Answers That Matter.

September 2011 Produced by Eli Lilly and Company Limited Erl Wood Manor, Windlesham, Surrey GU20 6PHwww.lilly.co.uk

Lilly Research Centre – Erl WoodInnovation starts here

ContentsInnovation starts here 1

Drug Discovery 2

Target and Validation 2

Lead Generation 4

Lead Optimisation 5

Drug Development 8

First Human Dose Preparation 8

Phase I Clinical Trials 10

Phase II Clinical Trials 11

Phase III Clinical Trials 11

Registration 11

Post Launch Activities – Phase IV 12

A tradition of innovationEli 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.

Innovation starts here

The 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.

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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

At the core of Lilly Research Laboratories’ mission is discovering and developing innovative therapies for many of the world’s unmet medical needs.

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.

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Discovery 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

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 ValidationWhen 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 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.

Drug Discovery

In vitro and In vivoA 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.

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.

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 GenerationHaving 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;

optimisation’ phases is to increase activity against the chosen target, reduce activity against unrelated targets and improve the ‘drug-like’ 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

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

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,

The rise of the machinesThe 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.

Statistics in Drug Discovery and Development 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.

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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

Discovery

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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-, environmental- or 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 develop-ment 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 proc-esses can be observed and under-stood. 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

Predicting the therapeutic effects of Neuroscience drugsAt 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 five-and-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.

A safe workplace in a hazardous environmentIn 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.

Discovery

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.

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.

Drug Development

An 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 PreparationBefore the NME can be studied in humans, a number of issues must be addressed. Firstly, practical methods for the preparation of very large

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

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).

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

The European teamsThe 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.

Ethical and Safe productionAll 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.

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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 I Clinical TrialsIn Phase I trials, the drug is tested in

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

testing, the so-called Phase II clinical trials.

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.

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.

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).

RegistrationOnce 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

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

Ethics in Clinical ResearchThe 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.

Better than Placebo?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.

Registration Around the WorldIn 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).

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Drug Development

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.

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.

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Drug Development

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.