Comparison of numbers and timing of new medication regulatory approvals in Canada and New Zealand.

The Canadian federal government has proposed significant revisions to the way its patented medicines price regulator assesses the excessiveness of medication prices that are to take effect in 2019. The changes have the potential to decrease Canada's attractiveness as a market for innovative medicines. The objective of this analysis was to compare the number of new drugs given regulatory approval in Canada between 2002 and 2017 with the number in New Zealand and, of those approved in both countries, to compare approval dates. Of 374 new drugs approved in Canada between 2002 and 2017, 139 (37.2%) were approved in Canada alone - the percentage increased from 20.2% to 48.2% for drugs approved in 2002-2006 and 2012-2017. Two hundred and thirty-five drugs (62.8%) were approved in both countries of which 182 (77.4%) were approved first in Canada with a median delay of 10 months before approval in New Zealand. Due to lapsed approvals and a lack of availability, less than 70% of the 235 drugs were accessible in New Zealand in mid-2018. Tight drug cost-containment saves money but at the expense of manufacturers either not seeking regulatory approval for new therapies or only doing so after approval in many other countries.

Canadian, European and United States new drug approval times now relatively similar.

The objectives of this analysis were to assess whether consistency in Health Canada's (HC's) approval times identified in 2011 has been sustained and to compare HC's approval times with those of the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). Between 2002 and 2016, 460 new drugs were approved by at least one of the agencies: 351 (76.3%), 319 (69.3%) and 392 (85.2%) by HC, the EMA and the FDA, respectively - all three approved 252 (54.8%). Overall medians and inter-quartile ranges of approval times for HC, the EMA and the FDA were 364 days (343-651), 371 days (322-434) and 304 days (209-455), respectively. The EMA's annual median approval time was consistent over the 15 years, while HC's and the FDA's median times were only consistent with each other and the EMA after 2005. Almost 80% of the drugs approved by all three agencies were submitted to HC later than to the other two agencies, which led to a median delay of a year between the agency first giving approval (FDA or EMA) and HC's approval. Rates of drugs withdrawn for safety reasons were 1.4% in Canada, 0.9% in Europe and 0.8% in the United States.

Drug safety: withdrawn medications are only part of the picture.

In a research article published in BMC Medicine, Onakpoya and colleagues provide a historical review of withdrawals of medications for safety reasons. However, withdrawn medications are only one part of the picture about how regulatory agencies manage drug risks. Moreover, medications introduced before the increased pre-marketing regulations and post-marketing monitoring systems instituted after the thalidomide tragedy have little relevance when considering the present drug safety picture because the circumstances under which they were introduced were completely different. To more fully understand drug safety management and regulatory agency actions, withdrawals should be evaluated within the setting and timeframe in which the medications are approved, which requires information about approvals and safety warnings. Studies are needed that provide a more comprehensive current picture of the identification and evaluation of drug safety risks as well as how regulatory agencies deal with them. Please see related research article: http://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-016-0553-2.

Health Canada's use of priority review status for drugs for unmet needs.

The processes for granting priority review status to new drug submissions in Canada and the United States are not exactly the same, but reasonable concordance should be expected since the selection criteria are similar in the two countries. This study compared new therapeutic drugs approved by both Health Canada and the Food and Drug Administration (FDA) between 2000 and 2014 to evaluate concordance on priority review status. New therapeutic drugs approved in both countries totalled 301; 86 (28.6%) and 136 (45.2%) were given priority review status in Canada and the United States, respectively, with 73 (24.3%) in both. Sensitivity and specificity were 53.7% and 92.1%. Overall concordance on review type was 74.8%. κ was 0.47 indicating moderate agreement. Agreement on review type was >70% for all drugs, except oncology therapies. Broad agreement exists between Health Canada and the FDA on drugs that should not have priority review status. Concordance on drugs that should have this status was generally satisfactory and, for critical drugs, was high. Agreement would improve if more oncology drugs received priority review status in Canada. Despite a higher number of drugs receiving priority review status in the United States, there is reasonable concordance between the two countries.

