Rare Disease Update: Status, Strides, Setbacks
July 16, 2021
It's a strange time to be alive if you have a rare disease.
On the one hand, medical scientists now understand the core dysfunctions underlying many of these diseases. As an outgrowth of this knowledge, life-changing therapies are tumbling into the market. But can you get your hands on these miracle therapies? It depends: on where you live, on whether your provincial payer approves your case, on the drug manufacturer’s ability to bridge the access gap.
Maybe your doctor can state your case to payers. Or maybe not. If you have a lot of stamina, perhaps you can do your own lobbying—which, as patient advocates like Bryarly Parker of Alberta can attest, often require Herculean efforts to succeed. The mother of a two-year-old boy with spinal muscular atrophy (SMA), Max, Parker engaged her network of family, friends and fellow advocates to ask the province to fund the SMA medication Zolgensma for her son. A one-time drug that replaces the faulty gene at the root of the disorder, Zolgensma costs upwards of $2 million. Parker’s tribe came through with a flood of emails, including 1,000 on a single day, asking the government to step up for Max.2 The government listened and Max got his medication. “Some paths led us down incredible roads, while other paths were extremely frustrating and led to many tears,” she wrote on Instagram after the decision19 —sentiments echoed by patient advocates throughout the country.
It’s a bit like a treasure hunt: You need to solve all the clues to get the grand prize: a life-changing medication. Miss one of the clues and you’re out of the game. How did our country, whose national health system other nations point to as a model, get to this awkward place?
Missing: A national vision
Rare diseases and conditions are a breed apart. The small number of affected people makes it difficult to collect the type of clinical trial evidence traditionally required by regulators. The rarity of these diseases also slows down clinicians’ understanding of their natural progression, making it challenging to establish optimal starting and stopping criteria for medications.20 Monitoring treatment efficacy and collecting real-world data pose similar problems.
Under the orphan drug umbrella, drugs for ultra-rare diseases (DURDs) also deserve special status. A 2018 analysis of CADTH submissions concluded that DURDs can be viewed as a distinct category and that applying normal rare-disease assessment criteria to these medications may have tipped the balance toward more negative recommendations.16
Despite a clear need for special consideration, Canada does not have a distinct framework or strategy for these drugs. By way of contrast, 26 out of 28 member EU countries boast separate pathways for reviewing rare-disease drugs.13 These frameworks may include commercial options such as outcomes-based agreements (OBAs) for high-cost drugs requiring additional evidence and budget impact schemes.4
Not surprisingly, the lack of a pan-Canadian framework makes it difficult for pharmaceutical manufacturers to launch rare-disease drugs in Canada. As an example, it took over a year for Health Canada to approve the cystic fibrosis medication Trikafta for children aged 12 and over, while the US authorized the drug for ages 6 and up within 3 months of submission. When a drug has the potential to change lives, as does Trikafta, such delays become ethically difficult to justify.9 Rather than wait—and potentially miss the window for useful intervention—regulators need mechanisms to approve medications with great promise but incomplete evidence.9
Fortunately, Health Canada’s “Notice of Compliance (NOC) with conditions” policy allows for accelerated review of drugs for severe, debilitating diseases with no existing treatments.9 When early evidence suggests a benefit from a drug, Health Canada can fast-track its approval on condition of additional post-marketing monitoring and testing. This process has sped up NOC for some rare-disease drugs.
A COMMON LANGUAGE FOR RARE DISEASES AND CONDITIONS
The language around rare diseases can get confusing. Here’s a primer:
Rare disease:1 A rare disease is a life-threatening, severely debilitating, or serious and chronic condition affecting a fairly small proportion of people – generally fewer than 1 in 2,000. Examples of rare diseases include cystic fibrosis, muscular dystrophy, and hemophilia.
Rare condition:15 This term includes rare diseases as well as rare subtypes of common diseases. These subtypes represent special cases, such as specific genetic mutations, that may respond to precision treatment. Adenosquamous carcinoma, a rare subtype of lung cancer, would be considered a rare condition.
Ultra-rare disease:16 disease that occurs in no more than 1 in 100,000 people.
