One of the enduring conundrums around ground-breaking and potentially paradigm-shifting treatments such as CAR-T is the ever-thorny question of how fast to move them to market when the promise seems so great, but the evidence remains so patchy.
So far, top tier regulators such as the US FDA and the European Medicines Agency (EMA) have sought to square the circle by granting speedy access, but under strict parameters and only as a last- or late-line therapy option.
The EMA, for instance, has been quick out of the starting blocks to offer orphan status to the majority of cell and gene therapies under development, but only on condition that subsequent evidence is periodically submitted thereafter. Notably it has performed accelerated assessments of the most highly touted of this novel class of medicines, including two cell therapies for treating aggressive B-cell lymphomas — Novartis’s CAR-T and Gilead’s Yescarta — and one ex vivo gene therapy, Bluebird Bio’s Zynteglo, which treats the rare blood disorder beta-thalassemia.
A High Wire Balancing Act
The FDA, for its part, has sought to walk the tightrope between the benefits of early access and the potential, still-unknown, long-term safety risks, by obliging providers to follow up with patients who receive cell and gene therapies for 15 years post- treatment. This constitutes a timeframe considerably longer than for traditional biologics and is a tough ask for drugmakers operating in a climate in which patients are travelling long distances, often internationally, to have the therapy administered.
If we don’t manage to move in the direction of using biomarkers and intermediate endpoints to get there initially, it’s frankly hard to see how we can handle hundreds of gene therapies, especially for rarer disorders
“Our calculus is that getting these therapies where they need to go based on a surrogate is the most viable way forward at present. At the end of the day, we’re looking to find accelerated endpoints that we can all agree are good enough to get these innovations over the line to an initial approval and will subsequently allow us then to get the confirmatory endpoints over longer periods of time,” explains Peter Marks, director of the Centre for Biologics Evaluation and Research (CBER) within the US FDA.
“If we don’t manage to move in the direction of using biomarkers and intermediate endpoints to get there initially, it’s frankly hard to see how we can handle hundreds of gene therapies, especially for rarer disorders… Attempting to get there with hard clinical endpoints that meet the statutory standard of substantial evidence of effectiveness for the final clinical endpoint upfront would be immensely challenging and result in significant delays,” he concedes.
Overcoming the Data Deficit
Some stakeholders however still fret over the prevailing knowledge gaps when it comes to side effects and safety profiles over the long term. Not only are the most severe toxicities related to CAR-T cell therapy – cytokine release syndrome (CRS) and immune effector cell associated neurologic syndrome (ICANS) – completely unlike those commonly associated with classical chemotherapy and oncology, but there exist a myriad of more personalised, milder but nonetheless disconcerting side effects that are still relatively poorly understood and are adversely impacting the patient experience.
“Unfortunately, too many of our members simply have not felt prepared for what ultimately happened to them. We obviously prime patients well for known high-intensity side effects like CRS and neurotoxicity, but often the greater patient concerns are more around smaller, lesser-known symptoms like weight issues, muscle cramping, and persistent ongoing fatigue,” warns Lorna Warwick, CEO of the Lymphoma Coalition, a worldwide network of patient groups. “We’re obviously keen to get these revolutionary treatments into the hands of patients as quickly as possible, but, in our eagerness, we mustn’t forget that there’s an urgent need for more data, insights and visibility so that we can give patients greater transparency over the treatment pathway and manage their expectations better,” she argues.
We urgently need to create systems where data can continue to be collected, especially for kids that are treated when they are younger
And for paediatric oncology, 15 years of data may not even be enough, according to Navin Pinto, associate professor of paediatrics at the University of Washington School of Medicine and an attending physician at Seattle Children’s Hospital. “15 years after a two-year-old patient receives treatment they will be 17 and will probably not have had any children, meaning a lack of any data on fertility. Moreover, chest radiation during Hodgkin lymphoma therapy creates a risk of breast cancer for women in their 30s, which could be more than 15 years from when a patient was treated. We urgently need to create systems where data can continue to be collected, especially for kids that are treated when they are younger,” he counsels.
“In my opinion, patients should first be treated with medicine for which a strong evidence base has already been established before moving onto newer products for which less data exists such as CAR-T cells” suggests Nicolaus Kröger, president of the EBMT, an entity famed for having established a registry of more than 600,000 stem cell transplants. “We should focus on evidence-based medicine and not be swayed by the hype. Patients are in a very delicate position if they are ill and if they read about something that could save their life, they will naturally want it. However, we should be honest and counsel our patients around what is based on evidence and what on hope. This is only fair,” he declares.
