Created plan in outline.txt, added resources, and updated some sections.

Latex/Paper/Main.tex

@@ -57,10 +57,10 @@ completion of clinical trials\\ \small{Preliminary Draft}}
 \subfile{sections/10_CausalStory}
 \subfile{sections/02_data}
 
-% %---------------------------------------------------------------
+%---------------------------------------------------------------
-% \section{Causal Identification}\label{SEC:CausalIdentification}
+\section{Causal Identification}\label{SEC:CausalIdentification}
-% %---------------------------------------------------------------
+%---------------------------------------------------------------
-% \subfile{sections/03_CausalIdentification}
+\subfile{sections/03_CausalIdentification}
 
 %---------------------------------------------------------------
 \section{Econometric Model}\label{SEC:EconometricModel}

Latex/Paper/outline.txt

@@ -0,0 +1,34 @@
+Outlining for jmp
+<intro>
+Introduction and problem statement
+*Explain what I am doing:*
+</intro>
+<literature
+Describe what has been done
+- measuring failure rates & impact
+Introduce different types of failure
+- Scientific
+- Strategic
+- Operational
+Efforts to measure failures
+Medbio story to illuistrate failure modes.
+Operational and strategic failures undermine scientific process of discovery
+*My effort is to separate...*: place my work in context
+Introduce clinical trials' progressions, stages, and statuses.
+</literature>
+<causal model>
+Derive causal model
+</causal model>
+<data>
+Summarize data sources
+</data>
+<econometrics>
+Introduce econometric model
+</econmetrics>
+<results>
+Discuss econometric results
+</results>
+Conclusion
+Appendicies
+- in-depth data source info
+- More econometric results

Latex/Paper/sections/01_introduction.tex

@@ -3,7 +3,7 @@
 
 \begin{document}
 
-Developing new, effective pharmaceutical compounds is a fundamentally difficult task.
+Developing novel, safe, and effective pharmaceutical compounds is difficult.
 Starting with challenges identifying promising treatment targets and potential compounds, to ensuring the drug can be properly delivered within the body, the scientific work that needs to go well is massive.
 The regulatory and market conditions in which they exist add to this difficulty. 
 For example, regulations are designed to reduce the number of drugs released to market
@@ -25,60 +25,6 @@ on individual clinical trials.
 Understanding both why and how the development of drugs fail -- for both 
 novel and derivative pharmaceuticals -- is key to ensuring that both innovation
 and availability are maximized.
-There are myriad of reasons that a drug candidate may not make it to market, 
-regardless of it's novelty or known safety.
-These reasons for failure generally fall into one of the following categories:
-\begin{itemize}
-    \item Scientific concerns arise while asking the question
-        %Whether or not the drug is sufficiently safe and 
-        %efficatious for the disease it is trying to treat i.e. 
-        ``Will the drug work for patients?''
-        %E.Khm, Gupta, etc.
-    \item Strategic concerns ask: 
-        %Whether or not the drug will be profitiable, or align with
-        %the drug developer's future Research \& Development directions i.e.
-        ``Will producing the drug be beneficial to the 
-        company in the long term?''
-        %E.Khm, Gupta, GLP-1s, etc.
-    \item Operational concerns are answers to: 
-        %Whether or not the developer can successfully conduct
-        %operations to meet scientific or strategic goals, i.e. 
-        ``What has prevented the the company from being able to 
-        finance, develop, produce, and market the drug?''
-\end{itemize}
-It is likely that a drug fails to complete the development cycle due to some
-combination of these factors. 
-
-%MetaBio/CalBio GLP-1 story to illuistrate these different factors.
-\cite{flier_DrugDevelopment_2024} documents the case of MetaBio, a company
-he was involved in founding that was in the first stages of
-developing a GLP-1 based drug for diabetes or obesety before being shut down
-in . 
-MetaBio was a wholy owned subsidiary of CalBio, a metabolic drug development 
-firm, that recieved a \$30 million -- 5 year investment from Pfizer to 
-persue development of GLP-1 based therapies. 
-At the time it was shut down, it faced a few challenges:
-\begin{itemize}
-    \item The compound had a short half life and they were seeking methods to 
-        improve it's effectiveness; a scientific failure.
-    \item Pfizer imposed a requirement that it be delivered though a route
-        other than injection (the known delivery mechanism); a strategic failure. 
-    \item When Pfizer pulled the plug, CalBio closed MetaBio because they 
-        could not find other funding sources; an operational failure.
-\end{itemize}
-
-The author states in his conclusion:
-\begin{displayquote}
-    Despite every possibility of success, 
-    MetaBio went down because there were mistaken ideas about what was 
-    possible and what was not in the realm of metabolic therapeutics, and 
-    because proper corporate structure and adequate capital are always 
-    issues when attempting to survive predictable setbacks.
-\end{displayquote} 
-
-From this we see that there was a cascade of issues leading to the failure to 
-develop this novel drug. 
-
 
 
 

Latex/Paper/sections/03_CausalIdentification.tex

@@ -11,6 +11,23 @@
 % Begin Discussing Data
 % - Where did I get data for each node?
 
