Table 3.
Clinical evidence characteristics and hta outcomes of first vs subsequent indications
| Category | Variable | First indication n (%) |
Subsequent indication n (%) |
P value |
|---|---|---|---|---|
| REGULATORY APPROVAL | ||||
| Type of MA granted (all agencies) | Standard | 61 (51%) | 207 (74%) | 0.001 |
| Conditional | 34 (29%) | 39 (14%) | ||
| Priority review | 24 (20%) | 33 (12%) | ||
| Type of MA granted (excluding EMA) | Standard | 47 (53%) | 146 (69%) | |
| Conditional | 24 (27%) | 36 (16%) | 0.032 | |
| Priority review | 18 (20%) | 31 (15%) | ||
| Orphan Designationa | Yes | 55 (46%) | 65 (23%) | < 0.0001 |
| No | 64 (54%) | 214 (77%) | ||
| CLINICAL EVIDENCE | ||||
| Pivotal trial design | Phase II single arm | 42 (35%) | 56 (20%) | 0.009 |
| Phase III placebo RCT | 30 (25%) | 76 (27%) | ||
| Phase III head-to-head | 39 (33%) | 129 (46%) | ||
| Other | 8 (7%) | 18 (6%) | ||
| Type of primary endpoint | Clinical | 28 (24%) | 49 (18%) | |
| Surrogate | 81 (68%) | 194 (69%) | 0.221 | |
| Co-primary | 10 (8%) | 36 (13%) | ||
| Trial size |
Number of enrolled patients Mean [ 95% CI] |
486 [421 – 550] | 555 [504 -605] | 0.125 |
| MCBSb | Score of 1 | 54 (48%) | 88 (35%) | 0.012 |
| Score of 2 or 3 | 22 (20%) | 85 (34%) | ||
| Score of 4 or 5 | 35 (32%) | 80 (31%) | ||
| HTA OUTCOMESc | ||||
| G-BA | Proof of added benefit | 25 (86%) | 26 (45%) | 0.004 |
| Lesser/no added benefit | 4 (14%) | 32 (57%) | ||
| HAS | Reimbursed | 27 (96%) | 54 (90%) | 0.299 |
| Not-reimbursed | 1 (4%) | 6 (10%) | ||
| NICE | List/List with Criteria | 26 (96%) | 43 (90%) | 0.304 |
| Do not list | 1 (4%) | 5 (10%) | ||
| SMC | List/List with Criteria | 23 (88%) | 43 (86%) | 0.763 |
| Do not list | 3 (12%) | 7 (14%) | ||
| CADTH | List/List with Criteria | 22 (96%) | 41 (84%) | 0.152 |
| Do not list | 1 (4%) | 8 (16%) | ||
| PBAC | List/List with Criteria | 23 (92%) | 33 (66%) | 0.015 |
| Do not list | 2 (8%) | 17 (34%) | ||
p-values calculated based on χ2 -test (for categorical variables) and two sample t-tests (for mean comparisons)
Abbreviations: CADTH Canadian Agency for Drugs and Technologies in Health, GBA Federal Joint Committee (Germany), HAS Haute Autorité de Santé (France), HTA health technology assessment, MA marketing authorisation, NICE National Institute of Health and Care Excellence (England and Wales), PBAC Pharmaceutical Benefits Advisory Committee (Australia), PFS progression-free survival, SMC Scottish Medicines Consortium (Scotland), TGA Therapeutic Goods Administration (Australia)
aResults presented are aggregated across all countries. The requirements for orphan designations vary across settings. For the FDA, the disease or condition must (A) affect less than 200,000 persons in the United States, or (B) affect more than 200,000 in the United States and for which there is no reasonable expectation that the cost of developing and making available in the United States a drug for such disease or condition will recovered from sales in the United States of such drug. For the EMA, the prevalence of condition in the EU must not be more than 5 in 10,000 or it must be unlikely that marketing of the medicine would generate sufficient returns to justify the investment needed for its development. For the TGA, one of the following criteria must apply: a) the condition affects fewer than 5 in 10,000 individuals in Australia when the application is made; b) if it were included in the Register, would not be likely to be supplied to more than 5 in 10,000 individuals in Australia during each year that it is included in the Register; or c) it is not likely to be financially viable for the sponsor to market the medicine in Australia. Health Canada does not have an orphan designation
bThe magnitude of clinical benefit scale is a ranking of clinical benefit derived by the European Society for Medical Oncology, to grade the magnitude of benefit provided by a clinical trial. Ranking range from 1 (low) to 5 (high) clinical benefit. MCBS scores are grouped in terms of low benefit (1), moderate benefit (2 or 3) and substantial benefit (4 or 5) [20]
cExcludes indications that are not submitted for HTA approval. In Germany, indications which receive a rating of lesser benefit or no proof of added benefit are categorized as having a negative HTA outcome (DNL). In practice, these indications may still be reimbursed at a price determined based on reference pricing, and the HTA approval sequence does not necessarily reflect the order in which indications are launched within the country. In France, indications which receive an SMR rating of insufficient are categorized as having a negative HTA outcome (DNL)