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The Evaluation of Efficacy Endpoints: Discordant Conclusions from
Clinical Trials of HIV
Evaluation
of the results of clinical trials can be a slippery slope. In the
current study, published in the most recent issue of Journal
of Virology (July 2005), the authors examine and evaluate the
primary methodologies for assessing the effectiveness of HIV antiretroviral
drug regimens.
The
three main components of long-term efficacy for a combination of
antiretrovirals are
· Strength
of the antiviral effect;
·
Toxicity
profile; and
·
Patient
acceptability of the regimen.
Intent-to-treat
(ITT) analysis, where discontinuations and switches are considered
failures (ITT,
switch equals failure (ITT/S=F)], is a regulatory standard for analyzing
the efficacy of antiretrovirals.
A review of all clinical trials published in FDA product labels
was conducted, including all clinical trials of boosted protease
inhibitor- or nucleoside
reverse transcriptase inhibitor-based highly active
antiretroviral therapy in treatment-naive patients, and all clinical
trials of antiretrovirals in treatment-experienced patients.
Clinical
trials where the results are presented in the standard ITT/S=F method
were included.
For
randomized clinical trials in treatment-naive patients, the majority
of treatment discontinuations
have been either for toxicity
(32%) or patient refusal of treatment (41%), with only 27% of failure
endpoints for virological reasons among recent clinical trials in
naive patients.
Therefore,
there is the potential for the results from ITT/S=F analysis to
be driven by non-virological endpoints – a new treatment can be
classified as ‘more efficacious’ than control owing to fewer discontinuations
due to adverse
events or patient preference.
In
order to understand the intrinsic potency of the antiretroviral
regimen under study, ITT analysis needs to be supplemented by standardized
as-treated analyses, excluding withdrawals for toxicity or other
reasons.
To
evaluate the efficacy of a treatment strategy or sequential treatment
regimens, the ‘ITT, switch included’ (ITT/SI) method: where changes
from the initial randomized treatment are not classified as treatment
failure – can be used.
However,
interpretation of clinical trials using ITT/SI analysis is difficult
and depends on the frequency of treatment switching in the different
arms of a trial.
In
conclusion, the authors write, “Conclusions on efficacy from clinical
trials can depend on the primary analysis used; most commonly, treatments
could be significantly different by ITT/S=F analysis, but then interpreted
as equivalent using the ITT/SI or as-treated methods.”
07/13/05
Reference
A
Hill and R DeMasi and others. Discordant conclusions from HIV clinical
trials — an evaluation of efficacy endpoints. Antiviral Therapy 10(3):
367–374. 2005.
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