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Preface
European science and
technology and the competitiveness of European industry are in places
significantly influenced by the European Union’s research,
technology and development (RTD) Framework Programme. Member states
widely absorb the signals emanating from Brussels regarding science
and technology, incorporating them in their own national research
policy.
In recent years, the European Federation for Pharmaceutical Sciences
(EUFEPS) has recognised an imbalance within Europe’s pharmaceutical
sector. Fragmented research by academic institutions does not match
up to the needs of large pharmaceutical industry, while the implementation
of new methodologies, processes and techniques is hampered by the
strict demands placed on the drug development process by regulatory
authorities.
The EUFEPS foresees a dedicated effort to reverse the current situation
in the forthcoming EU RTD Framework Programme. To get the process
started, in 1999 we published a paper promoting a key action entitled
“New safe medicines faster” for the 6th EU RTD framework
programme . The paper was enthusiastically received by scientists,
industrialists and regulators engaged in pharmaceutical science,
including the European Federation of Pharmaceutical Industries and
Associations (EFPIA), European Federation of Biotechnology (EFB),
Danish Medicines Agency, the schools of pharmacy in Uppsala, Amsterdam,
Leiden, London, Paris, Copenhagen and Saarland, the industrial associations
LIF (DK) and Farmindustria (IT), and the COST B15 EU group.
The next step in promoting this initiative and procuring information
regarding the current bottlenecks in drug development and research
was to establish an organising committee, consisting of representatives
from EUFEPS, EFPIA and the Danish Medicines Agency. Their first
task was then to organise a workshop to elucidate ways of improving
the speed and efficiency of drug development. The workshop gained
support from the Quality of Life theme of the 5th EU RTD framework
programme.
This report represents a compilation of the bottom-up input received
from the workshop, held March 15-16, 2000 at Le Plaza, Brussels,
without filling any of the gaps that became visible during the editing
process. We are indebted to the lecturers, rapporteurs and participants
for their contribution to the workshop. Without them, this report
could not have been produced. Our thanks also go to those who received
and supplemented the written text.
Stockholm, June 30, 2000
Prof. G. Alderborn, Uppsala University, SE
Assoc. Prof. M.-I. Nilsson, PHARMACIA, Brussels, BE
Prof. O.J. Bjerrum, Novo Nordisk, DK (chair)
Dr. J. Reden, EFPIA, Brussels, BE
Prof. C.-M. Lehr, University of Saarbrücken, DE
Dr. J. Renneberg, Danish Medicines Agency, DK
Mr. H.H. Lindén, EUFEPS, Stockholm, SE
Prof. J. Vessman, AstraZeneca R&D, Mölndal, SE
The
organising committee
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1. Executive
summary
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A targeted effort to
speed up the development of safe, new medicines is sorely needed
in Europe. Stronger links between industry, academia and regulatory
authorities, more efficient use of modern technology, new methods
of drug exploration and targeted training are all vital elements
of a streamlining process that cries out to be set in motion. Without
it, the European pharmaceutical industry is in imminent danger of
losing important ground on global markets – a situation detrimental
both to European economies and the patients seeking relief from
illness and disease.
Despite being the fifth strongest industry in Europe, the pharmaceutical
industry is severely hampered by an approach to drug development
and approval that is ill-equipped to exploit the huge opportunities
presented by modern drug discovery. Growing demands regarding safety,
efficacy and quality documentation consume vast amounts of research
and development expenditure. But, at the same time, the average
number of years spent on getting a new drug through development
and onto the market appears to be on the increase, returning to
around 12 years after a brief drop to 10 just a few years ago.
In 1999, the European Federation for Pharmaceutical Sciences (EUFEPS)
took the initiative to get the ball of change rolling. A key action
entitled “New safe medicines faster” was proposed for
the EU’s forthcoming 6th RTD Framework Programme.
The key action has three main objectives:
- to seek new technology
capable of more effective selection of potential drug candidates
for innovative medicines while accommodating safety demands
- to use such technology
to increase the capacity of and speed up the pharmaceutical development
process and eliminate bottlenecks
- to cultivate a pan-European
interdisciplinary network that bridges the gap between industry,
academia and regulatory authorities
From March 15 to 16, 2000,
this proposal was supported by the European Federation of Pharmaceutical
Industries and Associations (EFPIA) and by the Danish Medicines Agency.
It was followed up by an EU supported workshop to identify bottlenecks
and speed limitations in the post-discovery phases of drug development
and map out a strategy to reduce them. More than 100 representatives
from the pharmaceutical industry, academic institutions and regulatory
authorities participated in the workshop, producing a description
of the research and technology required to bring safe new medicines
more rapidly onto the market.
Among the main views expressed was the need for a holistic approach
to drug development and research, pulling together all disciplines
and specialists from industry and academia and encouraging an earlier
involvement by regulatory authorities to alleviate the lengthy procedures
necessary in drug approval. Attention was also drawn to the lack of
new predictive methods which would allow more efficient decision-making
and earlier clinical trials. Workshop participants further recommended
that centres of expertise be established to provide scientists with
multidisciplinary training in modern technology.
The diversity of the entire drug development process is too great
to be covered by a single workshop. But, as the results obtained from
the workshop’s seven sessions suggest, an EU-supported effort
by industry, academia and regulatory authorities may be the most appropriate
means of setting new European standards – bringing new medicines
onto the market faster and in a more cost-effective way and establishing
Europe’s pharmaceutical industry as the best and most competitive
in the world.
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2. Drug development as
a key action
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New scientific
knowledge and technology are widely exploited in the search for new
safe medicines. The biotech boom in particular has been largely stimulated
by modern pharmaceutical research. During the complex process of producing
more and better drugs, the involvement of nearly all natural science
disciplines and many advanced techniques clearly underlines the importance
of an interdisciplinary, holistic strategy if optimum results are
to be obtained.
Traditionally the entire drug development process has been divided
into three largely separate phases: discovery, exploratory development
and clinical development. It is these phases that need to be brought
together to form a smooth, seamless procedure, ensuring all knowledge
and data are maintained and put to maximum use throughout.
Discovery relates to the research topics linked to the identification
of a drug target - where a medicine should work - and preparing the
target for screening active leads taken from compounds kept in large
libraries. Following selection, the drug candidate is subject to additional
functional testing, its chemical structure is elucidated, and it is
optimised in terms of potency and efficacy. Exploratory development
then characterises the candidate's metabolic behaviour. A production
procedure and formulation are developed, and further animal testing
is performed.
When the drug has passed these tests to the satisfaction of the investigator
and regulatory authorities, it is ready for the clinical phase when
it is tested in man - first in healthy volunteers and, later, in a
group of patients affected by the disease in question, the results
being compared with conventional or placebo treatment. Multi-centre
trials involving large groups of patients complete the clinical trials.
Finally, all the results are evaluated by both the manufacturer and
regulatory authorities in terms of quality, safety and efficacy. Only
then is the medicine ready for commercial production and sale.
In both the earlier and present EU RTD programmes, support for the
research connected with the discovery phase has been highly fruitful.
