The Rise of Brazil and Expanded Access Programs: A strategic opportunity?
Brazil’s pharmaceutical market is flourishing, and it is easy to see why. It has a large and growing population (>200 million), a rising middle-class, an aging society, and a government commitment to increased investment in healthcare (Figure 1)1-3. On paper, Brazil represents an exciting opportunity for pharmaceutical companies. That said, the complex and time-consuming approval and non-transparent reimbursement process in Brazil can be a significant hurdle and off-putting to many.
By Charlotte Marsh, Senior Writer - Value Communications
Figure 1. Factors as to why Brazil is an attractive, emerging market1-3
However, the legal provision allowing patients to access unlicensed medicines under clinical research4 opens a unique pathway for pharmaceutical companies. By leveraging Early Access Programs, pharmaceutical companies could not only penetrate the market early but also gather valuable real-world evidence to support future regulatory/ reimbursement submissions. For companies willing to navigate its intricacies, Brazil’s pharmaceutical landscape offers substantial potential. Here, we will delve into the use of Expanded Access Programs (EAPs) in Brazil and explore some of the challenges that pharmaceutical companies may need to consider.
Introduction to Early Access Programs in Brazil
Early Access Programs are ethical, controlled mechanisms that allow patients with serious or life-threatening conditions to access investigational drugs outside of the clinical trial space and before the product’s commercial launch5,6. In addition to their patient-centric approach, they allow companies to generate additional real-world evidence, which can help them gain greater insights into the safety and efficacy of their products and allow for early market penetration. Moreover, Early Access Programs increase the awareness of new treatments among patients and physicians and enable cross-functional team alignment within pharmaceutical companies in preparation for market launch.5
Figure 2. Types of Early Access Programs used in Brazil.
In Brazil, three types of Early Access Programs are available: Expanded Access, Compassionate Use, and Post-study Drug Supply7 (Figure 2). Expanded Access schemes provide access to patients with serious and/or life-threatening diseases to new and promising drugs that are not registered with the Brazilian Health Regulatory Agency (ANVISA) or commercially available in Brazil and are still undergoing Phase III clinical studies7,8. Compassionate Use Programs are increasing in popularity for patients with serious and/or life-threatening diseases with no satisfactory alternative treatment. These programs also enable patient access to investigational drugs outside of a clinical trial or pre-approval but are intended for specific individuals and are non- transferable7,8. Post-study Drug Supply programs allow patients within a terminated clinical study to continue to receive free access to the investigational drug7,8. EAPs are increasingly popular9, with the level of published scientific research on such programs increasing globally over recent years5. Five publications on Brazilian EAPs since 2014 have been identified10-14 across a range of therapeutic areas including ustekinumab for Crohn’s disease11, erdafitinib for metastatic urothelial carcinoma12, caplacizumab for acquired thrombotic thrombocytopenic purpura13, and nintedanib for idiopathic pulmonary fibrosis14. Interestingly, no information on previous or ongoing EAPs were identified on Government websites. A 2019 publication stated there were no accessible databases that characterize the benefit of Expanded Access and Compassionate Use of experimental drugs across South American countries15. This demonstrates that there is currently a lack of transparency surrounding EAPs in Brazil despite their use across therapeutic areas.
Routes to Early Access in Brazil
In 2013, the Brazilian government published Resolution RDC 38/2013 detailing regulations for Expanded Access, Compassionate Use, and Post-study Medication Supply Programs7. These programs are governed by a regulatory framework that involves key players such as the Ministry of Health, National Health Surveillance Agency (ANVISA), and General Management of Drugs and Biologic Products (GGMED)1,8,16.
Figure 3 outlines the steps to obtaining permissions for an Early Access Program in Brazil. Briefly, a request should be made to ANIVISA which should include a dossier with key documentation completed by the sponsor. The documentation required varies by Early Access Program (Figure 4). Within the submission, the sponsor must guarantee the supply of medicine authorised in the EAP and that it will not delay the execution of any ongoing clinical trials. The sponsor must present existing Phase 3 Randomised Controlled Trial (RCT) efficacy and safety data for the same clinical indication intended and stipulate any safety data collected should not replace clinical trial data for registration purposes7,8. Additional sponsor responsibilities include providing the drug free of charge and monitoring the product delivery8.
ANVISA reviews the technical information within the application and makes a decision on whether to approve or reject the request8. ANVISA considers the dossier contents against the severity and stage of disease; absence of a satisfactory therapeutic alternative; severity of clinical condition and presence of comorbidities, and the assessment of the risk-benefit relationship using the requested medication7,8.
A decision from ANVISA should be returned within 45 calendar days and the application for EAPs is exempt from fees. If the documentation meets the requirements of RDC 38/2013, ANVISA issues a special notice (Expanded Access or Compassionate Use) or letter (Post-study Drug Supply). If the documentation does not meet the requirements of RDC 38/2013, ANVISA sends a deficiency letter which should be responded to within 120 days8. An Import Licence must be obtained by the sponsor, in accordance with Resolution RDC 39/20088.
