As the field of modern medicine is changing, so should the development strategies of new medicines, including advanced therapy medicinal products (ATMPs). Many ATMPs are being developed for rare/orphan diseases with an unmet medical need. The inherent complexity of ATMPs poses several challenges to the translation of these products to the clinic, like not being able to follow standardized CMC, non-clinical and clinical development strategies. Instead, comprehensive and product-specific development programs may be required prior to marketing approval. Altogether, a bumpy road to market authorization lies ahead.
In general, in the translation of an ATMP from research to market authorization, it’s worthwhile to pay careful attention to the following aspects:
- Business strategy and investors
- Product Definition
- Chemistry, Manufacturing, and Controls (CMC)
- Nonclinical development
- Clinical development
- Regulatory strategy
In this blog, we will briefly touch upon these areas.
1: Business strategy and investors
Building a solid business case early is a strong prerequisite for being successful in partnering with investors and co-developers. And as
You need to address essentials like:
- Company organization
- Partnerships & collaborations
- Roles and responsibilities of the management team and board
- IP and freedom to operate
- Competitor analysis
In this way, you cover a major investment
2: Product definition
A target product profile (TPP) is an important tool to facilitate the interactions with health agencies to align your development with regulatory expectations. In addition, the TPP is also a valuable instrument to facilitate both internal and external communication and can be translated into a Quality TPP (QTPP). Both are dynamic documents that facilitate the integration of all development disciplines into a predefined and suitable process.
3: CMC development
ATMPs are usually manufactured using complex biological and technological processes for which many protocols are to be developed
Some things to keep in mind:
- Changes to an ATMP design to obtain improved product characteristics pose a challenge to the evaluation of the impact on the safety and efficacy profile of the product. It is beneficial to design a solid TPP and a project development plan that properly defines the required product and process characteristics. In conjunction, major milestones and related criteria for the anticipated go-no-go reviews should be defined beforehand. Such a work plan may help to reduce a need for later bridging studies or guide the design of these bridging studies in case they would be required to link early to mid and late-stage development.
- To create more value you can investigate how to expand your development platform or processes to other indications or products. For example, a change in transgene could possibly treat a different indication with the same vector backbone and promoter.
- To save time and resources, it is important to perform a solid process development to minimize the gap between non-GMP and GMP manufacturing.
- Also, the tech-transfer between these should start in an early phase to assure alignment of the development and manufacturing of the ATMP.
Overall, it’s crucial to engage early with regulatory agencies to align your pharmaceutical development, your manufacturing strategy and your comparability plans and discuss the impact on the performed and planned non-clinical and clinical development activities. This not only speeds up the marketing process but also builds confidence in your company and current product for potential investors.
4: Non-Clinical development
Prior to the clinical administration of an ATMP, adequate non-clinical information should be provided using a relevant animal model. Due to the specific characteristics of ATMPs and differences in regulatory requirements, non-clinical development may not follow a “standardized” approach. Products used in non-clinical studies should be representative of the product that will be administered to humans in clinical studies. In addition, the animal models used should have a predictive value to the clinical use of the product in humans bearing the disease indication in mind.
The final product should be based on the right data. This might sound like a no-brainer, but in reality, products are being developed that aren’t. For instance, during development imposed differences in isolation of cell sources, other vector backbone or differences in matrix preparation can induce a huge discrepancy in outcome parameters and present the risk of not being able to connect your non-clinical development to a product that can be used in clinical trials.
Non-clinical studies should be performed using the most relevant in vitro and in vivo models available, the rationale for the selection of these models needs a solid justification. The animal model needs to be suited to allow for translation to the clinical use of the product. In case a single animal model isn’t sufficient to bridge non-clinical study outcomes to a clinical prediction, various different animal models may need to be employed. Very important notice on this is that early interaction with regulatory authorities has proven beneficial in convincing on the justification of the proposed animal models.
Dosing is always a difficult issue. As ATMPs are being developed in animal models that for example are different in size, metabolism, immunological status compared to humans, the administered dose cannot be translated on a one to one basis for human use. The best you can do is to make an educated estimate on the dose and stay on the safe side. Also, take into consideration the method of administration, as different routes of administration can have different tolerability and efficacy outcomes.
In gene therapies, the risk of viral spreading into the environment should be addressed in non-clinical studies. Non-clinical studies are required to estimate the potential shedding of the viral vector. A challenge in the design of meaningful shedding studies relates to the fact that many viral vectors used in gene therapies do not infect and rarely replicate in nonhuman species. One way to address this is to take advantage of the fact that many vector types have been used clinically with different indications and publically available shedding data may be applied in the environmental risk assessment.
5: Clinical development
Many ATMPs are first in man clinical trials and/or first in class medicinal products. Consequently, the clinical trial design
- The mode of delivery that should be described in an extensive TPP at an early stage of development
- Setting your inclusion and exclusion criteria right
- Selection of a starting dose and a staggered approach for patient enrolment
These clinical trial design aspects are important considerations as the safety profile of ATMPs can be evaluated only limitedly in non-clinical studies. In some cases, an estimated risk can be accepted when the potential clinical benefit outweighs the potential risk within a specific population. Clinical study design should be able to detect clinically meaningful endpoints but surrogate endpoints can be accepted for example in the context of rare disease indications.
Potential safety issues may relate to inflammatory responses, immunogenicity, disturbed gene control and off-target effects and there is a potential risk of transmission to third parties. Also, for gene therapies, other concerns relate to the persistence of viral vectors and genomic integration into the host's genome. For cell therapies and tissue-engineered products, specific risks may relate to graft failure, oncogenicity
Given the unique character of ATMPs specific requirements for long-term follow up are demanded. The design of the long-term follow-up regimen needs to be determined on a case-by-case basis depending on the product and the trial population.
6: Regulatory strategy
A scattered regulatory landscape poses inherent challenges for the development of a globally acceptable development strategy. In many cases, not only the large agencies as EMA and FDA are involved but also different national agencies. So, transitioning from preclinical development to market authorization requires a carefully considered regulatory strategy and close collaboration with Health Authorities (global and local) to support the development of your ATMP.
It’s advised to apply a risk-based development approach as described by EMA in their risk-based approach guideline to ATMPs.
As indicated by EMA in this guideline: “The risk-based approach is based on the identification of various risks associated with the clinical use of an ATMP and risk factors inherent to the ATMP with respect to quality, safety
A solid regulatory strategy will not only expose any regulatory challenges but also create regulatory opportunities. It will allow you to:
- Set milestones and deliverables
- Identify risks and mitigation strategies
- Set up a strategy for communication with Health Authorities
This will all be beneficial in guiding your ATMP through the regulatory maze and make sure opportunities turn into reality
To date, only a few ATMPs obtained marketing authorization and most academia and startups are usually more focused on the science and technology than the actual development of these innovative and often complex products. Wrapping up, we stress the importance of creating a development plan that identifies all the interdependencies between non-clinical, CMC and clinical development early on.
Although each ATMP is unique and needs a tailored development and regulatory strategy, critical steps can actually be identified and anticipated on beforehand and a tailor-made regulatory strategy can provide you with the guidance and focus required for successful development. Especially in the early stage of development, engagement with regulatory agencies supports to align development milestones and assure regulatory compliance in the end.
When you realize that all the different aspects of ATMP development are intertwined and changing one might have a huge impact on another, you are on the right track. So get ready to save time and get your development plan and regulatory strategy straight!
Blog by: Harm Hermsen & Merel Stok