Around the Globe

Reliance, Convergence, eLabeling, ATMPs, and Master Protocols: Innovations for Patients in Latin America
Voices from the Latin America Regulatory Conference

urrent global regulatory trends and challenges, how they fit into the regulatory environment of Latin America and the Caribbean, and opportunities for action in the region remain “hot topics” in support of improved regulatory efficiencies in this region. Alongside adoption of reliance approaches, proper product lifecycle management, and identification of regulatory requirements that are convergent with international guidelines and standards, there is an ongoing focus on the key role electronic labelling (eLabeling) plays for improved patient safety in the region, as well as on innovative ways for industry and regulators to respond to new demands and new technologies in the areas of manufacturing and clinical trials.

Regulatory Reliance to the Rescue

The role of good reliance practices in regulatory decision-making is becoming more prominent, along with other tools for strengthening regulatory systems that increase the efficiency of regulators, producing better public health outcomes.

According to the World Health Organization (WHO), almost no single regulator can fulfil all regulatory responsibilities alone and independently; the future of medical product regulation is in collaboration and networking based on reliance and trust, with regulators starting to operate more as a functional network rather than as individual players, and individual players focusing on where they can add the best value.

A Center for Innovation in Regulatory Science (CIRS) project systematically reviewed twenty jurisdictions in Latin America and the Caribbean to identify the characteristics of regulators relating to their use of reliance pathways. This study allowed for identification of barriers to, and enablers of, reliance in the region.

The pharmaceutical and medical devices industry in the region believes that, when optimally implemented, reliance mechanisms enable regulatory capacity building, strengthen regulatory systems, improve public safety, and ensure sustainable access to innovative medical treatments. There is a growing understanding that, as an approach that supports the best use of available resources and expertise, reliance plays an important role in facilitating timely access to safe, effective, and quality-assured medicines and medical devices, as well as in helping regulatory preparedness and response, particularly in the context of public health emergencies.

Lifecycle Management

Globalization of the supply chain and medicinal product markets has resulted in a growing number of different procedures, rules, and regulations that Market Authorization Holders (MAH) must follow when Chemistry, Manufacturing and Controls (CMC) changes are introduced, because they are so critical to products’ lifecycle.

A globally harmonized approach regarding technical and regulatory considerations for lifecycle management will benefit patients, industry, and regulatory authorities by promoting innovation and continual improvement in the pharmaceutical sector, strengthening quality assurance, and supporting an adequate medicines supply. COVID-19 has also highlighted the need to implement CMC changes in an efficient, agile, and flexible way to make products readily accessible.

The increasing complexity of lifecycle management (LCM) must be matched by regulatory solutions that ensure timely product supply to patients. The Brazilian regulator ANVISA has refined its post-approval changes (PAC) procedures, including measures adopted during the pandemic, to accelerate their review. Other ANVISA tools include reliance, harmonization, and science-based risk management approaches (e.g., reducing prior approval for non-critical changes).

The concept of Post-Approval Changes Management Protocols (PACMP) in line with ICH Q12 and WHO Guidelines is a feasible solution to facilitate LCM, such as a solution sponsored by Heads of Quality of major pharmaceutical companies that allows the management of PAC in the Pharmaceutical Quality System (PQS) aligned with ICH Q10 guidelines.

Evolution in Manufacturing and Advanced Therapies

Industry has accumulated significant experience and learned many lessons in advancing vaccine manufacturing, especially from a quality perspective, including alliances with other companies, quality agreements, and supplier qualification.

For example, the mRNA-based comirnaty vaccine provides a new platform for vaccine manufacturing. To ensure timely completion of this highly complex, accelerated, and critical project, the clinical study phases were conducted in parallel and used an existing platform for the plasmid manufacturing, allowing for expedited synthesis of the drug substance. Single-use technology (used as an alternative to reusable equipment in manufacturing sterile products) scaled up the process and allowed for quick market deployment. Testing and process validation demanded acceleration to expedite the release of the product. Strong partnership and real time cross-institutional collaboration were paramount to ensure success of this project.

ANVISA’s regulatory model for ATMPs (Advanced Therapies Medical Products, or ATMPs, considered special medicines in Brazil) includes risk/benefit regulatory assessments. Specific Good Manufacturing Practices (GMP) requirements for ATMPs are still under discussion in ANVISA, since their current requirements are based on the Pharmaceutical Inspection Co-operation Scheme (PIC/S), and include variability in the starting materials, traceability, characterization assays, out-of-specification products, and transport logistics, among other topics. Several clinical trials applications for ATMPs in Brazil have already been approved or are currently in Agency review, and ANVISA approved two gene therapy products in 2020.

Quality considerations for ATMPs indicate that these products are generally not well characterized due to small batch sizes and hard-to-define Critical Quality Attributes (CQAs, such as dose, strength, purity, and impurities). In addition, their shelf life is generally short when compared to traditional pharmaceutical products and the analytical methods used for typical biologics might not be appropriate for ATMPs. The nature of ATMPs requires changes in mindsets and approaches driven by flexible and innovative regulatory processes and oversight, regulatory convergence, and use of reliance procedures to increase efficiencies and improve regulatory capacities spanning the entire product lifecycle (regulatory review, inspections, and post-approval changes). Regulators could refrain from requiring in-country testing and recognize Certificates of Analyses from countries with mature National Regulatory Authorities (NRAs) is one practical suggestion.

