As the technology behind gene therapy products continues to evolve, applicants face the challenge of adapting their programmes to increasingly demanding and detailed regulation. This article provides an overview of current regulatory expectations and the challenges they may present to industry.
Introduction
Gene therapy (GT) refers to a general class of therapeutic tools, which act by modifying the genetic material of living cells, with the intention of treating or curing a disease. They are based on recombinant nucleic acid sequences which, once introduced in a patient, can repair, replace, add, remove and/or regulate a genetic sequence.
Vectors such as adeno-associated viruses (AAV) and lentiviruses can be used to deliver the genetic material directly into the patient (in vivo gene therapy) or to transduce cells that are then administered to the patient (ex vivo gene therapy).
With its unique potential to offer treatment for or even cure a range of unmet genetic disorders, GT is a rapidly evolving therapeutic tool. The evolution of GT processes and product understanding is paralleled by continuous efforts from regulatory bodies, to provide the necessary guidance to the biopharmaceutical industry to ensure appropriate controls on product safety, quality and efficacy.
The last two years have seen an increase in regulatory guidance released by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Both regulatory bodies have published final versions of their recommendations on quality, nonclinical and clinical requirements for GT products (see Table 1 to Table 4).
The Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products were released in 2017 [26]. The guideline explores the expectations of quality standards, in the manufacturing of this class of therapeutics.
Additionally, Japan’s Ministry of Health, Labour and Welfare (MHLW) released the document Ensuring the Quality and Safety of Gene Therapy Products in 2019[27]. In 2020, the Centre for Drug Evaluation (CDE) in China published the Technical Guideline for Drug Research and Evaluation of Gene Therapy Products[28].
CMC development and registration
The regulatory requirements for GT are designed to ensure patient safety throughout the programme, with the expectation to improve process and product understanding as the programme evolves. Consequently, the regulatory framework becomes increasingly rigid, as the product moves from nonclinical to clinical phases.
A degree of flexibility is acknowledged by regulatory bodies, since earlier process and product knowledge for GT products might not be leveraged to the same extent, as for more conventional biotherapeutics.
As a result, health agencies have implemented special considerations for CMC strategies. Programmes like the EMA’s PRIME support the development of products for unmet medical conditions to expedite access to patients. This is achieved by providing applicants with early-stage scientific advice and enhanced guidance, in the preparation of Module 3 quality data packages. Several alternative approaches to CMC development and the submission of dossier contents related to quality are described in the PRIME document[10]. These focus on starting materials, comparability, process validation, analytical control strategy, specifications, and stability.
As for any other product, data must be gathered throughout the development phases to ensure that the specified identity, quality, purity, and potency of the product can be consistently achieved. Due to the novelty of the technology behind GT product manufacturing, process and product understanding are still evolving. Therefore, the critical process parameters (CPPs) and critical quality attributes (CQAs), which demonstrate process and product control, will be evaluated and redefined until the filing of the marketing authorisation application (MAA) or biologics license application (BLA).
For products in expedited programs like EMA’s Accelerated Assessment or FDA’s Breakthrough Therapy, the challenge is in identifying and generating the amount of quality data necessary to support approval, whilst operating under constricted timelines.
A constrained control strategy based on additional specification tests, in-process controls and additional Critical Process Parameters (CPPs) with narrower ranges can be leveraged to support the deferral of some activities related to process validation. When suitable data has been gathered postapproval, an appropriate variation could be submitted to relax the control strategy, for example by downgrading a CPP to non-critical or removing the CPP.[10]
The option of deviating from the traditional requirements of three process performance qualification (PPQ) batches is made available to PRIME applicants, provided that a strong benefit over risk can be demonstrated. Plans to gather the necessary data to demonstrate the effectiveness and reproducibility of the process post approval will need to be agreed with the regulatory agency.[10]
Concurrent validation, where the execution of validation studies is performed concurrently with the commercialisation of the validation batches, is also discussed in the PRIME guidance.[10] A robust quality risk management should demonstrate that the benefits of this approach to patients overcome safety concerns.
Due to the novelty of GT products, analytical method development is expected to mature from early to late clinical phases. Some tests might not be in place at early stages, and developers may be able to access state-of-the-art analytical platforms only as they get closer to pivotal clinical studies.
