2.3. SELECTION OF STUDY DESIGN
When an E-R analysis using an adjustment model concludes a positive E-R
relationship it is difficult to discern whether there is a true positive
E-R relationship, or there are additional hidden confounders. The only
approach that allows for certainty in a positive E-R relationship is to
study multiple dose levels of the drug in large, registrational trials.
These trials should have randomized groups with balanced baseline
characteristics. Studying multiple dose levels allows for the
identification of a true E-R relationship because the dose-response
relationship is not confounded by the prognostic factors that confound
the E-R relationship. ncology phase 3 trials typically only study a
single dose level, and the exposure range included in the E-R analysis
for OS is limited. Including additional arms or performing separate
trials to increase this exposure range allows for a more robust E-R
analysis. In the previously described case of trastuzumab, the HELOISE
trial studying high dose and standard dose trastuzumab revealed that the
case-matching analysis conducted for the ToGA study was confounded, and
that there appeared to be no causal relationship between exposure and
response for trastuzumab in metastatic gastric
cancer.2, 3 A similar scenario was observed with
pembrolizumab in melanoma and NSCLC. Pembrolizumab was studied across a
5-fold dose range. Two case-matching analyses were performed for
patients receiving 2 mg/kg and 10 mg/kg dose levels, respectively. In
the unmatched analysis a steep E-R relationship was observed across
exposure ranges within each dose level. While case-matching analysis
corrected this E-R relationship to a certain degree it still suggested a
positive E-R relationship. When examining hazard ratios across the two
dose levels, however, the apparent E-R relationship was flat and
suggested that higher exposures do not increase OS. The case-matching
analysis was unable to fully account for
confounders.40
Because dose-response relationships are not confounded by the prognostic
factors that confound E-R relationships studying multiple dose levels is
a robust approach to examine E-R relationships. Unlike statistical
approaches discussed in the previous sections it requires no assumptions
about covariates or the structure of the E-R relationship. The major
limitation with this approach is the time and cost associated with
additional trials or treatment arms. In addition, this approach may not
be feasible in rare populations. The utility of studying multiple dose
levels may also depend on characteristics of the drug. If a drug has a
wide therapeutic window (i.e. monoclonal antibodies), and tested doses
appear to be at the top of the dose-response curve studying multiple
dose levels in registrational trials may not be necessary. It may be
useful if a drug has a narrow therapeutic window and requires
quantification of E-R relationships for optimal dose selection.
Ultimately, limitations in feasibility motivate sponsors to consider
alternative approaches to E-R analyses before studying multiple dose
levels.