- Email: [email protected]
An analysis of original research contributions toward FDA-approved drugs
Accepted Manuscript Title: An analysis of original research contributions toward FDA-approved drugs Author: Eric V. Patridge Peter C. Gareiss Michael S. Kinch Denton W. Hoyer PII: DOI: Reference:
S1359-6446(15)00236-6 http://dx.doi.org/doi:10.1016/j.drudis.2015.06.006 DRUDIS 1634
To appear in: Received date: Revised date: Accepted date:
4-3-2015 9-6-2015 12-6-2015
Please cite this article as: Patridge, E.V., Gareiss, P.C., Kinch, M.S., Hoyer, D.W.,An analysis of original research contributions toward FDA-approved drugs, Drug Discovery Today (2015), http://dx.doi.org/10.1016/j.drudis.2015.06.006 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Highlights The first manuscript for more than half of FDA-approved drugs originated in Academia. Industry has closed the gap in recent years in terms of publishing
Ac ce p
te
d
M
an
us
cr
ip t
NMEs first published by industry NMEs are twelve years closer to market than those from Academia
Page 1 of 8
An analysis of original research contributions toward FDAapproved drugs Eric V. Patridge1, Peter C. Gareiss1, Michael S. Kinch2, and Denton W. Hoyer1
ip t
1
Yale Center for Molecular Discovery, West Haven, CT 06516, USA Washington University in St Louis, St Louis, MO 63110, USA Corresponding author: Patridge, E.V. ([email protected]) Keywords: new molecular entity; drug discovery; academia; industry; research effort Teaser: More than half of FDA-approved drugs originate from academic research in North America. Furthermore, in academia, it takes twice as long as in industry to carry a drug from its first publication to market.
cr
2
an
us
Academic [LM1]researchers shaped the landscape of drug discovery for nearly two centuries, and their efforts initiated programs for more than half of the US Food and Drug Administration (FDA)-approved new molecular entities (NMEs). During the first 50 years of the 20th century, contributions from industry-based discovery programs steadily increased, stabilizing near half of all first publications for NMEs. Although academia and industry have made similar contributions to the discovery of FDA-approved NMEs, there remains a substantial difference in the gap-to-approval; on average, industry NMEs are 12 years closer to market at the time of the first publication. As more drug discovery efforts shift from industry to academia, including high-throughput screening resources, academia could have an increasingly crucial role in drug discovery. Historical advances in drug discovery
Ac ce p
te
d
M
Academia, industry, and biotech each make varied contributions to the research landscape and their programs have benefitted from scientific and technological advances. Many publications address diverse perspectives on the history of drug discovery [1–4], but to our knowledge, no study has yet assessed the relative contributions of each sector to the discovery process for NMEs*. Perhaps this is because there is more interest in the market value of NMEs approved by the FDA rather than in the process of their discovery and development. As part of an effort to examine the changing landscape of drug discovery, researchers in the Yale Center for Molecular Discovery assessed the trends in original research contributions leading to FDA-approved NMEs and we focus here on the contributions of academic institutions. As detailed in the first publication of this series [5], we cataloged all legacy drugs and recent NMEs, including those drugs that were subsequently removed from market. Other than morphine and aspirin, all included NMEs were reviewed by the Food, Drug and Insecticide Organization (est. 1927) and its successor, the FDA. Before 1910, academic researchers were responsible for all first publications leading to FDA-approved NMEs, and most of these were contributions from Europe and/or Russia†. During this time, natural products had a central role in drug discovery, which we previously examined in greater depth [6]. The first study that led to an FDAapproved NME was published in 1732 by Leiden University, the Netherlands; they reported on urea, or ‘the native salt of urine,’ which became FDA approved in 1966 [7]. It was not until 1910 that the Wellcome Research Laboratories, London became the first corporation to publish original research leading to an FDA-approved NME; they reported the synthesis of dopamine, or ‘3:4-dihydroxy-β-phenylethylamine’, which became FDA approved in 1974 [8]. Both of these NMEs highlight the significant time that it takes to carry a drug from its first publication to market, which we refer to here as the ‘gap-to-approval’. Urea holds the record for the longest gap-to-approval of 223 years. From a historical context, it is relevant to consider that NME discovery is tied to scientific advances and transformative technologies that have shaped the landscape of drug discovery. During the first decades of the 20th century, the scientific concepts of ‘receptive substances’ and selective ‘magic bullets’ inspired several drug discovery efforts focused on receptor–drug interactions. Soon after, the identification of sulfonamides and -lactams provided a basis for broad-spectrum antibiotic programs. During the latter half of the century, the structure of DNA was elucidated and quantitative structure–activity relations were introduced, broadening the fields of molecular biology, medicinal