Download Lilly Research Centre – Erl Wood Innovation starts here

Lilly Research Centre – Erl Wood
Innovation starts here
September 2011
Produced by Eli Lilly and Company Limited
Erl Wood Manor, Windlesham, Surrey GU20 6PH
www.lilly.co.uk
Answers That Matter.
Innovation starts here
At the core of Lilly Research
Laboratories’ mission is discovering
and developing innovative therapies
for many of the world’s unmet
medical needs.
T
he Lilly Research Centre
at Erl Wood in Surrey was
established in 1967 and has
played a key role in some of the
company’s most important scientific
breakthroughs, including the
discovery of olanzapine (Zyprexa®)
for the treatment of schizophrenia
and bipolar disorders. Launched in
1996, Zyprexa® became Lilly’s most
successful medicine and has been
used to treat millions of patients
worldwide.
This long and illustrious history
in neuroscience research continues
today. Over 600 people, representing
45 nationalities and 30 different
functional disciplines, continue to
collaborate on the discovery and
development of new medicines to
meet areas of major unmet medical
need.
Contents
Innovation starts here
1
Drug Discovery 2
Target and Validation 2
Lead Generation
4
Lead Optimisation
5
Drug Development
First Human Dose Preparation
8
8
Phase I Clinical Trials
10
Phase II Clinical Trials
11
Phase III Clinical Trials
11
Registration
11
Post Launch Activities – Phase IV
12
In discovery research, the focus
is on treatments for Alzheimer’s
disease and other neurodegenerative
diseases, cognitive disorders and,
more recently, sleep disorders,
including insomnia.
In development, scientists
collaborate with colleagues around
the world on the broader Lilly
research and development portfolio,
working on potential medicines for
the treatment of cancer, diabetes,
neuroscience and auto-immune
disorders.
Continuing investment at Erl Wood
means that world class scientists
have world class facilities in which to
pursue their objectives. But despite
advances in technology and in the
understanding of biological systems,
drug discovery is still a lengthy,
expensive and difficult process with a
high rate of attrition.
Typically only one in 10,000
molecules synthesised in discovery
laboratories gets to market and only
one in seven of those is a commercial
success. Currently, the average
research and development cost of
each New Molecular Entity (NME) is
more than £1 billion.
The site also provides a physical
environment that is in harmony
with its surroundings and which
seeks to minimise its impact on the
environment.
Teamwork and communication are
key to being successful at developing
new treatments for disease. This
brochure provides an overview of how
people working in the many different
functions on site work together in
the highly complex process of drug
discovery and development.
A tradition of innovation
Eli Lilly and Company was founded in 1876 by Colonel Eli Lilly in Indianapolis, U.S.
A 38 year old pharmacist and veteran of the U.S. Civil War, Colonel Lilly was frustrated by the ineffective and often
poorly prepared medicine of the day and set himself the task of founding a company to manufacture pharmaceutical
products of the highest possible quality.
As his business flourished, in 1886 he hired a young chemist to work as a full-time scientist to use and improve
upon the latest techniques for quality evaluation. Together they laid the foundation for a dedication to quality and the
discovery of new and better pharmaceuticals.
Since those early days Lilly has grown to become one of the world’s largest research based pharmaceutical
companies, with over 35,000 employees and annual sales of over $20 billion.
Approximately 20 per cent of sales revenues, some $4.8 billion in 2010, are ploughed back into R&D each year
and 20 per cent of the company’s workforce is engaged in R&D activities. Lilly is among industry leaders in our
commitment to Research and Development. Eli Lilly, grandson of the company’s founder, described research as
“the heart of the foundation, the soul of the enterprise”.
This continuing commitment to researching innovative medicines that deliver real value to patients and healthcare
providers, has resulted in a product portfolio spanning oncology, diabetes, depression, schizophrenia, bi-polar
disorder, attention deficit hyperactivity disorder, erectile dysfunction, osteoporosis and growth disorders.
The company’s guiding principles of ‘integrity, excellence and respect for people’ are as valid today as they were
over 100 years ago.