The degree of method development, qualification and validation expected for GT products depends on the phase. Early phase regulatory expectations focus on a core set of assays to control and demonstrate safety. Analytical methods for identity, purity and content (including viral genome and viral particle concentrations) should also be established, although they are not expected to be validated prior to the initiation of pivotal (Phase III) clinical studies.
With regard to potency, the EMA states that “a potency assay indicative of at least one aspect of the mechanism of action (MOA) should be developed and qualified before first-in-human (FIH) study” and that “surrogate potency markers can be considered for release test”, provided their relevance to the MOA is demonstrated.[1] The FDA indicates that “a potency assay is not required to initiate early phase clinical studies, but having a well-qualified assay to determine dose is recommended.[17]
With safety being the focus of Phase I studies, regulatory bodies will expect methods for sterility, mycoplasma, endotoxin, adventitious viruses, in vitro and replication competent viruses to be developed, qualified, and validated at this point. A model of the CMC approach for the phase appropriate programme development is summarised in Table 5.
Table 1: EMA guidelines on gene therapy
| Title | Latest Update |
|---|---|
| Guideline on quality, nonclinical and clinical requirements for investigational advanced therapy medicinal products (ATMPs) in clinical trials[1] | 2019 |
| Guideline on safety and efficacy follow-up and risk management of ATMPs[2] | 2008 |
| Quality, nonclinical and clinical aspects of gene therapy medicinal products[3] | 2018 |
| Guideline on development and manufacture of lentiviral vectors[4] | 2005 |
| Nonclinical studies required before first clinical use of gene therapy medicinal products[5] | 2008 |
| Nonclinical testing for inadvertent germline transmission of gene transfer vectors[6] | 2006 |
| Risk-based approach according to Annex I, part IV of Directive 2001/83/EC applied to ATMPs[7] | 2013 |
| Follow-up of patients administered with gene therapy medicinal products[8] | 2009 |
| Scientific requirements for the environmental risk assessment of gene therapy medicinal products[9] | 2008 |
| Toolbox guidance on scientific elements and regulatory tools to support quality data packages for PRIME marketing authorisation applications[10] | 2021 |
Table 2: EMA reflection papers on gene therapy
| Title | Latest Update |
|---|---|
| Design modifications of gene therapy medicinal products during development[11] | 2012 |
| Quality, nonclinical and clinical issues relating specifically to recombinant adeno-associated viral vectors[12] | 2010 |
| Management of clinical risks deriving from insertional mutagenesis[13] | 2013 |
Table 3: EMA questions and answers on gene therapy
| Title | Latest Update |
|---|---|
| Questions and answers on comparability considerations for ATMPs[14] | 2019 |
| Questions and answers on gene therapy[15] | 2010 |
| Questions and answers on the principles of good manufacturing practice (GMP) for the manufacturing of starting materials of biological origin used to transfer genetic material for the manufacturing of ATMPs[16] | 2021 |
Table 4: FDA guidelines on gene therapy
| Title | Latest Update |
|---|---|
| Chemistry, manufacturing, and controls (CMC) information for human gene therapy investigational new drug applications (IND)[17] | 2020 |
| Testing of retroviral vector-based gene therapy products for replication competent retrovirus (RCR) during product manufacture and patient follow-up[18] | 2020 |
| Long-term follow-up after administration of human gene therapy products[19] | 2020 |
| Human gene therapy for haemophilia[20] | 2020 |
| Human gene therapy for retinal disorders[21] | 2020 |
| Human gene therapy for rare diseases[22] | 2020 |
| Interpreting sameness of gene therapy products under the orphan drug regulations[23] | 2020 |
| Human gene therapy for neurodegenerative diseases[24] | 2021 |
| Potency tests for cellular and gene therapy products[25] | 2011 |
Quality considerations: analytical method development and comparability
Given the complex action mechanism of GT products, a suitable potency assay should be defined to represent the elements involved in delivering the pharmacological effect. Ideally, quantitative, in vitro potency assays should be developed. The assays must be able to measure the product specific biological function and demonstrate a correlation to clinical efficacy. Recommendations are given for a matrix approach, where a single biological or analytical assay might be insufficient in appropriately describing potency.[25] In these cases, , it is recommended to rely on a combination of complementary assays, or assay matrix, to provide an adequate measure of potency.
The correlation of all these assays to a relevant biological activity needs to be demonstrated, to provide an adequate measure of product potency. The assays included in the matrix can be either biological (relying on the use of live cells) and/or analytical, with a qualitative and at least one quantitative read-out. Surrogate (non-biological) analytical assays including immunochemical, biochemical, and molecular methods, can also be proposed, if the biological method to prove potency cannot be validated to regulatory expectations. A clear link between the surrogate and potency assay should be demonstrated, based on the available product characterisation.
