Jacques Galipeau, MD FRCP(C)
President, ISCT
Don and Marilyn Anderson, Professor in Oncology
Associate Dean for Therapeutics Development
University of Wisconsin School of Medicine and Public Health
The Cell and Gene Therapy (CGT) field has now repeatedly demonstrated that cells - as living therapeutics - cleverly engineered with synthetic biology, can provide durable cancer remission, and cure hereditary hematological disorders. This milestone is historically analogous to Chuck Yeager showing in 1947 that strapping the human frame to a jet engine will allow it to break the sound barrier. A scant 22 years later, Neil Armstrong stepped on the moon. We can unabashedly claim that in 2023 we collectively met our Chuck Yeager moment and envisage an aspirational moon shot whereas a person with serious medical need can go to a living therapeutics dispensary and receive an off-the-shelf CGT to harmlessly cure what ails them. Our wizard’s grimoire keeps growing and evermore wonderous feats are foreordained. Although exciting, technical genius is only the first chapter in a trilogy where regulatory approval followed by patient accessible deployment need follow.
Recently scanning though my LinkedIn feed, I came upon a presentation by MIT economics Professor Andrew Lo[i] given in 2022 at a CGT conference addressing this issue[ii]. He introduces us to the economic concept of uncertainty which can be metricized as the denominator of the Sharpe ratio—where unknown expected returns (rewards) and volatilities (risks) are expressed statistically. In essence, the unknown unknowns – eg: uncertainty, are the drivers (or headwinds depending on your perspective) that inform behavior of the single most important ‘OMIC in CGT development and deployment: econOMICs. Economics as in providing resources to reach marketing approval and economics as in sustainable deployment in real-world adoption of CGTs[iii].
Recognizing the impact of economics on meeting our moon shot goals, we also need to better understand the policy culture that impacts the vexing uncertainty of rapidly evolving field captured mathematically by Sharpe ratio. The historic development of supersonic flight does give some insights. Following Yaeger’s breakthrough, the US Navy’s transition to jets from fixed wing planes is a bit where we are. The U.S. Naval War College published a review speaking to the challenges in rapidly transitioning from obsolescent propellered planes to new disruptive technology of jet powered flight, the rapid incremental cycling of remedies to meet those challenges, and crucially the culture change that needed to take place to allow innovation to occur and to chip away at uncertainty[iv].
Here is where the culture of economics and regulatory policy need to evolve in parallel to CGT technical innovation to allow for emergence of beneficent CGT cures. Indeed, as recently highlighted in a Nature editorial[v] the legacy approval and reimbursement regulatory schemes for development and commercialization of traditional medicinal chemistry treatments are entirely maladapted to the promise of one-and-done living therapeutics cures.
Living cell therapies are distinct from medicinal chemistry inasmuch as that GMP-compliant manufacture of Phase I clinical trial investigational cell drugs can be readily done by contract manufacturing organizations as well as by a large inventory of accredited hospital centers affiliated with elite academic institutions worldwide. This decentralized, distributed manufacturing and phase I trial capacity would allow for rapid cycling through first-in-human studies that are the single most important step change in reducing uncertainty for a novel CGT. A “successful” phase 1 clinical trial, where a living cell drug is deemed safe and an anecdotal signal to efficacy is observed would render the strategy RMAT eligible (in USA) and conditionally approved (in Japan). But, a successful Phase 1 trial is simply the end of the beginning along the journey of marketing approval. The toll for the rest of the road is high. Therefore, de-risked CGTs would be meritorious for robust economic investment following the Sharpe ratio logic and creative thinking around sustainable reimbursement schemes permissive for patient access are also needed to meet our moon shot aspirations.
That said, the FDA and other international regulatory organizations have come through with pathways to accelerate cost-effective CGT development such as FDA RMAT designation[vi] and EMA PRIME scheme[vii]. The Japanese PMDA went a step further to grant risk-adapted early conditional approval of CGTs after Phase I[viii] and further chip away at the economic uncertainty that impairs development of promising CGT technologies in Japan. These early designation endorsements by regulators – identifying likely CGT winners in the marketing approval clinical development scheme – goes a long way to mitigate perception of economic risk and uncertainty. This type of policy should assuage financial partners in industry and government to invest. Reducing uncertainty while maintaining safety should be at the heart of evolving regulatory policy worldwide. Drug Regulators should give merit to this path and further reduce friction for development if their remit is to provide their citizenry with access to curative living therapeutics.
We at ISCT are best positioned to bring to the table an international perspective on CGT discovery, manufacturing, regulatory, commercialization and end user clientele viewpoints to provide tractable solutions addressing the uncertainties of living therapeutics development and striving for the highest Sharpe ratio achievable where reward outweighs risk in making living therapeutics cures a reality.
Much to chat about in Paris!
#Feature
#ISCTCommunity
#Feature
#ISCTCommunity
#CommunityFeature