Timeliness of Health Technology Assessments and Price Negotiations for Oncology Drugs in Canada.

Purpose: To evaluate whether time targets for Canadian Agency for Drugs and Technologies in Health (CADTH) reimbursement reviews and pan-Canadian Pharmaceutical Alliance (pCPA) price negotiations are being achieved for oncology drugs. Materials and Methods: Recommendations, dates of submission and publication, and indications for oncology medicines issued between January 2014 and December 2023 were recorded from CADTH's reimbursement reports webpage. The date any negotiation began and the date it was completed (successfully or not), or when a decision was made not to pursue negotiation was extracted from the pCPA's webpage. The duration of each CADTH review and pCPA negotiation was calculated, together with time between CADTH's recommendation and start of the pCPA negotiation or a decision not to negotiate. Percentages of reviews completed within CADTH's target and of times taken by the pCPA to decide whether to negotiate and by its price negotiations completed within the relevant targets were calculated. Results: CADTH achieved its 270-days target in 88.2% to 100% of reviews issued between 2015 and 2019 but only in 65.9% to 73.1% of reviews issued in the last three years of the decade. CADTH's "typical timeline" of 180 days was achieved in under 40% of reviews issued in 2015 and not attained in any review in 2021, 2022 or 2023. The pCPA's target of 60 days for deciding whether to negotiate was achieved for all recommendations issued in 2014 but dropped below 40% for the last seven years of the decade; its target of 130 days for negotiations was achieved for over 85% of the recommendations in 2014 but decreased to only 14.3% in 2016 and then gradually increased to 61.5% in 2023. Conclusion: CADTH's "typical timeline" and the pCPA's targets were not met sufficiently to be meaningful. Their processes take too long for cancer drugs.

Canadian patients and providers are often frustrated and concerned about the timeliness of the country's health technology assessment (HTA) and price negotiation processes, especially for cancer drugs. HTAs are carried out to evaluate the benefit of a medicine in comparison with its cost to see whether the drug is of sufficient value to add it to the benefit lists of government drug plans. HTAs are performed by the Canadian Agency for Drugs and Technologies in Health (CADTH) for all of Canada, except the province of Quebec, and price negotiations with drug developers are carried out by the pan-Canadian Pharmaceutical Alliance (pCPA) on behalf of all government drug plans. We used data from the websites of CADTH and the pCPA on HTA reviews of cancer drugs issued between January 2014 and December 2023 and price negotiations for these drugs to assess whether CADTH and the pCPA complied with their stated target times for completing their processes. We found that CADTH's reviews and the pCPA's price negotiations failed to meet their targets for cancer drugs in the past 10 years and that the timeliness of their performance has, in most cases, deteriorated. HTA and price negotiation processes for cancer drugs take too long in Canada.

Is Canada Moving towards a More Agile Regulatory Approval and Reimbursement Process with a Shifting Role for Real-World Evidence (RWE) for Oncology Drugs?

