Is Canada missing out? An assessment of drugs approved internationally between 2016 and 2020 and not submitted for Health Canada review

Of new drugs approved in the US and Europe, how many do not come to Canada?

We examined submissions of new active substances for Health Canada approval and found that, at most, one-third of those with a recent international approval are not submitted for approval in Canada. Submissions are indicative of the intent of manufacturers to bring new products to Canada, whereas their actual launch and formulary listing status are affected by Health Canada’s review outcome and public and private drug plans, respectively (Figure 1).

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Figure 1:

Launch and diffusion process of new active substances in Canada. Note: HC = Health Canada, NOC = Notice of Compliance.

Of 230 new active substances with an approval by the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA) or both between 2016 and 2020, 154 (67%) had been submitted for Health Canada approval by Feb. 10, 2023 (Figure 2). Of those, 142 (92%) received a Notice of Compliance (NOC), 8 (5%) were under review and 5 (3%) were cancelled by the sponsor or received a Notice of Non-Compliance, meaning that the submission was found to be incomplete or noncompliant with the requirements of the Food and Drugs Act.11

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Figure 2:

Health Canada submission status of new active substances, 2016–2020.*Four submissions were cancelled by the sponsor and 1 received a Notice of Non-Compliance. As of Feb. 10, 2023. Sources: Meds Entry Watch 2016, 2017, 2018, 5th and 6th editions;6^–10 Health Canada’s Notice of Compliance database; Health Canada’s New Drug Submissions Completed website; and Health Canada’s New Drug Submissions Under Review website. Note: We defined new active substances as active medicinal ingredients with a first regulatory approval from Health Canada, the US Food and Drug Administration or the European Medicines Agency during the inclusion period. We also considered combination products to be new active substances if at least 1 of their active ingredients met that criterion. We used Meds Entry Watch reports for years 2016–20206^–10 to identify 230 pharmaceuticals, which we included in the analysis. We excluded 2 substances listed in the reports because they received Health Canada Notices of Compliance under alternate brand names before 2016: Smallpox and Monkeypox Vaccine, Live, Non-Replicating, and Coagulation Factor VIIA (recombinant).

The remaining 75 new active substances (33% of those approved by the FDA or the EMA or both) had not yet been submitted for Health Canada review. However, important delays have been documented in the submission of drugs to different international agencies,12 and a subset of the new active substances not submitted in Canada — especially those with a first international approval toward the end of our study window — is likely to be filed for review in the coming years. Although it is impossible to predict with certainty, we can reasonably expect the longer-term submission rate of new active substances to exceed two-thirds and reach 70%–80%.

What kinds of new active substances are not submitted for approval in Canada?

We found that the new active substances not yet submitted for Health Canada approval are mainly from small manufacturers, indicated for modest patient populations, with multiple related drugs already marketed in Canada, or with no additional benefit relative to existing treatments. Table 1 shows trends in the characteristics, indications, approval status and sales levels in peer countries of the new active substances not submitted for Health Canada approval, as listed in Appendix 1, Table 1 (available at www.cmaj.ca/lookup/doi/10.1503/cmaj.230339/tab-related-content).

Less than one-quarter (n = 18) of new active substances not submitted in Canada were licensed by a manufacturer ranked in the top 25 by market capitalization. About half (n = 37) were indicated for rare diseases and received an orphan designation from the EMA or the FDA, and 11 were indicated for diseases to affect fewer than 5000 patients in the US, as estimated by the National Institutes of Health. More information on the characteristics of the new orphan substances not submitted in Canada is presented in Appendix 1, Table 2. Of the 17 infectious disease treatments in the new active substances list, 8 were antibiotics or add-ons to antibiotics with indications to be used in specific or complicated cases. Given that Canada has one of the lowest drug resistance indexes, second only to Sweden,14 there may be limited clinical need for these therapies. A further 6 were indicated for diseases that have a low incidence in Canada (e.g., plasmodium vivax malaria, hepatitis D and Chagas disease).

In most cases, multiple drugs in the same therapeutic class and with a similar chemical profile were already available to Canadians. For 58 (77%) of the new active substances not submitted in Canada, more than 5 drugs were marketed in Canada in the same pharmacologic subgroup (Table 1). This classification level groups drugs with a similar chemical profile indicated for the same therapeutic class and corresponds to the third level of the World Health Organization Anatomic Therapeutic Chemical classification system code (ATC3). Not all drugs within an ATC3 treat the same indication. Some ATC3s are broadly defined and feature drugs that treat a cluster of related but distinct indications. Of the 7 new active substances with 5 or fewer drugs currently marketed in Canada in their pharmacologic subgroup, only 2 showed sales in the US or a group of 11 peer countries used for international price comparisons of patented medicines by the Patented Medicine Prices Review Board (PMPRB11). These were istradefylline, indicated in adjunctive treatment to levodopa–carbidopa in adult patients with Parkinson disease, and osilodrostat, indicated for the treatment of endogenous Cushing disease in adults.

Of new active substances not submitted in Canada but reviewed by the Institute for Quality and Efficiency in Health Care (IQWiG), Germany’s federal agency tasked with conducting health technology assessments, 13 (93%) were found to show no additional benefit relative to existing treatments. Only 1 drug (bezlotoxumab, indicated for the prevention of recurrence of Clostridium difficile infection) was assessed to have nonquantifiable added benefit.

How widely marketed in peer countries are the new active substances not submitted to Health Canada?