chemistry, and bioinformatics. In the closing years of the millennium, discovery programs became focused on biologics, combinatorial chemistry, and high-throughput screening approaches, and the field of cheminformatics was established by efforts across both academia and industry [1,9,10]. Several other transformative technologies have also shaped drug discovery, including mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy, which were commercialized in 1942 and 1952, respectively [9]. Beyond these, innovations such as the modern computer and genomic sciences also helped to redefine the landscape of drug discovery, and they continue to accelerate advances across academia and industry. Herein, we assess the research efforts leading to FDA-approved NMEs (n = 1453 as of December 31, 2013). In addition to examining the contributions of academia, industry, and biotech to the discovery process, we also examined the gap-to-approval for each sector, as well as the research efforts for prolific geographic areas. We
Page 2 of 8
considered academic efforts to include all contributions from unaffiliated individuals as well as those from colleges, universities, hospitals, and government institutions. As described in our earlier publication [11], we separated pharmaceutical (industry) from biotechnology (biotech) organizations, defining biotech as companies founded after the Cetus Corporation (1971). Analysis of the research origins and academic development for all NMEs
Ac ce p
te
d
M
an
us
cr
ip t
To build our publication data set, we first turned to PubMed, which is the largest bibliographic index for the life sciences and also the first database of choice for biomedical and life-science researchers. We then followed references from within each publication and used their NME naming conventions to query PubMed, SciFinder ®, Google Search or Scholar, and each journal website. We repeated this process for each NME until we found the earliest peer-reviewed publication to report the NME in a synthesis or purified formulation, and we extracted all authoring institutions. For the purposes of this study, we used the primary institution to define the research origins. In a few cases, we turned to dissertations, monographs, and books for the research origins of early NMEs, such as with Runge’s isolation of caffeine in 1820, which he called ‘kaffebase’ [12]. We rejected earlier references where the chemical material was known to be impure. Our literature review was exhaustive, and we found that many NMEs were first reported using descriptive adjectives, proprietary codes, structures, or outdated chemical nomenclature. In a few cases, a series of sequential articles served to announce NMEs in the same journal issue, and we selected the first publication in the series to represent the research origins. Our final assessment revealed that 55% (801/1453) of all NMEs were first reported by academic organizations. A decade-by-decade analysis confirmed that role of industry in the discovery process developed over the 20th century; through the year 1900, all NMEs (n = 58) were first reported by academia and, after 1900, academic contributions were steadily diluted by industry efforts (Figure 1A). The fraction of NMEs first reported by academia stabilized near 50% during the 1950s (n = 232), reaching as low as 46% during the 1990s (n = 200). On an annual basis, the number of contributions from each sector varied, reaching overall highs and lows in each decade since 1950. Biotech efforts accounted for just 3% of the NMEs, with a yearly high of 17% during the early 2000s. When Figure 1A is organized by year of FDA approval, the overall trends were the same (Figure S1A in the supplementary material online). Through further analysis, we found that the ‘gap-to-approval’ shifted over the 20th century, highlighting changes in carrying NMEs from their first publication to market. Our assessment of the 1453 NMEs revealed that, after their first publication, 17% were approved within 3 years, and 47% were approved after 10 years. A decadeby-decade analysis reveals a more detailed picture (Figure 1B). The NMEs approved before 1930 (n = 3) had a gapto-approval averaging 47 years. These NMEs indeed pre-date the FDA, which was established in 1931 as the successor to other institutions that had existed since the 19th century. After the 1937 sulfanilamide disaster, the FDA was granted increased authority over NMEs through Congressional approval of the 1938 Federal Food, Drug, and Cosmetic Act. Following this, the gap-to-approval shifted to an average of 14 years through 1970; 39% were approved within 3 years and 69% were approved within 10 years. Then, after the thalidomide tragedy and resulting 1962 Kefauver-Harris Amendment, the gap-to-approval slowed to approximately 18 years; by sector, the average gap-to-approval of industry slowed from 5 years to 12 years, whereas that of academia slowed from 20 to 24 years (Figure 1C). The increased time interval between discovery and approval is likely to reflect the requirement to demonstrate efficacy (as opposed to simply safety) as mandated by Kefauver-Harris. Our assessment further suggests that the Hatch-Waxman Act of 1984 had little impact on the gap-to-approval as measured from the year of first publication. Of all NMEs approved since 1970, just 10% were approved within 3 years and 50% were approved within 10 years. Across all years, the persistent difference