The phases that follow this part, though, have been somewhat neglected
and, for this reason, it was decided to make them the focus of the
"New safe medicines faster" workshop. Genomics, proteomics,
metabolomics and modern chemistry and research technologies have made
the later phases of drug development an important focus area as many
more drug candidates than previously will be generated in the years
ahead. Here, technological and methodological breakthroughs are a
particular need to stem the tide of development bottlenecks.
Although equally important to the process, the clinical phase did
not undergo the same thorough analysis at the workshop as exploratory
development. A separate workshop focusing on the clinical phase would,
then, be appropriate. The process-oriented research used in drug development
makes it a well-suited subject for a key action in the 6th EU RTD
framework programme, incorporating:
- well-defined deliverables
to society
- interfaces to many
scientific areas
- bottlenecks that need
to be addressed
- a need for pan-European
collaboration
- potential for job
generation
- room for start-up
companies and small and medium-sized enterprises (SMEs)
- links to topics of
former programmes
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| 2.1 |
The academic
perspective
Effective pharmaceutical research will, in the years ahead, require
the formation of numerous research groups consisting of experts from
many fields – chemistry, physics, biology and medical and engineering
sciences among them. Only in this way will it be possible to solve
the complicated multidisciplinary problems that face drug development.
In light of the close link between high quality research and education,
this means there is a need for advanced training of pre-graduate and
PhD students.
Unique research related to the development of effective medicines
is conducted by scientists working within pharmaceutical schools and
other related faculties throughout Europe. In some areas of emerging
importance, these scientists represent world-leading groups. Most
of these schools and faculties, though, are of limited size in terms
of active research scientists and often not fully integrated into
a broader academic environment of use to pharmaceutical development.
The ULLA consortium, consisting of schools of pharmacy in Uppsala,
London, Leiden, Amsterdam, Copenhagen and Paris, is a rare example
of inter-school collaboration, much more of which is to be desired.
Due to these factors, the opportunities to conduct advanced research
and training in pharmaceutical sciences are limited. One of the ideas
of the key action is to stimulate the formation of consortia and centres
at which advanced education and training can take place at PhD level,
incorporating both specialist components and a holistic view of drug
development. These education centres should be based on input from
academia, industry and regulatory authorities.
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The industrial
perspective
Faster and more effective drug development is the only way to tackle
the serious threats the European pharmaceutical industry will face
in the years ahead. This view was strongly expressed by workshop lecturers
concerned that the rising cost of research and development is not
matched by a corresponding increase in the number of new products
launched (see appendix 1).
Total pharmaceutical research and development expenditure grows by
$3 billion a year. In the UK, such expenditure has increased by up
to 12% a year since 1994. At the same time, calculations show that,
for the healthy growth of large pharmaceutical companies with an annual
turnover of $5-10 billion, 3-6 products should be launched a year.
The current annual average is less than 0.5 new products, the mean
time to launch having recently returned to around 12 years after briefly
declining to 10.
The reason for this is that the chance of a lead molecule becoming
a commercial medicine is less than 2%, while the success rate for
candidates that reach the exploratory development phase is just 10%.
Although the genomic revolution has generated more leads which could
improve this success rate, the techniques currently available for
rapidly selecting the most promising candidates are inadequate, for
which reason valuable leads may be lost. An improvement of the entire
research and development process is, thus, essential to keep expenditure
down and avoid further costly expansions in development capacity.
The many mergers among pharmaceutical companies reflect this situation
but have not removed limitations to drug development. As a result,
the past reluctance of companies to co-operate has been replaced by
the realisation that more interaction and collaboration with the public
sector is necessary in order to implement new faster drug development
technologies.
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The regulatory
perspective
Increased interaction between regulatory authorities, academia and
industry, right from the initial planning phase through to the market
launch of a new drug, would without doubt stimulate the introduction
of new techniques and methods designed to make drug development smoother
and faster.
Co-operation of this kind would give regulatory bodies the role of
ensuring no development pathways are detrimental to drug safety and
efficacy. All the requirements for pre-clinical studies should, then,
have been agreed before clinical trials commence. This would mean
involving regulatory authorities in joint projects with industry and
academia to develop new in-vitro test systems and settling
future requirements for pre-clinical and toxicological tests.
The next steps in drug development, such as the first series of clinical
tests, test procedures and the duration of the test period, represent
other areas of significant concern to the authorities. The complexity
of producing biopharmaceuticals, too, requires a more proactive regulatory
role. By joining in working groups with academia and industry, the
authorities could contribute to the development of new methods designed
to ensure effective, safe drugs. As a result, new pharmacovigilance
approaches could become part of the marketing authorisation procedure.
Commitments to conduct follow-up studies instead of completed investigations,
such as those already performed on drug treatments for HIV infections,
would thus secure faster access to the market.
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The role
of the EU
EU funding would undoubtedly be an effective means of stimulating
the necessary interaction between academia, industry and regulatory
authorities – giving industry better access to new, accepted
development techniques, fuelling academic research and encouraging
authorities to play a more active role throughout drug development
processes.
At the present time, pharmaceutical companies have no tradition for
sharing research results obtained from the public sector or through
academic collaboration with industrial partners. A reluctant attitude
to the implementation of new methodologies and technical solutions
in exploratory and clinical development is also evident within industry,
as the regulatory authorities only respond to such initiatives after
the investment has been made. These impediments clearly slow down
the introduction of faster, more efficient procedures.
With EU support, this situation within industry could be radically
changed. Academic researchers would also gain access to funds which
can be channelled into the many science and technology areas linked
to drug development (see chapter 4). Regulatory authorities, too,
would be able to overcome their natural hesitation to get in touch
with the industry they are to control. Under the auspices of the EU
RTD Framework Programme, the authorities would be provided with a
neutral platform on which to interact with both industry and academia
in the effort to speed up development procedures. This way, the actors
can be sure that all new methods and techniques fulfil safety requirements
from the outset.
A research-based solution is the only way forward for Europe’s
pharmaceutical industry, providing the fastest and most cost-effective
route to safe new medicines for patients everywhere.
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3. Organisation of
the workshop
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All workshop participants
attended by invitation, the aim being to gain the broadest view
of the pharmaceutical industry’s needs by covering as many
European companies as possible. A total of 115 took part, comprising
75 representatives from 36 pharmaceutical companies and contract
research organisations (CROs), 24 academics from 20 universities
and schools of pharmacy and five regulators from four European agencies
(see appendix 2). The female ratio was 15%. A number of European
Commission officials and civil servants were also in attendance.
Clinical pharmacology was unfortunately under-represented.
For practical reasons, seven fora for discussion were created. The
drug development process itself was divided into four sessions,
with the fifth session taking a look at the overall process, the
sixth at the use of information technology and the seventh the creation
of commercial products from new biotech molecules. The sessions
were given the following headings:
- How to select candidate
drugs faster (the discovery and selection phase)
- How to bring candidate
drugs faster into humans (aspects of exploratory development)
- How to bring candidate
drugs faster into full-scale production (up-scaling and analytical
chemistry)
- How to bring drugs
faster to regulatory acceptance (regulatory demands and clinical
trials)
- How to reshape the
drug development process from the beginning
- How to utilise IT
in speeding up the drug development process
- How to turn new biotech
molecules into deliverable products (special aspects of biotech
products)
Distinguished lecturers
were invited to chair each of the seven workshop sessions (see appendix
1) and rapporteurs nominated from the organising committee. Session
participants were then asked to engage themselves in active discussion
about the main aspects of faster drug development: new strategy,
research and innovation, new techniques, methodologies and processes,
strengthened academic research and training and flexible regulatory
authorities. The outcome of the sessions was then reported to the
participants as a whole followed by a general discussion. At the
end of the workshop, the organisers put forward the conclusions
and recommendations.
