From 12007e6689fd5e1822d8d7bee681522552367ff2 Mon Sep 17 00:00:00 2001 From: Will King Date: Sat, 25 Jan 2025 07:11:19 -0800 Subject: [PATCH] edited intro with claude.ai and spellchecked some stuff --- Paper/Main.tex | 2 +- Paper/sections/11_intro_and_lit.tex | 205 +++++----- Paper/sections/11_intro_and_lit.tex.bak | 352 ++++++++++++++++++ .../sections/12_clinical_trial_background.tex | 12 +- .../12_clinical_trial_background.tex.bak | 114 ++++++ 5 files changed, 589 insertions(+), 96 deletions(-) create mode 100644 Paper/sections/11_intro_and_lit.tex.bak create mode 100644 Paper/sections/12_clinical_trial_background.tex.bak diff --git a/Paper/Main.tex b/Paper/Main.tex index ba77a1b..b8e498c 100644 --- a/Paper/Main.tex +++ b/Paper/Main.tex @@ -57,7 +57,7 @@ completion of clinical trials\\ \small{Preliminary Draft}} %--------------------------------------------------------------- -\section{Causal Story and Data}\label{SEC:Data} +\section{Causal Story and Data}\label{SEC:CausalAndData} %--------------------------------------------------------------- \subfile{sections/10_CausalStory} \subfile{sections/02_data} diff --git a/Paper/sections/11_intro_and_lit.tex b/Paper/sections/11_intro_and_lit.tex index 3528264..1bb009f 100644 --- a/Paper/sections/11_intro_and_lit.tex +++ b/Paper/sections/11_intro_and_lit.tex @@ -3,39 +3,81 @@ \begin{document} -In 1938 President Franklin D Rosevelt signed the Food, Drug, and Cosmetic Act, -granting the Food and Drug Administration (FDA) authority to require -pre-market approval of pharmaceuticals. -\cite{commissioner_milestonesusfood_2023} -As of Sept 2022 \todo{Check Date} they have approved 6,602 currently-marketed -compounds with Structured Product Labels (SPLs) -and 10,983 previously-marketed SPLs -\cite{commissioner_nsde_2024}, -%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 -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. -Multiple derived datasets such as the Cortellis Investigational Drugs dataset -or the AACT dataset from the Clinical Trials Transformation Intiative -integrate these data. -This brings up a question: -Can we use this public data on clinical trials to identify what effects the -success or failure of trials? -In this work, I use updates to records on -\url{https://ClinicalTrials.gov} -to do exactly that, disentangle the effect of participant enrollment -and competing drugs on the market affect the success or failure of -clinical trials. +In 1938, President Franklin D. +Roosevelt signed the Food, Drug, and Cosmetic Act, establishing the Food and +Drug Administration's (FDA) authority to require pre-market approval of +pharmaceuticals [Com14]. +This created a regulatory framework where pharmaceutical companies must +demonstrate safety and efficacy through clinical trials before bringing drugs +to market. +The costs of these trials - both in time and money - form a significant barrier +to entry in pharmaceutical markets. +Understanding what causes clinical trials to fail is therefore crucial to +predict the impact of policies, intended or unintended. + +Existing research has examined how drugs progress through development +pipelines, but we know relatively little about the relative contribution of different +challenges to the early termination of clinical trials. +%HWANG et al do discuss a few different reasons +When a trial terminates early due to operational challenges rather than safety +or efficacy concerns, potentially effective treatments may be delayed or +abandoned entirely. +%Example of GLP-1s + +This paper provides the first empirical framework to separate +market-driven and safety/efficacy based terminations from +one form of operational failure +-- enrollment challenges -- +in Phase III clinical trials. +Using a novel dataset constructed from administrative data registered on +ClinicalTrials.gov, I exploit variation in enrollment timing and market +conditions to identify how extending the enrollment period affects trial completion. +Specifically, I answer the question: +\textit{ + ``How does the probability of trial termination change + when the enrollment period is extended?'' +} +This approach differs from previous work that focuses for the most part +on the drug development +pipeline and progression between clinical trial phases. + + + +% In 1938 President Franklin D Rosevelt signed the Food, Drug, and Cosmetic Act, +% granting the Food and Drug Administration (FDA) authority to require +% pre-market approval of pharmaceuticals. +% \cite{commissioner_milestonesusfood_2023} +% As of Sept 2022 \todo{Check Date} they have approved 6,602 currently-marketed +% compounds with Structured Product Labels (SPLs) +% and 10,983 previously-marketed SPLs +% \cite{commissioner_nsde_2024}, +% %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 +% 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. +% Multiple derived datasets such as the Cortellis Investigational Drugs dataset +% or the AACT dataset from the Clinical Trials Transformation Intiative +% integrate these data. +% This brings up a question: +% Can we use this public data on clinical trials to identify what effects the +% success or failure of trials? +% In this work, I use updates to records on +% \url{https://ClinicalTrials.gov} +% to do exactly that, disentangle the effect of participant enrollment +% and competing drugs on the market affect the success or failure of +% clinical trials. + +\subsection{Background} %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. +performance of the originator 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), @@ -51,45 +93,44 @@ reference drug. % Introduce my work In the world of drug development, these trials are classified into different -phases of development. +phases of development\footnote{ \cite{anderson_fdadrugapproval_2022} provide an overview of this process while \cite{commissioner_drugdevelopmentprocess_2020} -describes the actual details. -Pre-clinical studies primarily establish toxicity and potential dosing levels -\cite{commissioner_drugdevelopmentprocess_2020}. +describes the process in detail.