Proper Regulatory Pathways and Endpoints for Immuno-Oncology Drugs

Primary endpoint criteria for clinical studies of immuno-oncology (IO) drugs rely on the most widely used evaluation criteria to demonstrate clinical benefit and request regulatory approval by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). The important goal of this work is to find solutions that advance patients’ access to treatments to improve and/or prolong their lives. In Latin America alone, 1.3 million new cancer cases are diagnosed annually and more than half a million people die from the disease.

It is important to interpret endpoints in the neoadjuvant and adjuvant settings in the context of surrogate efficacy endpoints when used for registration purposes. Both FDA and EMA have accepted surrogate and intermediate endpoints in neoadjuvant and adjuvant settings to support regulatory approval of oncology drugs. It is challenging to find early signals of activity using currently accepted endpoints, such as Event Free Survival/Progression Free Survival (EFS/PFS) and overall survival (OS) in clinical trials. New endpoints that allow the assessment of efficacy at an earlier point in time would be valuable because they could potentially bring novel and improved therapies earlier to the market for to benefit patients. FDA, EMA, and other health authorities have been open to establishing new, earlier endpoints for regulatory decision-making. Defining a study design that addresses different disease stages is critical in this new oncology era and it is important to embrace these approaches.

Is eLabeling in Latin America a Viable Concept?

eLabeling has potential benefits for different stakeholders (patients, industry, regulators, and healthcare professionals). Due to the global need for a unified and consistent vocabulary for stakeholder discussions (and growing understanding of digital health), regulators around the world are implementing eLabeling and it may possibly come soon to Latin America. Experiences in Europe illustrate how open dialogue with all stakeholders are shaping policy and driving reflections on how to move forward globally while stressing that (new) regulations cannot become outdated as technology continues to evolve.

One option to be explored by regulators is allowing pilot projects that use global electronic standards and technologies to facilitate learning, which can lead to eLabels being accepted as the authoritative source of approved information and in the future allow for possibility eliminating the requirement for paper labeling.

ANVISA has considered possible pilot projects to demonstrate the practical considerations, and benefits to patients in Brazil and the surrounding region, of implementing eLabeling. These include a risk-based approach to a gradual implementation which considers different product types, different continent sizes, different local realities, limitations in internet access, and other risk factors; and different approaches for different types of products (e.g., medicines for hospital-only use, vaccines, or prescription drugs).

Innovative Clinical Trial Designs Accelerate Medical Innovation for Patients

The value of master protocols has become understood and accepted through the world’s unprecedented multi-stakeholder response to the COVID-19 pandemic, which has seen therapeutics and vaccines developed in record time. This has been possible largely through to use of innovative clinical study designs such as master protocols, which use a single infrastructure, trial design, and protocol to simultaneously evaluate multiple drugs and/or disease populations in multiple sub-studies (and may contain elements of adaptive design).

Innovative clinical trial designs in combination with alternative data sources such as the use of real-world scenarios outside of traditional research sites (e.g., data collected through digital technologies and in clinic/hospital settings), are contributing to evolving regulatory frameworks and accelerating patient access to new medicines in Latin America.

Several regulatory authorities such as the FDA, ANVISA (Brazil), and ANMAT (Argentina) have established regulatory frameworks for these innovative clinical trial designs (including basket, umbrella, and platform trials) and already identified opportunities and challenges to standardizing and harmonizing their processes to optimize their own resources. For sponsors, pre-submission meetings, well-detailed protocols, and prospectively planned modifications become critically important parts of the regulatory submission process.

Regulatory Convergence in a Pandemic

There have been many global “lessons learned” during the COVID-19 pandemic and many examples of good regulatory practices that make efficient use of resources and foster timely access to quality, safe, and efficacious medical treatments. These lessons learned include best practices for leveraging the work of trusted regulators by applying reliance practices; developing innovative pathways, such as for emergency use; using real-world evidence to expedite access and monitor product performance; and for regulatory convergence through adopting internationally accepted standards to ensure consistent and predictable product characteristics and requirements.

Challenges have been experienced in research and development, clinical trials, supply chain, human factors studies, stockpiling, and the lack of digital processes to submit, review and approve regulatory submissions and product modifications. Rerouting medicines high- to low-supply areas has also been discussed but presents further complications from customs/import challenges and non-language appropriate labeling.

While unprecedented regulatory challenges emerged from COVID-19, those challenges were met with extraordinary efforts and highlight the opportunity for industry and regulators to build smarter regulation that ensures improved and timely access to medical treatments even during a future pandemic.

Members of the DIA Latin America Regulatory Conference 2021 Program Committee who prepared this article: Ana Padua, EMD Serono; Cammilla Gomes, Roche; Carlos Pinoargote, BRCR Global; Leonardo Semprun, MSD; Maria Cristina Mota Pina, Abbvie; Maria Guazzaroni Jacobs, Pfizer; Renata de Lima Soares, ANVISA; Roberta Mele Mazza, Roche; and Sonia Viejobueno, Janssen.

The authors recognize the support from Viktoria Magyar, University of Southern California, and from the conference speakers in the preparation of this article.

Disclaimer: The opinions expressed in the paper are solely the authors’ and do not necessarily represent the views of their organizations.