Towards a New Way of Evaluating Orphan Drugs at CADTH

Transcription

1 White Paper Towards a New Way of Evaluating Orphan Drugs at CADTH Executive Summary A rare disease is defined in Canada as a life-threatening, seriously debilitating, or serious chronic condition that only affects a very small number of patients (typically less than 5 in 10,000 persons). The very small number of patients with a specific rare disease creates challenges in designing clinical trials that are statistically powered to identify significant changes in relevant clinical outcomes over a time frame consistent with the natural history of the disease. At the same time, a large total number of Canadians are impacted by rare diseases. It is estimated that there are 7,000 rare diseases and that 1 in 12 Canadians, or about 2.8 million individuals, have been diagnosed with a rare disease. Therefore, although individual rare diseases have a low prevalence, collectively they have a large societal, clinical, and economic burden. Research over the past two decades has led to the development of innovative drugs that, in many cases, offer patients with rare diseases potentially effective therapies for the first time. Unfortunately, Canada has historically lagged behind other countries in providing access to orphan drugs. This is borne out by the lack of an official national orphan drug policy in Canada and by studies of reimbursement recommendations that show a lower positive recommendation rate for orphan drugs in Canada relative to other jurisdictions. In March 2016, however, the Canadian Agency for Drugs and Technologies in Health (CADTH) published a new recommendation framework that may have important implications for orphan drug reimbursement in Canada and is a significant step in the right direction. Included in this framework is the public recognition by CADTH that, in certain exceptional cases, there may be practical challenges in conducting robust clinical trials and pharmacoeconomic evaluations. In these cases, where there is also significant unmet medical need, CADTH s drug expert committees may now issue a recommendation to reimburse with clinical criteria and/or conditions. The framework lists examples of commonly used conditions and hints that real-world evidence will likely play an important role in future recommendations for orphan drugs.

2 Introduction Patients with rare diseases have always felt that orphan drugs should be evaluated differently. Now it appears that public payers are coming around to their point of view. In March 2016, the Canadian Agency for Drugs and Technologies in Health (CADTH) published a new recommendation framework for Common Drug Review (CDR) and pan-canadian Oncology Drug Review (pcodr) submissions. 1, 2 Included in this framework is the public recognition by CADTH that, in certain exceptional cases, there may be practical challenges in conducting robust clinical trials and pharmacoeconomic evaluations. As a result, in situations where there is also significant unmet medical need, CADTH s drug expert committees may now issue a recommendation to reimburse with clinical criteria and/or conditions even though there is uncertainty with the clinical evidence. 1, 2 This represents a significant step in the right direction for patients with rare diseases. This paper will discuss CADTH s new recommendation framework as it relates specifically to recommendations for orphan drugs and demonstrates why a new approach to evaluating orphan drugs was needed. It will place the framework in both the Canadian and international contexts for orphan drug reimbursement and examine the framework s potential implications on orphan drug reimbursement in Canada moving forward. Why Orphan Drugs Should Be Evaluated Differently Micro Challenges: Rare diseases are defined as severe conditions that affect a very small number of individuals; however, there is no globally accepted prevalence-based definition. 3,4 In the United States (US) the Food and Drug Administration (FDA) defines a rare disease as one that affects 200,000 citizens (or approximately 6.4 in 10,000) whereas in the European Union (EU) the definition is not greater than one in 2,000. Canada defines a rare disease as a life-threatening, seriously debilitating, or serious chronic condition that only affects a very small number of patients (typically less than 5 in 10,000 persons). 