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Pharma 2020 - Virtual R&D

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Innovation, Research and Development progression within the pharmaceutical industry. …

Innovation, Research and Development progression within the pharmaceutical industry.
Article by PricewaterhouseCoopers.

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  • 1. Pharmaceuticals and Life SciencesPharma 2020: Virtual R&DWhich path will you take?Pharma 2020: Virtual R&D 1
  • 2. Table of contents of contentsInnovation essentials 1Getting to know ourselves 4Making research more predictive 6Expediting development 9Collaborating to bring treatments to the market 15Imperatives for change 18Acknowledgements 19References 20Contacts 21 Pharma 2020: Virtual R&D – Which path will you take? is the second in a series of papers published by PricewaterhouseCoopers exploring the future of the pharmaceutical industry. Published in June 2007, Pharma 2020: The vision – Which path will you take? highlighted a number of issues that will have a major bearing on the industry over the next 13 years and outlined the changes we believe will best help pharmaceutical companies realise the potential the future holds to enhance the value they provide to shareholders and society alike. This paper explores the opportunities to improve the R&D process. It proposes new technologies will enable the adoption of virtual R&D; and by operating in a more connected world, the industry in collaboration with researchers, governments, healthcare payers and providers, can address the changing needs of society more effectively.
  • 3. Innovation essentials Pharma is at a pivotal point inSeven major trends reshaping the pharmaceutical marketplace its evolution. As we* indicatedThe pharmaceutical marketplace is changing dramatically, with huge ramifications in “Pharma 2020: The vision” byfor the industry as a whole. We have identified seven major socio-economic trends. PricewaterhouseCoopers, published in June 20071, the social, demographicThe burden of chronic disease is clinical advances render previously fatal and economic milieu in which thesoaring. The prevalence of chronic diseases chronic. The self-medication industry operates is undergoing hugediseases like diabetes is growing sector is also increasing as more changes (see sidebar, Seven majoreverywhere. As greater longevity forces prescription products are switched to trends reshaping the pharmaceuticalmany countries to lift the retirement age, over-the-counter status. The needs marketplace). These challenges havemore people will still be working at the of patients are changing accordingly. been compounded by the dearth ofpoint at which these diseases start. The Where treatment is migrating from the good new compounds in its pipeline.social and economic value of treatments doctor to ancillary care or self-care,for chronic diseases will rise accordingly, patients will require more comprehensivebut Pharma will have to reduce its information. Where treatment isprices and rely on volume sales of such migrating from the hospital to theproducts because many countries will primary-care sector, patients will requireotherwise be unable to afford them. new services such as home delivery.Healthcare policy-makers and payers The markets of the developing world,are increasingly mandating what where demand for medicines is likelydoctors can prescribe. As treatment to grow most rapidly over the next 12protocols replace individual prescribing years, are highly varied. Developingdecisions, Pharma’s target audience countries have very different clinicalis also becoming more consolidated and economic characteristics,and more powerful, with profound healthcare systems and attitudesimplications for its sales and marketing towards the protection of intellectualmodel. The industry will have to work property. Any company that wants tomuch harder for its dollars, collaborate serve these markets successfully willwith healthcare payers and providers, therefore have to devise strategies thatand improve patient compliance. are tailored to their individual needs.Pay-for-performance is on the rise. Many governments are beginningA growing number of healthcare payers to focus on prevention rather thanare measuring the pharmacoeconomic treatment, although they are not yetperformance of different medicines. investing very much in pre-emptiveWidespread adoption of electronic measures. This change of emphasismedical records will give them the will enable Pharma to enter the realmoutcomes data they need to determine of health management. But if it is tobest medical practice, eschew do so, it will have to rebuild its image,products that are more expensive since healthcare professionals andor less effective than comparable patients will not trust the industry totherapies and pay for treatments provide such services unless they arebased on the outcomes they deliver. sure it has their best interests at heart.So Pharma will have to prove that its The regulators are becoming moremedicines really work, provide value for risk-averse. The leading national andmoney and are better than alternative multinational agencies have becomeforms of intervention. much more cautious about approvingThe boundaries between different truly innovative medicines, in the wake * PricewaterhouseCoopers refers to the networkforms of healthcare are blurring. The of the problems with Vioxx. of member firms of PricewaterhouseCoopers International Limited, each of which is a separateprimary-care sector is expanding as and independent legal entity.Pharma 2020: Virtual R&D 1
  • 4. Table of contentsPharma’s traditional strategy of Figure 1: The decline in R&D productivityplacing big bets on a few molecules,promoting them heavily and turningthem into blockbusters worked well 50,000 60for shareholders for many years. No. of NME, BLA Approvals R&D Spending (US$ Millions) 45,000However, its productivity in the lab 50 40,000is now plummeting, as it switches 35,000 40its attention from diseases that are 30,000relatively common and easy to treat to 25,000 30those that are much more complex or 20,000unusual. In 2007, the US Food and Drug 20 15,000Administration (FDA) approved only 19 10,000 10new molecular entities and biologics – a 5,000smaller number than at any time since 0 01983 (see Figure 1)2. 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004* 2005* 2006* 2007*Moreover, the patents on many of the * Includes Biologics Global R&D Spending NME and New Biologics Approved (BLA)medicines the industry launched inthe glory days of the 1990s will expire NME:over the next few years, leaving Big New chemical or biological prescription therapeutic: excludes vaccines,Pharma very exposed. US research firm antigens and combination therapies which do not include at least one new constituentsSanford C. Bernstein estimates thatgeneric erosion will knock between 2%and 40% off the revenues of the top Source: FDA CDER, PhRMA and PricewaterhouseCoopers analysis10 companies between now and 2015(see Figure 2). Worse still, it calculatesthat only four of the 10 have pipelinescontaining products sufficiently valuableto offset these losses.32 PricewaterhouseCoopers
