ANALI PAZU HD Vol. 9, No. 1-2, pp. 95 123 oktober 2023 https://doi.org/10.18690/analipazuhd.9.1-2.95-123.2023 Besedilo , 2023 S VELIKIH FARMACEVTSKIH PODJETJIH Sprejeto 1. 5. 2023 Recenzirano 18. 9. 2023 Izdano 25. 10. 2023 PELA B 1 , LEA KNEZ 2 , PELA KNEZ 3 , T MLAKAR 4 , SARA UHAN 5 , U VEZONIK 6 , ZDENKO ASAR 7 1 Univerza v Ljubljani, Fakulteta za farmacijo, Ljubljana, Slovenija. E- 2 Ludwig Maximilians E- 3 biotehnologijo in imunologijo, Slovenija. E- 4 Univerza v Ljubljani, Fakulteta za kemijo in kemijsko tehnologijo, Katedra za biokemijo, Ljubljana,Slovenija. E- 5 E- 6 University of Vienna, Institut of Organic Chemistry, Dunaj, Avstrija. E- 7 Univerza v Ljubljani, Fakulteta za farmacijo, Ljubljana, Slovenija. E- -lj.si. DOPISNI AVTOR zdenko.casar@ffa.uni-lj.si. farmacevtska podjetja, inovativnost, , raziskave in razvoj, SARS-CoV-2 Povzetek zadnjih nekaj desetletijh azmerje znanstvenih objav in podeljenih patentov, je v zadnjih desetletjih vztrajno padal. Predvsem v zadnjih letih mnoga podjetja i delovanja razvojnih oddelkov. ANALI PAZU HD Vol. 9, No. 1-2, pp. 95 123 October 2023 https://doi.org/10.18690/analipazuhd.9.1-2.95-123.2023 Text , 2023 STRATEGIES FOR INCREASING INNOVATION IN BIG PHARMACEUTICAL COMPANIES PELA B 1 , LEA KNEZ 2 , PELA KNEZ 3 , T MLAKAR 4 , SARA UHAN 5 , U VEZONIK 6 , ZDENKO ASAR 7 Accepted 1. 5. 2023 Revised 18. 9. 2023 Published 25. 10. 2023 1 University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia. E-mail: spelabarbi@gmail.com. 2 Ludwig Maximilians University Munich, Germany. E-mail: lea.knez07@gmail.com. 3 University of Ljubljana, Faculty of Biotechnology, Department of Genetics, Animal Biotechnology and Immunology, Slovenia. E-mail: spela.knez@gmail.com. 4 University of Ljubljana, Faculty of Chemistry and Chemical Technology, Chair of Biochemistry, Ljubljana, Slovenia. E-mail: tjasamlakar.15@gmail.com. 5 - Cancer Immunology, Germany. E-mail: sara.uhan@charite.de. 6 University of Vienna, Institute of Organic Chemistry, Vienna, Austria. E-mail: uros.vezonik@univie.ac.at. 7 University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia. E-mail: zdenko.casar@ffa.uni-lj.si. CORRESPONDING AUTHOR zdenko.casar@ffa.uni-lj.si. Abstract The overall technological, scientific and managerial progress of the last few decades is expected to be reflected in increased innovation and research efficiency in many entities, including large pharmaceutical companies. However, often the opposite can be observed. The efficiency of research and development (R&D), which can also be described as the input- output ratio, usually estimated by the number inhouse developed and launched medicines on the market or published scientific publications and granted patents, has been steadily declining in recent decades in the pharmaceutical industry. Nevertheless, especially in recent years many companies have shown successful resistance to this trend with an obvious increase in innovation, which among other things can be attributed to the improved financial efficiency and the design of new R&D models. Keywords: pharmaceutical companies, innovation, efficiency, research and development, SARS-CoV-2 : 97. 1 Uvod , , vztrajno zrcali v razvoj le- kvantificirata pomembnega kontrasta med n razumevanja fizike mikroprocesorjev. nasprot tudi obratna korelacija med velikostjo organizacije in njenim potencialom za rategija 98 ANALI PAZU HD . individualnega prevzemanja odgovornosti kot tudi zaradi optimiziranega sistema nagrajevanja ter prepozn mnogi poudarjajo tudi marsikatere prednosti velikih korporativnih podjetij, v katerih lahko ostajata gla poudarkom predvsem na spodbujanju ino podjetjih, ki so bodisi z novo zasnovo modelov bodisi porast v inovativnosti. S porastom inovativnosti velikokrat stopi v korak tudi porast produktivnosti, kar je pomembno tako za obstoj farmacevtskih podjetij kot tudi 2 podjetjih Med najbolj pogostimi strategijami, ki jih farmacevtska podjetja uporabljajo za smiselno upravljanje portfelja, o virtualne raziskave in razvoj, o o : 99. interni start- 2.1 Smiselno upravljanje portfelja zvoja - kandidate za zdravilo (Douglas idr., 2010). Pri implementaciji te strategije v praksi se izrazite ovire pojavijo v vedenjski ideologiji in organizacijski strukturi podjetja. , v organizacijskem leksikonu je primarnega interesa, saj bi se k definiciji ukinitvi neperspektivnih izdelkov. V ta namen je predvsem potrebno radikalno preoblikovanje tradicionalnega sistema rezultati (Douglas idr., 2010; Peck idr., 2015). V letu 2011 je AstraZeneca po temeljitem pregledu preteklih strategij raziskav in prava ivo, pravo varnost, pravi bolnik in pravi potencial za komercializacijo. gradnja prave kulture nadaljevanja projektov (Cook idr., 2014; Morgan idr., 2018). Aplikacija tega modela 100 ANALI PAZU HD . -2010 na 19 % v letih 2012-2016 (Morgan idr., 2018). 