In this blog post, we continue to explore some of the most significant, complex, and difficult manufacturing challenges in gene therapy.
Adverse events post-treatment
The challenges of gene therapy commercialization are not just limited to product development and manufacturing. Adverse events that may occur in patients post-treatment must also be considered and prevented. Although several gene therapies have been approved and adopted, patient deaths associated with these inventions have occurred. Cytokine release syndrome, neurological toxicity, and anaphylaxis are adverse events that have been associated with gene-modified cell therapies. The critical stakeholders driving these novel treatments, including the drug company’s researchers, engineers, product development scientists, doctors, and patients, must be mindful of potential pitfalls as they continue to implement strategies to mitigate the risks associated with these treatments.
Analytical methods used in vector manufacturing
Many of the well-characterized assays used to assess quality and safety of traditional biologic medicine products are not well suited for use with gene therapies. Some of the early-stage academic research-based assays do not appear to provide rigorous assessment of the new products because they are lengthy, cumbersome, expensive, and not compliant with current good manufacturing practice (cGMP) regulations.
One of the most critical raw materials in the gene therapy supply chain is the vector used to introduce the therapeutic gene of interest into the patient. The complex nature of viral vectors poses a large challenge for characterization and quality control testing methods. Many new methods need to be developed and refined in the coming years. The key to developing a large-scale viral vector is having accurate and reproducible analytical tools to monitor critical quality attributes (CQAs) of consistent efficacious product.
Globalization
Globalization of gene therapy and widespread distribution of treatments will provide another challenge for industrialization. Most approved commercial gene therapy products are currently only available in a small number of countries and regions, with very few adopted globally. No multi- agency regulatory clearances have yet been negotiated to allow for initiation of pivotal clinical trials on a global scale. The lack of cohesiveness surrounding many critical activities, including logistics of administration of drugs to patients, import/export regulations across borders, reimbursement policies of each nation, regulatory approvals, market variability, and differences in clinical adoption, have prevented global gene therapy products.
Funding
In general, the typical drug life cycle begins in research laboratories of academic institutions and small and large drug development companies. Scientists, doctors, and engineers seek to identify the underlying cause of a disease state and subsequently search for potential treatments that correct the disorder. Once a potential therapy is identified, the drug candidate is transitioned into clinical trials. Currently, for a variety of reasons, many gene and cell therapies move into phase I clinical trials without significant optimization of production methods. Therefore, production processes for these early phase trials are rarely robust enough to generate quantities of the drug product to treat entire patient populations in a cost-effective manner.
When promising results are obtained in early phase clinical trials, the sponsors of the trial typically begin to perform process optimization and increase utilization of quality systems that comply with regulatory requirements. The vision is to create a cost-effective, industrialized manufacturing process that will generate safe products at yields that are adequate to not only treat entire patient populations but also to do so in a manner that allows for recoupment of development costs and leads to profit that can be used for future drug development.
Every stage of the product life cycle requires significant investment from various sources and the financial commitment is substantial. The cost of drug development for standard biologics has been well documented. The estimated cost to bring newly approved compounds to market is $1395 million dollars (2013 dollars) (1). This burden of drug development is taken on by governments, private investors, entrepreneurs, private foundations, small biotech companies, and large pharmaceutical companies. The funding entity involved is loosely related to the development stages where governments of developed countries and private foundations invest heavily in basic research and early clinical trials. These stages are also highly funded by biotech and large pharmaceutical companies (1). Risk is inherent throughout the entire process because only approximately 14% of the drugs that enter clinical trials become approved and commercially available for treatment of patients (2). If new treatments are to continue to move us into the next generation of medicine, commitment to fund the overall process from all parties is required.
In summary, the challenges associated with gene therapy manufacturing and the journey to industrialization are significant. But perhaps the greatest challenge is understanding how to overcome these difficulties. Manufacturers must find a way to successfully produce, supply, and scale up therapies for gene therapy commercialization.
References
- DiMasi JA, Grabowski HG, Hansen RW. Innovation in the pharmaceutical industry: New estimates of R&D costs. J Health Econ. 2016;47:20-33.
- Wong CH, Siah KW, Lo AW. Estimation of clinical trial success rates and related parameters. Biostatistics. 2019;20(2):273-286.