feature

Does process excellence handcuff drug

development?
Jochen Koenig
R&D expenditures in the pharmaceutical industry have been increasing, whereas the number of new
drugs has stagnated. The patent cliff and increasing pricing pressure from payers urge for greater
effectiveness and efciency throughout the industry, including R&D.Good processes are at the heart of
increasedefciency, while carefully maintaining and expanding freedomfor scientic explorationand
innovation.Primary targets for process improvement are service platforms, administration and
interactions with suppliers, which are already applicable during the early research phase for new
products. Further down the value stream, developments such as quality by design (QbD) promise
increased exibility in manufacturing processes on the condition of increased process understanding
and control, based on mature process governance and management.
Introduction
For more than a decade, the pharmaceutical
industry has been struggling with decreasing
approval numbers. At best, the gures provided
by the FDA indicate stagnation at 2025 inno-
vative new drugs annually [1]. This is particularly
remarkable because the industrys R&D invest-
ment has increased by 12% on average year-on-
year since 1970 [2] (Fig. 1).
A recent study estimated that it takes nearly
US$ 1.8 billion over a period of 13.5 years to
develop a new drug [3]. For the past 50 years,
these costs have increased signicantly faster
than the general ination rate [1], despite all the
scientic advances made during that time.
During the 1980s R&D investments by PhRMA-
member companies climbed in relation to sales
revenue from an average of 9.0% (19701980) to
plateau at a new level of 16.6% (19922009) [2].
Taking into consideration the length of the drug
development cycle, there is no indication that
dedicating a larger share of revenues to R&D
helped the industry increase the number of new
drug approvals. Making things worse for the
industry, payers are continuing to increase the
pressure to reduce the retail prices of new and
existing products. As a result, the annual growth
rate of net sales shows a distinct downward
trend for the past decade and could even
become negative, despite the growth rates in
emerging markets. Based on this, it might not be
sustainable to increase R&D investments or even
maintain them at current levels. In fact, 2008 and
2009 both saw lower absolute R&D investments
compared to the previous year (2007) for the
rst time since PhRMA began reporting these
gures in 1970.
Responding to this combination of stagnating
productivity and rising cost pressure, the
industry is pursuing two complementary stra-
tegies: increasing the economic power of com-
panies through market consolidation and
attempting to increase productivity in the
remaining companies.
Market consolidation: mergers and
acquisitions
The past few years have been characterized by
massive consolidation among pharmaceutical
and biotechnological companies. The acquisi-
tions of Genentech by Roche, Wyeth by Pzer
and ScheringPlough by Merck are just the most
prominent examples from an extensive list [4]. A
recent analysis of pharmaceutical industry pro-
ductivity in terms of new drug applications
indicated that the strategy of strength through
mergers and acquisitions could well fail to
increase the involved companies productivity
and might even harm the industry as a whole [1].
Some analysts have issued warnings that the
recent reduction of the pharmaceutical work-
force in particular shedding old hands from
R&D, manufacturing and QA is leading to
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unrecoverable loss of drug development
experience and could compromise the future
ability of the industry to provide safe and
effective drugs [5,6].
Increasing productivity
Two independent studies, one led by the FDA
and another by the EFPIA (European Federation
of Pharmaceutical Industries and Associations),
analyzed the reasons for the industrys lack of
productivity. Concordantly, they prioritized three
areas with the highest potential to benet from
change [7,8]:

Predictivity of safety evaluation.

Predictivity of efcacy evaluation.

