Imagine working in a hospital that cannot access or safely deliver the medications needed to treat your patients? For anybody working in healthcare, this doesn’t take imagination. It is an experience frequently encountered and for a myriad of different reasons from economic to resourcing to infrastructural limitations. But imagine intentionally spending years and hundreds of millions on developing new medicines that either can’t be delivered or don’t have an addressable population? It may sound bizarre but less so to those working within pharmaceuticals. Healthcare systems adapt, that is their role, they adapt so that they can effectively treat patients. It aims for structure within a fluidly evolving treatment landscape, but there are trade-offs and there are practical limitations. Evolving takes time.
Cell therapies have emerged as the pre-eminent achievement of synthetic biology in the 21st century, with potentially curative outcomes in late-stage treatment refractory cancers, and promise in genetic, rare and autoimmune diseases. In vivo CAR gene therapies offer an off-the-shelf alternative that can bypass complex manufacturing and logistics, potentially expanding access to many more patients but scalability is still a major question. Could these move into front-line settings? Could they virtually eliminate late-stage diseases and mortality? But are these therapies sufficiently scalable to reach all patients?
We have been here before. The first cytotoxic chemotherapies emerged in the 1940s from an unlikely source – chemical warfare research, after mustard gas exposure was observed to suppress the bone marrow. When nitrogen mustard was first turned against lymphoma, the drug worked, but severe myelosuppression, intractable nausea and life-threatening infection meant that, for years, the treatment could be nearly as perilous as the disease. It was only decades later, with the arrival of effective antiemetics, granulocyte colony-stimulating factors and antibiotic prophylaxis, that chemotherapy could be given at the doses and scale its promise demanded. There are lessons here that we should apply again today.
Patient need
Healthcare infrastructure throughout the world varies significantly between and within countries. There is no one model, and effective solutions need to be flexible to work within diverse healthcare settings. In the USA, by some estimates, less than 20 percent of cancer patients are treated in large hospitals. By contrast, in the hub and spoke system across much of Europe, virtually all cancer patients are treated under the auspices of large hospitals. Although large US centers often appear to have the resources to lead innovation and adapt to challenges, arguably, Europe may be better placed when it comes to broadly embedding new technologies.
There is a strong global movement at present to broaden access to cell therapies and other advanced therapies like bispecific antibodies, particularly in the US where some estimates suggest up to 80 percent of cancer care occurs in the community setting. Multiple efforts are ongoing to democratize access by broadening the availability of emerging therapeutics into the community, but challenges persist. Recently, pharmaceutical companies have been making efforts to launch drugs into large treatment centers along with smaller centers and community treatment centers by including these sites within their clinical trials.
There are significant challenges ahead to universally broaden access. Educational programs are well placed to reach all sites, providing the training tools and the resourcing blueprints needed. Recently, key opinion leaders across a range of malignancies have been urging community doctors and patients themselves to demand access to these emerging therapies and to act as the catalyst needed for change.
Broadening access to emerging therapies
Similarly to the first chemotherapies, emerging medicines come with bespoke challenges. Cell therapies and bispecific antibodies are associated with severe and prolonged hematological toxicities. Certain patients receiving bispecific antibodies can spend over 100 days in hospital during their first year of treatment and so even where access is universal, practical concerns, such as caregiving at home can affect patient choice, but providing patient access is the first hurdle.
There are also existential challenges. The skillsets required to manage patients on these therapies are typically held by hematologists, but with application extending into solid cancers, autoimmune diseases and beyond, who is going to manage these patients? Other than having many more hematologists, the successful delivery of these therapies will require whole new medical disciplines to be upskilled.
Scalability requires methods to reduce non-relapse-related morbidity, and to find ways to put the brakes on treatment-related toxicities. Either we replace the existing therapies with more tolerable versions, or we expand the toolkit to better manage the toxicities. Drug development is inherently expensive, lengthy, and risky, therefore simply waiting for more tolerable therapies is not realistic.
Addressing systemic barriers
Today the supportive care toolkit (the medicines used to manage toxicities) is largely unchanged from a few decades ago. The regulatory pathways for supportive care drug development are poorly suited, and inward investment in this area has been chronically weak. Indications can be difficult to define; therapeutic benefits can be difficult to measure; and intra-trial subjects can have diverse underlying diseases making drug development in these areas challenging. Curiously, in Europe, the EMA does not typically consider iatrogenic conditions – that is, conditions caused by medical interventions – as eligible for orphan protection, further limiting incentives to address these important unmet medical needs.
Lack of innovation has meant that clinicians largely rely on repurposed options. But reimbursement for repurposed medications can be notoriously difficult. In the UK, the NICE single technology appraisal system has only overseen a handful of non-pharmaceutical sponsored submissions. And further challenging their use, drugs that are not available in the supply chain and are used off-label often need to be requested from the manufacturer on a named patient basis.
Take Cytokine Release Syndrome (CRS) as an example. Up until the first CAR T-cell approval in 2017, CRS was largely unknown. It was seen sporadically in the literature but became ubiquitous as CAR T-cell and T-cell engaging therapies progressed into clinical trials. Immunotherapy-induced CRS is a distinct condition. In many ways, it is an ideal condition for drug development. Tocilizumab, an IL-6 monoclonal antibody, and steroids have become the mainstay of treatment. There is strong supporting evidence for this treatment option, but this comes from many sources and without properly powered studies there isn’t a firm understanding of their long-term effects on related conditions, with some suggesting that they could be counterproductive by increasing neurological toxicities. Whatever the case, there is a strong demand from the healthcare system for an effective preventative CRS treatment. Beyond its direct effects on reducing the intensive monitoring requirements, and in some cases hospitalization periods, there is a larger picture that effective supportive care therapies may play a pivotal role in equitable access to medicine for all. A risk of hospitalization may appear low, but to a late-stage cancer patient, or a patient with family circumstances requiring their presence at home; these are major factors.
Health economists sometimes ask, provocatively, whether medicine is an invention or an innovation. There is no doubt that we are living through a boom in medical invention, but scientific breakthroughs alone will not ensure that advanced therapies reach the patients who need them. There is a perception that we will solve these problems by developing iteratively safer and more effective drugs but this is a linear, cumbersome and wasteful solution to an intractable challenge. To turn invention into innovation, we must with vigor and enthusiasm proactively develop the supportive care medicines, the clinical expertise, and infrastructural healthcare models required to manage these treatments safely and at scale. Only then can the promise of these breakthrough therapies be fully realized.
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