New legal framework for clinical trial with human subjects approved in Brazil

After more than seven years of deliberation in Brazil’s National Congress, Law No. 14,874 – regulating clinical trial with human subjects in Brazil – was enacted and published in the Federal Official Gazette (DOU) on May 28, 2024.

The original bill was approved by the Federal Senate in 2017 (Bill No. 200/2015) and sent to the House of Representatives for review (Project No. 7082/2017). It then returned to the Senate with changes and was approved on April 23, 2024 (Bill No. 6007/2023).

The new law is divided into nine chapters, covering topics such as the establishment of the National System of Ethics in Research with Human Subjects, the operation of Research Ethics Committees, parameters for the protection and compensation of research subjects, and the responsibilities of investigators and sponsors.

In addition to covering clinical trial conducted with drugs, the law also applies to medical devices and experimental advanced therapy products, where applicable.

The law defines research with human subjects as research that, individually or collectively, involves human participants directly or indirectly, including through the handling of their data, information, or biological material.

Beyond the primary concept of clinical trial – which comprises a set of scientific procedures systematically developed to evaluate the action, safety, and efficacy of medications, products, techniques, procedures, medical devices, or health care for therapeutic, preventive, or diagnostic purposes; to verify the distribution of risk factors, diseases, and health conditions in the population; or to assess the effects of factors/states on health – the law introduces two more categories of research:

• Experimental clinical trials: experimental clinical trial to evaluate the safety, clinical performance, or efficacy of a medical device, experimental drug, or advanced therapy;
• Scientific, technological, or innovation research: research not aimed at obtaining sanitary registration for the product under analysis.

The text published in the DOU includes two vetoes related to the bill of law sent for presidential approval:

• The requirement to notify the Public Prosecutor’s Office when a member of an indigenous group participates in research (Paragraph 3 of Article 24 of the bill). The justification for the veto indicates that the paragraph would violate the principle of equality, as it suggests a potential situation of state guardianship over indigenous peoples, a situation that, according to the justification, has already been overcome by legislation;
• The maximum period of five years for post-trial provision of the experimental drug, counted from the commercial availability of the drug in Brazil (item VI of Article 33 of the bill). Reasons for the veto indicate that establishing a maximum period for the post-trial provision of the drug would be contrary to the public interest, violating the rights of clinical trial participants, and compromising the ethical development of research based on the principles of dignity, beneficence, and justice. Additionally, there is currently no maximum period for the continued free post-trial provision of the experimental drug for research participants, and the provision should continue regardless of its commercial availability by the private sector.

Despite the publication of the new law, the vetoes will still be reviewed by the National Congress and must be either rejected or confirmed. From the publication of the law, a 30-day period begins for the deliberation of the presidential vetoes by senators and representatives in a joint session, requiring an absolute majority of the National Congress to reject the veto (Article 57, Paragraph 3, item IV and article 66 of the Federal Constitution). If the regulatory period elapses without deliberation, the matter is included in the agenda and takes precedence over other deliberations until the final vote.

Finally, if the vetoes are rejected, the corresponding parts of the law will be sent to the President for enactment within  forty-eight (48) hours (Article 66, Paragraph 7 of the Constitution).

Establishment of the National System of Ethics in Research with Human Subjects

The National System of Ethics in Research with Human Subjects consists of:

• The national ethics agency, responsible for issuing regulatory norms on research ethics and acting as the appellate body for decisions made by the Research Ethics Committees (CEPs);
• The ethics review agency, represented by the CEPs linked to research centers, which are responsible for the preliminary ethical review of research to ensure the dignity, safety, and well-being of research participants.

Working together, the national ethics agency will accredit and certify the CEPs, ensuring they are qualified to perform ethical reviews of research according to the level of risk involved. Additionally, it will monitor, support, and oversee the CEPs in their protocol reviews and compliance with relevant norms.

Research Ethics Committee (CEP)

As the ethics review agency, the CEP must be accredited by the national ethics agency and will consist of an interdisciplinary team in medical, scientific, and non-scientific areas.

The CEP’s responsibilities include ensuring the rights, safety, and well-being of research participants, especially those in vulnerable situations; reviewing submitted research protocols and monitoring the research execution; and ensuring appropriate means are provided to obtain the consent of the research participant or their legal representative.

All research involving human subjects must undergo prior ethical review by the CEPs, which must be completed within thirty (30) business days from the acceptance of all required research documents. The CEP must then issue an acceptance or denial within ten business days from the submission date.

Research deemed strategically important for Brazil’s public health system (SUS) and crucial for addressing public health emergencies will receive priority and will be subject to special review procedures, including expedited approval timelines, as regulated by the Federal Executive Branch.

Protection and compensation for research subjects

The law ensures protection for research subjects, requiring their explicit authorization or that of their legal representative through the signing of a Free and Informed Consent Form (TCLE).

Participants are not to be compensated or granted any advantages for their participation in research. However, Law No. 14,874/2024 allows for the payment of healthy individuals for their participation in Phase I clinical trials or bioequivalence studies, provided certain requirements outlined in the law are met.