Industrialization of development and manu-

facturing processes.
The studies further mention knowledge
management and education and training for
scientists and technical staff as being important
measures that would support sustained
improvements.
Publicprivate partnerships were launched
based on the two studies: the Innovative Med-
icines Initiative (IMI; http://imi.europa.eu/) in
Europe and the Critical Path Institute (C-Path;
http://www.c-path.org/) in the USA. Both provide
a framework for multiple projects addressing
specic aspects of drug development. One
example of a successful project is the Predictive
Safety Testing Consortium (PSTC; http://www.c-
path.org/pstc.cfm), which published a series of
articles reporting on success in improving how
the safety of new drug candidates is evaluated,
with respect to drug-induced kidney damage, at
the early stages of new compound develop-
ment. The group described a panel of safety
biomarkers [9] and collaborated with the FDA to
dene a methodology and process for qualifying
new biomarkers for routine use and regulatory
evaluation [10,11]. Remarkably, the qualication
of these preclinical biomarkers marked the rst
time that the FDA had approved a technology,
protocol or method to test a drug [11,12].
Innovation versus standardization
A recent analysis of factors inuencing drug
development productivity shows that two fac-
tors have the highest impact on overall success
and productivity [3]: having the best possible
scientic understanding of a particular drug and
target; and having the ability to lter out can-
didates early on that will fail in clinical trials
because of safety or efcacy issues. IMI and C-
Path are both very much in tune with this
assessment. However, the study also shows the
huge inuence that immediate cost and cycle
times of individual phases of development have
on the total investment per successful New Drug
Application (NDA) or new Biologics License
Application (BLA). Cost and cycle time directly
reect the quality and efciency of the under-
lying processes. According to the model, a mere
5% increase in efciency would translate to
savings of >US$ 150 million per newly
approved drug. This amount corresponds to
the out-of-pocket cost of funding eight projects
from target through preclinical testing, thus
directly impacting the pipeline.
Innovation and standardization are generally
considered to be mutually exclusive but, in
reality, they are not. To comply with the scientic
method and to produce valid results, all scientic
work, including early research, must be repea-
table. To achieve this, the experimental set-ups
and conditions must be completely and com-
prehensively documented and systematically
optimized. In addition, the cliche of a genius
achieving a breakthrough single-handedly holds
less truth than ever these days [13]. That said,
workable and reliable rules for collaboration are
essential whenever division of labor is a key
success factor. Thus, process thinking and
innovation are not opposites; rather, they are
complementary when dealing with a series of
actions and events that is meant to be repro-
ducible, and they lead to reliable results and at
any interface between people or functions.
Naturally, certain processes are more amenable
to standardization and optimization than others.
Although there is ongoing and very active
debate over whether innovation can be cap-
tured in a formal process at all, discussions over
the past ve years have shown that other aspects
of R&D can certainly be looked at in a process-
centric manner [1416]. Optimized processes
provide many benets, including reduced
administrative efforts, increased transparency of
agreed services and quality and shared best
PERSPECTIVE Drug Discovery Today

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R&D investment and new drug approvals since 1970
0%
2%
4%
6%
8%
10%
12%
14%
16%
18%
20%
0
10
20
30
40
50
60
1970 1975 1980 1985 1990 1995 2000 2005
R
&
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a
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&

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;

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&
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s
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n
d
i
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g

