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Will King 1 year ago
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18
Paper/Main.tex
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@ -46,21 +46,15 @@ completion of clinical trials\\ \small{Preliminary Draft}}
%--------------------------------------------------------------- %---------------------------------------------------------------
\subfile{sections/11_intro_and_lit} \subfile{sections/11_intro_and_lit}
% \subfile{sections/01_introduction}
% %---------------------------------------------------------------
% \section{Literature Review}\label{SEC:LiteratureReview} %---------------------------------------------------------------
% %--------------------------------------------------------------- \section{Literature Review}\label{SEC:LiteratureReview}
% \subfile{sections/05_LitReview} %---------------------------------------------------------------
\subfile{sections/05_LitReview}
\section{Clincal Trial Background}\label{SEC:ClinicalTrials} \section{Clincal Trial Background}\label{SEC:ClinicalTrials}
\subfile{sections/12_clinical_trial_background} \subfile{sections/12_clinical_trial_background}
The paper proceeds as follows.
Then section \ref{SEC:data} covers the data sources and the proposed
data generating process as well as the causal identification.
Section \ref{SEC:EconometricModel} describes the econometric model
used.
Section \ref{SEC:Results} discusses the results of the analysis.
\todo{Review this after writing a few mor sections.}
%--------------------------------------------------------------- %---------------------------------------------------------------
\section{Causal Story and Data}\label{SEC:Data} \section{Causal Story and Data}\label{SEC:Data}

15
Paper/sections/05_LitReview.tex
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@ -22,6 +22,15 @@
% - % -
% - % -
The current literature revolving around clinical trials are usualy centered
around drug development and tend to fall into a few different categories
\begin{itemize}
\item Drug Development and Clinical trials Failure rates
\item Drug Development incentives
\item
\end{itemize}
\subsection{Drug development process and failure rates} \subsection{Drug development process and failure rates}
% Abrantes-Metz, Adams, Metz (2004) % Abrantes-Metz, Adams, Metz (2004)
% - What correlates with successfully passing clinical trials and FDA review? % - What correlates with successfully passing clinical trials and FDA review?
@ -60,9 +69,9 @@ from phase III to Phase II would reduce out of pocket costs by 5.6\%.
% - Atrition of drug candidates from four major pharma companies % - Atrition of drug candidates from four major pharma companies
% - Looked at how phisicochemical properties affected clinical failure due to safety issues % - Looked at how phisicochemical properties affected clinical failure due to safety issues
% Don't think this is applicable. % Don't think this is applicable.
%
\subsection{Market incentives and drug development} % \subsection{Market incentives and drug development}
%%%%%%%%% What do we know about drug development incentives? % %%%%%%%%% What do we know about drug development incentives?
\subsection{What do we know about drug development incentives?} \subsection{What do we know about drug development incentives?}
% Introduce section % Introduce section
% - Dranov et al 2022 - demand pull seems to bias follow up drug development. % - Dranov et al 2022 - demand pull seems to bias follow up drug development.

16
Paper/sections/06_Results.tex
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@ -45,9 +45,9 @@ the correlation (measured at $0.34$) is apparent.
% Estimation Procedure % Estimation Procedure
I fit the econometric model using mc-stan I fit the econometric model using mc-stan
\cite{standevelopmentteam_StanModelling_2022} \cite{standevelopmentteamStanModellingUsersGuide2022}
through the rstan through the rstan
\cite{standevelopmentteam_RStanInterface_2023} \cite{standevelopmentteamRStanInterfaceStan2023}
interface using 4 chains with interface using 4 chains with
%describe %describe
2,500 2,500
@ -152,14 +152,18 @@ Three points lead me to believe this:
\begin{itemize} \begin{itemize}
\item The low fractions of E-BFMI suggest that the sampler is struggling \item The low fractions of E-BFMI suggest that the sampler is struggling
to explore some regions of the posterior. to explore some regions of the posterior.
According to \cite{standevelopmentteam_RuntimeWarnings_2022} this is According to
\cite{standevelopmentteam_RuntimeWarnings_2022}
this is
often due to thick tails of posterior distributions. often due to thick tails of posterior distributions.
\item When we examine the results across different ICD-10 groups, \item When we examine the results across different ICD-10 groups,
\ref{fig:pred_dist_dif_delay2} \ref{fig:pred_dist_dif_delay2}
we note this same issue. we note this same issue.
