Clinical
`Practice
`
`
`
`Minireview
`
`
`
`Nephron Clin Pract 2009;113:c125-c131
`DOI: 10.1159/000232592
`
`Published online: August 12, 2009
`
`Drug Development: From Concept to
`Marketing!
`
`Nihad A.M. Tamimi
`
`PeterEllis
`
`Pfizer Inc., Sandwich, UK
`
`Key Words
`Drug discovery = Clinical trials : Drug approval « Drug safety
`
`Abstract
`Drug developmentis an expensive, long and high-risk busi-
`ness taking 10-15 years and is associated with a high attri-
`tion rate. It is driven by medical need, disease prevalence
`and thelikelihood of success. Drug candidate selection is an
`iterative process between chemistry and biology, refining
`the molecular properties until a compound suitable for ad-
`vancing to man is found. Typically, about one in a thousand
`synthesised compoundsis ever selected for progression to
`the clinic. Prior to administration to humans, the pharmacol-
`ogy and biochemistry of the drug is established using an
`extensive range of in vitro and in vivo test procedures.It is
`also a regulatory requirement that the drug is administered
`to animals to assess its safety. Later-stage animal testing is
`also required to assess carcinogenicity and effects on the
`reproductive system. Clinical phases of drug development
`include phase |
`in healthy volunteers to assess primarily
`pharmacokinetics, safety and toleration, phase Il ina cohort
`of patients with the target disease to establish efficacy and
`dose-response relationship and large-scale phaseIll studies
`to confirm safety and efficacy. Experience tells us that ap-
`proximately only 1
`in 10 drugs that start the clinical phase
`will make it to the market. Each drug must demonstrate safe-
`
`ty and efficacy in the intended patient population andits
`benefits must outweighits risks before it will be approved
`by the regulatory agencies. Strict regulatory standards gov-
`ern the conductof pre-clinical and clinicaltrials as well as the
`manufacturing of pharmaceutical products. The assessment
`of the new medicinal product's safety continues beyond the
`initial drug approval through post-marketing monitoring of
`adverse events.
`Copyright © 2009 5. Karger AG, Basel
`
`Introduction
`
`Getting drugs to the market is an expensive and high-
`risk business which takes on average 10-15 years to com-
`plete. The Tufts Center for the Study of Drug Develop-
`ment announced in November2001 that the average cost
`to develop a new prescription drug was USD 802 million
`[1]. Whenthe costs offailed prospective drugs are factored
`in, the actual cost for discovering, developing and launch-
`ing a single new drug would have exceeded 1,5 billion.
`This compares with USD 4 million in 1962 and USD 231
`million in 1987 [2, 3]. The problem is compoundedby the
`high attrition rate, as it is estimated that approximately
`only 1 in 10 drugsthat enter clinicaltrials will makeit to
`the market. In a recent study, it was shownthat the aver-
`age success rate for drugs to be approvedforall therapeu-
`
`
`
`KA RG E R
`Fax +4161 306 12 34
`E-Mail karger@karger.ch
`www.karger.com
`
`© 2009S, Karger AG, Basel
`1660-21 10/09/1133-0125$26,00/0
`
`Accessible onling at:
`www.karger.com/nec
`
`Pfizer Laboratories
`Ramsgate Road
`Sandwich CTI3 YN] (UR)
`Tel, +44 1304 641 627, Fax +44 1304 652 629
`E-Mail tamimis@gmail,com
`
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`~ ~ Approval
`andpost-
`approval
`
`
`
`Hypertension
`Hyperlipidaemia
`Arthritis
`
`Asthma
`Chronic kidney disease
`Obesity
`Psychotic disorders
`Malignancy
`TypeII diabetes mellitus
`Stroke
`
`Heartfailure
`Liver cirrhosis
`Chronic obstructive
`pulmonary disease
`AIDS
`
`Gastro-oesophageal reflux
`disease
`
`Epilepsy
`Type | diabetes mellitus
`
`Fig. 1. Phases of drug development.
`
`Fig. 2. Drivers for discovering new drugs
`with examples.