Canada is known to have a complex pathway for new drug approval and reimbursement, resulting in delayed access for patients with serious and life-threatening diseases, such as cancer. Several recent publications from key stakeholders, including patients, physicians and policymakers, highlight patient helplessness, physician frustrations and policymakers entangled in a massive network of bureaucracy unable to make headway. Several quantitative and qualitative assessments using time from regulatory approvals to successful reimbursements confirm long review times and high rejection rates for oncology drugs, especially those receiving conditional approvals. A consensus forum of 18 Canadian oncology clinicians recently voiced frustration with the process and inability to deliver guideline-supported efficacious therapies to their patients. This manuscript compares data extracted from publicly available data sources from 2019 to June 2024 to previous publications. Methods: Public databases from Health Canada, the Canadian Agency for Drugs and Technologies in Health (CADTH), which is in the process of changing to Canada's Drug Agency, and the pan-Canadian Pharmaceutical Alliance (pCPA) were reviewed and the data collected were analyzed with descriptive statistics. Results: From the data, three trends emerge, (i) an increasing number of oncology drugs are receiving conditional approvals from Health Canada, (ii) the percentage of conditionally approved oncology drugs receiving positive reimbursement recommendations from CADTH is still low but appears to be improving, but delays in access are now contingent upon pCPA deciding whether to negotiate price and then the duration of any negotiation, and (iii) real-world evidence is no longer part of the decision-making for conditional approvals. A slight increase in the positive endorsement of RWE used to support CADTH recommendations was observed. Conclusions: The lack of timely access to oncology drugs hurts Canadian patients. While a small trend of improvement appears to be emerging, longer-term data collection is required to ensure sustained patient benefits.

New Anticancer Drugs: Reliably Assessing "Value" While Addressing High Prices.

Countries face challenges in paying for new drugs. High prices are driven in part by exploding drug development costs, which, in turn, are driven by essential but excessive regulation. Burdensome regulation also delays drug development, and this can translate into thousands of life-years lost. We need system-wide reform that will enable less expensive, faster drug development. The speed with which COVID-19 vaccines and AIDS therapies were developed indicates this is possible if governments prioritize it. Countries also differ in how they value drugs, and generally, those willing to pay more have better, faster access. Canada is used as an example to illustrate how "incremental cost-effectiveness ratios" (ICERs) based on measures such as gains in "quality-adjusted life-years" (QALYs) may be used to determine a drug's value but are often problematic, imprecise assessments. Generally, ICER/QALY estimates inadequately consider the impact of patient crossover or long post-progression survival, therapy benefits in distinct subpopulations, positive impacts of the therapy on other healthcare or societal costs, how much governments willingly might pay for other things, etc. Furthermore, a QALY value should be higher for a lethal or uncommon disease than for a common, nonlethal disease. Compared to international comparators, Canada is particularly ineffective in initiating public funding for essential new medications. Addressing these disparities demands urgent reform.

Access to Oncology Medicines in Canada: Consensus Forum for Recommendations for Improvement.

Patient access to new oncology drugs in Canada is only possible after navigating multiple sequential systemic checkpoints for national regulatory approval, health technology assessment (HTA) and collective government price negotiation. These steps delay access and prevent health care providers from being able to prescribe optimal therapy. Eighteen Canadian oncology clinicians from the medicine, nursing and pharmacy professions met to develop consensus recommendations for defining reasonable government performance standards around process and timeliness to improve Canadian cancer patients' access to best care. A modified Delphi methodology was used to identify consensus on 30 questions involving five themes: accountability, disparities, endpoints, timeliness, and cost-effectiveness. It was agreed that greater transparency is required across regulatory and HTA processes. Health professionals in oncology are frustrated for their patients because they are unable to deliver the modern guideline-supported therapies they want to provide due to delays in approval or funding. Canadian health care providers request improvements in timely access to life-saving therapeutics in line with other comparator countries. Clinicians expect urgent improvements in Canadian health systems to give our patients their best chance of survival.

Canadians Need Improved Access to Drugs for Rare Diseases, Not More Denial.

Sirrs et al. (2023a) discuss what they consider "explosive growth" (p. 11) in the research and development (R&D) and commercialization of expensive drugs for rare diseases (DRDs). They contend that the "status quo is no longer an option" (Sirrs et al. 2023b: 75), so it is critical to drastically reduce the prices of DRDs and/or ration access.

The aging Canadian population and hospitalizations for acute myocardial infarction: projection to 2020.

