DE-RISKING PRECLINICAL DEVELOPMENT - THE EMERGENCE OF THE CONTRACT VIVARIUM - MISPRO BIOTECH SERVICES - Mispro ...
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DE-RISKING
PRECLINICAL
DEVELOPMENT
THE EMERGENCE OF THE
CONTRACT VIVARIUM
MISPRO BIOTECH SERVICES
©FEBRUARY 2021Executive Summary
R
ecent studies examining success rates of drug development in the
biopharmaceutical industry have reported that about 50% of all
drugs brought to clinical trials fail due to the inability of independent
labs to reproduce efficacy as demonstrated in preclinical trials.(4) At a cost
estimate of approximately $28 Billion(2) in failed clinical trials, the industry
has taken notice and even qualified the trend as a crisis. More specifically,
as the ‘reproducibility crisis’.
This reproducibility crisis was enough for AstraZeneca, one of the world’s
leading pharmaceutical companies, to take a closer look at its R&D processes
with the goal of improving reproducibility in clinical trials. Their investigation
noted that speed-to-market was outweighing truth-seeking in preclinical
studies, which was impacting data validation in early-stages and, thus,
reproducibility in clinical. As a response,
THE CONTRACT VIVARIUM AstraZeneca introduced a ‘5R’s’ Framework’
(3)
for its preclinical drug development that
(CV) MODEL OFFERS EARLY-
positively impacted both productivity and
STAGE BIOTECHS A RISK- shareholder confidence.
ADVERSE, HIGH-POTENTIAL
But for early- to mid-stage biotechs who
STRATEGY FOR DRUG rely on incremental funding to scale through
DEVELOPMENT. preclinical stages and who in most cases do
not have access to the research facilities and
infrastructure of an established pharmaceutical company, bringing a drug
to market is even more perilous. If they’ve made it to clinical, odds are, they
are laying it all on the table — funding, safety and efficacy validation, and in
many cases, the future of the company itself. It’s risky business.
So how can emerging biotechs take a page from AZ’s ‘5R’s Framework’
to increase productivity in preclinical, especially without access to the
facilities and infrastructure enjoyed by major biopharma companies?
In this paper we propose a 6th ‘R’, which is that of the ‘Right Control’. The
Contract Vivarium (CV) model offers early-stage biotechs a risk-adverse,
high-potential strategy for drug development by giving them access
to the facilities and infrastructure required to conduct in vivo studies,
thereby giving them control, which increases productivity in preclinical
and minimizes risk of failed clinical trials.
2 Mispro Biotech Services ©2021CONTENT
2 EXECUTIVE SUMMARY
SETTING THE STAGE
4 THE REPRODUCIBILITY CRISIS
A $28 Billion problem for drug development
5 ASTRAZENECA’S 5R’S FRAMEWORK FOR INCREASED
PRODUCTIVITY
6 THE IMPACT OF AZ’S 5R’S FRAMEWORK
7 THE SILENT 6TH R FOR BIOTECH STARTUPS: THE RIGHT
CONTROL
8 HOW THE CV ENABLES CONTROL: OPTIONS FOR
CONDUCTING PRECLINICAL RODENT STUDIES
EXAMINING THE SOLUTION
9 DE-RISKING PRECLINICAL
DEVELOPMENT
The benefits of the Contract Vivarium (CV)
10 HOW THE CV HELPS TO DE-RISK PRECLINICAL
DEVELOPMENT
12 CONCLUSION
13 ABOUT MISPRO BIOTECH SERVICES
14 REFERENCES
3 Mispro Biotech Services ©2021SETTING THE STAGE
THE REPRODUCIBILITY
CRISIS
A $28 Billion problem for drug
development
O
ver the past 10 years, there has been a recognition in the life sciences
industry of systematic weaknesses in how research is conducted.
In particular, irreproducible preclinical research(8) resulting in an
inability to demonstrate efficacy at the clinical trial stage is the leading
cause of more than half of clinical trial failure.(4) This situation, dubbed
the ‘reproducibility crisis,’ refers to the inability of independent clinical trial
laboratories to replicate data generated by preclinical trials.