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4. The workshop sessions
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This chapter
reports the outcome of the seven workshop sessions. The editors have
merely organised the input received, adding explanatory text where
this was deemed necessary.
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| 4.1 |
How to
select candidate drugs faster
This session dealt with the early phase of drug development up to
drug candidate selection. The obvious connection to drug discovery
is evident in the focus on target identification and validation as
well as early and efficient profiling of potential drug candidates
with validated tests. Research and procedures connected to the discovery
aspect of drug development have attracted most attention over the
past decade. In the EU RTD Framework Programmes, this can be seen
in the biotechnology research initiatives which have included the
genome, proteome and metabolome triad.
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Bottlenecks
A smooth and seamless transition from drug discovery to the exploratory
development phase is essential to avoid losing a wealth of information
in the process. At this early stage, the demands of regulatory authorities
play a minor role. Critical issues concerning training and education
were not touched upon during the session.
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Research
and technology aspects
Areas of potential interest and focus for future research collaborations
include the discovery aspects of target identification, selection
and prioritisation; cellular and animal models; screening and prediction
tools; and the upgrading and development of technology and methods.
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i)
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Discovery aspects
The following disciplines and research areas were selected as being
the most important for generating targets to be acted upon by new
medicines.
- Functional genomics
and functional gene analysis
- Target prioritisation
in relation to a pathophysiological understanding of diseases
- Disease models both
in vivo and in vitro
- Cell biology, knowledge
of cell architecture (functional understanding) and cell protein
trafficking
- Population genetics,
especially human polymorphism
- Toxicogenomics
- Computational tools,
e.g. for bioinformatics.
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ii)
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Cellular and animal
models
Reliable models for the understanding of disease processes are a
particular need, as are models for predicting the efficacy and safety
of potential drug molecules. Research activities include:
- In vitro/in vivo
models
- Early in vivo pharmacology
modelling
- "Humanised"
predictive cell-based models
- Validated predictive
models, including transgenic animals, for safety, pharmacokinetics/toxicokinetics
and efficacy assessment
- Validated biomarkers
(end-point markers) to reduce the time required to observe and
document the effect of drug candidates
- Automation/miniaturisation
of various tests, facilitating analyses and increasing the throughput
and speed of the selection process.
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iii)
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Screening and prediction
tools
These tools remain in their infancy and require further research
to improve their versatility and precision. They include:
- Molecular modelling
to select drug candidates for further testing in screens of various
kinds, including multi-receptor high throughput methods
- Methods for predicting
the pharmacokinetic, metabolic and toxicological properties of
drug candidates
- Physicochemical simulations
regarding the absorption, bioavailability and transport of drug
compounds
- Tools to improve the
quality of lead selection, both of small and biotech molecules
- Computational tools
in laboratory test measurements and regarding data systematisation
- Cheminformatics, including
the handling of more diverse compound libraries
- Overall improved management
of data informatics.
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iv)
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Upgrading and development
of technology and methods
The diversity of the drug selection process provides numerous opportunities
for innovation and the generation of start-up companies. To ensure
the most beneficial opportunities are pursued, it is important to
focus on the existing needs of the drug development process. The
following includes some examples of focus areas:
- Biobank technology
(gene and pre-clinical public data banks)
- Gene and protein microarrays
- Improved immunoassays
- Proteomics and related
tools
- Phenotyping analysis
of patients, e.g. for identifying slow and fast drug metabolisers
- Non-invasive imaging
techniques (position emission tomography, magnetic resonance imaging,
nuclear magnetic resonance)
- Innovative and improved
scaling techniques that enable predictions between animal species,
e.g. from rat/mouse/dog/monkey to man
- Bioinformatics –
computer hard and software
- High throughput technologies,
including chip technology and robotics
- Lead optimisation
- high performance molecular modelling and computational chemistry
software
- High throughput chemistry
– medium-scale production of chemical compounds to increase
the supply of test compounds
- High speed and accurate
in situ analytical methods, "new" analytical probes,
direct analysis in cell biophases.
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Interface
areas
New research areas are expected to be based on feedback from studies
in exploratory drug development and clinical phases. Other requirements
are more animal research in general, including ethical considerations,
and broad genetic and genomic studies, including environmental exposure,
population genetics and ethics.
Special research initiatives and other efforts will be enabled by
virtual Centres of Excellence established by scientists in academia,
regulatory agencies and pharmaceutical industries in co-operation,
sharing knowledge and costs.
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Deliverables
- Smooth and seamless
transition from drug discovery to exploratory drug development
- Improved target selection
procedures, reducing the risk of failures after drug identification
- Innovative, more reliable
and efficient and faster techniques for assessing drug efficacy
and safety
- Improved, efficient
and predictive techniques, methods or tools, ensuring potential
drug candidates have optimal pharmaceutical, biopharmaceutical
and pharmacokinetic properties for further downstream development
- High quality predictions
of in vitro/in vivo (animal) results to proceed smoothly
into humans.
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How to
bring candidate drugs faster into humans
The second session covered that part of the drug development process
normally described as exploratory development. It is here the selected
drug candidate is evaluated in more detail in relation to absorption,
distribution, metabolism and excretion (ADME), safety/tolerability
and relationships between pharmacokinetics (PK) and pharmacodynamics
(PD). A test formulation is also produced.
At present, attrition rates are too high: 27% for phase I and 51%
for phase II. This means too many drug candidates reach clinical development
only to be withdrawn later. Although statistics obtained from the
Tufts Centre for Study of Drug Development show that the clinical
development times for new chemical entities (NCE) dropped some 18%
from 1993-95, more recent information indicates an increase. Thus
the need remains to reshape and optimise the drug development process
to make it more efficient.
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Bottlenecks
The four most important issues in connection with research and development
were identified as being:
- Lack of predictive
models:
Research regarding modelling is needed both from a theoretical
and practical point of view
- Inefficient use of
pre-clinical data:
Data produced during the characterisation of drug candidates for
general information and regulatory purposes is not exploited further
downstream
- Inefficient target
identification and validation:
The target for which the lead or drug candidate has been selected
often represents the first choice. Further characterisation and
validation is needed at the same time as the pre-clinical testing
of the drug candidate.
- Improvement paradigm:
More candidates
should be tried earlier on man with the purpose of giving feedback
to discovery rather than testing fewer, better characterised candidates
on patients.
With regard to education
and training, the introduction and expansion of pharmacometrics
(modelling and simulation) were identified as urgent needs. The
encouragement of conversion training between disciplines, for example
within informatics, was also considered important along with more
training in subjects such as clinical pharmacology to improve scientists’
understanding of the entire drug development process.
The regulatory process must evolve in parallel with technological
advances. This calls for research activities within European regulatory
agencies, including the European Agency for the Evaluation of Medicinal
Products (EMEA). Regulations based on scientific evidence are also
sparse.