2.2 pomembne i raziskovalnih projektov ter no delno izpolnitev ciljev, usmerjene v produktne inovacije (Schuhmacher, Gassmann multinacionalnih farmacevtskih podjetij prihajalo iz zunanjih virov (Schuhmacher, Germann, Trill in Gassmann, 2013). inovativnosti (Melnychuk et al., 2021). Pfizer je na primer samo v letu 2021 pridobil Amplyx Pha Fosmanogepix, 2. - 9 milijard dolarjev. ko je podjetje Takeda sklenilo pogodbo o prevzemu podjetja Shire za 58.6 milijard podjetij na s Tudi podjetje Bristol-Myers Squibb (Bristol Myers Squibb : 101. inovativnosti raziskav in razvoja (LaMattina, 2011). Eden izmed razlogov je, da se v podjetja pripravljena veliko bolj vlagati v tvegane projekte. 2.3 V preteklosti so bile dejavnosti, povezane z raziskavami in razvojem, popolnoma integrirane znotraj farmacevtskega podjetja od interno ustvarjenih idej pa vse do inovacije in razvoja znotraj farmacevtskih podjetij Pojem odprte inovacije predstavlja fleksibilen poslovni model, v katerem inovacije novih izdelkov izvirajo tako iz notranjih kot tudi iz zunanjih idej in nadaljnje razvijanje produkta na posameznih stopnjah lahko poteka v sodelovanju z zunanjimi podjetji ali akademskimi institucijami. Dejstvo je, da so velika farmacevtska podjetja zelo odvisna od akademskega znanja pri odkritju in razvoju zdravil. Raziskovanje in razvoj novih zdravil je dolgotrajen in , tega vodilna farmacevtska podjetja ugotavljajo, da delovanje le znotraj podjetja ni (Melnychuk et al., 2021). Pogosto je temelj inovacije v farmaciji osnovno 102 ANALI PAZU HD . Harvard (Pfizer, Roche, Sanofi), UCSF (Pfizer, Sanofi, Bayer), MIT (Novartis, Sanofi, Pfizer, Merck), Vanderbilt (Janssen, Bristol-Myers Squibb, AstraZeneca) in druge (Thomas & McKew, 2014). Leta 2012 je bil ustanovljen tudi sindikat razvoj zdravil ADDC (angl. Academic Drug Discovery Consortium) (Academic Drug Discovery Consortium, 2022). Leta 2020 je Pfizer Pfizer investiral do 500 2.3.1 Virtualne raziskave in razvoj Virtualni model raziskav in razvoja (R&R) lahko definiramo kot organizacijo, ki uporablja zunanje vire, ljivost, so Organizacija Chorus je iniciativa znotraj podjetja Lilly divizije e.Lilly, ki se je od leta znotraj Eli Lilly, ki je specializirana za razvoj zdravil od izbire kandidatov do - v pozni fazi. desetlet farmacevtskimi raziskavami in razvojem (Owens, 2014). Podjetje Boehringer Ingelsheim je leta 2021 oznanilo triletno sodelovanje s : 103. Ingelheim na novo ustanovilo tudi Kvantni laboratorij (Quantum Lab) (Boehringer Ingelheim, 2021). V letu 2021 je podjetje Boehringer Ingelheim sodelovalo z okoli 120 partnerskimi institucijami, 50 % vseh proizvodov, ki so trenutno v razvoju, pa podjetje razvija v sodelovanju z zunanjimi izvajalci (Boehringer Ingelheim, 2022). 2.3.2 v sodelovanju ter dostopu do rezultatov in izdelkov za vsakogar. Osebe, ki sodelujejo poslovnemu modelu farmacevtskega sektorja, kjer je bilo varovanje intelektualne prednosti open source inovacij (Schuhmacher idr., 2016). Leta 2009 je podjetje Eli Lilly implementirala spletno platformo, imenovano Odprt inovativni program za odkrivanje zdravil (Open Innovation Drug Discovery, OIDD), ki izmenjavo znanja in idej (Alvim-Gaston, 2014). Podjetje je s pobudo za odkrivanje Phenotypic Drug Discovery, PD2, 2009) in za optimizacijo zdravil (Target Drug Discovery, TD2, 2011) odprlo proces raziskav in razvoja za zunanje sodelovanje, kjer je bre u raziskav (Mroczkowski, 2011). Zunanji raziskovalci morajo podpisati in sprejeti pogodbo o prenosu dokumentov, da lahko postanejo podlagi predstavitve se Lilly in raziskovalci pogajajo za licenciranje ali sodelovanje. Sanofi spodbuja sodelovanje s sponzoriranimi raziskavami; globalne nagrade iAwards za biomedicinske inovacije, iDEA Awards (Severna Amerika) 2018 in ka partnerstva z glavnimi institucijami na da sodelujejo z vrhunskimi akademskimi znanstveniki iz ZDA, Evrope in Izraela, ki 104 ANALI PAZU HD . se ukvarjajo z inovativnimi raziskavami. V ZDA je program v prvih dveh letih prinesel osem projektov v portfelj v zgodnji fazi razvoja (Sanofi iDEA Awards, -2019 in 2019-2020), in pet projektov v teku (cikel 2020-2021). Izbrani projekti prejmejo osnovno financiranje do 150.000 $ za eno leto (Topol, 2018). Pomembnosti sodelovanja se zavedajo tudi v podjetju AstraZeneca, kjer so kot 20 inovativnih ce z Daiichi Sankyo za skupen razvoj datopotamab derextecana, potencialnega novega zdravila proti raku. Junija - zdravljenje raka. 2.3.3 Crowdsourcing informacije (posamezne storitve ali ideje) od internetnih uporabnikov. Podobno kot Schuhmacher idr., 2018). Podjetje Lilly je ustanovilo problemov, ki povezuje podjetja, ki predlagajo raziskovalni izziv s potencialnimi InnoCentive, ki deluj Leta 2008 je Roche obja : 105. $ (Birkinshaw in Crainer, 2008). CoSolve program, katerega cilj je podreti tradicionalne ovire sodelovanja in najti znotraj start-upov in 2.4 farmacevtskih