}. +Pre-clinical studies primarily establish toxicity and potential dosing levels. +% \cite{commissioner_drugdevelopmentprocess_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 +Participants typically are healthy 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_drugdevelopmentprocess_2020}. +% \cite{commissioner_drugdevelopmentprocess_2020}. Phase II trials typically involve a few hundred participants and is where investigators will dial in dosing, research methods, and safety. -\cite{commissioner_drugdevelopmentprocess_2020}. -A Phase III trial is the final trial befor approval by the FDA, and is where +% \cite{commissioner_drugdevelopmentprocess_2020}. +A Phase III trial is the final trial before 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_drugdevelopmentprocess_2020}. -Occassionally, a trial will be a multiphase trial, covering aspects of either +% \cite{commissioner_drugdevelopmentprocess_2020}. +Occasionally, a trial will be a multi-phase 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_drugdevelopmentprocess_2020}. -Phase IV trials are used after the drug has recieved marketing approval to +``two large, controlled clinical trials.'' +% \cite{commissioner_drugdevelopmentprocess_2020}. +Phase IV trials are used after the drug has received 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 +Throughout this whole process, the FDA is available to assist in decision-making +regarding topics such as study design, document review, and whether 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_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 describing how drug candidates transition between different phases and their probability of final approval. % Lead into lit review @@ -111,9 +152,9 @@ Continuing on this theme, %DiMasi FeldmanSeckler Wilson 2009 \authorcite{dimasi_trendsrisksassociated_2010} examine the completion rate of clinical drug -develompent and find that for the 50 largest drug producers, +development 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) +successfully moved from Phase I to receiving 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 @@ -130,20 +171,14 @@ 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 -\authorcite{dimasi_valueimprovingproductivity_2002} -and -\authorcite{dimasi_trendsrisksassociated_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_competitionattritiondrug_2021} -on a causal identification strategy +who created 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. +higher if those strategic terminatations were eliminated. The work that is closest to mine is the work by \authorcite{hwang_failureinvestigationaldrugs_2016} @@ -152,59 +187,51 @@ 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, +They found that for late stage trials that did not go on to receive 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_competitionattritiondrug_2021} +Unfortunately the work of both +\authorcite{hwang_failureinvestigationaldrugs_2016} and +\authorcite{khmelnitskaya_competitionattritiondrug_2021} +ignore a potentially large cause of failures: operational challenges, i.e. when +issues running or funding the trial cause it to fail before achieving its +primary objective. +In a personal review of 199 randomly selected clinical trials which terminated +before achieving their primary objective, +I found that +14.5\% cited safety or efficacy concerns, +9.1\% cited funding problems (an operational concern), +and +31\% cited enrollment issues (a separate operational concern)\footnote{ +Note that these figures differ from \authorcite{hwang_failureinvestigationaldrugs_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 principal investigator or other key member leaves for another opportunity, -or other studies prove that the trial requires a protocol change. +because I sampled from all stages of trials, not just Phase III trials +focused on drug development. +}. -% 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 +The main contribution of this work is the model I develop to separate +the causal effects of market conditions (a strategic concern) from the effects of participant enrollment (an operational concern) on Phase III Clinical trials. -This allows me to answer the question +This allows me to answer the question posed earlier: \textit{ ``How does the probability of trial termination change when the enrollment period is extended?'' } using administrative data. + + To understand how I do this, we'll cover some background information on clinical trials and the administrative data I collected in section \ref{SEC:ClinicalTrials}, -explain the approach to causal identification strategy and the required data in section -\ref{SEC:Data}, +explain the approach to causal identification, the required data, and describe how the data used matches these requirements in section -\ref{SEC:}. +\ref{SEC:CausalAndData}. Then we'll cover the econometric model (section \ref{SEC:EconometricModel}) and results (section @@ -212,7 +239,7 @@ and results (section Finally, we acknowledge deficiencies in the analysis and potential improvements in section \ref{SEC:Improvements}, -then summarize everything in the conclusion \ref{SEC:Conclusion} +then end with my thoughts in the conclusion \ref{SEC:Conclusion} % \subsection{Market incentives and drug development} % %%%%%%%%% What do we know about drug development incentives? diff --git a/Paper/sections/11_intro_and_lit.tex.bak