TOWARDS APPROPRIATE AND SUSTAINABLE ACCESS TO DRUGS FOR RARE DISEASES (DRDs): WHERE ARE WE NOW IN CANADA AND WHAT CAN WE LEARN FROM ABROAD? Tania Stafinski, MSc, PhD Dev Menon, MHSA, PhD Derek Clark, BScN, MPH Hilary Short, BSc, MSc

OVER THE NEXT 12 MINUTES… Where are we now in Canada? - Current mechanisms for determining which DRDs to provide - Impact on access - Current challenges - Efforts towards a pan-Canadian approach What can we learn from international experience? - Similarities and differences in healthcare systems Where could we go from here? Thank you, Stuart. And thank you Bill for putting this panel together. Over the next 12 minutes, I’ll talk about where we are now in Canada in terms of reimbursement decision-making on drugs for rare diseases or orphan and ultra orphan drugs, what that has meant for access across provinces and territories, what the key challenges facing payers are and what has been done or is being done on a pan-Canadian level to address them I’ll also talk about what other countries have done in this area and what we might be able to learn from their experiences as we move towards appropriate and sustainable access to these drugs.

WHERE ARE WE NOW IN CANADA? DRD manufacturer application for reimbursement CADTH pCODR/CDR Pan-Canadian Pharmaceutical Alliance (pCPA) Briefly these drugs, as well as any newly approved drug being considered for reimbursement in Canada are first reviewed by one of two centralized drug review processes – the common drug review (CDR) for non-cancer drugs and the panCanadian Oncology Drug Review (pCODR) for cancer. Based on the reviews, a listing recommendation is made. Prior to 2010, those recommendations were sent to the participating federal, provincial or territorial drug plans for them to make a final decision. In 2010, the pan-Canadian Pharmaceutical Alliance (pCPA) was established which conducts joint provincial/territorial pricing negotiations on drugs, particularly orphan drugs, breakthrough drugs or drugs that have the potential to change the treatment landscape. Manufacturers submit a proposal to the pCPA, which includes the CDR or pCODR recommendation, budget impact analysis for each jurisdiction and the value of the offer to each jurisdiction. The offer may take the form of rebates, expenditure caps, results or outcomes based arrangements, which may be called conditional listing agreements or managed entry agreements. Once negotiations between the manufacturer and pCPA have taken place a letter of intent is finalized and manufacturers move on to negotiate the actual agreement with each jurisdiction, which makes the final decision. These steps combined represent the general reimbursement process. Drug plans within participating jurisdictions

WHERE ARE WE NOW IN CANADA? Reimbursement decision-making mechanism General reimbursement process 1 Case by case review DRD specific program 1 Where orphan drugs fail to receive a positive recommendation from the CDR or pCODR or where manufacturers fail to reach a listing agreement with jurisdictions, patients may be able to gain access to the drug on a case-by-case basis. In all provinces and territories, individual cases are considered, usually after a physician makes a request, by the drug plan as part of safety net programs. In addition to general reimbursement processes and case-by case reviews, 5 provinces have established specific processes for programs for expensive drugs from rare diseases. They include BC, Alberta, Saskatchewan, Ontario, and New Brunswick. 1Uses Non-Insured Health Benefits Program general reimbursement review process

WHERE ARE WE NOW IN CANADA? DRD specific programs - 5 provinces - 2 types Separate plan containing defined set of DRDs Separate decision-making processes for DRDs Alberta’s Rare Disease Drug Coverage Program New Brunswick’s Drugs for Rare Diseases Plan BC’s Expensive Drugs for Rare Diseases (EDRD) Advisory Committee Ontario’s DRD Evaluation Framework and DRD Working Group Saskatchewan’s EDRD Process These programs fall into one of two categories. The first comprises plans that provide access to a defined set of drugs. The two examples are Alberta’s Rare Disease Drug Coverage Program covers drugs for genetic lysosomal storage disorders affecting less than 1 in 50,000 and New Brunswick’s program that provides access to one of the specified drugs on the plan for rare metabolic disorders. The second comprises dedicated decision-making processes. In BC, the Expensive Drugs for Rare Diseases Advisory Committee considers individual requests for non-oncology drugs that treat conditions with a prevalence of less than 1.7 per 100,000 Canadians, and positive recommendations usually take the form of provide with ongoing monitoring and continued coverage contingent upon clinical criteria. The second is Ontario’s DRD Evaluation Framework through which drugs that treat conditions with an annual incidence of < 150,000 individuals in Canada and for which there are no clinical studies measuring clinically important outcomes have been considered. The last one is Saskatchewan’s EDRD process, which also considers drugs that treat conditions occurring in less than 1 in 150 000 individuals in Canada. Positive recommendations are usually conditional for a fixed time period during which a progress report of the patient’s treatment response must be completed. So what do these, as well as the general reimbursement review processes and case-by-case mechanisms mean in terms of access to these drugs across the country?