1
Drug Discovery
In the past, many medicines were discovered
either by identifying the active ingredient
in traditional remedies or by serendipitous
discovery. More recently, understanding how
diseases are controlled at the molecular
and physiological level has become key
to creating new medicines. Even with this
greater understanding, the drug discovery
process is far from routine.
D
2
iscovery is focussed on
creating new molecular
entities (NME), which have
promising activity against a
particular biological target, for
example an enzyme or a receptor
(a protein that receives chemical
signals and helps turn them into
a biological action), thought to be
important in disease and so have
the potential to become a drug.
By the end of the discovery phase
information is gathered about target
engagement (whether the drug
can get to and interact with the
biological target in animals) and
“structure activity relationships”,
but little is known about the how
the human body will react to the
medicine (safety, toxicity).
In spite of the numerous scientific
advances in all fields relating to
drug-discovery and development,
the process is unpredictable and far
from routine. In fact, launching a
new medicine is more difficult today
than it has ever been; the number of
molecules approved by regulators
has dropped substantially over the
last decade and for every medicine
that is successfully launched, an
average of 5,000-10,000 potential
Lilly as part of a FIPNet
With R&D being such a high-risk endeavour, Lilly uses strategic alliances with other
companies and research institutions that allows access to new technologies and skills,
providing synergies that maximise the chances of delivering medicines to patients and
reducing the cost, and therefore the risk, in doing so.
FIPNet refers to Lilly being part of a Fully Integrated Pharmaceutical Network.
Rather than Lilly possessing all of the capabilities to perform drug discovery and
development internally, the company collaborates with external companies and
academics. This provides a greater flexibility for all parties and allows Lilly to share
some of the risk, and benefits, with them.
The Global External Research Development (GERD) group are responsible for
identifying opportunities for collaborations and partnerships with other pharmaceutical
or biotechnology companies and academia. These collaborations may be to access
scientific and medical capabilities or capacity, as well as the more traditional search
for new drug candidates.
Chorus Europe is the latest addition to the teams at Erl Wood. Chorus is Lilly’s
independently operating, early phase integrated drug development unit. It uses as
radically different clinical development process – rapid “Proof of concept” – and was
based on the assumption that early stage compounds are more likely to fail than
succeed – so getting to a decision point very quickly is critical. Another unique feature
of the Chorus teams is that they are part funded through venture capital in addition to
contributions from Lilly.
medicines were prepared and tested
during drug discovery.
Discovery encompasses a wide
variety of scientific activities focused
on identifying new targets and
confirming their role in disease. This
is a highly collaborative endeavour,
where Lilly scientists at Erl Wood
cooperate with colleagues at other
Lilly R&D sites in the USA, Spain and
China and with external partners in
the USA, UK, Europe and Asia.
All research during this phase is
covered by Good Research Practice
(GRP) guidelines which ensure
that all experiments are carried
out in a safe, ethical, thorough and
reproducible fashion.
Target Validation
When Lilly begins the search for
a potential new medicine, a large
amount of information is required to
establish the approach used in the
discovery programme.
Firstly, the disease mechanism
(how the disease occurs at the
molecular level) must be understood
so that suitable points to intercept
a particular metabolic or signalling
pathway that is specific to a disease
condition or pathology, can be
identified. These points are typically
proteins that regulate the production
or effect of biomolecules that are key
to the biological process in question
and are referred to as drug targets.
During target validation an
understanding is gained of how the
target functions in normal physiology
and how it is involved in the disease
state. This may come from, for
example, genetic linkage studies in
humans that show an association
between mutations in the biological
target and certain disease states, or
by removing a gene in animals to see
if this reproduces the disease state.
This is known as the gene “knockout”
approach and it allows scientists to
check that their hypothesis is valid,
although this does not mean that
success is guaranteed if a suitable
drug is found.
Another approach is the use
of previously published ‘tool’
compounds that selectively block or
activate the target in normal subjects
to determine if the disease state is
reproduced. These ‘tool’ compounds
are typically not suitable for use
as drugs for a variety of reasons,
but can be used to gain better
understanding of the disease.
During this stage it is important
to determine whether the target
is ‘drugable’. This means that it is
capable of binding a small molecule
and that its activity can be modulated
by this binding.
