Over the last two decades, there have been several breakthroughs related to the development of gene therapies. Further, post the onset of the COVID-19 pandemic, there has been a steady increase in the investigational new drug (IND) applications filed for cell and gene therapies. Promising results from ongoing clinical research initiatives have encouraged government and private firms to make investments to support therapy product development initiatives in this domain. Presently, more than 250 companies are engaged in the development of various early and late-stage gene therapies, worldwide. Driven by the collective and consistent efforts of developers and the growing demand for a single dose of effective therapeutic, the gene therapy market is anticipated to grow at a CAGR of ~18% in the forecast period, according to Roots Analysis.
Regulatory Guidelines in the US
In the US, the Department of Health and Human Services (DHHS) is responsible for regulating clinical trials, with the support of two other organizations, namely Office for Human Research Protections (OHRP) and the United States Food and Drug Administration (USFDA). It is important to highlight that all investigators are required to comply with the regulations established by the aforementioned authorities, while conducting gene therapy focused clinical trials. According to the OHRP, clinical research involving human subjects should be necessarily reviewed and approved by the Institutional Review Board’s (IRB). Another DHHS agency, the National Institutes of Health (NIH), is responsible for conducting federally funded clinical trials, in compliance to a series of guidelines specified in the Code of Federal Regulations (CFR).
Further, based on the risks associated with the complex nature of gene therapy products and the required expertise, the Office of Cellular, Tissue, and Gene Therapies (OCTGT) at Center for Biologics Evaluation and Research (CBER) regulates gene therapy products (including medical device-based gene therapy products) and reviews applications related to the use of gene therapies under / intended for clinical investigation, or licensure. It is worth mentioning that the biologics which are being regulated under Section 351 of the Public Health Services Act are termed as 351 Products. Accordingly, such biologics (including gene therapy products) are bound to receive pre-market approval and fulfil the good manufacturing practices (GMP). Moreover, for gene therapy products intended for clinical investigation in human subjects, the concerned developers are required to file an Investigational New Drug (IND) application in the US.
Regulations Governing Gene Therapies in the US
The following section provides key takeaways related to the regulations governing the development and approval of gene therapies in the US:
- The manufacturers are responsible for analyzing all components of their gene therapy products in order to determine the application area. Additionally, the guidelines include preclinical, manufacturing, licensing and post-approval requirements, which are applicable to the product, or to specific manufacturing components; for instance, there are set of regulations governing the use of cell lines and adherence to current Good Tissue Practices (cGTPs).
- To determine which component of the gene therapy product is responsible for the therapeutic effect, the manufacturer may submit a Request for Designation (RFD) to the Office of Combination Products (OCP). This agency uses a codified decision-making algorithm to determine the primary mode of action of such therapies.
- The NIH guidelines for Research Involving Recombinant Synthetic Nucleic Acid Molecules contain information on responsibilities and procedures for conducting clinical investigations and an index of points, which needs to be considered for designing clinical protocols. Section IV-B-2-a-(1) of the guidelines calls for the use of an Institutional Biosafety Committee (IBC) to oversee the trial. The IBC is required to ensure patient and environmental safety, and evaluate the risk and safety associated with the use of the investigational agent and the overall conduct of the clinical trial.
- Only the USFDA has the authority to approve or deny a protocol for a trial in an IND application. In addition, it is the only organization that can make any legally binding decisions related to product identification, application or review determination of report submitted in product applications, including clinical investigations and supplemental materials.
- The investigator should anticipate and document all the risks associated with the delivery mechanism used for the gene therapy, based on the nature of the delivery vehicle (for instance, AAVs are known to induce inflammatory responses and lentiviral vectors have the potential to cause mutagenesis).
- All the gene therapy products should undergo bio-distribution testing to determine the expression of the vector and the impact of its translation products in both on and off-target cells and tissues, as well as the dosing regimen required to achieve the desired level of expression.
- According to the USFDA, manufacturers of investigational gene therapy products are required to submit a Quality Control (QC) Plan, along with the Chemical, Manufacturing and Control (CMC) portion of the IND, specifically designed for the oversight of production methods, in addition to standard quality control processes associated with GMP.
- As some of the gene therapy products may modify the genome of a host or alter the pre-therapy expression of a target through genetic intervention / manipulation, the potential for long-term risks must be carefully assessed. Patients receiving certain types of therapies should be monitored closely for delayed adverse effects, which are not evident during or soon after the clinical testing.
- Gene therapies are considered high-risk therapies and therefore, only serious clinical conditions should be considered for treatment using such ATMPs.
- In 2009, President Barack Obama signed the executive order 13505 (Removing Barriers to Responsible Scientific Research Involving Human Stem Cells), which allowed researchers to receive NIH funding and pursue research on prohibited cell lines.