\item In Figure \ref{fig:parameters_ANR_by_group}, we see that some some ICD-10 categories \item In Figure \ref{fig:parameters_ANR_by_group}, we see that some some ICD-10 categories
\todo{add figure} \todo{add figure}
have \todo{note fat tails}. have
\todo{note fat tails}.
\item There are few trials available, particularly among some specific \item There are few trials available, particularly among some specific
ICD-10 categories. ICD-10 categories.
\end{itemize} \end{itemize}
@ -177,7 +181,7 @@ due to the low amounts of data overall.
Figure \ref{fig:pred_dist_dif_delay2} shows how this overall Figure \ref{fig:pred_dist_dif_delay2} shows how this overall
result comes from different disease categories. result comes from different disease categories.
\begin{figure}[H] \begin{figure}
\includegraphics[width=\textwidth]{../assets/img/dist_diff_analysis/p_delay_intervention_distdiff_by_group} \includegraphics[width=\textwidth]{../assets/img/dist_diff_analysis/p_delay_intervention_distdiff_by_group}
\caption{Distribution of Predicted differences by Disease Group} \caption{Distribution of Predicted differences by Disease Group}
\label{fig:pred_dist_dif_delay2} \label{fig:pred_dist_dif_delay2}
@ -207,7 +211,7 @@ Overall, this suggests that extending a clinical trial's enrollment period will
\end{figure} \end{figure}
% - % -
Overally it is hard to escape the conclusion that more data is needed across Overall it is hard to escape the conclusion that more data is needed across
many -- if not all -- of the disease categories. many -- if not all -- of the disease categories.
\end{document} \end{document}

85
Paper/sections/11_intro_and_lit.tex
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@ -6,11 +6,11 @@
In 1938 President Franklin D Rosevelt signed the Food, Drug, and Cosmetic Act, In 1938 President Franklin D Rosevelt signed the Food, Drug, and Cosmetic Act,
granting the Food and Drug Administration (FDA) authority to require granting the Food and Drug Administration (FDA) authority to require
pre-market approval of pharmaceuticals. pre-market approval of pharmaceuticals.
\cite{commissioner_MilestonesUS_2023}. \cite{commissioner_milestonesusfood_2023}
As of Sept 2022 \todo{Check Date} they have approved 6,602 currently-marketed As of Sept 2022 \todo{Check Date} they have approved 6,602 currently-marketed
compounds with Structured Product Labels (SPLs) compounds with Structured Product Labels (SPLs)
and 10,983 previously-marketed SPLs and 10,983 previously-marketed SPLs
\cite{commissioner_NSDE_2024}. \cite{commissioner_nsde_2024},
%from nsde table. Get number of unique application_nubmers_or_citations with most recent end date as null. %from nsde table. Get number of unique application_nubmers_or_citations with most recent end date as null.
In 1999, they began requiring that drug developers register and In 1999, they began requiring that drug developers register and
publish clinical trials on \url{https://clinicaltrials.gov}. publish clinical trials on \url{https://clinicaltrials.gov}.
@ -42,7 +42,8 @@ Hyrimoz, Idacio, Simlandi, Yuflyma, and Yusimry),
the biosimilars are required to prove they have similar efficacy and safety to the the biosimilars are required to prove they have similar efficacy and safety to the
reference drug. reference drug.
When registering these clinical trials %TODO? Decide whether to include this or not
%When registering these clinical trials
% discuss how these are registered and what data is published. % discuss how these are registered and what data is published.
% Include image and discuss stages % Include image and discuss stages
% Discuss challenges faced % Discuss challenges faced
@ -51,24 +52,25 @@ When registering these clinical trials
In the world of drug development, these trials are classified into different In the world of drug development, these trials are classified into different
phases of development. phases of development.
\cite{FDADrugApprovalProcess_2022} \cite{anderson_fdadrugapproval_2022}
provide an overview of this process provide an overview of this process
\cite{commissioner_DrugDevelopment_2020} while
while describes the actual details. \cite{commissioner_drugdevelopmentprocess_2020}
describes the actual details.
Pre-clinical studies primarily establish toxicity and potential dosing levels Pre-clinical studies primarily establish toxicity and potential dosing levels
\cite{commissioner_DrugDevelopment_2020}. \cite{commissioner_drugdevelopmentprocess_2020}.