To be able to identify potential
drug molecules, biological studies,
known as assays, that show how
well a compound is capable of
interacting with the chosen target
are needed. Biologists therefore
look to create ‘in vitro’ assays to
test these compounds in artificial
In vitro and In vivo
A biological experiment that is
performed in vitro (from the latin
‘within glass’), is performed in a
controlled environment such as a
test tube or petri dish, while an in
vivo (from the latin ‘with the living’)
study is one that is performed in a
whole live organism. It is necessary
to determine actions in vivo because
there are many complex interactions
that occur in living systems that is it
not possible to model in vitro.
3
Discovery
Statistics in Drug Discovery and Development
in the body for sufficient time to give
adequate response. Drugs that are
eliminated from the body too rapidly
may need to be administered more
than once daily, which is often not
desirable and leads to some patients
failing to take the required dosage.
For these reasons, the solubility,
permeability and metabolism
(i.e. how the molecule is altered by
chemical reaction in order for it to be
more readily excreted from the body)
of compounds are among the key
properties which are studied at an
early stage in discovery, contributing
very significantly to the medicinal
chemistry efforts. Both experimental
and computationally predicted data
are used to try to learn more about
the properties of the molecule at a
very early stage.
In a similar fashion, the potential
that a drug will interact with
co-administered medications is
also studied to help minimise the
risk of the two drugs in combination
causing side effects that would not
be present for each single drug
(drug-drug interactions). These
concerns are addressed by the ADME
(Absorption, Distribution, Metabolism
& Excretion) group.
During the lead generation phase,
biologists will look to develop
systems using cells that have been
specially modified to produce a pure,
concentrated form of the target
protein. In order to develop these cell
lines, the DNA sequence of the target
protein must be identified.
When searching for new drugs, it
is important to find molecules that
interact specifically with the biological
target, so developing assays of this
type may provide an early indication
of how likely a potential drug
candidate is to achieve this goal.
These assays form the basis
of the next phase of discovery;
understanding how well small
molecules interact with this target.
In addition, the three-dimensional
structure of the target may be
determined.
Lead Generation
4
Having isolated pure target proteins,
biologists can test molecules that
have been prepared by chemists for
their degree of interaction with the
target.
Discovery chemistry begins with the
identification of active compounds,
often called ‘hits’. The ideal would
see only activity at the desired target
with no activity on other targets,
though this is seldom achieved. This
property is called selectivity.
The ‘hits’ are compounds that
interact with the target to some
extent (although most likely in a
sub-optimal fashion), but are quite
unlikely to have suitable properties
for a drug. Molecules having these
suitable properties must be found
before development of a safe and
efficacious drug can begin.
Chemists seek new molecules
aiming to improve how well they
interact with the target and also
improve other properties of the
molecule. They can study the data
that is obtained from the biological
assays, to investigate how changes
in molecular structure might affect
the affinity and drug-like properties
(Structure-Activity Relationships;
SAR) and can try to apply this to
the design of the next generation of
molecules to be made. If through
this research compound series begin
to show sufficient promise, then
these can be moved forward to the
next stage of the process, called
Lead Optimisation.
The aim of discovery chemistry in
both the ‘lead generation’ and ‘lead
The rise of the machines
The activity of the hits is confirmed at Erl Wood using highly sophisticated robots that
are capable of rapidly testing many compounds in in vitro assays. A cell culture robot,
developed with other Pharma companies and costing $1million, maintains the cells
needed for these assays.
optimisation’ phases is to increase
activity against the chosen target,
reduce activity against unrelated
targets and improve the ‘druglike’ properties of the molecule. In
reality, this is an unpredictable and
significantly inventive activity.
In order to be an efficacious drug
in man, the compound has to be
administered by an appropriate
route and must reach the biological
target effectively enough to elicit the
desired response
For an oral drug, the compound
must be well absorbed in the
digestive system with little variability
between patients and must remain
Statisticians use mathematics to understand and quantify uncertainty. Drug discovery
and development are processes which are highly unpredictable with a high risk of
failure. There is much uncertainty from beginning to end, meaning that statisticians
are engaged from early discovery right through to post-marketing authorisation
activities.
