edited intro with claude.ai and spellchecked some stuff
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 1938, President Franklin D.
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Roosevelt signed the Food, Drug, and Cosmetic Act, establishing the Food and
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Drug Administration's (FDA) authority to require pre-market approval of
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pharmaceuticals [Com14].
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This created a regulatory framework where pharmaceutical companies must
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demonstrate safety and efficacy through clinical trials before bringing drugs
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to market.
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The costs of these trials - both in time and money - form a significant barrier
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to entry in pharmaceutical markets.
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Understanding what causes clinical trials to fail is therefore crucial to
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predict the impact of policies, intended or unintended.
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Existing research has examined how drugs progress through development
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pipelines, but we know relatively little about the relative contribution of different
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challenges to the early termination of clinical trials.
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%HWANG et al do discuss a few different reasons
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When a trial terminates early due to operational challenges rather than safety
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or efficacy concerns, potentially effective treatments may be delayed or
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abandoned entirely.
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%Example of GLP-1s
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This paper provides the first empirical framework to separate
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market-driven and safety/efficacy based terminations from
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one form of operational failure
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-- enrollment challenges --
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in Phase III clinical trials.
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Using a novel dataset constructed from administrative data registered on
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ClinicalTrials.gov, I exploit variation in enrollment timing and market
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conditions to identify how extending the enrollment period affects trial completion.
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Specifically, I answer the question:
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\textit{
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``How does the probability of trial termination change
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when the enrollment period is extended?''
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}
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This approach differs from previous work that focuses for the most part
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on the drug development
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pipeline and progression between clinical trial phases.
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% In 1938 President Franklin D Rosevelt signed the Food, Drug, and Cosmetic Act,
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% granting the Food and Drug Administration (FDA) authority to require
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% pre-market approval of pharmaceuticals.
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% \cite{commissioner_milestonesusfood_2023}
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% As of Sept 2022 \todo{Check Date} they have approved 6,602 currently-marketed
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% compounds with Structured Product Labels (SPLs)
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% and 10,983 previously-marketed SPLs
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% \cite{commissioner_nsde_2024},
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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 1999, they began requiring that drug developers register and
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% publish clinical trials on \url{https://clinicaltrials.gov}.
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% This provides a public mechanism where clinical trial sponsors are
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% responsible to explain what they are trying to acheive and how it will be
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% measured, as well as provide the public the ability to search and find trials
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% that they might enroll in.
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% Multiple derived datasets such as the Cortellis Investigational Drugs dataset
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% or the AACT dataset from the Clinical Trials Transformation Intiative
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% integrate these data.
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% This brings up a question:
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% Can we use this public data on clinical trials to identify what effects the
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% success or failure of trials?
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% In this work, I use updates to records on
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% \url{https://ClinicalTrials.gov}
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% to do exactly that, disentangle the effect of participant enrollment
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% and competing drugs on the market affect the success or failure of
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% clinical trials.
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\subsection{Background}
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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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%TODO? Decide whether to include this or not
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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\footnote{
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\cite{anderson_fdadrugapproval_2022}
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provide an overview of this process
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while
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\cite{commissioner_drugdevelopmentprocess_2020}
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describes the process in detail.}.
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Pre-clinical studies primarily establish toxicity and potential dosing levels.
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% \cite{commissioner_drugdevelopmentprocess_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 healthy 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_drugdevelopmentprocess_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_drugdevelopmentprocess_2020}.
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A Phase III trial is the final trial before 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_drugdevelopmentprocess_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_drugdevelopmentprocess_2020}.
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Phase IV trials are used after the drug has received 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 decision-making
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regarding topics such as study design, document review, and whether
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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_drugdevelopmentprocess_2020}.
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In the economics literature, most of the focus has been on describing 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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\authorcite{abrantes-metz_pharmaceuticaldevelopmentphases_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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\authorcite{dimasi_trendsrisksassociated_2010}
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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_valueimprovingproductivity_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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A key contribution to this drug development literature is the work by
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\authorcite{khmelnitskaya_competitionattritiondrug_2021}
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who created 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_failureinvestigationaldrugs_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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Unfortunately the work of both
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\authorcite{hwang_failureinvestigationaldrugs_2016}
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and
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\authorcite{khmelnitskaya_competitionattritiondrug_2021}
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ignore a potentially large cause of failures: operational challenges, i.e. when
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issues running or funding the trial cause it to fail before achieving its
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primary objective.