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Research
and technology aspects
In order to test drugs in man at an earlier stage of the development
process, the candidate selection procedure needs to be optimised.
Micro or homeopatic doses used in association with imaging technologies,
such as Position Emission Tomography (PET) and Magnetic Resonance
Imaging (MRI), to monitor the destiny of the drugs deserve further
consideration.
Predictive and validated models are required for toxicological studies,
especially for toxicogenomics and transgenic animals involved in the
genetic expression of human genes. More research in new disease models
is needed to develop animal models of major human diseases for which
we do not yet have an effective cure. The identification of proper
biomarkers or surrogate end-points in these animal models is equally
important.
Microdialysis research should be promoted as a technique to monitor
the destiny of drugs and measure pharmacological responses to them
in order to improve continuity, objectivity, sensitivity, repeatability
and validity. For this, input should be gathered from industry and
academic and governmental institutions.
Research into gene pattern expressions of the target cells and organs
for different drug classes is also needed, utilising bioinformatics
and functional genomics to interpret the DNA sequences identified.
Mathematical tools of use to the exploratory phase include: artificial
intelligence such as fuzzy logic, genetic algorithms and artificial
networks for mathematical modelling and computer simulation; non-parametric
and physiologically-based pharmacokinetic (PK) models; mechanistically-based
pharmacodynamic (PD) models and integrated PK/PD models for different
kinds of pharmacodynamic data. Mathematical input would further contribute
to the prediction methods used during the progression from chemistry
data to toxicology to man, clinical trial simulation and design, and
the establishment of public databases.
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Interface
areas
Support from governments and regulatory agencies is considered important
for relevant animal studies and from governments and the EU for the
use of genomics data, including ethical issues. The same goes for
statistical methods of standardised toxicological and safety studies,
embryogenesis and methods to correlate toxicity outcome and genomic
information. Good manufacturing practices (GMP) should be implemented
early in the discovery phase.
Access to and sharing data in the public domain is viewed as another
area of importance. Public databases should be created for pre-clinical
and genomic data as well as in vivo toxicity data. This may
require that the quality problem is addressed, for example in relation
to old data. The workshop representative from the large pharmaceutical
company AstraZeneca was positive to this, providing such databases
are developed in a stepwise fashion. In vitro screen methodologies
between companies and academic institutes, too, should be shared.
In relation to this, the COST B15 EU Programme (Modelling & Simulation
in Drug Development) should be incorporated in the key action.
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| 4.2.4 |
Deliverables
- High quality predictions
via modelling and simulation for a fast track from in vitro
and animal studies to man
- More reliable, efficient
and faster techniques for refining the assessment of drug efficacy
and safety
- Extended use of in
vitro tests in pharmacology and toxicology testing, reducing
the use of animals
- Pan-European access
to cell lines suitable for in vitro toxicology testing
- Improved non-invasive
testing methods, e.g. imaging technologies for use in both animals
and humans
- Improved pharmaceutical
products based on better formulation principles and more precise
characterisation and production methods.
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| 4.3 |
How to
bring candidate drugs faster into full-scale production
After a drug candidate has been identified and its validity as a concept
estimated to be satisfactory, the drug formulation and production
procedures have to be decided and, via technology transfer and up-scaling,
carried through to full-scale commercial production. This part of
the development phase has, until now, been somewhat neglected, but
holds great opportunity to shorten the development time, cut costs
and improve the quality and reliability of the products.
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| 4.3.1 |
Bottlenecks
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i)
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Research
and development
The low availability of active substances is due to the choice of
cost-effective routes of synthesis, scale-up problems and excessive
"validation". In the pharmaceutical development phase, more
possibilities are required to work with smaller amounts of material
in small-scale predictive studies. In other words, new methodology
is needed to work with a tiny amount of substance and gain results
transferable to a larger scale.
Another problem is that key ingredients, such as excipients with their
auxiliary function, are not always available with the right quality,
hampering new approaches in drug delivery. If traditional excipients
have to be replaced by new versions, they will require expensive safety
testing and toxicity studies. New methods are also required to characterise
the relevant properties of excipients. Such functionality-related
testing has been taken up by pharmacopoeias but needs to be accepted
by users and producers.
Excessive and time-consuming end process testing is used to document
or characterise the production process in terms of product quality.
Process analytical chemistry, leading to parametric release, may represent
a solution but, like other alternatives, must be discussed with the
regulatory authorities.
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ii)
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Education
and training
Process analytical chemistry is not identified as a strategic research
discipline within the EU and lags behind other initiatives in the
US. This has resulted in a lack of experienced process analytical
chemists. Training is, therefore, needed and a pan-European concept
would be the method of choice. The thin and uneven distribution of
expertise in applied mathematics, such as multivariate analysis and
experimental design (chemometrics), means additional training is required
here, too. The same goes for applied spectroscopy, which is used to
take measurements in laboratory and process environments.
Differing skills among researchers employed in research and development
and manufacturing also impede the transfer of technology. These deliverer/recipient
problems call for holistic training courses.
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iii)
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Regulatory
problems
The introduction of new technologies for control and advanced in-process
testing is hampered by the absence of a common scientific platform
for industry, academia and regulators. Common projects involving all
three partners would facilitate integration.
When an application for approval is sent to the authorities, the integrated
process from formulation to manufacture is not considered as the documentation
is presented step-by-step, and this causes delays in the assessment.
To remedy this, integrated processes should be developed and documented
with regulatory authorities. Smoother validation techniques would
also alleviate the heavy workload involved in repeating the documentation
process when changes have to be made.
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| 4.3.2 |
Research and technology
aspects
A series of manufacturing areas require further research and the
development of new and better techniques.
- Predictive methods
are required for up-scaling. This includes process system engineering
for the quantitative prediction of chemical processes.
- Real-time quantitative
measurements of properties at molecular level, i.e. of physicochemical,
functional properties as well as an indication of interactions,
are needed during manufacturing. Measurements taken in the production
of pharmaceutical dosage forms should go from being indirect to
direct. By combining measurements of indirect process parameters,
such as temperature, pressure or flow, with selective measurements
of molecular properties, it becomes possible to follow changes
in the reaction processes in much more detail.
- Pan-European process
analytical chemistry initiatives should be supported and developed,
consolidating national efforts conducted at different levels and
increasing their scientific critical mass.
- Sensors devoted to
the phenomena taking place in pharmaceutical process environments
should be developed. This particularly concerns information-rich
sensors, such as those tailor-made for quantitative molecular
information and based on process system engineering research.
- Applied spectroscopy
should be further developed to support pharmaceutical processes,
along with mathematical tools for the exploitation of real-time
direct measurements. In this way, it should be possible to move
from pure empirical modelling to a combination of empirical modelling
with fundamental physical models.
- More toolboxes for
the simulation and modelling of chemical processes would provide
much-needed quantitative models for predictive up-scaling.
- Sameness testing and
its acceptance should be facilitated through an interaction between
industry and regulatory authorities. Instead of single parameters,
then, the regulatory guidelines should involve the entire information
package, preferably using non-invasive tools.