At each stage, statisticians are working with other scientists to understand
the scientific data that is generated (for example variation between patients) and
consequently increase our understanding of the drugs.
disease models that will provide
an understanding of how well the
molecule might affect the disease
state in real systems. These models
are typically very specialised and
may be performed in vitro using
tissue samples or in vivo models
where appropriate.
Statisticians help biologists by
identifying appropriate outcomes
from experiments to characterise
drug effects. They identify
appropriate methods and build
tools so that biologists can produce
the results on an on-going basis.
Techniques are also developed
to monitor study quality and
estimate the overall variation in the
experimental outcomes, which is
used to guide decisions.
The ability to obtain pure isolated
protein may allow structural
information to be obtained about
the target. Using this information
to improve the interaction of the
molecule with the target is known
as Structure-Based Drug Discovery.
Two main approaches are used here
at Erl Wood:
Fragment-based Drug Discovery
(FBDD), in general terms, involves
finding very small molecules
(fragments) that interact weakly
with the target and then using the
structural knowledge of the target
to add structural elements to the
fragments that enhance these
interactions.
Computer aided drug discovery
(CADD), in general terms, involves
building computational models of the
target and potential drug molecules
(that need not have been made in the
lab) and simulating their interaction.
This can be done using either
structural knowledge of the target or
knowledge of other molecules that
are known to interact with the target.
One of the issues with this approach
is that it is very difficult to predict
and control the drug-like properties
of the molecules.
Both of these drug discovery
methods are complementary to
existing approaches.
Lead Optimisation
Once one or more lead molecules
are identified, further research in
terms of their target engagement,
5
Discovery
Predicting the therapeutic effects of Neuroscience drugs
6
At Erl Wood our research interests are focussed on Alzheimer’s disease,
schizophrenia and sleep disorders. Many of the in vivo assays are required
to measure the cognitive abilities of rats and mice; for example, how they
control their attention to stimuli and how they form memories and learn
to perform specific tasks. These are all aspects that are severely impaired
in schizophrenia and Alzheimer’s disease. For sleep disorders, patterns of
electrical activity in the brain are continuously recorded so that stages of
sleep and wakefulness can be quantified throughout the day.
Protecting our Inventions
Research involves gaining new understanding of how a disease works and then
applying this knowledge in an attempt to develop a treatment. It is in the interests of
both the scientific community and society in general that this information be made
available, but in so doing, competitors could exploit the expensive research to their own
commercial ends.
By patenting these findings, time is granted to the inventor without commercial
challenge to enable them to recoup the cost of the research and possibly generate
further funds to enable research in new areas. Patent attorneys work closely with
research scientists throughout the process with a view to arriving at a solution which
can be the subject of a valid and enforceable patent.
Inventions that can be the subject of patent protection include new molecular
entities, combinations of substances, manufacturing processes and new applications
for known chemical substances. Patents must be filed in each country in which
protection is required and typically last around 20 years. A term extension of up to fiveand-a-half years is available in some countries if certain criteria are met.
Innovative companies only have limited patent life in which to get a return on the
investment in research before competition from generics can significantly impact sales.
While patents are expected to last 20 years (plus any extensions), their validity may
be challenged prior to this date. It is also the role of our patent attorneys and national
advocates to seek to preserve exclusivity on these patents and allow the research
expenditure to be recouped.
drug-like properties and other
dimensions is attempted. The aim
is that by the end of this phase the
optimal molecular structure will have
been found and that molecule can
begin development to become a drug.
A lot of effort is made to
validate the choice of target using
pharmacological-, environmentalor genetics-based animal models
together with physiological,
biochemical or behavioural assays
that provide quantification of the
drug’s effects.
Data from models and assays that
are the first indicators of potential
clinical efficacy are generally
obtained during lead optimisation,
where appropriate animal models
are used to investigate the biological
effects of the potential drugs.
Many aspects of drug development are directed towards satisfying
the regulatory requirements of drug
licensing authorities. These generally
require determination of the potential
toxicities of the NME before human
testing can begin. While some of
these tests can be performed using
in vitro methods (e.g. with isolated
cells), many tests can only be made
by using experimental animals, since
it is only in an animal model that the
complex interplay of biological processes can be observed and understood. Such tests help scientists to
decide whether a molecule merits
further development as a potential
new drug.
