Academic development of advanced therapies—How to foster their future in the clinic

Abstract

Academia is key for early development of ATMPs, but the alignment with regulatory requirements is limited and needs to be nurtured in the right direction.

Gene and cell therapies, categorized as advanced therapy medicinal products or ATMPs in Europe,¹ are increasingly arriving to the clinic, with more than 1000 ongoing clinical trials with gene therapies in 2023 and industry predicting that 2024 would be ‘breakout year’ for gene therapies approvals.² That number could rightly give the impression that cell and gene therapies are taking their long announced place in the therapeutic arsenal, but the transition into clinical use has been substantially slower than predicted.

For the past decade, both the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) have expected applicants for around 10 to 20 new ATMPs to knock on their doors each year to seek marketing authorization.^{2, 3} The reality has been more modest. Although around 30 ATMPs are currently approved for use in patients on either side of the Atlantic,^{4, 5} (taking into account that the definitions do not match exactly and many products are common to the EMA and the FDA), the complexity of these therapies has meant that delays and postponements are very frequent. And achieving marketing authorization is only the first step. Once authorized, ATMPs face further challenges in reaching patients,⁶ which leads to claims that the current process from laboratory to clinic is inefficient.⁷

Considering the costs and uncertainties of new medicines' development, the machine works very well for small (synthetic) molecules and for most biologicals, including those considered complex in the past, like monoclonal antibodies.⁸ And although biologicals and biosimilars are, in general, substantially more expensive than many small molecules,⁹ they are still widely used in the Global North and account for a large part of the expenditures in medicines in Europe and the United States.⁸

Clinical use of advanced therapies shows a different trend. Although the step up in complexity and novelty of cell and gene therapies is well acknowledged,¹⁰ a clear additional factor determining their translation from the laboratory to the clinic is the entity doing the initial development and its familiarity with the pharmaceutical regulatory system as the established path to the market and the clinic.¹¹

The large majority of medicines reach the market via commercial entities. For decades, pharmaceutical companies big and small have effectively brought medicines to the market and, ultimately, the clinic. In recent years, although partnership opportunities for academia have increased to leverage academic discoveries,¹² both early and late development of most medicines are still driven by commercial actors. Indeed, of the 27 ATMPs that have so far been authorized in the EU, the marketing authorization holders of all but one (for Strimvelis) are commercial companies.⁴

In contrast, the basis for the knowledge, techniques, process and protocols for early-stage development of these therapies lies and will continue to lie, in the academic environment. Universities, clinics, clinical research centres, hospitals and other research institutions, very frequently organizations where research and clinical delivery coexist in the same location, are the originators and early developers of medicines, devices, delivery methods and other elements of the advanced medicines ecosystem.^{13, 14} It has been suggested that at least 25% of currently approved ATMPs in the EU clearly originated in an academic environment,¹¹ but this percentage is probably much higher if we also consider the very early development of these medicines.^{13, 14}

This acknowledged fact places the early stages, and prime drivers of ATMP development, in the hands of a group of professionals who are traditionally involved in the development, but not the marketing, of medicines. The majority of these academics historically have had little need to interact with regulators, and, as a result, they generally have little interest in or knowledge of regulatory science and practices. This is reflected in observations of low regulatory knowledge in academia, including centres that are actively developing ATMPs.^{11, 15}

And yet, the regulatory path is the necessary gatekeeper to market and patients, and the substantial risk and uncertainty that come with these advanced therapies make the public health regulatory imperative even more relevant. Drawing a parallel with the field of transplantations, which in the EU are not considered a medicine, is not helpful, as both the science and the consequences for public health of these treatments are generally not comparable. Furthermore, the fact that the classification of some new therapies can be on the borderline between transplant and medicine is another challenge, and it remains to be seen whether this may be addressed in the future, as legislators in Europe are currently revising the blood and tissues and the pharma legislation in two separate processes.^16-18

The regulatory system has been in place for decades and works extremely well for small molecules and biologicals. Nonetheless, for advanced therapies, there are good reasons to review current practices.

The first reason is to increase the volume of therapies that could be brought from academia, via a commercial entity, to the market. Changes in the system could allow pharmaceutical and biotechnological developers to build on developmental programmes that are aligned with clinical needs and supported by evidence that meets regulatory standards from the beginning. Even with the large uncertainty and the attrition rate inherent to ATMP development, a larger pool would increase the numbers of medicines getting to the finish line and the speed with which they get there. Further alignment with payers' requirements and patients' expectations will help them to reach and stay on the market after they have received marketing authorization.⁴

The second reason deals with the non-profitability of some therapies. Market forces alone would not take to market therapies that nonetheless will address existing patients' needs, will create learning space and experience and will evolve knowledge that can later be applied in more common and therefore profitable, disease areas.

An important aspect underlying this problem is the difference in incentives between parties. Unlike for-profit medicine development that by and large drives the pharmaceutical industry, academic research focuses on publications and grants as measures of success, and those in turn determine further funding and the sustainability of the research group. However, patents are increasingly becoming a mark of success, with universities increasingly becoming aware of the importance of protecting their intellectual property. In addition, funders, especially those providing public funds, and non-profit organizations are increasingly pushing for more connections between research and clinical outcomes.^19-21

Such translational initiatives focus on the premise that investigational medicines should reach the patients who need these therapies. In practice, this is not only difficult to achieve but also difficult to measure. Although the ultimate goal of translation, a medicine in clinical use, is easy to assess, the steps that point to progress along the way can be difficult to define, encourage and nurture, and this applies to the whole ecosystem (medicines, but also biomarkers, medical devices, delivery methods, companion diagnostics, etc.).

When looking for solutions to improve the status quo, two elements play key roles: the need to produce evidence from early development that is suitable for regulatory decision-making on marketing authorization from early development and the possibility for patients to access the medicine once such authorization is granted.