Phase I trials are the first attempt to evaluate safety and efficacy in humans. Phase I trials are the first attempt to evaluate safety and efficacy in humans.
Participants typically are heathy individuals, and they measure how the drug Participants typically are heathy individuals, and they measure how the drug
affects healthy bodies, potential side effects, and adjust dosing levels. affects healthy bodies, potential side effects, and adjust dosing levels.
Sample sizes are often less than 100 participants. Sample sizes are often less than 100 participants.
\cite{commissioner_DrugDevelopment_2020}. \cite{commissioner_drugdevelopmentprocess_2020}.
Phase II trials typically involve a few hundred participants and is where Phase II trials typically involve a few hundred participants and is where
investigators will dial in dosing, research methods, and safety. investigators will dial in dosing, research methods, and safety.
\cite{commissioner_DrugDevelopment_2020}. \cite{commissioner_drugdevelopmentprocess_2020}.
A Phase III trial is the final trial befor approval by the FDA, and is where A Phase III trial is the final trial befor approval by the FDA, and is where
the investigator must demonstrate safety and efficacy with a large number of the investigator must demonstrate safety and efficacy with a large number of
participants, usually on the order of hundreds or thousands. participants, usually on the order of hundreds or thousands.
\cite{commissioner_DrugDevelopment_2020}. \cite{commissioner_drugdevelopmentprocess_2020}.
Occassionally, a trial will be a multiphase trial, covering aspects of either Occassionally, a trial will be a multiphase trial, covering aspects of either
Phases I and II or Phases II and III. Phases I and II or Phases II and III.
@ -77,7 +79,7 @@ After a successful Phase III trial, the sponsor will decide whether or not
to submit an application for approval from the FDA. to submit an application for approval from the FDA.
Before filing this application, the developer must have completed Before filing this application, the developer must have completed
"two large, controlled clinical trials." "two large, controlled clinical trials."
\cite{commissioner_DrugDevelopment_2020}. \cite{commissioner_drugdevelopmentprocess_2020}.
Phase IV trials are used after the drug has recieved marketing approval to Phase IV trials are used after the drug has recieved marketing approval to
validate safety and efficacy in the general populace. validate safety and efficacy in the general populace.
Throughout this whole process, the FDA is available to assist in decisionmaking Throughout this whole process, the FDA is available to assist in decisionmaking
@ -85,14 +87,14 @@ regarding topics such as study design, document review, and whether or not
they should terminate the trial. they should terminate the trial.
The FDA also reserves the right to place a hold on the clinical trial for The FDA also reserves the right to place a hold on the clinical trial for
safety or other operational concerns, although this is rare. safety or other operational concerns, although this is rare.
\cite{commissioner_DrugDevelopment_2020}. \cite{commissioner_drugdevelopmentprocess_2020}.
In the economics literature, most of the focus has been on evaluating how In the economics literature, most of the focus has been on evaluating how
drug candidates transition between different phases and their probability drug candidates transition between different phases and their probability
of final approval. of final approval.
% Lead into lit review % Lead into lit review
% Abrantes-Metz, Adams, Metz (2004) % Abrantes-Metz, Adams, Metz (2004)
\cite{abrantes-metz_pharmaceutical_2004}, \authorcite{abrantes-metz_pharmaceuticaldevelopmentphases_2004}
described the relationship between described the relationship between
various drug characteristics and how the drug progressed through clinical trials. various drug characteristics and how the drug progressed through clinical trials.
% This descriptive estimate was notable for using a % This descriptive estimate was notable for using a
@ -107,7 +109,8 @@ from the purpose of Phase III.
Continuing on this theme, Continuing on this theme,
%DiMasi FeldmanSeckler Wilson 2009 %DiMasi FeldmanSeckler Wilson 2009
\cite{dimasi_TrendsRisks_2010} examine the completion rate of clinical drug \authorcite{dimasi_trendsrisksassociated_2010}
examine the completion rate of clinical drug
develompent and find that for the 50 largest drug producers, develompent and find that for the 50 largest drug producers,
approximately 19\% of their drugs under development between 1993 and 2004 approximately 19\% of their drugs under development between 1993 and 2004
successfully moved from Phase I to recieving an New Drug Application (NDA) successfully moved from Phase I to recieving an New Drug Application (NDA)
@ -120,7 +123,7 @@ They note that this may reduce the cost of new drugs by eliminating late
and costly failures in the development pipeline. and costly failures in the development pipeline.