podjetij in strokovnjakov iz akademskega sveta (Schuhmacher idr., institucij. Eden izmed primerov je Pfizer, ki je v letu 2014 ustvaril novo raziskovalno znanimi univerzami, kot so Massachusetts Institute of Technology (MIT) in Harvard med drugimi tudi Eli Lilly, AstraZeneca, Sanofi, GSK in Novartis (Cambridge Open Data, 2022). Leta 2019 je podjetje Eli Lilly ustanovilo laboratorij za inovacije Lilly Gateway Labs ponudil delavcev ter izpostavljenost znanstvenemu in funkcionalnemu strokovnemu znanju Lilly (Lilly, 2019). Podjetje Sanofi je leta 2014 ustanovilo francosko- Alsace BioValley 106 ANALI PAZU HD . Leta 2004 je firma Roche ustanovila center za raziskave in zgodnji razvoj Roche Center Shan enih 271 patentnih prijav in 144 odobrenih na pogodbenimi raziskovalnimi organizacijami znotraj in zunaj Kitajske, da bi spodbudil dejavnosti odkrivanja zdravil in translacijske medicine na Kitajskem (Burton, 2021). V proizvodnje in druga partnerstva (Yining, 2020). inovacijo (anlg. CTI Pfizer's Centers for Therapeutic Innovation). CTI sodeluje z laboratorijev v Cambridgeu, MA, New Yorku, San Franciscu in San Diegu. 2.5 Interni start- -up Novartisov program, ki spodbuja in Za ustvarjanje inovacijam prijaznega delovnega okolja je Novartis najprej vpeljal model organizacije brez vodje oz. unbossing ekip. V okviru Genesis Labs so tako spodbudili sodelavce, da poleg vsakodnevnega : 107. dela opravljajo tudi osebne stranske projekte. Svoje ideje lahko predstavijo preko in tvorijo multidisciplinarno skupino znanstvenikov. Predstavitev projektov poteka na 2 leti, kjer raziskovalne skupine predlagajo ideje z visokim tveganjem, katerih cilj je revolucionirati odkrivanje in razvoj zdravil. Zmagovalne ekipe umaknejo iz vsakodnevnega delovanja organizacije, za 18 mesecev pa prejmejo osnovno financiranje za sodelovanje ter dobijo laboratorijske prostore in vire, kjer lahko svojo idejo razvijejo v prototip. 3 razvoj vlagat oddelka. V obdobju med letoma 2010 in 2020, novih molekularnih entitet (angl. New Molecular Entity) na trgu izstopajo Eli Lilly, Novartis, AstraZeneca in Roche titet pa zadnjih pet let. V absolutnem - e inovativnosti v podjetju. Deset velik potencial kitajskega znanja in produktivnosti (Xie, 2014). Eli Lilly, ki je nekoliko e vidno na primeru Chorus-a in OIDD portala. 108 ANALI PAZU HD . -2020), razmerje med -2020 ter s strani FDA odobrenih NME v obdobju 2015- strani prodaje) Vir: AstraZeneca, BMS, Eli Lilly, GSK, J&J, Merck, Novartis, Pfizer, Roche, Sanofi, 2011-2021 Med izbranimi desetimi farmacevtskimi giganti v Tabeli 1 je opazen trend segmentu namenila 21,9 % sredstev (AstraZeneca, BMS, Eli Lilly, GSK, J&J, Merck, Novartis, Pfizer, Roche, Sanofi, 2011-2021). Relativno 29 e : 109. Slika 2: -2020), s strani FDA odobrenih NME v obdobju 2015- -2020 ter s strani FDA na novo odobrenih NME v obdobju 2015-2020) Vir: AstraZeneca, BMS, Eli Lilly, GSK, J&J, Merck, Novartis, Pfizer, Roche, Sanofi, 2011-2021 Ob vse zdravil sirota (angl tudi zdravila, pri katerih 110 ANALI PAZU HD . Slika 3: na novo odobrenih NME Vir: (FDA, 2022). Med letoma 2005 in 2009 je po podatkih CMR-ja (angl. Centre for Medicines zdravil potreben - se agencija za hrano in zdravila, ang. U.S. Food and Drug Administration) za trg v ZDA cev, podjetja na odprtem trgu prihranijo okrog 100 milijonov (Brown, 2021). : 111. 4 -CoV-2 pandemije Pandemija covid- covid-19 je zelo pomembno sodelovanje podjetij pri (Pfizer, Amgen, Takeda, Bristol Myers Squibb, Astellas, Sanofi, GSK, Jannsen, tno organizacijo Accumulus Synergy, Laland, 2021) etjem BioNTech razvil enega prvih covid- 2021). Aprila 2020 je AstraZeneca v sklopu odgovora na covid- sodelovanje z Univerzo v Oxfordu z namenom globalnega razvoja, proizvodnje in dobave njihovega cepiva (Vaxzervia) (Astrazeneca, 2020). Medtem nekatera farmacevtska podjetja med seboj ne sodelujejo v razvoju, ampak v proizvodnji cepiv. Takeda je s sodelovanjem z Novavax licencirala tehnologijo cepiva proti covid- cepivo proti covid-19, v okviru partnerstva z Moderno (Takeda, 2020). Farmacevtska podjetja so za razvoj cepiv proti SARS-CoV- sredstva; Sanofi in GSK skleneta pogodbo za razvoj rekombinantnega cepiva, pri s katerim u angl. Biomedical Advanced Research and razvoj in odobritev cepiv proti covid- 100 milijonov odmerkov cepiva ter nadaljnjih 500 milijonov odmerkov v vrednosti 2 milijardi dolarjev (Zimlich, 2021). zasnovalo Roche Canada COVID-19 Innovation Challenge, program financiranja covid-19. 