INTRODUCTION
In annual reports, Health Canada identifies orphan drugs approved by either the Food and Drug Administration or the European Medicines Agency.1
According to the definition used by the Canadian Patented Medicine Prices Review Board (PMPRB), there are 125 expensive drugs for orphan diseases in Canada accounting for 12.2% of all drug expenditures.2 To help provinces cope with funding orphan drugs, in March 2023, the federal government announced a three-year C$1.4 billion cost-sharing program.
To help determine how this investment should be allocated, this study investigates therapeutic benefits from orphan and non-orphan drugs for oncology and all non-oncology indications. It also compares the drug and clinical trial characteristics and review type of orphan and non-orphan drugs.
METHODS
Data Availability
The methods used in gathering data and a description of the types of regulatory reviews used were previously described by Lexchin who looked at drugs approved from September 1, 2012, to March 31, 2022.3
Therapeutic Benefit
Increase in therapeutic benefit was categorized as major, moderate, little to none based on rankings from the PMPRB, the French bulletin Prescrire International and the German Institute for Quality and Efficiency in Health Care that take into account the balance of benefits and harms.4 If a drug was evaluated by more than one organization, the highest ranking was used. The search for therapeutic evaluations was done from October 15–20, 2023.
Data Analysis
Characteristics of orphan and non-orphan drugs, their clinical trials, and review types were compared for oncology indications and non-oncology indications using a Mann-Whitney test as the data was not normally distributed. Review types and therapeutic benefits were compared using either a chi-square or Fisher exact test. A p value of < 0.05 was considered significant. Statistical calculations were done using Prism 10.1.0 (GraphPad Software LLC).
RESULTS
Health Canada approved a total of 296 new drugs of which 94 were orphans. Eighty-eight (29.7%) were for oncology indications (67 orphan and 21 non-orphan) and 208 (70.3%) for non-oncology indications (73 orphan and 135 non-orphan).
Drugs for Oncology Indications
Table 1 summarizes the data for orphan and non-orphan drugs. There were no differences in drug characteristics. The only differences in clinical trial characteristics were in the number of patients enrolled and in the trial outcome, with orphan drugs using surrogate outcomes more often (p < 0.0001, chi-square test). The distribution of therapeutic benefits was almost identical between the two groups of drugs (p = 0.9656, chi-square test) (Table 1). Therapeutic evaluations were not available for 7 (10.4%) orphan and 1 (4.8%) non-orphan drugs.
Table 1.
Comparison of Characteristics and Review Types of Orphan and Non-Orphan Drugs for Oncology Indications
| Orphan oncology drugs | Non-orphan oncology drugs | p value | |
|---|---|---|---|
| Total number | 67 | 21 | |
| Drug characteristics | |||
| Indications per drug | |||
| Number (median, IQR) | 1 (1,1) | 1 (1,1) | 0.4139, Mann-Whitney test |
| First in class | |||
| Yes (%) | 23 (34.3) | 7 (31.8) | 0.8625, chi-square test |
| No (%) | 44 (65.7) | 14 (68.2) | |
| Type of drug | |||
| Small molecule (%) | 47 (70.1) | 11 (50.0) | 0.2161, chi-square test |
| Biologic (%) | 20 (29.9) | 10 (50.0) | |
| Clinical trial characteristics | |||
| Pivotal trials | |||
| Number per drug, median (IQR) | 1 (1,1) | 1 (1,1) | 0.3809, Mann-Whitney test |
| Pivotal trial phase used for approval | |||
