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Cell & Gene Therapies: A roadmap to solving 6 challenges over the next decades

Paolo Siciliano

By Dr Paolo Siciliano

Cell and Gene

20 September 2021


This article was first published in Cell & Gene

This past year has seen remarkable progress in the growth of cell and gene therapies with the approval of new therapies, their adoption in the clinical space, and the growth of RNA therapeutics to address COVID-19.

This progress will lead to a better understanding of the underlying physiology and pathology of disease and greater availability of personalized treatments, especially for rare indications. In addition, advances in cell reprogramming, genetic editing, and manufacturing mean affordable off-the-shelf (allogeneic) cell & gene therapies will be available globally for a broad range of diseases and uses. However, the pathway to this outcome is and will be difficult.

In this article, we will review six major issues affecting the cell & gene therapy space and provide recommendations for life sciences companies to be successful.

1. Early research: better understanding of the patient and indication

Several cell & gene therapies are being and have been developed for rare and genetic diseases. However, the preclinical models of these indications are often poor in their predictive values (e.g., limited durations in vivo models compared to patients), resulting in them having a limited translation to the clinical setting. These models often have short durations that do not accurately reflect the patients’ condition at the time they will present for enrollment in trials or for treatment. This is accompanied by limited data from biomarkers or surrogate measures from dose response studies that can be used to predict allometric scaling for first in human trials. Finally, companies need to robustly examine results from preclinical studies across a number of outcome measures to determine if they are sufficiently encouraging to move into clinical trials.

Cell & gene therapy developers need to focus on understanding the underlying pathology of diseases from a genetic and molecular perspective to model the biology and effects of potential therapies. This requires investment in multi-omics research and the use of AI and Big Data analytics to model and predict disease occurrence and progression. These tools can better identify target antigens, providing truly personalized medicine. Larger patient populations in more common indications (e.g., Alzheimer’s disease) can be broken down to focus on contributing factors resulting in greater responses to novel interventions. In addition, organizations should investigate expanding to new and currently underserved indications along with orphan indications to capitalize on new technologies early and capture novel markets (Kiriiri et al 2020 Underserved indications, Jayasundara 2019 Orphan drug development costs). The intelligent use of these new data sets will provide investigators with key insights in the development of cell & gene therapy.

2. Clinical trials: smarter designs to support study execution

Cell & gene therapies are often aimed at addressing rare and orphan indications with low patient prevalence. Finding sufficient numbers of patients to conduct studies to establish safety profiles of novel therapeutic platforms is problematic with traditional study designs. Dose response curves will be difficult to ascertain due to the limited statistical power associated with the small numbers of patients available to establish treatment cohorts. Similarly, traditional randomized controls trials may not be suitable or ethically acceptable when working in life-threatening indications.

Developers need to be innovative in increasing the efficiency of studies and accelerating their execution in patients with unmet needs. To do so, cell & gene therapy companies need to work with regulatory agencies early in the development pathway to create and refine hypothetical study designs, such as reducing cohort sizes with stratified patient groups. Once study designs are agreed upon, there will be a need to maintain good communications throughout clinical trials as knowledge is gathered on their execution and outcomes. The FDA provides early discussions at the time of the pre-IND meeting to discuss clinical studies with the INitial Targeted Engagement for Regulatory Advice on CBER producTs (INTERACT).

To expand the pools of patients available for recruitment in early-phase safety studies, sponsors should consider basket-type designs with the inclusion of multiple similar indications (e.g., chronic inflammatory diseases) in the same trial in early-phase safety studies accelerating their completion. This can be accompanied by establishing and/or using patient registries to identify potential subjects. Sponsors should foster relationships with patient advocacy groups and institutions to help provide educational materials and forums to inform both the lay public and medical professionals on the relevant diseases and bases of these novel therapies.

