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% Clinical Trials Background Outline
% - ClinicalTrials.gov
% - Clincial trial progression
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To understand how my administrative clinical trial data is obtained
and what it can be used for, 
let's take a look at how trial investigators record data on 
\url{ClinicalTrials.gov} operate.
Figure \ref{Fig:Stages} illuistrates the process I describe below.
During the Pre-Trial period the trial investigators will design the trial, 
choose primary and secondary objectives, 
and decide on how many participants they need to enroll. 
Once they have decided on these details, they post the trial to \url{ClinicalTrials.com}
and decide on a date to begin enrolling trial participants.
If the investigators decide to not continue with the trial before enrolling any participants,
the trial is marked as ``Withdrawn''. 
On the other hand, if they begin enrolling participants, there are two methods to do so.
The first is to enter a general ``Recruiting'' state, where patients attempt to enroll.
The second is to enter an "Enrollment by invitation only" state.
After a trial has enrolled their participants, they wil typically move to an 
"Active, not recruiting" state to inform potential participants that they are
not recruiting. 
Finally, when the investigators have obtained enough data to achieve their primary
objective, the clinical trial will be closed, and marked as ``Completed'' in
\url{ClinicalTrials.gov}
If the trial is closed before achieving the primary objective, the trial is 
marked as ``Terminated'' on
\url{ClinicalTrials.gov}.


\begin{figure}%[H] %use [H] to fix the figure here.
    \includegraphics[width=\textwidth]{../assets/img/ClinicalTrialStagesAndStatuses}
    \par \small 
        Diamonds represent decision points while
	Squares represent states of the clinical trial and Rhombuses represend data obtained by the trial.
    \caption[Clinical Trial Stages and Progression]{Clinical Trial Stages and Progression}
    \label{Fig:Stages}
\end{figure}

Note the information we obtain about the trial from the final status: 
``Withdrawn'', ``Terminated'', or ``Completed''.
Although 
\cite{khmelnitskaya_competitionattritiondrug_2021}
describes a clinical failure due to safety or efficacy as a 
\textit{scientific} failure, it is better described as a compound failure.
Discovering that a compound doesn't work as hoped is not a failure but the whole
purpose of the clinical trials process. 
On the other hand, when a trial terminates early due to reasons 
other than safety or efficacy concerns, the trial operator does not learn
if the drug is effective or safe. 
This is a knowledge-gathering failure where the trial operator 
did not learn if the drug was effective or not.
I prefer describing a clinical trial as being terminated for 
\begin{itemize}
    \item Safety or Efficacy concerns
    \item Strategic concerns
    \item Operational concerns.
\end{itemize}

Unfortunately it can be difficult to know why a given trial was terminated,
in spite of the fact that upon termination, trials typically record a 
description of \textit{a single} reason for the clinical trial termination. 
This doesn't necessarily list all the reasons contributing to the trial termination and may not exist for a given trial.
For example, if a Principle Investigator leaves for another institution 
(terminating the trial), is this decison affected by 
a safety or efficacy concern, 
a new competitor on the market, 
difficulting recruiting participants,
or a lack of financial support from the study sponsor? 
Estimating the impact of different problems that trials face from these 
low-information, post-hoc signals is insufficient.
For this reason, I use clinical trial progression to estimate effects. 
\todo{not sure if this is the best place for this.}

As a trial goes through the different stages of recruitment, the investigators
update the records on ClinicalTrials.gov. 
Even though there are only a few times that investigators are required 
to update this information, it tends to be updated somewhat regularly as it is 
a way to communicate with potential enrollees. 
When a trial is first posted, it tends to include information
such as planned enrollment, 
planned end dates, 
the sites at which it is being conducted, 
the diseases that it is investigating, 
the drugs or other treatments that will be used,
the experimental arms that will be used,
and who is sponsoring the trial.
As enrollment is opened and closed and sites are added or removed, 
investigators will update the status and information
to help doctors and potential participants understand whether they should apply. 



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