Although avoiding and addressing issues during study
execution/conduct can eliminate the need for and
associated time with trying to address them during
submission, sometimes the issues are not recognized
until after study completion. Some of these issues can
be addressed during the analysis of the data.
Trial Analysis
Once the trial is completed, the results must be
obtained through analyses, in accordance with the
pre-specified SAP. A key aspect of this step is ensuring
that the statistical results are presented in a manner
that is jargon-free and understandable. In addition to
the pre-specified analyses, trial results can sometimes
be suggestive of data-driven hypotheses. Post hoc
analyses to explore these results can be informative
but must be conducted and interpreted properly to be
considered appropriate by regulatory authorities. If the
issue is identified prior to DBL (when the data are still
blinded), the analyses are typically more convincing
for regulatory agencies than post hoc analyses, which
occur based on knowledge of the unblinded data.
Ideally, the SAP and eventual CSR would include a
summary of the changes in the paragraph(s) explaining
the need for additional analyses in the SAP.
EXAMPLE
Review of the data after study
completion highlights some potentially
interesting findings that were not
considered in the initial study
design and SAP.
Results from a Phase II dose response study
indicated a strong dose response. After
reviewing all study results, the sponsor
wanted to use those results to better plan the
subsequent Phase III study to determine if
they could identify the subjects most likely to
respond, if dose timing might be improved,
and dose titration options. These available
valuable data would make it possible to
evaluate these opportunities and would
be valid in improving the planned Phase
III design. Any changes in design could be
justified to the FDA based on the planned
post hoc analysis.
Trial Submission
Once the trial has completed and the analyses
conducted, the trial sponsor submits the total package,
including the trial protocol, electronic case report
forms, SAP, and CSR or ISSE, for regulatory review
to seek approval for a marketing claim. Ideally, this
package is sufficiently complete and supportive that
it allows for an approval. However, in many cases, the
regulatory agency requires additional information
from the sponsor prior to a final approval decision.
These additional information requests are generally
conveyed in a letter, although they might sometimes
be provided in a face-to-face meeting or telephone
call with the regulatory review team.
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In many cases, the regulatory
agency requires additional
information from the
sponsor prior to a final
approval decision.
These changes often lead to one or two additional
review rounds in which the trial sponsor provides the
additional requested information and the review team
considers the information and ultimately reaches an
approval decis