Gene therapies in Chile or the ‘torment of Tantalus’ between regulation and innovation

Andrea Abascal Marín
Bofill Mir, Santiago
aabascal@bofillmir.cl

Andrés Sepúlveda Matteo
Bofill Mir, Santiago
asepulveda@bofillmir.cl

Introduction

It is no surprise that technological progress and the increasing momentum of research and development, alongside the rise of artificial intelligence, represent one of the greatest challenges facing the pharmaceutical sector, particularly in relation to available therapies and the registration of medicinal products.

As science progresses, developing countries such as Chile are making efforts to remain at the forefront of regulatory standards. However, this progress is often too rapid, and just as it seems that an objective has been achieved, a new technological breakthrough generates yet another regulatory gap in the country.

On the other hand, the Chilean authorities, specifically the Public Health Institute (Instituto de Salud Pública or ISP), frequently look to high-surveillance agencies to determine what and how to regulate. Yet these agencies, much like local authorities, often face the same challenge in terms of keeping their regulatory frameworks in step with scientific advancements.

In this context, gene therapies have entered the innovation landscape, not only as scientific and medical breakthroughs, but also as substantial regulatory challenges.

Gene therapies in Chile in the face of legal uncertainty

So-called advanced therapies do not yet have a specific regulatory framework in Chile. Consequently, in order to determine the applicable regime and the appropriate pathway for assessing potential product registrations in this category, local authorities and registrants are forced to assemble a regulatory puzzle to determine the applicable registration route. In addition to the regulations governing the registration of biological medicinal products,  which is the category attributed to gene therapies in Chile, it must also be assessed whether the product qualifies as an orphan drug, is focused on cancer treatment or is part of a clinical trial, among other factors, to determine the correct regulatory approach.

Despite the absence of a specific regulatory framework that governs and promotes the registration of gene therapies in Chile, at present at least one clinical trial is underway in this field (a Phase III clinical trial of abcb5+ mesenchymal stromal cells (MSC abcb5+) for epidermolysis bullosa (EB), initiated in September 2023) and at least one gene therapy product has been registered (Zolgensma, ISP Marketing Authorisation No. B-2945/22, for the treatment of spinal muscular atrophy, which in Chile is not registered as a gene therapy as such).

In addition, the Chilean authorities have carried out inspections of facilities participating or seeking to participate in research on advanced therapies. These inspections have revealed that such facilities do not meet the standards of good manufacturing practices (GMPs) or good clinical practices (GCPs), which, in the ISP’s view, are essential for the development of gene therapies, particularly when potential medicinal product manufacturing is involved.

Currently, only one facility in Chile has been explicitly authorised by the ISP as a clinical laboratory for the development and research of advanced therapies. However, it is not authorised to develop advanced therapies itself. Furthermore, a total of 17 gene therapy research projects have been funded by the Chilean state between 2021 and 2023.

This demonstrates the drive for innovation in Chile on these matters and that research is ongoing despite the insufficient regulatory framework.

Between the search for regulatory benchmarks in gene therapy and the loss of opportunities for innovation

It is also worth noting that a debate on distinguishing conventional biological pharmaceuticals from those derived from advanced therapies, such as gene therapy, is currently underway. The ISP has begun work on a draft regulation concerning good manufacturing practices for advanced therapy products, following the guidance issued by high-surveillance agencies, particularly in regard to the Pharmaceutical Inspection Co-operation Scheme (PIC/S) developed in South Korea and Brazil’s Health Regulatory Agency (Agência Nacional de Vigilância Sanitária or ANVISA), which issued a similar document at the end of 2023.

Both the health authority and industry stakeholders agree on the need to establish a specific institutional framework for advanced and gene therapies, encompassing both a dedicated organisational structure and a specific legal framework. Without such a framework, there is a tangible risk that the final stages of domestic research in this field will have to be completed abroad.

This is exactly what occurred in 2020, in Chile, when the Millennium Institute of Biomedical Neuroscience (BNI), which is part of the University of Chile’s Faculty of Medicine, licensed the results of its gene therapy research for Parkinson’s disease, Alzheimer’s disease and amyotrophic lateral sclerosis (ALS) to the Belgian company, Handl Therapeutics. This led to the creation of two therapies (Proteostaser-1 and Uprplus) whose clinical phases are now being conducted abroad.

Although it was technically possible to continue the clinical phase in Chile at the time, one must ask whether the decision to licence the research was driven by the lack of clear regulation or by a lack of incentives to complete the research process in Chile.

Forward-looking regulation: a necessity to overcome the ‘torment of Tantalus’ in gene and advanced therapies

While high-cost diseases are both a current and growing concern, driven in part by better diagnostic capabilities, and while many of these diseases lack economic coverage in Chile, leading to litigation and increased public expenditure, the question arises: Will regulation alone suffice to create optimal conditions for access to these products?

Or are we facing an unavoidable crossroads, wherein, despite joint efforts, gene therapies and personalised medicine will not be prioritised by the state for patient access?

The ISP has hinted at the direction it intends to pursue as a regulatory authority in the field of gene therapy. Among the potential benefits of regulation, cancer has emerged as a particularly promising area for these therapies. With respect to regulatory mechanisms, particular emphasis has been placed on comparable international experiences with conditional approvals, a mechanism promoted by high-surveillance agencies. The US FDA has issued guidance on the application of this mechanism to advanced therapies, including the use of surrogate endpoints in clinical trials. Likewise, the European Medicine Agency’s accelerated and rolling review processes have been cited by the Chilean authorities as highly useful models.

To overcome the ‘torment of Tantalus’ in this area, an honest dialogue between industry, researchers and the state is required, one that considers how to ensure that gene therapy products are researched and registered in Chile, while also made accessible to patients.

It would seem that we will continue to fall short of these objectives unless a strong public–private partnership emerges to confront this reality.