| 1 (%) | 4 (6.0) | 3 (14.3) | 0.3513, Fisher exact test |
| 2 (%) | 33 (49.3) | 7 (33.3) | |
| 3 (%) | 28 (41.8) | 10 (47.6) | |
| No information (%) | 2 (3.0) | 1 (4.8) | |
| Number of arms per trial | |||
| 1 (%) | 25 (37.3) | 6 (28.6) | 0.3989, Fisher exact test |
| 2 (%) | 35 (52.2) | 11 (52.4) | |
| 3 (%) | 4 (6.0) | 1 (4.8) | |
| 4+ (%) | 2 (3.0) | 1 (4.8) | |
| No information (%) | 1 (1.5) | 2 (9.5) | |
| Patients enrolled per trial | |||
| Median (IQR) | 189 (110, 392) | 429 (184, 734) | 0.0165, Mann-Whitney test |
| Outcome used | |||
| Clinical (%) | 11 (16.4) | 17 (81.0) | < 0.0001, chi-square test |
| Surrogate (%) | 56 (83.6) | 4 (19.0) | |
| Randomized | |||
| Yes (%) | 37 (55.2) | 13 (61.9) | 0.8483, Fisher exact test |
| No (%) | 29 (43.3) | 8 (38.1) | |
| No information (%) | 1 (14.9) | 0 (0) | |
| Control | |||
| Placebo (%) | 13 (19.4) | 5 (23.8) | 0.9355, Fisher exact test |
| Active (%) | 16 (23.9) | 4 (19.0) | |
| No (%) | 29 (43.3) | 10 (47.6) | |
| Other (%) | 9 (13.4) | 2 (9.5) | |
| Blinded | |||
| Yes (%) | 13 (19.4) | 7 (33.3) | 0.2890, Fisher exact test |
| No (%) | 50 (74.6) | 14 (66.7) | |
| No information (%) | 4 (6.0) | 0 (0) | |
| Review type | |||
| Type of review | |||
| Standard (300 days) | 24 (35.8) | 7 (33.3) | 0.8437, chi-square test |
| Priority (180 days) | 15 (22.4) | 6 (28.6) | |
| Notice of compliance with conditions/priority + notice of compliance with conditions (conditional approval subject to results of confirmatory studies) | 28 (41.8) | 8 (38.1) | |
| Therapeutic value | |||
| Major (%) | 13 (21.7) | 4 (18.2) | p = 0.9656, chi-square test |
| Moderate (%) | 16 (26.7) | 5 (22.7) | |
| Little to none (%) | 31 (41.7) | 11 (50.0) | |
Drugs for Non-Oncology Indications
There were statistically significant differences in many areas between orphan and non-orphan drugs (Table 2). However, there was no difference in the distribution of therapeutic benefits between the two types of drugs (p = 0.0821, chi-square test) (Table 2). Therapeutic evaluations were not available for 19 (26.0%) orphan and 22 (16.3%) non-orphan drugs.
Table 2.
Comparison of Characteristics and Review Types of Orphan and Non-Orphan Drugs for Non-Oncology Indications
| Characteristic | Orphan non-oncology drugs | Non-orphan non-oncology drugs | p value |
|---|---|---|---|
| Total number | 73 | 135 | |
| Drug characteristics | |||
| Indications per drug | |||
| Number (median, IQR) | 1 (1,2) | 2 (2,3) | < 0.0001, Mann-Whitney test |
| First in class | |||
| Yes (%) | 37 (50.7) | 38 (28.1) | 0.0006, chi-square test |
| No (%) | 29 (39.7) | 91 (67.4) | |
| No information (%) | 7 (9.6) | 6 (4.4) | |
| Type of drug | |||
| Small molecule (%) | 45 (61.6) | 102 (75.6) | 0.0519, chi-square test |
| Biologic (%) | 28 (38.4) | 33 (24.4) | |
| Clinical trial characteristics | |||
| Pivotal trials | |||
| Number per drug, median (IQR) | 1 (1,1) | 1 (1,1) | 0.7957, Mann-Whitney test |
| Pivotal trial phase used for approval | |||
| 1 (%) | 0 (0) | 2 (1.5) | 0.4285, chi-square test |
| 2 (%) | 6 (8.2) | 6 (4.4) | |
| 3 (%) | 58 (79.5) | 105 (77.8) | |
| No information (%) | 9 (12.3) | 22 (16.3) | |
| Number of arms per trial | |||
| 1 (%) | 0 (0) | 7 (5.2) | 0.077, chi-square test |
| 2 (%) | 6 (8.2) | 74 (54.8) | |
| 3 (%) | 58 (79.5) | 29 (21.5) | |
| 4+ (%) | 9 (12.3) | 11 (8.1) | |
| No information (%) | 0 (0) | 14 (10.4) | |
| Patients enrolled per trial | |||
| Median (IQR) | 137 (52, 260) | 870 (590, 1605) | < 0.0001, Mann-Whitney test |
| Outcome used | |||
| Clinical (%) | 35 (47.9) | 46 (34.1) | < 0.0291, Fisher exact test |