BACKGROUND: The risk of experiencing an acute myocardial infarction (AMI) increases with age and Canada's population is aging. The objective of this analysis was to examine trends in the AMI hospitalization rate in Canada between 2002 and 2009 and to estimate the potential increase in the number of AMI hospitalizations over the next decade. METHODS: Aggregated data on annual AMI hospitalizations were obtained from the Canadian Institute for Health Information for all provinces and territories, except Quebec, for 2002/03 and 2009/10. Using these data in a Poisson regression model to control for age, gender and year, the rate of AMI hospitalizations was extrapolated between 2010 and 2020. The extrapolated rate and Statistics Canada population projections were used to estimate the number of AMI hospitalizations in 2020. RESULTS: The rates of AMI hospitalizations by gender and age group showed a decrease between 2002 and 2009 in patients aged ≥ 65 years and relatively stable rates in those aged < 64 years in both males and females. However, the total number of AMI hospitalizations in Canada (excluding Quebec) is projected to increase by 4667 from 51847 in 2009 to 56514 in 2020, a 9.0% increase. Inflating this number to account for the unavailable Quebec data results in an increase of approximately 6200 for the whole of Canada. This would amount to an additional cost of between $46 and $54 million and sensitivity analyses indicate that it could be between $36 and $65 million. CONCLUSIONS: Despite projected decreasing or stable rates of AMI hospitalization, the number of hospitalizations is expected to increase substantially as a result of the aging of the Canadian population. The cost of these hospitalizations will be substantial. An increase of this extent in the number of AMI hospitalizations and the ensuing costs would significantly impact the already over-stretched Canadian healthcare system.

Health technology assessment and price negotiation alignment for rare disorder drugs in Canada: Who benefits?

BACKGROUND: Since 2014, the Canadian Agency for Drugs and Technologies in Health (CADTH), which performs health technology assessments for all federal, provincial and territorial government drug programs (except Quebec's) and the pan-Canadian Pharmaceutical Alliance (pCPA), which conducts price negotiations with manufacturers for all government drug programs, have been aligning their processes. OBJECTIVE: To examine trends in CADTH recommendations for non-oncology drugs for rare disorders (DRDs) released between 2014 and 2021, results of pCPA negotiations for the same drugs, and listings in government drug plans to assess who benefits from the alignment. RESULTS: Recommendations were positive in 87% of the reviews, although all included clinical criteria for use and/or economic conditions. Almost 90% of the DRDs with a positive recommendation had a successful price negotiation and 71% of those with a negative recommendation had no negotiation. Although no recommendation published before mid-2016 had a specified price reduction, almost 95% of those issued afterwards included the price reduction required to achieve a specific low cost-effectiveness threshold. The median time between the DRDs receiving marketing approval and a completed price negotiation was 663 days. Negotiations for DRDs completed after 2017 generally had fewer listings in government drug plans, but there was no distinct trend. The drug's price likely played a role in listing decisions. When DRDs were listed, drug plans had access criteria consistent with CADTH's or stronger for all the DRDs. CONCLUSIONS: The governments who own, fund and manage CADTH and the pCPA benefit from their alignment. The alignment is less beneficial for patients waiting for access to the DRDs. The time taken by CADTH and pCPA actions and individual government drug plans to make listing decisions delays access. CADTH's clinical criteria have become more extensive and are applied rigorously by drug plans which restricts patient access to DRDs. Canadians with rare disorders urgently need their governments to implement a long-overdue, comprehensive rare disease strategy to ensure DRDs are reviewed and reimbursed quickly and equitably to provide adequate health care to all who need them.

Leading Causes of Mortality and Prescription Drug Coverage in Canada and New Zealand.

