Gene Therapy Products Translation to Clinic
In the past twenty years, a revolutionary approach to therapy has emerged, fundamentally altering the potential treatment of severe illnesses. Rather than relying on conventional methods, medical practitioners can now utilize the healing capabilities of cells to regenerate and potentially provide a cure for diseases that currently pose significant medical challenges. This shift represents a substantial advancement in addressing unmet medical needs.
Gene therapy in the field of medicine refers to a therapeutic approach that involves transferring DNA to patient’s cells in order to correct a defective gene or gene product, aiming to treat diseases that are not curable using conventional drugs. There is a growing emphasis in the field of gene therapy to establish a clear trajectory towards clinical implementation and market availability. As per New Drugs and Clinical Trial Rules (NDCTR) 2019, Gene Therapy Product (GTP) is classified under new drug.
To date, 32 gene therapy products have received approval, and more than two thousand human gene therapy clinical trials have been documented worldwide. Despite facing numerous challenges and failures over the past three decades, it has made significant strides in making its way into clinical practice and the market. In 2017, the Food and Drug Administration (FDA) approved Luxturna, the first gene therapy medication for hereditary retinal degeneration, and it was made available on the US market.
The initiation of any gene therapy trial necessitates thorough review and approval from regulatory authorities. Both regulatory agencies and investigators, have a shared objective: to help patients by facilitating the introduction of innovative therapies that are both safe and effective
. These authorities play a crucial role by independently assessing research protocols to ensure they meet the necessary criteria for minimizing risks to patients. To maximize the process of converting scientific discoveries into clinical practice, it is essential for physicians and scientists to have a comprehensive understanding of how regulatory agencies evaluate new applications.
To conduct preclinical evaluation of GTPs, it is crucial to choose an animal model that possesses homologous genotype and phenotype. To use gene therapy in the paediatric population, several important steps and considerations must be considered. Age-dependent dose-escalation and safety studies are necessary to ensure the appropriate dosage and safety profile for children. Additionally, an environmental risk assessment should be conducted to screen for the presence of the gene therapy product in the body fluids of test animals. Germline gene therapy can be misused by selecting desired characters in foetus (designer babies), so this therapy is banned in India.
The clinical phenotype of the target genetic disease must be thoroughly described, supported by various imaging, biochemical, structural, or morphological data. Understanding the inheritance pattern of the disease, requires sequencing validation among the family members. Stratifying the patient population based on disease severity, comorbidities, and genetic information is advised to tailor the treatment approach.
According to National Guidelines on Gene Therapy Product Development and Clinical Trials 2019, Gene Therapy Advisory and Evaluation Committee (GTAEC) will evaluate GTP clinical trial application and will forward to Review Committee on Genetic Manipulation (RCGM) and CDSCO for final approval. Approval from participating IEC has to be obtained before starting the trial.
However, after some deliberation between stakeholders the Gene Therapy Advisory and Evaluation Committee (GTAEC) involvement no longer exists.
Usually in GTP trials, number of patients enrolment tend to be less and, in some cases, blinding during gene therapy trials may not be feasible due to ethical concerns, clinical reasons, or the surgical complexity of the administration route. Hence, it is advised to stratify patient population based on disease severity, comorbidities, and surgical information. However, subjects recruited prior to gene therapy administration can withdraw from the trial at any point without impacting their ongoing treatment. Once the gene therapy is administered, patients are encouraged not to withdraw and should be followed up to assess long-term risks and benefits.
Prompt reporting of adverse events and serious adverse events to the ethics committee and regulatory authorities is mandatory. The primary objective of gene therapy is to improve the patient’s quality of life (QoL) and attempts to cure the root cause. Follow-up of patients for at least 5 years post-GTP administration and 10 years post-marketing is recommended to evaluate the treatment’s long-term effects.
The goal remains to ensure the safety and efficacy of the treatment for the benefit of the patient’s well-being.
Regulatory agencies worldwide are actively encouraging the safe and effective exploration of innovative therapies and are available for pre-submission consultations for researchers who are developing such novel products.
According to Alireza et al., the market for gene therapy has grown significantly in the last several years and is projected to continue expanding at a significant rate until 2030, as indicated by Grand View Research. A recent report published by Roots Analysis titled ‘Gene Therapy Market (2nd Edition), 2018-2030’ reveals that there are approximately 300 product candidates currently undergoing various stages of development for a wide range of applications. This signifies the increasing interest and investment in gene therapy, highlighting its potential to address diverse medical needs.