in the gap-to-approval for academia and industry suggests that, at the time of their first publication, NMEs from industry are closer to market than are NMEs from academia. This is probably because academic researchers are incentivized to publish discoveries at the earliest opportunity, whereas industry researchers are incentivized to delay publishing until late in the development process. For biotech, the average gap-to-approval has steadily increased, doubling from 4.5 years in the 1970s to 9 years in the current decade. Along this same vein, we previously reported on ‘Big Pharma’ companies and examined successes in drug discovery, development, and obtaining FDA approval [5]. We paralleled this work in the current study for the 801 NMEs contributed from academic efforts. Across all years, we identified 13 institutions that produced at least eight NMEs, with the University of Michigan being the largest single contributor, at 20 NMEs (Table 1). Altogether, these 13 institutions produced 11% of the 1453 NMEs (21% of those contributed from academia). In a decade-bydecade analysis, we found no notable trends, except in NMEs contributed by the National Institutes of Health (NIH). From 1940 to 1970, the FDA approved one NME per decade for the NIH, and this number steadily rose through the next two decades, stabilizing at five NMEs per decade during the 1990s. We then assessed the 801 NMEs for how they were carried to market (Table 2). Using our definition of academic efforts, academic institutions filed the investigational new drug (IND) application for 21 NMEs and were key players in the End of Phase II (EoP2) meetings for seven of these. Among these, we found only one academic institution (the US Army) that was granted FDA approval for an NME (perfluoropolymethylisopropyl ether; poly tetrafluoroethylene). Geographic analysis of all NMEs
Drug discovery is dependent on academic, scientific, health, and political infrastructure; therefore, we analyzed the geographic origins for each NME. We extracted the primary authoring institutions for every publication, and these
Page 3 of 8
Concluding remarks and implications
d
M
an
us
cr
ip t
were binned according to their metropolitan area. For example, institutions within a distance of 90 miles from London were binned together. If several prolific areas were close in proximity, such as New Haven, New York, and Philadelphia, then a distance of 50 miles from each city was used to bin the institutions. In turn, these metropolitan areas were grouped by region, with the most prolific being North America, Europe, and Asia. An overall assessment revealed that 52% of all NMEs originated in North America, 39% originated in Europe, and 8% originated in Asia (and 94% of all NMEs contributed by Asia originated in Japan). A decade-by-decade analysis (Figure 2A) revealed that NMEs approved before 1930 originated in Europe (n = 3). However, North American research efforts quickly outpaced all others, peaking at 67% of NMEs approved during the 1950s. Research efforts from Asia gradually reached a plateau of 12% of NMEs approved during the 1980s. Comparing the most prolific metropolitan areas, the local trends paralleled regional trends (Figure 2B); after 1940, New York and London averaged, respectively, 20 NMEs and 11 NMEs per decade, or 11% and 6% of those NMEs produced each decade. Our assessment also showed that the 12 most prolific metropolitan areas produced almost half (46%) of all NMEs, and we profiled their contributions across academia, industry, and biotech (Figure 2C). This number expanded to 66% of all NMEs if one included the 25 most prolific areas. Respectively, New York and London were the first and second most prolific areas; New York produced 150 NMEs (55 academic; 91 industry; three biotech), whereas London produced 90 NMEs (47 academic; 41 industry; one biotech). Ranking the most prolific academic areas, New York is followed by London, Bethesda (43 NMEs; 41 academic; one industry; one biotech), and then Boston (38 NMEs; 30 academic; four industry; four biotech). Ranking the most prolific industry areas, New York is followed by Basel (68 NMEs; 18 academic; 50 industry), Philadelphia (69 NMEs; 22 academic; 45 industry; two biotech), and London. We then examined research programs, capturing the most disparate portfolios across the most prolific metropolitan areas. In terms of targets and indications, there were no significant differences, except with San Francisco and London, which produced an increased number of NMEs for oncology and pain/itch, respectively. We also worked from previous definitions [6] to assess the fraction of NMEs that were biologics, biochemical natural products (BCNPs), and nonmammalian natural products (NMNPs), and synthetics (Figure S1B in the supplementary material online). The top four most-prolific areas had similar research portfolios, averaging 6.3% biologics, 12% BCNPs, 26% NMNPs, and 56% synthetics. Other areas had a larger focus on biologics (averaging 29%), including San Francisco (53 NMEs total), Bethesda (43 NMEs total), and Boston (38 NMEs total). A few metropolitan areas had a larger focus on synthetics (averaging 73%), including Paris (34 NMEs total), Beerse (30 NMEs total), and Chicago (26 NMEs total). Finally, other areas had a larger focus on natural products (averaging 28% BCNPs and 31% NMNPS), including Tokyo (41 NMEs total), Berlin (25 NMEs total), and Madison (19 NMEs total).