6 The very small number of available patients with a specific rare disease makes it challenging to design clinical trials that are statistically powered to identify significant changes in relevant clinical outcomes over a time frame consistent with the natural history of the disease. As a result, shortterm data from small clinical trials is often all that is available to evaluate orphan drugs from a regulatory and health technology assessment (HTA) perspective. In addition, the small available patient populations for approved drugs make it difficult to recover drug development costs, unless the drugs are premium priced. This high cost in turn creates issues for payers where the application of traditional measures of efficacy and cost-effectiveness, originally used to evaluate drugs for more common diseases, may disqualify drugs for rare diseases, severely limiting patient access. Macro Challenges: Although rare diseases have a low individual prevalence, collectively they can impart a large societal, clinical, and economic burden. Approximately 7,000 rare diseases have been identified and it is estimated that 1 in 12 Canadians, or about 2.8 million individuals, have been diagnosed with a rare disease. 3, 7 This large total number of Canadians who are severely impacted by rare diseases makes it imperative that a fair and realistic evaluation framework be implemented to review orphan drugs for reimbursement. Access to Orphan Drugs in Canada vs. Other Jurisdictions Research over the past two decades has significantly enhanced our understanding of the biological mechanisms behind rare diseases. This has led to the development of innovative drugs that, in many cases, offer patients potentially effective therapies for the first time. In response to the increasing number of orphan drugs, many countries have modified both their regulatory and reimbursement processes to allow more patients to access these drugs. Historically, Canada has lagged behind other countries in this regard. In October 2012, however, the Canadian government took steps to address rare diseases with the creation of a framework to facilitate research and authorization of new drugs for rare diseases (although final details relating to the initiative have yet to be released). 8, 9 As in other countries, the final regulatory framework is expected to focus on orphan drug designation criteria, scientific advice and assistance in clinical trial design, post-marketing plans tailored to assess long-term risk/benefit profiles, and collaboration with other jurisdic- 3, 6, 8, 9 tions. Public payer reimbursement recommendations for drugs in Canada (with the exception of Quebec) are based on recommendations made by the expert drug committees of CDR (for non-oncology drugs) and pcodr (for oncology drugs). 10, 11, 12, 13 Both CDR and pcodr are part of CADTH and have similar review and evaluation processes. In the absence of a national orphan drug policy, orphan drugs go through the same review and evaluation process as any other drug at both agencies. For a non-oncology drug, CDR reviews the clinical and economic evidence relating to the drug and prepares summary reports for the Canadian Drug Expert Committee (CDEC) who, after review, issues a recommendation to participating publicly funded drug plans. 10, 11 Historically, CDEC deliberations were based on clinical studies demonstrating the safety, efficacy and effectiveness of the drug compared to alternatives, cost and cost-effectiveness of the new drug relative to current accepted therapy and, more recently, patient input. 11,12 The evaluation procedures used were developed to assess the efficacy and economic implications of drugs for more common diseases. The procedures were not designed to assess these outcomes for high cost drugs utilized in small patient populations where, in many cases, there is no treatment alternative and where surrogate outcomes and patient quality of life may be more relevant to patients. As a result, the CDEC deliberative framework did not specifically recognize the potential limitations of clinical and economic data for orphan drugs. In particular, information on the effectiveness and cost-effectiveness of orphan drugs with respect to current accepted therapy is frequently absent for orphan drugs because in many cases they are the first drug specifically targeted for the disease and the alternative is a standard 2