The Tufts Center for the Study of Drug Development estimated that the
average cost of bringing a new drug to market was estimated to be $2.6
billion.(5) However, the prevalence of irreproducible preclinical research
exceeds 50%, representing losses of $28 billion worth
WITH COMPANIES FACING A of research in the US alone.(2)
50% CHANCE OF FAILURE IN With companies facing a 50% chance of failure
CLINICAL...IT IS IMPORTANT TO in clinical, clearly it is important to build a solid
BUILD A SOLID FOUNDATION foundation of validated preclinical data before going
to clinical trials. Recognizing an issue with their
OF VALIDATED PRECLINICAL
productivity (i.e. proportion of pipeline molecules
DATA BEFORE GOING TO that have advanced from preclinical investigation to
CLINICAL TRIALS. completion of Phase III clinical trials(9)), AstraZeneca
examined their R&D strategy and, in response,
created a ‘5R’s Framework’ for development decision making that
improved productivity by close to 400%.(3)
But can developing a robust strategy for preclinical development go
beyond focus on the targets and pathways of a study to also include
where the research is conducted and by whom?
4 Mispro Biotech Services ©2021AstraZeneca’s
5R’s FRAMEWORK FOR
INCREASED PRODUCTIVITY
The lack of productivity in research and development (R&D) is an issue for
pharmaceutical companies and shareholders alike. AstraZeneca took a
close look at their productivity gap by reviewing its own R&D strategy and
scientific decision making.
A core finding of the company’s review shed light on a lack of scientific
curiosity and truth-seeking in early-stage development, with these traits
being outweighed by the greater desire to push projects through phases
even with only marginal results. While these progress-prioritized projects
appeared to increase productivity, AstraZeneca found that “projects that
showed greater confidence in target validation...[were] less likely to fail
owing to lack of efficacy”.(3)
As a result of this eye-opening analysis, AstraZeneca developed a ‘5R’s
Framework’ to help guide the decision-making process in bringing a drug
to market. The ‘5R’s Framework’ for increased productivity is:(9)
1 Right Target
Uncover, select and validate new targets with a strong
link to disease.
2 Right Tissue
Ensure that new drug candidates have good
bioavailability and display the right effect in the
intended tissue.
3 Right Safety
Establish safety as far as possible in humanized
systems before initiating clinical trials.
4 Right Patient
Recognize that patients have unique, genetic, molecular
and functional disease profiles, and target medicines to
populations who will derive the greatest benefit.
5 Right Commercial
Develop a unique value proposition for new medicines
based on the size and unmet needs of the target
population.
5 Mispro Biotech Services ©2021THE IMPACT OF AZ’s 5R’s
FRAMEWORK
When the ‘5R’s Framework’ was initiated it aimed to improve project
success rates from preclinical to launch from 4% to 8%. This target was
exceeded, with the rate of candidate drug nomination to successful phase
III completion reaching 19%, a four-fold improvement in productivity.(7)
Two other outcomes of improved R&D productivity(6) were highlighted by:
• An increase in buy recommendations for AstraZeneca stock from 18%
in 2012 to 62% in 2016.(7)
• An 85% increase in share price on the London stock exchange as of
the end of 2016.(7)
AstraZeneca demonstrated that taking a truth-first rather than a
progress-first approach can lead to improved decision making, increased
productivity, and deliver significant benefits for both investor confidence
and share price.
4X Improvement in productivity
244% of AstraZeneca stock
Increase in buy recommendations
85% Increase in share price
ASTRAZENECA DEMONSTRATED THAT
TAKING A TRUTH-FIRST RATHER THAN
A PROGRESS-FIRST APPROACH CAN
LEAD TO IMPROVED DECISION MAKING,
INCREASED PRODUCTIVITY, AND
DELIVER SIGNIFICANT BENEFITS FOR
BOTH INVESTOR CONFIDENCE AND
SHARE PRICE.