WHERE ARE WE NOW IN CANADA? Proportion of CDR-reviewed DRDs (non-oncology) reimbursed in each province/territory through one of three mechanisms About a year and a half ago, we compiled an inventory of all non-cancer drugs for indications with a prevalence of less than 1 in 2000 in Canada that had been reviewed by the CDR since its inception. We surveyed the provincial and territorial drug plans and publicly available formulary list to determine which drugs were available. It didn’t matter through what mechanism, what mattered was whether patients could get access to them. There were 33 drugs that we considered and the graph here shows the percentage of those drugs that were available in each jurisdiction. There wasn’t a clear correlation between higher proportions of provided drugs and the presence of a specific DRD program.

WHERE ARE WE NOW IN CANADA? Degree of agreement on reimbursement status across jurisdictions by Anatomic, Therapeutic and Chemical Classification (ATC) group ATC Group Kappa Alimentary tract and metabolism products 0.051 Antineoplastic and immunomodulating agents 0.57 Blood and blood-forming organ agents 0.11 Cardiovascular system agents 0.45 Musculoskeletal system agents 0.49 Nervous system agents 0.71 Respiratory system agents -0.083 Systemic anti-infective agents 0.15 Systemic hormonal preparations 0.17 All DRDs (non-oncology) 0.48 Kappa score interpretation < 0 Less than chance agreement 0.01–0.20 = Slight agreement 0.21– 0.40 = Fair agreement 0.41–0.60 = Moderate agreement 0.61–0.80 = Substantial agreement 0.81–0.99 = Almost perfect agreement We also looked at the degree of agreement between jurisdictions on drugs available using the kappa statistic, which measures agreement beyond that due to chance, alone. We looked at this for all 33 drugs and by anatomic therapeutic and chemical classification group. Unsurprisingly, groups with the lowest kappa scores contained those drugs associated with some of the highest price tags.

WHERE ARE WE NOW IN CANADA? Current challenges Many DRDs High per patient cost ? Sustainability ? Value ? Clinical benefit These drugs challenge payers for the main reasons. They are often associated with limited clinical evidence. Because of small patient numbers and disease heterogeneity, there aren’t multiple high quality clinical trials defined by currents levels of evidence scales. Therefore, the kind of clinical evidence that payers are used to seeing and have grown to expect simply isn’t there. This creates significant uncertainty around clinical benefit. And then there is the high price tag for many of these drugs and they are life long. These combined lead to uncertainties around value. Then, finally, when payers consider the growing number of these drugs, they start to have legitimate concerns around sustainability. All of this amounts to significant risk. So what sorts of things are being done or have been looked at to address these challenges in Canada?

WHERE ARE WE NOW IN CANADA? Efforts towards appropriate and sustainable access to DRDs 1. Regulatory level - Vanessa’s Law - Draft Orphan Drug Regulatory Framework 2. Reimbursement level - Pan-Canadian framework for EDRD - Pan-Canadian plan for rare diseases - pCPA - Improved access to pharmaceuticals one of the priorities of new gov’t - A place in the Health Accord? At the regulatory level, both Vanessa’s law and the draft orphan drug regulatory framework have the potential to reduce uncertainties in the clinical evidence. Vanessa’s Law by increasing Health Canada’s ability to require safety information post market and in the case of the Draft Orphan Drug Regulatory Framework, by requiring data collection through the drug’s lifecycle increasing transparency and information sharing with key decision-makers, providers, HTA producers, and patients. At the reimbursement level, its been almost a decade since the first framework for evaluating expensive drugs for rare diseases was drafted by provincial and territorial drug plans but never implemented. Canada remains one of the few if not the only developed country without a plan for rare diseases. At the same time, the pCPA has certainly helped payers deal with some of the issues around high prices through their negotiations of listing agreements. There also appears to be a renewed political commitment to improving access to pharmaceuticals, including those for rare diseases in Canada. Last July, it was identified as a key priority at the annual meeting of Canada’s provincial premiers. Whether this topic finds a place in the upcoming health accord or not, the challenges involved in making reimbursement decisions on these drugs will still need to be addressed and soon. In doing so, is there anything we can learn from international experience?