Ac ce p
te
It is widely recognized that the traditional model for taking drugs to market is no longer sustainable, and that the transition from first publication to market is so difficult that it is commonly called the ‘valley of death’ [13–23]. To our knowledge, the original research efforts and gap-to-approvals for each NME have not yet been assessed in the literature, and this study provides specific insight into NME discovery and development. While building our data set, it became clear that locating data on FDA-approved NMEs is difficult, as is crossreferencing variable chemical nomenclature. Querying PubMed with generic or proprietary names was not sufficient for identifying each first publication. As described, we conducted extensive bibliographic searches and implemented earlier chemical nomenclature; in doing so, we added a total of approximately 10 000 years of research history across all 1453 NMEs, with an average of 7 years per NME. Figure S1C in the supplementary material online depicts the difference (in years) between our final data set and the original PubMed data set, including the average number of years and the 95th percentile covering first publications. The landscape of drug discovery has faced increasing challenges. As industry reorganizes and strategizes to maintain profitability, more resources are finding homes in academia, such as high-throughput screening centers and medicinal chemistry capabilities [23–30]. There are now 105 academic screening centers listed in the Society for Laboratory Automation and Screening Directory (http://www.slas.org) and 127 according to the Academic Drug Discovery Consortium (http://addconsortium.org). Most of the prolific institutions (Table 1) already have small molecule-screening facilities. These centers represent a valuable opportunity for academia to increase their drug discovery efforts, perhaps significantly, because they are already responsible for introducing more than half of all NMEs. It is also important to consider that both public and private funding resources will be crucial for insuring the success of academic screening facilities. References 1 Drews J. (2000) Drug discovery: a historical perspective. Science 287, 1960–1964 2 Newman, D.J. and Cragg, G.M. (2012) Natural products as sources of new drugs over the 30 years from 1981 to 2010. J. Nat. Prod. 75, 311– 335 3 Munos B. (2009) Lessons from 60 years of pharmaceutical innovation. Nat. Rev. Drug. Discov. 8, 959–968 4 Kaitin, K.I. and DiMasi, J.A. (2011) Pharmaceutical innovation in the 21st century: new drug approvals in the first decade, 2000–2009. Clin. Pharmacol. Ther. 89, 183–188 5 Kinch, M.S. et al. (2014) An overview of FDA-approved new molecular entities: 1827–2013. Drug Discov. Today 19, 1033–9 6 Patridge, E. et al. (2015) An analysis of FDA-approved drugs: natural products and their derivatives. Drug Discov. Today. Published online January 21,2015. http://dx.doi.org/10.1016/j.drudis.2015.01.009
Page 4 of 8
19 20 21 22 23 24 25 26 27 28 29 30
ip t
16 17 18
cr
11 12 13 14 15
us
10
Boerhaave, H. (1727) Process 98: the native salt of urine. In Elementa Chemiae (2nd edn) (Boerhaave, H., ed.), pp. 317–318, Caspar Fritsch Barger, G. and Ewins, A.J. (1910) CCXXXVII. Some phenolic derivatives of β-phenylethylamine. J. Chem. Soc. Trans. 97, 2253–2261 Pina, A.S. et al. (2010) An historical overview of drug discovery. In Ligand–Macromolecular Interactions in Drug Discovery (editor details), [LM2]pp. 3–12, Springer Martin, Y.C. (1995) Accomplishments and challenges in integrating software for computer-aided ligand design in drug discovery. Perspect. Drug Discov. Design 3, 139–150 Kinch, M.S. (2014) The rise (and decline?) of biotechnology. Drug Discov. Today 19, 1686–1690 Runge, F.F. (1820) Neueste phytochemische Entdeckungen zur Begründung einer wissenschaftlichen Phytochemie, Reimer Tralau-Stewart, C.J. et al. (2009) Drug discovery: new models for industry–academic partnerships. Drug Discov. Today 14, 95–101 Kozikowski, A.P. et al. (2006) Why academic drug discovery makes sense. Science 313, 1235–1236 Rai, A.K. et al. (2008) Pathways across the valley of death: novel intellectual property strategies for accelerated drug discovery. Yale J. Health Policy Law Ethics 8, 53–89 Hamburg, M.A. and Collins, F.S. (2010) The path to personalized medicine. N. Engl. J. Med. 363, 301–304 Butler, D. (2008) Translational research: crossing the valley of death. Nat. News 453, 840–842 Melese, T. et al. (2009) Open innovation networks between academia and industry: an imperative for breakthrough therapies. Nat. Med. 15, 502–507 Edwards, A. (2008) Open-source science to enable drug discovery. Drug Discov. Today 13, 731–733 Lombardino, J.G. and Lowe, J.A. (2004) The role of the medicinal chemist in drug discovery: then and now. Nat. Rev. Drug. Discov. 3, 853– 862 Scannell, J.W. et al. (2012) Diagnosing the decline in pharmaceutical R&D efficiency. Nat. Rev. Drug. Discov. 11, 191–200 Ekins, S. et al. (2013) Four disruptive strategies for removing drug discovery bottlenecks. Drug Discov. Today 18, 265–271 Frearson, J.A. and Collie, I.T. (2009) HTS and hit finding in academia: from chemical genomics to drug discovery. Drug Discov. Today 14, 1150–1158 Slusher, B.S. et al. (2013) Bringing together the academic drug discovery community. Nat. Rev. Drug. Discov. 12, 811–812 Frye, S. et al. (2011) US academic drug discovery. Nat. Rev. Drug. Discov. 10, 409–410 Oprea, T.I. et al. (2009) A crowdsourcing evaluation of the NIH chemical probes. Nat. Chem. Biol. 5, 441–447 Tralau-Stewart, C.J. et al. (2009) Drug discovery: new models for industry–academic partnerships. Drug Discov. Today 14, 95–101 Kirkegaard, H.S. and Valentin, F. (2014) Academic drug discovery centres: the economic and organisational sustainability of an emerging model. Drug Discov. Today 19, 1699–1710 Peter, R. and Roy, A. (2011) A roadmap for achieving self-sustainability of academic high throughput screening core facilities. Drug Discov. 12, 59 Jorgensen, W.L. (2012) Challenges for academic drug discovery. Angew. Chem. Int. Ed. 51, 11680–11684
an
7 8 9
M
Figure 1. Roles of pharma and academia in the overall discovery and approval of new molecular entities (NMEs). (A) The origin of the 1453 US Food and Drug Administration (FDA)-approved NMEs is shown for each sector, charted by the year of each first publication. (B) The gap in approval, from first publication to FDA approval is shown for all NMEs, over time, aggregated into the fraction of NMEs brought to FDA approval in: 3 years or less, 4–9 years, 10–50 years, and greater than 50 years. (C) The gap in approval, from first publication to FDA approval is shown for all NMEs, over time, aggregated into the average number of years and reported by sector.