`
`
`
`Diseaseprevalence
`
`Medical need
`
`
`
`Genetic storage diseases
`
`Inflammatory bowel
`disease
`Irritable bowel syndrome
`
`Cystic fibrosis
`Multiple sclerosis
`Septic shock
`Transplant rejection
`
`Medium
`ed
`
`tic areas is approximately 11%. The successrate varies be-
`tween therapeutic areas ranging from 20% for cardiovas-
`cular drugs to only 5-8% for oncology and central nervous
`system disorder drugs [4]. Improvements in predicting
`the potential success or failure of a productin clinicaltri-
`als is essential to aid in reducing the spiralling devel-
`opmentcosts. Unfortunately, increasing costs combined
`with the high attrition rate are forcing pharmaceutical
`companies to reduce investmentin research and develop-
`ment, focussing on a more limited product portfolio.
`Drug developmentis a significant challenge. Every
`product must notonly be safe andefficacious, butits ef-
`ficacy has also to be proven across racial and ethnic
`groups as well as across different age groups. Every drug
`has to pass a global regulatory review in whatis current-
`ly the most regulated industry in the world. Once this is
`done, approved products must appeal to global markets
`across different cultures, healthcare systems anddistri-
`bution systems.
`It is interesting to note that in a recent survey, the pub-
`lic perception was that the pharmaceutical industry dis-
`
`covers only 27% of new drugs whilst the reality is that
`more than 90% of all new drugsare discovered by the in-
`dustry [5].
`This minireview will address the process of drug de-
`velopmentfrom discovery through the stages of develop-
`ment up to approval and marketing(fig.1).
`
`Discovery
`
`Selecting therapeutic areas or indications to invest in
`is driven by ‘medical need’ and theprevalence ofthe dis-
`ease(fig. 2). Additionalfactors also include technical fea-
`sibility, research and developmentcosts and commercial
`considerations such as competition in the market place
`and potential market share. Evenifthese criteria are met,
`there is only a limited research and development budget
`and each new project must be prioritized against the
`companyresearch and developmentportfolio, with only
`high priority projects within the budget beingselected for
`progression. For many companies,this is typically an an-
`
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`nual review processfor productsatall stages of develop-
`ment. This maylead to stopping a programmeeven at an
`advancedstage of development.
`Early chemical starting points have been identified
`from naturally occurring substances in plants, humansor
`animals but lead compoundsare moreoften sourced from
`targeted chemical synthesis directed to bind to the known
`structures of receptors and enzymes or from random or
`receptor-targeted high-throughputscreening [6]. This has
`become more popularin the last few yearsasit is helpful
`in accelerating drug discovery. Initial problems encoun-
`tered in the last decade have eased with improving tech-
`nology. With the advent ofmodern computer technology,
`robotics and multi-well assay plates (384 growingto 1,536
`wells per plate), high-throughput screening can test vast
`‘libraries’ of chemical compounds in multiple screens
`(which can deliver up to 120,000 assays every 24 h). An-
`other methodoflead identification is ‘virtual screening’
`(also namedin silico screening) which is defined as the
`‘selection ofcompoundsbyevaluatingtheirdesirability in
`a computational model’ [7]. Compoundstesting positive
`in screening have their potencyandselectivity confirmed
`by in vitro biochemical or cellular assays. This is typi-
`cally followed by functional biochemical and pharmaco-
`logical testing in vitro, followed by pharmacodynamic
`and pharmacokinetic testing in vitro and in vivo [8]. The
`next step is to complete pilot toxicology testing to inform
`us of the likely safety profile. Onceall preclinical testing
`has satisfied the minimum selection criteria, the com-
`pound transitions from a ‘lead’ to a ‘candidate’ and is
`nominated for progression to the clinic.