Incorporating the Patient Perspective
The drug developers themselves, meanwhile, have been investing heavily in the collection of evidence because they realise that demonstrated durability of treatment will go a long way towards getting their discoveries moved on to front-line treatments. Moreover, most stand convinced of the ultimate superiority of their therapies compared to existing classic treatments and so do not fear the data they acquire.
“Thus far, in the case of our flagship CAR-T therapy, any findings from real-world evidence that we have managed to compile in addition to the randomised clinical trial data has not only validated the existing efficacy profile nicely, but has even improved upon it,” proudly exclaims Stefan Hendriks, global head of cell and gene at Novartis Oncology.
What’s more, the company fully appreciates the centrality of improved data to being able to realise its grand vision for creating properly patient-centric care pathways. “We take plugging the data gaps tremendously seriously and contributing to building evidence has become a major plank of our patient engagement,” confirms Marc Boutin, the firm’s global head of patient engagement, pointing to an ongoing collaboration with the Global Lymphoma Coalition by way of illustration.
Boutin also stresses the importance of compiling different types of data so as to be able to create a superior patient experience. “We have identified a strong need to build a set of meaningful patient-reported outcomes (PROs) which complement the so-called ‘hard’ medical data. As CAR-T therapies may soon be deployed in earlier lines of therapy, the quality of life before, during and after therapy will be an important parameter. Complete remission (CR), progression-free survival (PFS) and event-free-survival (EFS) are key – but for patients it will be paramount, ‘how’ these outcomes are achieved, and we must not overlook that,” he declares.
RWE: the Next Data Frontier
Putting in place the capabilities to amass real world evidence is therefore considered a fundamental priority for industry sponsors. “The first type of data to be collected is that which comes from clinical trials; this tends to be highly regulated and standardised as it is subject to very intense regulation. Then comes the post-market authorisation commitments which also tend to be highly prescriptive with registries such as that of the European Society for Blood and Marrow Transplantation (EBMT) hosting the data. However, we are looking to go a step beyond all that and tap into an emerging ecosystem of more fluid health data, which is sometimes summarised as real-world evidence (RWE) data,” confides Karin Blumer, director of global patient engagement at Novartis Oncology. “This can take the form of multiple sources with patients tracking their data via apps on their smartphones and watches or be the fruits of joint initiatives with patient advocacy groups,” she elaborates.
“RWE is especially important for cell therapies, since most are approved courtesy of abbreviated pathways based on phase II studies data where there is no randomisation,” emphasises Nicolaus Kröger. “This essentially means that we do not know what would happen with the patients not selected to be part of the trials so it’s crucial to have RWE to get some visibility into how these therapies perform in real life, outside of the artificial setting of the clinical trials regime,” he exclaims. “One of my ambitious goals is to include patient reported outcomes in our registry, which we are presently working on.”
Altogether Now
Still, numerous obstacles to evidence compilation abound. “Everyone is very interested in collecting data for late effects; not just those in the first year after treatment, but in the following ten or even twenty, but there are practical barriers,” notes Sam Volchenboum, associate professor of paediatrics and associate director of the Institute for Translational Medicine at the University of Chicago. “Convincing a 20-year-old to continue giving up their data five years after they have been cured is not going to be easy. Never has it been more important to devise standardised ways to collect data directly from patients and their families and then put it all in one place for researchers to use,” he opines.
Never has it been more important to devise standardised ways to collect data directly from patients and their families and then put it all in one place for researchers to use
Some CAR-T sponsors are therefore calling for a brand-new model of cooperation whereby organisations focus less on owning and monetising data and more on connecting and combining it to drive valuable insights that can transform healthcare. “The industry does not need to own or manage this data itself but should instead help build data repositories that comply to the highest ethical and regulatory standards. These repositories would then be accessible to interested parties – whether academia or industry – to freely analyse and garner insights,” boldly envisions Karin Blumer.
Simplifying and streamlining processes could also help. “Currently, quality-of-life questionnaires are handed out by physicians to patients, but many forget to do so. One very practical idea would be to allow patients to upload their insights digitally direct to the registry and cut out the physician in the middle,” proposes Nicolaus Kröger.