112 ANALI PAZU HD . lastnine prevzelo podjetje Roche (Roche, 2020). Pharmaceuticals za 350 milijonov dolarjev za ekskluzivne pravice za raziskovanje, razvoj in distribucijo molekule AT-527 kot peroralnega protivirusnega zdravljenja za covid- covid-19, je Roche 2021 prekinil sodelovanja z Atea Pharmaceuticals, ki je prevzel polne pravice za izv -527 v prihodnosti (Sagar, 2021). sklenilo raziskovalno sodelovanje s podjetjem AbCellera z namenom raziskovanja monoklonskih protiteles proti covid-19. AbCellera je s svojo platformo za odziv na pandemijo razvilo protitelo Bamlanivimab in Betelovimab, medtem ko je podjetje Eli Lilly odgovorno za razvoj, proizvodnjo in distribucijo. Zaradi nedelovanj Bamlanivimaba na covidne variante je Eli Lilly 2021 izgubil 375 milijonov dolarjev v prodaji (Brennan, 2021). 5 i kompleksnosti biomedicinskih raziskav. Ta trend upadanja produktov. Dejstvo je, da po spodbujanje inovativnih posameznikov. Skozi pregledovanja literature in : 113. Najpogosteje se pojavljajo strategije, ki temeljijo na smiselnem upravljanju portfelja, inovacijskimi i ter internimi start- i ali inkubatorji znotraj nizko produktivnost, saj le-to pr didate za zdravilo. Pri smiselnem elikokrat v tem kontekstu prihaja do prevzemanja tehnologij, znanja in produkta drugega podjetja. Dejstvo je vegane projekte. Na ja je sodelovanje oziroma model odprte inovacije, kjer gre za fleksibilen poslovni model, pri katerem razvoj poteka v sodelovanju z majhnimi podjetji ali akademskimi institucijami. Pogosto je farmacevtska industrija v razvoju odvisna od akademskega znanja in/ali tehnologijo za razvoj zagotovijo zunanji viri. Strategiji v sklopu odprte inovacije internetnih uporabnikov. V kontekstu sodelovanja z akademijo se podjetja informacij. Verjetno ena izmed redkih strategij, kjer se veliko farmacevtsko podjetje znotraj podjetja, ki ga je kot prvo vzpos 114 ANALI PAZU HD . litera lansirala podjetja Eli Lilly, Novartis, AstraZeneca in Roche (Tabela 1). Ta razvojnega cikla zdravi absolutnem smislu najbolj izstopa podjetje Novartis, kjer lahko zaradi zagnanega farmacevtskimi velikani pa je opaz % relativno jejo z redkih obolenj. Pandemija SARS-CoV- (primer sodelovanja med podjetjem Pfizer in BioNTech). Eden izmed primerov sodelovanja je tudi novoustanovljena platforma Accumulus Synergy, ki podpira izzivov, kot ga je leta 2020 oblikovalo podjetje Roche, imenovano Roche Canada COVID- lna sodelovanja so bila prav tako zelo s problemom inovativnosti v raziskavah in razvoju. Prav tako je opazno, da so -19 prispevale k utrjevanju sodelovanj med podjetji in drugimi institucijami. Zanimivo bo opazovati, kako se bodo trendi : 115. Literatura in viri Academic Drug Discovery Consortium. (2022). Academic Drug Discovery Consortium (ADDC). Academic Drug Discovery Consortium. Pridobljeno dne 27. 03. 2023 na: https://www.addconsortium.org/about-landing.php. Laland, P. (2021). Ten leading biopharma companies announce formation of Accumulus Synergy to develop global data sharing platform. GlobeNewswire. Pridobljeno dne 21. 10. 2022 na: https://www.globenewswire.com/news-release/2021/01/22/2162826/0/en/Ten-Leading- BioPharma-Companies-Announce-Formation-of-Accumulus-Synergy-to-Develop-Global- Data-Sharing-Platform.html. Alvim-Gaston, M., Grese, T., Mahoui, A., Palkowitz, A., Pineiro-Nunez, M., Watson, I. (2014). Open Innovation Drug Discovery (OIDD): A Potential Path to Novel Therapeutic Chemical Space. Current Topics in Medicinal Chemistry, 14, 3, str. 294 303. Pridobljeno na: https://doi.org/10.2174/1568026613666131127125858. AstraZeneca. (2022). Collaboration across industry verticals to support local innovations. AstraZeneca. Pridobljeno dne 15. 10. 2022 na: ttps://www.astrazeneca.com/media- centre/articles/2022/collaboration-across-industry-verticals-to-support-local- innovations.html. AstraZeneca (2020). Collaboration will enable global development, manufacturing and distribution of the vaccine. AstraZeneca. Pridobljeno dne 15. 10. 2022 na: https://www.astrazeneca.com/media-centre/press-releases/2020/astrazeneca-and-oxford- university-announce-landmark-agreement-for-covid-19-vaccine.html#. AstraZeneca. (2021). Annual Report 2020. AstraZeneca. Pridobljeno dne 15. 10. 2022 na: https://www.astrazeneca.com/content/dam/az/Investor_Relations/annual-report- 2020/pdf/AstraZeneca_AR_2020.pdf. AstraZeneca. (2019). Annual Report 2018. AstraZeneca. Pridobljeno dne 15. 10. 2022 na: https://www.astrazeneca.com/content/dam/az/Investor_Relations/annual-report- 2018/PDF/AstraZeneca_AR_2018.pdf. AstraZeneca. (2017). Annual Report 2016. AstraZeneca. Pridobljeno dne 15. 10. 2022 na: https://www.astrazeneca.com/content/dam/az/Investor_Relations/Annual-report- 2016/AZ_AR2016_Full_Report.pdf. AstraZeneca. (2015). Annual Report 2014. AstraZeneca. Pridobljeno dne 15. 10. 2022 na: https://www.astrazeneca.com/content/dam/az/Investor_Relations/annual-reports- homepage/2014-Annual-report-English.pdf. AstraZeneca. (2013). Annual Report 2012. AstraZeneca. Pridobljeno dne 15. 10. 2022 na: https://www.astrazeneca.com/content/dam/az/Investor_Relations/annual-reports- homepage/2012-Annual-report-English.pdf AstraZeneca. (2011). Annual Report 2010. AstraZeneca. Pridobljeno dne 15. 10. 