3 of care which may be poorly defined and shows extensive regional variation. 14 The result was that orphan drug submissions to CDR, in many cases, failed to meet criteria for a positive recommendation. The disparity between positive CDR recommendations for orphan drugs vs. other drugs was demonstrated in a recent study conducted by Rawson. 15 This study showed that between 2004 and 2015, from 250 final recommendations for all drugs, 52% were positive (i.e., recommendation was that the drugs be listed with or without criteria defining their use). In contrast, for 29 drugs for rare disorders (defined for the study as a disease with a prevalence of less than 1 in 10,000) over the same period, only 35% were recommended for listing, a much lower recommendation rate. There is also evidence that the rate of positive CDR recommendations for orphan drugs is lower than in other jurisdictions. 16, 17 A recent McKesson analysis of CDR submissions for orphan drugs between 2003 and 2015 found that the positive recommendation rate for the same drugs was 88.1% in Australia, 60% in Scotland, 62% in New Zealand, and 66% in Quebec, which maintains its own HTA system for drugs, independent of CDR. 17 It should also be noted that there was a considerable lack of concordance in HTA decisions between the different agencies. For the drugs reviewed by all five jurisdictions, there was only a 33.3% concordance in decisions, suggesting a lack of standardization in the methods used to assess the strengths and weaknesses of the limited clinical and economic data available for orphan drugs. 17 This was particularly apparent in orphan drug reimbursement concordance between CDR and Quebec. In this case concordance was only 68%, reflecting variable interpretation of common efficacy data in a health care system with presumably similar cost constraints. Despite the importance that CDR attaches to economic evaluations in the drug review process, McKesson s analysis suggests that clinical parameters alone play a major role in most CDR recommendations relating to orphan drugs (47.1% of submissions for orphan drugs were assessed on the basis of clinical parameters alone compared to 41.2% assessed on clinical and price parameters). 17 This highlights the reality that challenges in conducting robust clinical trials are a significant factor in the negative recommendations that orphan drugs have historically received from CDR. The result is that Canadian patients with rare diseases have had reduced access to effective drug therapy. Patients are often left to engage in lobbying of provincial payers and there have been examples of patients and their families resorting to press coverage or social media in an attempt to gain access to treatment. 18 Increasingly, individual provinces are finding ways to accommodate the special status of orphan drugs through negotiated agreements that include specific clinical or listing criteria. 19 However, this long process, which includes the CDR review and extensive provincial negotiations, also means that patients may have to wait a considerable period of time before they gain access to much needed drug therapy. CADTH s New Evaluation Framework In March 2016, following input from relevant stakeholders, including several patient advocacy groups, CADTH released a new recommendation framework for both CDR and pcodr. 1,2 This establishes a single recommendation framework to support drug expert committees in making recommendations to the participating jurisdictions to guide their reimbursement decisions. The final recommendation categories for both CDR and pcodr are now: Reimburse; Reimburse with clinical criteria and/or conditions; or Do not reimburse. In response to the challenges in evaluating drugs where there is uncertain evidence, CADTH s new framework also includes an important section on considerations for significant unmet need. Of significant relevance to the evaluation of drugs for rare diseases, the framework states the following: 1,2 In exceptional cases where there is uncertain clinical and pharmacoeconomic evidence, the CADTH drug expert committees may issue a recommendation to reimburse with clinical criteria and/or conditions, due to practical challenges in conducting robust clinical trials and pharmacoeconomic evaluations and in the presence of significant unmet medical need. In these situations, although there is uncertainty with the clinical evidence, the available evidence must reasonably suggest that the drug under review could substantially reduce morbidity and/or mortality associated with the disease. Significant unmet clinical need is identified on a population or subpopulation basis (i.e., not on an individual basis) through the CDR and pcodr processes. Potential Implications of CADTH s New Evaluation Framework on Orphan Drug Access In the category Reimburse with clinical criteria/conditions, one of the scenarios that could be considered is as follows: The drug under review demonstrates clinical benefit, with a greater degree of uncertainty and an acceptable balance between benefits and harms, in a therapeutic area with significant unmet clinical need. In such cases, if the cost/cost-effectiveness relative to one or more appropriate comparators is unacceptable, a condition may include a reduced price. 