`At this stage, drug productionis scaled up to meet the
`increased compound demand, work commences on de-
`veloping a suitable formulation for clinical use (often a
`tablet is the preferred dosage form) and the candidateis
`progressed through the required toxicology testing (in-
`cluding genotoxicity, safety pharmacologyin all biologi-
`cal systems, single and multiple dose toxicity and toxico-
`kinetic studies) to enable the first in human and subse-
`quent clinical studies. Reproductive toxicology in male
`and female animals (required prior to testing in women
`of child-bearing potential) and long-term carcinogenici-
`ty testing are also prerequisites forfiling a drug approval
`request [9].
`In parallel with lead development/candidate nomina-
`tion, a key decision on when to patent the compound or
`chemicalseries is taken. Early patenting mitigates against
`competitors beating a company to a claim, but delaying
`the patent application allows for introduction of addi-
`tional data to strengthen the patent and extends thepat-
`
`ent expiry date. The patentlife is typically 25 years but as
`it takes 10-15 years to develop a drug, there could only be
`10 years remainingto sell the product and recoup the
`high developmentcosts.
`
`Phasesof Clinical Drug Development
`
`Phase I. Phase I starts with thefirst administration of
`the new medicinal product to humans. Usually this phase
`involves healthy volunteers with the exception of cyto-
`toxic drugs(e.g. oncology drugs) which get tested in pa-
`tients without the requirementto test in healthy volun-
`teersfirst. The purposeofthis stageis to evaluate the safe-
`ty, tolerability, pharmacodynamic(effect of the drug on
`the body e.g. effect on heartrate, blood pressure, electro-
`cardiogram (ECG),etc.) and pharmacokinetic (effect of
`the body on the drugi.e. absorption, distribution, metab-
`olism and excretion) effects of the tested drug. Phase I
`studies are usually conducted in dedicated phase I units
`whichare research units attachedto a general or teaching
`hospital and mannedbyresearch physicians whoarefa-
`miliar with conducting such studies. Full resuscitation fa-
`cilities are available at these units. Phase I studies require
`approval from an ethics committee andtherelevant regu-
`latory agency. In the United States, an Investigational
`New Drug (IND)application, which summarises the es-
`tablished preclinical and manufacturing information
`along with investigator guidance, mustbe in place prior
`to starting clinical trials. A pre-IND consultation pro-
`grammeis offered by the US Food and Drug Administra-
`tion (FDA)to provide guidance on the data necessary for
`the IND submission. Subjects are usually compensatedfor
`participating in these studies. Developmentof the drug
`could be stoppedifit is found thatthe half-life ofthe drug
`is too short or too longorif it has poor bioavailability.
`Similarly, if the drug is not well tolerated at effective con-
`centrationsit is dropped from development. Phase I stud-
`ies usually start with single sub-pharmacological doses
`which are escalated gradually and followed by multiple
`doses. Stoppingrules to dose escalation include severe ad-
`verse events,clinically significant ECG abnormalities and
`clinically significant laboratory abnormalities.
`Otherphase I studies to support drug development are
`conducted throughout phase II and II of development.
`These include drug-drug interaction studies, effect of
`food on absorption, age and genetic influences. A typical
`phase I study can cost up to USD 500,000, with speciality
`studies (such as detailed QTc ECG assessments) costing
`up to USD 1.5 million.
`
`Drug Development
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`Role of Translational Medicine/Biomarkers
`The American Physiological Society has defined trans-
`lational research as ‘the transfer of knowledge gained
`from basic research to new and improved methodsofpre-
`venting, diagnosing, or treating disease, as well as the
`transfer of clinical insights into hypotheses that can be
`tested and validated in the basic research laboratory’[10].
`Biomarkers are quantitative measures of biological ef-
`fects that provide informative links between mechanisms
`of action and clinical effectiveness [11]. Effectively apply-
`ing translational research measures to a development
`programmein phase I and phaseII resultsin earlier iden-
`tification of efficacy (or just as important, lack ofeffica-
`cy) resulting in increased overall productivity and poten-
`tially a quicker route to drug approval. There are 3 fun-
`damental classifications of biomarkers: (1) markers of
`diseasee.g. proteinuria as a biomarker of chronic kidney
`disease (CKD); (2) markers ofpharmacological activity of
`a drug e.g. inhibition of angiotensin-converting enzyme
`increases plasmalevels of angiotensin-1 and decreases
`plasmalevels of angiotensin-2; (3) surrogate biomarkers
`of efficacy e.g. using a measure of penile rigidity mea-
`sured by plethysmography (Rigiscan) as a surrogate for
`sexual intercourse. An example of a biomarker with di-
`agnostic rather than efficacy potential is neutrophil gela-
`tinase-associated lipocalin or NGAL, which serves as
`biomarkerofacute renal injury as increased levels are de-
`tected in urine and blood within hoursof kidneyinjury.
