rewrote the introduction and introductory literature review. Fixed bib.
will king
1 year ago
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\documentclass[../Main.tex]{subfiles}
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\graphicspath{{\subfix{Assets/img/}}}
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\begin{document}
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In 19xx the United States Food and Drug Administration (FDA) was created to "QUOTE".
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As of Sept 2022 \todo{Check Date} they have approved 6,602 currently-marketed compounds with Structured Product Labels (SPL)
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and 10,983 previously-marketed SPLs.
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%from nsde table. Get number of unique application_nubmers_or_citations with most recent end date as null.
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In 2007, they began requiring that drug developers register and publish clinical trials on \url{https://clinicaltrials.gov}.
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This provides a public mechanism where clinical trial sponsors are responsible to explain
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what they are trying to acheive and how it will be measured, as well as provide the public the ability to
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search and find trials that they might enroll in.
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Data such as this has become part of multiple datasets
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(e.g. the Cortellis Investigational Drugs dataset or the AACT dataset from the Clinical Trials Transformation Intiative)
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used to evaluate what drugs might be entering the market soon.
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This brings up a question: can we use this public data on clinical trials to describe what effects their success or failure?
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In this work, I use updates to records on \url{https://ClinicalTrials.gov} to disentangle
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the effect of participant enrollment and drugs on the market affect the success or failure of clinical trials.
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%Describe how clinical trials fit into the drug development landscape and how they proceed
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Clinical trials are a required part of drug development.
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Not only does the FDA require that a series of clinical trials demonstrate sufficient safety and efficacy of
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a novel pharmaceutical compound or device, producers of derivative medicines may be required to ensure that
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their generic small molecule compound -- such as ibuprofen or levothyroxine -- matches the
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performance of the originiator drug if delivery or dosage is changed.
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For large molecule generics (termed biosimilars) such as Adalimumab
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(Brand name Humira, with biosimilars Abrilada, Amjevita, Cyltezo, Hadlima, Hulio,
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Hyrimoz, Idacio, Simlandi, Yuflyma, and Yusimry),
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the biosimilars are required to prove they have similar efficacy and safety to the
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reference drug.
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When registering these clinical trials
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% discuss how these are registered and what data is published.
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% Include image and discuss stages
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% Discuss challenges faced
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% Introduce my work
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In the world of drug development, these trials are classified into different
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phases of development.
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\cite{FDADrugApprovalProcess_2022}
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provide an overview of this process
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\cite{commissioner_DrugDevelopment_2020}
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while describes the actual details.
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Pre-clinical studies primarily establish toxicity and potential dosing levels
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\cite{commissioner_DrugDevelopment_2020}.
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Phase I trials are the first attempt to evaluate safety and efficacy in humans.
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Participants typically are heathy individuals, and they measure how the drug
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affects healthy bodies, potential side effects, and adjust dosing levels.
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Sample sizes are often less than 100 participants.
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\cite{commissioner_DrugDevelopment_2020}.
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Phase II trials typically involve a few hundred participants and is where
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investigators will dial in dosing, research methods, and safety.
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\cite{commissioner_DrugDevelopment_2020}.
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A Phase III trial is the final trial befor approval by the FDA, and is where
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the investigator must demonstrate safety and efficacy with a large number of
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participants, usually on the order of hundreds or thousands.
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\cite{commissioner_DrugDevelopment_2020}.
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Occassionally, a trial will be a multiphase trial, covering aspects of either
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Phases I and II or Phases II and III.
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After a successful Phase III trial, the sponsor will decide whether or not
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to submit an application for approval from the FDA.
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Before filing this application, the developer must have completed
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"two large, controlled clinical trials."
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\cite{commissioner_DrugDevelopment_2020}.
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Phase IV trials are used after the drug has recieved marketing approval to
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validate safety and efficacy in the general populace.
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Throughout this whole process, the FDA is available to assist in decisionmaking
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regarding topics such as study design, document review, and whether or not
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they should terminate the trial.
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The FDA also reserves the right to place a hold on the clinical trial for
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safety or other operational concerns, although this is rare.
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\cite{commissioner_DrugDevelopment_2020}.
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In the economics literature, most of the focus has been on evaluating how
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drug candidates transition between different phases and their probability
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of final approval.
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% Lead into lit review
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% Abrantes-Metz, Adams, Metz (2004)
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\cite{abrantes-metz_pharmaceutical_2004},
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described the relationship between
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various drug characteristics and how the drug progressed through clinical trials.
