diff --git a/Latex/Paper/Main.tex b/Latex/Paper/Main.tex index 3452aa9..0505c32 100644 --- a/Latex/Paper/Main.tex +++ b/Latex/Paper/Main.tex @@ -45,11 +45,12 @@ completion of clinical trials\\ \small{Preliminary Draft}} \section{Introduction}\label{SEC:Introduction} %--------------------------------------------------------------- -\subfile{sections/01_introduction} -%--------------------------------------------------------------- -\section{Literature Review}\label{SEC:LiteratureReview} -%--------------------------------------------------------------- -\subfile{sections/05_LitReview} +\subfile{sections/11_intro_and_lit} +% \subfile{sections/01_introduction} +% %--------------------------------------------------------------- +% \section{Literature Review}\label{SEC:LiteratureReview} +% %--------------------------------------------------------------- +% \subfile{sections/05_LitReview} %--------------------------------------------------------------- \section{Causal Story and Data}\label{SEC:Data} diff --git a/Latex/Paper/sections/11_intro_and_lit.tex b/Latex/Paper/sections/11_intro_and_lit.tex new file mode 100644 index 0000000..e39f6b9 --- /dev/null +++ b/Latex/Paper/sections/11_intro_and_lit.tex @@ -0,0 +1,306 @@ +\documentclass[../Main.tex]{subfiles} +\graphicspath{{\subfix{Assets/img/}}} + +\begin{document} + +In 19xx the United States Food and Drug Administration (FDA) was created to "QUOTE". +As of Sept 2022 \todo{Check Date} they have approved 6,602 currently-marketed compounds with Structured Product Labels (SPL) +and 10,983 previously-marketed SPLs. +%from nsde table. Get number of unique application_nubmers_or_citations with most recent end date as null. +In 2007, they began requiring that drug developers register and publish clinical trials on \url{https://clinicaltrials.gov}. +This provides a public mechanism where clinical trial sponsors are responsible to explain +what they are trying to acheive and how it will be measured, as well as provide the public the ability to +search and find trials that they might enroll in. +Data such as this has become part of multiple datasets +(e.g. the Cortellis Investigational Drugs dataset or the AACT dataset from the Clinical Trials Transformation Intiative) +used to evaluate what drugs might be entering the market soon. +This brings up a question: can we use this public data on clinical trials to describe what effects their success or failure? +In this work, I use updates to records on \url{https://ClinicalTrials.gov} to disentangle +the effect of participant enrollment and drugs on the market affect the success or failure of clinical trials. + +%Describe how clinical trials fit into the drug development landscape and how they proceed +Clinical trials are a required part of drug development. +Not only does the FDA require that a series of clinical trials demonstrate sufficient safety and efficacy of +a novel pharmaceutical compound or device, producers of derivative medicines may be required to ensure that +their generic small molecule compound -- such as ibuprofen or levothyroxine -- matches the +performance of the originiator drug if delivery or dosage is changed. +For large molecule generics (termed biosimilars) such as Adalimumab +(Brand name Humira, with biosimilars Abrilada, Amjevita, Cyltezo, Hadlima, Hulio, +Hyrimoz, Idacio, Simlandi, Yuflyma, and Yusimry), +the biosimilars are required to prove they have similar efficacy and safety to the +reference drug. + +When registering these clinical trials +% discuss how these are registered and what data is published. +% Include image and discuss stages +% Discuss challenges faced + +% Introduce my work + +In the world of drug development, these trials are classified into different +phases of development. +\cite{FDADrugApprovalProcess_2022} +provide an overview of this process +\cite{commissioner_DrugDevelopment_2020} +while describes the actual details. +Pre-clinical studies primarily establish toxicity and potential dosing levels +\cite{commissioner_DrugDevelopment_2020}. +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 +affects healthy bodies, potential side effects, and adjust dosing levels. +Sample sizes are often less than 100 participants. +\cite{commissioner_DrugDevelopment_2020}. +Phase II trials typically involve a few hundred participants and is where +investigators will dial in dosing, research methods, and