All animal testing, whether for
efficacy or toxicity testing is highly
regulated and takes place within a
culture where the care and welfare
of the animals is of paramount
importance.
For any given drug, the relationship
between drug exposure (i.e. how
much of that drug is available to
perform its biological action after the
various protection processes that the
body has in place have taken their
effect) and drug effect is called the
pharmacokinetic/pharmacodynamic
(PKPD) relationship.
Phamacokinetics are the data
that describe how the body absorbs,
distributes, metabolises and excretes
the drug, while pharmacodynamics
are the data that describe what the
drug does to the body; that is, how
the drug alters the body’s function.
It is useful if data can be obtained
in animals in order to examine
this relationship early on in the
discovery/development process
and PKPD scientists may become
involved at this stage. A good
understanding of the predicted
human PKPD relationship can allow
a team to select molecules likely to
have an optimal ‘window’ between
drug potency and potential adverse
effects. At a high level, the role of
the PKPD scientist in estimating an
efficacious dose involves two stages:
firstly, understanding the predicted
pharmacokinetics of the drug
based on animal and in vitro data
and, secondly, understanding the
pharmacodynamics of the drug and
how these relate to the exposures
predicted to be observed in the first
volunteers given the drug.
As molecules are developed that
start to have the desired properties
for a potential drug, synthetic
methods are optimised to allow the
preparation of larger quantities of
materials in a more reliable and
efficient manner. One of the primary
objectives of the Discovery Chemistry
Synthesis Group (DCSG) is to develop
and execute synthetic routes that
can supply material for initial safety
studies right the way through to early
manufacturing. These materials are
also used to take a first look at the
formulation of the potential drug.
By the end of lead optimisation,
promising compounds should
have sufficient target potency and
selectivity and favourable drug-like
properties and there will be a good
understanding of their biological
effects in animals.
A safe workplace in a hazardous
environment
In creating NME’s that are intended to
interact with biological systems, it is
inherently the case that little or nothing
is known about their toxicity in humans.
As such, it is important to ensure that all
employees are protected from undesirable
exposure to chemical, physical and biological
hazards that exist in the workplace. The
Occupational Health team aims to identify and
eliminate risks before harm can occur. This
involves monitoring and assessing employee
health and the working environment.
7
Drug Development
The process of drug discovery involves the
identification of ‘candidate molecules’,
synthesis, characterisation, screening, and
assays for therapeutic efficacy.
Once a compound has shown its value in
these tests, it will begin the process of
drug development prior to clinical trials,
which will teach us more about the safety,
pharmacokinetics and metabolism of this
NME in humans.
A
8
n experimental drug is first
tested in the laboratory and
in animal studies. After this
pre-clinical testing, the medicine
can advance to clinical testing and
development. Unfortunately, most
new molecular entities fail during
development, either because they
have some unacceptable toxicity, or
because they simply do not provide
enough benefit in clinical trials.
Launching a new drug has never
been harder than it is today and
will continue to get harder as time
passes; more data is required from
clinical trials than ever before and
those who pay for these medicines
(governments and insurers) are
ever more vigilant about the cost of
treatment.
First Human Dose Preparation
Before the NME can be studied in
humans, a number of issues must be
addressed. Firstly, practical methods
for the preparation of very large
The European teams
The Erl Wood Millennium Centre (EMC)
and Research Office Building (ROB)
were designed to co-locate development
groups – including Medical, Marketing,
Regulatory, Health Outcomes, Statistics,
Pharmacokinetics/Pharmacodynamics,
Global Patient Safety and Clinical
Pharmacology – to optimise European
regional activities and to help product teams
in the development and commercialisation of
new products in Europe.
to give the first human volunteers
who will take the drug. If the dose is
too high, the risk of causing toxicity
is higher, too low and the chances
of reaching exposures that produce
efficacy are reduced. It can be very
difficult to understand where to
target the dose in humans and this is
the main aim of the PKPD scientist at
this stage of the process.
