Article
Orphan and non-orphan trial comparisons, taking into account associations between underlying population sizes and trial design features – an explorative investigation of the German drug market
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Authors
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Dirk Eyding
- Medizinischer Dienst Bund, Bereich Evidenzbasierte Medizin, Deutschland
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Stephan Rieks
- Medizinischer Dienst Bund, Bereich Evidenzbasierte Medizin, Deutschland
| Published: | August 30, 2022 |
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Outline
Text
Background/research question:Orphan drug trials are known for their lower quality compared to Non-Orphans which may be inevitable given the small Orphan populations. The German Early Benefit Assessment (EBA) of new approved drugs in the German market, installed in 2011, include an estimation of the size of the German target population to be treatable in 12 months (12-MTP), closely matched to the drug’s label. These data allow an Orphan-Non-Orphan comparison taking these actual population data into account.
Methods: We used data of all first EBAs conducted between 2011 and 2020. Data were from the deciding body’s website (www.g-ba.de). Added benefit was assessed against standard of care, which was defined by the GBA upfront, and which may have necessitated the formation of subgroups within each label. Logistic or linear regression was used for univariate analyses of the association between the 12-MTP and the endpoints. Adjusted logistic regression or ANCOVA, adjusting for the 12-MTP, was used for the multivariate analyses to compare Orphans and Non-Orphans. Unit of analysis was the subgroup.
Results: We assessed 437 EBAs, thereof 111 Orphans. There were 124 Orphan and 288 Non-Orphan subgroups with data. All endpoints were positively associated with the 12-MTP: trial(s) size, probability of RCT (vs. Non-RCT), probability of DB-ness, probability of a quantifiable added benefit and recruitment efficiency. Unadjusted analyses expectedly showed better quality (e.g. higher proportion of RCTs) in Non-Orphans than Orphans.
Of the Non-Orphans 75.7% had 12-MTPs within the observed Orphan range (≤3.6 patients/10,000 persons p.a.). The 12-MTP adjusted analyses showed no differences between Orphans and Non-Orphans for the trial size, the probability of RCT, the probability of DB-ness and the recruitment efficiency. RCTs, e.g., can be expected with c. 70% probability or more at 12-MTPs as little as 0.05 patients/10,000 persons per year, in Orphans and Non-Orphans. Only at the very low 12-MTP end Orphans outnumber Non-Orphans and small Non-RCTs with lower recruitment dominate.
Conclusion: Principally, well designed trials (i.e. doubleblind RCTs) were equally expectable in Orphans and Non-Orphans at the same 12-MTP. A more comprehensive analysis including non-approved drugs would allow to reappraise the suggestion from the results here, that trials of high quality in the Orphan 12-MTP range (down to about 0.05/10,000 patients) should be the primary source for clinical data without the necessity to relax trial requirements.
Competing interests: None
