Rubens Granja
Lefosse Advogados, São Paulo
rubens.granja@lefosse.com

Natássia Misae Ueno
Lefosse Advogados, São Paulo
natassia.ueno@lefosse.com

Brazil occupies a position of little prominence on the world stage^[1] when it comes to clinical trials. This remains true despite having characteristics that could turn the country into a world reference in clinical trials, such as keeping relevant demographic and economic indicators, and health regulations which are in line with the best international practices.

The non-realisation of this potential has been attributed to a supposed inadequacy of the current regulation for this field in the country: the current model has bottlenecks that make clinical trials highly expensive, pushing away potential stakeholders from conducting clinical studies in Brazil.

In order to change this scenario, the National Congress is in advanced discussions to approve the Bill of Law (PL) No. 7082/2017 establishing a new National System of Ethics in Research involving Human Beings that replaced the prior Senate Bill (PLS) No. 200/2015. The process of the Bill of Law has been prioritised by the National Congress, however the analysis is still pending.

Current regulatory context for clinical trials in Brazil

The Brazilian regulation on the clinical trials is based exclusively on infra-legal rules issued by the National Health Council (CNS) and the National Health Surveillance Agency (Anvisa). Respectively: Resolution CNS No. 251/1997, Resolution CNS No. 466/2012, Resolution RDC nº 9/2015 (drugs) and Resolution RDC No. 548/2021 (medical devices).

These rules define the rights of participants and the responsibilities of sponsors and researchers during and after the study. They also regulate the procedures for the necessary regulatory approvals, aligning the performance of clinical trials to the prior consent of these two different regulatory bodies, which are independent of each other.

The CEP/CONEP System, composed of the National Commission For Ethics in Research (CONEP) and Committees of Ethics in Research (CEPs), is linked to the CNS, and assesses the ethical aspects of the project to protect the rights, safety and wellbeing of future research participants:

a. The system is composed of (i) a network of CEPs which are local units organised by the institutions that carry out research on human beings and work on the regional ethical evaluation of clinical research protocols; and (ii) the CONEP, a federal collegiate that acts as a maximum instance of ethical evaluation, responsible for supervising research protocols that have been approved by institutional CEPs with regard the development of new drugs and medical devices.

b. Clinical research protocols involving certain specific topics, such as new or unregistered drugs and/or medical devices with a foreign sponsor without government co-participation are subject to double instances of analysis. That means that after evaluation by the CEP, they must be reassessed by CONEP.

Despite the efforts of Anvisa and the CNS to improve this model, criticisms persist regarding the way it works. This includes (i) the length of the processes for the necessary regulatory approvals, and (ii) the precariousness of the regulation on the provision of post-treatment study (since the current regulation generically determines that, in most cases, it is up to the sponsor to ensure that participants have free access, for an indefinite period, to the best effective prophylactic, diagnostic and therapeutic methods).

Anvisa assesses the technical aspects of the study and, if it is the case, authorises the import of the drug or health product that is the object of the clinical trial. The agency has established its own technical rules and requirements in specific standards for clinical trials with drugs,^[2] healthcare products^[3] and advanced therapy products:^[4]

a.      The approval takes place upon analysis of the dossier submitted by the company compiling the technical information of the product and the clinical trial. This data supports the registration or eventual post-registration amendments to the product.

b.     Anvisa has (i) 90 days to issue an opinion assessing dossiers involving drugs and health products in general; (ii) 180 days for dossiers of drugs in the case of biological products, or clinical development in the Phase I or II, or national development; and (iii) 30 to 180 days for dossiers involving advanced therapy products depending on the nature and complexity of the investigated product.

c.      In practice, those deadlines are not always strictly adhered to by Anvisa, since it may formulate requirements requesting the completion or clarification of the documentation as many times as it deems necessary. According to Resolution RDC No. 204/2005, these requirements generally need to be met within a non-extendable period of 120 days, and often interrupt the period for issuing a decision in the process.

d.     Anvisa also needs to previously approve substantial amendments on the clinical trial protocol (ie, any change in the protocol that interferes with the safety or physical or mental integrity of participants and/or alters its scientific value). There is no maximum period for the agency when addressing these amendments.