  • 5. Figure 2: The impact of generic erosion on Big Pharma’s revenues “Base Revenue Estimates” (US$ Millions) Company 2008 2015 % Change Novartis $40,529 $45,714 13% Schering-Plough $20,595 $20,216 (2%) Wyeth $22,367 $20,537 (8%) GlaxoSmithKline $22,858 $20,294 (11%) sanofi-aventis $43,177 $36,186 (16%) Merck & Co $29,724 $24,428 (18%) Bristol-Myers Squibb $21,603 $16,364 (24%) Eli Lilly $20,275 $15,286 (25%) Pfizer $48,639 $34,075 (30%) AstraZeneca $31,522 $18,878 (40%)Source: Bernstein estimates and analysisNote: These figures show each company’s “base revenues” from products that are already on themarket. They exclude any future pipeline contributionsThis “innovation deficit” has enormous We believe that, if the industry is tostrategic implications for the industry become more innovative and cut itsas a whole. Many pharmaceutical R&D costs, four features will be vital:companies need to decide what they • A comprehensive understanding ofwant to concentrate on doing and how the human body works at theidentify the core competencies they will molecular levelrequire, a process which may involveexiting from some parts of research and • A much better grasp of thedevelopment (R&D). But even those that pathophysiology of disease (byregard research and development as a which we mean the functionalcore element of their business will have changes associated with, or arisingto make fundamental alterations in the from, disease or injury)way they work. They may, for example, • Greater use of new technologies tohave to focus more heavily on speciality “virtualise” the research process andtherapies, since most of the diseases accelerate clinical development; andfor which there are currently no effectivemedications or cures are not amenable • Greater collaboration between theto mass-market treatments, as well as industry, academia, the regulators,reducing the time and costs involved governments and healthcarein researching and developing such providers.medicines to ensure that society can We shall discuss some of the changesafford them. we consider necessary in more detail in the following pages.Pharma 2020: Virtual R&D 3
  • 6. Getting to know ourselves At present, when pharmaceutical predictive models and generate furtherVirtual vermin companies start investigating biological knowledge.The American Diabetes Association targets, they may know relatively little Bioinformatics experts aim to create aand US biopharmaceutical company about how those targets are involved complete mathematical model of theEntelos have developed a diabetic in the diseases they want to treat. The molecular and cellular components of thevirtual mouse that is being used to information they possess usually comes human body – a “virtual” man – whichstudy cures for Type 1 diabetes. from academic literature and patents, can be used to simulate the physiologicalResearchers can simulate the effect and is often based on animal studies, effects of interacting with specific targets,of new medicines, including different which may not be relevant to the way in identify which targets have a bearing ondosing levels and dosing regimens, which a disease progresses in humans. the course of a disease and determineon different therapeutic targets, It is generally only in Phase II clinicalbiological pathways and functions. what sort of intervention is required trials that companies test whetherThe model is based on years of data modulating a particular target with a (i.e. an agonist, antagonist, inversefrom experiments on real animals, particular molecule is efficacious in agonist, opener, blocker etc.). However,but virtual animals could be created treating a disease in man. developing such a model will require afor any species for which there are monumental global effort far exceeding This helps to explain why just 11% of that of any similar work, e.g., the Humansufficient data. the molecules that enter pre-clinical Genome Project. development reach the market,4 and hence why costs per drug are so Numerous organizations are building high. The Tufts Center for the Study of models of different organs and cells, or Drug Development puts the average creating three-dimensional images from bill for producing a new medicine at the resulting data (see sidebar, Virtual $868m.5 Clearly, there are significant vermin).8 One of the biggest problems variations, depending on the therapeutic with these models is that they are only area concerned (see Figure 3).6 as good as the data on which they are Nevertheless, given average costs and based, and little is currently known average attrition rates in each phase of about many physiological processes. the R&D process, we estimate that the Ultimately, they must also be integrated cost of conducting R&D is $454m per into a validated model in order to product.7 predict the effects of modulating a biological target on the whole system, It is now widely recognised that one and that model must be capable of the elements required to overcome of reflecting common genetic and the problems in the research process phenotypic variations. The computing and make significant advances in the power required to run such a model will treatment of disease is a comprehensive be enormous. understanding of how the human body works at the molecular level, Despite these difficulties, various together with a much better grasp of academic collaborations to create a the pathophysiology of disease. This digital representation of the human knowledge can then be used to build body are already underway. The Step4 PricewaterhouseCoopers
  • 7. Figure 3: Costs per drug for medicines in selected therapeutic areas 1400 Average Cost of R&D by Therapy Area 1200 1000 US$ Millions 800 600 400 200 0 d r y r al al c ry y IV la ce ar or iti oo et ic to H cu as in an ns og el ira Bl ur as ar sk Se C l sp ro ito tip ov lo eu Re en cu di An N ar G us C MSource: Christopher P. Adams & Van V. Brantner, “Spending on New Drug Development”Consortium is, for example, developing biosimulation is already playing aa methodological and technological growing role in the R&D process.framework for investigating the human Scientists at University College, London,body as a single complex system.9 have, for example, used computerMeanwhile, the Living Human Project modelling to simulate the efficacy ofis working on an in silico model of the an HIV treatment in blocking one ofhuman musculoskeletal apparatus,10 the key proteins used by the virus.12and the Physiome Project aims to Similarly, when Roche was developingcreate a computational framework for Pegasys, its combination treatment forunderstanding the integrative function hepatitis C, it used computer modellingof cells, organs and organisms.11 The to determine the optimum dose forcommercial potential of virtual man different subpopulations of patients onmight also attract the interest of some whom the therapy had not been testedof the largest technology providers, and in real life.13 We anticipate that this trendgrid computing will deliver the resources will continue and that, by 2020, virtualrequired to support R&D on demand. cells, organs and animals will be widelyIt is probably unrealistic to think that employed in pharmaceutical research,virtual patients will be available within reducing the need to experiment onthe next 12 years. However, predictive living creatures.Pharma 2020: Virtual R&D 5
