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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}. 
Figure \ref{Fig:Stages} illustrates the different states that a trial can 
transition between while it is operating.
These states are defined by the National Library of Medicine with respect to 
clinical trial results
\cite{usnlm_protocolregistrationdata_2024-06-17}.
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participants, the trial is marked as ``Withdrawn''. 
If they begin enrolling participants, there are two methods to do so.
The first is to enter an "Enrollment by invitation only" state where the 
trial operators extend invitations through their own connections to doctors 
and patients they are working with.
The second is to enter a general ``Recruiting'' state, where participants apply 
to join the trial, and the sponsoring organization may extend invitations as 
before.
After a trial has enrolled their participants, they Will typically move to an 
"Active, not recruiting" state to inform potential participants that they are
not recruiting. 
During this time, the trial operators continue monitoring participants for 
adverse events and tracking their disease severity and compliance with treatment. 
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}.
Trials can be terminated because safety or efficacy evidence suggested it was 
not worth continuing, enrollment rates were too low to achieve the primary
objective within time and budget contstraints.

\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 represent 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''.
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 includes 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,
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. 


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 Principal Investigator leaves for another institution 
(terminating the trial), is this decision affected by 
a safety or efficacy concern, 
a new competitor on the market, 
difficulties 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.
Because there are many things that contribute to the decision to terminate a 
trial but no way for the results to be described in detail, 
we must use another way to infer the relative impact of operational difficulties.


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.
I prefer describing a clinical trial as being terminated for 
 Safety or Efficacy concerns, Strategic concerns, or Operational concerns


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