Preclinical and CMC data must
be submitted to the appropriate
national or international regulatory
body for approval before clinical
trials can begin. This interaction
with the regulators is handled by
the Regulatory Affairs group. The
Erl Wood Regulatory Affairs group
coordinates regulatory activities for
European countries and Australia
and works directly with the European
Medicines Agency (EMA).
In Europe, a Clinical Trial
Application (CTA) is submitted
to the national competent
authorities in the countries in
which the trial will be conducted
and in the USA an Investigational
New Drug Application (IND) is
submitted to the Food and Drug
Administration (FDA).
quantities of the NME to the high
standards required for the upcoming
trials must be developed.
This requires the Chemical
Process Research and Development
team (based in Indianapolis) to begin
optimising the synthetic route and
ensure that the material can be
made on manufacturing scale when
required.
This also requires the development
of analytical methods to characterise
the physicochemical properties of
the molecule including its chemical
structure, physical properties,
stability and presence of impurities
(Pharmaceutical Analysis). Together
these processes are known in
preclinical development as CMC:
Chemistry, Manufacturing and
Control.
Secondly, the method of
administration of the molecule must
also be considered. Finding the most
appropriate method to deliver the
best possible biological response
in humans – for example, capsules,
tablets, injections or aerosols – is
key to progression.
In preparation for a clinical trial, it
is important to understand what dose
Ethical and Safe production
All manufacturing is carried out under
GMP (Good Manufacturing Practice)
guidelines, which ensure the highest
possible quality of materials for
clinical trials and later, retail. These
regulations cover personnel, rooms,
equipment, quality of raw materials,
storage, the production process,
packaging, production hygiene,
analysis, distribution records and
complaints procedures.
Clinical trials are required before
the regulatory authority approves
marketing of the drug or device, or
a new dose of the drug, for use on
patients. Trials are typically designed
to assess the safety and efficacy of a
new medication on a specific kind of
patient or for an existing medication
in a new indication (i.e. a disease
for which the drug is not already
approved).
In order to demonstrate the
efficacy of a potential new drug,
development and submission
strategies must be put in place
to ensure that the correct data
is collected and shared with the
regulators in the most appropriate
manner. This is extremely important
in ensuring that the regulators are
able to make the correct decision
on approving this potential drug
9
Drug Development
Better than Placebo?
10
testing, the so-called Phase II
clinical trials.
for use and involves collaboration
between the Regulatory Affairs
group, Medical, Manufacturing and
Marketing.
Clinical trials can last for a very
long time as it can take months, if
not years, to prove that a treatment
has a clear beneficial effect on
patients. They are often extremely
expensive as they can involve large
numbers of patients at in-patient
clinics and hospitals around the
world with full-time supervision from
trained medical staff. Also, recruiting
enough patients to test the drug’s
efficacy can take several years.
All such trials must be conducted
ethically and they are reviewed and
approved by ethics committees with
all trial participants made aware of
the risks and potential benefits of the
trial and must give informed consent
to participate. These standards
are covered by a general set of
guidelines known as GCP (Good
Clinical Practice).
Typically, clinical testing is divided
into three main phases (Phases
I-III). The trials start by looking at
safety in small numbers of people
and work their way up to looking at
efficacy and safety in large groups
(thousands) of patients. Phases II
and III carry the bulk of the cost
(larger patient numbers).
Phase II Clinical Trials
In Phase II trials, the drug is given
to a larger group of people (typically
100-300) who have the disease that
the drug is intended to treat so as
to test its efficacy, determine the
effective dose range and further
evaluate its safety.
For every five molecules that
enter phase II only two go on to
phase III trials. This is the highest
rate of attrition in any phase of
clinical development. These trials
typically last approximately
two years.
Phase I Clinical Trials
In Phase I trials, the drug is tested in
Ethics in Clinical Research
The Declaration of Helsinki was developed
by the World Medical Association (WMA), as
a set of ethical principles regarding human
clinical trials. This declaration states
that the individual has the right to make
informed decision regarding participation
in research, both initially and during the
course of the research. The investigator’s
duty must be solely to the patient or
volunteer and the subject’s welfare must
always take precedence over the interests
of science.
