The commercialization of cell and gene therapies: regulatory challenges
Despite a promising global demand and clinical potential, a number of regulatory challenges are impeding the translation of cellular based therapeutics from “bench to bedside”.
David Pettitt1 & David Brindley2
1Academic Surgeon & SENS Research Foundation Doctoral Scholar, University of Oxford, UK; email@example.com
2 University of Oxford, UK; firstname.lastname@example.org
Cell and gene-based therapies are exciting platform technologies that have the prospect of potentially curing what were once considered untreatable diseases (1) and transforming the current medical and surgical landscape. They are distinct from conventional pharmaceuticals, biologics and medical devices through their capacity to facilitate the de novo production of functional tissue (2, 3) and potential ability to remedy, rather than ameliorate, a spectrum of medical and surgical diseases.
Despite its relative infancy, the cell and gene therapy market has successfully established itself as a billion-dollar industry (4, 5), which is projected to continue growing with the support of an increasing number of marketable products, fiscal investment and strong M&A (merger and acquisition) activity (6). In 2014 alone, venture capital investment into the biotech sector surpassed US$9 billion (7) and transformed an industry that has historically been plagued by overly exuberant investments and multibillion-dollar losses (8). It has since matured into a stable and sustainable market that appears attractive for both future investment and long-term value.
A number of cell therapy products have achieved success across European Union (EU), United States (US) and global marketplaces. However, despite a promising global demand and favorable investment landscape, the translation of cellular based therapeutics from “bench to bedside” remains challenging. Producing cell therapies requires modernized approaches and complex manufacturing procedures that often involve the extensive manipulation of cells and/or the solicitation of cells for new or distinct functions (9). As such, cell therapies are considered as a different asset class to conventional biotech and pharmaceutical therapeutics (who use small- and macromolecule drugs) (10) and require highly specific regulatory and quality requirements to ensure patient safety.
In Europe, the US and other high-income economies such as Japan, Singapore and Hong Kong, cell therapies (and allied regenerative medicine initiatives) are required to advance through established clinical phase trials prior to approval – commonly known as the ‘pharmaceutical model’ (11, 12). In some cases, especially where cell and gene therapies are concerned, there is an insufficient number of patients for conventional trials, and in others, the ethics of randomizing potentially terminal patients into placebo arms when there appears to be a medicine targeted to their specific disease has been questioned.
These conventional drug development models can also take in excess of 15 years for market approval to be reached, have a failure rate that can exceed 95% and require levels of financing that can exceed US$2 billion (11, 13). This reliance on conventional clinical trial data unfortunately has a tendency to translate into spiraling development costs and significant delays in therapeutics reaching the clinic.
The technological and scientific progress that is commonplace with cell therapy products is outpacing the requisite regulatory guidance (14). Consequently, challenges relating to regulation are widely cited in the literature and presently, a number of regulatory barriers are impeding the progress of cellular based therapeutics and reducing their potential clinical impact. This is due to a number of factors but includes concerns regarding evidentiary standards, the need to navigate through convoluted regulatory pathways and the time ‘lag’ between technological progressions and accompanying regulation.
In the US, critics have challenged the suitability of the existing HCT/P regulatory frameworks, citing them as both outdated and fragmented, and have also contended the need for the Food and Drug Administration’s (FDA) extensive authority over cell based therapies, especially autologous therapies (1, 15, 16). In the EU, new drugs seeking EU-wide marketing approval must obtain authorization via the European Medicinal Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP), whereby marketing authorization applications (MAA) detailing product quality, safety and efficacy are evaluated in accordance with Regulation [EC] No 726/2004 and Directive 2001/83/EC (17, 18).
The inherent complexity of the EU and Member State autonomy can make regulatory harmonization difficult. Pearce et al (19) reported that member states have even classified the same cell therapy products differently – in part driven by the fact that classification requests submitted to the EMA are non-legally binding and subject to individual member state interpretation.
