Continuing to work on introduction and lit review

Latex/Paper/Main.tex

@@ -12,6 +12,7 @@
 \input{../assets/preambles/GeneralPreamble}
 
 \usepackage{float}
+\usepackage{csquotes}
 
 
 %setup paragraph level indexing

Latex/Paper/sections/01_introduction.tex

@@ -13,24 +13,73 @@ These regulations, such as clinical trial standards \todo{add citation to clinic
 increase the costs of developing new drugs, adding to the business conserns already present, including 
 competitors already in the market or close to entering and the overall demand to address a given condition.
 
+This work is the first that endeavors to separate the causal effect
+of an operational concern (participant enrollment) from that of strategic 
+concerns (market size and competitors in the market) 
+on individual clinical trials. 
+
 %begin discussing failures
 %I am thinking I'll discuss marketing and operational failures
 %I somehow need to step away from the drug development framing and soften it to ... what? drug investigation?
 
-While discovering that a drug doesn't work or is unsafe is a scientific failure, other failure modes occur.
+Understanding both why and how the development of drugs fail -- for both 
-\cite{khmelnitskaya_competitionattritiondrug_2021} explored how to identify business related failures within the drug development pipeline. 
+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} 
 
-Thoughts so far
+From this we see that there was a cascade of issues leading to the failure to 
-types of failure: 
+develop this novel drug. 
-- scientific: unsafe or ineffective
+Knowing how to separate 
-- business: concerns about profitability
-- operational: cannot actually complete the steps required to bring things to market.
 
-Things that influence each
-- scientific: phamokynetics, biology. Take as given.
-- business: regulation, competitors, demand levels, patents, etc
-- operational: regulation, finding participants, finding competent PIs etc.
 
-Maybe financial and operational terminology?
 
 \end{document}

Latex/Paper/sections/05_LitReview.tex

@@ -18,17 +18,6 @@
 %           - Issues with PI/Sponsors
 %           - profitability expectations
 %           - Financial support
-% Trials can fail due to issues in one of four categories
-% - Scientific: The compound-indication combo is not sufficiently safe or efficatious
-% - Strategic: The result from the trial won't meet the company's strategic needs. Profitability for the most part or entry into a drug category they don't want to invest in.
-% - Operational: They can't bring resources to bear to achieve goal, e.g. site planning, PI's, delivering enough financial support, etc.
-% - Tactical: The plans to discover if the approach is scientifically valid are insufficient. Study design, enrollment strategies, etc.
-
-% The literature examines many different aspects of these.
-% strategic influences: elasticicity of innovation, demand pull, patents, etc
-% Strategic vs scientific khmelniskaya, hwang.
-% operational: Adam George Interview
-% tactical: enrollment prediction.
 
 
 % - Discuss how most studies are about clinical trials as part of the drug development pipeline.
@@ -53,37 +42,6 @@
 %       - 
 %   - 
 
-This paper sits within an intersection of health and industrial organization economics
-that is frequently studied.
-Encouraging a strong supply of novel and generic pharmaceuticals contributes 
-in important ways to both public health and fiscal policy.
-Not only to the pathway to drug approval long, as many as 90\% of compounds
-that begin human trials fail to gain approval 
-(\cite{khmelnitskaya_competition_2021}).
-Complicating this is the complex regulatory and competitive environment in
-which pharmaceutical companies operate. 
-
-%%%%%%%%% Why are drugs so expensive?
-
-% van der Grond, Uyle-de Groot, Pieters 2017
-% - What causes high costs of drugs? 
-% - High level synthesis of discussion regarding causes
-% - Academic and non-academic sources
-% Not particularly applicable
-
-%%%%%%%%%%%%%%%% What do we know about clinical trials?
-
-% Hwang, Carpenter, Lauffenburger, et al (2016)
-% - Why do investigational new drugs fail during late stage trials?
-\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.
-For context, this current work hopes to be able to distinguish some of the 
-mechanisms behind those commercial or other failures.
-
 % Abrantes-Metz, Adams, Metz (2004)
 % - What correlates with successfully passing clinical trials and FDA review?
 % - 
@@ -98,6 +56,20 @@ 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?
+
+\subsection{Understanding Failure Modes}
+
+% Hwang, Carpenter, Lauffenburger, et al (2016)
+% - Why do investigational new drugs fail during late stage trials?
+\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.
+
+
 % Ekaterina Khmelnitskaya (2021)
 % - separates scientific from market failure of the clinical drug pipeline
 In her doctoral dissertation, Ekaterina Khmelnitskaya studied the transition of
@@ -113,22 +85,31 @@ higher if those strategic terminatations were elimintated
 % 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
-% not Applicable in this version
+% Possibly Applicable in this version
 
 
 
 
+\subsection{What about incentives?}
 %%%%%%%%% 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. 
+They find that when Medicare part D was implemented -- increasing senior 
+citizens' ability to pay for drugs -- there was a (delayed) increase 
+in drug development, with effects concentrated among compounds that were least
+innovative according to their classification of innovations.
+
 
 % Acemoglu and Linn
 % - Market size in innovation
 % - Exogenous demographic trends has a large impact on the entry of non-generic drugs and new molecular entitites.
-On the side of market analysis, %TODO:remove when other sections are written up.
+On the side of market analysis, 
 \citeauthor{acemoglu_market_2004} 
 (\citeyear{acemoglu_market_2004})
 used exogenous deomographics changes to show that the
@@ -149,4 +130,6 @@ She found that this delay averages around 3 years.
 % - Retrospective on impact from COVID-19 pandemic
 % Not in this version
 
+%DiMasi FeldmanSeckler Wilson 2009
+
 \end{document}