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Wrote comments on things that should be improved

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will king 1 year ago
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75
Paper/sections/08_PotentialImprovements.tex
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@ -4,13 +4,15 @@
\begin{document} \begin{document}
As noted above, there are various issues with the analysis as completed so far. As noted above, there are various issues with the analysis as completed so far.
Below I discuss various issues and ways to address them that I believe will improve the analysis. Below I discuss various issues and ways to address them that I believe
will improve the analysis.
\subsection{Increasing number of observations} \subsection{Increasing number of observations}
The most important step is to increase the number of observations available. The most important step is to increase the number of observations available,
Currently this requires matching trials to ICD-10 codes by hand. specifically the number of trials matched to ICD-10 codes with corresponding
Improvements in Large-Language-Models may make this data more accessible, or population estimates in the Global Burden of Disease Dataset.
Improvements in Large Language Models may make this data more accessible, or
the data may be available in a commercial dataset. the data may be available in a commercial dataset.
@ -24,13 +26,11 @@ In most cases the trial sponsor reports the anticipated enrollment value
while the trial is still recruiting and only updates the actual enrollment while the trial is still recruiting and only updates the actual enrollment
after the trial has ended. after the trial has ended.
Some trials do publish an incremental record of their enrollment numbers, Some trials do publish an incremental record of their enrollment numbers,
but this is rare. but this is not the norm.
Due to the bayesian model used, it would be possible to It may be possible to impute the enrollment process if a suitible model
include a model of the missing data can be created.
\cite{mcelreath_statisticalrethinkingbayesian_2020}. % Due to the bayesian model used, this would be easy to incorporate
which would % \cite{mcelreath_statisticalrethinkingbayesian_2020}.
allow me to estimate the direct effect of slow enrollment
on clinical trial termination rates.
There has been substantial work on forecasting There has been substantial work on forecasting
multi-site enrollment rates and durations by multi-site enrollment rates and durations by
@ -51,24 +51,31 @@ multi-site enrollment rates and durations by
avalos-pacheco_validationpredictiveanalyses_2023, avalos-pacheco_validationpredictiveanalyses_2023,
} }
but choosing between the various single and multi-site models presented is but choosing between the various single and multi-site models presented is
difficult without a dataset to validate the results on. difficult without a dataset with which to validate the results.
% In addition to needing a well calibrated model, I would require more trials,
% specifically those that report their enrollment incrementally so
% that there is data on what happens when enrollment is slower than anticipated.
\subsection{Improving Population Estimates} % It may also be possible to estimate the probability that enrollment goals
% have been met if data can be extracted that details planned observation times.
The Global Burden of Disease dataset contains the best estimates of disease % Of course, this is speculative at this point.
population sizes that I have found so far. %FIXTAG: Avoid speculation here.
Unfortunately, for some conditions it can be relatively imprecise due to
its focus on providing data geared towards public health policy. % \subsection{Improving Population Estimates}
For example, GBD contains categories for both %
drug resistant and drug suceptible tuberculosis, but maps those to the same % The Global Burden of Disease dataset contains the best estimates of disease
ICD-10 code. % population sizes that I have found so far.
In contrast, there is no category for non-age related macular degeneration. % Unfortunately, for some conditions it can be relatively imprecise due to
Thus not every trial has a good match with the estimate of the population of % its focus on providing data geared towards public health policy.
interest. % For example, GBD contains categories for both
Finding a way to focus on trials that have good disease population estimates % drug resistant and drug suceptible tuberculosis, but maps those to the same
would improve the efficiency of the analysis. % ICD-10 code.
% In contrast, there is no category for non-age related macular degeneration.
% Thus not every trial has a good match with the estimate of the population of
% interest.
% Finding a way to focus on trials that have good disease population estimates
% would improve the efficiency of the analysis.
% %FIXTAG: What am I trying to say here. IHME is among the best data sources.
% % How do I propose getting other data? Should probably just remove this.
\subsection{Improving Measures of Market Conditions} \subsection{Improving Measures of Market Conditions}
@ -78,18 +85,24 @@ In addition to the fact that many diseases may be treated by non-pharmaceutical
means (e.g. diet, physical therapy, medical devices, etc), means (e.g. diet, physical therapy, medical devices, etc),
off-label prescription of pharmaceuticals is legal at the federal level off-label prescription of pharmaceuticals is legal at the federal level
\cite{commissioner_understandingunapproveduse_2019}. \cite{commissioner_understandingunapproveduse_2019}.
%FIXTAG: Discuss how there isn't much data about off label prescription (I have a source)
These two facts both complicate measuring competing treatments, These two facts both complicate measuring competing treatments,
a key part of market conditions. a key part of market conditions.
One way to address non-pharmaceutical treatments is to concentrate on domains One way to address non-pharmaceutical treatments is to concentrate on domains
that are primarily treated by pharmaceuticals. that are primarily treated by pharmaceuticals.
Another way to address this would be to focus the analysis on just a few specific Another way to address this would be to focus the analysis on just a few specific
diseases, for which a history of treatment options can be compiled. diseases, for which a history of treatment options can be compiled.
%FIXTAG: Get rid of 'another', doesn't match context
This second approach may also allow the researcher to distinguish the direction This second approach may also allow the researcher to distinguish the direction
of causality between population size and number of drugs on the market; of causality between population size and number of drugs on the market;
%FIXTAG: join better to prior sentence
for example, drugs to treat a chronic, non-fatal disease will probably not for example, drugs to treat a chronic, non-fatal disease will probably not
affect the market size much in the short to medium term. affect the market size much in the short to medium term.
This allows the effect of market conditions to be isolated from This would require identifying diseases that are prime candidates and then
the effects of the population. trials and drugs associated with those diseases.
% This allows the effect of market conditions to be isolated from
% the effects of the population.
% %FIXTAG: I am already proposing these as fixes
% Alternative approaches % Alternative approaches
% - diseases with constant kill rates? population effect should be relatively constant? % - diseases with constant kill rates? population effect should be relatively constant?