Acceptance criteria should be set, which will likely be tightened as clinical evidence develops.
Before entering the pivotal clinical study, a potency assay, with at least one quantitative element should be established, with predefined acceptance and rejection criteria.
The scope of current ICH guidelines extends to the CMC aspects of GT products, including ICH Q6B for Drug Substance and Drug Product characterisation.[29] Although the analytical method development for GT products is not as advanced as for conventional biotherapeutics, product characterisation is still expected to be executed to the extent possible. For GT products, this entails a thorough molecular and structural description of the viral vector and the transgene, including any product-specific variants such as post-translationally modified viral proteins and aggregates. Of particular importance is the identification, characterisation, and control of product-related impurities, such as empty viral particles and particles incorporating genomic sequences other than the expected transgene. This is due to their potential involvement with immunogenic response.
Extended product characterisation should be introduced as early as possible in the development programme. Despite challenges regarding the availability of suitable analytical methods, early investment in extended product characterisation will generate additional product and process knowledge. This will then prove invaluable in the definition of any comparability study which might be needed to support process changes.
An extended product characterisation will also be beneficial for demonstrating lot-to-lot consistency, as well as identifying additional impurities to inform stability protocols. Advanced understanding of product CQAs will also facilitate the development of a matrix approach and surrogate assays to measure potency. This is achieved by strengthening the link between product quality attributes and biological activity.
As for other biotechnological products, regulatory criteria for the comparability studies of GT products are derived from the ICH Q5E. However, several aspects of the GT programmes make meeting expectations challenging.[30] Most products target rare conditions and therefore affect a smaller patient population. Consequently, compared to other biologics manufacturing is typically performed at a smaller scale and with limited batch numbers.
This means that representative material from pre-change processes is not always available, thus precluding side-by-side testing.
Comparison of historical batch data to support comparability therefore relies on a thorough understanding of the method performance.
Although ICH Q5E guidance expects comprehensive comparability studies, a reduced study involving a selection of CQAs could be justified for accelerated approval schemes and when sample availability may limit the extent of the comparability exercise. A risk-based strategy should be used to support the inclusion of a subset of CQAs in the study, based on their connection to efficacy and safety and the extent to which they may be impacted by process change(s).
A lack of suitable reference standards for most viral vectors exacerbates the importance of analytical method development. A thorough understanding of the method performance is required, as retained samples from pre-change batches are not always available, therefore preventing the execution of side-by-side testing.
Of note is the work being performed by The Standards Coordinating Body for Gene, Cell, and Regenerative Medicines and Cell-Based Drug Discovery (SCB) [Standards Coordinating Body], who are collaborating with cell and GT manufacturers to develop standards. The establishment of internationally recognised and certified standards over the next five years is expected to accelerate analytical development.
Table 5: Example of phase appropriate CMC development for gene therapy products
| Phase | Major CMC milestones |
|---|---|
| Early stage to nonclinical | Establishment of target product profile (TPP) and development of quality target product profile (QTPP), definition of potential CQAs |
| Phase I |
|
| Late Phase II/III |
|
| Postapproval |
|
Conclusion
The evolving regulation of GT products reflects its novelty and complexity. Accelerated approval pathways are of extreme benefit to the patients. However, they impose time constraints on programme development, thus challenging aspects of CMC development as the programme moves rapidly through clinical phases. Early interaction and scientific advice by regulatory bodies should be leveraged whenever possible, especially when alternative pathways are being considered for accelerated approval. Based on the rigorous evaluation of risks and benefits, the flexibility for phase-appropriate CMC development can be explored and justified. However, this does not mean limiting the overall amount and quality of data submitted to support marketing authorisation. Flexibility in regulatory expectation and CMC commitments is reflected in identifying and justifying opportunities for submitting ad interim sub-packages of data at different times, compared to canonical approval pathways, and deferring to post-approval commitments for providing the complete body of data.
As sponsors gain additional understanding of GT processes and products, additional knowledge and experience becomes available to regulatory bodies to guide the industry.
