Background
Definition and methodology of indirect comparisons
Adjusted indirect comparison
Unadjusted indirect comparison
Mixed-treatment-comparisons (MTC)
Bayesian and frequentist approach
Individual participant/patient data (IPD)
Underlying assumptions of indirect comparisons
IQWiG and G-BA requirements in Germany [7]
Requirements for indirect comparisons in other European countries
France [17]
England[18]
Scotland
Methodology of indirect comparison | Explanation | Acceptance by | |||
---|---|---|---|---|---|
IQWiG | HAS | NICE | SMC | ||
Unadjusted | •Naïve use of single study arms of different trials (violation of randomization) | − | − | − | / |
•Application of matching procedures and multivariate analysis | |||||
Adjusted | •Meta-analytical summary of RCT outcomes | + | + | + | / |
•Subtraction of realized therapeutic effects (control group vs. verum group(s)) | |||||
•Comparison of adjusted verum groups | |||||
MTC | •Combination of evidence from direct and indirect comparisons | − | + | + | / |
•Basic assumptions of adjusted indirect comparison are applied | |||||
•Efficacy ranking of examined therapies | |||||
•Bayesian and frequentist approach |
EUNETHTA Guidance[6]
Methods
Results
Indirect comparisons submitted to IQWiG
Drug substance | Trade name | Method used for indirect comparison | Reasons for rejection by IQWiG | ||
---|---|---|---|---|---|
Abirateron acetat | Zytiga | Adjusted indirect comparison | Bucher’s method, pair wise | •Comparator | •Incompleteness of the used study pool |
•Inclusion criteria of the bibliographic search and data used for each population remained unclear | |||||
•Formal | •Different appropriate comparator as determined by G-BA | ||||
Aclidinium bromide | Eklira | MTC | Bayesian approach | •Formal | •Data was not presented adequately (outcomes differ from original source, lacking traceability of data, inadequate inclusion of studies etc.) |
Aflibercept | Eylea | Unadjusted indirect comparison | Descriptive | •Methodology | •Comparison does not fulfill the requirements of an adjusted indirect comparison |
Axitinib | Inlyta | Unadjusted indirect comparison | simulated treatment comparison | •Methodology | •Comparison does not fulfill the requirements of an adjusted indirect comparison |
•Formal | •Description of the simulated comparison (documented in a | ||||
•Program code) was missing | |||||
Collagenase clostridium histolyticum | Xiapex | Unadjusted indirect comparison | - | •Formal | •Comparison does not fulfill the requirements of an adjusted indirect comparison |
•Missing common comparator | |||||
•Methodology | •Patient population was not in line with the application population | ||||
Dapagliflozina | Forxiga | Adjusted indirect comparison | Bucher’s method, frequentist approach | •Comparator | •Methodological mismatch: study population within the studies used for comparison was not the same as the indication population |
•Methodology | •Different appropriate comparator as determined by G-BA | ||||
Fingolimod | Gilenya | MTC | Bayesian approach | •Methodology | •Inconsistencies in the study search and an inadequate population |
•Formal | |||||
Ingenolmebutat | Picato | Unadjusted indirect comparison | - | •Methodology | •Comparison does not fulfill the requirements of an adjusted indirect comparison |
•Common comparator was missing | |||||
Linagliptin | Trajenta | Adjusted indirect comparison | Bucher’s method | •Comparator | •Different appropriate comparator as determined by G-BA |
Perampanel | Fycompa | Adjusted indirect comparison | Bucher’s method | •Comparator •Methodology | •Different appropriate comparator as determined by G-BA •Examination of a part of the population was criticized |
Retigabine | Trobalt | MTC | Frequentist approach | •Comparator | •Different appropriate comparator as determined by G-BA |
Ticagrelora | Brilique | Adjusted indirect comparison | Bucher’s method, frequentist approach | - | •Missing validity of endpoints, quality of trials and evidence |