| Surrogate (%) | 37 (50.7) | 89 (65.9) | |
| No information (%) | 1 (1.4) | 0 (0) | |
| Randomized | |||
| Yes (%) | 60 (82.2) | 124 (91.9) | 0.0111, Fisher exact test |
| No (%) | 12 (16.4) | 6 (4.4) | |
| No information (%) | 1 (1.4) | 5 (3.7) | |
| Control | |||
| Placebo (%) | 40 (54.8) | 88 (65.2) | 0.0145, chi-square test |
| Active (%) | 12 (16.4) | 33 (24.4) | |
| No (%) | 15 (20.5) | 10 (7.4) | |
| Other (%) | 3 (4.1) | 3 (2.2) | |
| No information (%) | 3 (4.1) | 1 (0.7) | |
| Blinded | |||
| Yes (%) | 43 (58.9) | 109 (80.7) | < 0.0001, chi-square test |
| No (%) | 24 (32.9) | 12 (8.9) | |
| No information (%) | 6 (8.2) | 14 (10.4) | |
| Review type | |||
| Type of review | |||
| Standard (300 days) | 29 (39.7) | 115 (85.2) | < 0.0001, chi-square test |
| Priority (180 days) | 41 (56.2) | 17 (12.6) | |
| Notice of compliance with conditions/priority + notice of compliance with conditions (conditional approval subject to results of confirmatory studies) | 3 (4.1) | 3 (2.2) | |
| Therapeutic value | |||
| Major (%) | 12 (22.2) | 11 (9.7) | p = 0.0821, chi-square test |
| Moderate (%) | 11 (20.4) | 23 (20.4) | |
| Little to none (%) | 31 (57.4) | 79 (69.9) | |
DISCUSSION
Orphan and non-orphan drugs for oncology indications were quite similar in most drug and clinical trial characteristics including in the distribution of therapeutic benefits with only 21.7% orphan drugs and 18.2% non-orphan drugs showing major therapeutic gains. The reliance on surrogate outcomes 5,6 and the smaller trial size7 may have influenced the number of orphan drugs showing major therapeutic gains.
The failure to show any difference in therapeutic benefits between orphan and non-orphan drugs for non-oncology indications may have been due to the lack of therapeutic evaluations for almost a fifth of drugs. Additionally, orphan drugs may offer major therapeutic benefits for subsets of non-orphan indications.
Limitations
The three organizations analyze drugs early in their lifecycle, and therefore their ratings may not reflect therapeutic benefits as drugs become more mature.
Conclusion
Orphan drugs are likely to be no more therapeutically beneficial than non-orphan drugs, especially for oncology indications. This finding means that it is imperative for the federal government to develop clear criteria about how its funding will be allocated. To this end, when orphan drugs enter the market without high-quality evidence of additional therapeutic benefit, funding should be conditional on risk sharing agreements with manufacturers and further evidence generation should be undertaken with the understanding that funding will be withdrawn if the evidence is not convincing.
Declarations:
Conflict of Interest:
In 2020–2023, Joel Lexchin received payments for writing a brief on the role of promotion in generating prescriptions for Koski Minsky and from Strategy Institute for being on a panel discussing pharmacare. He is a member of the Board of Canadian Doctors for Medicare. He receives royalties from University of Toronto Press and James Lorimer & Co. Ltd. for books he has written. He is participating in projects funded by the Canadian Institutes of Health Research.
Footnotes
Publisher's Note
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References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The methods used in gathering data and a description of the types of regulatory reviews used were previously described by Lexchin who looked at drugs approved from September 1, 2012, to March 31, 2022.3