- In 2016, the NIH made some changes in the aforementioned policy, which currently approves research involving the implantation of human pluripotent stem cells in animal embryos.
Guidance Document Framework for Gene Therapies
In 2018, the USFDA announced a new framework for the development, review and approval of gene therapies, which was complementary to the policy framework designed for regenerative medicines. Additionally, the USFDA released six scientific guidance documents to help the new gene therapy products in meeting the gold standards set for safety and effectiveness. The three drafted guidance documents have been mentioned below:
- Human gene therapy for hemophilia: The guidance document assists stakeholders who are involved in developing human gene therapy products for the treatment of hemophilia. Further, it provides recommendations on the clinical trial design and preclinical considerations for the development of new products. In addition, it helps in addressing the variations that may arise in factor VIII and factor IX activity assays. However, the draft does not include recommendations for products targeting hemophilia C.
- Human gene therapy for retinal disorders: The guidance document assists stakeholders who are engaged in the development of human gene therapy products for retinal disorders affecting both adult and pediatric population. Further, it provides recommendations on the development of product, preclinical testing and clinical trial design.
- Human gene therapy for rare diseases: The guidance document assists stakeholders who are engaged in the development of human gene therapy products for the treatment of rare diseases in both adult and pediatric population. Further, it provides recommendations regarding manufacturing, preclinical and issues related to clinical trial design. In addition, the draft helps in designing clinical trials for those products, where there is a limitation in the study population size, feasibility and other safety issues.
Furthermore, the USFDA has updated three existing guidance documents related to gene therapy manufacturing:
- CMC Information for Human Gene Therapy IND Applications: The draft provides recommendations to industry players regarding the CMC information necessary to assure product identity, quality, purity, strength, potency and safety of the investigational product.
- Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus (RCR) during Product Manufacture and Patient Follow-up: The draft provides recommendations to industry players on RCR testing during gene therapy products manufacturing and during follow-up monitoring of patients. In addition, it provides general guidelines, such as the amount of material to be tested and information on the testing methods.
- Long Term Follow-up after Administration of Human Gene Therapy Products: This draft helps in designing long term follow-up observational studies with specific considerations for different gene therapy products. Exposure of investigational gene therapy product for longer duration may lead to delayed adverse outcomes. Hence, long term follow-up observations are important to monitor the safety of gene therapy product. In addition, the document provides recommendations on patient monitoring for licensed gene therapy products.
It is worth mentioning that, in January 2020, the USFDA finalized the above-mentioned draft guidance documents focused on the development of gene therapies. This draft supersedes the CMC guidance that was released in April 2008. In addition, a new draft guidance was released, along with these documents, which focused on the USFDA process of interpreting similarity of two gene therapy products targeting the same indication, under the orphan drug regulations.
In January 2021, the USFDA released a new draft guidance document focused on gene therapies targeting neurodegenerative diseases. The drafted document has been highlighted below:
- Human gene therapy for neurodegenerative diseases: The draft assists stakeholders who are engaged in the development of human gene therapy products for the treatment of neurodegenerative diseases affecting pediatric and adult population. Further, it provides recommendations on the development of product, preclinical testing and clinical trial design. In addition, the draft helps in designing marketing approval pathways for new investigational gene therapy products.
During the same time frame, another guidance document was released by the USFDA related to the manufacturing of both licensed and investigational gene therapy products. The document featured the following considerations:
- Manufacturing Considerations for Licensed and Investigational Cellular and Gene Therapy Products During COVID-19 Public Health Emergency: The guidance document provides risk-based recommendations in order to minimize the transmission of infection during the development of therapy products. Further, it specifically highlights the manufacturing process of cell and gene therapy products and the consideration of source material (cells or tissues) for any contamination with coronavirus.
In September 2021, the USFDA issued a draft guidance providing an elaborative structure to study multiple versions of a cell and gene therapy product for a particular indication in a single early-phase trial. Brief description of the draft guidance document has been mentioned below:
- Studying Multiple Versions of a Cellular or Gene Therapy Product in an Early-Phase Clinical Trial: The draft assists the stakeholders to conduct umbrella trials for a single indication, wherein each candidate will have a unique IND application. Further, the early-phase clinical study will aid in selecting a suitable therapy candidate for later phases of development.
During the same month, the USFDA issued a final guidance to obtain an orphan drug designation and exclusivity to bring all the gene therapy products targeting rare diseases under the same umbrella. Brief description of the guidance document has been mentioned below:
- Interpreting Similarity of Gene Therapy Products Under the Orphan Drug Regulations: The guidance assists both industrial and academic stakeholders seeking orphan drug designation for gene therapies targeting rare diseases. It specifies the list of factors intended to be used by the USFDA in determining the orphan drug status for such products.
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