6 Mispro Biotech Services ©2021The silent 6th ‘R’ for biotech startups:
THE RIGHT CONTROL
Given the industry-wide crisis of data reproducibility − and the urgent
need to address it − early- to mid-stage biotech companies are wise to
benefit from the ‘5R’s’ framework for
their preclinical program. However,
THE INNOVATIVE AND
for biotech startups without big
EMERGING CONTRACT pharma resources, they contend
VIVARIUM (CV) MODEL with a silent 6th ‘R’ that is critical to
OFFERS A DO-IT-YOURSELF adopting a truth-first strategy: the
SOLUTION FOR EARLY- TO Right Control.
MID-STAGE BIOTECHS THAT Companies who do not have access
GIVES THEM CONTROL to a vivarium facility to conduct
OF PRECLINICAL RODENT their early-stage in vivo studies and
choose, for example, to outsource
STUDIES...ENSURING A
their in vivo program to a contract
GREATER LIKELIHOOD OF research organization (CRO), are
REPRODUCIBILITY IN LATER- giving up control to the CRO who
STAGE TRIALS. takes on the responsibility to
conduct the study effectively and
report results accurately. When looking at high failure rates of clinical-
stage trials, giving up control of studies is a risky strategy.
It can then be proposed that companies who do not have the facilities and
infrastructure to conduct their own animal studies seek a solution that
offers them control of their in vivo program. This control will enable them to
take a ‘truth-first’ approach to their preclinical strategy and validate with
confidence the first 3R’s of AstraZeneca’s proven framework, which are:
1. They are working on the right target.
2. Their investigational therapeutics are targeting the right tissue.
3. Those therapeutics have the right safety profiles.
The innovative and emerging Contract Vivarium (CV) model offers
a do-it-yourself solution for early- to mid-stage biotechs that gives
them control of preclinical rodent studies, which in-turn significantly
contributes to the validation of preclinical data sets, thus ensuring a
greater likelihood of reproducibility in later-stage trials.
7 Mispro Biotech Services ©2021How the CV enables control
OPTIONS FOR CONDUCTING
PRECLINICAL RODENT STUDIES
Companies without access to a vivarium facility and the infrastructure
required for animal research have three primary options for preclinical
rodent studies:
1. Building a dedicated vivarium research facility
This approach involves significant capital, operational expenses, and
infrastructure management. Additionally, with at least a year needed to
build a facility, timelines to research programs are significantly impacted.
2. Outsourcing studies to a CRO
This approach removes the substantial expense and operational
complexities of internalizing a dedicated vivarium, but it can be
challenging to find CRO’s with the right domain expertise, especially
for novel therapies. Additionally, long wait times for studies to begin
and for results to be produced can also be a challenge for organizations
operating within a strict timetable and financial constraints.
3. Renting space in a full-service Contract Vivarium (CV)
This emerging model in the industry offers research organizations the
ability to launch quickly and control their studies in fully- outfitted and
-resourced animal research facilities. Importantly, contract vivarium
facilities also include all of the animal care and compliance oversight
infrastructure and services required to support animal research.
WHAT IS A A Contract Vivarium
(CV) is a full-service,
CONTRACT
fully-equipped animal
VIVARIUM? research facility where
multiple companies
can pursue in vivo drug
development studies,
most commonly with
rodents
8 Mispro Biotech Services ©2021EXAMINING THE SOLUTION
DE-RISKING PRECLINICAL
DEVELOPMENT
The benefits of the Contract
Vivarium (CV)
A
s established earlier, the risk–reward profile for bringing new
therapeutics to market is high, and investors are supportive of
any measures that can reduce risk in preclinical.