`Taking the example of proteinuria in CKD,interven-
`tions that reduce proteinuria can be potentially beneficial
`in the treatment of CKD. Therefore measuring changes
`in the biomarkerin both preclinical models (e.g. sub-total
`nephrectomy model in therat) and the clinic can be in-
`dicative of activity of a potentially new drug for treating
`that indication (i.e. slowing progression of non-diabetic
`CKD). The challengeis to use or develop a biomarkerin
`which we have confidence thatit will reflect changes in
`the importantregistrable endpoints that we will assess in
`phaseIIItrials and whichareessential to gain regulatory
`approval.
`PhaseII. Once the drug’ssafety, pharmacokinetics and
`doseselection has been established in healthy volunteers,
`the nextstep is to investigate the efficacy andsafety ofthe
`drug in the target population. For example, if a drug is
`being developedfor the treatment ofhypertension, phase
`II trials will involve investigating the drug in a hyperten-
`sive patient population. Phase II is usually divided into
`phaseIIa and phaseIIb. Phase Ila is when the drug (usu-
`ally limited to a single high/maximaltolerated doselevel)
`is tested in a small cohort (12-100) of patients; this is
`
`called the ‘proof of concept’. Phase IIb follows on from
`the proof of concept in which severaldose levels are test-
`ed in the target population (dose-ranging studies) to de-
`fine the minimally effective or non-effective dose and to
`decide the optimal dose, based on clinical efficacy and
`safety, to take to the next stage. Occasionally phases IIa
`and IIb are combined in one large study. A complete
`phase II programmecould involve several hundred pa-
`tients and can cost several million dollars.
`Withever increasing developmentcosts and expiry of
`valuable patents on major products, the pharmaceutical
`industry is compelled to develop moreefficient and cost-
`effective ways of doing drug development. These include
`the use of biomarkers, as discussed, but also application
`of enhanced quantitative drug design ‘EQDD’to under-
`stand exposure-responserelationships and optimise dose
`selection, thus facilitating regulatory review and maxi-
`mising the commercial valueofthe drug.
`However, positive phase II data is no guarantee ofpro-
`gression to phaseIII. At this key stage of development,
`costs will increase significantly and detailed analyses of
`the drug candidate and the market (patient, payer and
`physician perspectives) are conducted. This will include
`drug efficacy relative to the competitors, safety profile,
`probability of technical and regulatory success, remain-
`ing patent life of the drug, cost of goods to produce the
`drug, potential market share and pricing and reimburse-
`ment. Onceagain,the drugwill be prioritised againstall
`other candidates in the portfolio and only if the outlook
`is favourable and the priority is within the research and
`development budgetwill it go forward.
`A successful phaseII is followed by an ‘endofphase IT’
`meeting with regulatory agencies such as the FDAto dis-
`cuss the results from phaseII and discuss and agree the
`clinical and statistical analysis plans for phase III. This
`negotiation, which also includes the target labelling, is
`critical to ensure alignment between the regulatory agen-
`cy and sponsor.
`Phase III. This is the final stage of drug development
`prior to registration and will confirm the clinical doses,
`frequency and timing ofadministration for approval. Be-
`fore embarking on a costly phase III programme, the
`sponsor should have a high level of confidence in the
`drug’s safety and efficacy in the target patient population
`and the dose rangeto be tested. PhaseIII trials (usually a
`minimum of 2) can involve up to several thousands of
`patients, depending on the indication, so that an ade-
`quate database (with 90% powerto detectstatistically sig-
`nificant differences) is created to assess the efficacy and
`safety profile, in addition to enabling accurate druglabel-
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`Regulatory Submission/Approval
`
`if the rate is too high, additional study centres will be re-
`cruited. This ensures adequate patient numbers for ap-
`proval, butis costly in incurring delays to the programme.