d
Figure 2. Geography of productivity and outcomes. The research origin of US Food and Drug Administration (FDA)-approved new molecular entities (NMEs) is shown by region and year of FDA approval, for (A) NMEs produced in North America, Europe and/or Russia, and Asia; and (B) the most prolific cities in each region: New York, London, and Tokyo. (C) The origin of all FDA-approved NMEs is charted for the most prolific 12 cities, with NMEs aggregated into their academic and pharma origins.
te
*A new molecular entity (NME) is a drug that contains an active moiety that has never been approved by FDA or marketed in the USA [LM3]. †Each one of the FDA-approved NMEs from Russia (n = 7) originated in Moscow or Kazan; therefore, we grouped these with Europe. For our convention of geographic divisions, we divided Europe from Asia along the Bosphorus, the Dardanelles, the Caucasus, and the Urals; we divided Africa from Asia at the Isthmus of Suez; and we divided North and South America at the Isthmus of Panama.[LM4]
Ac ce p
Table 1. Most proliferative academic institutions accounting for all author contributions to first publications No. of NMEs
Institution
20 19 19 18 16 12 11 11 8 8 8 8 8
University of Michigan National Institutes of Health University of Wisconsin Harvard University Columbia University Johns Hopkins University Yale University University of Berlin University of California, Los Angeles University of California, San Francisco University of London Oxford University University of Pennsylvania
Table 2. Summary of all 21 NMEs controlled by academic institutions at the time of IND applicationa NME
Original publication
Filed IND application
Alemtuzumab Algluceraseb Azacitidineb Cladribine Collagenase clostridium histolycumb Decitabine
Cambridge University NIH Czech. Academy of Sciences University of Hokkaido Syracuse University The Ohio State University
Cambridge University NIH NCI (NIH) Scripps Clinic Stony Brook University NCI (NIH)
Page 5 of 8
Brown University NCI (NIH) Georgia State University University of Texas Royal Alexandra Hospital University of Texas Research Triangle Institute Viz Principe Eugenio SRI International University of Palermo University of Michigan University of Vermont Southwest Foundation for Biomedical Research Detroit Institute of Cancer Research Yale University
NCI (NIH) Brigham Women's Hospital WRAIR Duke University NICHD (NIH) NCI (NIH) NCI (NIH) US Army Memorial Sloan Kettering NCI (NIH) University of Michigan NIH NICHD (NIH) NCI (NIH) NCI (NIH)
ip t
Didanosine L-Glutamine Mefloquineb Nelarabine Nitric oxided Omacetaxine Paclitaxelb Perfluoropolymethylisopropyl ether; poly tetrafluoroethylenec,d Pralatrexate Teniposide Tositumomab Trimetrexate Ulipristalb Zalcitabineb Zidovudine
NCI, National Cancer Institute; NICHD, National Institute of Child Health and Human Development; NWRAIR, Walter Reed Army Institute of Research.
b
NMEs where academic institutions were key participants at EoP2 Meeting (n = 7)
The one NME for which an academic institution was granted FDA approval.
d
M
an
us
The two NME synthetic compounds for which an academic institution was granted FDA approval.