1 The considerations defining significant unmet need are summarized in Table 1. These considerations now explicitly define a rare disease and identify key areas that patients with rare diseases have long considered relevant in the evaluation of orphan drugs. In particular, CADTH has recognized a wider societal impact of these diseases by acknowledging the burden on caregivers and will consider the absence of alternative therapies, presumably recognizing that in some cases there is no existing viable treatment for patients. The revised recommendations also explicitly state that existing treatment options may include best supportive care and non-pharmaceutical health technologies or procedures which, in light of the other recommendations, may be particularly relevant to rare diseases where in many cases there may be no indicated treatment for the condition. 1 3

4 Table 1: CADTH considerations for defining significant unmet need * Consideration Description Rarity of condition - The drug under review is approved by Health Canada for the treatment of a rare disease with the following characteristics: is life-threatening, seriously debilitating, or both serious and chronic in nature affects a relatively small number of patients (incidence of fewer than 5 in 10,000, but typically closer to 1 in 100,000) is often genetically based, onset at birth or early childhood, and leads to a shortened lifespan places a heavy burden on caregivers and the health care system is difficult to study because of the small patient population. Population - Need is identified on a population or subpopulation basis (i.e., not on an individual basis). Absence of alternatives - There is an absence of clinically effective drug or non-drug alternative treatments. - Substantial morbidity and mortality exist despite the available drug or non-drug alternative treatments. *From Recommendation Framework for CADTH Common Drug Review and pan-canadian Oncology Drug Review Programs: Guidance for CADTH s Drug Expert Committees 1 Uncertainty of clinical benefit has also been defined in detail (Table 2). This uncertainty includes absence of comparator groups, reliance on surrogate end points, and short clinical trial time frames. All of these sources of uncertainty have, in the past, been prominent critical points in CDEC reviews of rare disease drugs and have played a large role in negative reimbursement decisions. 15 Table 2: CADTH defined factors that contribute to uncertainty of clinical benefit* Consideration Description Clinical data Limited number of clinical studies Small sample sizes (e.g., due to rare disease that affects a relatively small number of patients (incidence of fewer than 5 in 10,000, but typically closer to 1 in 100,000) Absence of comparator groups Alternative or adaptive trial designs for rare diseases Short study durations or follow-up Inability to distinguish disease severity in heterogeneous manifested rare diseases Limited to surrogate end points Insufficient evidence on meaningful clinical end points Greater uncertainty in statistical analyses *From Recommendation Framework for CADTH Common Drug Review and pan-canadian Oncology Drug Review Programs: Guidance for CADTH s Drug Expert Committees 1 While the new framework lists factors that contribute to uncertainty of clinical benefit, no changes to CADTH s policies on health economic evaluations are mentioned. This absence is significant, because in many cases orphan drugs have not been recommended for reimbursement by CADTH because of unacceptable costeffectiveness ratios. 15,17 Although the revised reimburse with clinical criteria and/or conditions state that a reduction in price may be required, it is unclear at the moment how the recognition of clinical uncertainty for orphan drugs will affect the interpretation of costeffectiveness data. There has been debate, particularly in Europe, about the limitations of using conventional cost-utility analyses and quality-adjusted life years (QALYs) to drive funding decisions; alternatives such as a multi-criteria framework, where criteria relevant to a specific rare disease are incorporated into the economic assessment, or modified cost-utility thresholds for drugs have been suggested. 20, 21, 22 Currently, CADTH has not defined an acceptable cost-effectiveness threshold for reimbursement recommendations. Therefore, it remains unclear how the cost per QALY for a specific drug is incorporated into the evaluation process. CADTH is, however, currently updating their guidelines for economic evaluation of pharmaceuticals and this may provide additional information on how the economic impact of orphan drugs will be addressed. 4