•Methodological restrictions for simple adjusted indirect comparison | |||||
Telaprevir | Incivo | MTC | Bayesian approach | •Comparator | •Different appropriate comparator as determined by G-BA |
•Methodology | •Adequate data for handling subgroups was missing (interaction test) | ||||
Dabrafenib | Tafinlar | Adjusted indirect comparison | Bucher’s method | •Comparator | •Different appropriate comparator as determined by G-BA |
Elvitegravir, Cobicistat, Emtricitabin, Tenofovirdisoproxila | Stribild | Adjusted indirect comparison | Frequentist approach | •Methodology | •Patient population and applied transferability of patient data cannot be followed |
Fampridin | Fampyra | Unadjusted indirect comparison | - | •Comparator | •Comparison does not fulfill the requirements of an adjusted indirect comparison |
•Patients, who did not receive best supportive care (physiotherapy) are not similar to patients with placebo treatment (Placebo as common comparator) | |||||
•Methodology | •No data considered with appropriate comparator | ||||
Lixisenatid | Lyxumia | Adjusted indirect comparison | Bucher’s method, pair wise | •Comparator | •Different appropriate comparator as determined by G-BA in one indication |
•Methodology | •Differences in patient population, common comparator and application of comparators is not as authorized within included trials | ||||
Saxagliptin | Onglyza | Adjusted indirect comparison | Frequentist approach | •Methodology | •Use of inadequate patient population and study period |
•Differences in used common comparators | |||||
Saxagliptin (new indication) | Onglyza | Adjusted indirect comparison | Frequentist approach | •Comparator | •Different appropriate comparator as determined by G-BA |
Saxagliptin/Metformin (new indication) | Komboglyze | Adjusted indirect comparison | Frequentist approach | •Methodology | •Use of inadequate patient population and study period |
•Application of comparators is not as authorized within included trials | |||||
Sitagliptin | Januvia, Xelevia | Adjusted indirect comparison | Bucher’s method, pair wise | •Methodology | •Use of inadequate patient population and study period |
•Application of comparators is not as authorized within included trials | |||||
•Formal | •Missing sensitivity analyses | ||||
Teriflunomid | Aubagio | Adjusted indirect comparison | Bucher’s method, MTC | •Methodology | •Incomplete study pool |
•Formal | •Heterogeneity of included studies and non consideration of heterogeneity within indirect comparison | ||||
Vildagliptina | Galvus, Jalra, Xiliarx | Adjusted indirect comparison | Bucher’s method | •Methodology | •Use of inadequate patient population and study period |
•No statement towards authorization conform patient population | |||||
•Differences in used common comparators |
Formal deficiencies
Methodological deficiencies
Comparison to HTA processes in England, France and Scotland
Drug substance | Trade name | Acceptance of indirect comparison | |||
---|---|---|---|---|---|
Germany | France | England | Scotland | ||
Abirateron acetat | Zytiga | No |
Yes
| - | - |
Aclidinium bromide | Eklira | No | |||
Aflibercept | Eylea | - | Noe |
Yes
| |
Axitinib | Inlyta | No | Ongoing | Unclear | |
Collagenase clostridium histolyticum | Xiapex | - | - | ||
Dapagliflozina | Forxiga | No | |||
Fingolimod | Gilenya | ||||
Ingenolmebutat | Picato | - | - | ||
Linagliptin | Trajenta | Unclear | |||
Perampanel | Fycompa | ||||
Retigabine | Trobalt |
Yes
|
Yes
| ||
Ticagrelorb | Brilique | Yes |
No
| - | - |
Telaprevir | Incivo | No | - | ||
Dabrafenib | Tafinlar | Ongoing | |||
Elvitegravir, Cobicistat, Emtricitabin, Tenofovirdisoproxila | Stribild | -c | |||
Fampridin | Fampyra | ||||
Lixisenatid | Lyxumia | Unclear | |||
Saxagliptin | Onglyza |
Yes
| |||
Saxagliptin (new indication) | Onglyza | - | - | ||
Saxagliptin/Metformin (new indication) | Komboglyze | ||||
Sitagliptin | Januvia, Xelevia | Ongoing | -c | Unclear | |
Teriflunomid | Aubagio | - | No | - | |
Vildagliptina | Galvus, Jalra, Xiliarx | -c | Uncleard |