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International Clinical Trials
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Mark Egerton of Quotient Clinical
discusses a new development paradigm underpinned by horizontal
integration of supply chains that offers a more intensive assessment of
drug candidates in early development
As we progress into an era that will deliver unprecedented insights into
the molecular basis of disease, it is ironic that the pharmaceutical
industry has entered into a period of cataclysmic change. Major
pharmaceutical businesses are under pressure, with a potential $250
billion of pharmaceutical sales under threat from generic competition
between now and 2015 (1). R&D productivity remains low and has
failed to deliver sufficient innovative products into industry
pipelines. Consequently, we are witnessing cuts in R&D budgets, site
closures and job losses.
Many organisations have chosen to outsource major components of their
development operations. A number of the world’s largest pharmaceutical
companies have formed strategic partnerships with some of the world’s
largest contract research organisation (CROs), streamlining workflows
for the companies taking this approach and providing cost advantages
through more efficient working practices.
However, with the cost of developing a new medicine now estimated to
exceed $1.5 billion, it is essential that the industry not only
continues its drive to innovate the disease mechanisms that it targets
for intervention, but that it also drives innovation of the drug
development process and the supply chains that underpin it (2).
RE-ENGINEERING THE R&D PARADIGM
Numerous leaders within the industry have commented on their approaches
to improve R&D productivity. A recent article by Steven Paul and
colleagues provides a very useful insight into the strategic R&D
thinking that has taken place at Eli Lilly (3). Like others, they have
identified a reduction in Phase 2 and Phase 3 attrition, currently
running at 66 per cent and 30 per cent respectively, as a central
objective to improving productivity.
The conundrum, however, is that late stage attrition has to be cut back
at a time when the number of unprecedented mechanisms being addressed by
the industry has never been higher. The number of new drug candidates
being progressed into development must increase, with an expectation
that many of these will fail. In essence, early development has become
part of the research continuum and, for the above strategy to deliver,
it is imperative that each drug candidate is exquisitely interrogated in
early development to remove technical uncertainty. As a result, the
winners can be differentiated from the losers prior to a commitment to
allocate the funds for full development. Paul et al describe this as the
‘quick win, fail fast’ development paradigm.
SAVING TIME & MONEY
At the same time, R&D leaders are continually striving to shorten
timelines and reduce costs. The implications of the ‘quick win, fail
fast’ strategy across a development portfolio are profound when one
considers that approximately 70 per cent of all projects will fail prior
to or at the proof of concept stage (4). In other words, around 70 per
cent of the funds invested into early development will not deliver a
successful drug candidate into full development. With the spend on a
traditional early development programme by a large pharmaceutical
company estimated to be in the region of $20 million per molecule, and a
typical portfolio containing upwards of 20 molecules, this is a
significant amount of money to invest without any return (3).
The development project team is also presented with a paradox. On the
one hand, it is challenged to accelerate development timelines, while at
the same time being driven to undertake increasingly complex clinical
investigations to identify any risks associated with the drug candidate
that will be carried forward into full development.
Ultimately, organisational structures and development processes must
evolve to enable a much more flexible and interrogative approach to
early development. Early development plans must be tailored to
individual molecules and focused on scientific interrogation to address
the key questions that must be answered before the molecule can be
progressed into full development.
RE-ENGINEERING SUPPLY CHAINS & PROCESSES
Current structures and processes to support early development have
evolved from legacy working practices and organisational structures
initially formed decades ago within the large pharmaceutical businesses.
The industry has subsequently consolidated around two vertically
integrated supply chains: one that is focused on the ‘making’ of test
materials (that is drug substances and drug products); and one focused
on the ‘testing’ of those materials (that is preclinical and clinical).
This approach has been further replicated in the outsourcing industry
with a strong demarcation between contract development and manufacturing
organisations (CDMOs) responsible for drug substance and drug product,
and clinical CROs responsible for preclinical and clinical testing (see
Figure 1).
Transfer of material between the make and test supply chains can be
time-consuming and complex. For example, a biotechnology organisation
seeking to use outsource partners to implement an early development
programme (first-in-human (FIH) study through to proof-of-concept study)
may use up to four different suppliers to deliver the drug product to
the clinical centre(s), including a drug substance supplier, formulation
development specialist, drug product manufacturer and packaging house.
In addition to the obvious management burden that this process invokes,
it also carries a signifi cant time penalty owing to the extended
characterisation of the drug product (for example shelf life assignment)
required to support its passage within the make and test supply chains.
BOOSTING SUCCESS THROUGH HORIZONTAL INTEGRATION OF SUPPLY CHAINS
A translational pharmaceutics platform in which the processes, teams and
facilities required to support formulation development, GMP drug
product manufacturing and clinical testing are integrated can drive
innovation within early development – especially those processes leading
up to the FIH dose or in subsequent work to optimise the drug product
prior to full development.
Such a platform can enable the rapid and seamless
manufacturing-to-clinic transfer of drug product, with manufacturing
often taking place within a 24 to 72 hour period prior to dosing. The
timeline savings – not to mention the cost savings – that can be
delivered by this approach are signifi cant, typically being reduced by a
third to half that of a conventional approach. In addition, the ability
to undertake real-time manufacturing of the drug product in close
proximity to the clinical dosing period means that the data from one
clinical period can inform the drug product to be manufactured and
tested in the next clinical period(s).
This approach enables innovative thinking for alternative designs of the
early development programme, including the FIH single ascending dose
(SAD) and multiple ascending dose (MAD) studies and, potentially, the
proof of concept investigations.