Orphan drug:17 Defined as medications for rare diseases that are debilitating or life threatening, these drugs respond to a public health need but may be difficult to develop and launch under standard marketing conditions.18
Expensive drugs for rare diseases (EDRD):17 This term describes medicines with at least one FDA or EMA orphan designation and estimated treatment costs exceeding $100K per year for non-oncology drugs and $7,500 per 28 days for oncology drugs. Orkambi and Symdeko (both for cystic fibrosis) as well as Vimizim (for Morquio syndrome) fall into this category.
Listing lags
Next hurdle: payer listing. Indeed, delays between NOC and listing average 559 days, or 670 days excluding Quebec—far longer than the figure for most other developed countries such as the US (120 days), UK (38 days) or Germany (a mere 13 days).21 As described by Homira Osman, VP of Research & Public Policy at Muscular Dystrophy Canada, the wait triggers a lot of anxiety among patients:2 When will it be reimbursed? Will it be case-by case? Will my case qualify?
Even when most provinces agree that a rare disease drug treatment offers benefits that justify the costs, the drug almost never meets conventional cost-effectiveness criteria.22 Caught between these contradictions, provinces struggle to come up with fair reimbursement schemes.
In some cases “the bar set for reimbursement is just not attainable,” says Dr. Vijay Ramaswami, a pediatric oncologist at Sick Kids in Toronto, citing the medication Vitrakvi as an example.2 The first tumour-agnostic cancer medication approved by Health Canada, Vitrakvi received a negative listing recommendation by the pan-Canadian Oncology Drug Review (pCODR) committee in August 2019—a reversal of an initial recommendation from pERC to reimburse the drug for four tumour types.23 As a rationale for its decision, which to Dr. Ramaswamy “makes no sense,” pCODR cited uncertainty about clinical benefit relative to available treatment options or best supportive care.23 After generating additional evidence, Vitrakvi manufacturer Bayer resubmitted to CADTH and pCODR and received a positive draft “recommendation with conditions” in May 2021.24 While good news for patients, this outcome took two years to achieve—a testament to the twists and turns in the process.
Some patients can get into clinical trials before a medication is listed—perhaps because they live close or can be transported to a trial site. Others are out of luck. While patients in the trials can proceed to the open-label extension, “we can’t get these incredible new technologies to [other patients] because of the long process to approval and reimbursement,” says Dr. Angela Genge, an amyotrophic lateral sclerosis (ALS) trialist and Director of the Clinical Research Unit of the Montreal Neurological Institute.2 “It is unfair for patients.”
“The bar set for reimbursement of rare-disease drugs is just not attainable.”
Stop-gap solutions
Patients in the access queue have a few other options while waiting for a listing. Those fortunate enough to live in Quebec can obtain “medically necessary drug funding” via the Patient d’exception program. Upwards of 50 thousand patients have used the service, which costs the province 4 to 5 million dollars per year.2 The program boasts an impressive track record, reviewing 80% of patients in 25 days and approving about three-quarters of applications.2
Traditionally, provincial health ministers have had the latitude to make funding decisions on specific cases. While formalized CADTH and pCPA processes have made this tactic less prevalent over the years, case-by-case coverage still exists for some medications. Coverage for Spinraza for adult patients, for example, is granted on a case-by-case basis in Ontario, Saskatchewan, and Alberta.25
Private insurance offers another common route to access. In 2020 alone, Canadian Life and Health Insurance Association (CLHIA) members paid out more than $650 million for rare disease drugs to over 13,000 insured Canadians.26 Compelled by ethical considerations, these plans may step in when medications previously covered by special access programs receive NOC. While helpful to patients, this ad-hoc arrangement highlights a significant gap in the current access pathway. A case in point is trientine, a generic medication for a rare and potentially fatal liver disorder called Wilson disease. Until recently, patients had to go through a special review process to obtain the medication, which costs up to US$333,000 per year.27 Following NOC in 2020, coverage of this high-cost drug has landed firmly in the private payer sphere.