Introduction: Canada may soon see the introduction of a national pharmaceutical insurance system. New Zealand has a government-funded healthcare system used by all residents that operates within a tight cost-containment budget. The objective of this analysis was to compare the main mortality causes in Canada and New Zealand and examine listings in current Canadian provincial public drug plans and the New Zealand national drug formulary. Materials and Methods: Age-standardized mortality rates from 2000 to 2015 and data on hospital discharges and average length of stay in hospital for Canada and New Zealand were obtained from the Organization for Economic Cooperation and Development's website. Information on insured medications was obtained from Canadian provincial drug plan lists and the New Zealand Pharmaceutical Schedule current in mid-2019. Results: Hospital discharge rates for cardiovascular disorders, malignancies and respiratory disorders and mortality rates for acute myocardial infarction, ischemic heart disease and cerebrovascular disease were higher, on average over the observation period, in New Zealand than in Canada, but mortality rates for malignancies and respiratory disorders were similar. Reimbursement listing rates for cancer drugs and some cardiovascular medications were lower in New Zealand than in Canada. Discussion: Higher hospital discharge and mortality rates suggest poorer patient health in New Zealand compared with Canada. This may be due to lower reimbursement listing rates for some medications in New Zealand. New Zealand's drug coverage system has contained costs, but it restricts or denies access to new innovative medicines with the potential to improve patients' lives. Although a New Zealand-style national pharmacare scheme in Canada would offer the opportunity to restrain drug expenditure, it would likely fail to satisfy patients and healthcare providers and could diminish health outcomes, resulting in higher costs in other healthcare sectors.

National Pharmacare in Canada: Equality or Equity, Accessibility or Affordability Comment on "Universal Pharmacare in Canada: A Prescription for Equity in Healthcare".

Canada's federal government intends to take steps to implement national pharmacare so that all Canadians have prescription drug coverage they need at an affordable price. Relatively limited funds have so far been pledged to support national pharmacare, which raises the question: what kind of program is envisioned? Since the government has already introduced regulations intended to reduce new drug prices drastically, national pharmacare seems likely to be a basic system designed to assist low-income Canadians with accessing primary care medicines. What Canadians actually need is a system that provides access to the medicine considered appropriate by the patient and their healthcare provider for the patient's specific condition. Equitable national pharmacare will not be achieved if patients are denied access to new high-cost specialized medicines that can improve or extend their lives, any more than if patients who cannot afford basic drugs are not helped.

Alignment of health technology assessments and price negotiations for new drugs for rare disorders in Canada: Does it lead to improved patient access?

A previous assessment of submissions for rare disorder drugs made to the Canadian Agency for Drugs and Technologies in Health (CADTH) found that, from 2012, all positive recommendations included criteria advocating a price reduction. Since 2016, CADTH and the pan-Canadian Pharmaceutical Alliance (pCPA), which conducts drug price negotiations with manufacturers for all public drug programs, have aligned their processes. This analysis examined drugs for rare and ultra-rare disorders (DRDs and DURDs)-prevalence of ≤20 to >2 and ≤2 per 100,000, respectively-with a completed pCPA negotiation or no negotiation between 2014 and 2018, together with their reimbursement recommendations and listings in public drug programs. A positive recommendation led to a successful price negotiation for 81.8% and 78.6% of the DRD and DURD submissions and a negative recommendation to no negotiation for 100.0% and 66.7%. Less than half the recommendations for DURDs reported before 2016 mentioned the need for a substantial price reduction, but this increased to 80% in those reported from 2016 onwards. A successful price negotiation led to listing in the majority of the public drug programs and a negative recommendation usually led to no listing. The CADTH-pCPA alignment is working for the governments who own and fund public drug programs but has yet to lead to coverage for all appropriate patients in all provinces. There is still a way to go to ensure that patients with unmet needs can access high-cost innovative medicines that alleviate suffering, prevent premature death, and/or significantly improve their quality of life.

Regulatory approval and public drug plan listing of new drugs for rare disorders in Canada and New Zealand.