Regulatory requirements for the authorization of a medicine are well beyond those required to publish a research article in a peer-reviewed scientific journal. A marketing authorization application consists of thousands of pages and contains large amounts of pharmaceutical, preclinical and clinical data. All data are reviewed in detail over a period of months or years by multidisciplinary teams of specialists (experts in pharmaceutical manufacturing quality, non-clinical and clinical studies, statisticians, toxicologists, pharmacovigilance and epidemiology experts and more) and evidence needs to show both the consistency and reproducibility of product quality and an overall positive benefit–risk balance.²² Research shows that most academics involved in basic research in medicines development are only superficially aware of these requirements,²³ and, more worrying, that some consider them unnecessary, expensive and damaging to their research.¹¹

Guidance for developers is available from regulatory agencies.^{24, 25} However, these resources are frequently not taken advantage of by academics who work in medicines development. The same can be said for scientific advice (SA),²⁶ which allows developers to discuss with regulators the design and plans for development, ideally before expensive and non-reversible steps regarding the design of clinical trials are taken.^{27, 28} Yet, it is worth noting that the regulatory system has appropriate mechanisms and policies in place on the handling of competing interests to enable such early interactions and guarantee the independence of scientific assessments and decision-making at the MA stage. Early interactions should become the norm for all future marketing authorization holders, regardless of the type of developer and medicinal product being developed.

One aspect of this issue may be that such interactions with regulatory bodies are not free, although regulators are catching up with these shortcomings and many have special provisions to alleviate them.^{23, 29, 30} Regardless of existing initiatives, for relatively new stakeholders in interactions with regulatory agencies, there is still a long way to go.

Medicines for rare diseases are a special case that exemplify the complex reality of bringing ATMPs to the clinic. The majority of approved ATMPs in the EU target orphan diseases and a recent study concluded that 84.6% of licenced indications for ATMPs are considered orphan diseases.³¹ Not only for ATMPs but also as a whole, it is more difficult to recruit patients for medicine trials in orphan diseases: More than a quarter of clinical studies between 2016 and 2020 were terminated earlier due to insufficient patient enrolment according to Global Data.³² Because ATMPs are so expensive to develop and produce, many therapies developed for orphan diseases will never be profitable, especially those for the treatment of very rare conditions. In the EU, these are frequently developed by academic researchers over the course of many years, often supported by large sums of taxpayers' or charities' money.

Serious consideration is now being given to the final step in the process of moving medicines from the lab to the patient: the economic aspects that frequently are the key to access. Provision of a new therapy in Europe's national health systems (reimbursement and payments) generally passes through an assessment by a specialist body such as a health technology assessment agency (HTA), which determines if a product will be reimbursed or provided in the public health system for a particular group of patients. HTA decisions have serious consequences for the financial viability of a marketed product. Of the 27 medicines that have received a marketing authorization in the EU, only 16 remain on the market.⁴ The rest were taken out by the marketing authorization holders for commercial reasons.

Likewise, the involvement of patients early in the process of new medicines development is an area where traditional pharmaceutical companies have made great progress in recent years but is less commonly practiced by academic developers.³³ Patient reported outcomes are perhaps more used in the clinical part of the development, but patient input can be very useful to developers from the very early stages. Such input may provide a deeper understanding of the unmet clinical needs in the therapeutic area, the complementarity or potential disruption in the current and future clinical setting and the alternatives: All of them will determine the crucial step of reimbursement and therefore access to the medicine by the patients who need it.^{6, 33}

The complexity and expense required to navigate the regulatory system have also been blamed for the poor translation. Indeed, taking a medicine to market is not a simple process, and it can be expensive. Education is therefore a key element to increase the translational value of academic ATMP development and in this domain, initiatives supported by non-profit organizations and public institutions certainly play an important role as a complement to regulator's support. The Advance project has now finished, but it was a good example of a training initiative to support early-career biomedical scientists in developing currently missing scientific knowledge, transversal skills and competences to meet the key challenge areas existing in the ATMP development cycle.³⁴

In addition, regulators have also proven that there is flexibility in the system, and such flexibility has been applied in the evaluation of many of the advanced therapies that achieved marketing authorizations.³⁵ This includes adaptation of the traditional phases (I, II and III) of clinical trials, development of new statistical methodologies to enhance study design options and flexibility in the required number of patients included in pivotal studies and versatility in the statistical analyses, particularly for clinical programmes targeting rare diseases. An additional consideration is to align, to a greater extent than what is currently done, the manufacturing, non-clinical and clinical elements of academic development with reimbursement requirements,³⁶ as well as regulatory requirements. Effective generation of suitable data for HTAs should be considered when planning any development that aims for later introduction in the clinic, especially as ATMPs will be amongst the first category of products, with oncology, to be subject to parallel joint clinical assessments starting in 2025 according to the new HTA regulation.³⁷

Considering the high level of uncertainty, their one-off nature and how expensive ATMPs are to develop and produce, costs of treatment will continue to be high, and this problem will grow as more and more indications of non-orphan disease arrive.³⁸ The engagement of academic developers of advanced therapies with the regulatory world, including the use of regulatory tools available, will help the production of convincing evidence and the progression of potential medicines to a better translation into the clinic. To achieve this, early engagement is essential, as many of the critical elements spanning across manufacturing, non-clinical and clinical development need to be addressed early on. Consequently, the fee reductions to be applied to non-profit entities seeking scientific advice in the new fee regulation are welcome.³⁸ This however also requires a clear commitment from regulatory agencies to support and promote such interactions in a way that also works for non-profit organizations.

The views expressed in this article are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the regulatory agency or organization with which the authors are employed/affiliated.

The authors declared no competing interests for this work.