2022 na: https://www.astrazeneca.com/content/dam/az/Investor_Relations/annual-reports- homepage/2010-Annual-Report-English.pdf. 116 ANALI PAZU HD . Betz, U. A. K. (2011). Portfolio management in early stage drug discovery a traveler's guide through uncharted territory. Drug Discovery Today, 16, 13-14, str. 609 618. Pridobljeno na: https://doi.org/10.1016/j.drudis.2011.04.012. Birkinshaw, J. in Crainer, S. (2008). Extended case study: ROCHE Original. Innocentive. Pridobljeno dne 21. 10. 2022 na: https://www.innocentive.com/wp-content/uploads/2019/09/roche- case-study.pdf. Boehringer Ingelheim. (2021). Quantum Computing: Boehringer Ingelheim and Google Partner for Pharma R&D. Boehringer Ingelheim. Pridobljeno dne 27. 05. 2022 na: https://www.boehringer-ingelheim.com/press-release/partnering-google-quantum- computing. Boehringer Ingelheim. (2021). Our Human Pharma Research and Development Pipeline. Boehringer Ingelheim. Pridobljeno dne 27. 05. 2022 na: https://www.boehringer- ingelheim.com/science/human-health/research-and-development-pipeline. Brennan, Z. (2021). UPDATED: US pauses use of Eli Lilly's Covid-19 treatment nationwide due to variants. EndpointsNews. Pridobljeno dne 13. 04. 2022 na: https://endpts.com/us-pauses- use-of-eli-lillys-covid-19-treatment-nationwide-due-to-variants/. Bristol Myers Squibb. (2021). Annual Report 2020. Bristol Myers Squibb. Pridobljeno dne 31. 03. 2022 na: https://s21.q4cdn.com/104148044/files/doc_financials/annual_reports/2020/Final_BMS_ 2020_Annual_Report.pdf. Bristol Myers Squibb. (2019). Annual Report 2018. Bristol Myers Squibb. Pridobljeno dne 31. 03. 2022 na: https://s21.q4cdn.com/104148044/files/doc_financials/annual_reports/2018/2018- BMS-Annual-Report.pdf. Bristol Myers Squibb. (2017). Annual Report 2016. Bristol Myers Squibb. Pridobljeno dne 31. 03. 2022 na: https://s21.q4cdn.com/104148044/files/doc_financials/annual_reports/2016/2016- Annual-Report.pdf. Bristol Myers Squibb. (2015). Annual Report 2014. Bristol Myers Squibb. Pridobljeno dne 31. 03. 2022 na: https://s21.q4cdn.com/104148044/files/doc_financials/annual_reports/2014/BMS- 2014-Annual-Report.pdf. Bristol Myers Squibb. (2013). Annual Report 2012. Bristol Myers Squibb. Pridobljeno dne 31. 03. 2022 na: https://s21.q4cdn.com/104148044/files/doc_financials/annual_reports/Bristol-Myers- Squibb-2012AR-lr.pdf. Bristol Myers Squibb. (2011). Annual Report 2010. Bristol Myers Squibb. Pridobljeno dne 31. 03. 2022 na: https://s21.q4cdn.com/104148044/files/doc_financials/annual_reports/BMS_2010_AR_lo wres.pdf. Brown, D. G., Wobst, H. J., Kapoor, A., Kenna, L. A. in Southall, N. (2022). Clinical development times for innovative drugs. Nature Reviews Drug Discovery 21, 11, str. 793 794. Pridobljeno na: https://doi.org/10.1038/d41573-021-00190-9. Bristol Myers Squibb. (2019). Bristol-Myers Squibb Completes Acquisition of Celgene, Creating a Leading Biopharma Company. Bristol Myers Squibb. Pridobljeno dne 31. 03. 2022 na: : 117. https://news.bms.com/news/corporate-financial/2019/Bristol-Myers-Squibb-Completes- Acquisition-of-Celgene-Creating-a-Leading-Biopharma-Company/default.aspx. Accelerator. Pharma boardroom. Pridobljeno dne 21. 10. 2022 na: https://pharmaboardroom.com/articles/roche-hoping-to-spearhead-created-in-china-push- with-new-innovation-accelerator/. Cook, D., Brown, D., Alexander, R., March, R., Morgan, P., Satterthwaite, G. in Pangalos, M. N. (2014). -dimensional framework. Nature Reviews Drug Discovery, 13, 6, str. 419 431. Pridobljeno na: https://doi.org/10.1038/nrd4309. Cambridge Open Data. (2022). Life Sciences and Technology Company Listing: January 2022. Cambridge Open Data. Pridobljeno dne 18. 01. 2023 na: https://data.cambridgema.gov/Economic-Development/Life-Sciences-and-Information- Technology-Company-L/fv53-bvhy. Douglas, F., Narayanan, V., Mitchell, L. in Litan, R. E. (2010). The case for entrepreneurship in R&D in the pharmaceutical industry. Nature Reviews Drug Discovery, 9, 9, str. 683 689. Pridobljeno na: https://doi.org/10.1038/nrd3230. Edmondson, A. C., Gulati, R., Healy, P. J. in Herman, K. (2019). The Genesis Lab at Novartis. Harvard Business School Case 620-007. Pridobljeno dne 28. 06 2022 na: https://www.hbs.edu/faculty/Pages/item.aspx?num=57275. Eli Lilly. (2019). Our Approach to Partnering. Eli Lilly. Pridobljeno dne 31. 05. 2022 na: https://www.lilly.com/partners/our-partnering-approach. Eli Lilly. (2021). Annual Report 2020. Eli Lilly. Pridobljeno dne 08. 02. 2022 na: https://investor.lilly.com/static-files/ebc0157d-811b-46fb-82ab-10a1f34d1b2b. Eli Lilly. (2019). Annual Report 2018. Eli Lilly. Pridobljeno dne 08. 02. 2022 na: https://investor.lilly.com/static-files/9a86e5d8-705c-4315-a3b2-56bfc208d1ca. Eli Lilly. (2017). Annual Report 2016. Eli Lilly. Pridobljeno dne 08. 02. 2022 na: https://investor.lilly.com/static-files/77e65332-ec0d-460e-b29b-2f740617a5b2. Eli Lilly. (2015). Annual Report 2014. Eli Lilly. Pridobljeno dne 08. 