Even for privately insured patients, high co-pays may impede access. Patients cannot be expected to afford, say, 20% of a medication that costs a half a million dollars per year. In such cases the manufacturer often ends up picking the tab. Manufacturer-funded bridging and compassionate use programs via patient support programs also plug up access gaps for many patients waiting for coverage to kick in or for those without any coverage at all. As of 2020, a patient association noted that the Vertex Pharmaceuticals compassionate care program for CF medications was supplying free product for life to 130 Canadian patients.28
Manufacturers cannot be expected to supply free product indefinitely, of course. From a business standpoint, the viability and sustainability of compassionate programs depends on the expectation of a future public listing. What’s more, manufacturer support hardly ensures fair access. As noted by Eva Villalba of the Quebec Cancer Coalition, “not all patients are referred to patient support programs, which means that some patients get access and others don’t.”4
In brief: the current access landscape is far from smooth, with each disease and each drug following its own trajectory. Each patient has a different story to tell, not all of them with happy endings. Fortunately, stakeholders recognize the opportunity to do better and are working on more consistent, sustainable access solutions.
Work in progress
The will is there, but what is the way? It starts at the top: coordination at the federal level. In recognition of this need, the federal government recently published a discussion paper outlining three key motives for a national strategy for rare disease drugs: to improve patient access, to optimize decisions on drug coverage, and to ensure the expenditures don’t erode the sustainability of Canada’s healthcare system.9 The paper invites patients and patient groups, regulatory agencies, researchers, payers and industry to weigh in on the development of such a strategy, earmarked for a 2022-23 launch.
In line with this vision, CADTH is working on a policy change for rare disease drugs, proposing to use real-world evidence and managed entry agreements as part of the process.20 Going still further, Quebec’s INESSS has proposed a national strategy for the entire rare disease care path, from screening to treatment.20 These initiatives could kick off by mid-to-late 2021.
The national-strategy vision finds further support among patient groups, with the Canadian Organization for Rare Diseases (CORD) leading the charge. In a recent Health Insight article, CORD president & CEO Durhane Wong-Rieger describes the sophisticated and seamless treatment arc currently available to hemophilia patients and proposes the country play catch-up with other rare diseases.29 To this end, CORD put forth its vision for a national strategy, broken down into 12 action steps, in a letter addressed directly to Prime Minister Trudeau and to Health Minister Patty Hadju.30 The proposed steps include establishing a viable market for early drug launches (through such measures as early access programs, patient registries, and patient support programs) and leveraging OBA-style agreements for approved medications with strong potential but uncertain evidence. Also pleading the case are the RQMO [Regroupement Québécois des Maladies Orphelines] and the Quebec Cancer Coalition.31,15
Manufacturers have the same idea. The Canadian Forum for Rare Disease Innovators (RAREi), a national network of biopharmaceutical organizations that develop therapeutics for rare diseases, envisions a separate rare-disease pathway that offers managed access options, encourages dialogue, and draws inspiration from jurisdictions such as the US and Europe.25
The evidence-access loop
For a national strategy to do any good, it must address the biggest problem facing rare disease drugs: incomplete evidence. The difficulty of gathering evidence for rare disease drugs puts them in a catch-22 position: just as new job seekers face the self-reinforcing spiral of inexperience, lack of evidence for rare disease medications drags down their progress through the drug life cycle—further limiting the ability to gather evidence.
Solving this conundrum requires a greater reliance on real-world evidence (RWE) and a way to get that evidence. As noted by Dr. Craig Campbell, a physician/scientist and associate professor at the University of Western Ontario, “right now, access is [already] happening before reimbursement. Why not make that work for us by systematically collecting RWE?”25 To this end, he suggests a post-marketing commitment—from the entire stakeholder community serving a disease—to generate data on what’s working and what isn’t. With rare diseases—and especially with those classified as ultra-rare—such evidence-gathering efforts need to draw on multiple sources, from prospective trials to system-level data. Existing registries, such as the robust Canadian Fabry Disease Initiative,32 serve as a natural launch pad for this approach.
“Access is already happening before reimbursement. Why not make that work better by systematically collecting RWE?”
Systematic RWE collection takes time, of course, and time is exactly what many rare-disease patients don’t have. When evidence is limited but patients can’t wait, innovative funding models such as outcomes-based agreements (OBAs) provide a mechanism to speed up access. As detailed in Health Canada’s proposed national strategy for high-cost drugs, such agreements depend on clear, objective measures of benefit.9 If the evidence ultimately reveals a more modest benefit than expected, OBAs allow for reduction or discontinuation of reimbursement.
Private payers appear ready to champion such arrangements. In a recent submission to the Government of Canada, CLHIA lent its support to innovative coverage models that tie funding of rare disease treatments to their effectiveness, noting the potential for these models to facilitate access to treatment and mitigate financial risks. 26
“Access to rare disease therapies requires a different way of thinking. We need to be OK with trying things, even if they may fail.”