Changes proposed by Bill of Law No. 7082/2017 and perspectives

The changes proposed by the current wording of Bill of Law No. 7082/2017 reveal the legislator's will to effectively reduce the bureaucracy of the regulatory flow for clinical trials in Brazil and solve gaps in the current regulation. Among the main changes, the following topics stand out:

a.     Linking CONEP straight to the Ministry of Health: The understanding is that the Ministry of Health (MoH) would have greater technical competence, exemption and a more adequate structure than that of the CNS. It would also be capable of enabling the functioning of a more uniform and impartial ethical evaluation system.

b.     End of the double evaluation system for the special thematic areas in the ethical evaluation processes: The change would encompass a large part of the research started in Brazil and sponsored by foreign pharmaceutical companies without government co-sponsorship. Currently, the regulation subjects the approval of a research to successive analysis by CEP and CONEP. In this case, the CEPs would become mainly responsible for the ethical analysis of clinical study projects and CONEP would assume the position of appeal regarding the decisions made by the CEPs.

c.     Reduction and limitation of deadlines for evaluation by Anvisa: Anvisa would have a maximum of (i) 60 days to evaluate the dossier of the investigated drug in order to subsidise its registration; (ii) 30 days to evaluate clinical trial amendments and modifications; (iii) 30 days to evaluate the dossier of the investigated drug in the case of drugs of strategic interest to the Unified Health System (SUS) and relevant to a responding public health emergency; and (iv) five days to inspect and release imported products for research purposes. If Anvisa does not respond within the stipulated deadlines, clinical development may begin after the relevant ethical approvals have been received.

d.     Limitation of the number of amendments by Anvisa and reduction of time for their fulfillment: Anvisa would be able to require amendments just once during the process. The deadline for compliance by the company would be 30 days, extendable for an equal period upon justification.

e.     Regulation of post-study drug supply: The current wording of the Bill of Law No. 7082/2017 tightly regulates the post-study supply of drugs. The new regulatory configuration reinforces the need for continuity of treatment with the investigated drug. Proposing, however, that the post-study supply takes place over a defined period.

The main aspects of this new regulation encompass:

• The need for possible post-study provision for the participants would be justified to the CEP via the post-study access plan submitted before the start of the clinical trial. The responsibility for the supply will be with the sponsor.
• At the end of each individual’s participation, the researcher will assess the need for continuation of the experimental treatment with regard to the participant, considering the benefits and risks arising from the use of the drug, and aspects such as the severity of the disease, possible availability of therapeutic alternatives, better risk-benefit ratio than other available treatments, among other elements.
• The supply of the experimental drug would be interrupted if justified and approved by the CEP as long as (i) certain circumstances are confirmed (eg the participant's own decision, whether the disease has been cured, treatment proves to be ineffective, adverse reactions making its continuation unfeasible and difficulties in manufacturing the drug, in which case the sponsor will need to provide an equivalent alternative); or (ii) as soon as it is already available in the public health system; or (iii) up to five years after the product is marketed in the country.
• These same rules would apply to healthcare products and experimental advanced therapy products subject to clinical trials.

f.      Possible remuneration of the participant: This situation would be restricted to cases of healthy individuals in Phase I clinical trials when there is no direct therapeutic benefit to research participants, provided that certain requirements are observed (ie, that the participant enrolls in a specific national registry for this purpose and does not participate in another clinical research simultaneously).

g.     Express possibility of the legally incapable patient’s participation in clinical research: This would occur by means of the signature of a term of responsibility by the representative of the legally incapable person and the responsible researcher upon the notification of the Public Prosecutor's Office.

In view of the proposed changes, it is expected that the (probable) approval of Bill of Law No. 7082/2017 should resolve the main regulatory obstacles that currently prevent the full development of clinical trials in Brazil.

At least in theory, the proposed changes should speed up and provide greater predictability to the processes for obtaining regulatory approvals and eliminate the main uncertainties in the current regulatory framework. It is hoped that the new rules will promote the Brazilian regulatory scenario for clinical trials making it more receptive to potential interested parties.

However, this does not mean that the Bill of Law is immune from criticism. The current version of the Bill of Law has been criticised for expanding the original scope of the Bill of Law by research associations in the areas of Humanities and Social Sciences. They defend that the idea was initially to regulate only clinical research with humans, however the new version proposes to encompass all research with humans in all areas of knowledge, unless there is specific regulation to the contrary, imposing the same technical rules aimed at medical and pharmacological research on the human sciences.

These entities argue that research in the humanities and social sciences has its own practices and methods which are sometimes ‘incompatible’ with research in the areas of health, medicine and biomedicine. They argue that these areas can be made unfeasible if submitted to the same system designed for medical and pharmacological research.

In the same sense, CNS and several committees for ethics in research have also spoken out against the Bill of Law with regard to the CEP/CONEP System possibly being transferred to the competence of MoH. It is argued that joining the MoH could undermine CONEP's independence and neutrality and could favour political interests.

Regardless of these criticisms, which are relevant and should be considered by the Congress when debating the topic, the potential approval of Bill of Law No. 7082/2017 could bring several benefits. It could attract significant investments to the Brazilian national economy, increase scientific production, facilitate patient access to innovative technologies and strengthen SUS by training Brazilians professionals in healthcare practices and improving infrastructure at research centres.

Notes