  • 8. Making research more predictive In silico methods are currently used predicting the efficacy of a molecule to design new molecules, where the in man (especially when the target is a structure of the target is known and new one). So Pharma needs a faster the interactions between the target and and more predictive way of testing virtual molecules can be modelled. But molecules before they go into man. researchers more commonly use in vitro With the advent of virtual patients, it screens to find molecules that “hit” a will be possible to “screen” candidates designated target, and further screens in a digital representation of the to test the physical and toxicological human body which can be adjusted to properties of these molecules. reflect common genetic variations and Thereafter, they test the most promising disease traits, such as a weakened candidates in animals before forwarding cardiovascular system. This will show them for initial testing in man (see whether a molecule interacts with any Figure 4). unwanted targets and produces any This approach has numerous side effects, and in what circumstances drawbacks. It usually produces a it does so. Predictive analysis will then reasonably clear picture of how the enable researchers to assess how molecule being researched interacts the molecule is likely to be absorbed, with the target, and how safe it is. But distributed, metabolised and excreted; in vitro assays and animal models of a what long-term side effects it might disease are often unrepresentative of have; what free plasma concentration is that same disease in human beings, needed to provide the optimal balance and are thus an unreliable means of between efficacy and safety; and whatFigure 4: The current research process Hit ID/ Testing of Testing of Design of Synthesis of Initial testing Target ID screening of molecule molecule molecule molecule in man molecule in vitro in vivo Mixed Computer/Lab Lab work Testing in manSource: PricewaterhouseCoopers6 PricewaterhouseCoopers
  • 9. Figure 5: What the research process might look like when virtual man exists Taking the pain out of the process When bioinformatics provider Design of Testing of Synthesis of Initial testing BioWisdom wanted to identify which Target ID ion channels might be promising treatment treatment treatment in man targets for developing pain treatments, Primary it began by creating a vocabulary In silico pharmacology for 349 human ion channels. Then Lab work Wide-ligand profiling it trawled MEDLINE to find every Testing in man (testing for side-effects) document in which these 349 ion ADME properties channels, or any of their 4,000 Pharmaceutical science synonyms, were mentioned in Toxicology conjunction with the central and peripheral sites that are knownSource: PricewaterhouseCoopers to be relevant in mediating pain. Further analysis of the literature on the 59 ion channels this processformulation and dosing levels might (e.g. headache and migraine) in different produced showed that 11 ionwork best. This suggests that much of sources, it cannot readily be connected. channels were clearly associated with Conversely, where two concepts share the three key mechanisms of painthe work currently undertaken in the the same name but are fundamentally (central sensitisation, allodynia andclinical environment can be tackled different, they will be treated as if hyperalgesia), while another 10 lookedmuch earlier within discovery. Figure they are identical. As a result, it is worthy of additional exploration.5 shows what we think the researchprocess might look like, once robust very difficult to aggregate data fromcomputer models of the entire human multiple sources and make meaningfulbody are available. associations between them, without the application of intelligent reasoning.However, as we have already indicated,the “birth” of virtual man is still many Semantic technologies, by contrast, willyears off. In the more immediate allow scientists to connect disparatefuture, two other advances – semantic data sets, query the data using “naturaltechnologies and computer-aided language” and make correlationsmolecule design – will play a much bigger that would otherwise have been unobservable (see sidebar, Taking thepart in enhancing the research process. pain out of the process).14 This willTraditional informatics systems are make it much easier to identify the linksconstrained both by the structure of the between a particular disease and thedata they represent and how they can biological pathways it affects, or therepresent those data. Thus, if the same links between a particular molecule andconcept is called by different names its impact on the human body.Pharma 2020: Virtual R&D 7
  • 10. Table of contentsMeanwhile, computer-aided molecule a medicine which is known to work in now pays its researchers a bonus onlydesign (utilising greater knowledge the clinic has no impact in a “predictive” when a candidate molecule reaches theabout biological targets and their in vivo model, it will be clear that the proof-of-concept stage or when theystructure) will give researchers a much model is flawed. solve major problems, such as figuringbetter starting point in the search for out how to make a previously insoluble Similarly, the industry can change thepotent molecules and reduce the need compound soluble.15 way in which it rewards research. Mostto run high throughput screens to find companies have traditionally promoted This has two advantages: it encourageshits, which is effectively like looking their best scientists to management researchers to focus on creatingfor a needle in a haystack. It will still positions, although scientific expertise is compounds which have a real chance ofbe necessary to test these molecules no guarantee of managerial competence. success in the clinic; and it strengthensin in vitro and in vivo assays, untilcomplete models of the anatomical They also reward researchers for the links between the research andand physiological characteristics of the getting candidate molecules to the development functions. But it is nothuman body in a healthy and diseased stage preceding submission of the enough merely to reward success;state are available. But some parts investigational drug application for it is equally important to promote aof the research process will become testing in man, thereby encouraging “fail early, fail cheaply” mindset, byincreasingly virtualised within the next those researchers to push unviable providing incentives for pulling the plug12 years (see Figure 6). molecules further down the pipeline so on unpromising candidates as fast as that they can meet their targets. possible.Moreover, while Pharma waits forvirtual nirvana, it can take several other A better way of stimulating genuinesteps to improve the way in which it innovation would be to reward scientistsconducts research. It can, for example, for “what they do, not for what the restpay more attention to validating in of the company does”, as Jean-Pierrevivo disease models and making them Garnier, outgoing chief executive ofmore predictive by using products with GlaxoSmithKline recently noted. GSKproven clinical efficacy to test them. If has overhauled its incentive scheme andFigure 6: What the research process might look like in 2020 Design & Further testing Testing of Synthesis of Initial testing Target ID initial testing of treatment treatment treatment in man of treatment in vitro in vivo Mixed Computer/Lab Lab work In silico Testing in manSource: PricewaterhouseCoopers8 PricewaterhouseCoopers