A NATURAL FIT: OBAs FOR RARE DISEASES & CONDITIONS
OBAs seek to accomplish two things: improve patient access and mitigate financial risk. They work best for innovative, costly medications that promise to change lives—if they get to patients in time.
Rare diseases tick all the boxes for OBAs: low patient populations, high unmet need, innovative and high-priced treatments. The risk-management safeguards built into OBAs, from discounts and budget caps to pay-for-performance schemes based on predetermined outcomes, enable patients to benefit from new treatments as early as possible, when it matters most. In theory, an OBA could kick in right after NOC, giving patients immediate access while the evidence required for a fuller review process rolls in. If the medication works, everybody wins. If it doesn’t, the payer and patient have a fair exit strategy. Of course, OBAs only work if stakeholders agree on the outcomes to measure, with patients a key source of input. And not all rare-disease drugs require an OBA: for some medications a simple market access agreement may do the job.
No time to lose
The will is there. Stakeholders agree not only on the need for change, but on such priorities as a national plan and innovative market access agreements. But persistent ground-level inequities make it clear the needle needs to move faster.
No medication exemplifies the choppy playing field more poignantly than the SMA drug Zolgensma, which received a conditional listing just 6 weeks after NOC in one province. By the spring of this year, Alberta had received two applications for Zolgensma coverage, for a boy named Max and a girl named Reign.33 On paper, neither application met CADTH’S recommended criteria for coverage. Max’s request got the green light. Reign’s did not.
In a March 2021 letter to Health Canada, Catherine Boivin, a SMA patient and advocate based in Montreal, pointed out another inconsistency in Zolgensma access: The province of Ontario, which now offers newborn screening for SMA, has the means to diagnose babies before they develop symptoms, when treatment can make the greatest difference. Elsewhere in Canada patients can only access the medication after having suffered a significant deterioration. To rectify this imbalance, “a national framework must include strategies for early diagnosis.”34
Less talk, more action
Must, should, need: such “planning” words don’t suffice for Tania Stafinski, Director, Health Technology & Policy at the University of Alberta’s School of Public Health and a key player in the School’s PRISM [Promoting Rare-Disease Innovations Through Sustainable Mechanisms] initiative. Recalling the stalled efforts of the Expensive Drugs for Rare Disease (EDRD) working group, Stafinski maintains that rare diseases “require a different way of thinking. We all need to be OK with trying things, even if they may fail. What we can’t do is continue to wait.”
“Access to rare disease therapies requires a different way of thinking. We need to be OK with trying things, even if they may fail.”
A report from Montreal research group InVivo concurs that the waiting game has gone on too long. As outlined in the report, Health Canada announced its intention to develop a policy framework in 2012—and almost 10 years later, Canadians with rare diseases are still waiting for this framework to materialize.13 Lack of political will also knocked the wind out of Alberta’s limited rare disease policy, established in 2008 to cover just a handful of rare diseases.35
A further hindrance to implementation: lack of trust between stakeholders. As with many hot-button issues, funding for expensive drugs tends to raise the emotional temperature and inhibit productive discussion. In a recent Standing Committee on Health meeting, a provincial cancer association characterized Cystic Fibrosis Canada (CF Canada) as being “too aligned to industry,”12 and the February 2021 PMPRB communication plan called out patient groups for “spreading disinformation.”36 CF Canada’s Kelly Grover countered that “specifically targeting the credibility of this community [is] not reasonable or appropriate for a federal agency.”12
Less pricing, more patient
The resolute focus on costs and budgets, while understandable, is detracting from the more important issue at hand: levelling the playing field for Canadian patients who, through no fault of their own, struggle to attain the quality of life most others take for granted.
How then to balance costs with doing the right thing? Perhaps Boivin expresses it best: “When making decisions about covering costs while keeping access top of mind, policymakers must consult multiple stakeholders including patients and clinicians, with the understanding that patients and those who care for them have valuable insights toward making informed, cost-effective decisions.”34
And where does all of this this leave patients with rare diseases and conditions? While waiting for life-saving therapies, patients are getting louder. They have no other choice. They understand, perhaps better than any other stakeholder group, the urgency of finding equitable access solutions and the need for collaboration— not tomorrow, but today.
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