All clinical studies should be carried out
according to International Conference on
Harmonisation (ICH) / WHO Good Clinical
Practice standards. This provides a unified
standard for the European Union (EU),
Japan, and the United States, as well as
Australia, Canada, Scandinavia. Thus, any
country that adopts this guideline will
follow the same standard.
a small group of patients or healthy
volunteers (20-80) at low doses to
evaluate its safety and identify side
effects, rather than test its efficacy.
These first studies are guided by the
information that was obtained in the
pre-clinical animal studies.
For every 10 molecules that enter
phase I only five go on to phase II
trials. These trials typically last
approximately one year.
The doses are gradually increased
to measure the effect that the
medicine has on the participants
and to determine how well the drug
is absorbed, how long it remains
in the body and which doses are
safe and well tolerated (human
pharmacokinetic profile).
The pharmacokinetics of the drug
in the human volunteers may be
continually assessed to ensure that
a safe and efficacious exposure
range can be defined for future
trials and that the variability in
pharmacokinetics between patients
is such that patient’s exposures
may be maintained within a range
where the drug can be effective
(‘therapeutic window’).
For biological targets that have not
previously been tackled by drug-like
molecules, Phase I clinical trials
can offer the opportunity to obtain
proof-of-concept, where the efficacy
in humans can first be assessed,
however this is most commonly
obtained in the next stage of clinical
In these larger clinical trials, large
amounts of data may be collected
that describe the behaviour of the
drug in patients. This can be used
to investigate the impact of patient
characteristics (e.g. body weight,
gender, ethnicity or genetic or
environmental factors) on the action
of the drug. If the variability in drug
action as a result of these factors,or
‘covariates’, is known then doses
may be ‘individualised’ based on
a subject’s characteristics. This
is known as tailored therapeutics,
where drugs and their doses can be
tailored to the individual patient.
The most effective dosages for
the potential drug are determined
and the most appropriate method
of delivery (e.g., tablets, extended
release capsules, infusions,
injections, etc.) is also studied.
Phase III Clinical Trials
For every two molecules that
enter phase III only one goes
on to registration. These trials
typically last approximately
three years.
The drug is given to large numbers
of people (typically 1,000-3,000) to
explore further its effectiveness,
monitor its safety, compare it to
commonly used treatments (for
which a large amount of data is
known), and collect information that
will allow the drug or treatment to
be used safely.
These trials are often randomised
and ’double-blinded’. This means
that during the trial, neither the
investigator nor the participant
know who in the trial is getting the
new drug or a placebo (inactive)
pill or another medicine that
is already established as the
standard of care for the treatment
of the disease being studied.
Because of their size and
long duration, they are the most
expensive, time-consuming and
difficult trials to design and run,
especially in therapies for chronic
medical conditions (medical
conditions that are either long
lasting or recurrent).
Registration
Once a drug has proved satisfactory
in Phase III trials, the results are
combined into a large document
containing a comprehensive
description of the methods and
results of human and animal
studies, manufacturing procedures,
formulation details, and shelf life.
This collection of information
makes up the ‘regulatory
submission’ that is provided for
review to the appropriate regulatory
authorities in different countries.
This step is known as registration. If
regulators agree that the data prove
the quality, efficacy and safety of the
drug, a marketing authorisation is
granted. The drug can now be made
commercially available to patients.
The task of assembling registration
Registration Around the
World
In the European Union, a Market
Authorization Application (MAA)
for most new medicines is filed
with the European Medicines
Agency (EMA). In the U.S., a New
Drug Application (NDA) is filed
with the U.S. Food and Drug
Administration (FDA).
documents for worldwide use is
very complex as countries have
different regulations and format
requirements. Registration can take
months to years, depending on how
the data is interpreted and whether
further trials are required to satisfy
individual regulators.
If the registration documents
that were compiled for the
registration of Efient (Prasugrel)
with the FDA had been printed out
on standard paper and stacked,
the resulting tower would have
been as tall as the Empire State
Building.
Having discovered and developed
a potential new medicine, its
commercial potential must be
realised to try to recover the R&D
outlay. To do so, this NME must
become a product. This involves
creating a brand and ensuring that
both prescribers and payers are
aware of the product and its benefits
to patients.