+When any clinical trial is conducted, it goes through three distinct stages:
+pre-trial, active, and decision to conclude.
+In figure \ref{Fig:Stages}, you can see the component parts of each stage. 
+
+\begin{figure}[H] %use [H] to fix the figure here.
+    \includegraphics[width=\textwidth]{../assets/img/ClinicalTrialStagesAndStatuses}
+    \caption{Model of Statuses}
+    \label{Fig:Stages}
+\end{figure}
+
+In the pre-trial stage, the sponsoring organization chooses to run the trial,
+they register the trial on  \url{ClinicalTrials.gov}, and then decide if they
+will begin enrollment. 
+Many registered trials are withdrawn at this point, before the trial has opened
+for enrollment. 
+Once enrollment has opened 
+
 Because running randomized experiments on companies running clinical trials 
 is unlikely to to happen anytime soon, 
 causal identification will depend on observational methods. 
@@ -57,63 +74,4 @@ Trials must be registered
 % 
 
 
-While conducting a trial, the safety and efficacy of a drug are driven by
-fundamental pharmacokinetic properties of the compounds. 
-These are only imperfectly measured both prior to and during any given trial.
-Previously measured safety and efficacy inform the decision to start the trial
-in the first place while currently observed safety and efficiency results
-help the sponsor judge whether or not to continue the trial.
-Of course, these decisions are both affected by the specific condition being
-treated due to differences in the severity of the symptoms.
-
-When a trial has been started, it comes time to recruit participancts.
-The enrollment of participants in a trial depends on a few factors.
-Participants usually depend on the advice of their physician when deciding 
-to join a trial or not. 
-As these physicians have a duty to seek their patients best interest; they, along
-with their patients will evaluate if the previously observed safety and efficacy
-results justify joining the trial in contrast to using the current standard 
-of care. 
-Thus enrollment rates are influenced by the treatments currently on the market. 
-Recruitment can also be hindered if disease has a low impact 
--- in which participants might have little incentive to join -- 
-or if there are few people who have the disease. 
-The overall impact of the disease also influences whether or not there are 
-already drugs on the market to treat that disease. 
-
-The condition or disease of interest and how it progresses will determine how long
-recruitiment will be held open versus just an observation of treatment arms.
-Aditionally, a trial that has already reached a high enough enrollment will often
-close recruitment. 
-Both of these are reported as "Active, not recruting" to ClinicalTrials.gov. 
-Finally, enrolling participants depends on how difficult it is to find people 
-who suffer from the condition of interest.
-
-The preceeding issue of population size also affects the number of alternatives available.
-When there are less people affected by the disease, the smaller market reduces 
-possible profitability, all else equal.
-Thus the likelihood of companies paying the sunk costs to develop drugs for
-these conditions may be lower.
-Finally, the number of alternatives on the market may affect the return on
-investment directly, causing a trial to terminate early if the return is
-not high enough.
-
-\begin{figure}[H] %use [H] to fix the figure here.
-    \scalebox{0.6}{\tikzfig{../assets/tikzit/CausalGraph2}}
-    \caption{Causal Model}
-    \label{Fig:CausalModel}
-\end{figure}
-% 
-By using Judea Pearl's do-calculus, I can show that by choosing an adjustment 
-set of the decision to condut a phase III trial, the condition of interest, 
-the current status of the trial, and the population size will casually
-identify the direct effects of enrollment and market alternatives on the
-probability of termination.
-This is easily verified through the backdoor criterion, which states that
-if every path between the exposure and outcome that starts with an arrow 
-flowing into the exposure is blocked by one of the values in the adjustment
-set, then the effect of the exposure on outcome is causally identified
-(\cite{pearl_causality_2000}).
-It can be easily visually verified by the DAG on the graph that this is the case.
-
 \end{document}

