September 5th, 2018, marked a momentous day for Canadian health care as Novartis announced Health Canada’s approval of Kymriah™, the first genetically manipulated cell therapy to be approved in Canada.
With the ability of CAR Ts like Kymriah to treat and, potentially cure, otherwise hard-to-treat cancers such as leukemia and lymphoma, Canadian taxpayers will finally reap the rewards of years of intensive, publicly-funded research. Despite an exciting debut, the approval of cell therapies in Canada does not immediately translate to market access. Getting Kymriah to patients on home soil has been no small feat for any jurisdiction following approval. Even so, Canada will face several unique challenges in order to successfully integrate CAR T into our health-care system.
Though a point of pride for our country, the structure of the Canadian health-care system provides the first obstacle for making CAR Ts in Canada stick. Siofradh McMahon, Senior Manager of Clinical Translation and Regulatory Affairs at CCRM notes: “The review period for Health Canada is quick…the challenge comes when you start talking about reimbursement where we are not really one country anymore since most reimbursement decisions happen at the provincial level.”
While several other countries also offer public health care, most operate on a single-payer system, which can stymie prolonged negotiations and rapidly expedite market access. For example, the UK’s National Health Service (NHS) enabled market access of Kymriah a mere 10 days after its approval by the European Medicines Agency. Conversely, there has yet to be a patient in Canada to receive Kymriah outside clinical trials in the four months since the approval.
Further complicating matters, the delivery of CAR T requires intensive clinical care before and after treatment. Since clinical standards vary between provinces, province-specific hospital costs must be integrated into Kymriah’s pricing assessment. Moreover, additional efforts must be made to ensure adequate quality-of-care for recipients from British Columbia to Newfoundland.
In an effort towards harmonization, the Canadian Agency for Drugs and Technologies In Health (CADTH) and Institut national d’excellence en santé et en services sociaux (INESSS) in Quebec, have recently published a report that presents pan-provincial recommendations on how to use Kymriah in the Canadian health-care system. The report also provides a pricing assessment that takes both the drug and accessory care into consideration.
McMahon warns, however, “even if something is recommended for reimbursement across the whole country at certain criteria, the provinces themselves can add additional criteria.” As these changes can affect both how Kymriah treatments are followed and who is eligible for coverage, clinical manifestations of the treatment may be strikingly different across the country.
Regulatory obstacles aside, the real elephant-in-the-room for CAR T is cost: reimbursements at market price (US$475,000) just aren’t feasible for our health-care system.
Many have pointed to Kymriah’s curative potential as justification for the steep upfront costs. From an economic perspective, curing a disease will enable patients to live longer and, in turn, increase their contribution to the Canadian economy. However, Dr. Chris McCabe, Executive Director and CEO of the Institute of Health Economics in Alberta, suggests that using patient longevity to justify the price tag of CAR T has its limits: “For pediatric indications that’s a massive payoff… in adult patients where the average age of diagnosis is in their 50s-60s? We’re going to die of something else relatively quickly.”
These sentiments were presumably echoed during NHS negotiations for Kymriah, as coverage was only agreed for patients up to 25 years. Furthermore, in a statement released last fall, the NHS agreed to fund no more than 200 therapies per year, even after negotiating huge discounts with Novartis. CADTH’s recommendations for coverage were also limited to pediatric patients, though they did not expressly place a cap on the number of patients covered per year.
This arrangement reflects the uncertainty from both the public health-care system and Novartis on Kymriah’s long-term value. On the payer side, McCabe suggests that full coverage of 200 patients by the NHS may be “just enough individuals to generate data to see what the actual benefits are.”
This may also be why Novartis buckled to drastic discounts despite a major investment in R&D to get Kymriah to market. McCabe elaborates: “I think they’ve [Novartis] gone in believing this will become a mature technology… but they don’t necessarily expect to make much profit… they’re knowingly doing a lot of research on-market about this type of technology, trying to find out if they can make the technology work commercially.”
Others are looking past the cost of CAR T and, instead, seeing how Canada can gain from the emergence of this new technology. With some experts projecting CAR T to be a US$20 billion industry by 2025, the development of a sustainable CAR T manufacturing infrastructure in Canada could boost our burgeoning life sciences sector and the Canadian economy as a whole.
Profiting from innovation is something Canada has long struggled with, and many small-to-medium enterprises (SME) leave the country before they can affect a significant economic impact. For many Canadian entrepreneurs and researchers, the emergence of the immunotherapy industry is an opportunity that Canada cannot let pass by.
In 2017, BioCanRx announced that it secured CAD$5 million in funding to generate the first “made-in-Canada” CAR T, using exclusively Canadian expertise and infrastructure from the BC Cancer Agency and the Biotherapeutics Manufacturing Centre at The Ottawa Hospital.
Toronto’s CCRM is also doing its part to beef up Canada’s immunotherapy infrastructure, opening the doors to its own Good Manufacturing Practices (GMP) facility, the Centre for Cell and Vector Production (CCVP), in October 2018. In addition to existing facilities in Montreal, Edmonton and Ottawa, the CCVP will be the fourth facility in Canada suitable for the manufacture of CAR T, as well as other forthcoming cell and gene therapeutics.
With protocols and facilities in place, the establishment of a self-sustaining CAR T infrastructure in Canada may encourage other immunotherapy-focused SMEs to anchor roots in Canadian soil. In the words of BioCanRx’s CEO and President, Dr. Stephanie Michaud, “Having the ability to manufacture complex cell therapies ourselves will give companies confidence that Canada can run successful clinical trials and make Canada more attractive for investment as a whole.”
It is important to note that while these facilities will be able to accommodate small-to-medium-sized clinical trials (Phase I/II), they’re still not yet suitable for long-term commercial manufacturing (Phase III). However, it may only be a matter of time before commercial scale cell manufacturing in Canada is realized. Dr. Elizabeth Csaszar, Development Manager at CCRM, hinted that “CCRM has been thinking about this for a while and kind of envisions a concept of a commercial scale manufacturing facility in southern Ontario that would be built over the next several years and in existence by the time some of these therapies hit commercial scale.”
As Canada often punches above its weight on international matters, it is easy to forget that we are a relatively diverse and sparsely populated country with challenges that are unique from our American neighbours and Commonwealth cousins. The introduction of an expensive, complex and potentially game-changing treatment like Kymriah will undoubtedly be a shock to our health-care system.
Though the science of CAR T is sound, the regulatory, economic and commercial aspects of this treatment are largely experimental, with everyone watching closely to see how this new technology will perform. Much to the delight of CAR T bandwagoners, Canada is jumping at the challenge, giving existing regulatory frameworks a much-needed tune-up to make the introduction of Kymriah — and hopefully other, advanced therapies — as smooth as possible.
The Canadian government is currently undergoing a modernization initiative that includes changes to Health Canada’s regulatory framework to better prepare for new advanced therapies. A push for National Pharmacare is also underway, which may help close the gap between approval and access.
In addition to aligning with other single-payer, publicly-funded national health care programs, a single-payer system could harmonize reimbursement and standard-of-care across the provinces to ensure that no Canadian is left behind.
Finally, health technology assessment agencies, like CADTH, are piloting a value-based system for drug pricing that takes into consideration the wider societal benefits of a drug, such as patient longevity. McCabe reflects that “There’s lots of moving parts going on in the moment…and these CAR Ts are arriving bang in the middle of a kind of perfect storm of change.”
It’s one big experiment, and a risky one at that. Whether it works or not, Kymriah is changing how Canada responds to health care innovation – a change that will ideally carve out a brighter future for Canadian patients, providers, entrepreneurs and researchers alike.
Erika Siren
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