- Technology for reliable
quantitative measurements of sameness with a specified quality
should be prioritised. Current positive experiences with non-invasive
techniques, like Near Infrared and Raman Spectrometry, should
be extended to other fields.
- The development of
characterisation methods for relevant polymer excipients, also
known as functionality-related testing, should strengthen the
material sciences. In this, cross-disciplinary approaches should
be used, involving for example physical chemistry, material sciences
and analytical chemistry for an optimum outcome.
- The field of crystallisation
and polymorphic control is becoming more and more important and
represents a natural part of the development phase. Early studies
with relevant techniques are necessary, and new approaches have
to be developed.
- Recycling and energy-saving
aspects of the production process and closed processes for hazardous
chemicals need to be considered, along with continuous processes
as an alternative to present batch production. For the continuous
processes, different quality control aspects have to be developed
with the authorities involved. The application of information
system technology combined with advanced measurement technologies,
too, need to be implemented for the steering and monitoring of
processes (see also 4.3.3).
- High throughput analysis
instrumentation and automation are required. The approach used
in the discovery phase should also be utilised in the development
process after adapting to the different situation represented
by the dosage forms.
|
| 4.3.3 |
Interface areas
The research and technology aspects can only be solved by a collective
effort that covers many disciplines and technologies. These include:
- The pharmaceutical
sciences (material science, physical chemistry, analytical chemistry,
formulation design, pharmaceutical technology, biotechnology)
- Scale-up, i.e. from
milligrams to a few grams. How can sufficient material of appropriate
quality be obtained for early formulation and toxicity studies?
This is a problem involving more than 100 substances.
- Process analytical
chemistry (sensor technology, non-invasive spectrometry, chemometrics,
process interfacing, pharmaceutical technology, process system
engineering and control technology)
- Process system engineering
(measurement technology, including process analytical chemistry,
chemical engineering, pharmaceutical engineering, fermentation
technology, process modelling, process control technology and
multivariate statistics)
- Process validation
(strategy to apply, for example, chemometrics at an early phase
of process development and, thus, prevent unnecessary validation
programmes)
- Formulation technology
design for strengthening the multidisciplinary concept and developing
generic tools for industrial pharmaceutical applications.
- Application of information
system technology in the steering and monitoring of processes.
Instruments and software need to be developed to consolidate all
the measurement data generated (cheminformatics). Tools are required
for data reduction. Improvements are needed in the logistics area
and the design of production lines.
EU collaboration should
be established by creating cross-functional research programmes
involving scientists from academia and industry and regulators.
A common scientific platform for these three interested parties
would ease the introduction of new technologies, including the generation
of ideas, tests of technological concepts and evaluation of new
technology on a realistic scale. Resources could also be pooled
for expensive equipment and educational needs and to enable virtual
Centres of Excellence to make special research efforts.
|
| 4.3.4 |
Deliverables
Investments in research, technologies, collaboration, training and
education would result in:
- Faster processes and
products with an improved and more consistent quality. This would
benefit all parties (producer, regulator, retailer, consumer and
taxpayer).
- A considerable reduction
in the overall time needed for developing drug substances and
drug products, whether biotechnological or conventional therapeutics
- Process models based
on information gathered from quantitative measurements of material
properties at the molecular level
- A seamless development
process and, most importantly, improved scale-up and technology
transfer via predictive process models
- A considerable reduction
in traditional quality control costs following the introduction
of parametric release, i.e. by measuring product quality during
instead of at the end of the process
- Continuous information
from process analytical chemistry with product quality measurements
during processing – considerably superior to the end-of-process
quality control used today.
- A better understanding
of the advantages of new technologies due to joint programmes
involving regulatory authorities, the pharmaceutical industry
and academia. This will remove hurdles within companies and hesitation
among regulators.
- New improved methods
for producing active pharmaceutical ingredients and solid dosage
forms.
- Cleaner and greener
reactions and processes through safer and more energy-saving processes.
|
| 4.4 |
How to
bring drugs faster to regulatory acceptance
The opinions of industry and authorities will always differ regarding
matters of importance to the authorisation procedure for human medicine.
Companies usually prioritise speed, though never at the expense of
safety and efficacy, while the regulatory authorities put public health
interests in relation to efficacy and safety first.
This workshop session dealt with how to improve the efficiency of
the authorisation procedure. Aspects concerning the provision of the
necessary data before drugs can be used in humans and market acceptance
were not discussed. This clinical part of the drug development process
would benefit from a separate workshop.
|
| 4.4.1 |
Bottlenecks
The following regulatory issues were considered important in relation
to research and development and training and education:
- Industry-regulation
interface
It is extremely important that the needs and demands regarding
a specific development plan for a new drug are discussed by industry
and regulatory authorities as early as possible. Continuous discussion
during the whole research and development period will also cut
the time to market.
- Clinical development
An initial dialogue between the developer and authorities will
reduce the clinical development time.
- Pharmacovigilance
Risk groups should be discussed from the beginning of the clinical
planning phase to ensure all potential patients are included in
the safety programme, facilitating the authorisation process.
- Quality of the review
process
The procedures followed by regulators and industrial experts should
be fully transparent. Evaluation projects should be conducted
to compare the procedures and decisions of agencies in Europe,
the USA and Canada.
- Improvement of IT
support
All submissions should be sent electronically in safe systems
like the newly-developed EUDRASAFE.
- Joint assessor courses
The courses already initiated between authorities and industry
should be extended to include academic partners as well. Examples
are the pre-clinical “assessor” courses held in Portugal
and Denmark in 1998 and 1999 respectively.
|
| 4.4.2 |
Research and technology
aspects
The following initiatives involving industry and regulatory authorities
were proposed:
- Assessment of the
quality of applications submitted through the central procedure
(CP) and the mutual recognition procedure (MR). The aim is to
obtain more identical procedures in terms of quality and time
to approval.
- Assessment of reasons
for major public health objections from single member states in
the mutual recognition procedure and submission withdrawals. Misuse
of the phrase “major public health concern” in the summary
of product characteristics is not acceptable.
- Comparative assessment
of EU advice procedures and those in the US with input from both
industry and academia. Both positive and negative aspects should
be covered.
- Acceptance criteria
should be determined to initiate clinical trials of new biotech/gene
products in man and identify surrogate end-points in major therapeutic
areas.
- Current and future
problems should be solved regarding the translation of regulatory
matters as new member states join the EU. Joint projects involving
industry, academy and authority are required to limit the amount
of double and triple information sent to different authorities.
The usefulness of IT in this area is clear. Pilot projects between
industry and the US authorities are already running. Ways to shorten
the process of obtaining adverse event information in summaries
of product characteristics and patient product information could
be other subjects of important joint projects.
- Inter-authority quality
assessment projects with academia would raise the quality of the
review process. What do the quality assessment of reviews and
mutual recognition and central procedures have in common during
their development? The need for joint projects involving all three
interested parties was put forward. Cross-authority analyses of
review outcome are already running within the EU. In the future,
these should also include US and European analyses of projects
to assess the quality of marketing authorisation applications.
|
| 4.4.3 |
Interface
areas
|
|
i)
|
Research
European regulatory IT initiatives were considered significant and
necessary for improving the regulatory process. The general view was
that the EUDRAWATCH and EUDRANET programmes should be expanded. These
relatively new systems should be used as correspondence tools for
both industry and authorities all over Europe. Many agencies and companies
have not yet joined the systems, suggesting that forced commitment,
possibly in project form, could be initiated.