Latex/Paper/sections/05_LitReview.tex

@@ -3,45 +3,26 @@
 
 \begin{document}
 
-% TODO:
+% Outline
-%Need to distinguish that this isn't about drug development specifically, but 
+% - Introduce and frame problem
-% more around clinical trials progress.
+%   - Phases & regulatory part
-% Thoughts:
+%   - Large number of failures at each phase
-% - What types of failures do clinical trials have an why do clinical trials fail? 
+%   - There are multiple ways to measure this
-%   - What is cited in termination reasons?
+%   - Estimation of failures at phase and failures per development path
-%   - Discussion on different types of failures: 
+%   - Talk about impact of making these closer together
-%       1. Failure to find safe and effective drug
+% - Trying to develop more by tweaking external world:
-%       2. Failure to collect enough information to determine 1
+%   - Pull incentives 
-%           - recruiting
+%   - Increase in market sizes.
-%           - New information (other studies, changes in standards of care, etc)
+%   - Uncertanty in Intellectual Property
-%       3. Failure due to other operational/strategic concern.
+% - Understanding failure modes
-%           - Issues with PI/Sponsors
+%   - EK and Hwang
-%           - profitability expectations
+%   - discuss missing section of operational concerns
-%           - Financial support
+%   - Introduce metabio
-
+% - Once again bring up my work here.
-
-% - Discuss how most studies are about clinical trials as part of the drug development pipeline.
-% - Review what we know about causes for failure. 
-%   - Things that correlate with failures. (adams) 
-%   - Causes for failure (khmelnitskaya & hwang)
-% - Then talk about studies on clinical trials themselves. 
-%   - Interview with Adam George
-%   - Poor studies of enrollment prediction.
 %   - 
-% - Then talk about what drives approvals/clinical trial activity for drugs
-%   - Elasticity of innovation
-%   - No demand pull for novel drugs, but yes for derivatives
-%   - Population and Market size interact & drive development (jointly determined)
-%       - This doesn't apply to single trials though
-%   - 
-% - Sumarize
-%   - Thus when trying to study what affects clinical trials we must separate
-%       - Market & competition effects
-%       - Population effects
-%       - Multiple trial failure modes (safety & efficacy, Operational etc)
-%       - 
 %   - 
 
+\subsection{Drug development process and failure rates}
 % Abrantes-Metz, Adams, Metz (2004)
 % - What correlates with successfully passing clinical trials and FDA review?
 % - 
@@ -56,47 +37,34 @@ They found that as trials last longer, the rate of failure increases for
 Phase I \& II trials, while Phase 3 trials generally have a higher rate of 
 success than failure after 91 months.
 
-%%%%%%%%%%%%%%%% What do we know about clinical trials?
+%DiMasi FeldmanSeckler Wilson 2009
-
+\cite{dimasi_TrendsRisks_2010} examine the completion rate of clinical drug 
-\subsection{Understanding Failure Modes}
+develompent and find that for the 50 largest drug producers, 
-
+approximately X\% of their drugs under development
-% Hwang, Carpenter, Lauffenburger, et al (2016)
+\todo{FILL IN X}
-% - Why do investigational new drugs fail during late stage trials?
+successfully completed the process. 
-\citeauthor{hwang_failure_2016} (\citeyear{hwang_failure_2016}) 
+They note a couple of changes in how drugs are developed over the years they 
-investigated causes for which late stage (Phase III)
+study (clinical development started between 1993 and 2004). 
-clinical trials fail across the USA, Europe, Japan, Canada, and Australia. 
+This included that drugs began to fail earlier in their development cycle in the 
-They found that for late stage trials that did not go on to recieve approval,
+latter half of the time they studied. 
-57\% failed on efficacy grounds, 17\% failed on safety grounds, and 22\% failed
+This may be an operational change to reduce the cost of new drugs. 
-on commercial or other grounds.
 
+\cite{dimasi_ValueImproving_2002}
+used data on 68 investigational drugs from 10 firms to simulate how reducing
+time in development reduces the costs of developing drugs. 
+He estimates that reducing Phase III of clinical trials by one year would 
+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\%. 
 
-% Ekaterina Khmelnitskaya (2021)
-% - separates scientific from market failure of the clinical drug pipeline
-In her doctoral dissertation, Ekaterina Khmelnitskaya studied the transition of
-drug candidates between clinical trial phases. 
-Her key contribution was to find ways to disentangle strategic exits from the 
-development pipeline and exits due to clinical failures.
-She found that overall 8.4\% of all pipeline exits are due to strategic 
-terminations and that the rate of new drug production would be about 23\% 
-higher if those strategic terminatations were elimintated
-(\cite{khmelnitskaya_competition_2021}).
-% causal separation of strategic exits etc.
 
 % Waring, Arrosmith, Leach, et al (2015)
 % - Atrition of drug candidates from four major pharma companies
 % - Looked at how phisicochemical properties affected clinical failure due to safety issues
-% Possibly Applicable in this version
+% Don't think this is applicable.
-
-
-
 
-\subsection{What about incentives?}
+\subsection{Market incentives and drug development}
 %%%%%%%%% What do we know about drug development incentives?
 
