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Brazil is ranked as the seventh largest pharmaceutical market globally[1]. It boasts a vast and ethnically diverse population (exceeding 203 million inhabitants[2]), and it also showcases a robust infrastructure of highly qualified researchers and esteemed research institutions. These attributes, combined with a cost-competitive environment accentuated by the favorable exchange rate of the Brazilian currency, make Brazil a very fertile ground for the conduct of clinical research. However, despite these advantages, the country still struggles to establish itself as a global hub in this sector.

The December 2022 update of Interfarma's comprehensive study on clinical research in Brazil, co-authored with IQVIA, underscores this reality. The study reveals that Brazil occupies the 20th position among countries hosting the most clinical research, accounting for only 2% of such studies worldwide. The country has already been surpassed by nations with lower GDPs and little to no relevance in the pharmaceutical market, such as Egypt (ranked 14th with 3.4% of research) and Turkey (ranked 17th with 2.5% of research). Conversely, the study indicates that by effectively leveraging its potential, Brazil could ascend to the 10th position in the ranking (currently held by Italy), accounting for 4.5% of research[3].

Such a significant leap is projected to attract annual investments exceeding 3 billion BRL, with the potential for even greater economic ramifications estimated at 5 billion BRL. Increasing the number of clinical studies could also lead to the employment of over 48,000 professionals and the inclusion of more than 55,000 patients in cutting-edge therapeutic advancements[4]. This expanded access would provide these patients with an invaluable opportunity to receive the most advanced novel therapies available globally. Beyond these direct benefits, a more robust clinical research landscape in Brazil would foster an environment conducive to scientific advancement and development. Furthermore, it would solidify the standing of research institutions and incentivize the participation of professionals in a diverse array of international projects, facilitating the exchange of knowledge and expertise.

In response to the challenges hindering Brazil's ascension as a leader in clinical research, Law #14,874/2024 was enacted in 2024. This legislation stemmed from Bill #200, introduced in the Brazilian Senate in 2015 with the primary objective of establishing a comprehensive legal framework for human subject research.

Previously, this domain was governed solely by regulations issued by the Brazilian National Health Council (CNS) for ethical aspects and the Brazilian Food and Drug Agency (Anvisa), which is equivalent to the FDA in the United States. The shift to a legal framework represented a significant development, particularly by removing the CNS's exclusive authority over ethical parameters, which is the central focus of Law #14,874/2024. However, the effectiveness of this legislation hinges not merely on its hierarchical status, but rather on the substance of its provisions. This raises a critical question: does Law #14,874/2024 effectively address the core impediments identified by stakeholders seeking to conduct clinical trials in Brazil?

While a comprehensive analysis of the law falls beyond the purview of this article, we will delve into two key issues. The first concerns the bureaucratic hurdles and protracted approval times associated with research protocol applications (Part I). This, along with the legislative gap, constituted the primary obstacle identified during the proposal of Bill #200/2015[5]. The second issue pertains to the unreasonable requirement for sponsors to provide indefinite post-study access to the experimental product (Part II), which also garnered significant attention during the legislative process. Let us now examine the first issue in greater detail.

Bill #200/2015 justification stated that the ethical review process adopted in Brazil is “slow and bureaucratic,” noting that “according to industry experts, the average timeframe to approve clinical research in Brazil is one year, and can reach up to 15 months, while in most developed countries it varies from three to six months”[6].

The study conducted by Interfarma and IQVIA indicates that this timeframe has decreased since then, although it remains far from ideal. From 2020 to 2022, the average actual approval time was 215 days (approximately 7.2 months). This remains significantly longer than leading developed nations like the United States (ranked 2nd with an average of 32 days or approximately 1 month) and even some lower-ranked Latin American countries like Argentina (ranked 23rd with an average of 113 days or approximately 3.8 months)[7].

The primary inefficiency involved a duplicative analysis system. Research protocols related to specific thematic areas outlined in Item IX.4 of CNS Resolution #466/2012 previously required review by both the Research Ethics Committees (CEPs) affiliated with the research institution and the Brazilian National Research Ethics Commission (CONEP). Law #14,874/2024 eliminates this redundancy, delegating sole responsibility for such review to the CEPs (Articles 13 et seq).

The elimination of the dual review process will have a profound impact, given the breadth of research protocols encompassed by these thematic areas. Illustratively, the category of "research with coordination and/or sponsorship originating outside Brazil" alone constituted 93% of all protocols submitted in 2023[8]. Moreover, CNS Operational Norm #1/2013 imposed a 115-day (approximately 3.8 months) maximum timeframe for completing ethical review, of which 75 days (approximately 2.5 months) were allocated exclusively to CONEP analysis (Items 2.2, "D" and "E," and 2.3, "F" of Operational Norm #1/2013).