5 Two decades ago, McKesson pioneered the development of Phase IV Studies in Canada for the purposes of collecting real-worldevidence that demonstrated the safety and effectiveness of drugs. Now, 20 years later, we see that the gathering of real-worldevidence through our Registries, Studies, and Patient Support Programs is more important than ever in helping patients secure access and reimbursement for drugs particularly drugs for rare diseases. Conclusion Rather than discussing economic factors, CADTH s new framework emphasises clinical considerations instead, and hints that real-world evidence will likely play an important role in future recommendations. Under examples of common conditions that CADTH s drug expert committees will use in formulating a reimbursement recommendation, the framework lists: Real-world evidence development for scenarios where there is uncertain clinical benefit, but significant unmet need. As discussed above, the clinical evidence is often uncertain with orphan drugs. Therefore, it follows that CADTH may recommend the gathering of real-world evidence more frequently as a condition for orphan drug reimbursement. This requirement for real-world evidence as a condition for reimbursement is in fact the path that various provinces and international jurisdictions are taking with respect to the reimbursement of orphan drugs. Generally, most countries do not have a specific HTA review process for orphan drugs but have modified their normal review processes to accommodate this drug class. In many jurisdictions, drugs that fail conventional standards of cost-effectiveness during the normal HTA review are re-considered for a safety net type program to allow patient access. 23 In Australia, for example, there are no specific evaluation procedures for orphan drugs. 24 However, patients can get access to orphan drugs through the Life Saving Drugs Program (LSDP), which provides funding for drugs that may have been rejected because of an unacceptable cost-effectiveness ratio in the normal drug review. Drugs eligible for the LSDP are defined by a number of criteria including disease rarity, impact of the disease on patient life-expectancy, and current treatment alternatives. 25, 26 Access to LSDP drugs requires the treating physician to apply for coverage for each patient and in most cases patient follow-up is required and continuation of therapy will occur only if the patient meets specific response criteria. 27 In Canada, despite the negative recommendations from CDR for many orphan drugs, five provinces have established their own rare disease programs with some variation in program structure and in the definition of a rare disease. 19 With the exception of Ontario, all provinces appear to deal with drug access on a case-by-case basis where a treating physician must apply for coverage for patients who meet specific criteria. 19 In Ontario, drugs that treat non-cancer related diseases with an annual incidence of <1 in 150,000 are reviewed by the Drugs for Rare Diseases Evaluation Framework (DRDEF). 19, 28, 29 The DRDEF recommendations are relevant for all patients for whom the drug is indicated rather than individual patients. 19 Interestingly, most provinces appear to use value-based assessments to allow continuation of therapy where regular monitoring of patient outcomes is required to continue treatment. 19 Historically, Canada has lagged behind other countries in terms of access to orphan drugs. This is borne out by the lack of a national orphan drug policy and by positive reimbursement recommendation rates that are lower than other jurisdictions. However, the new recommendation framework released by CADTH is a significant step in the right direction and may lead in the future to improved access to much needed drug therapy for patients with rare diseases. Included in this framework is the public recognition by CADTH that, in certain exceptional cases, there may be practical challenges in conducting robust clinical trials and pharmacoeconomic evaluations. 5

6 References 1 CADTH. Recommendation framework for CADTH Common Drug Review and pan-canadian Oncology Drug Review Programs: Guidance for CADTH s Drug Expert Committees. March Available at: cdr/templates/pre-sub-phase/cdr_pcodr_ recommendations_framework.pdf. Accessed 2 CADTH/pCODR. Recommendation framework for CADTH Common Drug Review and pan- Canadian Oncology Drug Review Programs: Guidance for CADTH s Drug Expert Committees. March Available at: media/cdr/templates/pre-sub-phase/pcodr_ CDR_recommendations_framework.pdf. Accessed 3 Loorand-Stiver L. Drugs for Rare Diseases: Evolving Trends in Regulatory and Health Technology Assessment Perspectives [Environmental Scan, Issue 42]. Ottawa: Canadian Agency for Drugs and Technologies in Health; Available at: pdf/es0281_rarediseasedrugs_es_e.pdf. Accessed 4 Drugs for rare diseases: evolving trends in regulatory and health technology assessment perspectives. Ottawa; CADTH; 2013 Oct [updated 2016 Feb]. (Environmental scan; issue 42). 