A previous assessment of the alignment of health technology assessments and price negotiations for new drugs for rare disorders in Canada completed between 2014 and 2018 demonstrated that it is working for governments but has yet to lead to improved access in a timely manner for all appropriate patients in all provinces. In this analysis, drugs for rare and ultra-rare disorders with a completed price negotiation or no negotiation between 2014 and 2018 in Canada, and their reimbursement recommendations and listings in Canadian public drug programs are compared with their regulatory approval in New Zealand and listing in the New Zealand National Formulary. The results show that pharmaceutical manufacturers generally seek regulatory approval for rare disorder drugs in Canada before New Zealand, and fewer rare disorder medicines receive regulatory approval in New Zealand. One reason for this difference might be New Zealand's smaller population. However, another reason is likely the restrictive drug formulary in New Zealand. Drugs not given coverage in New Zealand are frequently made unavailable by the manufacturer. Planned changes to Canada's pricing regulations and guidelines will significantly diminish the country's attractiveness as a place in which pharmaceutical companies want to do business, which has the potential to negatively impact the health of all Canadians irrespective of whether they have private or public drug coverage.

Access to linked administrative healthcare utilization data for pharmacoepidemiology and pharmacoeconomics research in Canada: anti-viral drugs as an example.

PURPOSE: Administrative healthcare utilization data from Canadian provinces have been used for pharmacoepidemiology and pharmacoeconomics research, but limited transparency exists about opportunities for data access, who can access them, and processes to obtain data. An attempt was made to obtain data from all 10 provinces to evaluate access and its complexity. METHODS: An initial enquiry about the process and requirements to obtain data on individual, anonymized patients dispensed any of four anti-viral drugs in the ambulatory setting, linked with data from hospital and physician service claims, was sent to each province. Where a response was encouraging, a technical description of the data of interest was submitted. RESULTS: Data were unavailable from the provinces of New Brunswick, Newfoundland and Labrador, and Prince Edward Island, and inaccessible from British Columbia, Manitoba and Ontario due to policies that prohibit collaborative work with pharmaceutical industry researchers. In Nova Scotia, patient-level data were available but only on site. Data were accessible in Alberta, Quebec and Saskatchewan, although variation exists in the currency of the data, time to obtain data, approval requirements and insurance coverage eligibility. CONCLUSIONS: As Canada moves towards a life-cycle management approach to drug regulation, more post-marketing studies will be required, potentially using administrative data. Linked patient-level drug and healthcare data are presently accessible to pharmaceutical industry researchers in four provinces, although only logistically realistic in three and limited to seniors and low-income individuals in two. Collaborative endeavours to improve access to provincial data and to create other data resources should be encouraged.

Response to Letter to the Editor.

Author's response to comments from Dr Lexchin's Letter to the Editor regarding our article.

Manitoba and Saskatchewan administrative health care utilization databases are used differently to answer epidemiologic research questions.

OBJECTIVES: To evaluate the use of two Canadian provincial databases by a systematic review of published studies that used them as a primary data source to answer epidemiologic and health services research questions. STUDY DESIGN AND SETTING: PubMed, EMBASE, BIOSIS, and CINAHL (keywords: "Manitoba" 1970-2004 and "Saskatchewan" 1969-2004) and the web sites of the provincial data custodians were searched to address our objective. Broad screening of citations and data abstraction were performed using a predefined collection form. Information on study characteristics, therapeutic areas studied, databases used, authors' affiliation, and issues related to data validity was recorded. RESULTS: Three thousand nine hundred and forty-nine citations were screened, 610 studies retrieved, and 325 included. In Saskatchewan, the principal research type was assessment of exposures and health outcomes (48.2%) with 50.4% using a cohort or case-control design, whereas, in Manitoba, it was health services utilization (47.8%) and 86.6% were descriptive. Local investigators performed 83.3% of the Manitoba studies, compared with 35.5% of the Saskatchewan studies. Only 6.2% of the studies assessed the validity and reliability of the database for research purposes and few incorporated relevant information about the validity of their diagnostic data. CONCLUSION: Important differences exist in the administration and use of these databases. Similar systematic evidence synthesis should be conducted on other databases.