safety. +\cite{commissioner_DrugDevelopment_2020}. +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 +participants, usually on the order of hundreds or thousands. +\cite{commissioner_DrugDevelopment_2020}. +Occassionally, a trial will be a multiphase trial, covering aspects of either +Phases I and II or Phases II and III. + + +After a successful Phase III trial, the sponsor will decide whether or not +to submit an application for approval from the FDA. +Before filing this application, the developer must have completed +"two large, controlled clinical trials." +\cite{commissioner_DrugDevelopment_2020}. +Phase IV trials are used after the drug has recieved marketing approval to +validate safety and efficacy in the general populace. +Throughout this whole process, the FDA is available to assist in decisionmaking +regarding topics such as study design, document review, and whether or not +they should terminate the trial. +The FDA also reserves the right to place a hold on the clinical trial for +safety or other operational concerns, although this is rare. +\cite{commissioner_DrugDevelopment_2020}. + +In the economics literature, most of the focus has been on evaluating how +drug candidates transition between different phases and their probability +of final approval. +% Lead into lit review +% Abrantes-Metz, Adams, Metz (2004) +\cite{abrantes-metz_pharmaceutical_2004}, +described the relationship between +various drug characteristics and how the drug progressed through clinical trials. +% This descriptive estimate was notable for using a +% mixed state proportional hazard model and estimating the impact of +% observed characteristics in each of the three phases. +They found that as Phase I and II trials last longer, +the rate of failure increases. +In contrast, Phase 3 trials generally have a higher rate of +success than failure after 91 months. +This may be due to the fact that the purpose of Phases I and II are different +from the purpose of Phase III. + +Continuing on this theme, +%DiMasi FeldmanSeckler Wilson 2009 +\cite{dimasi_TrendsRisks_2010} examine the completion rate of clinical drug +develompent and find that for the 50 largest drug producers, +approximately 19\% of their drugs under development between 1993 and 2004 +successfully moved from Phase I to recieving an New Drug Application (NDA) +or Biologics License Application (BLA). +They note a couple of changes in how drugs are developed over the years they +study, most notably that +drugs began to fail earlier in their development cycle in the +latter half of the time they studied. +They note that this may reduce the cost of new drugs by eliminating late +and costly failures in the development pipeline. + +Earlier work by +\authorcite{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\%. + +Like much of the work in this field, the focus of the the work by +\citeauthor{dimasi_ValueImproving_2002} +and +\citeauthor{dimasi_TrendsRisks_2010} +tends to be on the drug development pipeline, i.e. the progression between +phases and towards marketing approval. +A key contribution to this drug development literature is the work by +\authorcite{khmelnitskaya_CompetitionAttrition_2021} +on a causal identification strategy +to disentangle strategic exits from exits due to clinical failures +in the drug development pipeline. +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. + +The work that is closest to mine is the work by +\authorcite{hwang_FailureInvestigational_2016} +who investigated causes for which late stage (Phase III) +clinical trials fail -- with a focus on trials in the USA, +Europe, Japan, Canada, and Australia. +They identified 640 novel therapies and then studied each therapy's +development history, as outlined in commercial datasets. +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. + +% Begin Discussing what I do. Then introduce +Unlike the majority of the literature, I focus on the progress of +individual clinical trials, not on the drug development pipeline. +In both +\authorcite{khmelnitskaya_CompetitionAttrition_2021} +and +\authorcite{hwang_FailureInvestigational_2016} +the authors describe failures due to safety, efficacy, or strategic concerns. +There is another category of concerns that arise for individual clinical trials, +that of operational failures. +Operational failures can arise when a trial struggles to recruit