02. 2022 na: https://investor.lilly.com/static-files/a536af75-8510-4315-9920-335ef3926825. Eli Lilly. (2013). Annual Report 2012. Eli Lilly. Pridobljeno dne 08. 02. 2022 na: https://investor.lilly.com/static-files/df12fc52-42fa-4757-8538-5dbf9d4bcab3. Eli Lilly. (2011). Annual Report 2010. Eli Lilly. Pridobljeno dne 08. 02. 2022 na: https://investor.lilly.com/static-files/51db3908-2dbd-482e-b3bf-f5e1731a34a9. FDA. (2022). Compilation of CDER NME and New Biologic Approvals 1985-2022. Pridobljeno dne 19. 11. 2022 na: https://view.officeapps.live.com/op/view.aspx?src=https%3A%2F%2Fwww.fda.gov%2Fm edia%2F135307%2Fdownload&wdOrigin. 118 ANALI PAZU HD . Giannuzzi, V., Conte, R., Landi, A. Ottomano, S. A.; Bonifazi, D.; Baiardi, P.; Bonifazi, F. in Ceci, A. (2017). Orphan medicinal products in Europe and United States to cover needs of patients with rare diseases: an increased common effort is to be foreseen. Orphanet Journal of Rare Diseases, 12, 64. Pridobljeno na: https://doi.org/10.1186/s13023-017-0617-1. GlaxoSmithKline. (2021). Annual Report 2020. GlaxoSmithKline. Pridobljeno dne 13. 03. 2022 na: https://www.gsk.com/media/7962/annual-report-2020.pdf. GlaxoSmithKline. (2019). Annual Report 2018. GlaxoSmithKline. Pridobljeno dne 13. 03. 2022 na: https://www.gsk.com/media/7991/annual-report-2018.pdf. GlaxoSmithKline. (2017). Annual Report 2016. GlaxoSmithKline. Pridobljeno dne 13. 03. 2022 na: https://www.gsk.com/media/8100/annual-report-2016.pdf. GlaxoSmithKline. (2015). Annual Report 2014. GlaxoSmithKline. Pridobljeno dne 13. 03. 2022 na: https://www.gsk.com/media/8088/annual-report-2014.pdf. GlaxoSmithKline. (2013). Annual Report 2012. GlaxoSmithKline. Pridobljeno dne 13. 03. 2022 na: https://www.gsk.com/media/8077/annual-report-2012.pdf. GlaxoSmithKline. (2011). Annual Report 2010. GlaxoSmithKline. Pridobljeno dne 13. 03. 2022 na: https://www.gsk.com/media/8069/annual-report-2010.pdf. Hunter, J. in Stephens, S. (2010). Is open innovation the way forward for big pharma? Nature Reviews Drug Discovery, 9, 2, str. 87 88. Pridobljeno na: https://doi.org/10.1038/nrd3099. Johnson&Johnson. (2021). Annual Report 2020. Johnson&Johnson. Pridobljeno dne 13. 04. 2022 na: https://www.investor.jnj.com/annual-meeting-materials/2020-annual-report. Johnson&Johnson. (2019). Annual Report 2018. Johnson&Johnson. Pridobljeno dne 13. 04. 2022 na: https://www.investor.jnj.com/annual-meeting-materials/2018-annual-report. Johnson&Johnson. (2017). Annual Report 2016. Johnson&Johnson. Pridobljeno dne 13. 04. 2022 na: https://www.investor.jnj.com/annual-meeting-materials/2016-annual-report. Johnson&Johnson. (2015). Annual Report 2014. Johnson&Johnson. Pridobljeno dne 13. 04. 2022 na: https://www.investor.jnj.com/annual-meeting-materials/2014-annual-report. Johnson&Johnson. (2013). Annual Report 2012. Johnson&Johnson. Pridobljeno dne 13. 04. 2022 na: https://www.investor.jnj.com/annual-meeting-materials/2012-annual-report. Johnson&Johnson. (2011). Annual Report 2010. Johnson&Johnson. Pridobljeno dne 13. 04. 2022 na: https://www.investor.jnj.com/annual-meeting-materials/2010-annual-report. Khare R., Good B. M., Leaman R., Su A. I. in Lu Z. (2016). Crowdsourcing in biomedicine: challenges and opportunities. Briefings in Bioinformatics, 17, 1, str. 23 32. Pridobljeno na: https://doi.org/10.1093/bib/bbv021. LaMattina, J. L. (2011). The impact of mergers on pharmaceutical R&D. Nature Reviews Drug Discovery, 10, 8, str. 559 560. Pridobljeno na: https://doi.org/10.1038/nrd3514. Melynchuk T., Schultz C. in Wirsich A. (2021). The effects of university-industry collaboration in : 119. Journal of Product Innovation Management 38, 3, str. 355 378. Pridobljeno na: https://doi.org/10.1111/jpim.12572. Merck. (2021). Annual Report 2020. Merck. Pridobljeno dne 09. 06. 2022 na: https://s21.q4cdn.com/488056881/files/doc_financials/2020/q4/4df43d8f-8b85-45da- 92ef-7ad82f343c3b.pdf. Merck. (2019). Annual Report 2018. Merck. Pridobljeno dne 09. 06. 2022 na: https://s21.q4cdn.com/488056881/files/doc_financials/2018/Q4/2018-Form-10-K- (without-Exhibits)_FINAL_022719.pdf. Merck. (2017). Annual Report 2016. Merck. Pridobljeno dne 09. 06. 2022 na: https://s21.q4cdn.com/488056881/files/doc_financials/2017/Q4/merck-q4-10k.pdf. Merck. (2015). Annual Report 2014. Merck. Pridobljeno dne 09. 06. 2022 na: https://s21.q4cdn.com/488056881/files/doc_financials/2014/annual/2014-Form-10- K_FINAL_022715.pdf. Merck. (2013). Annual Report 2012. Merck. Pridobljeno dne 09. 06. 2022 na: https://s21.q4cdn.com/488056881/files/doc_financials/2012/annual/MRK_form_10_k_2 012.pdf. Merck. (2012). Annual Report 2011. Merck. Pridobljeno dne 09. 06. 