Developing novel, safe, and effective pharmaceutical compounds is difficult.
Starting with challenges identifying promising treatment targets and potential compounds, to ensuring the drug can be properly delivered within the body, the scientific work that needs to go well is massive.
The regulatory and market conditions in which they exist add to this difficulty.
For example, regulations are designed to reduce the number of drugs released to market
with significan issues, such as in the case of VIOXX \cite{krumholz_whathavewe_2007}
or the Perdue Pharma scandal \cite{officepublicaffairsjusticedepartment_2020}.
These regulations, such as clinical trial standards \todo{add citation to clinical trials here},
increase the costs of developing new drugs, adding to the business conserns already present, including
competitors already in the market or close to entering and the overall demand to address a given condition.
For example, regulations are designed to reduce the number of drugs released
to market with significan issues, such as in the case of VIOXX
\cite{krumholz_whathavewe_2007}
or the Perdue Pharma scandal
\cite{officepublicaffairsjusticedepartment_2020}.
These regulations, such as clinical trial standards
\todo{add citation to clinical trials here},
increase the costs of developing new drugs, adding to the business concerns
already present, including competitors already in the market or close to
entering and the overall demand to address a given condition.
This work is the first that endeavors to separate the causal effect
of an operational concern (participant enrollment) from that of strategic
@ -20,7 +24,17 @@ on individual clinical trials.
%begin discussing failures
%I am thinking I'll discuss marketing and operational failures
%I somehow need to step away from the drug development framing and soften it to ... what? drug investigation?
%I somehow need to step away from the drug development framing and soften it to
%... what? drug investigation?
From these general challenges we can begin to classify failures in drug
% - What correlates with successfully passing clinical trials and FDA review?
% -
In \citeyear{abrantes-metz_pharmaceutical_2004},
\citeauthor{abrantes-metz_pharmaceutical_2004}
\cite{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
This descriptive estimate used a
mixed state proportional hazard model and estimated 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
Phase I and II trials, while Phase 3 trials generally have a higher rate of
success than failure after 91 months.
%DiMasi FeldmanSeckler Wilson 2009
@ -64,6 +63,16 @@ from phase III to Phase II would reduce out of pocket costs by 5.6\%.
\subsection{Market incentives and drug development}
%%%%%%%%% What do we know about drug development incentives?
\subsection{What do we know about drug development incentives?}
% Introduce section
% - Dranov et al 2022 - demand pull seems to bias follow up drug development.
% - increasing demand doesn't necessarily result in new compounds (check this). Risks.
\cite{dranove_DoesConsumer_2022} examined whether increased demand for drugs
will increase the development of novel drugs.
Using measures of the scientific novelty of drug compounds after the creation
of Medicare part D, they found that most development occurred in the least
novel categories of drugs, in spite of a relatively constant growth in novel
compounds.
\cite{dranove_DoesConsumer_2022} use the implementation of Medicare part D
to examine whether the production of novel or follow up drugs increases during
@ -78,8 +87,11 @@ follow up development.
This is what leads risk-adverse companies to prefer follow up development.
% Acemoglu and Linn
% - Market size in innovation
% - acemoglu and linn 2004 - population size matters.
% - Population ties into the number of drugs available, and operational (recruitment) concerns
% - In general, there are going to be many confounding variables.
% -
% - 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}
@ -91,6 +103,56 @@ 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.
% Cerda 2007 - Endogenous innovations in the pharmaceutical industry
% from abstract %TODO: Read better
% Market size, population, and existence of drugs are endogenous
% from the abstract I get the impresssion that it is:
% - large population -> large market -> more profitable -> more drugs
% - more drugs -> better survivability -> larger market
% Applicable because: Need to separate population and market effects.
% Does this mess with my results? I don't think so because of the relatively short time in trials. Not enough time to effect population back, but it might have another effect.
\cite{cerda_EndogenousInnovations_2007}
suggests a two-way, long term relationship between market size and drug
development.
They suggest that a large population with a condition implies a (relatively)
larger market, which improves the profitabilty and thus number of drugs with that
condition.
Then the drugs improve mortality, increasing the relative population.
They do find evidence of the impact of both population and market size
on the creation of new drugs.
% van der gronde et al 2017 Addressing the challenge of high-price prescription drugs
% Massive number of policies used to try to reduce costs. These will affect production decisions.
% Some of the unintended consequences of that (in terms of reduced development incentives) include
% - reducing development costs - side effect of lower quality evidence
% - Preference policy (e.g. policies about using generics first etc) - side effect of shorter life cycle for patented (novel) drugs.
% - these are focused on reducing expenditures, i.e. they reduce profit. Some of them feed back into the development process.
\cite{vandergronde_AddressingChallenge_2017}
documents many of the things driving drug development choices.
\begin{itemize}
\item Policies that encourage low cost generics shorten the life cycle of
patented/novel drugs.
\item Some diseases have lower safety and efficacy standards applied to them
compared to similar diseases. These tend to have higher R\&D due to the
lower costs involved.
\item As much of the "low hanging fruit" in drug development has been developed,
R\&D expenses have been increasing.
\end{itemize}
% Dubois et al 2015 - Market Size and pharmaceutical innovation
% estimate the relationship between marekt size and the innovation in pharmaceuticals
% elasticity of innovation w.r.t. expected market size of 0.23, thus $2.5 billion in
% market size required to get a new chemical entity.
\cite{dubois_MarketSize_2015}
examined the ``elasticity of innovation'', i.e. the ``additional revenue required
to support the invention of a new chemical entity.''
They found that a marginal drug will require approximately a \$2.5 billon increase
in expected revenue.
% Gupta
% - Inperfect intellectual property rights in the pharmaceutical industry
\cite{gupta_OneProduct_2020} discovered that uncertainty around which patents
@ -98,9 +160,32 @@ 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{What do we know about how Clinical Trials operations?}
%interview with Adam George
% - clinical trials are often handled by contractors
% - they plan sites, start times, etc from beginning.
% - Running late is normal.
In a personal interview with someone who works for a company that runs clinical
trials, I learned about how clinical trials will typically proceed.
\todo{Figure out best way to cite this}
\begin{itemize}
\item Quote a job (one side of company): N, timeline, etc
\item Allocate resources (sites, doctors, etc) to try to accomplish
\item Sales vs Operations conflict, leading to lateness/issues delivering, etc.
\end{itemize}
% Bess Stillman - look at difficulties joining oncology trials
% Random sample of Clinicaltrials.gov - how many closed due to operational problems?
% TODO: random sample 171, about 30% mentioned recruitment issues
% Results on enrollment projection
% - nothing really good exists.
% - Multiple models, no comparison.
% - no cross validation, only tested on a few trials.
% Thus we should look at the effects that operational concerns have.
\subsection{Understanding Failures in Drug Development}
Will King
will king