Study execution can also be accelerated via the use of adaptive/flexible trial designs to reduce study durations and cohort sizes (Bothwell et al 2018 Adaptive designs). This is aided by maintaining databases of previous trials to refine expected marker levels, providing an enhanced rationale in designing study cohorts. There is also a commercial basis for this approach to gain and maintain an advantage when searching for patients from indications with relatively small prevalence. Studies that recruit and complete on schedule are more likely to be successful. Finally, this approach reassures regulators that you are trying to maximize the data collected from each patient enrolled in a study.

3. Manufacturing and supply chain: relieving bottlenecks

Production of cell & gene therapies is a complex process requiring specialist manufacturing contractors with skilled labor pools using expensive reagents and equipment. Backlogs are common when establishing manufacturing cycles to produce materials for early clinical studies, for scaling up for later studies, and eventually for entering the commercial market. The production pathways for affordable off-the-shelf cell & gene therapies commonly take up to two weeks or more between receipt of starting materials and their release for use and may require multiple rounds of manufacturing to establish multiple banks of drug substance and the final drug product. These production runs also carry an inherent of risk of batches being out of specification or lost due to sterility issues, both of which are associated with higher numbers of processing steps and/or manual handling.

Scale-up and standardization of manufacturing processes must be incorporated early in the development cycle to avoid expensive and time-consuming challenges when larger volumes are required for later trials and commercialization. Automation must be leveraged to reduce the number of steps in the production process. This will reduce variability in manufacturing, the loss of product when drug substance is transferred between containers, and overall risks in the production process. Cell & gene therapy developers need to devise in-line and release tests for processes to improve quality and reduce costs as well as accelerate the release cadence.

In parallel, there is a need to work with material suppliers early to ensure consistency, availability, and quality to remove bottlenecks in supply chains. This may require forward planning over a 12- to 18-month period. Finally, there must be a focus on coordinating manufacturing pathways to align their scheduling with the patient journey and clinical activities, especially in products with shorter shelf lives.

4. Regulatory interactions: dispersing the fog of uncertainty

Traditionally, preparing for regulatory approvals for trials and licensing has been burdensome and unclear as developers moved through IND supporting studies and product design. Fortunately, now that a number of cell & gene therapy products are on the market, there are exemplar pathways for developers and regulatory agencies to follow and build upon. Regulatory agencies have developed accelerated pathways for the investigation and approval of cell & gene therapy products. For example, sponsors may apply for Regenerative Medicine Advanced Therapy (RMAT) designation for products addressing an unmet medical need. There are also Breakthrough Therapy designations and Fast Track designations that provide accelerated timelines and rolling reviews. The European Medicines Agency (EMA) provides accelerated assessment of medicines intended to target an unmet medical need via the PRIority MEdicines (PRIME) program.

However, every cell & gene therapy product is unique in some manner and regulatory interactions have not reached the level of a “tick box exercise” outlining all the requirements (boxes) for approval. Novel production or therapy platforms also produce extra challenges as regulatory authorities come to grips with these new technologies. Finally, while competent authorities in different territories are moving toward harmonization of the regulatory pathways for advanced therapies, they may have different requirements and outlooks on the data packages required for approval of novel products that need to be addressed by companies as they look to expand clinical trials across regions.

Companies need to work closely and openly with regulators from the beginning of the product design and testing cycle to understand their requirements for approving cell & gene therapy products (Warner et al 2020, regulatory interactions). They should consider the regulatory landscape when making portfolio decisions across programs and make use of expedited development programs for diseases with unmet need. Discussions should be held on how to leverage technologies and develop mechanisms to collect real-world evidence. Finally, while alignment among regulatory agencies in different regions is underway, companies in this sector need to lobby for international standardization and certainty in the regulation of cell & gene therapy products.

5. Reimbursement: achieving true value of Cell & Gene therapies

Cell & gene therapies may have truly life-changing and/or live-saving results with a “one and done” therapy affecting a lifelong change into young patients. Despite their ability to provide a solution to currently untreatable conditions, one of the main barriers to the wide adoption of cell & gene therapy is the extremely high price tag associated with them. While some currently available CAR-T therapies can range between $300K and $500K per dose, certain gene therapies hit a jaw-dropping cost of over $2 million per injection.

