite access to the best prophylactic, diagnostic, and therapeutic methods that have proven to be effective. Access must also be guaranteed to participants between the time they stop their participation in the trial and the end of the study.

There is no indication of what is considered an acceptable stipend. 

5.8 Is it permitted to pay participant stipends (i.e., is it permitted to pay the patients for their participation in the clinical trial)? If so, what is the average range?

Please refer to Section 5.7 above.

5.9 Specific labeling requirements for clinical study product

Brazilian labeling requirements are the same for over-the-counter (OTC) and prescription drugs. As a general rule, neither labeling nor advertisements may include geographic names, symbols, figures, designs, or other indications that might be misleading. In addition, any unauthorized modification of the label is punishable by cancellation of the registration.

Preclearance of labeling is required as part of the registration procedure. The package label must include the following:

1. Name of product (trademark or generic)
2. Pharmaceutical form
3. Number of units in the package
4. Active ingredients
5. Complete formula of the product with quantitative composition
6. Name and address of the manufacturer
7. Responsible pharmacist
8. License number and date of issue
9. Batch number
10. Expiration date and date of manufacture
11. Storage instructions
12. For prescription products, a statement that it is supplied on prescription only 
13. Indications
14. Side effects
15. Precautions (if any)

Package inserts are not compulsory for all products, but if the company intends to include a package insert, it must be approved in advance. Inserts are usually physician-oriented. 

Once labeling is approved, all changes must be submitted for review, including a technical justification for the proposed change.

Investigational product (IP) labeling in Brazil must comply with the requirements set forth in Resolution No. 9, GCP, and the Quality Requirements Submission Manual for Research Products Used in Clinical Trials.

https://www.gov.br/anvisa/pt-br/centraisdeconteudo/publicacoes/medicamentos/pesquisa-clinica/manuais-e-guias/manual-de-submissao-dos-requisitos-de-qualidade-referente-aos-produtos-sob-investigacao-utilizados-em-ensaios-clinicos-2013-produtos-biologicos-3a-edicao.pdf/view

Specifically, the following labeling information must be included on the primary package label (or any intermediate packaging), and the outer packaging:

1. Sponsor name
2. Pharmaceutical form, route of administration, quantity of dosage units, and the drug name and concentration in the case of open studies
3. Batch or product identification code
4. Clinical trial reference code
5. Clinical trial participant identification code
6. Instructions for use (reference may be made to an explanatory pamphlet or other document that guides the trial participants or person administering the IP)
7. Storage conditions
8. Expiration date
9. Warning phrases in capital letters such as: “EXCLUSIVE USE IN CLINICAL TRIALS” and “KEEP OUT OF REACH OF CHILDREN”

All of the text labeling must be written in Portuguese. Symbols, pictograms, and warnings may also be included on both the primary and outer packaging.

It is not necessary to include the primary contact’s address and telephone number on the label to obtain IP or clinical trial information, or to break the blinding code. The trial participant receives a leaflet or card containing contact information in the case of trial-related concerns or adverse events. If the expiration date changes, additional labeling may be superimposed on the previous label to update the shelf life so that the new information does not conflict with the original batch number.

The labeling of the other study IPs should also follow the same model as the experimental product, and when any field(s) is not applicable, justification should be provided.

The IP should be coded and labeled in a manner that protects the blinding, if applicable, and be suitably packaged to prevent contamination and unacceptable deterioration during transport and storage. While a label template is requested for each clinical trial application (Clinical Drug Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM)) submission, if the label template differs between studies in a multicenter clinical trial, a note should be included in the DDCM to explain that separate templates will be provided for the specific dossiers.

The following external packaging information must also be provided with the IP to be imported into Brazil:

1. Special Notice (CE), Specific Special Notice (CEE), or Document for Importation of Product(s) under Investigation
2. IP quantity
3. Special storage precautions (e.g., temperature, humidity, and brightness)
4. IP physical/pharmaceutical form
5. Period of validity of the IP
6. Batch number or serial number

5.10 What documents need to be submitted (including relevant fee if any), and to whom, if a permit is needed for an investigational/study product being shipped from outside the country? Are there any specific requirements for biologics?

ANVISA is also responsible for authorizing the import of IPs. The sponsor may request approval to import/export IPs for study purposes at the same time that he/she submits a DDCM to ANVISA.

Following DDCM analysis and approval, ANVISA issues an authorizing document known as a Special Notice (Comunicado Especial (CE)) that may also be used for IP import/export requests for the trial. ANVISA may also issue either a Specific Special Notice (Comunicado Especial Específico (CEE)) to permit the sponsor to import/export an IP while his/her DDCM is still awaiting review and is within ANVISA’s 90-day approval window, or a Document for Importation of Product(s) Under Investigation in the case of non-manifestation of the DDCM.

The sponsor is required to present one of these ANVISA documents at the location where IPs for import/export are unloaded.

The documentation required to source a drug import license authorization is as follows:

1. Copy of the CE (note: per ResNo9, other ANVISA authorizations may need to be included as well—i.e., CEE and Document for Importation of Product(s) under Investigation).
2. Shipment document (includes shipment date, proof of IP deposit to the importer, and carrier/transportation type: Airborne Cargo - Air Waybill (AWB), Aquatic Cargo - Bill Landing (BL), and Land Cargo – Knowledge of International Transport by Highway (CTR)).
3. Access inspection authorization.
4. Commercial invoice.
5. Finished product analysis certificate or copy of IP purchase invoice, specifying all lots; and statement signed by technical manager containing number of lots, IP active ingredient name, and trade name if IP is produced by a manufacturer other than the importer/clinical study sponsor.

5.11 What is the turn-around time to get an import permit?

The processing time is 60 days.

5.12 Does local authority allow the destruction of clinical supplies at an off-site location (e.g. third-party vendor in or outside the country) after study completion? Are certificates of destruction required?

There is no specific guidance on the location of destruction.