`The overall success rate of phase III is around 70% and
`dependingon the size can cost up to USD 100 million. A
`successful phaseIII is usually recognised by the financial
`markets with an impact on the sponsor’s shareprice.
`
`ling. PhaseIII trials are primarily designed and powered
`to test the hypothesisofefficacy but at the sametime, ad-
`verse events are collected to assess benefit-risk potential
`of the drug. Use of novel endpointsin phaseIII is a high-
`risk strategy, but can prove valuable in demonstrating
`benefits relative to competitors or established therapies;
`however,
`these endpoints do require validation and
`should be included in phase II and discussed with the
`regulatory authoritiespriorto the start of phaseIII.
`Clinical studies that use mortality and morbidity end-
`points are often very large and can take several years to
`complete. Oncologyis an exception, with phase III stud-
`Oncethe phaseIII studies have completed and deliv-
`ies often limited to a few hundredpatients. In diseases in
`ered a positive outcome, compilation of the data to sub-
`which there is an established ‘gold standard’ treatment,
`mit to the regulatory agenciesstarts. This usually takes
`European regulatory authorities will require phase III
`several months and can be donebyoneregion at a time,
`e.g. in the United States, or could be doneglobally, target-
`studies to include a comparator arm to demonstrate non-
`inferiority or superiority comparedto the standardther-
`ing major regions simultaneously. Classically, the major
`apy. Efficacy can be demonstrated either by demonstrat-
`markets include the United States, the European Union
`ing superiority to placebo in placebo-controlled trials or
`and Japan. However, recently moreattention is given to
`by showing superiority to an active-control treatment.
`the ‘emerging markets’ such as Latin America, India and
`Sometimesthe new drugentity is comparedto a reference
`China, amongstothers. As for the United States, a routine
`New Drug Application ‘NDA’ can take up to 15 months
`treatment without the objective of showing superiority.
`This can be either an equivalencetrial, which showsthat
`for review. However,in cases ofparticularly high medical
`the response to treatments differs by an amount whichis
`needorin areaslacking treatments(e.g. oncology and hu-
`clinically not significant (specify upper and lower equiv-
`man immunodeficiencyvirus), an expedited review can
`alence margins), or a non-inferiority trial which has the
`be granted.If the new drugis a biologic, then a biologic
`license application “BLArather than a “NDA,is submit-
`objective of showing that the new drugis notclinically
`inferior to the comparator (only lower equivalence mar-
`ted.
`gin is specified). The choice of specified margins should
`In Europe, the sponsor submits a marketing authori-
`sation application (MAA), which could be granted either
`be clinically justified.
`Depending on the nature of the study and the end-
`underthe centralised procedure(valid for the entire com-
`points used for the indication, a “Data Safety Monitoring
`munity market) or through the mutual recognition pro-
`cess.
`Board’ (DSMB)maybe required throughoutthe conduct
`During the review by the regulatory agencies, ques-
`of the trial. This is especially so in studies that incorpo-
`rate mortality and morbidity as primary or secondary
`tions are referred back to the sponsor. To facilitate the
`review process, the sponsorwill typically establish a rap-
`endpoints. DSMB membersmustincludeaclinician with
`expertise in the disease area under investigation as well
`id response team to coordinate the responsesto the au-
`thority. Drug label negotiations take place during the re-
`as a biostatistician as a minimum. Each DSMB must have
`view process. Regulatory agencies could request post-ap-
`a charter and written operating procedures detailing
`proval studies from the drug companies to address any
`members’ responsibilities and the plan of communica-
`safety concernsthat the regulatory agencies may have. At
`tion. DSMB members mustdisclose potential conflict of
`the same time, the drug companywill have presentedits
`interest to the sponsor.
`For the sponsor, phase III trials involve a large cross-
`plansto detect, assess and report adverse events.