  • 11. Expediting developmentOf course, even the most robustly When is a medicine not a medicine?modelled molecules will still have to betested in real human beings – just as Most medicines come in oral formulations and many patients do not take themthe Boeing 777, which was completely properly. However, several emerging sciences will enable Pharma to developdesigned on computers, had to be better ways of delivering existing therapies and totally new forms of treatmentflown by test pilots before it could be which improve compliance – and hence outcomes.used to carry passengers. However, the With advances in nanotechnology, for example, it will be possible to deliverdevelopment process will also change therapeutic agents to specific cells in the human body, and develop nano-scaledramatically. machines for monitoring how medicines are distributed and metabolised. MoreSome of the new therapies Pharma than 100 nanotech-based medicines and delivery systems are already beingdevelops will not be conventional developed.pharmacological agents capable of Gene therapies also hold great promise. Dozens of human trials are underwaybeing tested in conventional ways (see to assess the efficacy of gene therapies in treating diseases that are currentlysidebar, When is a medicine not a treated with pharmacological agents, one such instance being heart disease. Inmedicine?).16 These new treatments the short term, these efforts could result in the development of single treatmentswill be more difficult to make and they that remain effective for many months or years. In the long term, gene therapieswill have a very different commercial may even provide a cure for hypertension and its related pathophysiology, butprofile from traditional medicines taken they have many other applications, too.on a long-term basis, but they will alsobe much harder to replicate and will Regenerative medicine – the replacement or regeneration of human cells, tissuestherefore help the industry to protect its or organs to establish or restore normal function – also has the potential to reverseintellectual property more effectively. the course of disease. Commercial products for treating skin ulcers and knee cartilage damage already exist, but a number of other medical conditions, suchThe development of clinical biomarkers as heart disease, insulin-dependent diabetes, spinal cord injuries and Parkinson’sand new technology platforms will disease, likewise look as though they could be amenable to cell-based therapy.likewise have a profound impact onPharma 2020: Virtual R&D 9
  • 12. the way in which all new therapies arePervasive monitoring tested. When biomarkers for diagnosingPervasive monitoring – the use of miniature devices and wireless networks to and treating patients more accuratelymonitor patients on a real-time basis outside a clinical setting – has numerous are more widely available, the industryapplications in clinical trials and everyday medical practice alike. Most of the will be able to stratify patients withmonitors currently on the market are wearable devices with limited applications, different but related conditions and testbut several devices that are reliable enough for medical purposes have either new medicines only in patients whorecently been launched or are in the pipeline. suffer from a specific disease subtype. That will, in turn, allow it to reduce theTheranos has, for example, developed a handheld device for detecting adverse number and size of the clinical studiesdrug reactions in real time. The device tests tiny blood samples, using a required to prove efficacy. Using clinicalbiochip, and transmits the data to a central database. Evidence of too high a biomarkers that are reliable surrogatesconcentration of medication in the bloodstream automatically triggers an alert. for a longer-term endpoint, likeSimilarly, Microsoft Research is working on the development of a wearable survival, will also help to cut endpointsystem for monitoring a wide range of physiological signals, which has been observation times.piloted on 20 patients in a study of sleep apnoea. The regulators are backing variousTechnological advances will also facilitate the development of embedded initiatives to create new biomarkers.monitors. In a recent paper on the future of healthcare, for example, British The FDA is, for example, providingTelecommunications (BT) suggests that electronic circuits could be painlessly scientific and strategic support for the“printed” onto the skin. These circuits might comprise an upper layer with a Predictive Safety Testing Consortium,polymer display and a deeper, more permanent player housing components an alliance between the C-Path Institutewhich are in contact with a patient’s blood capillaries and nerve endings. They and 15 pharmaceutical companies, tomight even include a smart membrane that opens on command to let medication validate preclinical biomarkers for drug-through. induced nephrotoxicity, hepatotoxicity and other forms of toxicity.17 It has also established a biomarker qualification10 PricewaterhouseCoopers
  • 13. programme in which the European A number of healthcare providers are it is not until the end of Phase II thatMedicines Evaluation Agency (EMEA) already piloting remote monitoring scientists have a reasonable grasp ofand Japanese Pharmaceutical and programmes. The new European the safety and efficacy of the moleculesMedical Devices Agency are actively Centre for Connected Health, based in they are testing (see Figure 7). Evenparticipating.18 Meanwhile, the Northern Ireland, is testing technologies then, that understanding may beEuropean Commission and European that enable people with chronic, long- fatally flawed; in one recent review ofFederation of Pharmaceutical Industries term conditions to live independently 73 clinical candidates which failed inand Associations have launched the at home. The UK government is also Phase III, for example, 31% were pulledInnovative Medicines Initiative (IMI), conducting a large tele-care trial, with because they were unsafe and 50%which aims, among other things, to the installation of remote monitoring because they were ineffective.22create a framework for developing new devices in the homes of 7,000 patients,20 However, armed with a much betterbiomarkers and disease-specific centres and new technologies will facilitate understanding of the pathophysiologyfor validating them.19 the development of increasingly of disease and how the body behaves sophisticated, embedded systemsSemantic technologies will also play a at a molecular level, and much better (see sidebar, Pervasive monitoring).21major role in improving the development systems for monitoring patients, Indeed, with nano-scale devices thatprocess. They will enable the industry to pharmaceutical companies will be able can measure absorption rates, it willlink clinical trial data with