WHAT CAN WE LEARN FROM INTERNATIONAL EXPERIENCE? Proportion of DRDs with regulatory approval reimbursed by country A couple of years ago, Rare Diseases Europe or EURORDIS commissioned a survey on the availability of 60 orphan drugs with market approval in the European Union. By availability, they mean whether or not the drug is provided by the healthcare system to patients with the approved condition. These four countries had the highest proportion of drugs available. In France, it was just over 90% and in Italy it was approximately 70%. Source:

WHAT CAN WE LEARN FROM INTERNATIONAL EXPERIENCE? National price versus mean EU price in countries with greatest number of reimbursed DRDs When they looked at the national price compared to the mean EU price, both reported as effective prices, the two countries with the highest proportion of drugs available to patients had the lowest prices among these 4. The prices were roughly 15% lower than the mean EU value. So the next question is what do their reimbursement processes for orphan drugs look like? Source:

WHAT CAN WE LEARN FROM INTERNATIONAL EXPERIENCE? Reimbursement decision-making processes in the same four countries Country Reimbursement decision-making mechanisms DRD specific mechanisms or considerations Conditions of reimbursement: Conditional listing agreements/Managed Entry Agreements (MEAs) France General reimbursement Case by case (individual or cohort) None - Frequently used - Common framework for all MEAs based on payment by results (financial) - Few payment by results (clinical) Netherlands No economic evaluation required - In past, mainly coverage with evidence development - Increasing use of payment by results (clinical) Denmark - Rarely used - Not formally a part of reimbursement system Italy AIFA 5% Fund - Payment by results (mainly clinical) - Monitoring registries In France, orphan drugs go through the same reimbursement process as any other drug. However, most decisions are tied to conditional listing agreements or managed entry agreements. And most of these are financial and based on a common framework. These include price volume agreements, agreement on daily costs or expenditure caps. Less frequently, risk sharing arrangements where the price is set on the basis of study results or coverage with evidence development are used. Neither the Netherlands nor Denmark have separate processes for orphan drugs although in the Netherlands, the economic evaluation is waived for the review, managed entry agreements in the form of coverage with evidence development schemes are used.. While Italy also does not have a separate process, it has created a special fund for orphan drugs called the 5% fund generated through a requirement that pharmaceutical companies donate 5% of their annual promotional expenditures to this fund. Off label orphan drugs or those for which there are no active treatment alternatives are provided through this fund. Italy also makes use of managed entry agreements, and most orphan drugs are monitored through registries. That is fairly simple for Italy to do since they have a national electronic health record. Despite these processes, these countries are also facing concerns about sustainability.

WHERE DO WE GO FROM HERE? Dealing with uncertainties in clinical benefit - Registries? - MEAs – payment by clinical results? Dealing with high prices - MEAs – payment by financial results? - Discounts? - Single Canadian purchasing – increased buying power? So where does this leave us? Afterall, one key difference between these 4 countries and Canada is the organization of the pharmacare system. Theirs is centralized, while ours is decentralized. In dealing with uncertainties in clinical benefit, is it feasible to have a registry for each orphan drug when we don’t have a national electronic health record? Is there a place for registries originally developed by manufacturers? While pCPA has used outcomes based agreements or pay for performance, they were difficult to execute and created high administrative burden. Thus there is reluctance to use this approach unless it is administratively simple. And while Vanessa’s law and the draft orphan drug regulatory framework may generate some valuable clinical evidence, that evidence is unlikely to be available when the drug first reaches payers’ desks. In terms of managing high prices, while financially based conditional listing agreements may be possible, what is the incentive for manufacturers to bring attractive offers to the pCPA table when there is no guarantee that individual jurisdictions will accept them? Given all this, it may be time to once again consider a pan-Canadian approach to pharmacare for these drugs, especially if it means that we could place ourselves in a better position to move towards addressing the challenges associated with them.

THANK YOU. Contact: Tania Stafinski E-mail: tanias@ualberta THANK YOU! Contact: Tania Stafinski E-mail: tanias@ualberta.ca Tel: 780 492 4791