b/Paper/sections/11_intro_and_lit.tex.bak new file mode 100644 index 0000000..087b06b --- /dev/null +++ b/Paper/sections/11_intro_and_lit.tex.bak @@ -0,0 +1,352 @@ +\documentclass[../Main.tex]{subfiles} +\graphicspath{{\subfix{Assets/img/}}} + +\begin{document} + +In 1938, President Franklin D. +Roosevelt signed the Food, Drug, and Cosmetic Act, establishing the Food and +Drug Administration's (FDA) authority to require pre-market approval of +pharmaceuticals [Com14]. +This created a regulatory framework where pharmaceutical companies must +demonstrate safety and efficacy through clinical trials before bringing drugs +to market. +The costs of these trials - both in time and money - form a significant barrier +to entry in pharmaceutical markets. +Understanding what causes clinical trials to fail is therefore crucial to +predict the impact of policies, intended or unintended. + +Existing research has examined how drugs progress through development +pipelines, but we know relatively little about the relative contribution of different +challenges to the early termination of clinical trials. +%HWANG et al do discuss a few different reasons +When a trial terminates early due to operational challenges rather than safety +or efficacy concerns, potentially effective treatments may be delayed or +abandoned entirely. +%Example of GLP-1s + +This paper provides the first empirical framework to separate +market-driven and safety/efficacy based terminations from +one form of operational failure +-- enrollment challenges -- +in Phase III clinical trials. +Using a novel dataset constructed from administrative data registered on +ClinicalTrials.gov, I exploit variation in enrollment timing and market +conditions to identify how extending the enrollment period affects trial completion. +Specifically, I answer the question: +\textit{ + ``How does the probability of trial termination change + when the enrollment period is extended?'' +} +This approach differs from previous work that focuses for the most part +on the drug development +pipeline and progression between clinical trial phases. + + + +% In 1938 President Franklin D Rosevelt signed the Food, Drug, and Cosmetic Act, +% granting the Food and Drug Administration (FDA) authority to require +% pre-market approval of pharmaceuticals. +% \cite{commissioner_milestonesusfood_2023} +% As of Sept 2022 \todo{Check Date} they have approved 6,602 currently-marketed +% compounds with Structured Product Labels (SPLs) +% and 10,983 previously-marketed SPLs +% \cite{commissioner_nsde_2024}, +% %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 +% 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. +% Multiple derived datasets such as the Cortellis Investigational Drugs dataset +% or the AACT dataset from the Clinical Trials Transformation Intiative +% integrate these data. +% This brings up a question: +% Can we use this public data on clinical trials to identify what effects the +% success or failure of trials? +% In this work, I use updates to records on +% \url{https://ClinicalTrials.gov} +% to do exactly that, disentangle the effect of participant enrollment +% and competing drugs on the market affect the success or failure of +% clinical trials. + +\subsection{Background} + +%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. + +%TODO? Decide whether to include this or not +%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\footnote{ +\cite{anderson_fdadrugapproval_2022} +provide an overview of this process +while +\cite{commissioner_drugdevelopmentprocess_2020} +describes the process in detail.}. +Pre-clinical studies primarily establish toxicity and potential dosing levels. +% \cite{commissioner_drugdevelopmentprocess_2020}. +Phase I trials are the first attempt to evaluate safety and efficacy in humans. +Participants typically are healthy 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_drugdevelopmentprocess_2020}. +Phase II trials typically involve a few hundred participants and is where +investigators will dial in dosing, research methods, and safety. +% \cite{commissioner_drugdevelopmentprocess_2020}. +A Phase III trial is the final trial before 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_drugdevelopmentprocess_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_drugdevelopmentprocess_2020}. +Phase IV trials are used after the drug has received marketing approval to +validate safety and efficacy in the general populace. +Throughout this whole process, the FDA is available to assist in decision-making +regarding topics such as study design, document review, and whether +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_drugdevelopmentprocess_2020}. + + +In the economics literature, most of the focus has been on describing how +drug candidates transition between different phases and their probability +of final approval. +% Lead into lit review +% Abrantes-Metz, Adams, Metz (2004) +\authorcite{abrantes-metz_pharmaceuticaldevelopmentphases_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 +\authorcite{dimasi_trendsrisksassociated_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_valueimprovingproductivity_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\%. + +A key contribution to this drug development literature is the work by +\authorcite{khmelnitskaya_competitionattritiondrug_2021} +who created 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_failureinvestigationaldrugs_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. + +Unfortunately the work of both +\authorcite{hwang_failureinvestigationaldrugs_2016} +and +\authorcite{khmelnitskaya_competitionattritiondrug_2021} +ignore a potentially large cause of failures: operational challenges, i.e. when +issues