Outsourcing of drug discovery processes offers a vast opportunity to scientists to develop and commercialize new and innovative methods and technologies as well as other discoveries that could be of use to pharmaceutical industry. Specifically, this is of special value for investigations that are either too complex or too infrequent to be performed in-house and can be carried out faster and at less overall cost by outsourcing.Uporaba vanjskih usluga u procesu razvoja novih lijekova pruža brojne prilike znanstvenicima za razvijanje i komercijalizaciju inovativnih metoda i tehnologija te otvara put k novim otkrićima, koja se mogu upotrijebiti u farmaceutskoj industriji. To je osobito dragocjeno u istraživanjima koja se u farmaceutskoj industriji rijetko
provode ili su presložena da bi se isplatilo njihovo uvođenje u vlastitome laboratoriju. Uporabom vanjskih usluga znanstvenika mnoga se farmaceutska istraživanja mogu provesti brže i djelotvornije

Smiljka Vikić-Topić

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Outsourcing in Pharmaceutical Research and Development.Opportunities and Challenges*Smiljka Viki}-Topi}PLIVA-Research Institute Ltd., Prilaz baruna Filipovi}a 29, 10000 Zagreb, Croatia(E-mail: smiljka.vikic-topic@pliva.hr)RECEIVED MARCH 4, 2005; REVISED MARCH 21, 2005; ACCEPTED APRIL 5, 2005Outsourcing of drug discovery processes offers a vast opportunity to scientists to develop andcommercialize new and innovative methods and technologies as well as other discoveries thatcould be of use to pharmaceutical industry. Specifically, this is of special value for investiga-tions that are either too complex or too infrequent to be performed in-house and can be carriedout faster and at less overall cost by outsourcing.Keywordsdrug discovery processpharmaceutical industryoutsourcingContract Research Organization* Dedicated to Professor @eljko Ku}an on the occasion of his 70th birthday.INTRODUCTIONIn the last few decades, R&D costs have skyrocketedand it is becoming increasingly harder to put a new drugon the market (Figure 1).1 The reasons for this are nu-merous. Regulatory requirements are more rigorous, ask-ing for more detailed non-clinical and clinical data be-fore approving a new drug. Product and production qualityis more demanding. Genomics and proteomics togetherwith new technology platforms have increased the costof the early discovery phase. All of this has raised thecost of drug development by about 250 % in the last tenyears.2On the other hand, many best-selling drugs that arethe main source of R&D expenditure will be losing theirpatent protection within the next few years. In this envi-ronment, pharmaceutical companies are trying to cutcosts and speed up the drug discovery process either byacquiring other companies and thus overcoming the lackof expertise and knowledge and/or by outsourcing partof their activities. At the same time, Contract ResearchOrganizations (CRO) have emerged that offer activitieswithin the drug discovery process with great expertiseand specialized knowledge in specific areas at a compet-itive price. The CRO industry is growing rapidly andthis is expected to continue in the years to come.3CROATICA CHEMICA ACTACCACAA 78 (3) 333¿336 (2005)ISSN-0011-1643CCA-3016Feature ArticleFigure 1. Growth in R&D expenditures is not followed by the num-ber of new chemical entities on the market.What Activities Are Outsourced, When and Why?First of all, a strategic decision has to be taken as towhat will be outsourced and what will remain in-house.Scientific methods and technologies are developing andimproving every day; they are expensive, sometimes com-plicated and it is impossible to implement all of them in-house, hence CROs represent a perfect solution to over-come this gap. Skills or activities that are needed rarelyor for a short period of time are better outsourced thandeveloped in-house, thereby lowering the cost. Whenthere is internal lack of knowledge, time, people or equip-ment, outsourcing is also the best option. CROs are usuallyhighly qualified and experienced in their field since theyhave a team of people working within a narrow range ofactivities, which make them sometimes unbeatable com-petitors.4Many pharmaceutical companies have establishedwhole departments that organize and deal with contractresearch as part of their outsourcing. The main reasonfor this is to sort out and control an increasing number ofcontracts and to lower the costs by finding the best part-ner companies for their needs. The task of the outsourc-ing specialist is to support the goals of programs andprojects by facilitating collaboration with outsourcingproviders. Searching and selecting the CROs, negotiat-ing the prices and other contract provisions, such as lia-bility, intellectual property rights, confidentiality issues,etc., and establishing and maintaining good relationshipswith CROs through meetings and other means of com-munication are some of the tasks that outsourcing spe-cialists perform.5Relationships between »sponsors« and »vendors«are changing all the time. The