If the Early Access Program is approved, the sponsor is responsible for monitoring the patients, collecting data, and reporting any adverse events to ANVISA within 15 calendar days. The sponsor must also submit an annual report to ANVISA8.
General conditions described within the identified EAP publications include the need for a patient to meet a specific eligibility criterion for inclusion including that the patient has a specified condition for which there is no approved treatment or where previous treatment has failed. Further, patients must provide informed consent and the treatments being made available through the EAP must not be approved for general use in Brazil. Monitoring and follow-up processes to assess the effectiveness, safety and tolerability of products in addition treatment response were described. However, there was variation in the treatment response rates and EAP timelines described11,13,14.
Key Challenges for EAPs
EAPs offer clear benefits, but they also pose some challenges and limitations. Pharma companies must plan and manage their EAPs well, taking into account the clinical, ethical, and regulatory aspects.
One challenge in Brazil is the limited or no revenue collection from the EAPs, as pharmaceutical companies are expected to provide the product free of charge until a final decision about reimbursement is made. Costs relating to any adverse events must also be covered7. This can be a significant cost for the manufacturers, especially if the product is expensive to produce17,18. Alternative funding sources could be explored such as grants; sponsors can also ask participants to foot the costs personally or through private healthcare although this is uncommon18.
Another challenge is the increased risk for adverse events or lack of clinical response among the patients in EAPs. Patients who participate are likely to be sicker than the average population, as they have no other therapeutic options available. They may also have different characteristics or comorbidities to the clinical trial population that could affect the safety and efficacy of the product9. ANVISA require pharmaceutical companies to conduct thorough safety monitoring within EAPs and provide a yearly report8. Implementation of a rigorous monitoring and reporting system within an EAP would support the ANVISA requirement. Further, educating patients so that they are aware of the potential benefits and risks of a product may be beneficial.
A third challenge is the conflict with ongoing clinical trials. Enrolment in an EAP cannot compete with enrolment into ongoing clinical trials, as this could compromise the validity and integrity of the trial results18. Therefore, open communication between ongoing EAPs and clinical trials would be advantageous alongside a clear trial eligibility criterion.
A fourth challenge is the planning timeframes for EAP. If the program begins too early, there may not be enough supplies of the drug to meet the needs of both the program and any ongoing clinical trials. If the program is started too late, too few patients may be served to justify the effort and resources invested in the program19,20. A feasibility assessment and demand forecast may be beneficial to estimate the optimal timing and supply mechanisms for an EAP.
Brazil’s regulatory processes, healthcare structure, and geography also pose challenges. As previously mentioned, Brazil’s regulations are complex and hard for pharma companies to navigate without a local presence. The limited availability of open access, relevant information in English can make it increasingly difficult for companies to participate in EAP. The healthcare system is decentralized and coordinated at a state or municipal level. This can create difficulties in implementing large programs, such as EAPs, across the country. The system also causes regional gaps in funding and access to care. Poorer and lower-class patients face more difficulties in accessing care. Moreover, Brazil’s huge size creates geographic barriers to access. Most of the healthcare facilities and resources are in urban areas, leaving rural or remote areas with limited services including EAPs1,21, 22. To overcome challenges relating to Brazil’s regulatory processes, healthcare structure and geography, collaboration with local experts or consultants in the disease area who have experience and knowledge may be advantageous.
Key Benefits for EAPs
Pharmaceutical companies may have concerns about investing in EAPs in Brazil due to non-transparent pricing and reimbursement policies. This is not unique to EAPs and is experienced by all wishing to seek access to the strict price-controlled Brazilian market. When deciding whether to include a product within the public healthcare system, the National Committee for Technology Incorporation (CONITEC) assesses factors such as scientific evidence, budget impact, and recommendations from specialist groups and professionals23. As discussed previously, the benefits of EAPs include increased brand awareness and additional real-world efficacy and safety data. Consequently, these may help strengthen the product’s likelihood for a positive recommendation from CONITEC and thus reimbursement.
Similarly, for the private healthcare sector, once a drug has received authorization from ANVISA, it may be included in National Supplementary Health Agency’s List of Procedures, which is updated every two years24. Brand awareness and additional clinical data may help influence a product’s inclusion on this list and subsequent access for up to 50 million people in Brazil with private healthcare insurance23.
Table 1. Summary of potential challenges and opportunities
Brazil is an attractive, emerging market and EAPs are a way of providing new treatments to patients with life-threatening conditions. That said, there are some clear challenges. By successfully navigating these challenges, pharmaceutical companies can secure early market penetration for their products, which can support product registration, commercial launch, and reimbursement discussions later. Given this, pharmaceutical companies should consider the role of EAP in their future strategic plans for Brazil and other emerging markets.
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