Earlier work by Earlier work by
\authorcite{dimasi_ValueImproving_2002} \authorcite{dimasi_valueimprovingproductivity_2002}
used data on 68 investigational drugs from 10 firms to simulate how reducing used data on 68 investigational drugs from 10 firms to simulate how reducing
time in development reduces the costs of developing drugs. time in development reduces the costs of developing drugs.
He estimates that reducing Phase III of clinical trials by one year would He estimates that reducing Phase III of clinical trials by one year would
@ -128,13 +131,13 @@ reduce total costs by about 8.9\% and that moving 5\% of clinical trial failures
from phase III to Phase II would reduce out of pocket costs by 5.6\%. from phase III to Phase II would reduce out of pocket costs by 5.6\%.
Like much of the work in this field, the focus of the the work by Like much of the work in this field, the focus of the the work by
\citeauthor{dimasi_ValueImproving_2002} \authorcite{dimasi_valueimprovingproductivity_2002}
and and
\citeauthor{dimasi_TrendsRisks_2010} \authorcite{dimasi_trendsrisksassociated_2010}
tends to be on the drug development pipeline, i.e. the progression between tends to be on the drug development pipeline, i.e. the progression between
phases and towards marketing approval. phases and towards marketing approval.
A key contribution to this drug development literature is the work by A key contribution to this drug development literature is the work by
\authorcite{khmelnitskaya_CompetitionAttrition_2021} \authorcite{khmelnitskaya_competitionattritiondrug_2021}
on a causal identification strategy on a causal identification strategy
to disentangle strategic exits from exits due to clinical failures to disentangle strategic exits from exits due to clinical failures
in the drug development pipeline. in the drug development pipeline.
@ -143,7 +146,7 @@ terminations and that the rate of new drug production would be about 23\%
higher if those strategic terminatations were elimintated. higher if those strategic terminatations were elimintated.
The work that is closest to mine is the work by The work that is closest to mine is the work by
\authorcite{hwang_FailureInvestigational_2016} \authorcite{hwang_failureinvestigationaldrugs_2016}
who investigated causes for which late stage (Phase III) who investigated causes for which late stage (Phase III)
clinical trials fail -- with a focus on trials in the USA, clinical trials fail -- with a focus on trials in the USA,
Europe, Japan, Canada, and Australia. Europe, Japan, Canada, and Australia.
@ -157,14 +160,14 @@ on commercial or other grounds.
Unlike the majority of the literature, I focus on the progress of Unlike the majority of the literature, I focus on the progress of
individual clinical trials, not on the drug development pipeline. individual clinical trials, not on the drug development pipeline.
In both In both
\authorcite{khmelnitskaya_CompetitionAttrition_2021} \authorcite{khmelnitskaya_competitionattritiondrug_2021}
and and
\authorcite{hwang_FailureInvestigational_2016} \authorcite{hwang_failureinvestigationaldrugs_2016}
the authors describe failures due to safety, efficacy, or strategic concerns. the authors describe failures due to safety, efficacy, or strategic concerns.
There is another category of concerns that arise for individual clinical trials, There is another category of concerns that arise for individual clinical trials,
that of operational failures. that of operational failures.
Operational failures can arise when a trial struggles to recruit participants, Operational failures can arise when a trial struggles to recruit participants,
the principle investigator or other key member leaves for another opportunity, the principal investigator or other key member leaves for another opportunity,
or other studies prove that the trial requires a protocol change. or other studies prove that the trial requires a protocol change.
% In a personal review of 199 randomly selected clinical trials from the AACT % In a personal review of 199 randomly selected clinical trials from the AACT
@ -189,23 +192,27 @@ or other studies prove that the trial requires a protocol change.
This paper proposes the first model to separate the causal effects of This paper proposes the first model to separate the causal effects of
market conditions (a strategic concern) from the effects of market conditions (a strategic concern) from the effects of
participant enrollment (an operational concern) on Phase III Clinical trials. participant enrollment (an operational concern) on Phase III Clinical trials.