epidemiological to refine their trial designs to reduce even be able to identify variations inand early research data, identify any the number of studies they perform efficacy as a result of non-compliance.significant patterns and use that and the number of patients on whominformation to modify the course of its We believe that these scientific new medicines are tested. They willstudies without compromising their and technological advances will start by administering a treatment to astatistical validity. Similarly, pervasive ultimately render the current model single patient who has been screenedmonitoring will allow Pharma to track of development, with its four distinct to ensure that he or she meets thepatients on a real-time basis wherever phases of clinical testing, obsolete. inclusion/exclusion criteria, which arethey are. At present, as we have already noted, likely to include specific genotypic andFigure 7: The current development process 8 years 1.5 years 2 years 3 years 1.5 years Submission Phase I Phase II Phase III Phase IIIb/IV MAA/NDA Submission of CTA/IND CIM CIS Launch CIM Confidence in Mechanism CIS Confidence in Safety IND Investigational New Drug CTA Clinical Trial Application MAA Marketing Authorisation ApplicationSource: PricewaterhouseCoopersPharma 2020: Virtual R&D 11
  • 14. Table of contents phenotypic characteristics as well as variant of diabetes will be used to shapeModel trial the relevant disease subtype. the development of medicines for otherEntelos has developed a virtual variants of diabetes. Once there is evidence that theresearch lab for simulating clinical treatment does not cause any One last change to the way in whichtrials of new treatments for a range immediate adverse events, it will be trials are designed will help to ensureof diseases, such as asthma, sequentially administered to other that Pharma directs its efforts morerheumatoid arthritis and diabetes. patients – from as few as 20 to as many productively. The industry hasScientists can model the impact of atherapy using multiple variables, for as 100 – all of whom have also been traditionally focused on establishingexample in genotype, phenotype and screened to ensure that they have the whether new molecules are safepathophysiology. right medical profile. The data they and efficacious, not on whether they generate will be compared to data provide value for money. In future,The virtual lab has already proved from the modelling that preceded the it will have to address the payer’sits worth. When Johnson & Johnson study and subjected to techniques like perspective. We believe that, bywanted to design a Phase I trial of Bayesian analysis to adapt the course 2020, pharmaceutical companies willa diabetes treatment with a novel of the study, but the study itself will be collaborate with healthcare payersmechanism of action, Entelos conducted in a single, continuous phase in different jurisdictions to developsimulated the effects of using various (see sidebar, Model trial).23 criteria for assessing the value of newdosing levels. As a result of this work, treatments – i.e. measurable increasesJohnson & Johnson redesigned The development process will also in efficacy and ease of compliance orthe trial, with a 40% saving in time become much more iterative, with decreases in healthcare costs – andand a 66% saving in the number data on a molecule for one disease they will integrate the criteria into theirof patients on whom the treatment subtype getting fed back into the trial protocols.needed to be tested. The real-life trial development of new molecules for othersubsequently confirmed the accuracy disease subtypes in the same cluster We predict by 2020 the clinicalof the predictions the simulation had of related diseases (see Figure 8). So, environment will marry the needs ofproduced. for example, information that is derived patients, payors and providers, and from developing a medicine for one regulators by working much more12 PricewaterhouseCoopers
  • 15. closely on a common agenda agreed sector has long been a major barrier Numerous countries are currentlybetween them. They will share a to “interoperability”. However, the developing national health informationcommon infrastructure and access to FDA and EMEA are actively promoting networks, and several European Unionoutcomes data and results. the creation of common formats for member states have already made collecting and reporting biological data. considerable progress. One of theThese are not the only elements of the Various standards-setting organizations, main planks of the UK Connecting fortrial design and development process including the Clinical Data Interchange Health programme, for example, is thethat will change. The current system Standards Consortium and Society for creation of a new IT system that linksof conducting trials at multiple sites Clinical Data Management, are also data about patients from different partsis very inefficient. By 2020, we think working towards this end. of the National Health Service, so thatthat it will be replaced by a system healthcare practitioners throughout thebased on clinical supercentres – one They have already made considerable country can access the informationor two per country, perhaps – to recruit progress in simplifying the standards safely, securely and easily, wheneverpatients, manage trials and collate trial that are used to exchange clinical data and wherever it is needed, anddata. The supercentres will be owned between pharmaceutical companies, transmit prescriptions electronically.25and run independently of the industry, contract research organizations, trial Similarly, France has embarked on anpossibly by a new generation of site investigators and the regulators, ambitious programme to develop amanagement organizations, and they although many challenges remain. There national system of patient smart cardswill act as centres of excellence in the is still, for example, no consensus on and electronic health records, whichdelivery of new medicines to patients. how different data and applications it aims to have working by the end should be integrated, or a set ofTwo technological advances will be of this year;26 Austria is developing a common business processes fornecessary to facilitate this transition decentralised system that includes performing many clinical activities.24– electronic data interchange and electronic health records, electronic Nevertheless, these problems will beelectronic medical records – but both prescriptions, electronic referrals and resolved within the next 12 years.are already on the horizon. The diversity electronic medication histories;27 andand complexity of the information Use of electronic medical records Portugal is piloting an electronic identitythat is generated by the life sciences will also be widespread by that time. card with a chip that will ultimately beFigure 8: What the development process might look like in 2020 1.5 years Confidence in Mechanism from Research work 1 year 0.5 year Epidemiological Data First into Man Automated Limited Disease Knowledge (Adaptive Design) 20-100 pts submission/approvals Clinical Use Knowledge / Data from clinical usage or similar products Proof of value requirements Launch CIE CIS Clinical Data / Knowledge incorporated into studies on future indications/populationsSource: PricewaterhouseCoopersPharma 2020: Virtual R&D 13