Reimbursement for transportation, food, or material provision, and other necessary reimbursements according to the research project are not considered compensation or advantages for research participants.

Additionally, the current regulation mandates that sponsors must compensate research subjects for any damages incurred due to their participation in the research and provide necessary health assistance related to these damages.

Responsibilities of sponsors and investigators

The law defines a “sponsor” as an individual or entity, public or private, that supports research through funding, infrastructure, human resources, or institutional support.

Sponsor responsibilities include implementing and maintaining quality assurance and control systems, establishing contracts among research parties, and designating an investigator to be responsible for clinical decisions related to the research, especially in clinical trials.

The sponsor is also responsible for storing research data and essential documents after the research is concluded or discontinued, in compliance with current regulations from the Brazilian Health Regulatory Agency (Anvisa).

As per Anvisa’s existing regulations, the sponsor may delegate specific functions to Contract Research Organizations (CROs), which will share responsibility concerning the delegated tasks. Moreover, the sponsor must ensure that research participants consent to direct access to their data and information for monitoring, auditing, review by competent ethical entities, and inspections by regulatory agencies.

The investigator is responsible for conducting the research at an institution or research center and shares responsibility for the integrity and well-being of research participants with the sponsor. Their duties include submitting research documentation, including any amendments, for CEP approval and conducting the research in accordance with the CEP-approved protocol.

While the law outlines the responsibilities of each party in accordance with current ethical regulations, it also clarifies that all institutions and organizations involved in the research share responsibility for its conduct and for providing comprehensive assistance to participants concerning any complications and damages arising from the research.

Post-trial provision

The law addresses this crucial topic, setting forth rules regarding the provision of experimental drug after the trial’s end.

To ensure greater legal security and predictability for both the sponsor and, primarily, the research subject, Law No. 14,874/2024 mandates that before starting the research, the sponsor and the investigator must submit a post-trial access plan to the responsible CEP. This plan should present and justify the need, or lack thereof, for the free provision of the experimental drug to participants who need it after the clinical trial ends.

For these cases, a post-trial provision program will be developed – subject to regulatory approval – ensuring the continuation of safety monitoring and the delivery of the experimental treatment for a specified period after the clinical trial ends.

At the end of the clinical trial, each participant will be assessed individually for the necessity of continuing experimental treatment. The provision must occur whenever the experimental treatment is considered the best therapy for the participant’s clinical condition, offering a more favorable risk-benefit ratio compared to other available treatments or alternatives.

The law also outlines situations where the post-trial provision program can be interrupted after submitting a justification to the responsible CEP for evaluation. Notable cases include:

• Inability to obtain or manufacture the experimental drug due to technical or safety issues, provided the sponsor offers an equivalent or superior alternative available in the market;
• Cure of the disease or health condition targeted by the clinical trial, or the introduction of a satisfactory therapeutic alternative;
• Lack of benefit from the continued use of the experimental drug for the research participant;
• Occurrence of adverse reactions that, in the investigator’s judgment, make the continuation of the experimental drug unfeasible, despite potential benefits;
• Availability of the experimental drug in the public health system.

The version of the law approved by Congress also included a provision allowing the interruption of post-trial provision five years after the drug becomes commercially available in Brazil. However, as previously discussed, this provision was removed through a presidential veto.

Sanctions and other provisions

The new law addresses other relevant issues, such as data storage in biobanks for future research and the importation, use, manufacture, and export of products for clinical trial with human subjects.

To expedite the availability of new products in the market, the law sets a maximum approval period for human clinical trials by Anvisa. The sanitary analysis related to primary petitions for clinical trials with humans – involving the sanitary registration of the product under investigation – must be completed within ninety (90) business days. If the health authority does not respond within this period – following the proper receipt of the primary clinical trial petition – clinical development can begin, provided it has the necessary ethical approvals.

Failure to comply with the law may constitute an ethical violation and subject the violator to disciplinary sanctions under the legislation of the relevant professional council. In some cases, it may also constitute a sanitary violation, without prejudice to applicable civil and criminal sanctions.

Seen as significant progress by the sector, the new clinical trial law aims to improve rules and address sensitive issues previously handled only through regulatory acts. It seeks to promote and encourage clinical trial in Brazil, thereby allowing Brazilian citizens greater access to innovative therapies. It will be critical for the bodies and authorities involved in the regulation and approval process of clinical trial to work swiftly and harmoniously towards the regulation and implementation of the new law.

In this regard, Anvisa has opened Public Consultation No. 1,257, aiming to review the Resolution No. 9/2015, which currently regulates clinical trials with drugs in Brazil from a regulatory-sanitary perspective. Open for contributions until July 4, 2024, the consultation seeks to adapt and harmonize sanitary regulations with the provisions introduced by Law No. 14,874/2024.

For more information on this topic, please contact Mattos Filho’s Life Sciences & Healthcare practice area.