running or funding the trial cause it to fail before achieving its +primary objective. +In a personal review of 199 randomly selected clinical trials which terminated +before achieving their primary objective, +I found that +14.5\% cited safety or efficacy concerns, +9.1\% cited funding problems (an operational concern), +and +31\% cited enrollment issues (a separate operational concern)\footnote{ +Note that these figures differ from +\authorcite{hwang_failureinvestigationaldrugs_2016} +because I sampled from all stages of trials, not just Phase III trials +focused on drug development. +}. + + + + +The main contribution of this work is the model I develop to separate +the causal effects of +market conditions (a strategic concern) from the effects of +participant enrollment (an operational concern) on Phase III Clinical trials. +This allows me to answer the question posed earlier: +\textit{ + ``How does the probability of trial termination change + when the enrollment period is extended?'' +} +using administrative data. + + +To understand how I do this, we'll cover some background information on +clinical trials and the administrative data I collected in section +\ref{SEC:ClinicalTrials}, +explain the approach to causal identification, the required data, +and describe how the data used matches these requirements in section +\ref{SEC:CausalAndData}. +Then we'll cover the econometric model +(section \ref{SEC:EconometricModel}) +and results (section +\ref{SEC:Results}). +Finally, we acknowledge deficiencies in the analysis and potential improvements +in section +\ref{SEC:Improvements}, +then end with my thoughts in the conclusion \ref{SEC:Conclusion} + +% \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/Paper/sections/12_clinical_trial_background.tex b/Paper/sections/12_clinical_trial_background.tex index c750a2e..c5ea257 100644 --- a/Paper/sections/12_clinical_trial_background.tex +++ b/Paper/sections/12_clinical_trial_background.tex @@ -17,8 +17,8 @@ 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} operate. -Figure \ref{Fig:Stages} illuistrates the process I describe below. +\url{ClinicalTrials.gov}. +Figure \ref{Fig:Stages} illustrates the process I describe below. 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. @@ -29,7 +29,7 @@ the trial is marked as ``Withdrawn''. On the other hand, if they begin enrolling participants, there are two methods to do so. The first is to enter a general ``Recruiting'' state, where patients attempt to enroll. The second is to enter an "Enrollment by invitation only" state. -After a trial has enrolled their participants, they wil typically move to an +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. Finally, when the investigators have obtained enough data to achieve their primary @@ -44,7 +44,7 @@ marked as ``Terminated'' on \includegraphics[width=\textwidth]{../assets/img/ClinicalTrialStagesAndStatuses} \par \small Diamonds represent decision points while - Squares represent states of the clinical trial and Rhombuses represend data obtained by the trial. + 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} @@ -74,10 +74,10 @@ 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 Principle Investigator leaves for another institution -(terminating the trial), is this decison affected by +(terminating the trial), is this decision affected by a safety or efficacy concern, a new competitor on the market, -difficulting recruiting participants, +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. diff --git a/Paper/sections/12_clinical_trial_background.tex.bak b/Paper/sections/12_clinical_trial_background.tex.bak new file mode 100644 index 0000000..a57043e --- /dev/null +++ b/Paper/sections/12_clinical_trial_background.tex.bak @@ -0,0 +1,114 @@ +\documentclass[../Main.tex]{subfiles} +\graphicspath{{\subfix{Assets/img/}}} + +\begin{document} + +% Clinical Trials Background Outline +% - ClinicalTrials.gov +% - Clincial trial progression +% - +% - +% - +% - +% - +% - +% - + +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} illuistrates the process I describe below. +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''. +On the other hand, if they begin enrolling participants, there are two methods to do so. +The first is to enter a general ``Recruiting'' state, where patients attempt to enroll. +The second is to enter an "Enrollment by invitation only" state. +After a trial has enrolled their participants, they wil typically move to an +"Active, not recruiting" state to inform potential participants that they are +not recruiting. +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}. + + +\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 represend 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''. +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 where the trial operator +did not learn if the drug was effective or not. +I prefer describing a clinical trial as being terminated for +\begin{itemize} + \item Safety or Efficacy concerns + \item Strategic concerns + \item Operational concerns. +\end{itemize} + +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 Principle Investigator leaves for another institution +(terminating the trial), is this decison affected by +a safety or efficacy concern, +a new competitor on the market, +difficulting 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. +For this reason, I use clinical trial progression to estimate effects. +\todo{not sure if this is the best place for this.} + +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 tends to include 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, +the experimental arms 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. + + + +% - +% - +% - +% - +% - +% - + + +\end{document}