5 Gammie T, Lu CY, Babar ZU-D. Access to orphan drugs: A comprehensive review of legislations, regulations and policies in 35 countries. PLoS One 2015; 10(10): e BIOTECanada. The Canadian Rare Disease Therapies Landscape: Bridging opportunity to reality. Available at: uploads/white_paper_mar_2.pdf. Accessed March 22, Canadian Institute of Health Research. New Emerging Team for Rare Diseases. Available at: Accessed March 22, Lee DK, Wong B. An orphan drug framework (ODF) for Canada. J Popul Ther Clin Pharmacol 2014;21:e Wong-Rieger, D. Canada s long journey toward an orphan drug framework. Advocate 2013;20:20-1. Available at: Orphan%20Drug%20Framework.pdf. Accessed 10 Tierney M, Manns B, with the members of the Canadian Expert Drug Advisory Committee. Optimizing the use of prescription drugs in Canada through the Common Drug Review. Can Med Assoc J 2008;178: Canadian Agency for Drugs and Technologies in Health. Procedure for the CADTH Common Drug Review. Available at: media/cdr/process/cdr_procedure.pdf. Accessed March 22, Canadian Agency for Drugs and Technologies in Health. Submission guidelines for the CADTH Common Drug Review. Available at: cadth.ca/media/cdr/process/cdr_submission_ Guidelines.pdf. Accessed March 22, CADTH Pan-Canadian Oncology Drug Review. Available at: what-we-do/products-services/pcodr. Accessed 14 Hyry HI, Stern AD, Cox TM, Roos JCP. Limits on use of health economic assessments for rare diseases. QJ Med 2014;107: Rawson NSB. Are the cost-effectiveness rules used by public drug plans denying coverage to Canadians with rare disorders? Canadian Health Policy, August 4, Toronto: Canadian Health Policy Institute (CHPI). 16 Blankart CR, Stargardt T, Schreyogg J. Availability of and access to orphan drugs. An international comparison of pharmaceutical treatments for Pulmonary Arterial Hypertension, Fabry Disease, Hereditary Angiodema and Chronic Myeloid Leukemia. Pharmacoeconomics 2011;29: McCormick J, Berescu D et al. Common Drug Review recommendations for orphan drugs in Canada: basis of recommendations and comparison with similar reviews in Quebec, Australia, Scotland and New Zealand. Manuscript in preparation (2016). 18 Weeks C. Canada lags behind on rare disease drugs. The Globe and Mail, February 27, Available at: life/health-and-fitness/health/canada-lagsbehind-on-rare-disease-drugs/article /. Accesssed April 21, Menon D, Clark D, Stafinski T. Reimbursement of drugs for rare diseases through the public healthcare system in Canada: Where are we now? Healthc Policy 2015;11: Schandler M, Garattini S, Holm S et al. Incremental cost per quality-adjusted life year gained? The need for alternative methods to evaluate medical interventions for ultra-rare disorders. J Comp Eff Res 2014;3: Gutierrez L, Patris J, Hutchings A, Cowell W. Principles for consistent value assessment and sustainable funding of orphan drugs in Europe. Orphanet J Rare Dis 2015;10: Paulden M, Stafinski T, Menon D, McCabe C. Value-based reimbursement decisions for orphan drugs : A scoping review and decision framework. Pharmacoeconomics 2015;33: Short H, Stafinski T, Menon D. A national approach to reimbursement decision-making on drugs for rare diseases in Canada? Insights from across the ponds. Healthc Policy 2015; 10: Guidelines for preparing submissions to the Pharmaceutical Benefits Advisory Committee. Available at: Accessed March 22, Life Savings Drug Program Criteria and Conditions. Available at: au/internet/main/publishing.nsf/content/lsdpcriteria. Accessed March 22, PBAC Guidelines: F.3 Other relevant factors: Accessed March 24, Life Saving Drugs Programme (LSDP) guidelines and application form for subsidised treatment for Mucopolysaccharidosis Type II disease (MPS II). Available at: main/publishing.nsf/content/lsdp-info/$file/ MPS-II pdf. Accessed April 7, Ontario Ministry of Health and Long-Term Care. Drugs for rare diseases. Available at: how_drugs_approv/review_rare_diseases.aspx. Accessed April 12, Winquist E, Bell CM, Clarke JTR et al. An evaluation framework for funding drugs for rare diseases. Value Health 2012;15: McKesson Canada Head Office 4705 Dobrin Street Saint-Laurent, Québec H4R 2P7 Nabil Tadros, PharmD Senior Manager, Consulting Services McKesson Pharmaceutical Solutions , ext nabil.tadros@mckesson.ca John McCormick, PhD Senior Consultant, Consulting Services McKesson Pharmaceutical Solutions , ext or john.mccormick@mckesson.ca McKesson Canada, All rights reserved. The Information contained in this document is proprietary to McKesson Canada. Copyright 2016 McKesson Canada All rights reserved.