SCA LRA Watchdog Update December 2023

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Co-Author:
Martin Hernán Bonamino, PhD
Instituto Nacional de Câncer
Brazil

Maroun Khoury, PhD
IMPACT, Center for Interventional Medicine for Precision and Advanced Cellular Therapy
Chile

Editor:
Fernando E. Figueroa, MD, FACP
Universidad de los Andes School of Medicine
Chile

Medical CARE and CAR-T in South and Central America (SCA)

The rapid advancement of genetic engineering in scientific, clinical, and commercial aspects has highlighted the need to bridge the widening gap that opens between basic research in advanced medical therapies (ATMPs) and clinical application on a global scale.

The emergence of gene-modified cell therapies for hematopoietic tumors known as chimeric antigen receptor (CAR-T cells), highlights this need. For example, with just 8 cell and gene therapies (CGT) approved at the global worldwide level, there is now a demand for more than 850 clinical studies for CART therapies in 25 countries mostly in North America (40%), China (49%) and Europe (9%). CART-cell therapy holds promise for those who have a good health plan and live in countries where the treatment is available. But the drive to heal previously untreatable diseases implies a moral duty for this life-saving treatment to be made available in the rest of the world, while lessening economic restrictions.

Regulatory landscape and approved CARs therapies in Brazil

Brazil, on the other hand, stands as a pioneer in the region regarding ATMPs regulation. Led by ANVISA, the Brazilian Health Regulatory Agency, Brazil has been working on establishing a regulatory framework for ATMPs. Given it is one of the latest advanced regulations set forth worldwide, -dating to 2018- and the fact it was built on a collaborative basis with a national network of scientists and clinical researchers, it seems reasonable to underscore its main components.

The process of establishing this successful ATMP framework in Brazil included steps such as:

Regulatory Authority Involvement:
The process usually begins with the Brazilian Health Regulatory Agency, ANVISA, taking a lead role. ANVISA is responsible for regulating and overseeing health-related matters in Brazil, including the approval and supervision of pharmaceutical products.
Drafting Regulations and Guidelines:
Regulatory authorities work on drafting specific regulations and guidelines that outline the requirements for the development, manufacturing, and marketing of ATMPs. This process involves considering scientific advancements, international standards, and the unique characteristics of ATMPs. At ANVISA, this process included the active participation of skilled scientists through the implementation of a technical chamber to help elaborating the framework.
Stakeholder Consultation:
During the development of the regulatory framework, regulatory authorities engaged in consultations with various stakeholders, including industry representatives, healthcare professionals, academics, and the public. This ensures that the regulations are comprehensive, well-informed, and address the needs of all relevant parties.
Public Consultation:
ANVISA conducted public consultations for the framework patches to gather input on proposed regulations. This allows for transparency and the inclusion of diverse perspectives in the regulatory decision-making process.
Legal Approval:
Once the regulatory framework is finalized, it undergoes legal review and approval. This may involve collaboration with other government bodies to ensure alignment with existing laws and regulations.
Publication and Implementation:
After approval, the final regulations are published, and the regulatory framework for ATMPs officially comes into effect. This includes the publication of guidelines, requirements, and any supporting documents that provide detailed information for stakeholders.
Training and Capacity Building:
ANVISA provided training sessions and capacity-building initiatives for industry professionals, researchers, and healthcare providers to ensure understanding and compliance with the new ATMP framework. It also engaged trained and skilled researchers and physicians in training ANVISA personnel to deal with specific challenges in ATMP evaluation.
Ongoing Monitoring and Updates:
The regulatory framework is a dynamic system that requires ongoing monitoring. Regulatory authorities in Brazil continue to evaluate the effectiveness of the regulations, monitor the safety and efficacy of ATMPs on the market, and make updates or revisions as needed.

It is important to note that the establishment of a regulatory framework is a complex process that involves collaboration among various stakeholders and careful consideration of scientific, ethical, and legal aspects and we can consider the Brazilian experience a successful journey. This effort in setting the ATMP framework turned Brazil into an attractive destination for testing new ATMP products. One specific aspect of the legislation, granting accelerated analysis if advanced phases clinical trials are conducted in the country provided a surplus attraction factor for products aiming to near future registration.