2022 na: https://s21.q4cdn.com/488056881/files/doc_financials/2011/annual/form-10-k-2011.pdf. Morgan, P., Brown, D. G., Lennard, S., Anderton, M. J., Barrett, J. C., Eriksson, U., Fidock, M., S., Snowden, M. A. in Pangalos, M. N. (2018). Impact of a five-dimensional framework on R&D productivity at AstraZeneca. Nature Reviews Drug Discovery, 17, 3, 167 181. Pridobljeno na: https://doi.org/10.1038/nrd.2017.244. Mullard, A. (2022). 2021 FDA approvals. Nature Reviews Drug Discovery 21, 2, str. 83 88.: Pridobljeno na: https://doi.org/10.1038/d41573-022-00001-9. Munos, B. (2009). Lessons from 60 years of pharmaceutical innovation. Nature Reviews Drug Discovery, 8, 12, str. 959 968. Pridobljeno na: https://doi.org/10.1038/nrd2961. Natesan, S. (2021). The Value of Industry-Academic Collaboration. Sanofi. Pridobljeno dne 24. 01. 2022 na: https://www.sanofi.com/en/science-and-innovation/stories/the-value-of-industry- academic-collaboration. Novartis. (2021). Annual Report 2020. Novartis. Pridobljeno dne 27. 05. 2022 na: https://www.novartis.com/sites/novartis_com/files/novartis-annual-report-2020.pdf. Novartis. (2019). Annual Report 2018. Novartis. Pridobljeno dne 27. 05. 2022 na: https://www.novartis.com/sites/novartis_com/files/novartis-annual-report-2020.pdf. Novartis. (2017). Annual Report 2016. Novartis. Pridobljeno dne 27. 05. 2022 na: https://www.novartis.com/sites/novartis_com/files/novartis-annual-report-2016-en.pdf. Novartis. (2015). Annual Report 2014. Novartis. Pridobljeno dne 27. 05. 2022 na: https://www.novartis.com/sites/novartis_com/files/novartis-annual-report-2014-en.pdf. 120 ANALI PAZU HD . Novartis. (2013). Annual Report 2012. Novartis. Pridobljeno dne 27. 05. 2022 na: https://www.novartis.com/sites/novartis_com/files/novartis-annual-report-2012-en.pdf. Novartis. (2011). Annual Report 2010. Novartis. Pridobljeno dne 27. 05. 2022 na: https://www.novartis.com/sites/novartis_com/files/novartis-annual-report-2010-en.pdf. Owens, P. K., Raddad, E., Miller, J. W., Stille, J. R., Olovich, K. G., Smith, N. V., Jones, R. S., & Scherer, J. C. (2014). A decade of innovation in pharmaceutical R & D: The Chorus model. Nature Reviews Drug Discovery, 14, 1, str. 17 28. Pridobljeno na: https://doi.org/10.1038/nrd4497. Paul, S. M., Mytelka, D. S., Dunwiddie, C. T., Persinger, C. C., Munos, B. H., Lindborg, S. R. in Schacht, A. L. (2010). How to improve R&D productivity: the pharmaceutical industry's grand challenge. Nature Reviews Drug Discovery, 9, 3, str. 203 214. Pridobljeno na: https://doi.org/10.1038/nrd3078. Peck, R., Lendrem, D., Grant, I. Landrem, B. C. in Isaacs, D. C. (2015). Why is it hard to terminate failing projects in pharmaceutical R&D?. Nature Reviews Drug Discovery, 14, 10, str. 663 664. Pridobljeno na: https://doi.org/10.1038/nrd4725. Pfizer. (2021). Annual report 2021. Pfizer. Pridobljeno dne 01. 06. 2022 na: https://s28.q4cdn.com/781576035/files/doc_financials/2021/ar/PFE-2021-Form-10K- FINAL.pdf. Pfizer. (2022). Pfizer invests $120 million in biotechnology innovation through the Pfizer breakthrough growth initiative. Pfizer. Pridobljeno dne 01. 06. 2022 na: https://www.pfizer.com/news/press-release/press-release-detail/pfizer-invests-120-million- biotechnology-innovation-through. Pfizer. (2021). Annual Report 2020. Pfizer. Pridobljeno dne 01. 06. 2022 na: https://s28.q4cdn.com/781576035/files/doc_financials/2020/AR/PFE-2020-Form-10K- FINAL.pdf. Pfizer. (2019). Annual Report 2018. Pfizer. Pridobljeno dne 01. 06. 2022 na: https://s28.q4cdn.com/781576035/files/doc_financials/2018/AR/2018-Financial- Report.pdf. Pfizer. (2017). Annual Report 2016. Pfizer. Pridobljeno dne 01. 06. 2022 na: https://s28.q4cdn.com/781576035/files/doc_financials/2016/AR/2016-financial- report.pdf. Pfizer. (2015). Annual Report 2014. Pfizer. Pridobljeno dne 01. 06. 2022 na: https://s28.q4cdn.com/781576035/files/doc_financials/2014/AR/2014_Pfizer_Financial_ Report.pdf. Pfizer. (2013). Annual Report 2012. Pfizer. Pridobljeno dne 01. 06. 2022 na: https://s28.q4cdn.com/781576035/files/doc_financials/2012/AR/financial2012.pdf. Pfizer. (2011). Annual Report 2010. Pfizer. Pridobljeno dne 01. 06. 2022 na: https://s28.q4cdn.com/781576035/files/doc_financials/2010/AR/financial2010.pdf. : 121. Philippidis, A. (2019). Top 10 M&A Deals of January June 2019. Genetic Engineering & Biotechnology News. Pridobljenodne 21. 10. 2022 na: https://www.genengnews.com/a- lists/top-10-ma-deals-of-january-june-2019/ Roche. (2020). Roche Canada establishes COVID-19 Open Innovation Challenge . Roche Canada. Pridobljeno dne 21. 10. 2022 na: https://www.rochecanada.com/en/media/roche-canada- news/Roche-Canada-establishes-COVID-19-Open-Innovation-Challenge11.html. Roche. (2021). Annual Report 2020. Roche. Pridobljeno dne 31. 10. 2022 na: https://assets.cwp.roche.com/f/126832/cc6ebb8b34/ar20e.pdf. Roche. (2019). Annual Report 2018. Roche. Pridobljeno dne 31. 10. 2022 na: https://assets.cwp.roche.com/f/126832/x/5b363fe899/ar18e.pdf. Roche. (2017). Annual Report 2016. Roche. Pridobljeno dne 31. 