What is a ‘platform-based' approach?
There is no standard definition for “platform-based” technology as this is something that has yet to be officially defined by the FDA in the context of gene therapies. There have, however, been developments on a regulatory definition for this phrase in the US:
Janet Woodcock, the former FDA Principal Deputy Commissioner, has alluded to the concept previously: “may be a large number of related drugs using a ‘platform technology,’ i.e., small modifications needed to address different mutations within the same gene.” [1, 2]
The FDA has described continuous manufacturing as a “platform” – in the FDA guidance on "Continuous Manufacturing of Drug Substances and Drug Products”, a “platform approach” was described in the context of process validation, considering elements such as prior facility experience in implementing a similar process and control system, availability of product-specific data arising from late-stage product development, etc. [3]
On the other hand, the EMA describes “platform technology” as a “technology that has already been approved for another medicinal product and has therefore been (at least partly) characterized previously”. [3]
Within the context of the BGTC Regulatory Playbook, at this stage we describe a “platform-based approach” as an overall concept rather than a specific definition when it comes to AAV gene therapies with the mission of progressing use cases as part of the BGTC work.
The idea of a platform-based approach is centered on streamlining regulatory requirements by:
Leveraging existing data and information or prior knowledge based on similar elements with approved AAV products
Developing standard minimum requirements based on this platform-based approach to increase efficiency of development and regulatory submissions
These concepts are pursued while still prioritizing meeting the threshold for safety.
A platform-based approach uses the principle that various aspects of gene therapies can be sufficiently similar to the ones used in prior approved therapies, especially specific components which require individual testing. Thus, leveraging prior knowledge, learnings, and data about specific components and addressing key questions can pave the way for you to adopt the platform-based approach effectively.
Some key questions to consider in your rationale for leveraging the platform approach
1. What are the similar components/aspects between the approved product and your therapy?
If certain components are sufficiently similar, specific evidence requirements related to those components may be waived or referenced. If there are differences, consider the downstream effects expected and how that might affect your approach.
2. What sources of data can you leverage for these components? What is the level or nature of prior information that exists?
The quality, completeness, rigor, etc. of available data directly determines what you may be able to leverage. For example, the BGTC approach focuses on referencing prior data that has been at least submitted at the IND level. It is also important to note that data sources may differ on a case-by-case basis – for example, a prior data source that you may refer to for one therapy may not work for another.
3. Where does variability matter?
Streamlining is highly dependent on the comparability of processes, elements, etc. across assets. Based on the two previous questions, you can ascertain where there might be variability as a result of attributes that are kept similar versus different, and consequently what can be streamlined – for example, what is within the “margin of error” or having confidence that an attribute will not “drift out of safe/efficacious ranges”.
Why pursue a platform-based approach?
There are about 10,000 different rare diseases impacting the human population, of which around 85% are thought to be monogenic disorders.
Monogenic disorders are ones caused by mutations in a single gene and are responsible for about 200 newly identified diseases each year
Even though recent advances in the medical and biotech field have allowed for approval of novel therapies, only 5% of the rare diseases have a specific regulatory approved treatment. With the current pace of only 3-5 rare diseases getting their first specific treatment approved each year, ~2000 years will be needed until specific treatments have been developed and approved for all rare monogenetic disorders. Additionally, "the traditional one-disease-at-a-time model of commercial therapeutic research and development is too inefficient to justify developing therapeutics for population sizes below a certain threshold”, [4] thus creating an obstacle for many potential therapeutics for rare monogenic disorders to be approved.
To address the operations problems that currently lie with gene therapies, various departments of the NIH collaborated to initiate the platform gene therapy (PaVe-GT) pilot project in 2019. PaVe-GT aims to increase the efficiency of clinical trial startup by using the same gene delivery system and common manufacturing methods for multiple rare disease gene therapies. PaVe-GT will identify redundancies and leverage data from one product to the other, with the overall aim to increase the efficiency in preclinical testing and clinical trial start up from one disease to the next. The experience and learnings from the project, in the form of templates, regulatory packages and program results, are being made publicly available on the PaVe-GT website: pave-gt.ncats.nih.gov. [4]
Through the use of a platform approach, sponsors may not only see reduction in time, cost, and risks but also an improvement in efficiency and submission process, as shown below.
| Reduce Time: Faster regulatory approval for AAV gene therapies - as the manufacturing/analytical processes will have been validated and optimized |
| Reduce Cost: Reduction in overall development cost - as the use of prior optimized/validated processes can prevent redundant experiments |
| Improve Efficiency: Sponsors can ensure that they follow regulatory requirements - in return can prevent setbacks and delays in the overall approval process |
| Reduce Risks: De-risk submission by having prior data from approved/pre-approved drugs as a template to refer to during the regulatory process |
To bring about significant change in the current path of rare disease therapeutic development, it is essential to adopt a platform-based approach. This approach should emphasize the biological and modality-relevant commonalities across various diseases, rather than focusing on one disease at a time.
How does the platform-based approach apply to AAV gene therapies?
AAV vectors are “intrinsically disease-agnostic because their applicability for a particular disease is governed more by their biodistribution as a function of capsid serotype, route of administration and dose, the genetic mechanism to address (for instance, loss of function versus gain of function), and the expression cassette used, rather than by pathophysiological specifics of the disease under consideration.” [4]
The AAV as a vector is fundamentally a platform modality – a programmable multipurpose vehicle that delivers a variety of different therapeutic payloads to disease-specific target cells.
We can leverage the fact that AAV modularity of functions facilitates the swapping of transgenes, selection of regulatory elements (enhancer, promoter, etc.), and other alterations of the capsid, lending itself as a modality that is very amenable to the platform-based approach. This can lead to optimized AAV vector production protocols, improvements in AAV target gene expression, and other standardized and harmonized minimum sets of requirements (please refer to Introduction to the BGTC Regulatory Playbook for more information on minimum requirements).
Where the BGTC approach comes in
The BGTC Regulatory Playbook expands on PaVe-GT’s valuable pilot work initiated in 2019 and its dissemination goals, thus bringing the platform-based approach to life. Future versions of this playbook will identify recommended minimum requirements for pre-clinical and CMC sections and streamlining considerations for various sections of the product development process.
The aim is to utilize the learnings gained with each asset, translate the information into a continually enhanced and validated set of minimum requirements, and apply this knowledge into future versions of the BGTC Regulatory Playbook and overall program – with opportunities for increased specificity based on serotypes, routes of administration, affected organ/tissue, etc.
The evolution of the platform-based approach through the BGTC Regulatory Playbook highlights further opportunities for FDA interaction and a subsequent positive feedback loop for the success of future AAV gene therapies.