`Pharmacovigilance is the term used in Europe de-
`functional team which involves, amongst others, clini-
`scribing the ongoing evaluation of the safety of the drug
`cians, project management, data management, drug safe-
`in the post-marketing period; it is a requirementthat all
`ty monitoring, document management, regulatory sup-
`port and clinical quality assurance. A key consideration
`pharmaceutical companies with a post marketed product
`must comply. The drug companywill also provide peri-
`for phase III is selection of study centres to ensure appro-
`odic safety update reports on the new drugafterits ap-
`priate patient recruitment and timely completion of the
`proval. Post-marketing or safety surveillance trials are
`study. Estimationsofpatient drop-outrates are made,but
`
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`sometimesreferred to as phase IV clinical trials. Harmful
`effects discovered during phase IV trials can lead to the
`withdrawal of the drug from the market as seen in the
`example of rofecoxib (Vioxx) and cerivastatin (Lipobay,
`also knownas Baycolin the United States).
`Orphan Drug Status. Pharmaceutical products devel-
`oped to treat rare diseases have beenreferred to as orphan
`drugs. The FDA Orphan DrugActspecifies the require-
`ments for granting a drug orphanstatus. The disease that
`the drug is intended for should affect less than 200,000
`people in the United States. This designation grants the
`companyfast-track review process as well as market ex-
`clusivity for a period of 7 years. In addition,it will beeli-
`gible for direct guidance from the FDAforthe design of
`a clinical plan to further develop the drug. In Europe,
`some drugs used to treat tropical diseases that are pri-
`marily found in developing countries can also be desig-
`nated as orphan drugs. For the drug companies,the cost
`of developing such drugs and marketing them will not be
`covered by the expected sales. Hence, the economic and
`regulatory incentives to encourage pharmaceutical com-
`panies to develop such drugs are needed.
`
`Regulatory Standards
`
`Preclinical studies are conducted according to good
`laboratory practice (GLP) guidelines, which regulate how
`laboratory studies are performed.Clinical trials are con-
`ducted according to goodclinical practice (GCP) guide-
`lines, which are internationally required quality andsafe-
`ty standards for designing, conducting and reporting
`clinical trials. GCP-compliantclinical trials are essential
`to ensure the rights and safety of clinical trial subjects.
`These standardsare subject to inspection by regulatory
`agencies at any time; regulatory agencies havethe right to
`halt ongoing clinical studies if they have concerns that
`the studies are not GCP-compliant. Finally drug manu-
`facturing is done according to good manufacturingprac-
`tice (GMP) guidelines, which dictates the standardsfor
`manufacturing and quality control of pharmaceutical
`products. This is also subject to regulatory inspection.
`
`Lifecycle Management
`
`The drug companywill plan thelifecycle of the drug
`throughout the patent life and beyondinto the future ge-
`neric marketplace. This may include different drug deliv-
`ery systems such as prolonged release formulations ver-
`
`sus immediate release, combinations with other drugs for
`improved efficacy, as well as seeking new indications.
`Oncea newindication is confirmed, the drug company
`can apply for a supplementary new drugapplication (s-
`NDA). Publication strategies are also another important
`partoflifecycle management,as additionalbenefits ofthe
`drug that cannot be addedto thelabel, such as patient-
`reported outcome measures, are published in peer-re-
`viewed journals.
`
`Interaction between Pharmaceutical Industry and
`Healthcare Professionals
`
`The Pharmaceutical Research and Manufacturers of
`America (PhRMA) represent research-based pharma-
`ceutical and biotechnology companies. PhRMAhavede-
`veloped guidelines on the basis of interactions between
`US healthcare professionals and the pharmaceutical in-
`dustry. The PhRMAcodewaslast updated in January
`2009 and regulates amongst other things: informational
`presentations by pharmaceutical company representa-
`tives and accompanying meals, prohibition on entertain-
`ment and recreation, pharmaceutical company support
`for continuing medical education, pharmaceutical com-
`pany support for third-party educationalor professional
`meetings, the employmentof healthcare professionals as
`consultants, speaker programmesand speaker training
`meetings, prohibition of non-educational and practice-
`related items as well as scholarships and educational
`funds. In the United Kingdom, the Association of the
`British Pharmaceutical Industry (ABPI) code wasestab-
`lished in 1958 and covers advertising, activities of repre-
`sentatives, supply of samples, provision of hospitality,
`promotional meetings and the sponsorship ofscientific
`and other meetings, including paymentoftravelling and
`accommodation expenses. The ABPI code doesnot apply
`to the promotion of over-the-counter medicines to the
`general public [12].
