Great. Thank you.
My name is Craig Campbell. I'm a pediatric neurologist at the Children's Hospital in London, Ontario, at Western University. I'm the head of the division of neurology there and deputy chair for research for the department of pediatrics. I'm also the deputy chair of the TREAT-NMD global registry oversight committee, which is a collaborative of over a hundred rare disease and ultra-rare disease patient registries for neuromuscular disorders.
I appreciate the opportunity to address the committee today and reflect my experience in this field.
I will first disclose that I work with many pharmaceutical companies to plan, implement, analyze, monitor and advise on clinical trials for rare neuromuscular diseases. More recently, I have been involved in advising on post-marketing pathways. I do this, however, on a voluntary basis. Any dollars that are not used directly for travel I donate immediately to charity.
I've been asked to address the committee on issues of access and coverage of rare disease drugs with evidence development in the context of the review process. I genuinely think this is a very negative focal point for many other aspects and issues that swirl around the whole conversation of development of a rare disease framework. As you'll no doubt know, there's a high level of tension in the rare disease space as a drug reaches the late clinical trial stages. The patient organizations, the clinical investigators and practitioners, and the industry sponsors and regulators all anticipate a pathway to access, and yet we are rarely coordinated or cohesive in approaching these critical decisions. From what I understand and in my experience, in most cases it ends in frustration for some, if not all, of the parties. The entire culture of this process needs to change, in my opinion.
As I called for in my 2017 CMAJ commentary, there needs to be a culture change from what appears to be a more adversarial environment to a much more congruent paradigm among all parties that really spans the life cycle of a rare disease drug, a process that has to have clear timelines, better consultation among stakeholders, and more transparency in the evidence review and the access decisions. Paradoxically, I think, this will almost certainly lead to a more rational approach. As it stands, many families have to parade their children through the media. Many drug companies are manipulating physicians and the public. Clinicians and patient groups are reacting in shock to decisions. Regulatory bodies appear to be stifled in real engagement by their internal bylaws and processes.
I would like to provide some thoughts in two areas: one, the paradigm of the process of evidence review; and two, the access to therapy with ongoing evidence development.
First, with regard to the review process, in almost every single interaction I've had with Canadian regulatory agencies that I've been a participant in, regulatory personnel have claimed that reviews for rare disease drug files can and will be done with more flexibility and be more considerate of the context and totality of the data. Further, they often claim that the existing approval processes and evidence review pathways are adaptable to rare disease drugs. However, when the final decisions are made, this rarely seems to be the case.
There's a reliance in the evidence review on the traditional ways of approaching the evidence, which does not acknowledge that rare diseases often do not have the accumulated natural history data and other datasets of interest—such as quality of life data, impact on daily activities, and cost analysis—that you might find help round out the typical review for non-rare disease.
I believe a new lens must be brought to the rare disease drug review at all levels. Ideally, this would be in the form of a comprehensive rare disease strategy and pathway, but smaller intermediate steps could be taken, such as the development of a rare disease review committee that helps inform any regulatory agency at any level when they're confronted with a rare disease drug review.
I would be reluctant to say that conservative evidence-based medicine approaches and a reliance on that sacred “p<0.05” on a primary outcome in a phase III clinical trial has handcuffed us from adequate evaluation of the data in the context of rare disease, but there does seem to be an adherence to this dogma.
In one instance, I was told by a Canadian regulator, after presenting a very compelling meta-analysis of two trials of a rare disease drug, that regulatory agencies do not use meta-analyses. That's surprising, in that this is considered the pinnacle of evidence-based medicine techniques. If used more widely, it would have saved countless lives, dollars and resources in many areas of medicine. In my opinion, we need to shift to a more pragmatic framework for reviewing rare disease drugs.
With this in mind, I would suggest that all levels of Canadian regulatory bodies adopt the GRADE guidelines—the grading of recommendations, assessment, development and evaluation—for reviewing evidence. This largely Canadian-developed guideline framework is used the world over in more than 70 review bodies, including the World Health Organization and NICE, but to our knowledge, this is not brought to bear on many Health Canada and CADTH decisions. They don't use this framework routinely. GRADE allows a more transparent presentation of the totality of the evidence, ranks it on quality and strengths, and then includes the context of patient preferences, risk-benefit balances and cost effectiveness in creating a final recommendation.
Second is the issue of access to novel therapies while evidence review proceeds. Clinicians and patients in Canada are committed to ongoing data collection for rare disease in the scenario where new therapies are emerging on the market. In my area of expertise, SMA and other neuromuscular diseases, we've created a nationwide neuromuscular disease registry with more than 4,000 patients with rare diseases enrolled. They contribute to longitudinal natural history data collection. High-quality data is collected directly from expert clinicians, and the data is curated and monitored in compliance with best standards in health care privacy law. Wide-ranging data items, from biomarkers to patient-recorded outcomes, can be retained and customized to answer questions that regulators may be interested in.
Investment in rare disease registries will build confidence for regulators that long-term data is being collected and that the real-world impact and implications of a new drug will be captured in a systematic way. Disease registries have significant advantages over drug-based registries in being able to capture a sample of patients that more fully represents the actual patient community while evidence review is going on.
In the case of nusinersen for SMA, in Canada we've spearheaded a global initiative that's resulted in a new natural history dataset that's informed by the availability of new treatments for SMA, and harmonization on this new dataset is now processing through 40 national or regional SMA registries around the world. To date, no one from a Canadian regulatory agency has approached the CNDR to discuss what critical items are needed for ongoing evidence development.
Other mechanisms that can bridge the gaps include revamping the special access program to provide access to drugs during the gap between Health Canada approval and pCPA decisions, envisioning various managed access scenarios that would creatively engage industry to get patients access to the drug while the reviews are proceeding, and creation of a national public pharmacare program for rare disease. My understanding is that there are other funding envelopes that exist for specific scenarios such as cancer and metabolic disease, and a funding envelope specific to rare disease would ideally triage and prioritize access in a more timely way, again while evidence review proceeds.
At present the journey of the person with a rare disease is completely unacceptable and seems unnecessary to me, given the collective interest and commitment of all the stakeholders in the rare disease community. In a compassionate country like Canada, we must find a way to be more definitive, more transparent and more responsive to our citizens struggling with access to medication for rare disease.
I appreciate the opportunity to address the committee, and I'm happy to answer any questions. I truly hope that the efforts of the committee will ultimately result in the realization of a rare disease strategy in Canada.
Thank you.