The authorities should introduce electronic communications wherever
possible. In the future, all written contact should be in the form
of electronic mails and electronic documentation forwarded in secure
mail systems such as EUDRANET. Technology allowing the secure electronic
exchange of information between industry and authorities should be
implemented. To ensure smooth communications, software applications
should be harmonised, removing incompatibilities.
|
|
ii)
|
Networking,
training and infrastructures
A pan-European network and forum for discussing acceptance criteria
should be established to initiate clinical trials with new biotech
or gene products in man. These initiatives are well supported by the
proposed changes to the new EU e-directive concerning clinical trials.
Another pan-European forum for discussing acceptance criteria of surrogate
end-points in major therapeutic areas is also required. This very
important task should top the list of joint projects involving industry,
academia and authorities. The training and education of assessors
within quality, safety and efficacy should be established at a European
level.
A central EU adverse event database regarding feasibility and development
aspects and an EU Centre of Excellence in pharmaco-epidemiology are
both great needs. Such European centres should be organised in such
a way that the necessary information can be simply obtained from national
agencies and industry.
|
| 4.4.4 |
Deliverables
The establishment of an early dialogue between regulatory authorities,
academia and industry regarding the implementation of new methodologies
and techniques would mean more new safe medicines could be brought
faster to the market.
|
| 4.5 |
How to
reshape the drug development process from the beginning
Scientific advances, competition and commercial considerations have
created a need to accelerate discovery and the development of new
and better medicines. Due to the fundamental change that has taken
place in drug discovery and development, pharmaceutical companies
are now developing, assessing and introducing new advanced technologies
to optimise the drug development process. Key issues here include
training and education and the crucial interface between regulatory
authorities and industry.
|
| 4.5.1 |
Bottlenecks
Research into the drug development process continues to be insufficient.
Opportunities to, for example, perform overlapping phases of clinical
development and combine multiple objectives and efforts in a given
trial remain relatively unexplored. More databases, benchmarking and
modelling tools for better decision-making processes are a necessity,
along with new technologies and research areas. Fields such as genomics,
proteomics, automation, miniaturisation and bioinformatics with their
tremendous potential still have to be integrated and used appropriately
throughout the drug development process.
High throughput procedures that use small quantities of material to
determine key parameters for predicting the efficacy and safety profile
of a product are often lacking in the clinical candidate selection
process. The generation, capture, analysis and mining of data have
to be more closely monitored and the proof of concept process streamlined
through the development of better prediction models within in silico
biology.
Optimisation of the drug development process requires technical and
scientific expertise in many areas. In some disciplines, such as bioinformatics
and applied mathematics, there is a lack of well-trained experts.
Due to the multidisciplinary nature of drug development, knowledge
covering a range of disciplines is required. This highlights the need
for a European syllabus for holistic drug development.
Regulatory requirements often do not reflect the latest scientific
developments. The interaction between regulatory authorities, academia
and industry is generally insufficient concerning the adaptation of
existing or establishment of new guidelines for drug development.
|
| 4.5.2 |
Research
and technology aspects |
|
i)
|
Without lowering scientific
and medical standards, it is necessary to intensify process research
in order to accelerate drug development. This involves:
- The implementation
of chemometrics and presence of high quality material in the right
quantities
- Developing IT-supported
information data management and decision-making processes, including
clinical data storage, retrieval and analysis tools and the integration
of pre-clinical and clinical data
- Introducing structure-based
predictive systems based on complex mathematical modelling and
analysis of data sets and simulation techniques, e.g. for drug
formulation and manufacture
- Integration of existing
and new structure-pharmacokinetic relationships in a network of
models supported by a growing volume of experimental data generated
by high throughput screening
- Genotyping, pharmacokinetics,
pharmacodynamics and phenotyping to be introduced as integral
parts of novel drug discovery and development
- Mathematical modelling
to connect disease with individual variance and biochemical symptoms
and disease progression.
|
|
ii)
|
Clinical candidate selection
requires new predictive methods for better and earlier decision
making. Efforts are needed to reduce the cycle time from drug discovery
to application of the first dose in man. These include:
- High throughput predictive
toxicology, absorption, distribution, metabolism and excretion
(ADME) screens and other cell assay predictors to study large
numbers of compounds available in small quantities. This requires
the implementation of nano-technology.
- The development of
new technologies based on human tissues, cells and membranes (in
vitro), new transgenic animals and new models of gene expression
(in vivo) to facilitate scaling up prior to use in man
- Increased efforts
in the field of innovative delivery systems
- Better computational
methods are necessary to determine the impact of physicochemical
properties on structure-function relationships
- In silico simulation
and modelling with high predictability will be of increasing importance
(e-ADME, e-toxicology)
- The establishment
of an optimised early drug supply chain to ensure the prediction
of biopharmaceutical and formulation properties. Large scale chromatography
and rapid scale up, parallel and automated production all of which
would provide a timely drug supply for clinical studies.
|
|
iii)
|
Proof of concept clinical
trials are used for "go/no go" decisions and are, therefore,
of critical importance to the entire development programme. These
require:
- New concepts for clinical
trial design and evaluation including statistical analyses
- Mathematical modelling
for a better understanding of diseases and simulation techniques
for elucidating biological and pharmacological issues
- Whole animal, mechanism-based
modelling to forecast human pharmacokinetics – the pharmacodynamic
relationship is essential
- The development of
cell assay systems in anticipation of down-stream development
issues
- Panels of biomedical
markers and surrogate end-points and their disease correlation
- Stronger early and
multi-centre clinical concept evaluation, including regulatory
definitions of the minimum requirements for entry into man
- The development of
pharmacogenetic profiling techniques for genome-based trial subject
selection.
|
| 4.5.3 |
Interface
areas
The interfaces between the various phases of the R&D process have
to be eliminated and a seamless discovery-development process established.
IT will play a major role here. Interfaces between different techniques
and disciplines, too, need to be overcome by forming interdisciplinary
project teams and providing training and education that combine a
number of disciplines.
In today’s drug development environment, networking is essential
at various levels, relating to co-operation within a given company,
among small, medium and large players in industry and between industry,
academic institutions and/or regulatory authorities. The legal, fiscal,
managerial and organisational foundations for such co-operation networks
need to be improved in order to benefit from the synergistic effects
created. Centralised databases and database networks based on a variety
of topics (e.g. antibiotic resistance and orphan diseases) should
be developed at a European level.
An official forum for interaction between regulators, academia and
industry would be conducive to reshaping and optimising the drug development
process, particularly in the light of new therapeutic approaches and
emerging technologies.
Training possibilities would increase if an inventory was established
with a detailed description of all the available education programmes
and training courses related to the pharmaceutical and biomedical
sciences involved in drug discovery and development. Action should
be taken to fill gaps and strengthen weak areas and training and education
in holistic oriented drug development made available.