The interaction between applicants and regulatory bodies continues to be vital for targeting currently unmet medical conditions. The newly launched Bespoke Gene Therapy Consortium, which the FDA joined in 2021, is an example of how the synergism between regulatory agencies and pharmaceutical developers is being explored to improve and accelerate gene therapy manufacturing and production processes, by streamlining regulatory requirements and tools for the approval of gene therapy products.[31]
References:
[1] EMA. Draft guideline on quality, nonclinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials (EMA/ CAT/852602/2018). 2019. Available at: httpsGuideline on quality, non-clinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials (europa.eu) (Accessed 21 March 2022).
[2] EMA. Guideline on safety and efficacy follow-up and risk management of advanced therapy medicinal products (EMEA/149995/2008). 2008. Available at:GUIDELINE ON SAFETY AND EFFICACY FOLLOW-UP - RISK MANAGEMENT OF ADVANCED THERAPY MEDICINAL PRODUCTS (europa.eu) (Accessed 21 March 2022)
[3] EMA. Guideline on the quality, nonclinical and clinical aspects of gene therapy medicinal products (EMA/CAT/80183/2014). 2018. Available at: Guideline on the quality, non-clinical and clinical aspects of gene therapy medicinal products (europa.eu) (Accessed 21 March 2022)
[4] EMA. Guideline on development and manufacture of lentiviral vectors (CHMP/ BWP/2458/03). 2005. Available at: Guideline on Development and Manufacture of Lentiviral vector (europa.eu) (Accessed 21 March 2022)
[5] EMA. Guideline on the nonclinical studies required before first clinical use of gene therapy medicinal products (EMEA/CHMP/GTWP/125459/2006). 2008. Available at: Guideline on the Non-Clinical Studies Required before First Clinical Use of Gene Therapy Medicinal Products (europa.eu) (Accessed 21 March 2022)
[6] EMA. Guideline on nonclinical testing for inadvertent germline transmission of gene transfer vectors (EMEA/273974/2005). 2006. Available at: Annex to NfG - nonclinical testing - germline transmission (europa.eu) (Accessed 21 March 2022)
[7] EMA. Guideline on the risk-based approach according to Annex I, part IV of Directive 2001/83/EC applied to Advanced Therapy Medicinal Products (EMA/ CAT/CPWP/686637/2011). 2013. Available at: Guideline on the risk-based approach according to Annex I, part IV of Directive 2001/83/EC applied to Advanced Therapy Medicinal Products (europa.eu) (Accessed 21 March 2022)
[8] EMA. Guideline on follow-up of patients administered with gene therapy medicinal products (EMEA/CHMP/GTWP/60436/2007). 2009. Available at: Guideline on Clinical follow-up gene therapy (europa.eu) (Accessed 21 March 2022)
[9] EMA. Guideline on scientific requirements for the environmental risk assessment of gene therapy medicinal products (EMEA/CHMP/GTWP/125491/2006). 2008. Available at: Guideline on Scientific Requirements for the Environmental Risk Assessment of Gene Therapy Medicinal Products (europa.eu) (Accessed 21 March 2022)
[10] EMA. Draft toolbox guidance on scientific elements and regulatory tools to support quality data packages for PRIME marketing authorisation applications. 2021. Available at: Draft Toolbox guideline on scientific elements, regulatory tools to support quality data packages in PRIME marketing authorisation applications (europa.eu) (Accessed 21 March 2022)
[11] EMA. Reflection paper on design modifications of gene therapy medicinal products during development (EMA/CAT/GTWP/44236/2009). 2012. Available at: Reflection paper on design modifications of gene therapy medicinal products during development (europa.eu) (Accessed 21 March 2022)
[12] EMA. Reflection paper on quality, nonclinical and clinical issues relating specifically to recombinant adeno-associated viral vectors (EMEA/CHMP/GTWP/587488/2007 Rev. 1). 2010. Available at: reflection-paper-quality-non-clinical-clinical-issues-related-development-recombinant-adeno_en.pdf (europa.eu) (Accessed 21 March 2022)
[13] EMA. Reflection paper on management of clinical risks deriving from insertional mutagenesis (EMA/CAT/190186/2012). 2013. Available at: Reflection paper on the clinical risks deriving from insertional mutagenesis (europa.eu) (Accessed 21 March 2022)
[14] EMA. Questions and answers on comparability considerations for Advanced Therapy Medicinal Products (ATMP) (EMA/CAT/499821/2019). 2019. Available at: Question and Answers. Comparability considerations for Advanced Therapy Medicinal Prodcuts (ATMP) (europa.eu)(Accessed 21 March 2022)