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% This descriptive estimate was notable for using a
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% mixed state proportional hazard model and estimating the impact of
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% observed characteristics in each of the three phases.
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They found that as Phase I and II trials last longer,
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the rate of failure increases.
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In contrast, Phase 3 trials generally have a higher rate of
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success than failure after 91 months.
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This may be due to the fact that the purpose of Phases I and II are different
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from the purpose of Phase III.
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Continuing on this theme,
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%DiMasi FeldmanSeckler Wilson 2009
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\cite{dimasi_TrendsRisks_2010} examine the completion rate of clinical drug
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develompent and find that for the 50 largest drug producers,
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approximately 19\% of their drugs under development between 1993 and 2004
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successfully moved from Phase I to recieving an New Drug Application (NDA)
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or Biologics License Application (BLA).
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They note a couple of changes in how drugs are developed over the years they
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study, most notably that
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drugs began to fail earlier in their development cycle in the
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latter half of the time they studied.
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They note that this may reduce the cost of new drugs by eliminating late
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and costly failures in the development pipeline.
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Earlier work by
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\authorcite{dimasi_ValueImproving_2002}
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used data on 68 investigational drugs from 10 firms to simulate how reducing
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time in development reduces the costs of developing drugs.
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He estimates that reducing Phase III of clinical trials by one year would
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reduce total costs by about 8.9\% and that moving 5\% of clinical trial failures
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from phase III to Phase II would reduce out of pocket costs by 5.6\%.
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Like much of the work in this field, the focus of the the work by
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\citeauthor{dimasi_ValueImproving_2002}
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and
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\citeauthor{dimasi_TrendsRisks_2010}
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tends to be on the drug development pipeline, i.e. the progression between
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phases and towards marketing approval.
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A key contribution to this drug development literature is the work by
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\authorcite{khmelnitskaya_CompetitionAttrition_2021}
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on a causal identification strategy
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to disentangle strategic exits from exits due to clinical failures
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in the drug development pipeline.
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She found that overall 8.4\% of all pipeline exits are due to strategic
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terminations and that the rate of new drug production would be about 23\%
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higher if those strategic terminatations were elimintated.
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The work that is closest to mine is the work by
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\authorcite{hwang_FailureInvestigational_2016}
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who investigated causes for which late stage (Phase III)
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clinical trials fail -- with a focus on trials in the USA,
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Europe, Japan, Canada, and Australia.
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They identified 640 novel therapies and then studied each therapy's
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development history, as outlined in commercial datasets.
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They found that for late stage trials that did not go on to recieve approval,
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57\% failed on efficacy grounds, 17\% failed on safety grounds, and 22\% failed
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on commercial or other grounds.
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% Begin Discussing what I do. Then introduce
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Unlike the majority of the literature, I focus on the progress of
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individual clinical trials, not on the drug development pipeline.
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In both
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\authorcite{khmelnitskaya_CompetitionAttrition_2021}
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and
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\authorcite{hwang_FailureInvestigational_2016}
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the authors describe failures due to safety, efficacy, or strategic concerns.
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There is another category of concerns that arise for individual clinical trials,
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that of operational failures.
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Operational failures can arise when a trial struggles to recruit participants,
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the principle investigator or other key member leaves for another opportunity,
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or other studies prove that the trial requires a protocol change.
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% In a personal review of 199 randomly selected clinical trials from the AACT
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% database, the
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% \begin{table}
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% \caption{}\label{tab:}
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% \begin{center}
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% \begin{tabular}[c]{|l|l|}
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% \hline
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% Reason & Percentage Mentioned \\
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% \hline
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% Safety or Efficacy & 14.5\% \\
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% Funding Problems & 9.1\% \\
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% Enrollment Issues & 31\% \\
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% \hline
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% \end{tabular}
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% \end{center}
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% \end{table}
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This paper proposes the first model to separate the causal effects of
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market conditions (a strategic concern) from the effects of
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participant enrollment (an operational concern).
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This will allow me to answer the questions:
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\begin{itemize}
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\item What is the marginal effect on trial completion of an additional
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generic drug on the market?
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\item What is the marginal effect on trial completion of a delay in
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closing enrollment?
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\end{itemize}
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To undderstand how I do this, we'll cover some background information on
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clinical trials in section \ref{SEC:ClinicalTrials},
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explain the data in section \ref{SEC:DataSources},
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and then examine causal identification and econometric model in sections
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\ref{SEC:CausalIdentificationAndModel}.