In a conventional development paradigm, the FIH programme is typically
undertaken with a single drug product in a relatively simple format –
for example drug-in-solution or drug-in-capsule. Decisions on the nature
of the drug product, such as formulation and dose strength(s), are
taken while the drug candidate is still in the preclinical phase,
sometimes even before the pivotal toxicology studies are initiated.
Although this represents the standard industry approach, it carries a
number of potentially significant drawbacks:
- All up-front investment in pharmaceutical sciences and chemistry
manufacturing and controls (PS/CMC), typically in the region of
$300-500,000 , is lost if the molecule fails the FIH-enabling toxicology
studies
- Significant quantities of costly drug substance are consumed by
the manufacture of large batch sizes of drug product to ensure product
supply throughout the programme and of multiple dose strengths to allow
fl exibility in dose selection during the ascending dose studies ●
Decisions on drug product formulation and dose strength are made
(guessed) in the absence of any human clinical data – data which are
pivotal in driving the development of an optimal drug product confi
guration
- Depending on the FIH clinical data, the simple drug product used
in the initial studies may not be appropriate for a proof-of-concept
study. Consequently, there may be a lengthy hiatus before an optimised
product is delivered for downstream development activities
The early development PS/CMC programme can be optimised by employing a
translational pharmaceutics platform to deliver signifi cant benefi ts
to the drug development project team (see Table 1). The ability to
undertake drug product manufacturing in real-time allows major PS/CMC
investment to be postponed until initial read-outs from the pivotal
toxicology studies have been obtained, while at the same time
maintaining the timeline to fi rst-subject-fi rst-dose in the FIH
programme. Real-time manufacture also allows the results from one
clinical study period to drive the product to be manufactured and dosed
in the next – allowing the project team to respond immediately to
emerging safety, pharmacokinetic and pharmacodynamic data.
Moreover, it allows the development team to undertake up front,
molecule-specific ‘what if?’ risk assessments based on available
biopharmaceutical and preclinical data, which can enable provision of
contingency, or ‘second-generation’ formulations that can be immediately
manufactured and dosed within the study protocol. Such formulations
could be required in response to emerging data that highlight concerns
over tolerability, solubility, bioavailability or half-life, or
formulation switches can be deliberately planned within the protocol to
transition from a fit for purpose FIH formulation to an enhanced drug
product for downstream assessment. In both scenarios the clinical
programme is able to respond instantly to emerging data, maintaining an
accelerated timeline, while optimising PS/CMC investment.
This approach provides much greater fl exibility in the design of an
early development programme and, when implemented within a regulatory
environment that is permissive for early development, equips the project
team with a powerful toolbox to interrogate development molecules and
readily identify the winners from the losers. Ultimately, this approach
will provide a fi rm foundation to deliver the new R&D paradigm and
improve pharmaceutical R&D productivity.
The commitment from the pharmaceutical industry to a drug development
outsourcing model appears irreversible. In a number of the strategic
partnerships that have been announced in the public domain, it is
evident that the major pharmaceutical partner has transferred major
components of operational resource, sometimes in combination with an
R&D facility, to the CRO partner (for examples see press
announcements for the Sanofi Aventis-Covance, AstraZeneca- Quintiles,
and Eli Lilly-Covance partnerships). These deals are multi-year
partnerships and it is inconceivable that, at the end of the deal term,
the pharmaceutical partner could recreate these competencies internally
and remain competitive. Consequently, the outlook for the outsourcing
industry is positive, with the market set to grow at rates of fi ve to
ten per cent per annum over the short- to medium-term (5). However, to
respond effectively to its customers in the context of a rapidly
evolving R&D paradigm the outsourcing industry must itself drive
innovation.
CONCLUSION
The strong demarcation between CDMOs and CROs that exists today is a
barrier to innovation of the drug development process. Certainly in
early development, there is an opportunity to make marked effi ciency
improvements by integrating make-andtest supply chains. Such horizontal
integration marks a change in direction from the vertical integration
demonstrated by the industry to date, however the benefi ts that can be
gained are signifi cant. Shortened timelines, reduced costs and effi
ciency of supply chain management are headline benefi ts that any
customer will appreciate. Arguably of greater importance, however, is
the ability to undertake a more intensive assessment of drug candidates
in early development to identify the winners from the losers that
warrant the downstream expenditure of full development.
As the pharmaceutical industry traverses this period of reinvention, it
will no longer be suffi cient for outsourcers to compete on the basis of
time, cost and quality. There is a significant opportunity for those
companies that, in addition to these fundamental business attributes,
can deliver innovative solutions the enhance drug development
efficiency.
References
1. Evaluate Pharma Alpha World Preview 2014, Evaluate Pharma Report, 2009
2. DiMasi JA and Grabowski HG, The cost of biopharmaceutical R&D: Is
biotech different?, Manage Decis Econ 28: pp469-479, 2007
3. Paul SM, Mytelka DS, Dunwiddie CT, Persinger CC, Munos BH and
Lindborg SR, How to improve R&D productivity: the pharmaceutical
industry’s grand challenge, Nature Reviews Drug Discovery 9: pp203-214,
2010
4. Kola I and Landis J, Can the pharmaceutical industry reduce attrition
rates?, Nature Reviews Drug Discovery 3: pp711-715, 2004
5. The CMO Market Outlook and The CRO Market Outlook to 2014, Business Insight Reports, 2009
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