To ensure that new medicines
meet unmet medical needs and
11
Drug Development
Global product protection security team
At the completion of the phase III trial and
prior to market approval, a risk assessment
is carried out into the likelihood of the new
product being counterfeited. Counterfeit
medicines are manufactured to look identical to
the genuine product, including the packaging,
to encourage the patient to believe they have
the genuine product.
The medicine itself may or may not contain
the correct active ingredient, and even if it
does this may not necessarily be at the correct
quality or dosage and may contain other
impurities. Counterfeit medicines are a global
problem and a serious threat to public health.
Lilly’s Global Product Protection Security
Team monitors the internet to identify what is
for sale and makes test purchases to establish
the provenance of the product being sold. A
number of successful criminal and civil actions
have followed.
12
offer value to payors, patients and
shareholders, there is a new product
planning process that spans early
clinical development through to
the introduction of the medicine in
countries around the world.
Recently, Lilly formed business
units for different therapy areas
designed to ensure that the company
develops and commercialises
medicines that meet patients’
needs and to speed the delivery of
these medicines to the market. The
international arms of these business
units are based here at Erl Wood.
Post Launch Activities (Phase IV)
Once a drug is on the market, its
safety profile needs to be constantly
monitored, evaluated and reported to
the regulatory authorities.
No drug is free from side
effects in certain people and the
collection, evaluation and reporting
of information on undesirable side
effects is extremely important to
ensure that doctors, pharmacists
and patients can be well informed to
avoid possible harm.
This important role is performed
by Global Patient Safety (GPS), a
function that takes care of the Lilly
pharmacovigilance system, which
operates throughout the lifecycle of
the drug. At the initiation of clinical
trials, the safety profile of the drug
is developed from pre-clinical
data (e.g. toxicology data and data
available from similar compounds).
From first human dose and
throughout the course of clinical
trials, data are collected and
monitored to provide updated
information regarding the safety
profile of the drug. Important
risks (potential and identified)
are documented, along with
pharmacovigilance and risk
minimisation activities related to
them.
At the time of marketing approval,
appropriate safety data from
clinical trials are documented in the
approved labelling for the product.
Post-marketing studies may also
be conducted to continue to collect
information in a structured format.
In addition, healthcare
professionals and patients submit
reports as a result of their
experiences, including side-effects
or ‘adverse events’, with medicines.
If analyses of these data indicate
a change in benefit-risk profile of
the medicine, action is taken. This
may include notifying regulators,
communicating with healthcare
professionals and changing patient
information leaflets.
Statisticians collaborate closely
with the Health Outcomes team to
provide the various public and private
healthcare providers in the EU with
evidence that the new products are
not only safe and efficacious, but
also provide value for money.
All pharmacovigilance activities
are strictly regulated and controlled
internally and externally to ensure
that Lilly products are used by
healthcare providers for the right
patients in the right way and at
the right dose – thus ensuring that
medicines bring a true benefit to
patients.
It is also the responsibility of the
Regulatory Affairs group to ensure
that all marketing authorisations
are kept up-to-date thereby allowing
the products to stay on the market,
particularly in the early life of a
medicine, when it is more likely
that changes will be made to the
prescribing information.
After a period of time on the
market, some medicines are found
to be useful for the treatment
of conditions that they were not
originally intended for. Medicines
must be approved for use in these
new conditions in much the same
way as when they were originally
registered. Also, new formulations
(e.g. a change of tablet composition
or manufacturing method) can be
made to improve the effectiveness
of the medicine, but similar
requirements must be met.
A range of other functions are
based at the site to support all the
teams more directly involved in drug
discovery and development – without
whom the site would not function.
These include Facilities Management
(including Project and Instrument
Engineering), Finance, Procurement,
Human Resources, Environment,
Health & Safety, Occupational Health
and IT.
Supporting functions at
Erl Wood
A range of other functions are
based at the site to support all the
teams more directly involved in drug
discovery and development – without
whom the site would not function.
These include Facilities Management
including Project and Instrument
Engineering), Finance, Procurement,
Human Resources, Environment,
Health & Safety, Occupational Health
and IT.