  • 16. used to store various kinds of personalManaging the trial process in 2020 information, including medical records.28When John Doe’s doctor asks whether he would be willing to participate in a With common data standards, electronicstudy for a new treatment for AD3, the subtype of Alzheimer’s disease with which medical records and electronic datahe was recently diagnosed, he jumps at the chance. So his doctor forwards interchange, it will be possible toJohn’s medical details to the national clinical supercentre. Soon afterwards, John manage clinical trials long-distance andreceives an email from the supercentre confirming that his clinical profile fits the almost completely electronically, usingscreening criteria and asking him to call one of the nursing staff there to discuss a small number of supercentres whichthe process in more depth. have been globally accredited by theThree weeks later, John attends the clinical supercentre, where he is given a slow- regulators and have direct links withrelease implant containing the new medicine and closely supervised on an inpatient specialist medical units. They will sourcebasis for five days. All the evidence suggests that John is responding well, so he is patients from local healthcare providersthen injected with a saline solution containing thousands of micron-sized robots, and satellite centres, use remotewhich will track how he responds in the longer term. monitoring devices to track how those patients respond to new medicinesThe trial investigator explains how the data these robots capture will be and analyse the data before forwardingtransmitted to a central database at the supercentre and electronically filtered, them (in blinded form) to the sponsoringusing intelligent algorithms and pre-programmed safety parameters, to detect companies (see sidebar, Managing theany abnormalities. If John experiences an adverse reaction, the system will trial process in 2020).29immediately notify the supercentre, which will then contact him to discuss theimplications. John’s doctor will also be informed, if he requires medical care. For This approach has numeroushis part, John will only have to make one additional visit to the supercentre for a advantages. It will accelerate trialfinal check. recruitment and ensure that trials are managed more efficiently andWhen John goes home, he is reassured by the knowledge that he is being consistently. It will also make all trialmonitored around the clock. Most of the time he forgets about the steady stream data more transparent, enabling themof data his nano-monitors are transmitting, but he knows that the supercentre to be scrutinised more comprehensivelyis analysing and collating them with clinical data from other patients, using (and more impartially, since it is oftencontinuous feedback loops to refine its research. difficult for scientists who have spent several years developing a new medicine to retain their objectivity). Lastly, it may encourage more patients and healthcare providers to participate in clinical studies.14 PricewaterhouseCoopers
  • 17. Collaborating to bringtreatments to the marketThe regulatory approval process will commercial failure on its hands. restricted basis. With each incrementalchange equally substantially. At present, Moreover, securing the marketing increase in evidence of safety, efficacya regulator reviews the evidence on licence and getting a product approved and value, the regulator will extend thea candidate molecule at the end of for reimbursement may take several licence to cover more patients, differentdevelopment, when the sponsoring years – years in which the clock on the indications or different formulationscompany submits the supporting dossier. patent is ticking away. (see Figure 9).If it is satisfied with the data, it issues a By 2020, we believe that decisionsmarketing licence permitting the company With the advent of the “live licence” about reimbursement will fall withinto market the medicine throughout the approach will need to modify our the remit of the regulatory body whicharea over which it has jurisdiction. existing practices to realise its full conducts the quality, safety and efficacyThereafter, the new medicine is review and that this cumbersome, all- potential. An analogy today is whereincreasingly likely to be subjected to a or-nothing approach will be replaced organizations can obtain conditionalhealth technology assessment – which by a cumulative process, based on approvals in smaller patient populationsis usually undertaken by a completely the gradual accumulation of data. The utilising the Orphan Drug Regulations.different agency – to determine sponsoring company will collaborate This approach is similar to the generalwhether or not it should be eligible for with the regulator to establish the “live licence” approach envisionedreimbursement. A growing number evidence it is required to provide, in 2020, but is not as seamless orof healthcare payers now conduct and when it is required to do so. Itpharmacoeconomic evaluations of new will submit the data electronically at connected with the other stakeholderstreatments and refuse to reimburse predetermined milestones, in line with in the healthcare environment. A moveproducts for which they do not believe this timetable. toward the live-licence approach willthere is sufficient evidence of economic require the use of novel clinical trial Once there is sufficient evidence toas well as clinical value. designs and changes in regulatory show that a medicine genuinely worksAny pharmaceutical company which and is cost-effective in the initial trial strategies whilst also leveragingis launching a new treatment must population, the regulator will issue a electronic health records and pervasivethus overcome two external hurdles “live licence” allowing the sponsoring monitoring in a way that has never beento ensure that it does not have a company to market the treatment on a done before.Figure 9: What the regulatory process might look like in 2020 1.5 years Clinical use US Clinical use US 1 year 0.5 year Clinical use FR Clinical use FR First into Man Automated Up to 1.5 years Clinical use DE Clinical use DE (Adaptive Design) submission 20-100 pts /approvals Up to 1 year Up to 0.5 year Clinical use UK Clinical use UK Data New Indication Automated Clinical use ES Clinical use ES /Population Studies submission/ from Clinical (Adaptive Design) approval of CIE Limited new indication/ Clinical use CA Clinical use CA Use 20-100 pts CIS Launch population Data Clinical use IT from Clinical use IT Clinical Clinical use SW Use Clinical use SW CIE Broader Enhanced CIS Launch Clinical use FI Clinical use FI Clinical use IS Clinical use IS Clinical use IN Clinical use CHI Clinical use MXSource: PricewaterhouseCoopers Clinical use BZPharma 2020: Virtual R&D 15