-% Dranov, Garthwaite, and Hermosilla (2022)
-% - does the demand-pull theory of R&D explain novel compound development?
-% - no, it is biased towards follow-on drug R&D.
-% TODO
 \cite{dranove_DoesConsumer_2022} use the implementation of Medicare part D 
 to examine whether the production of novel or follow up drugs increases during 
 the following 15 years. 
@@ -134,22 +102,91 @@ She found that this delay in delivery is around 3 years.
 % - Retrospective on impact from COVID-19 pandemic
 % Not in this version
 
-%DiMasi FeldmanSeckler Wilson 2009
+\subsection{Understanding Failures in Drug Development}
-\cite{dimasi_TrendsRisks_2010} examine the completion rate of clinical drug 
+
-develompent and find that for the 50 largest drug producers, 
+% DISCUSS: Different types of failures
-approximately X\% of their drugs under developm
+There are myriad of reasons that a drug candidate may not make it to market, 
-successfully completed the process. 
+regardless of it's novelty or known safety.
-They note a couple of changes in how drugs are developed over the years they 
+In this work, I focus on the failure of individual clinical trials, but the 
-study (clinical development started between 1993 and 2004). 
+categories of failure apply to the individual trials as well as the entire
-This included that drugs began to fail earlier in their development cycle in the 
+drug development pipeline.
-latter half of the time they studied. 
+They generally fall into one of the following categories:
-This may be an operational change to reduce the cost of new drugs. 
+\begin{itemize}
+    \item Scientific  Failure: When there are issues regarding 
+        safety and efficacy that must be addressed. 
+        The preeminient question is: 
+        ``Will the drug work for patients?''
+        %E.Khm, Gupta, etc.
+    \item Strategic Failure: When the sponsors stop development because of 
+        profitability
+        %Whether or not the drug will be profitiable, or align with
+        %the drug developer's future Research \& Development directions i.e.
+        ``Will producing the drug be beneficial to the 
+        company in the long term?''
+        %E.Khm, Gupta, GLP-1s, etc.
+    \item Operational concerns are answers to: 
+        %Whether or not the developer can successfully conduct
+        %operations to meet scientific or strategic goals, i.e. 
+        ``What has prevented the the company from being able to 
+        finance, develop, produce, and market the drug?''
+\end{itemize}
+It is likely that a drug fails to complete the development cycle due to some
+combination of these factors. 
+
+
+%USE MetaBio/CalBio GLP-1 story to illuistrate these different factors.
+\cite{flier_DrugDevelopment_2024} documents the case of MetaBio, a company
+he was involved in founding that was in the first stages of
+developing a GLP-1 based drug for diabetes or obesety before being shut down
+in . 
+MetaBio was a wholy owned subsidiary of CalBio, a metabolic drug development 
+firm, that recieved a \$30 million -- 5 year investment from Pfizer to 
+persue development of GLP-1 based therapies. 
+At the time it was shut down, it faced a few challenges:
+\begin{itemize}
+    \item The compound had a short half life and they were seeking methods to 
+        improve it's effectiveness; a scientific failure.
+    \item Pfizer imposed a requirement that it be delivered though a route
+        other than injection (the known delivery mechanism); a strategic failure. 
+    \item When Pfizer pulled the plug, CalBio closed MetaBio because they 
+        could not find other funding sources; an operational failure.
+\end{itemize}
+
+The author states in his conclusion:
+\begin{displayquote}
+    Despite every possibility of success, 
+    MetaBio went down because there were mistaken ideas about what was 
+    possible and what was not in the realm of metabolic therapeutics, and 
+    because proper corporate structure and adequate capital are always 
+    issues when attempting to survive predictable setbacks.
+\end{displayquote} 
+
+From this we see that there was a cascade of issues leading to the failure to 
+develop this novel drug. 
+
+% NOW discuss efforts to measure the impact of different aspects
+
+\citeauthor{hwang_failure_2016} (\citeyear{hwang_failure_2016}) 
+investigated causes for which late stage (Phase III)
+clinical trials fail across the USA, Europe, Japan, Canada, and Australia. 
+They found that for late stage trials that did not go on to recieve approval,
+57\% failed on efficacy grounds, 17\% failed on safety grounds, and 22\% failed
+on commercial or other grounds.
+
+
+In her doctoral dissertation, Ekaterina Khmelnitskaya studied the transition of
+drug candidates between clinical trial phases. 
+Her key contribution was to find ways to disentangle strategic exits from the 
+development pipeline and exits due to clinical failures.
+She found that overall 8.4\% of all pipeline exits are due to strategic 
+terminations and that the rate of new drug production would be about 23\% 
+higher if those strategic terminatations were elimintated
+(\cite{khmelnitskaya_competition_2021}).
+% causal separation of strategic exits etc.
+
+% I don't think I need to include modelling enrollment here. 
+% If it is applicable, it can show up in those sections later.
+
 
-\cite{dimasi_ValueImproving_2002}
-used data on 68 investigational drugs from 10 firms to simulate how reducing
-time in development reduces the costs of developing drugs. 
-He estimates that reducing Phase III of clinical trials by one year would 
-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\%. 
 
 \end{document}