Challenges navigating regulatory requirements within the US, EU and globally have contributed to the materialization of a cottage industry in a phenomenon known as “stem cell tourism”. Here, providers are able to exploit loopholes or less stringent regulatory stipulations and offer untested cell therapies direct to consumers (20). Clinics are often situated overseas where treatments are more accessible and comparably inexpensive (21). In the US alone, a recent study estimated that up to 570 such clinics are currently in active operation (22). Regulatory bodies must therefore collaborate to develop appropriate implementation strategies that mitigate legal disparities concerning cell therapies across the EU and global markets.
Regulation of such a complex market is no doubt challenging and initiatives to expedite regulatory approval are being actively explored.Such initiatives include adaptive licensing or pathway processes in the EU and a number of accelerated mechanisms in the US, including breakthrough therapy designation and accelerated approval programs (23). However, before harmonization can be achieved on an international scale, regulatory frameworks must first be optimized at a regional level.
The transition to regulatory harmonization poses a number of practical and logistical challenges, which extend far beyond the scope of regulation itself. Besides ensuring that the requisite infrastructure is devised, implemented and stabilized, multiple stakeholders must also collaborate in order to surpass a number of wider translational or ‘commercialization’ barriers. These include the optimization of manufacturing processes, the design and implementation of novel clinical trial models, suitable cell therapy reimbursement mechanisms and market access strategies. Considerable coordination is also required between non-regulatory entities, which in the cell therapy arena, consists of a close interplay between academia and industry.
Presently, unified approaches are endeavoring to overcome such translational barriers – modified clinical trial models such as adaptive clinical trial designs are starting to become more prominent and regulators have reassuringly recognized the need for expediting the approval of promising therapeutic candidates whilst mitigating the potential dangers of unregulated products. Going forwards, it is essential that unified regulatory frameworks continue to safeguard patients whilst facilitating a streamlined approval process in order to achieve optimum patient benefit, economic sustainability and a valid contribution to global regulatory harmonization.
We express sincere thanks to the following organizations that have contributed to the CASMI Translational Stem Cell Consortium (CTSCC) as funding and events partners, without whom the consortium and the benefits it will bring to stem cell translation would be constrained:
GE Healthcare, the Center for Commercialization of Regenerative Medicine (CCRM), Sartorius Stedim Biotech (formerly TAP Biosystems), Lonza, the California Institute for Regenerative Medicine (CIRM), the Strategies for Engineered Negligible Senescence (SENS) Research Foundation, UK Cell Therapy Catapult, NIH Centre for Regenerative Medicine, the New York Stem Cell Foundation (NYSCF), ThermoFisher Scientific, Eisai, Medipost (US), Medipost (Korea), Celgene, Roche and Oxford Biomedica.
DB gratefully acknowledges personal funding from the Oxford Musculoskeletal National Institute for Health Research (NIHR), the Saïd Foundation and the SENS Research Foundation. DP gratefully acknowledges support from the CASMI Translational Stem Cell Consortium (CTSCC) and the Strategies for Engineered Negligible Senescence (SENS) Research Foundation.
Financial & competing interests disclosure
DB gratefully acknowledges personal funding from the Oxford Musculoskeletal National Institute for Health Research (NIHR) the Saïd Foundation, and the SENS Research Foundation. DB is a stockholder in Translation Ventures Ltd. (Charlbury, Oxfordshire, UK) and IP Asset Ventures Ltd. (Oxford, Oxfordshire, UK), companies that among other services provide cell therapy biomanufacturing, regulatory and financial advice to pharmaceutical clients. J Smith is a consultant with IP Asset Ventures Ltd.
DB also is subject to the CFA Institute’s codes, standards, and guidelines, so he must stress that this piece is provided for academic interest only and must not be construed in any way as an investment recommendation. Additionally, at time of publication, DB and the organizations with which he is affiliated may or may not have agreed and/or pending funding commitments from the organizations named herein.
DP gratefully acknowledges support from the CASMI Translational Stem Cell Consortium (CTSCC) and the Strategies for Engineered Negligible Senescence (SENS) Research Foundation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
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