JobMarketPaper/Latex/Paper/sections/05_LitReview.tex

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% TODO:
%Need to distinguish that this isn't about drug development specifically, but 
% more around clinical trials progress.
% Thoughts:
% - What types of failures do clinical trials have an why do clinical trials fail? 
%   - What is cited in termination reasons?
%   - Discussion on different types of failures: 
%       1. Failure to find safe and effective drug
%       2. Failure to collect enough information to determine 1
%           - recruiting
%           - New information (other studies, changes in standards of care, etc)
%       3. Failure due to other operational/strategic concern.
%           - Issues with PI/Sponsors
%           - profitability expectations
%           - Financial support
% Trials can fail due to issues in one of four categories
% - Scientific: The compound-indication combo is not sufficiently safe or efficatious
% - Strategic: The result from the trial won't meet the company's strategic needs. Profitability for the most part or entry into a drug category they don't want to invest in.
% - Operational: They can't bring resources to bear to achieve goal, e.g. site planning, PI's, delivering enough financial support, etc.
% - Tactical: The plans to discover if the approach is scientifically valid are insufficient. Study design, enrollment strategies, etc.

% The literature examines many different aspects of these.
% strategic influences: elasticicity of innovation, demand pull, patents, etc
% Strategic vs scientific khmelniskaya, hwang.
% operational: Adam George Interview
% tactical: enrollment prediction.


% - Discuss how most studies are about clinical trials as part of the drug development pipeline.
% - Review what we know about causes for failure. 
%   - Things that correlate with failures. (adams) 
%   - Causes for failure (khmelnitskaya & hwang)
% - Then talk about studies on clinical trials themselves. 
%   - Interview with Adam George
%   - Poor studies of enrollment prediction.
%   - 
% - Then talk about what drives approvals/clinical trial activity for drugs
%   - Elasticity of innovation
%   - No demand pull for novel drugs, but yes for derivatives
%   - Population and Market size interact & drive development (jointly determined)
%       - This doesn't apply to single trials though
%   - 
% - Sumarize
%   - Thus when trying to study what affects clinical trials we must separate
%       - Market & competition effects
%       - Population effects
%       - Multiple trial failure modes (safety & efficacy, Operational etc)
%       - 
%   - 

This paper sits within an intersection of health and industrial organization economics
that is frequently studied.
Encouraging a strong supply of novel and generic pharmaceuticals contributes 
in important ways to both public health and fiscal policy.
Not only to the pathway to drug approval long, as many as 90\% of compounds
that begin human trials fail to gain approval 
(\cite{khmelnitskaya_competition_2021}).
Complicating this is the complex regulatory and competitive environment in
which pharmaceutical companies operate. 

%%%%%%%%% Why are drugs so expensive?

% van der Grond, Uyle-de Groot, Pieters 2017
% - What causes high costs of drugs? 
% - High level synthesis of discussion regarding causes
% - Academic and non-academic sources
% Not particularly applicable

%%%%%%%%%%%%%%%% What do we know about clinical trials?

% Hwang, Carpenter, Lauffenburger, et al (2016)
% - Why do investigational new drugs fail during late stage trials?
\citeauthor{hwang_failure_2016} (\citeyear{hwang_failure_2016}) 
investigated causes for which late stage (Phase III)
clinical trials fail across the USA, Europe, Japan, Canada, and Australia. 
They found that for late stage trials that did not go on to recieve approval,
57\% failed on efficacy grounds, 17\% failed on safety grounds, and 22\% failed
on commercial or other grounds.
For context, this current work hopes to be able to distinguish some of the 
mechanisms behind those commercial or other failures.

% Abrantes-Metz, Adams, Metz (2004)
% - What correlates with successfully passing clinical trials and FDA review?
% - 
In \citeyear{abrantes-metz_pharmaceutical_2004}, 
\citeauthor{abrantes-metz_pharmaceutical_2004} 
described the relationship between
various drug characteristics and how the drug progressed through clinical trials.
This non-causal 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 trials last longer, the rate of failure increases for
Phase I \& II trials, while Phase 3 trials generally have a higher rate of 
success than failure after 91 months.

% Ekaterina Khmelnitskaya (2021)
% - separates scientific from market failure of the clinical drug pipeline
In her doctoral dissertation, Ekaterina Khmelnitskaya studied the transition of
drug candidates between clinical trial phases. 
Her key contribution was to find ways to disentangle strategic exits from the 
development pipeline and exits due to clinical failures.
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
(\cite{khmelnitskaya_competition_2021}).
% causal separation of strategic exits etc.

% Waring, Arrosmith, Leach, et al (2015)
% - Atrition of drug candidates from four major pharma companies
% - Looked at how phisicochemical properties affected clinical failure due to safety issues
% not Applicable in this version




%%%%%%%%% What do we know about drug development incentives?

% Dranov, Garthwaite, and Hermosilla (2022)
% - does the demand-pull theory of R&D explain novel compound development?
% - no, it is biased towards follow-on drug R&D.
% TODO

% Acemoglu and Linn
% - Market size in innovation
% - Exogenous demographic trends has a large impact on the entry of non-generic drugs and new molecular entitites.
On the side of market analysis, %TODO:remove when other sections are written up.
\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 averages around 3 years. 

% Agarwal and Gaule 2022
% - Retrospective on impact from COVID-19 pandemic
% Not in this version

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