New product types, techniques and therapeutic approaches sometimes
fail to gain social acceptance. More efforts are required to inform
and educate the public adequately. This calls in particular for the
training and education of ethical committees.
|
| 4.5.4 |
Deliverables
Under the leadership of the EU RTD Framework Programme and with the
appropriate support and incentives, drug research and development
could take a big step forward. An improved, science-based, decision-making
process, helping to avoid study delays and bottlenecks, would provide
patients with faster access to better medicines.
More research and interaction between industry, academia and regulatory
would result in the development of predictive models, including in
silico methods, and the establishment of a common database. Tested
and approved pre-clinical methodology for clinical candidate selection
would also emerge, along with modern, pragmatic and science-based
regulatory guidelines.
Validated and predictive biomarkers and surrogate end-points will
result from a better understanding of biochemical pathways and their
correlation to disease progression. More processes based on small-scale
experiments would contribute further to the optimisation of the supply
chain.
The establishment of Centres of Excellence would ensure better training
and education in cutting edge technologies and holistic drug development
methodologies – promoting the entire drug development process.
|
| 4.6 |
How to
utilise IT in speeding up the drug development process
This session covered the importance and expected impact of information
technology in the creation of a more effective drug development process.
|
| 4.6.1 |
Bottlenecks
A large and increasing number of activities related to the development
of medicines involve the use of advanced IT, such as informatics,
modelling and trial design. A series of barriers to more effective
use of IT in the development of medicines can, though, be identified:
- Too little understanding
of the potential impact of modern IT among scientists working
with drug development
- A need for information
systems with more user-friendly communication, data handling,
data storage, data presentation, etc.
- A need to implement
standardised and validated information systems
- Culture change in
data handling – from paper to electronic data
- Insufficient consideration
of key elements in data handling – the storage, use, share
and reuse of data
- Insufficient management
in all aspects of IT
- A lack of professionals
in the IT field and tough competition with other industrial branches
- A need for more effective
and secure systems for data handling with respect to the storage,
use, reuse and sharing of data.
|
| 4.6.2 |
Research
and technology aspects
Based on these barriers, a series of research and technology aspects
can be identified, facilitating progressive and necessary development.
These include research in IT relevant to the pharmaceutical sciences,
for example experimental design and data treatment, such as the design
of experiments, modelling of data, generation of predictive models
and calculation of model precision.
The generic principles and models for information management and bioinformatics
are important issues. The same goes for cost-benefit analysis in drug
development in terms of data generation, utilisation and quality.
New ways of communication with regulatory agencies are needed, such
as continuous dialogue and integration or on-line delivery of data.
Streamlined systems are also required for electronic communication
within health care systems, hospitals and laboratories and among general
practitioners.
In silico testing of drug candidates in biological and developmental
models raises many intriguing problems for the regulatory authorities
with regard to the validity of the results obtained from such simulations.
Here, the authorities have to depend on the amount and comprehensiveness
of the data on which the results are based. The authorities determine
how much data has to be produced before the results are recognised
as consistent.
|
| 4.6.3 |
Interface areas
IT is highly relevant to the following elements of the drug development
process. The list is not exhaustive.
- Prediction of pharmacokinetic/pharmadynamic
behaviour
- Toxicokinetics
- Pharmacogenetics
- Computer-aided trial
design
- Assessing risk associated
with specific projects
- Elimination of failed/equivocal
studies
- Dose ranging/optimisation
early in the development programme – always in relation to
key studies of commercial doses and formulation
- Use of all data available
to the project teams – toxicology data, known class effects,
data from previous trials, competitor experiences
- Automation of trial
management process
- Web-based networks
for data capture
- Development planning
and trial design using real-time data
- Real-time adverse
event effects and outcome reporting
- In silico
trials
- Process analytical
chemistry towards parametric release, reducing quality control
costs
- Batch release based
on information-rich, non-invasive process analytical chemistry
methods, also known as chemometrics
- Web-based patient
recruitment.
Education in modern information
systems and their potential use by researchers, administrators and
other personnel involved in the drug development process should be
developed. Activities related to this include the formation of a European
demonstration centre with super computers and modern information systems
and Centres of Excellence for public clinical and toxicity data, which
can be shared among clinical scientists. Some representatives from
industry further expressed an interest in gradually sharing data with
such a centre.
|
| 4.6.4 |
Deliverables
A drug development process incorporating information systems (IS)
and information management (IM) would result in better decisions,
less expensive knowledge and faster, more efficient drug development
due to:
- Fewer but better trials
conducted in more focused development programmes
- Faster trial reporting
with real time data, attracting faster regulatory review
- Availability of public
databases for all types of clinical data
- Fully implemented
electronic communication between health care bodies and employees.
|
| 4.7 |
How to
turn new biotech molecules into deliverable products
Macromolecular drugs which have been discovered and are possibly being
produced by modern biotechnology methods represent some of the special
aspects of biotech products. Discovery of such compounds, including
peptides and proteins, antisense agents, such as oligonucleotides,
and vectors for somatic in vivo gene therapy, may be expected
to increase over the next few years, with many already awaiting adequate
pharmaceutical development. In the future, pharmaceutical biotech
products may also comprise genetically modified cells, artificial
organs and devices designed and manufactured by modern tissue engineering.
|
| 4.7.1 |
Bottlenecks
|
|
i)
|
Research
and development
Compared to classic drugs consisting of small organic molecules, macromolecular
biopharmaceuticals appear to be much more efficient. Not only do they
alleviate symptoms but, in some cases, even cure diseases, such as
cancer, or inherited metabolic disorders. They also impose particular
demands on the development process, mainly because of their structural
complexity, large size and poor metabolic stability. In addition,
they are plagued by a very difficult delivery, particularly via the
most common and preferred oral route and through the blood-brain barrier
to reach the brain and central nervous system. The pathophysiological
background required for the design of new biotech molecules, too,
is often lacking. These factors were identified as significant bottlenecks
in the development of these compounds.
Due to their biochemical structure, biotech compounds impose particular
needs and demands on the analytical techniques used for quantification
and quality control. A particular emerging problem relevant to proteins
may be their glycosylation. Animal models and bioassays relevant to
diseases and metabolic disorders are often lacking.
Immunogenic side effects of systemically administered macromolecules
deserve particular attention. How can they possibly be overcome or
avoided by adequate molecular design? Sufficient quantities of compounds
for clinical trials, though, have to be provided by processes that
meet the regulations of Good Manufacturing Practices (GMP) –
a prohibitive cost for proof of concept. Such process development
requires better access to cell banks, as well as adequate fermentation,
purification processes and facilities.
|
|
ii)
|
Education
and training
The development of pharmaceutical biotech products requires adequate
education and training of the scientists responsible for such projects.
In many respects, traditional pharmaceutical curricula do not provide
sufficient background in molecular biotechnology, while specialists
trained in molecular biology and biochemistry often lack knowledge
and skills relevant to the development of pharmaceutical products.
Facilities and institutions for relevant training in pharmaceutical
biotechnology at both an academic and post-academic level are considered
vital. These can be organised by multidisciplinary collaboration between
the existing Centres of Excellence in various disciplines, for example
pharmacy schools and faculties, molecular biology, biochemistry and
bioengineering departments and departments covering fermentation,
scaling up and purification. Their activities need to be co-ordinated
by the creation of virtual and international centres, securing the
necessary critical mass and fulfilling education and training goals.
|
|
iii)
|
Regulatory
problems
Like most traditional pharmaceutical scientists, the regulators responsible
for registering pharmaceutical products have a fair understanding
of how to handle small organic molecules, but lack experience in handling
the larger biotech molecules. This calls for a constructive dialogue
between scientists, developers and regulators. In this, the regulatory
authorities and their personnel must interact with both academic institutions
and industrial companies to develop constructive partnerships.
