| Summary: | Failure to adjust for effect modifiers (EMs) in indirect treatment comparisons (ITCs) can produce biased and
uncertain effect estimates. This is particularly important for health technology assessments (HTAs), where
the availability of new treatments is based on comparative effectiveness results. Much emphasis has been
placed on advancing ITC methods to adjust for EMs, yet whether EMs are appropriately identified for
the conduct of ITCs in the first place is unclear. To understand the extent of guidance and requirements
for the selection of EMs for ITCs currently available and if and how this guidance is applied in practice,
a series of pragmatic reviews of guidance documents from HTA and non-payer organizations, primary
published ITC analyses, and prior HTA submissions in two indications (non-small cell lung cancer and
psoriasis) was conducted. The reviews showed that current ITC guidance mainly focused on developing
analytical methods to adjust for EMs. Some organizations, such as HTA bodies in the UK, France and
Germany, recommended the use of literature reviews, expert opinion and statistical methods to identify
EMs. No detailed guidance on the selection process or the appropriate literature review approach was
found. Similar trends were identified through the database search and review of prior HTA submissions;
only few published ITCs and submissions included information on the EM selection process which was
either based on findings from the literature, trial subgroup analyses, or clinical input. No reference to a
systematic selection approach was found.
There is an urgent need to fill the guidance gap identified across the reviews by including a step in ITC
guidelines on how EMs should be identified through systematic reviews, formal expert elicitation, and a
quantitative assessment of the EM distribution. Researchers and manufacturers are also encouraged to
improve transparent reporting and justification of their selection of EMs to allow for an independent
review of the set of factors being considered for adjustment. Both will contribute toward reducing bias
in the ITC results and ultimately increase confidence in decision-making.
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