i
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B

U
S
$

NME & BLA Approvals
(FDA-CDER)
PhRMA R&D Spending
(billion USD)
PhRMA R&D Spending
(% of total sales)
Drug Discovery Today
FIG. 1
R&D investments by PhRMA-member companies [2] and approval of new drugs (New molecular entities (NME) and new biologics applications (BLA)) [data
provided, with permission, from Ref. [1] since 1970.
378 www.drugdiscoverytoday.com
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practices. Administrative processes in day-to-day
work should become so streamlined as to be
hardly noticeable and leave more room for core
tasks. Additional standard processes in R&D
involve, for example, internal technology and
logistics services or the clinical supply chain. Bad
processes can be a major drain on work moti-
vation and are probably to spur evasion strate-
gies, cannibalizing the intended gains.
Transparency and collaboration
One important goal of implementing and
enforcing processes is achieving qualitative and
quantitative transparency on process perfor-
mance. By denition, a good process will ensure
effective and efcient delivery of a high-quality
product. Much of the confusion about process
improvement is related to dening the process
as such at various levels of detail and the
elements that can be subject to systematic
continuous improvement (CI). Although a CI
project is unlikely to dene a strict business
process for innovating the best chemical
synthesis route, it should be able to ensure that
there is a mechanism for efcient information
exchange and workload distribution between
medicinal chemists [17]. Common to all sys-
tematic CI methodologies is the fact that they
have dened a way to look at a business process
from end to end and then specically focus on
those parts of it that can be improved and would
benet most from any improvement. Critics of
business process management (BPM), Lean- or
Six-Sigma regularly state that many of the
changes introduced during a CI cycle can simply
be seen as applying common sense [18]; how-
ever, it should be considered a methodological
strength to sample, evaluate and integrate sys-
tematically the knowledge and experience of the
process participants and process owners to
achieve improvements in a data-driven and
transparent way.
BPM projects are typically structured into four
phases: strategy, design, implementation and
control (Fig. 2). The formalized approach avoids
rushing to the seemingly obvious solution
instead of conducting a thorough investigation.
Experienced CI eld practitioners avoid the
common pitfall of overwhelming project teams
with methodology-specic jargon and regularly
combine tools from the different schools to
achieve the best results for their projects.
Depending on the individual project, business
process implementation can be supported or
(partially) automated through IT, for example
through service-oriented architecture (SOA)
technology.
Because nearly all aspects of industrial drug
R&D interact with or are dependent on IT sys-
tems (Electronic Lab Book, Laboratory Informa-
tion Management System, Document
Management System, Clinical Trial Management
System, Electronic Data Capture and Product
Lifecycle Management, etc.), the proximity of
BPM to IT and integration and automation in
particular is a denite strength. BPM provides a
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Business process transformation roadmap
Measure &
analyze process
performance
Analyze
process & org.
structures
Monitor
SLAs & system
performance
Controlling
Transform
organization
Transform
business
processes
Transform
application
& IT systems
Implementation
Evaluate
processes
(static)
Identify
improvement
opportunities
Develop
to-be concept &
processes
Define
transformation
plan
Evaluate
processes
(dynamic)
Map detailed
as-is business
processes
Design
Understand
business
environment
Analyze
critical success
factors
Record
enterprise map
Define
end-to-end
scenarios
Strategy
Implement
BPM governance
model
Monitor
compliance
Identify &
manage
improvements
Define
project scope
& plan
Drug Discovery Today
FIG. 2
ARIS Value Engineering methodology for business process transformation supported by BPM. Business process management (BPM) is a management discipline
focused on systematic and continuous improvement (CI) of business processes and on maintaining them in a state of control. The intimate integration of IT to
support process control and maintenance, and automation aspects, gives the approach a broader scope than most CI methodologies like Lean or Six-Sigma.
Typically, a process-transformation project is structured in four phases: strategy, design, implementation and control. Following the principle of CI, these phases
should be seen as a continuous cycle that could be entered at various stages.
www.drugdiscoverytoday.com 379
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systematic approach to collecting and describ-
ing processes, their timeline and associated
responsibilities, ITsystems, input and output, and
interfaces. This ensures that the process
description is comprehensive and consistent, for
example with respect to nomenclature for roles
and systems, and is therefore meaningful in a
context beyond the isolated project. SOPs, reg-
ulatory documentation and training materials can
be generated, in an automated manner, based on
such process descriptions. Process understanding
captured during the process documentation is a
prerequisite for the service-oriented integration
of IT systems to streamline process ows and
address weak points and bottlenecks [19]. From
the start, CI projects should directly involve pro-
cess owners and process participants in describ-
ing and modeling the business process in
question, as well as evaluating the process and
dening improvements. This transparent and
collaborative approach values and levers the
teams experience and domain knowledge and
lays the foundation for sustainable increases in
efciency and quality. It is important to stress that
process transparency is not tiedtoprocess rigidity.
Particularly when applied to R&D processes, the
former clearly contributes to collaboration and
success, whereas the latter serves only to max-
imize frustration and strangle innovation. CI taken
beyondthebuzzwordlevel will analogous tothe
scientic methodsystematically use information
about the past and current state of a business
process to understand it and make predictions
about its response to manipulation. In other
words, it will develop process understanding as a