[15] EMA. Questions and answers on gene therapy (EMA/CHMP/GTWP/212377/2008). 2010. Available at: Questions and Answers on Gene Therapy (europa.eu) (Accessed 21 March 2022)
[16] EMA. Questions and answers on the principles of GMP for the manufacturing of starting materials of biological origin used to transfer genetic material for the manufacturing of ATMPs (EMA/246400/2021). 2021. Available at: Questions and answers on the principles of GMP for the manufacturing of starting materials of biological origin used to transfer genetic material for the manufacturing of ATMPs (europa.eu) (Accessed 21 March 2022)
[17] FDA. Guidance for FDA Reviewers and Sponsors. Content and review of chemistry, manufacturing, and control (CMC) information for human somatic cell therapy investigational new drug applications (INDs). 2020. Available at: Guidance for FDA Reviewers and Sponsors: Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy Investigational New Drug Applications (INDs) (Accessed 21 March 2022)
[18] FDA. Guidance for Industry. Testing of retroviral vector-based human gene therapy products for replication competent retrovirus during product manufacture and patient follow-up. 2020. Available at: Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus During Product Manufacture and Patient Follow-up; Guidance for Industry (fda.gov) (Accessed 21 March 2022)
[19] FDA. Guidance for Industry. Long term follow-up after administration of human gene therapy products. 2020. Available at: Long Term Follow-Up After Administration of Human Gene Therapy Products; Guidance for Industry (fda.gov) (accessed 5 August 2021).
[20] FDA. Guidance for Industry. Human gene therapy for haemophilia. 2020. Available at: Human Gene Therapy for Hemophilia; Guidance for Industry (fda.gov)
[21] FDA. Guidance for Industry. Human gene therapy for retinal disorders. 2020. Available at: Human Gene Therapy for Retinal Disorders; Guidance for Industry (fda.gov) (Accessed 21 March 2022)
[22] FDA. Guidance for Industry. Human gene therapy for rare diseases. 2020. Available at: Human Gene Therapy for Rare Diseases; Guidance for Industry (fda.gov) (Accessed 21 March 2022)
[23] FDA. Draft Guidance for Industry. Interpreting sameness of gene therapy products under the Orphan Drug Regulations. 2020. Available at: Interpreting Sameness of Gene Therapy Products Under the Orphan Drug Regulations; Guidance for Industry (fda.gov) (Accessed 21 March 2022)
[24] FDA. Draft Guidance for Industry. Human gene therapy for neurodegenerative diseases. 2021. Available at: Human Gene Therapy for Neurodegenerative Diseases; Draft Guidance for Industry (fda.gov) (Accessed 21 March 2022)
[25] FDA. Guidance for Industry. Potency tests for cellular and gene therapy products. 2011. Available at: Guidance for Industry Potency Tests for Cellular and Gene Therapy Products (fda.gov)
[26] Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products. Available at: atmp_guidelines_en_0.pdf (europa.eu) (Accessed 21 March 2022)
[27] Japan Ministry of Health, Labour and Welfare, Ensuring the quality and safety of gene therapy products. Notifications and administrative notices. 2019. 000235607.pdf (pmda.go.jp) (Accessed 21 March 2022)
[28] National Medical Products Administration: Technical Guidance for Pharmaceutical study and Evaluation of Gene Therapy Products. 2020
[29] ICH Q6B: Specifications: test procedures and acceptance criteria for biotechnological/ biological products. 1999. Available at: ICH Q6B Specifications: test procedures and acceptance criteria for biotechnological/biological products | European Medicines Agency (europa.eu) (Accessed 21 March 2022)
[30] ICH Q5E: Biotechnological/biological products subject to changes in their manufacturing process: comparability of biotechnological/biological products. 2004. Available at: Q5E Guideline.pdf (ich.org)(Accessed 21 March 2022)
31. Sumimasa Nagai. Flexible and Expedited Regulatory Review Processes for Innovative Medicines and Regenerative Medical Products in the US, the EU, and Japan. Int. J. Mol. Sci. 2019, 20, 3801; doi:10.3390/ijms20153801
32. FDA, NIH, and 15 private organizations join forces to increase effective gene therapies for rare diseases. 2021. Available at: FDA, NIH, and 15 private organizations join forces to increase effective gene therapies for rare diseases | FDA (Accessed 21 March 2022).
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