10. 2022 na: https://assets.cwp.roche.com/f/126832/x/6d826707e6/ar16e.pdf. Roche. (2015). Annual Report 2014. Roche. Pridobljeno dne 31. 10. 2022 na: https://assets.cwp.roche.com/f/126832/x/9397451885/gb14e.pdf. Roche. (2013). Annual Report 2012. Roche. Pridobljeno dne 31. 10. 2022 na: https://assets.cwp.roche.com/f/126832/x/eae55da0ac/gb12e.pdf. Schuhmacher, A., Gassmann, O., Bieniok, D., Hinder, M., Hartl, D. (2022). Open innovation: A paradigm shift in pharma R&D?. Drug Discovery Today, 27, 9, str. 2395-2405. Pridobljeno na: https://doi.org/10.1016/j.drudis.2022.05.018. Sanofi iDEA Awards. (2020). Sanofi iDEA-iTECH Awards. Sanofi. Pridobljeno na: https://www.sanofi.com/en/science-and-innovation/collaboration-and- awards/europe/idea-itech. Sanofi. (2018). Seed funding facilitates de-risking of AI approaches and data linkages to address business critical issues not yet solved internally. Sanofi. Pridobljeno dne 13. 04. 2022 na: https://www.sanofi.us/dam/jcr:d0cfb2bf-13b1-4242-9b17- c9bdf2e23711/iDEA_Initiative_summary.pdf. Sanofi. (2021). Annual Report 2020. Sanofi. Pridobljeno dne 13. 04. 2022 na: https://www.sanofi.com/dam/jcr:7dcce0b5-6c2e-49ef-a659- 52941512517b/2021_03_23_Sanofi_20F_FINAL_Acc.pdf. Sanofi. (2019). Annual Report 2018. Sanofi. Pridobljeno dne 13. 04. 2022 na: https://www.sanofi.com/dam/jcr:48c37b1e-48b3-42c2-98c3-a47f25751822/Sanofi-20-F- 2018-EN-PDF-e-accessible_01.pdf. Sanofi. (2017). Annual Report 2016. Sanofi. Pridobljeno dne 13. 04. 2022 na: https://www.sanofi.com/dam/jcr:02cfba1a-f6ab-47b4-96e5-45a3007b9306/20-F_2016.pdf. Sanofi. (2015). Annual Report 2014. Sanofi. Pridobljeno dne 13. 04. 2022 na: https://www.sanofi.com/dam/jcr:5cb50393-cb23-443f-b989-98d8d8be36f6/Sanofi_20- F_2014.pdf. 122 ANALI PAZU HD . Sanofi. (2013). Annual Report 2012. Sanofi. Pridobljeno dne 13. 04. 2022 na: https://www.sanofi.com/dam/jcr:36ed5227-bf13-4890-955d-94928b75a5a7/20- F_2012_V2.pdf. Sanofi. (2011). Annual Report 2010. Sanofi. Pridobljeno dne 13. 04. 2022 na: https://www.sanofi.com/dam/jcr:b4efceeb-0ea3-4068-bbcd-18f74012d04a/20F_2010.pdf. Sagar, V. (2021). Roche terminates partnership with Atea to develop Covid-19 antiviral drug. NS Healthcare. Pridobljeno dne 24. 12. 2022 na: https://www.ns-healthcare.com/news/roche- terminates-atea-partnership/#. Sambandan, B. H. R. P. (2015). Open Innovation in Pharmaceutical Industry : A case study of Eli Lilly Open Innovation in Pharmaceutical Industry : A case study of Eli Lilly. Master of Science Thesis, KTH School of Industrial Engineering and Management, Stockholm, Sweden. Scannell, J., Blanckley, A., Boldon, H. In Warrington, B. (2012). Diagnosing the decline in pharmaceutical R&D efficiency. Nature Reviews Drug Discovery, 11, 3, str. 191 200. Pridobljeno na: https://doi.org/10.1038/nrd3681. Schuhmacher, A., Germann, P. G., Trill, H. In Gassmann, O. (2013). Models for open innovation in the pharmaceutical industry. Drug Discovery Today, 18, 23-24, str. 1133 1137. Pridobljeno na: https://doi.org/10.1016/j.drudis.2013.07.013. Schuhmacher, A., Gassmann, O. In Hinder, M. (2016). Changing R&D models in research-based pharmaceutical companies. Journal of Translational Medicine, 14, 105. Pridobljeno na: https://doi.org/10.1186/s12967-016-0838-4. Schuhmacher, A., Gassmann, O., McCracken, N. in Hinder, M. (2018). Open innovation and external sources of innovation. An opportunity to fuel the R&D pipeline and enhance decision making? Journal of Translational Medicine, 16, 119. Pridobljeno na: https://doi.org/10.1186/s12967- 018-1499-2. Schuhmacher, A., Wilisch, L., Kuss, M., Kandelbauer, A., Hinder, M. in Gassmann, O. (2021). R&D efficiency of leading pharmaceutical companies - A 20-year analysis. Drug Discovery Today, 26, 8, str. 1784 1789. Pridobljeno na: https://doi.org/10.1016/j.drudis.2021.05.005. -19 Vaccine Candidate in Japan. Takeda. Pridobljeno dne 20. 09. 2022 na: https://www.takeda.com/newsroom/newsreleases/2020/novavax-and-takeda-announce- collaboration-for-novavax-covid-19-vaccine-candidate-in-japan/. Thomas, C., in McKew, J. (2014). Playing Well with Others! Initiating and Sustaining Successful Collaborations between Industry, Academia and Government. Current Topics in Medicinal Chemistry, 14, 3, str. 291 293. Pridobljeno na: https://doi.org/10.2174/1568026613666131127125351. Proceedings of the National Academy of Sciences of the United States of America, 111, str. 9437 9442. Pridobljeno na: https://doi.org/10.1073/pnas.1407709111. Yining, D. (2020). Boehringer Ingelheim launches innovation hub in Shanghai. Shine. Pridobljeno dne 20. 09. 2022 na: https://www.shine.cn/biz/company/2007021325/. : 123. Zimlich, R. (2021). An Overview of the Sanofi/GSK COVID-19 Vaccine. Very well health. Pridobljeno dne 20. 09. 2022 na: https://www.verywellhealth.com/sanofi-gsk-covid-19- vaccine-5093295.