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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


% - 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)
%       - 
%   - 

% 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.

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

\subsection{Understanding Failure Modes}

% 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.


% 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
% Possibly Applicable in this version




\subsection{What about incentives?}
%%%%%%%%% 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
\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

%DiMasi FeldmanSeckler Wilson 2009
\cite{dimasi_TrendsRisks_2010} examine the completion rate of clinical drug 
develompent and find that for the 50 largest drug producers, 
approximately X\% of their drugs under developm
successfully completed the process. 
They note a couple of changes in how drugs are developed over the years they 
study (clinical development started between 1993 and 2004). 
This included that drugs began to fail earlier in their development cycle in the 
latter half of the time they studied. 
This may be an operational change to reduce the cost of new drugs. 

\cite{dimasi_ValueImproving_2002}
used data on 68 investigational drugs from 10 firms to simulate how reducing
time in development adds to the 

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