`
`Conclusion
`
`Drug developmentis a long, expensive and highly reg-
`ulated process. Therisks are high, but continued invest-
`ment in pharmaceuticals is vital if we are to enjoy the
`benefits of long-term improvements in patient health-
`care.
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`5 Proteccién de la propiedad intelectual para
`productos farmacéuticos: qué es y por qué es
`esencial para la innovacién en salud? Con-
`sideraciones a la luz del DR-CAFTA.http://
`www.amchamsal.com/uploaded/content/
`category/2000065261.pdf (accessed January
`2, 2009).
`Dutta A: Discovery of new medicines; in
`Griffin JP and O’GradyJ (eds): The Textbook
`of Pharmaceutical Medicine. London, BMJ
`Books, 2002, p 25.
`International Union of Pure and Applied
`Chemistry: Glossary of terms used in com-
`binatorial chemistry, U-Z3. Research Trian-
`gle Park, International Union of Pure and
`Applied Chemistry. 1999. http://www.iupac.
`org/reports/1999/7112maclean/u-z.html
`(accessed January2, 2009).
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`Rester U: From virtuality to reality — virtual
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`Tweats DJ, Scales MDC: Toxicity testing; in
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`
`Editorial Comment
`
`M. El Nahas, Sheffield
`
`This minireview by TamimiandEllis, 2 senior execu-
`tives at Pfizer UK with considerable experience in drug
`development and with a genuineinterest in nephrology
`and chronic kidney disease (CKD),is timely. It reminds
`the reader of the huge and often prohibitive cost of new
`drug developments.It highlights the fact that thousands
`of new potentially promising products never makeit to
`the bedside. Giving the cost associated with drug develop-
`mentand the currentglobalfinancial situation, this mini-
`review sheds considerable light on the direction major
`pharmaceutical companies maybe taking.First, the drug
`industry is re-evaluatingits research priorities moving to-
`wardssaferclinical areas with projected quicker financial
`return. Pfizer has moved awayfrom its prior top research
`priorities and successful drug developmentareas, namely
`atherosclerosis and heart failure research. Instead, re-
`search and developmentof drugsto tackle the growing
`market ofAlzheimer’s disease are gathering pace. Second-
`
`ly, investments in lengthyclinical trials addressing chron-
`ic diseases such as CKD mayalso fall victim to the credit
`crunch. This editor knowsof more than oneclinicaltrial
`that has been cancelled or stoppedas the sponsors’ finan-
`cial situation worsened with the global credit crunch.Fi-
`nally, drug development mayitself be shelved for a more
`cost-effective approach consisting of acquiring generic
`drug makers. Overthe last few weeks alone, Novartis pur-
`chased Ebewe Pharma an Austrian makerof generic can-
`cer drugs for USD 1.3 billion, Pfizer agreed a licencing
`deal with 2 Indian generic makers and GlaxoSmithKline
`acquired a stake in South Africa’s Aspen. Such an ap-
`proach maybe the way forward for the drug industry to
`reach a sustainable business model. It may also offer the
`industry an opportunity to unlock emerging markets that
`may accountfor 70% ofnew pharmaceuticalsales by 2020.
`Drugs development and clinical trials have not been
`spared the ravagesof the credit crunch.
`
`Drug Development
`
`Nephron Clin Pract 2009;113:c125-c131
`
`c131
`
`MPI EXHIBIT 1047 PAGE 7
`
`MPI EXHIBIT 1047 PAGE 7
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1047, p. 7 of 7
`
`