Other specific problems identified for pharmaceutical biotech products
included the production of compounds under GMP conditions to obtain
an early proof of concept in clinical trials. In Europe, such facilities
are virtually non-existent. Special considerations and rules for conducting
clinical trials and registration procedures may further be enforced
for incipient compounds where clinical significance, i.e. orphan drug
status, must be demonstrated.
Considerations regarding substance purity, e.g. the presence of DNA
residues or differences in the glycosylation of recombinant peptides
and proteins, need special attention.
|
| 4.7.2 |
Research
and technology aspects
More specific research and the development of new methods are required
regarding the transportation of pharmaceutical biotech products across
biological barriers. New concepts and adequate targeting and delivery
systems are needed for this purpose.
Artificial gene-delivery systems, particularly non or pseudo-viral
ones which appear to be safer and easier to manufacture than the presently
favoured viral vectors, will be the key to the success of any in
vivo gene therapy, such as the treatment of cystic fibrosis by
CFTR-transfecting inhalation aerosols. Novel carrier systems, such
as nanoparticles, liposomes and micelles, also have to be investigated
and developed. In this context, the emerging, novel tools of bioinformatics
and nanotechnology have to be integrated in pharmaceutical sciences
and technology. Similarly targeting and stealth technologies, addressing
the various barriers imposed by the body’s immune system, will
be essential and have to be combined with the novel carrier systems.
The clarification of general structure-function relationships is another
need.
What research will bring regarding drug delivery through modified
cells and organs, newly designed peptides and proteins or special
medicotechnical devices can, at present, only be imagined. But technologies
that overcome biological barriers by facilitating cell entry or modulating
tight junctions in a physiologically acceptable way will have to be
developed in order to allow convenient, needle-free administration
to the patient. So-called alternative routes, e.g. pulmonary, buccal
and nasal, have to be explored physiologically and technologically.
Analytical methods for the quantification of biotech molecules still
often have to rely on complex and non-precise bioassays. These should
be replaced by modern alternatives, based on novel and emerging instrumental
analysis tools, including surface plasmon resonance, fluorescence
correlation spectroscopy, confocal laser and atomic force microscopy,
matrix-assisted laser desorption ionisation time-of-flight mass spectrometry
(MALDI-TOF-MS), possibly in conjunction with secondary ion mass spectrometry
(MS-SIMS). Valuable characterisation of biomolecules will be performed
by combining separation methods with various mass spectrometric techniques.
Medium to large-scale production requires new production and purification
methodologies, e.g. inducible expression systems, chemically defined,
serum-free media and inducible or infection systems, the latter replacing
transfection systems. Novel technologies, such as molecular imprinting
and transgenic animals, have to be adopted and further developed.
|
| 4.7.3 |
Interface
areas
The remarkable complexity of pharmaceutical biotech products within
analytical science, immunology, delivery/targeting and so on represents
particular scientific challenges. These can be solved by industry-academia
partnerships. The EU RTD Framework Programme should therefore address
the administrative and economic requirements which will make such
collaboration possible.
A holistic training approach to drug development requires further
expansion from the initial gene to product, including the process
system engineering necessary for biopharmaceuticals. Training networks
need to be established for on the job training in pharmaceutical biotechnology
and educational networks, too, for graduate students, such as the
European Masters Programme in Pharmaceutical Biotechnology with its
Ph.D. curriculum, visiting projects and summer schools.
Platforms for discussion and partnership between regulators, academia
and industry along with concerted actions to co-ordinate and discuss
transdisciplinary research programmes spanning from engineering to
cell biology are considered important tools. The rise of start-up
companies, particularly spin-offs from academic institutions, holds
great potential for the creation of new jobs for European society.
These enterprises, however, need funding to develop the necessary
core technologies and facilities to produce material that accords
with GMP for subsequent clinical trials.
|
| 4.7.4 |
Deliverables
Provided the proposed measures of this key action are implemented
and fulfilled during the coming 6th EU RTD Framework Programme, significant
progress may be expected for new pharmaceutical biotech products.
These will address the medical treatment needs of a variety of diseases
with a high impact on quality of life. Improved collaboration between
academic institutions, industrial companies and regulatory authorities
in relation to pharmaceutical biotech products will lead to sustainable
economic growth and create new job opportunities within both large
and small pharmaceutical companies in Europe.
|
|
|
5. Conclusions
|
| |
“New
Safe Medicines Faster” gained the full support of workshop participants
and several industrial, regulatory and academic organisations as a
key action in the coming 6th EU RTD Framework Programme. Further backing
from the cystic fibrosis patient organisation was obtained. With only
10 to 20 researchers per workshop session, it was not possible to
cover all aspects of the topics up for discussion. Nevertheless, through
the hard work and commitment of the participants, the required input
was produced. The discovery, pharmacogenetics and clinical research
aspects of the drug development process were also not subject to direct
analysis, the first being deliberately excluded and the latter failing
to receive necessary attention due to the lack of clinicians at the
workshop. Additional workshops in these three aspects are, then, required
to gain a complete picture of the road ahead for drug development
as a whole.
During the two days in Brussels, the following general conclusions
were drawn:
|
| 5.1 |
The drug
development process
The future prosperity of the European pharmaceutical industry is dependent
on the reshaping and optimisation of the drug development process
based on an integrated approach involving industry, academia and regulatory
authorities. While industry and academia have a tradition for co-operation,
direct interaction with Europe’s regulatory bodies lags behind.
The involvement of these authorities from the outset of the changes
of drug development process is considered vital.
The workshop deliberately focused on the development issues that follow
the discovery phase, all of which are of equal importance. Instead
of being viewed as a series of consecutive steps, drug development
requires parallel thinking to get the process to accelerate. At present,
the large number of lead candidates results in bottlenecks in the
ensuing development phases. What is required, then, is not just more
candidates, but candidates of a higher quality. IT is of paramount
importance for further integration of all the elements of the drug
development process.
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| 5.2 |
Focus research areas
and technology development
The multitude of research topics related to the drug development
process gives rise to a plenitude of interdisciplinary research
areas. Academia should take these topics on board with an early
involvement by regulatory authorities.
The following focus areas were mentioned:
- Functional gene analysis
- Pathophysiological
understanding of diseases for target prioritisation
- In vivo and
in vitro disease models and transgenic animals
- Pharmacogenetic profiling
and population genetics
- Predictive biomedical
markers and surrogate end points
- Drug and gene delivery
systems
- Modelling tools for
in silico testing to be applied wherever possible in the
drug development process
- Toolboxes containing
predictive methods and seamless scaling techniques
- Miniaturised fast
screens with a robotic base to be applied wherever possible in
the drug development process
- Pharmacometrics including
non-invasive testing methods and sensor technologies
- Process measurement
technologies to enable rational manufacturing
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