  • 18. Moreover, the regulator will decide The industry has often argued that the Second, as the delineation betweenwhether or not to licence a medicine regulatory process is an impediment pharmaceuticals, medical devices, geneusing specific risk/benefit analyses to innovation. However, the leading therapies and other treatments graduallyrather than data on average outcomes. agencies have clearly signalled that diminishes, the regulation of suchIt will ask sponsoring companies to they are willing to consider new ways products could be brought under thedisclose the gaps in their knowledge of developing and regulating medicines same roof (as has already happened inabout the risks associated with any (see sidebar, Agencies of change).30,31 the UK). At one time, distinct boundariesmedicines they submit for approval, In November 2007, for example, the existed between the medical device andand it will make reimbursement of new FDA and Duke University Medical biotechnology industries, and differenttherapies contingent on performance. Center launched a partnership to procedures are still used to regulate modernise clinical trials. This initiative them. But the development of drug-The burden of proof will thus become eluting stents, implanted wafers for the will, among other things, explore themore precise, but the benefits of controlled release of chemotherapy opportunities for streamlining clinicalthis precision will outweigh the agents and other such drug-device trials, minimising the administrativedisadvantages. This process will combinations highlights the increasing load in multi-site trials and switching toenable a company to reduce its time artificiality of this distinction. electronic data management systemsto market and earn revenue sooner that enable researchers to monitor data By 2020, then, there may well be a singlethereby recouping its costs more in real time and help them spot safety regulatory regime covering all healthcarequickly. Peak sales will most likely be problems more rapidly.32 products. Indeed, there may even be alower, but through step wise revenue single global system, administered bygrowth as each new part of the licence Two further trends could reinforce national or federal agencies responsibleis approved the revenue stream will the need for closer links between for ensuring that new treatments meet thebe boosted (see Figure 10). It will Pharma and its regulators. First, needs of patients within their respectivealso enable the regulators to manage a number of national and regional domains. This would help to reducetheir resources more effectively, since agencies have begun to share safety the costs of regulatory compliance andthey will be able to forecast their and efficacy data under mutual accelerate times to market even more,workload much more accurately. recognition agreements – data which but it would also mean that any productLastly, and equally importantly, greater could be very useful in reducing the time which failed to pass muster with onecollaboration between the industry and and costs associated with developing agency would be very unlikely to getits regulators, and greater transparency, new products. If the industry is to get licensed elsewhere, unless it treated awill help to restore public confidence in access to this information, it will have disease caused by a genetic variation in aPharma’s integrity. to be equally open. very restricted ethnic population.16 PricewaterhouseCoopers
  • 19. Figure 10: How the R&D cost/revenue curve might look by 2020 Agencies of change The US and European Union (EU) have both recognised the need for major Revenue changes in pharmaceutical research Future R&D and development. In March 2004, cost/revenue curve - with live licensing the FDA launched its Critical Path Faster to market - Step wise revenue increases on automated Initiative, which aims to bridge the gap reduced spend in initial R&D approvals between basic scientific research and $0 the development process. In March Traditional R&D 2006, it published its Critical Path cost /revenue Opportunities List, which identifies curve 76 projects for researching how new Time scientific discoveries – in fields such as genomics and proteomics, imaging and bioinformatics – can be usedSource: PricewaterhouseCoopers to predict the safety and efficacy of candidate molecules more accurately, streamline clinical trials, improveFor all these reasons, it is clear that pharmaceutical manufacturing andPharma must work much more closely deliver treatments that address urgent public health needs.with the regulators than it has done inthe past. Some companies have already Meanwhile, EMEA has produced arecognised this; it is no accident that the “Road Map to 2010”, which lays themost successful are those that are also foundations for major changes in thethe most willing to share information, way in which medicines are regulatedlisten and adapt. By 2020, we think that and thus how R&D is performed.every company will have to operate The ultimate objective of the Roadin the same fashion and that working Map is to ensure that EMEA and itswith the regulators will be built into the partners in the EU medicines systemremuneration packages of development adequately prepare the ground forscientists. future scientific advances.Pharma 2020: Virtual R&D 17
  • 20. Imperatives for changeTable of contentsIf Pharma is to remain at the forefront of medicines that only deliver marginal well as the skills of those who supportmedical research and continue helping enhancements in safety or efficacy. them.patients to live longer, healthier lives, it Indeed, the regulators may even refuse Those that regard R&D as an integralmust become much more innovative, as to approve such products. part of their activities may also need towell as reducing the time and money it The new technologies we have review the way in which they managespends developing new therapies. We identified can play a major role in their R&D and remunerate their scientificbelieve that incremental improvements staff. We now know that one-size helping Pharma move forward. Theyare no longer enough; the industry will medicines don’t fit all patients, and will enhance its ability to produceneed to make a seismic shift to facilitate the same is true of the R&D process treatments which deliver measurablefurther progress in the treatment of itself. The limitations of the approach improvements in safety, efficacy anddisease. on which the industry has relied for ease of compliance – treatmentsIt will have to learn much more about which have value in the eyes of many years have become increasinglyhow the human body functions healthcare payers as well as those of clear and, in future, each companyat the molecular level and the the companies making them. They will will have to chart its own course – or,pathophysiological changes disease also deliver substantial savings; indeed, rather, different courses for each of thecauses. Only then will it be able to we estimate that they could collectively projects it undertakes.develop a better understanding of how halve development times and attrition The challenges Pharma faces areto modify or reverse these changes. rates, thereby reducing costs per drug enormous, but we are confident that itThis is a huge undertaking – and one dramatically. can succeed. When Charles Babbagethat Pharma cannot complete alone. It first proposed building his difference However, technology is not the answer towill require the support of academia, engine nearly two hundred years ago, all Pharma’s