This will allow me to answer the questions: This allows me to answer the question
\begin{itemize} \textit{
\item What is the marginal effect on trial completion of an additional ``How does the probability of trial termination change
generic drug on the market? when the enrollment period is extended?''
\item What is the marginal effect on trial completion of a delay in }
closing enrollment? using administrative data.
\end{itemize} To understand how I do this, we'll cover some background information on
To undderstand how I do this, we'll cover some background information on clinical trials and the administrative data I collected in section
clinical trials in section \ref{SEC:ClinicalTrials}, \ref{SEC:ClinicalTrials},
explain the data in section \ref{SEC:DataSources}, explain the approach to causal identification strategy and the required data in section
and then examine causal identification and econometric model in sections \ref{SEC:Data},
\ref{SEC:CausalIdentificationAndModel}. and describe how the data used matches these requirements in section
Finally I'll review the results and conclusion in sections \ref{SEC:}.
\ref{SEC:Results} Then we'll cover the econometric model
and (section \ref{SEC:EconometricModel})
\ref{SEC:Conclusion} and results (section
respectively. \ref{SEC:Results}).
Finally, we acknowledge deficiencies in the analysis and potential improvements
in section
\ref{SEC:Improvements},
then summarize everything in the conclusion \ref{SEC:Conclusion}
% \subsection{Market incentives and drug development} % \subsection{Market incentives and drug development}
% %%%%%%%%% What do we know about drug development incentives? % %%%%%%%%% What do we know about drug development incentives?

4
assets/preambles/BibPreamble.tex
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@ -7,6 +7,7 @@
\usepackage[ \usepackage[
backend=biber, backend=biber,
autocite=inline, autocite=inline,
% style=author,
style=alphabetic, style=alphabetic,
]{biblatex} ]{biblatex}
@ -18,6 +19,7 @@
% \addbibresource{\bibpath} % \addbibresource{\bibpath}
% Manually add zotero library % Manually add zotero library
\addbibresource{~/.local/state/nvim_telescope_local_search/ZoteroLibrary.bib} %\addbibresource{~/.local/state/nvim_telescope_local_search/ZoteroLibrary.bib}
\addbibresource{../assets/preambles/References.bib}
\newcommand{\authorcite}[1]{\citeauthor{#1} \cite{#1}} \newcommand{\authorcite}[1]{\citeauthor{#1} \cite{#1}}

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assets/preambles/References.bib
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logs.org
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@ -0,0 +1,7 @@
* 2025
** 2025-W03
*** 2025-01-18 Saturday
**** [2025-01-18 Sat 11:54] [[[[file:/home/will/research/phd_deliverables/JobMarketPaper/Paper/sections/11_intro_and_lit.tex::45]]]]
Need to decide whether or not to include this set of sentences.
**** [2025-01-18 Sat 11:58] [[[[file:/home/will/research/phd_deliverables/JobMarketPaper/Paper/sections/11_intro_and_lit.tex::45]]]]
decide whether to include these details here

25
todo.org
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@ -0,0 +1,25 @@
* 2025
** 2025-W03
*** 2025-01-15 Wednesday
**** TODO Push work to overleaf
DEADLINE: <2025-01-15 Wed>
*** 2025-01-17 Friday
**** TODO Redo analysis using "Recruitng" as the base status
The goal is to get the $\beta$'s for active, not recruitng.
**** TODO Fix JMP based on Tom's Suggestions and send to committee
***** TODO Get references working properly
- setup author date format
- fix references, add to Overleaf version
***** TODO Read Backward
Identify poorly written portions (incomplete sentences and paragraphs) and what I was trying to communicate.
***** TODO fix issues
*** 2025-01-18 Saturday
**** TODO Decide if this section needs added
[[[[file:/home/will/research/phd_deliverables/JobMarketPaper/Paper/sections/11_intro_and_lit.tex::45]]]]
**** TODO Update citations in lit review section.
[[[[file:/home/will/research/phd_deliverables/JobMarketPaper/Paper/sections/05_LitReview.tex::25]]]]
**** TODO Ask CLAUDE to help Lit review flow better.
[[[[file:/home/will/research/phd_deliverables/JobMarketPaper/Paper/sections/05_LitReview.tex::25]]]]
**** TODO Rearrange the lit review.
[[[[file:/home/will/research/phd_deliverables/JobMarketPaper/Paper/sections/05_LitReview.tex::25]]]]
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