As a result of this efforts, as for November 2023, the following ATMPs products were registered for commercialization in Brazil.

Carvykti
Kymriah
Yescarta
Luxturna
Zolgensma

Complete list available at:
https://app.powerbi.com/view?r=eyJrIjoiZGRiYTU4ZTItMDY0Ny00M2E2LTlkYWEtNWE2NjU2MDRjOGNkIiwidCI6ImI2N2FmMjNmLWMzZjMtNGQzNS04MGM3LWI3MDg1ZjVlZGQ4MSJ9

Along with CAR and other ATMPs registered for commercialization, several clinical trials for industry-based CARs are underway in the country and two academic CAR-T initiatives are recruiting patients in clinical trials.

ANVISAs ATMP/CGT approach, if adapted to the reality of each country, could represent a formal path for establishment a regulatory framework to Central and South America. We can expect, as future developments, further regulatory convergence between ANVISA and other regulatory agencies. This might set the bar of ATMP regulations to an even higher level. Countries developing local early stages initiatives might struggle during the regulatory conversion process and this specific aspect of ATMP regulation must be carefully considered to protect and induce ATMP/CGT local development.

Strategy for accelerating Patient Access to Advanced Therapies and the implementation of CAR’s technology in Chile, Argentina, Peru, Ecuador and other SCA countries

Aside from Brazil, no other country in the SCA region has active ongoing clinical trials for CARs. This means that no therapy will be accessible for at least the next five years.

While Chile stands out in the region for the level of quantitative-qualitative research it conducts, CORFO the production development corporation operating under the wing of the ministry of Economy, and ANID the national research institute from the Ministry of Science and Technology have recognized this need, providing competitive funding for development and putting ATMPs-CGT-based consortiums with 10 years of funding in place such as Regenero (Chilean consortium for regenerative medicine) in 2013 and just recently the Center of Interventional medicine for precision ad cell therapy (IMPACT) in 2021.

However, after decades of successful work, the whole industry is confronted with an insurmountable barrier since the country lacks the minimum conceptual or operational regulatory framework. A recent study of this reality, which - with the exception of Brazil - extends to the Latin American level, concluded that it was imperative that regional regulations be adapted to the most advanced FDA/EMA/ICH formulations (terminology and definitions), through the implementation of frequent regulatory review, the establishment of a single approval route, and a series of processes in which the timely and continuous interaction of the agencies is criticized.

Chile, for example, has patchwork law that makes no mention of ATMPs. In 2015, the legislature in Chile passed the so called “Ricarte Soto” bill (No. 20.850), concerning the state subsidies for the treatment of rare or high-cost diseases. This noble bid was inexplicably tied to an entire new set of requirements for the approval of Clinical Trials, with an unworkable frame.

The Chilean Institute of Public Health (ISP) published a first and promising Technical Guide for Biological Therapies earlier this year, based on World Health Organization (WHO) principles. Of course, before it can be implemented, this plan must negotiate a difficult legal scenario.

As a result, therapies such as CARs face a long way to reach the patients, not just in Chile, but also in the whole continent.

The hurdles are of different nature including compliant manufacturing facilities, technical guidelines, clear and applicable regulation covering everything from quality control to clinical trials and marketing authorization. In this regard, Brazil might be an example to follow within the region.

Furthermore, emerging clinical and preclinical evidence is pointing at the potential application of CAR T cells beyond cancer, including heart failure, autoimmune diseases (Lupus), and persistent infections. Hence, reinforcing the expected cost-benefit and health impact of establishing new installations and facilities in the region.

What are the proposed strategies and initiatives for other countries within the region?

Reinforcing Public-private funding. As an example, in Chile ANID’s center of excellence awarding matching fund for 10 years. IMPACT is one of these centers, making its mission to make CGT therapy accessible to the Chilean population.
Round table with the regulators: a joint initiative is being proposed to support the development of a regulatory framework and a compliant pathway for providing access to CAR-T therapies for the SCA population.
To be part of a multicenter clinical trial.
Achieving agreements and resolutions to provide therapies to various healthcare institutions with capabilities to administer the treatment.
Achieving co-payment agreements initially with private insurances and then with public entities.
Public engagement and health gremials such as Pro Salud Chile advocating for innovation for the benefit of patients and people.