It can be difficult to determine reimbursement levels via the incremental cost-effectiveness ratio (ICER) incorporating differences in treatment costs against improvements in quality adjusted life years (QALYs) following the administration of advanced therapies. Cell & gene therapy companies will have limited amounts of clinical data at the time of approval of these therapies. This can make it difficult to estimate their positive effects over extended periods of time. It is also difficult to estimate the true value of these therapies in life-altering chronic indications.

ICER analysis can also be misleading in determining total patient care costs. Treatment costs for some life-altering and chronic indications can be relatively low when compared to their impact on the patients’ quality of life, skewing analysis and leading to lower than anticipated reimbursement values. There is also the possible loss of income in working-age patients and unpaid care from family members that may not be incorporated into the total costs of patient care. An example of this is the estimated medical costs of patient with Parkinson’s disease at $24,429 in 2017, with the non-medical costs estimated to be another $25,558 (Yang et al NPJ Parkinson’s Disease (2020) 6:15). All these issues make it difficult for cell & gene therapy companies to realize the value of their products and maintain investment in the sector.

There are strategies and tactical approaches that companies can undertake to aid in achieving consistent and appropriate reimbursement levels. These require an understanding of the elements of the ICER equation and how they contribute to the overall generation of the reimbursement level. First, focus on therapy areas with true unmet needs requiring ongoing care over extended time periods, as these are unlikely to have a widespread standard of care for efficiently treating those patients. Second, ensure you have the health economics capability to address and preempt payer concerns and make solid cases for reimbursement. Establish the tools and processes that need to be in place to monitor the effectiveness of a novel therapy. If they are not immediately available, determine how relevant metrics will be generated. Finally, work with payers to develop value-based contracts that are suitable for the market and the product over extended time periods that reflect the true costs of patient care.

6. Commercialization: expanding capabilities

Cell & gene therapy clinical research and initial adoption has traditionally occurred in a few tertiary centers of excellence with highly skilled staff and specialist infrastructure. However, relatively few healthcare systems offer this setting, resulting in the limited use of these products in the traditional secondary care health centers. Cell & gene therapy developers need to recognize the requirements for the use of their products in the clinic and tailor programs accordingly for their broader adoption. Finally, adoption of novel therapies requires a sufficiently large commercial opportunity that will justify investment by healthcare systems to address the cost of developing underlying infrastructure, staffing, and governance requirements for their delivery.

Adoption of novel therapies requires close collaborations with healthcare providers and the surrounding ecosystems. Cell & gene therapy companies need to develop hospital networks to provide training, support governance systems, and provide guidance to encourage the adoption of new therapies and procedures. Cell & gene therapy companies will need to work with healthcare providers to develop care pathways that encompass staffing, organizational capabilities, and infrastructure to support their therapies. Implementing cell & gene therapy is disruptive to current systems, requiring new routes of communication between hospitals, manufacturers, logistics firms, and materials providers. Governance, training needs, and IT compatibility need to be streamlined as much as possible to support all stakeholders within the healthcare setting. You also need to establish and maintain close relationships with key opinion leaders in relevant therapy areas to understand clinical thinking and requirements for the adoption of these novel therapies over the current standard of care. The relevant sales and medical teams need to be sufficiently skilled and able to leverage digital health platforms to educate and enable these healthcare providers to incorporate these new therapies in their treatment offerings and patient care.


It is undebatable that we are witnessing a revolution in therapeutics led by advances in regenerative medicine. Cell & gene therapies are likely to play a key role in reshaping the way we think about and approach medicine and disease treatment, across most therapeutic areas. However, the path to success for these revolutionary therapies is still paved with technical and commercial hurdles that need to be overcome for cell & gene therapies to achieve their full potential. Success will depend on companies forming new relationships with regulatory agencies, manufacturing groups, suppliers, payer organizations, and healthcare systems. All these stakeholders are interlinked to some extent and will need to cooperate closely to build a widely accessible new field of medicine. Today’s players must think in different ways to ensure they are part of tomorrow’s landscape.

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