As the field of modern medicine is changing, so should the development strategies of these new therapies such as cell and gene therapy (CAGT) products, also known as advanced therapy medicinal products (ATMPs). Many of these new products are being developed for rare/orphan diseases with a significant unmet medical need. The inherent complexity of these novel therapies poses several challenges for the translation of these products to the clinic, impeding the ability to follow standardized chemistry, manufacturing, and controls (CMC), nonclinical, 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 usually lies ahead.
In general, in the translation of a CAGT/ATMP from research to market authorization, it is critical to pay careful attention to the following mile markers for a smoother road to success.
- Business Strategy and Investors
- Product Definition
- Chemistry, Manufacturing, and Controls (CMC)
- Nonclinical Development
- Clinical Development
- Regulatory Strategy
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. As such, it is likely to be considered a solid proposition for investment if you are planning both for development of your product into clinical stages as well as market approval in the end.
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
- Product development plan
In this way, you cover a major investment requirement to position your cell and gene therapy development from a broader perspective and to provide a clear market assessment of your advanced therapy product.
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 target product profile (QTPP). Both are dynamic documents that facilitate the integration of all development disciplines into a predefined and suitable process. A well composed TPP is also advantageous for early dialogues with regulatory authorities and may result in shorter review times.
3: CMC Development
CAGT/ATMPs are usually manufactured using complex biological and technological processes for which many protocols must be developed. Procured cells and tissues, cell lines, or vectors are needed as starting materials and multiple steps are required to select, modify, and expand cells and/or produce your vector. Cell isolation, culturing, modification, harvesting, purification, formulation, and cryopreservation of the product all give rise to challenges regarding product quality characteristics like purity, potency, and safety.
Furthermore, both patient to patient variability of the starting material and inherent variability of manufacturing processes often demonstrate an inherent variability causing significant heterogeneity between batches, which also relates to the challenges in testing, characterization, and control.
Some things to keep in mind:
- Changes to a CAGT/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 understand the efficacy and biological properties of the product, start to develop a potency assay early on.
- 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 cell and gene therapy product.
Overall, it is 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 nonclinical 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: Nonclinical Development
Prior to the clinical administration of a CAGT/ATMP, adequate nonclinical information should be provided using a relevant animal model. Due to the specific characteristics of CAGT/ATMPs and differences in regulatory requirements, nonclinical development may not follow a “standardized” approach. Products used in nonclinical 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 all 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 nonclinical development to a product that can be used in clinical trials.
Nonclinical 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 is not sufficient to bridge nonclinical study outcomes to a clinical prediction, various different animal models may need to be employed. Early interaction with regulatory authorities has proven beneficial in convincing on the justification of the proposed animal models.
Dosing is another a complicated issue. As CAGT/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 nonclinical studies. Nonclinical 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 publicly available shedding data may be applied in the environmental risk assessment.
5: Clinical Development
Many CAGT/ATMPs are first in man (FIM) clinical trials and/or first in class medicinal products. Consequently, the clinical trial design harbors specific challenges:
- 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 enrollment
- Administration as a single dose or a dose escalating scheme
These clinical trial design aspects are important considerations as the safety profile of cell and gene therapies can be evaluated only limitedly in nonclinical 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, and unwanted immune responses.
Given the unique character of cell and gene therapies, 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 such 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 CAGT/ATMP.
It’s advised to apply a risk-based development approach as described by EMA in their risk-based approach guideline to CAGT/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 CAGT/ATMP and risk factors inherent to the CAGT/ATMP with respect to quality, safety and efficacy”. This statement in itself suggests that the design of an integrated development strategy would require a multidisciplinary integration of CMC, nonclinical, and clinical development and should be strongly connected to a regulatory strategy that accounts for the product as well as the regulatory challenges.
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 CAGT/ATMP through the regulatory maze and make sure opportunities turn into reality.
Considerations
To date, only a few CAGT/ATMPs have obtained marketing authorization. For a successful authorization, we stress the importance of creating a development plan that identifies all the interdependencies between nonclinical, CMC, and clinical development early on.
Although each CAGT/ATMP is unique and needs a tailored development and regulatory strategy, critical steps can be identified and anticipated 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 helps to align development milestones and assure regulatory compliance in the end.
When you realize that all the different aspects of cell and gene therapy 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!
