As leaders in cell and gene therapy consulting, Josee Champagne and Calley Hirsch, partners in the weCANtranslate network, are participating in this year’s blog carnival on behalf of the Stem Cell Network. Reflecting on this year’s topic, here are their thoughts on the impressive number of cell and gene therapies in clinical trials, whether regulatory approval will be a bottleneck, and ultimately if the system can handle all the new therapies getting approved.
Cell culture plate image: photo credit CCRM
With thousands of cell and gene therapy (CGT) products in clinical trials worldwide and 32 first-generation products approved by the U.S. Food and Drug Administration (FDA) for market use1, the timing is ideal to reflect on learnings and summarize the prospective challenges developers must overcome to enter an increasingly crowded market. Multiple experts would agree that three of the primary hurdles include (1) reducing product cost; (2) streamlining clinical development; and (3) gaining a clearer regulatory understanding. Below, three associated solutions are outlined. Together, they offer an integrated strategic approach supporting success from R&D through commercialization.
- Building scalable and cost-effective manufacturing processes for commercial success.
Reported “list prices” (defined as the initial price set by the company before negotiated discounts with payors) for approved autologous CAR T therapies range from USD$373,000 – $475,000/infusion while the hemophilia B gene therapy, SKYSONA, tops out at USD$3,000,000 even before considering associated costs like induction therapy, immune suppression, hospitalization, and side effect treatment expenses2,3. Combining these prices with the FDA projection of 10 – 20 CGT approvals yearly by 20254, it’s undeniable that the current trajectory is unsustainable and will continue to force reimbursement decision-makers to safeguard against bankrupting global health-care systems, unless the decreased cost of CGTs is realized.
Among the most significant CGT cost drivers are development time, manufacturing complexity and supplies. Investment in translational activities early in development is integral to cost effective translation from R&D discovery to clinical entry (an area that has recently become a priority for government grants and academic agencies). Unlike first generation CGTs, developers have entered an era where there’s no longer a need to “fly the plane as it’s being built” nor a reason for inefficient clinical/commercial transitions.
Translational leaders have the expertise to prepare blueprints, including target product profiles (TPPs), quality target product profiles (qTPPs) and process flow diagrams (PFDs) that integrate modular technology platforms, proven supply chains, and economies of scale to avoid unnecessary inefficiencies. With this framework, Quality by Design (QbD) principles are applied to streamline development in a focused manner, enabling ongoing comparability, early process understanding, and incremental improvements in product quality, manufacturability and cost-effectiveness. Together, these components promote lean development and steadily build toward robust and de-risked commercial processes backed by increasing regulatory compliance.
- Designing clinical trials focused on demonstrating clinically meaningful differentiation.
Among the CGTs approved for market use, many have emerged with overlapping functionalities, including CAR T products targeting identical antigens and indications that demonstrate incremental improvements compared to their competitors. This is similarly the case for numerous rare disease therapeutics and novel product compositions in clinical trials battling for identical patient populations. This shifts the benefit-risk proposition rapidly towards higher thresholds for safety and efficacy in those areas. As the future marketplace and trial landscape become more crowded, an increased focus on finding unmet clinical needs and differentiation is emerging, where truly disruptive products that show advancements in function, efficacy and/or safety will have a competitive edge.
Clinically meaningful product differentiation can only be proven through properly powered preclinical and clinical trial designs. This starts early in product development with the selection of appropriate (“relevant”) preclinical models for good laboratory practices (GLP) studies, which can be confirmed in pre-submission interactions with the regulators that start by outlining a preclinical strategy. This sets the stage for clinical trial designs guided by the TPP and tactical considerations related to clinician practices, health care infrastructure, site qualification and patient recruitment. As competition for patient access and clinician/medical institute support continue to raise challenges, the onus increasingly falls on developers to establish robust and promising preclinical datasets and implement creative trial design solutions, such as running basket trials to streamline Phase 1 safety readouts, to limit unnecessary clinical trial effort and expenses.
- De-risking regulatory uncertainty.
With clinical holds becoming more prevalent for next generation CGTs and first movers, the industry response has been to cite “regulatory uncertainty” as a barrier to CGT translation, implying or directly requesting that regulators should provide additional guidance. However, establishing new guidance requires significant experience and time, and inevitably leads to prescriptive expectations that are later deemed inflexible and often undesirable from the viewpoint of the CGT developers.
With a change of perspective and expert insights, regulatory uncertainty presents a unique opportunity to differentiate by navigating one’s own fate. Developers build in regulatory compliance based on extrapolation from current guidelines to reduce regulatory risk as they approach the clinic and market. This slant requires strategic dialogue with the regulators, where the developer is now the expert and educates the regulators on how their expectations are met in new ways, rather than consistently seeking guidance on how to proceed, and secondarily streamlines conversations to reduce the burden on regulators.
The CGT field is becoming increasingly competitive and quickly evolving beyond recycled concepts, products and the status quo. Furthermore, the global health-care system is unlikely to support the mass of products projected for market approval even with significant reductions in pricing. To be competitive, translational concepts and experts must be integrated early (following R&D discovery) to streamline development around products designed for commercial success, with clear and clinically differentiating outcomes, and a de-risked regulatory path to market.
Our blog is just one of many covering this topic as part of Signal’s seventh annual blog carnival. Click here to read what other bloggers think about this.
References
- Blog | BioInformant
- CAR-T: What Is Next? – PMC (nih.gov)
- PharmaBoardroom – Top Five Most Expensive Drugs in the World)
- Statement from FDA Commissioner Scott Gottlieb, M.D. and Peter Marks, M.D., Ph.D., Director of the Center for Biologics Evaluation and Research on new policies to advance development of safe and effective cell and gene therapies | FDA
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