te
d
Ac ce p
c
cr
a
Page 6 of 8
Academic
Industry
(B)
Biotech
<=3
100%
4 to 9
10 to 50
>50
Percentage of NMEs
us
100%
75%
M an
75% 50% 25%
0%
50% 25%
ce pt
Year of first manuscript
ed
0%
Year of FDA approval
(C)
Academic
Industry
Biotech
Average number of years
50
Ac
Percentage of NMEs
cr
(A)
i
Figures for main article
40 30 20 10
0
Page 7 of 8
Year of FDA approval
Europe/Russia
cr
(B) North America
New York
Asia
London
Tokyo
60
Number of NMEs
us
100%
50 40
M an
75% 50% 25%
30
20 10
ce pt
Year of FDA approval
0
ed
0%
Year of FDA approval
(C)
Academia
Industry
Biotech
Number of NMEs
150
Ac
Percent of NMEs
i
(A)
125 100
75 50 25 0
Page 8 of 8
S1359-6446(15)00236-6 http://dx.doi.org/doi:10.1016/j.drudis.2015.06.006 DRUDIS 1634
To appear in: Received date: Revised date: Accepted date:
4-3-2015 9-6-2015 12-6-2015
Please cite this article as: Patridge, E.V., Gareiss, P.C., Kinch, M.S., Hoyer, D.W.,An analysis of original research contributions toward FDA-approved drugs, Drug Discovery Today (2015), http://dx.doi.org/10.1016/j.drudis.2015.06.006 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Highlights The first manuscript for more than half of FDA-approved drugs originated in Academia. Industry has closed the gap in recent years in terms of publishing
Ac ce p
te
d
M
an
us
cr
ip t
NMEs first published by industry NMEs are twelve years closer to market than those from Academia
Page 1 of 8
An analysis of original research contributions toward FDAapproved drugs Eric V. Patridge1, Peter C. Gareiss1, Michael S. Kinch2, and Denton W. Hoyer1
ip t
1
Yale Center for Molecular Discovery, West Haven, CT 06516, USA Washington University in St Louis, St Louis, MO 63110, USA Corresponding author: Patridge, E.V. ([email protected]) Keywords: new molecular entity; drug discovery; academia; industry; research effort Teaser: More than half of FDA-approved drugs originate from academic research in North America. Furthermore, in academia, it takes twice as long as in industry to carry a drug from its first publication to market.
cr
2
an
us
Academic [LM1]researchers shaped the landscape of drug discovery for nearly two centuries, and their efforts initiated programs for more than half of the US Food and Drug Administration (FDA)-approved new molecular entities (NMEs). During the first 50 years of the 20th century, contributions from industry-based discovery programs steadily increased, stabilizing near half of all first publications for NMEs. Although academia and industry have made similar contributions to the discovery of FDA-approved NMEs, there remains a substantial difference in the gap-to-approval; on average, industry NMEs are 12 years closer to market at the time of the first publication. As more drug discovery efforts shift from industry to academia, including high-throughput screening resources, academia could have an increasingly crucial role in drug discovery. Historical advances in drug discovery
Ac ce p
te
d
M
Academia, industry, and biotech each make varied contributions to the research landscape and their programs have benefitted from scientific and technological advances. Many publications address diverse perspectives on the history of drug discovery [1–4], but to our knowledge, no study has yet assessed the relative contributions of each sector to the discovery process for NMEs*. Perhaps this is because there is more interest in the market value of NMEs approved by the FDA rather than in the process of their discovery and development. As part of an effort to examine the changing landscape of drug discovery, researchers in the Yale Center for Molecular Discovery assessed the trends in original research contributions leading to FDA-approved NMEs and we focus here on the contributions of academic institutions. As detailed in the first publication of this series [5], we cataloged all legacy drugs and recent NMEs, including those drugs that were subsequently removed from market. Other than morphine and aspirin, all included NMEs were reviewed by the Food, Drug and Insecticide Organization (est. 1927) and its successor, the FDA. Before 1910, academic researchers were responsible for all first publications leading to FDA-approved NMEs, and most of these were contributions from Europe and/or Russia†. During this time, natural products had a central role in drug discovery, which we previously examined in greater depth [6]. The first study that led to an FDAapproved NME was published in 1732 by Leiden University, the Netherlands; they reported on urea, or ‘the native salt of urine,’ which became FDA approved in 1966 [7]. It was not until 1910 that the Wellcome Research Laboratories, London became the first corporation to publish original research leading to an FDA-approved NME; they reported the synthesis of dopamine, or ‘3:4-dihydroxy-β-phenylethylamine’, which became FDA approved in 1974 [8]. Both of these NMEs highlight the significant time that it takes to carry a drug from its first publication to market, which we refer to here as the ‘gap-to-approval’. Urea holds the record for the longest gap-to-approval of 223 years. From a historical context, it is relevant to consider that NME discovery is tied to scientific advances and transformative technologies that have shaped the landscape of drug discovery. During the first decades of the 20th century, the scientific concepts of ‘receptive substances’ and selective ‘magic bullets’ inspired several drug discovery efforts focused on receptor–drug interactions. Soon after, the identification of sulfonamides and -lactams provided a basis for broad-spectrum antibiotic programs. During the latter half of the century, the structure of DNA was elucidated and quantitative structure–activity relations were introduced, broadening the fields of molecular biology, medicinal chemistry, and bioinformatics. In the closing years of the millennium, discovery programs became focused on biologics, combinatorial chemistry, and high-throughput screening approaches, and the field of cheminformatics was established by efforts across both academia and industry [1,9,10]. Several other transformative technologies have also shaped drug discovery, including mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy, which were commercialized in 1942 and 1952, respectively [9]. Beyond these, innovations such as the modern computer and genomic sciences also helped to redefine the landscape of drug discovery, and they continue to accelerate advances across academia and industry. Herein, we assess the research efforts leading to FDA-approved NMEs (n = 1453 as of December 31, 2013). In addition to examining the contributions of academia, industry, and biotech to the discovery process, we also examined the gap-to-approval for each sector, as well as the research efforts for prolific geographic areas. We