first generation of collabo-rations was a classical »sponsor/vendor« relationship,but nowadays this is becoming more and more a partner-ship, which assumes a joint spirit and risk-taking thatbrings more value to both parties.What Do Contract Research Organizations Do,Who Are They?There are a number of small to large CRO companies,from one-activity laboratories in some specific fields tothe global multiple activity companies able to cover alarge part of the drug development process. ClassicalCROs that perform clinical trials get the most moneyfrom the pharmaceutical industry since clinical trials arelarge and complex studies involving enormous numbersof patients and data. These CROs (also called »ClinicalResearch Organizations«) select and coordinate investi-gation sites and physicians involved in the studies, col-lect and manage the data and together with the sponsorgenerate a study report. Other CROs perform non-clini-cal studies consisting of safety/toxicology testing; phar-macology (pharmacokinetics, pharmacodynamics) andother in vitro and in vivo tests required by regulatory ag-encies and satisfying all of their quality requirements. Inaddition, there are companies that up-scale the laboratorysynthesis of compounds that need to be tested in clinicaltrials and produce the required quantities of the activecompound; analytical labs, which are able to performanalyses in accordance with strict regulatory and qualityrequirements (GLP – »good laboratory practice«); com-panies that package and prepare clinical trial material(new compound, reference compound and placebo), etc.6Among CROs, there are also a large number of newinnovative and science-based companies, founded by oneor a few scientists that have made their own or have ap-plied somebody else’s discovery, developed it into prac-tical technology and finally established an innovativecompany – a combination between knowledge and ap-plication. There are many examples of such innovativecompanies that usually start as »spin-offs« from the uni-versities or big pharmaceutical companies. One such uni-versity spin-off is »Dual Systems« in Switzerland, whoseco-founder is the Croatian molecular biologist IgorStagljar. The company uses a yeast two-hybrid system tostudy the influence of a drug on the interaction betweentwo proteins. Another such company is »CXR biosci-ences« in the UK that developed a transgenic mousemodel, based on inactivated hepatic P-450 enzymes whichare involved in the metabolism of many drugs. By test-ing drug candidates in their proprietary model, it is pos-sible to check toxicity and bioavailability of the intactcompound and distinguish it from the effect of its me-tabolites. »Ifcos«, a Canadian/German company is try-ing to develop »in silico« models for simulation of intra-cellular interactions and pathways that would enable cli-ents to check the influence of up- or down-regulation ofany gene within the cell on its interaction with upstreamor downstream proteins. Big pharmaceutical companies’spin-off examples are »Rosseta Inpharmatics«, a whollyowned subsidiary of Merck that develops and imple-ments technologies for improvement of drug discoveryand Pharmacia’s »Biovitrum«, a biotech company thatcombines the experience of a big pharmaceutical com-pany with the flexibility of modern biotechs. RNAi (smallRNA interference) is becoming a hot topic not only fortarget determination and validation, but efforts are beingmade to develop it as a therapy, especially for »undrug-gable« targets. New companies have appeared based onthis new discovery as producers of kits for using thetechnology in research or for the development of an RNAias a therapeutic. There are a number of other examplesof the transfer of a scientist’s discoveries and knowledgeto successful companies; a pool of companies in Cam-bridge Science Park, UK, is an excellent representativeof this approach. Many of these companies were estab-lished as a consequence of discoveries closely related tothe needs of the pharmaceutical industry.334 S. VIKI]-TOPI]Croat. Chem. Acta 78 (3) 333¿336 (2005)What Determines the Selection of a Particular CRO?Selection of a CRO is the most challenging task in theoutsourcing process. There are many parameters specificto each study that have to be taken into account.The CRO should work in compliance with the qualitystandards required by regulatory agencies (GLP, GMP,etc.) and demonstrate ability and willingness to performthe requested activity. Their experience is often a goodreference. A further criterion is cost-effectiveness (com-parison between quality and price). For some studies theprice is crucial and for the others quality or timing ismore important.If the CRO offers completely new and unique ideasand the expected outcome of a study can bring added va-lue to the project, this may be a unique decision-makingcriterion.Finally, it is very important to establish a friendlyand »easy-going« relationship between the partners anddefinitely the best reference for the CRO is its own ex-perience and track record. Performance metrics