participants, +the principle investigator or other key member leaves for another opportunity, +or other studies prove that the trial requires a protocol change. + +% In a personal review of 199 randomly selected clinical trials from the AACT +% database, the +% \begin{table} +% \caption{}\label{tab:} +% \begin{center} +% \begin{tabular}[c]{|l|l|} +% \hline +% Reason & Percentage Mentioned \\ +% \hline +% Safety or Efficacy & 14.5\% \\ +% Funding Problems & 9.1\% \\ +% Enrollment Issues & 31\% \\ +% \hline +% \end{tabular} +% \end{center} +% \end{table} + + + +This paper proposes the first model to separate the causal effects of +market conditions (a strategic concern) from the effects of +participant enrollment (an operational concern). +This will allow me to answer the questions: +\begin{itemize} + \item What is the marginal effect on trial completion of an additional + generic drug on the market? + \item What is the marginal effect on trial completion of a delay in + closing enrollment? +\end{itemize} +To undderstand how I do this, we'll cover some background information on +clinical trials in section \ref{SEC:ClinicalTrials}, +explain the data in section \ref{SEC:DataSources}, +and then examine causal identification and econometric model in sections +\ref{SEC:CausalIdentificationAndModel}. +Finally I'll review the results and conclusion in sections +\ref{SEC:Results} +and +\ref{SEC:Conclusion} +respectively + +% \subsection{Market incentives and drug development} +% %%%%%%%%% What do we know about drug development incentives? +% +% \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. +% They suggest that this is due to financial risk management, as novel +% pharmaceuticals have a higher probability of failure compared to the less novel +% follow up development. +% This is what leads risk-adverse companies to prefer follow up development. +% +% +% % 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, +% \citeauthor{acemoglu_market_2004} +% (\citeyear{acemoglu_market_2004}) +% used exogenous deomographics changes to show that the +% entry of novel compounds is highly driven by the underlying aged population. +% They estimate that a 1\% increase in applicable demographics increase the +% entry of new drugs by 6\%, mostly concentrated among generics. +% Among non-generics, a 1\% increase in potential market size +% (as measured by demographic groups) leads to a 4\% increase in novel therapies. +% +% % Gupta +% % - Inperfect intellectual property rights in the pharmaceutical industry +% \cite{gupta_OneProduct_2020} discovered that uncertainty around which patents +% might apply to a novel drug causes a delay in the entry of generics after +% the primary patent has expired. +% She found that this delay in delivery is around 3 years. +% +% % Agarwal and Gaule 2022 +% % - Retrospective on impact from COVID-19 pandemic +% % Not in this version +% +% \subsection{Understanding Failures in Drug Development} +% +% % DISCUSS: Different types of failures +% There are myriad of reasons that a drug candidate may not make it to market, +% regardless of it's novelty or known safety. +% In this work, I focus on the failure of individual clinical trials, but the +% categories of failure apply to the individual trials as well as the entire +% drug development pipeline. +% They generally fall into one of the following categories: +% \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. +% +% +% % I don't think I need to include modelling enrollment here. +% % If it is applicable, it can show up in those sections later. +% +% + +\end{document} diff --git a/Latex/assets/preambles/BibPreamble.tex b/Latex/assets/preambles/BibPreamble.tex index 5dd6caf..40448e0 100644 --- a/Latex/assets/preambles/BibPreamble.tex +++ b/Latex/assets/preambles/BibPreamble.tex @@ -4,6 +4,20 @@ %%% Setup Bibliography -\usepackage[backend=biber,autocite=inline]{biblatex} +\usepackage[ + backend=biber, + autocite=inline, + style=alphabetic, +]{biblatex} +% Simpl command to read the shell variable with my zotero bibliography +% \immediate\write18{echo $ZOTERO_BIB > \jobname.tmp} +% \CatchFileDef{\bibpath}{\jobname.tmp}{} +% Set up bibliography using the shell variable +% \addbibresource{\bibpath} + +% Manually add zotero library +\addbibresource{~/.local/state/nvim_telescope_local_search/ZoteroLibrary.bib} + +\newcommand{\authorcite}[1]{\citeauthor{#1} \cite{#1}}