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In a personal review of 199 randomly selected clinical trials which terminated
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before achieving their primary objective,
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I found that
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14.5\% cited safety or efficacy concerns,
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9.1\% cited funding problems (an operational concern),
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and
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31\% cited enrollment issues (a separate operational concern)\footnote{
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Note that these figures differ from
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\authorcite{hwang_failureinvestigationaldrugs_2016}
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because I sampled from all stages of trials, not just Phase III trials
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focused on drug development.
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}.
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The main contribution of this work is the model I develop to separate
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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) on Phase III Clinical trials.
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This allows me to answer the question posed earlier:
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\textit{
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``How does the probability of trial termination change
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when the enrollment period is extended?''
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}
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using administrative data.
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To understand how I do this, we'll cover some background information on
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clinical trials and the administrative data I collected in section
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\ref{SEC:ClinicalTrials},
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explain the approach to causal identification, the required data,
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and describe how the data used matches these requirements in section
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\ref{SEC:CausalAndData}.
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Then we'll cover the econometric model
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(section \ref{SEC:EconometricModel})
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and results (section
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\ref{SEC:Results}).
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Finally, we acknowledge deficiencies in the analysis and potential improvements
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in section
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\ref{SEC:Improvements},
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then end with my thoughts in the conclusion \ref{SEC:Conclusion}
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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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%
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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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%
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%
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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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%
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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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%
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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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%
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% \subsection{Understanding Failures in Drug Development}
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%
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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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%
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%
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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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%
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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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%
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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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%
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%
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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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%
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%
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\end{document}
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@ -0,0 +1,114 @@
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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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% Clinical Trials Background Outline
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% - ClinicalTrials.gov
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% - Clincial trial progression
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% -
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% -
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% -
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% -
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% -
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% -
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% -
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To understand how my administrative clinical trial data is obtained
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and what it can be used for,
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let's take a look at how trial investigators record data on
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\url{ClinicalTrials.gov}.
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Figure \ref{Fig:Stages} illuistrates the process I describe below.
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During the Pre-Trial period the trial investigators will design the trial,
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choose primary and secondary objectives,
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and decide on how many participants they need to enroll.
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Once they have decided on these details, they post the trial to \url{ClinicalTrials.com}
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and decide on a date to begin enrolling trial participants.
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If the investigators decide to not continue with the trial before enrolling any participants,
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the trial is marked as ``Withdrawn''.
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On the other hand, if they begin enrolling participants, there are two methods to do so.
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The first is to enter a general ``Recruiting'' state, where patients attempt to enroll.
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The second is to enter an "Enrollment by invitation only" state.
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After a trial has enrolled their participants, they wil typically move to an
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"Active, not recruiting" state to inform potential participants that they are
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not recruiting.
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Finally, when the investigators have obtained enough data to achieve their primary
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objective, the clinical trial will be closed, and marked as ``Completed'' in
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\url{ClinicalTrials.gov}
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If the trial is closed before achieving the primary objective, the trial is
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marked as ``Terminated'' on
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\url{ClinicalTrials.gov}.
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\begin{figure}%[H] %use [H] to fix the figure here.
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\includegraphics[width=\textwidth]{../assets/img/ClinicalTrialStagesAndStatuses}
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\par \small
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Diamonds represent decision points while
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Squares represent states of the clinical trial and Rhombuses represend data obtained by the trial.
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\caption[Clinical Trial Stages and Progression]{Clinical Trial Stages and Progression}
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\label{Fig:Stages}
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\end{figure}
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Note the information we obtain about the trial from the final status:
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``Withdrawn'', ``Terminated'', or ``Completed''.
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Although
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\cite{khmelnitskaya_competitionattritiondrug_2021}
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describes a clinical failure due to safety or efficacy as a
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\textit{scientific} failure, it is better described as a compound failure.
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Discovering that a compound doesn't work as hoped is not a failure but the whole
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purpose of the clinical trials process.
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On the other hand, when a trial terminates early due to reasons
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other than safety or efficacy concerns, the trial operator does not learn
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if the drug is effective or safe.
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This is a knowledge-gathering failure where the trial operator
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did not learn if the drug was effective or not.
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I prefer describing a clinical trial as being terminated for
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\begin{itemize}
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\item Safety or Efficacy concerns
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\item Strategic concerns
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\item Operational concerns.
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\end{itemize}
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Unfortunately it can be difficult to know why a given trial was terminated,
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in spite of the fact that upon termination, trials typically record a
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description of \textit{a single} reason for the clinical trial termination.
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This doesn't necessarily list all the reasons contributing to the trial termination and may not exist for a given trial.
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For example, if a Principle Investigator leaves for another institution
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(terminating the trial), is this decison affected by
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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}
|
||||
Loading…
Reference in New Issue