basis for optimizing quality and efciency.
Technology platforms
Over the past two decades, biomedical research
has seen the advent of a whole range of tech-
nology platforms, including HTS and high-con-
tent screening, microarrays and whole-genome
sequencing all of which introduced previously
unknown requirements for capital investment,
technical sophistication and data-analysis com-
plexity. As a result, many organizations host and
run the new technologies at centralized facilities,
often in competition with external service pro-
viders. For these groups, good processes trans-
late into shorter cycle times from sample to
report, and more-satised customers who can
rely on receiving a high-quality product
according to agreed criteria, including delivery
date, depth of analysis and level of documen-
tation. In turn, the service facility, based on
predened interfaces, can be certain to receive
required input materials, such as samples, and
necessary documentation in plenty of time,
avoiding unnecessary delays. Taken together,
this will facilitate better planning and more-
efcient use of resources [20]. The Broad Insti-
tutes sequencing group adopted a process-
centric mode of operation early in the 2000s and
is now probably the most productive and
innovative sequencing technology centre
worldwide [21].
Clinical supply chain
The growing complexity of clinical trials is
making it more challenging to provide the
required materials. Manufacturing processes and
nal product descriptions are still in develop-
ment at this stage. Guiding and documenting
changes with process-driven product lifecycle
management can be a key element in main-
taining transparency and supporting compli-
ance during this crucial phase. Electronic batch
documentation linked to a workow-driven
release process for manufacturing process
changes can be implemented during manufac-
turing ramp-up. Particularly during the later
phases of clinical testing, this can play a major
part in achieving better availability and shorter
time to patient. Further cost and quality
advantages can be realized by optimizing
planning and logistics processes.
The process of process development and
quality by design
Recognizing that pharmaceutical manufacturing
needs a regulatory framework that would facil-
itate incorporating tools to improve efciency
and quality, the International Conference on
Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human Use
(ICH; http://www.ich.org/) joining international
regulatory bodies and industry associations
developed new guidelines [Q8 (R2), Q9, Q10] to
transform the conventional quality by testing
approach into that of quality by design (QbD).
The goal is to foster innovation and the appli-
cation of the scientic method to drug manu-
facturing. Implementing QbD is expected to
deliver more-reliable built-in product quality
and more-robust manufacturing processes,
along with the opportunity for CI as knowledge
and experience accumulate [22]. However, the
success of a QbD implementation depends
heavily on the efciency and quality of the
business processes used to design, document
and govern the manufacturing process and its
changes throughout the product lifecycle.
Pharmaceutical quality system
ICH Q10 describes the requirements for estab-
lishing a pharmaceutical quality system (PQS),
dened as a quality management system for
pharmaceutical companies. As part of the PQS
corporate management is required to participate
in the design, implementation, monitoring and
maintenance of processes, assuring quality
within their area of responsibility. The document
strongly emphasizes knowledge management,
training and scientically rooted risk manage-
ment as crucial supporting elements. Process
models are specically referenced for their value
in maintaining and communicating all relevant
information, along with their function as a
meaningful foundation for CI efforts. BPM soft-
ware systems can be used to dene and drive
workows for Corrective and Preventive Actions
(CAPA), change management, review, sign-off
and training based on roles and responsibilities.
Connecting process models with process-
supporting IT systems makes it possible to
measure process parameters and performance.
Analysis of the data reveals process bottlenecks
and weak points or uncovers side tracks that
could compromise the process goals or regula-
tory compliance. BPM-enabled surveillance of
processes that affect product quality or the
effectiveness of the PQS can be combined with
dashboards or alerting functions to empower
management to full their regulatory supervi-
sion duties. This way, process governance and
compliance management are becoming self-
documenting greatly supporting regular
training and periodic audits.
Summary
Annual R&D investments >16% net income put
the pharmaceutical industry far ahead of any
other. However, analysis of the cost of bringing a
new drug from idea to market and the current
rate of new drug approvals show that success
rates for developing new products are lagging
far behind deating cost. It is extremely unlikely
that the pharmaceutical industrys current pro-
ductivity crisis can be overcome through
scientic innovation in the biomedical eld
alone. Instead, companies will have to address
both dimensions of productivity effectiveness
and efciency in concert and aim to optimize
them. BPM provides the methodology and tools
to increase and protect opportunities for inno-
vation, dene transparent processes and opti-
mize them through CI. Even moderate increases
in efciency in drug development translate into
signicant savings that can be used to fund
additional innovation projects. Opportunities for
BPM projects can be found across the entire
value chain from early development to manu-
facturing. The scenarios discussed here increase
efciency by automating administrative tasks,
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increasing transparency of processes and inter-
faces between functional units, and orchestrat-
ing CI. The process documentation generated as
a by-product of BPM is an important contribu-
tion toward achieving and maintaining regula-
tory compliance.
Conicts of interest
The author is an employee of Software AG. The
author declares no competing interest inuen-
cing the views presented in the article.
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Jochen Koenig
Software AG, IDS Scheer Consulting,
Altenkesseler Str. 17, D-66115 Saarbruecken,
Germany
[email protected]
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