Learn key considerations for the development of gene therapy products targeting rare diseases.
We know the medical landscape is changing, and vast leaps in gene therapy could significantly improve modern medicine The emerging biologic treatments offer new hope for rare conditions where there are no treatment options.
Nevertheless, the development of gene therapy products for rare diseases differs in many ways from other R&D processes. This all-encompassing guide goes on to detail the essential nature of data integrity in any development course.
Rare diseases
According to the National Institutes of Health (NIH), nearly 7,000 rare diseases affect more than 25 million Americans. Around 80% of these rare diseases are caused by a defect in just one gene and about half of all rare diseases affect children. Rare diseases as a group lack FDA-approved therapies. Therefore, there is an unmet need for the vast majority.
Most rare diseases are chronic, serious or life-threatening diseases with an urgent need for innovative therapies.
Of course, developing safe and efficacious treatments for rare diseases is much easier said than done. These are complicated diseases largely due to the rarity of patients to enrol in clinical trials as there is big variability over distinct clinical phenotypes and disease progression among affected individuals.
These same challenges are present in the development of gene therapy (GT) products, with some special considerations. Nevertheless, even when these difficulties are recognized, the landscape of gene therapy for rare diseases research has advanced at a blistering rate.
Research Data Integrity and Rare Disease
Although many of the chemistry, manufacturing and controls (CMC) issues relevant to general product manufacture, testing and release of GT products for rare diseases are the same as other GT products some unique aspects need to be considered.
E.g., reduced cohort sizes, tutorial lots and establishing critical quality attributes (CQAs).
As part of the normal product development process, CQAs are carefully assessed at each phase along the clinical development pathway.
Clinical outcomes correlate with data for multiple drug product lots, building comprehensive decisions. But with smaller study populations, it can be difficult to perform enough manufacturing runs to define the critical process parameters (CPP) that produce CQAs.
In addition, GT products are more likely to show a higher variability of CQAs as compared with conventional drugs or well-defined biologics, which also contributes to the uncertainty of these attributes. However, gain licensure and comply with regulatory standards, the system must demonstrate process and product control, i.e., consistent with defined CQAs.
Early Focus on Data Integrity
Going back to basics of establishing controls during manufacturing process, setting up appropriate analytical assays in early phase makes it very important. This should happen before the GT article is first administered to human subjects.
Where modifications to the manufacturing process are needed, a comparability assessment may be necessary. Sponsors must develop a thorough metabolic fingerprint of the product and define critical quality attribute (CQA) levels and manufacturing critical process parameters (CPPs) necessary to achieve such CQA levels prior to beginning clinical studies, in order to achieve consistent dose-to-dose product over time and compliance with regulatory requirements.
More creative approaches to evaluating CQAs might be to use information about related products, nonclinical data on product characterization, testing CPPs during engineering runs or making additional small lots in place of one big lot. This allows you to have a more complete picture of product variabilities and quality parameters.
Collaboration and Communication
Sponsors preparing GT products for rare diseases are advised to communicate with OTAT early and often as well as one of the office’s colleagues within the Centre for Biologics Evaluation and Research (CBER). These conversations are supposed to happen well before investigational new drug application (IND) submission, and during product development.
These forms of communication should be considered.
Variations in the Product: Different rare diseases may pose unique issues with regards to factors such as impurities in viral vectors or discordance in genetically modified cell therapies. Sponsors must create assays to define these variants.
Potency Assays A reliable potency assay is essential to determine the performance of a product, ensure batch consistency and stability. They support comparability after process changes post-manufacturing To consider a potency test suitable for this purpose, it needs to meet the following requirements before conducting clinical studies and analysing several characteristics of the product.
Manufacturing challenges include but are not limited to the availability of starting materials, reference materials or if the complexity of a process. Sponsors are advised to consider (where appropriate) commercial-scale manufacturing changes and product comparability studies early in development.
Preclinical Considerations
Prior to initiating clinical trials, a strong set of preclinical studies are required to characterize the benefit/risk profile of the investigational GT product in relevant preclinical models for the proposed patient population.
Objectives of a preclinical program for a GT product might include (1) determining biologically active dose range, (2) assessing feasibility and safety of the clinical route of administration, (3) supporting patient eligibility criteria, and (4) identifying toxicities.
For paediatric first-in-human clinical trials, the preclinical program should also provide evidence supporting direct benefit (as part of a demonstration of prospect of therapeutic benefit, when adult data are not available).
These studies — in vitro and in vivo proof-of-concept work, biodistribution data, full toxicology studies that are representative of the planned clinical trial parameters — represent critical elements of a preclinical program for an investigational GT product. This could require additional nonclinical studies that address, for example, developmental and reproductive toxicity or changes in the manufacturing process.
Conclusion
Bringing new gene therapy products to market for rare diseases is typically a long and difficult process, but with few (if any) treatment options available to the patients suffering from these often-terrible ailments there appears light at the end of the tunnel. The critical need for data integrity, from the earliest of development stages through clinical trials, is imperative for ensuring the success of these therapies.
Sponsors can overcome the challenges of developing GT products for rare diseases successfully by accounting for these special considerations and maintaining transparent communication with regulatory agencies, in addition to adequately designing preclinical programs.
The evolving landscape of research will require an ongoing recommitment to data integrity if we wish to maintain the trust of society, continue to drive the pursuit and application of scientific knowledge, and ensure that therapeutics reach those who need them most.
Reach out to BioBoston Consulting today or visit our website for additional information on how we can assist your organization.