The requirement for multiple CEP reviews in multicenter trials has also been eliminated.  Henceforth, the CEP linked to the research coordinating center will ideally conduct this review (Article 14, Paragraph 7 of the Law). This represents a significant improvement, as the previous iterative process, necessitating the circulation of amended documentation among all CEPs (including those having already approved the research), often led to undue delays and inefficiencies.

Law #14,874/2024 established a more streamlined framework for ethical review timelines. The CEP will have 10 business days from the complete submission of the research protocol to determine its acceptability. Following this, the CEP will have 30 business days to issue an opinion. This period may be extended by a maximum of 20 business days to allow for requests for additional information or modifications (Article 14). While these deadlines are not entirely novel, previously they were calculated in calendar days, whereas Law #14,874/2024 mandates the use of business days, effectively lengthening the timeframes. However, the new law eliminates the former 30-day period granted to the CEP for re-analyzing protocol changes requested from the researcher (Item 2.2, "D" and "E" of Operational Norm #1/2013). This provision results in a reduction of the deadline in such specific scenarios.

In any case, these changes theoretically condense the maximum ethical review period from 115 days to 40 business days, representing a significant improvement.

Although not its primary focus, Law #14,874/2024 also established a maximum timeframe of 90 business days for the health analysis phase. If Anvisa fails to act within this timeframe, provided the research has already received ethical approval, it may proceed (Article 58). The inclusion of a health analysis timeframe originated during the processing of Bill #200/2015 in the House of Representatives, with the approval of the substitute proposal presented by then-Representative Hiran Gonçalves[9].

Law #14,874/2024 reflects a nuanced approach to health analysis deadlines compared to the initial proposal. Initially, it mirrored Article 36 of Anvisa's Board of Directors' Rule (RDC) #9/2015, establishing a general 90-day timeframe with exceptions. These exceptions allowed for a 180-day extension for research promoting "national development, clinical development of biological products (including vaccines) and clinical development in phase I or II clinical trials” (Paragraph 3 of RDC #9/2015). Furthermore, administrative inaction after this extended period constituted implicit approval. Following discussions on ideal deadlines, the House of Representatives adopted a revised text, maintaining the 90-day timeframe with a sole exception for "complex products" defined by regulation, with a maximum analysis period of 120 days[10]. However, when the bill returned to the Senate, the Committee on Constitution, Justice, and Citizenship specified that the 90-day period should be counted in business days and that there should be no exceptions to this deadline.

Eliminating exceptions were quite significant, as they effectively extended the maximum analysis period from 90 days to 180 days (6 months) for a substantial portion of research protocols. For instance, Anvisa's Coordination of Clinical Research with Drugs and Biological Products (COPEC)'s 2023 annual report reveals that 97 of 307 submitted protocols (approximately 31.6%) qualified for the "phase I or II clinical development" exception[11].

While legislators' intentions were undoubtedly positive, it remains questionable whether Anvisa can realistically adhere to the 90-day deadline mandated by Article 58 of Law #14,874/2024 for all protocol types. COPEC's aforementioned report indicates that in 2023 the average analysis time for non-prioritized and non-simplified petitions was a staggering 233 days (approximately 7.8 months) – significantly exceeding the legislated deadlines of 90 or even 180 days. Unsurprisingly, 94 out of 299 petitions concluded that year were released due to deadline expiration (31%)[12].

The agency's capacity to meet these stringent deadlines is further compromised by a significant workforce reduction in recent years. Anvisa currently operates with a limited staff of approximately 1,600 employees[13], with only 18 of them dedicated to the COPEC[14]. Indeed, prior to the enactment of Law #14,874/2024, Anvisa expressed concerns regarding the imposition of a singular 90-day deadline during an online seminar dedicated to reviewing the draft of RDC #9/2015[15].

While establishing consequences for administrative delays may appear to incentivize efficiency, it could inadvertently create more substantial challenges. Being able to start the clinical research without having to wait forever for Anvisa’s approval is, of course, better than having to wait. Nevertheless, it may engender a cascade of unforeseen complications. For instance, what will happen to studies that were started based on Anvisa’s omission to review the protocol once the Agency decide on the protocol? Will they be interrupted if additions to the protocol are considered necessary by the Agency? Will Anvisa not accept data generated from these studies because they were not conducted as the Agency deemed appropriate, despite not having raised any concern due to its omission? Such uncertainties pose significant risks to sponsor investments.

The question remains, though, if the new legal framework for ethical review, without inspection mechanisms or consequences for CEP’s non-compliance with the deadlines, will be enough.

While the new legal framework offers promising advancements, it is evident that it alone cannot fully address the existing challenges. Adherence to the newly established deadlines by both CEPs and Anvisa is imperative. Consequently, industry stakeholders must maintain vigilance and actively engage with the Executive Branch to advocate for robust regulations in this and other critical areas unaddressed by Law #14,874/2024.

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