26
Paper/sections/09_Conclusion.tex
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@ -5,35 +5,39 @@
Identifying commercial impediments to successfully completing Identifying commercial impediments to successfully completing
clinical trials in otherwise capable pharmaceuticals will hopefully clinical trials in otherwise capable pharmaceuticals will hopefully
lead to a more robust and competitive pharmaceutical market. lead to a more robust and competitive pharmaceutical market.
%FIXTAG: too much "hopefully"
Although the current state of this research is insufficient to draw robust Although the current state of this research is insufficient to draw robust
conclusions, these early results suggest that delaying the close of conclusions, these early results suggest that delaying the close of
enrollment periods reduces the probability of termination of a trial. enrollment period reduces the probability of termination of a trial.
%FIXTAG: OK for now but I think there might be a better way to handle this for now
The successful completion of Phase III clinical trials is crucial for % The successful completion of Phase III clinical trials is crucial for
bringing new treatments to market. % bringing new treatments to market.
This research provides insights into how enrollment management %FIXTAG: needs to be earlier
impacts trial outcomes.
While the preliminary results suggest that delaying the close of enrollment
periods may reduce termination probability, the analysis
reveals significant variation across disease categories and highlights
important methodological challenges.
The primary limitation that must be addressed before drawing a strong conclusion The primary limitation that must be addressed before drawing a strong conclusion
is that of insufficient data. is that of insufficient data.
%FIXTAG: This needs rewritten
This takes two forms. This takes two forms.
%FIXTAG: needs better transition
The first is the small sample size. The first is the small sample size.
To overcome this requires an improved data matching To overcome this requires an improved data matching
approach and a revised data scraper. approach and a revised data scraper.
%FIXTAG: active voice: this can be overcome by...
The second is creating a model of enrollment that can be used to address The second is creating a model of enrollment that can be used to address
the causal identification issue from the joint determination of the causal identification issue from the joint determination of
enrollment statuses and elapsed durations of trials. enrollment statuses and elapsed durations of trials.
%FIXTAG: sentence is too complicated
Despite these limitations, this work establishes a framework for analyzing Despite these limitations, this work establishes a framework for analyzing
operational versus strategic factors in clinical trial completion. operational versus strategic factors in clinical trial completion.
%FIXTAG: analyzing replaced with "separating causal effects"
The approach developed here can be extended with additional data to The approach developed here can be extended with additional data to
provide more definitive guidance on enrollment management strategies. provide more definitive guidance on enrollment management strategies.
%FIXTAG: the approach here + additional data can provide
%FIXTAG: tie to next sentence better
Further research in this direction could help reduce operational Further research in this direction could help reduce operational
barriers to trial completion or estimating the impact policies may have through barriers to trial completion or estimating the impact policies may have through
operational channels. operational channels.%FIXTAG: clauses don't match. first clause needs tightened.
Ultimately this work will hopefully support more efficient drug Ultimately this work will hopefully support more efficient drug
development and increased market competition. development and increased market competition. %FIXTAG: wishy-washy and duplicative.
\end{document} \end{document}

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