problems. Many companiesgovernments, technology vendors, nobody could have envisaged the as well as regulators and vendors thathealthcare providers and the regulators. connected world that exists today. support the industry will have to makePatients must play their part, too; Connectivity – technological, intellectual significant strategic, organizational andwithout access to medical data and and social – will ultimately enable us behavioural changes. Pharma will, forvolunteers for clinical studies, the to make sense of ourselves and the example, have to decide whether theyindustry will be unable either to make diseases from which we suffer. want to produce mass-market medicinestheoretical advances or to translate or speciality therapies; where they want Equally we as a society mustthose advances into practice. to be located geographically to have acknowledge that we cannot afford toPharma will also need to virtualise much access to the best skills or cost base suffocate the investments made intoof the research it currently performs in wherever they may be; and whether they R&D by the pharmaceutical industry;the lab, transform the way in which it want to outsource some or even most of a concern that should be high on thedesigns and manages clinical studies, their research and development or keep socio-political agenda. We have to faceand pay greater heed to the views of it in-house. The choices they make will the issue that if Pharma is no longerhealthcare payers. By 2020, aggressive have a profound bearing on the business financially capable of this, where will themarketing will not be enough to salvage models and mix of skills they require as new medicine come from?18 PricewaterhouseCoopers
  • 21. AcknowledgementsWe would like to thank the many people at PricewaterhouseCoopers who helped usto develop this report and contributed to the content. We would also like to expressour appreciation for the input we have received from clients, and our particulargratitude to the following external experts who so generously donated their timeand effort to the project.David Jefferys, CEO, Eisai Europe LimitedDr Brian Albert Gennery MB FRCP FFPMPharmaceutical Medical ConsultantConsultant CMO to PharmaKodexPreviously Director of the Clinical Research Centre, University of SurreyDr Steven ManosResearch FellowCentre for Computational Science, Department of Chemistry,University College LondonDr Gordon BaxterChief Executive OfficerBiowisdom LtdClive PageProfessor Pharmacology, King’s College LondonDirector, Sackler Institute of Pulmonary Pharmacology, King’s College LondonCo-founder of Verona PharmaThe views expressed herein are personnal and do not reflect the views of theorganizations represented by the individuals concerned.Pharma 2020: Virtual R&D 19
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  • 23. Territory contactsArgentina India RussiaDiego Niebuhr Thomas Mathew Christian Ziegler[54] 4850 4705 [91] 22 6669 1234 [7] 495 232 5461 Alina LavrentievaAustralia Ireland [7] 495 967 6250John Cannings John M Kelly[61] 2 826 66410 [353] 1 792 6307 Singapore Enda McDonagh Abhijit GhoshBelgium [353] 1 792 8728 [65] 6236 3888Thierry Vanwelkenhuyzen[32] 2 710 7422 Israel South Africa Assaf Shemer Denis von HoesslinBrazil (SOACAT) [972] 3 795 4671 [27] 117 974 285Luis Madasi[55] 11 3674 1520 Italy Spain Massimo Dal Lago Rafael Rodríguez AlonsoCanada [39] 045 8002561 [34] 91 568 4287Gordon Jans[1] 905 897 4527 Japan Sweden Kenichiro Abe Liselott StenuddCzech Republic [81] 80 3158 5929 [46] 8 555 33 405Radmila Fortova[420] 2 5115 2521 Luxembourg Switzerland Laurent Probst Clive BellinghamDenmark [352] 0 494 848 2522 [41] 58 792 2822Erik Todbjerg[45] 3 945 9433 Peter Kartscher Mexico [41] 58 792 5630Torben TOJ Jensen Ruben Guerra[45] 3 945 9243 [52] 55 5263 6051 TurkeyFinland Netherlands Ediz GunselJanne Rajalahti Arwin van der Linden [90] 212 326 6060[358] 3 3138 8016 [31] 20 5684712Johan Kronberg United Arab Emirates Poland Sally Jeffery[358] 9 2280 1253 Mariusz Ignatowicz [971] 50 252 4907 [48] 22 523 4795France United KingdomJacques Denizeau Portugal Andrew Packman[33] 1 56 57 10 55 José Fonseca [44] 1895 522104 [351] 217 599 601GermanyVolker Booten[49] 30 2636 5217
  • 24. Table of contentsFor further information, please contact:Global EuropeSimon Friend Jo PisaniPartner, Global Pharmaceutical and Life Sciences Industry Leader Partner, European Pharmaceutical and Life SciencesPricewaterhouseCoopers (UK) Advisory Servicessimon.d.friend@uk.pwc.com PricewaterhouseCoopers (UK)[44] 20 7213 4875 jo.pisani@uk.pwc.com [44] 20 7804 3744Steve Arlington Sandy JohnstonPartner, Global Pharmaceutical and Life Sciences Advisory Partner, European Pharmaceutical and Life SciencesServices Leader Advisory ServicesPricewaterhouseCoopers (UK) PricewaterhouseCoopers (UK)steve.arlington@uk.pwc.com sandy.johnston@uk.pwc.com[44] 20 7804 3997 [44] 20 7213 1952Michael Swanick Kate MossPartner, Global Pharmaceutical and Life Sciences Tax Leader Director, European Pharmaceutical and Life SciencesPricewaterhouseCoopers (US) Advisory Servicesmichael.f.swanick@us.pwc.com PricewaterhouseCoopers (UK)[1] 267 330 6060 kate.p.moss@uk.pwc.com [44] 20 7804 2268United States Asia PacificAnthony Farino Sujay ShettyPartner, US Pharmaceutical and Life Sciences Advisory Associate Director, Pharmaceutical and Life SciencesServices Leader Advisory Services, IndiaPricewaterhouseCoopers (US) PricewaterhouseCoopers (India)anthony.l.farino@us.pwc.com sujay.shetty@in.pwc.com[1] 312 298 2631 [91] 22 6669 1305Mark Simon Beatrijs Van LiedekerkePartner, US Pharmaceutical and Life Sciences Industry Leader Associate Director, Pharmaceutical and Life SciencesPricewaterhouseCoopers (US) Advisory Services, Chinamark.d.simon@us.pwc.com PricewaterhouseCoopers (China)[1] 973 236 5410 beatrijs.vanliedekerke@cn.pwc.com [86] 10 6533 7223Michael MentesanaPartner, US Pharmaceutical and Life Sciences R&D Advisory MarketingServices LeaderPricewaterhouseCoopers (US) Attila Karacsonymichael.mentesana@us.pwc.com Director, Global Pharmaceutical and Life Sciences[1] 646 471 2268 PricewaterhouseCoopers (US) attila.karacsony@us.pwc.com [1] 973 236 5640 Melanie York Senior Manager, European Pharmaceutical and Life Sciences PricewaterhouseCoopers (UK) melanie.york@uk.pwc.com [44] 20 7804 1991pwc.com/pharmaThis publication has been prepared for general guidance on matters of interest only, and does not constitute professional advice. You should not act upon the information contained in this publicationwithout obtaining specific professional advice. No representation or warranty (express or implied) is given as to the accuracy or completeness of the information contained in this publication, and, to theextent permitted by law, PricewaterhouseCoopers does not accept or assume any liability, responsibility or duty of care for any consequences of you or anyone else acting, or refraining to act, in relianceon the information contained in this publication or for any decision based on it.© 2008 PricewaterhouseCoopers. All rights reserved. ‘PricewaterhouseCoopers’ refers to the network of member firms of PricewaterhouseCoopers International Limited, each of which is a separate andindependent legal entity.

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