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Finally I'll review the results and conclusion in sections
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\ref{SEC:Results}
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and
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\ref{SEC:Conclusion}
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respectively
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\subsection{Market incentives and drug development}
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%%%%%%%%% What do we know about drug development incentives?
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\cite{dranove_DoesConsumer_2022} use the implementation of Medicare part D
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to examine whether the production of novel or follow up drugs increases during
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the following 15 years.
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They find that when Medicare part D was implemented -- increasing senior
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citizens' ability to pay for drugs -- there was a (delayed) increase
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in drug development, with effects concentrated among compounds that were least
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innovative according to their classification of innovations.
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They suggest that this is due to financial risk management, as novel
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pharmaceuticals have a higher probability of failure compared to the less novel
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follow up development.
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This is what leads risk-adverse companies to prefer follow up development.
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% Acemoglu and Linn
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% - Market size in innovation
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% - Exogenous demographic trends has a large impact on the entry of non-generic drugs and new molecular entitites.
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On the side of market analysis,
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\citeauthor{acemoglu_market_2004}
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(\citeyear{acemoglu_market_2004})
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used exogenous deomographics changes to show that the
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entry of novel compounds is highly driven by the underlying aged population.
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They estimate that a 1\% increase in applicable demographics increase the
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entry of new drugs by 6\%, mostly concentrated among generics.
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Among non-generics, a 1\% increase in potential market size
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(as measured by demographic groups) leads to a 4\% increase in novel therapies.
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% Gupta
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% - Inperfect intellectual property rights in the pharmaceutical industry
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\cite{gupta_OneProduct_2020} discovered that uncertainty around which patents
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might apply to a novel drug causes a delay in the entry of generics after
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the primary patent has expired.
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She found that this delay in delivery is around 3 years.
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% Agarwal and Gaule 2022
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% - Retrospective on impact from COVID-19 pandemic
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% Not in this version
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\subsection{Understanding Failures in Drug Development}
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% DISCUSS: Different types of failures
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There are myriad of reasons that a drug candidate may not make it to market,
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regardless of it's novelty or known safety.
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In this work, I focus on the failure of individual clinical trials, but the
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categories of failure apply to the individual trials as well as the entire
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drug development pipeline.
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They generally fall into one of the following categories:
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\begin{itemize}
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\item Scientific Failure: When there are issues regarding
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safety and efficacy that must be addressed.
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The preeminient question is:
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``Will the drug work for patients?''
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%E.Khm, Gupta, etc.
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\item Strategic Failure: When the sponsors stop development because of
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profitability
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%Whether or not the drug will be profitiable, or align with
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%the drug developer's future Research \& Development directions i.e.
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``Will producing the drug be beneficial to the
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company in the long term?''
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%E.Khm, Gupta, GLP-1s, etc.
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\item Operational concerns are answers to:
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%Whether or not the developer can successfully conduct
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%operations to meet scientific or strategic goals, i.e.
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``What has prevented the the company from being able to
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finance, develop, produce, and market the drug?''
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\end{itemize}
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It is likely that a drug fails to complete the development cycle due to some
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combination of these factors.
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%USE MetaBio/CalBio GLP-1 story to illuistrate these different factors.
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\cite{flier_DrugDevelopment_2024} documents the case of MetaBio, a company
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he was involved in founding that was in the first stages of
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developing a GLP-1 based drug for diabetes or obesety before being shut down
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in .
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MetaBio was a wholy owned subsidiary of CalBio, a metabolic drug development
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firm, that recieved a \$30 million -- 5 year investment from Pfizer to
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persue development of GLP-1 based therapies.
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At the time it was shut down, it faced a few challenges:
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\begin{itemize}
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\item The compound had a short half life and they were seeking methods to
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improve it's effectiveness; a scientific failure.
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\item Pfizer imposed a requirement that it be delivered though a route
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other than injection (the known delivery mechanism); a strategic failure.
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\item When Pfizer pulled the plug, CalBio closed MetaBio because they
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could not find other funding sources; an operational failure.
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\end{itemize}
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The author states in his conclusion:
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\begin{displayquote}
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Despite every possibility of success,
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MetaBio went down because there were mistaken ideas about what was
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possible and what was not in the realm of metabolic therapeutics, and
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because proper corporate structure and adequate capital are always
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issues when attempting to survive predictable setbacks.
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\end{displayquote}
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From this we see that there was a cascade of issues leading to the failure to
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develop this novel drug.
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% I don't think I need to include modelling enrollment here.
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% If it is applicable, it can show up in those sections later.
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\end{document}
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