In large part, these new active substances are not widely marketed in peer countries, except for the US. For the 75 new active substances not submitted for Health Canada review, we investigated whether sales were recorded internationally in the IQVIA MIDAS database in calendar year 2021, which allowed for at least 1 full year of diffusion after a first international approval for all 75. MIDAS data reflect the national retail and hospital sectors internationally, including payers in all market segments (public, private and out of pocket).

In 2021, 45 of the 75 new active substances not submitted to Health Canada (60%) did not record sales in PMPRB11 peer countries (Figure 3). Of those that recorded sales, 26 were sold in fewer than half (≤ 5) of comparator countries and 4 recorded sales in more than half (≥ 6) of comparator countries. On average, those substances not submitted to Health Canada recorded sales in just 1.3 PMPRB11 countries. None recorded sales in all comparator countries.

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Figure 3:

Sales of new active substances not submitted to Health Canada in 11 Patented Medicine Prices Review Board (PMPRB11) comparator countries, 2021. Note: PMPRB11: Australia, Belgium, France, Germany, Italy, Japan, Netherlands, Norway, Spain, Sweden and the United Kingdom. Source: IQVIA MIDAS database.

Among comparator countries, Germany sold the most new active substances that were not submitted to Health Canada with 19 (25%), while the median country sold 8 (11%; Figure 4). Only 2 of the PMPRB11 countries, Japan and Australia, are not represented in the EMA and, like Canada, have their own drug approval body. Japan recorded sales for 14 of the new active substances not submitted to Health Canada (19%), and Australia recorded sales for 1 (1.3%). We included the US in the figure for context, given its geographic proximity to Canada and its status as a global outlier in both pharmaceutical spending and adoption of new drugs.1^,3^,10 The US recorded sales for 52 (69%) of the new active substances not submitted to Health Canada.

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Figure 4:

Distribution of 11 Patented Medicine Prices Review Board ( PMPRB11) comparator countries and the United States by number of new active substances not submitted to Health Canada with sales, 2021. Source: IQVIA MIDAS database.

Most new active substances sold in PMPRB11 countries in 2021 showed less than Can$10 million in sales across these countries (n = 18/30 [60%]), and only 2 recorded more than Can$100 million in sales (Table 1). The highest-selling product was etelcalcetide, used in the treatment of hyperparathyroidism for patients on dialysis in 10 PMPRB11 countries. As of Feb. 1, 2023, Canada had 29 drugs marketed in etelcalcetide’s pharmacologic subgroup, H05B (calcium homeostasis) (Appendix 1, eTable 1). The second was vibegron, indicated for the treatment of overactive bladder; the only PMPRB11 country with sales of this drug was Japan. Canada had 178 drugs marketed in the related G04B (urologicals) pharmacologic subgroup. A pharmacologic subgroup could not be identified for vibegron because it was not assigned an ATC code.

Should people in Canada be worried about access to innovative drugs?

Our analysis of the characteristics of new active substances not yet submitted for Health Canada approval provides some insight into the types of medicines that manufacturers choose not to introduce to Canada. First, most unsubmitted new active substances were produced by relatively small manufacturers, which may be constrained in their capacity to prepare multiple submissions to international regulators and therefore prioritize submissions to the FDA and the EMA, which provide access to larger patient populations. This would be consistent with previous findings of longer submission delays to Health Canada for smaller companies.12

Second, whether most of these new active substances would be considered therapeutically innovative or answer unmet needs in Canada is unclear. According to their ATC code, more than three-quarters would join pharmacologic subgroups with more than 5 drugs currently marketed in Canada. This means that multiple offerings in the same therapeutic class and with a similar chemical profile are available to Canadians, although the specific indications for treatment may differ. In addition, all but 1 of those reviewed by IQWiG in Germany were found to have no additional therapeutic benefit relative to existing treatments.

Third, most of the new active substances that were not submitted in Canada have not recorded sales in the group of countries used as comparators by the PMPRB, and only 4 recorded sales in more than half of these countries. Their low utilization in peer countries suggests a small market for these pharmaceuticals in Canada, which may have contributed to the manufacturers’ decisions not to make a Health Canada submission.

We acknowledge that our findings may have been affected by the COVID-19 pandemic, which has had complex effects on the pharmaceutical industry internationally since 2020. On one hand, manufacturers may have submitted fewer new active substances to Health Canada than they would have otherwise. On the other, marketing of new medicines may have been delayed, resulting in fewer unsubmitted medicines being marketed in peer countries by 2021. In addition, because we focused on Health Canada submissions, we did not investigate Health Canada review results, launches, formulary listing decisions and delays, which can also contribute to limiting access to new active substances for people in Canada.

Furthermore, some of the new active substances that were not submitted in Canada could provide important benefits to specific populations despite being used chiefly in the treatment of diseases with low prevalence and not being launched widely in other countries. Although access to pharmaceuticals not marketed in Canada is possible through Health Canada’s Special Access Program for drugs, this mechanism is restricted to “the treatment, diagnosis, or prevention of serious or life-threatening conditions when conventional therapies have failed, are unsuitable, or unavailable,” and Special Access Program requests may not be approved in all cases.5

A thorough review of the clinical impacts of each new active substance not submitted for Health Canada approval could provide a better understanding of the health consequences of limitations to their access. However, our analysis suggests that most of them would reach few Canadians and would have a limited health impact if they were approved.