The Contract Vivarium (CV) model helps companies de-risk preclinical
development by offering them access to a combination of research space
and laboratory animal services that lowers the
barrier to entry to drug development, especially
[CV’S ENABLE A] RESULTS- for biotech startups. The flexible space options
BASED BUDGETING offered by the CV also enables companies to
STRATEGY [THAT] DE-RISKS launch quickly, with minimal funds, then scale
DISPROPORTIONATE SPEND their animal studies program in relation to
IN EARLY-STAGE PRECLINICAL, results and additional funding. This results-based
ALLOWING FOR INVESTMENT budgeting strategy de-risks disproportionate
spend in early-stage preclinical, allowing for
DOLLARS TO BE FOCUSED ON investment dollars to be focused on funding the
FUNDING THE GROWTH OF THE growth of the strongest candidates.
STRONGEST CANDIDATES. Confidence in study results and, thus, the strength
of a candidate, is a variable that becomes more
manageable when companies and scientists have control over their
own studies. By enabling clients to keep their studies in-house rather
than outsource them to a CRO, the CV option enables research teams to
focus on truth-seeking and good science, which in turn provides greater
confidence in data collection and study results.
9 Mispro Biotech Services ©2021HOW THE CV HELPS TO DE-RISK
PRECLINICAL DEVELOPMENT
Let’s take a closer look at how the core benefits of the CV model help to
de-risk preclinical development:
Accelerated Timelines
In a contract vivarium, flexible space options in turn-key facilities enable
companies to launch quickly with minimal levels of investment, such as
by starting with a few cages in a shared housing room and also opting
for shared procedure space. If initial studies are successful, companies
can easily add capacity by scaling in shared spaces or moving into
private procedure and housing rooms or suites where they can
customize their workspace and keep special equipment.
With direct access to studies, reproducibility issues can be flagged early
and studies can be modified without incurring delays and additional
costs, which allows for timelines and funding to be allocated to high-
potential studies. Failing early and at a lower cost is the hallmark of a
results-based, truth-seeking program.
Expertly Managed Research Environments
To support multiple clients conducting animal research in a single
facility it is imperative that the facility be safe, stable and expertly
managed. Contract vivarium facilities are outfitted with state-of-the-
art environmental control systems and equipment that together ensure
a research environment free from confounding variables that could
influence study controls or results.
The contract vivarium research environment also includes animal science
services including veterinary care, animal husbandry, technical services,
and regulatory and compliance oversight that ensures the ethical and
humane treatment of research models. These services significantly
contribute to good science and reliable data sets, which reduces the
likelihood of failure in later-stage phases due to efficacy issues.
10 Mispro Biotech Services ©2021Benefits of the CV, cont’d
Focus on Science Instead of Infrastructure
The CV option lets organizations dedicate funds and resources
to research rather than infrastructure. By removing the costs and
operational complexities of staffing, compliance, and insurance,
research organizations are freed up to focus solely on science.
By minimizing these expenses and headaches and offering what
is essentially a predictive cost approach to development, the CV is
arguably the most strategically-sound and risk-adverse option for
early-stage biotechs who might have only one chance to bring their
drug to clinical.
Agile Investment Strategy
[BY OFFERING A] PREDICTIVE Choosing to conduct studies in a
COST APPROACH TO contract vivarium can significantly
DEVELOPMENT, THE CV reduce the up-front investment
IS ARGUABLY THE MOST needed to launch in vivo work,
STRATEGICALLY-SOUND AND allowing teams to start small and
then scale when they’re ready. When
RISK-ADVERSE OPTION FOR
trials fail, teams can nimbly scale
EARLY-STAGE BIOTECHS down and reallocate resources.
WHO MIGHT ONLY HAVE ONE Conversely, they can expand quickly
CHANCE TO BRING THEIR DRUG when data supports further inquiry.
TO CLINICAL. This agility provides organizations
greater flexibility across the lifecycle
of their development program, enabling them to budget funding
dollars proportionately on validating early-stage studies, then allocate
remaining funds or seek additional funds for results-based growth.
With merit-based incremental funding being a sound investment strategy,
companies pursuing funding as well as funding entities themselves
can therefore position the CV model as a risk-adverse option for
preclinical discovery.