intro-duced by relevant experts in the field have shown thatstrong working relationships bring about 25 % highervalue than poor relationships between partners.7PLIVA and OutsourcingPLIVA, as a global company, has developed a wide net-work of outsourcing partners. In terms of R&D, the out-sourcing money is spent predominantly on clinical trialsand non-clinical testing of drug candidates that, due toregulatory requirements, cannot be performed »in-house«.PLIVA has always, since its very beginnings, hadgood collaboration with its surrounding scientific com-munity. This policy has not changed during the, some-times turbulent, recent past for industry and science inCroatia. Nevertheless, the development and strengthen-ing of PLIVA’s R&D and the increasing use of outsourc-ing that has followed global trends, has not been matchedsufficiently by the development of Croatian science to-wards innovation and applicability. There are a numberof reasons for this. Our scientists were educated in anenvironment that did not pay enough attention to protec-tion of intellectual property rights or the possibilities ofcommercializing their discoveries. There is no doubt thatfundamental research is very important to all aspects oflife, but there should be a balance between basic and ap-plied research. The Croatian Ministry of Science starteda few years ago with »RAZUM«, programs that encour-age the establishment of small businesses based on know-ledge, innovation and new technologies; but in naturalsciences, biotechnology and non-clinical discovery phasethere is a lot of space for the formation of small biotechcompanies which would provide services to the pharma-ceutical industry within Croatia, and also to the industryin neighboring countries, as exemplified by develop-ments in Hungary, Slovenia and the Czech Republic. Ifthis were the case, PLIVA would be able to improve theratio between its spending on outsourcing in Croatia andin other countries that now amounts to only about 3–4 %(Figure 2).PLIVA will continue its fruitful and good collabora-tion with its scientific surroundings, in particular withthe Rudjer Bo{kovi} Institute, Medical Schools of Zag-reb and Rijeka, Faculty of Pharmacy and Biochemistry,Zagreb, Faculty of Science, Zagreb, and is willing to ex-tend that collaboration considerably if the services offer-ed are competitive with those found in other countries.CONCLUSIONOutsourcing, collaboration and partnership are relativelynew, but overwhelmingly accepted approaches in all mo-dern industries and as a part of the globalization process,represent a cost-effective opportunity for developing co-untries to participate and become competitive. Outsourcingof the drug discovery process is a challenge to scientiststo develop and commercialize their new and innovativemethods and technologies along with other discoveriesthat could be used by the pharmaceutical industry.Acknowledgment. – I wish to thank my colleague JasnaMarincel for valuable suggestions and critical review of themanuscript and to my husband, Dra`en Viki}-Topi} for com-ments, suggestions and technical help with the manuscript andimmense encouragement and support.REFERENCES1. Christina Prier Steffy, BioProcess International, Suppl. Ser.1, Sept. 2003.2. S. J. Giorgianni and, J. Grana, The Pfizer Journal 3 (1999)1–42.OUTSOURCING IN PHARMACEUTICAL RESEARCH AND DEVELOPMENT 335Croat. Chem. Acta 78 (3) 333¿336 (2005)PLIVA outsourcing expanditures8.314.8 14.512.216.90.3 0.5 0.7 0.6 0.30246810121416181999 2000 2001 2002 2003YearMilUSDWorldCroatiaFigure 2. The relationship between PLIVA R&D spending foroutsourced activities in Croatia (black columns) and abroad (pat-terned columns) in millions of US $.3. Dennis Gillings, CRO Retrospective, Suppl. to Applied Cli-nical Trials, Aug. 2004, 6–8.4. Derek B. Lowe, Contract Pharma, Sept. 2003, 24.5. Sarah W. Madley, Contract Pharma, May 2004, 40–47.6. J. R Minkel, Drug Discovery and Development, Oct. 2004,24–32.7. Personal notes from the conference »Partnership with CRO’sand Other Outsourcing Providers«, Orlando, April 26–28,2004; source: Negotiating and Managing Key Supplier Re-lationships: A Cross-Industry Study of 20 Best Practices,Vantage Partners, 2003.SA@ETAKUporaba vanjskih usluga u istra`ivanju i razvoju u farmaceutskoj industriji.Mogu}nosti i izazoviSmiljka Viki}-Topi}Uporaba vanjskih usluga u procesu razvoja novih lijekova pru`a brojne prilike znanstvenicima za razvijanje ikomercijalizaciju inovativnih metoda i tehnologija te otvara put k novim otkri}ima, koja se mogu upotrijebiti ufarmaceutskoj industriji. To je osobito dragocjeno u istra`ivanjima koja se u farmaceutskoj industriji rijetkoprovode ili su preslo`ena da bi se isplatilo njihovo uvo|enje u vlastitome laboratoriju. Uporabom vanjskih us-luga znanstvenika mnoga se farmaceutska istra`ivanja mogu provesti br`e i djelotvornije.336 S. VIKI]-TOPI]Croat. Chem. Acta 78 (3) 333¿336 (2005)

Uporaba vanjskih usluga u istraživanju i razvoju u farmaceutskoj industriji. Mogućnosti i izazovi

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