11 Mispro Biotech Services ©2021Conclusion
A
cross the pharmaceutical industry, clinical trials fail often, most
notably due to a lack of efficacy. Often this lack of efficacy is
precipitated by irreproducible and unreliable preclinical studies
leading to the propulsion of unsuitable candidates into clinical trials.
This can damage not only company finances and viability but also
investor confidence. For early-stage life science companies pursuing
drug development with limited funding, these pitfalls are especially
difficult to navigate.
By offering access to turn-key vivarium research facilities plus expert
animal care and compliance oversight services, the Contract Vivarium
(CV) model significantly reduces the barrier to entry to drug development
for early- and mid-stage biotech companies, enabling them to launch –
and, importantly, control – rodent studies with minimal funding and then
scale based on results.
Smart biotech startups recognize that access to future funding rests on
their ability to generate reliable preclinical data on accelerated timelines
at lower costs. The CV model offers the control and flexibility they need to
increase productivity while removing infrastructure headaches, allowing
them to focus on data validation and good science.
SMART BIOTECH STARTUPS
RECOGNIZE THAT ACCESS TO
FUTURE FUNDING RESTS ON
THEIR ABILITY TO GENERATE
RELIABLE PRECLINICAL DATA
ON ACCELERATED TIMELINES
AT LOWER COSTS.
View Case Study
12 Mispro Biotech Services ©2021ABOUT
MISPRO BIOTECH SERVICES
Mispro Biotech Services is an AAALAC-accredited Contract
Vivarium Organization (CVO) that offers biopharmaceutical
companies access to full-service vivarium research facilities for
preclinical in vivo drug development. Established in 2003, and
with locations in all major U.S. & Canadian biotech hubs, Mispro
is North America’s leading contract vivarium provider.
CAMBRIDGE • FARMINGDALE & NEW YORK CITY • MONTRÉAL
RESEARCH TRIANGLE PARK • SOUTH SAN FRANCISCO
Own your Science.
misprobiotech.com
13 Mispro Biotech Services ©2021References
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development and publication of trial results. Hwang, T. J., et
al. 2016, JAMA Intern. Med., pp. 1826-1833. DOI: 10.1001/
jamainternmed.2016.6008.
2. The Economics of Reproducibility in. Freedman, Leonard P.,
Cockburn, Iain M. and Simcoe, Timothy S. . 6, 2015, PLoS Biology,
Vol. 13, p. e1002165.
3. Impact of a five-dimensional. Morgan, Paul, et al. 2018, Nature
Reviews Drug Discovery, Vol. 17, p. 167.
4. Consider drug efficacy before first-in-human trials. Kimmelman,
Jonathan and Federico, Carole . 2 February 2017, Nature, Vol. 542,
pp. 541-542.
5. DiMasi, Joseph A., Grabowski, Henry G. and Hansen, Ronald W.
s.l. : Elsevier, 2016, Journal of Health Economics, pp. 20-33. doi.
org/10.1016/j.jhealeco.2016.01.012 .
6. Does size matter in R&D productivity? If not, what does? Ringel,
M., et al. 2013, Nat. Rev. Drug Discov., pp. 901–902. DOI: 10.1038/
nrd4164.
7. Animal models and the prediction of efficacy in clinical trials of
analgesic drugs: A critical appraisal and call for uniform reporting
standards. Rice, A., et al. 2008, Pain, pp. 243-247. doi: 10.1016/j.
pain.2008.08.017.
8. Replication and reproducibility in spinal cord injury research.
Steward, O., et al. 2012, Experimental Neurology, pp. 597-605. doi.
org/10.1016/j.expneurol.2011.06.017
9. Transforming AstraZeneca’s R&D productivity. https://www.
astrazeneca.com/what-science-can-do/topics/disease-
understanding/transforming-astrazenecas-rd-productivity.html
DE-RISKING PRECLINICAL DEVELOPMENT: THE EMERGENCE OF THE CONTRACT VIVARIUM (CV)
©FEBRUARY 2021 • MISPRO BIOTECH SERVICES
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