Page 2 of 8
considered academic efforts to include all contributions from unaffiliated individuals as well as those from colleges, universities, hospitals, and government institutions. As described in our earlier publication [11], we separated pharmaceutical (industry) from biotechnology (biotech) organizations, defining biotech as companies founded after the Cetus Corporation (1971). Analysis of the research origins and academic development for all NMEs
Ac ce p
te
d
M
an
us
cr
ip t
To build our publication data set, we first turned to PubMed, which is the largest bibliographic index for the life sciences and also the first database of choice for biomedical and life-science researchers. We then followed references from within each publication and used their NME naming conventions to query PubMed, SciFinder ®, Google Search or Scholar, and each journal website. We repeated this process for each NME until we found the earliest peer-reviewed publication to report the NME in a synthesis or purified formulation, and we extracted all authoring institutions. For the purposes of this study, we used the primary institution to define the research origins. In a few cases, we turned to dissertations, monographs, and books for the research origins of early NMEs, such as with Runge’s isolation of caffeine in 1820, which he called ‘kaffebase’ [12]. We rejected earlier references where the chemical material was known to be impure. Our literature review was exhaustive, and we found that many NMEs were first reported using descriptive adjectives, proprietary codes, structures, or outdated chemical nomenclature. In a few cases, a series of sequential articles served to announce NMEs in the same journal issue, and we selected the first publication in the series to represent the research origins. Our final assessment revealed that 55% (801/1453) of all NMEs were first reported by academic organizations. A decade-by-decade analysis confirmed that role of industry in the discovery process developed over the 20th century; through the year 1900, all NMEs (n = 58) were first reported by academia and, after 1900, academic contributions were steadily diluted by industry efforts (Figure 1A). The fraction of NMEs first reported by academia stabilized near 50% during the 1950s (n = 232), reaching as low as 46% during the 1990s (n = 200). On an annual basis, the number of contributions from each sector varied, reaching overall highs and lows in each decade since 1950. Biotech efforts accounted for just 3% of the NMEs, with a yearly high of 17% during the early 2000s. When Figure 1A is organized by year of FDA approval, the overall trends were the same (Figure S1A in the supplementary material online). Through further analysis, we found that the ‘gap-to-approval’ shifted over the 20th century, highlighting changes in carrying NMEs from their first publication to market. Our assessment of the 1453 NMEs revealed that, after their first publication, 17% were approved within 3 years, and 47% were approved after 10 years. A decadeby-decade analysis reveals a more detailed picture (Figure 1B). The NMEs approved before 1930 (n = 3) had a gapto-approval averaging 47 years. These NMEs indeed pre-date the FDA, which was established in 1931 as the successor to other institutions that had existed since the 19th century. After the 1937 sulfanilamide disaster, the FDA was granted increased authority over NMEs through Congressional approval of the 1938 Federal Food, Drug, and Cosmetic Act. Following this, the gap-to-approval shifted to an average of 14 years through 1970; 39% were approved within 3 years and 69% were approved within 10 years. Then, after the thalidomide tragedy and resulting 1962 Kefauver-Harris Amendment, the gap-to-approval slowed to approximately 18 years; by sector, the average gap-to-approval of industry slowed from 5 years to 12 years, whereas that of academia slowed from 20 to 24 years (Figure 1C). The increased time interval between discovery and approval is likely to reflect the requirement to demonstrate efficacy (as opposed to simply safety) as mandated by Kefauver-Harris. Our assessment further suggests that the Hatch-Waxman Act of 1984 had little impact on the gap-to-approval as measured from the year of first publication. Of all NMEs approved since 1970, just 10% were approved within 3 years and 50% were approved within 10 years. Across all years, the persistent difference in the gap-to-approval for academia and industry suggests that, at the time of their first publication, NMEs from industry are closer to market than are NMEs from academia. This is probably because academic researchers are incentivized to publish discoveries at the earliest opportunity, whereas industry researchers are incentivized to delay publishing until late in the development process. For biotech, the average gap-to-approval has steadily increased, doubling from 4.5 years in the 1970s to 9 years in the current decade. Along this same vein, we previously reported on ‘Big Pharma’ companies and examined successes in drug discovery, development, and obtaining FDA approval [5]. We paralleled this work in the current study for the 801 NMEs contributed from academic efforts. Across all years, we identified 13 institutions that produced at least eight NMEs, with the University of Michigan being the largest single contributor, at 20 NMEs (Table 1). Altogether, these 13 institutions produced 11% of the 1453 NMEs (21% of those contributed from academia). In a decade-bydecade analysis, we found no notable trends, except in NMEs contributed by the National Institutes of Health (NIH). From 1940 to 1970, the FDA approved one NME per decade for the NIH, and this number steadily rose through the next two decades, stabilizing at five NMEs per decade during the 1990s. We then assessed the 801 NMEs for how they were carried to market (Table 2). Using our definition of academic efforts, academic institutions filed the investigational new drug (IND) application for 21 NMEs and were key players in the End of Phase II (EoP2) meetings for seven of these. Among these, we found only one academic institution (the US Army) that was granted FDA approval for an NME (perfluoropolymethylisopropyl ether; poly tetrafluoroethylene). Geographic analysis of all NMEs
Drug discovery is dependent on academic, scientific, health, and political infrastructure; therefore, we analyzed the geographic origins for each NME. We extracted the primary authoring institutions for every publication, and these
Page 3 of 8
Concluding remarks and implications
d
M
an
us
cr
ip t
were binned according to their metropolitan area. For example, institutions within a distance of 90 miles from London were binned together. If several prolific areas were close in proximity, such as New Haven, New York, and Philadelphia, then a distance of 50 miles from each city was used to bin the institutions. In turn, these metropolitan areas were grouped by region, with the most prolific being North America, Europe, and Asia. An overall assessment revealed that 52% of all NMEs originated in North America, 39% originated in Europe, and 8% originated in Asia (and 94% of all NMEs contributed by Asia originated in Japan). A decade-by-decade analysis (Figure 2A) revealed that NMEs approved before 1930 originated in Europe (n = 3). However, North American research efforts quickly outpaced all others, peaking at 67% of NMEs approved during the 1950s. Research efforts from Asia gradually reached a plateau of 12% of NMEs approved during the 1980s. Comparing the most prolific metropolitan areas, the local trends paralleled regional trends (Figure 2B); after 1940, New York and London averaged, respectively, 20 NMEs and 11 NMEs per decade, or 11% and 6% of those NMEs produced each decade. Our assessment also showed that the 12 most prolific metropolitan areas produced almost half (46%) of all NMEs, and we profiled their contributions across academia, industry, and biotech (Figure 2C). This number expanded to 66% of all NMEs if one included the 25 most prolific areas. Respectively, New York and London were the first and second most prolific areas; New York produced 150 NMEs (55 academic; 91 industry; three biotech), whereas London produced 90 NMEs (47 academic; 41 industry; one biotech). Ranking the most prolific academic areas, New York is followed by London, Bethesda (43 NMEs; 41 academic; one industry; one biotech), and then Boston (38 NMEs; 30 academic; four industry; four biotech). Ranking the most prolific industry areas, New York is followed by Basel (68 NMEs; 18 academic; 50 industry), Philadelphia (69 NMEs; 22 academic; 45 industry; two biotech), and London. We then examined research programs, capturing the most disparate portfolios across the most prolific metropolitan areas. In terms of targets and indications, there were no significant differences, except with San Francisco and London, which produced an increased number of NMEs for oncology and pain/itch, respectively. We also worked from previous definitions [6] to assess the fraction of NMEs that were biologics, biochemical natural products (BCNPs), and nonmammalian natural products (NMNPs), and synthetics (Figure S1B in the supplementary material online). The top four most-prolific areas had similar research portfolios, averaging 6.3% biologics, 12% BCNPs, 26% NMNPs, and 56% synthetics. Other areas had a larger focus on biologics (averaging 29%), including San Francisco (53 NMEs total), Bethesda (43 NMEs total), and Boston (38 NMEs total). A few metropolitan areas had a larger focus on synthetics (averaging 73%), including Paris (34 NMEs total), Beerse (30 NMEs total), and Chicago (26 NMEs total). Finally, other areas had a larger focus on natural products (averaging 28% BCNPs and 31% NMNPS), including Tokyo (41 NMEs total), Berlin (25 NMEs total), and Madison (19 NMEs total).
Ac ce p
te
It is widely recognized that the traditional model for taking drugs to market is no longer sustainable, and that the transition from first publication to market is so difficult that it is commonly called the ‘valley of death’ [13–23]. To our knowledge, the original research efforts and gap-to-approvals for each NME have not yet been assessed in the literature, and this study provides specific insight into NME discovery and development. While building our data set, it became clear that locating data on FDA-approved NMEs is difficult, as is crossreferencing variable chemical nomenclature. Querying PubMed with generic or proprietary names was not sufficient for identifying each first publication. As described, we conducted extensive bibliographic searches and implemented earlier chemical nomenclature; in doing so, we added a total of approximately 10 000 years of research history across all 1453 NMEs, with an average of 7 years per NME. Figure S1C in the supplementary material online depicts the difference (in years) between our final data set and the original PubMed data set, including the average number of years and the 95th percentile covering first publications. The landscape of drug discovery has faced increasing challenges. As industry reorganizes and strategizes to maintain profitability, more resources are finding homes in academia, such as high-throughput screening centers and medicinal chemistry capabilities [23–30]. There are now 105 academic screening centers listed in the Society for Laboratory Automation and Screening Directory (http://www.slas.org) and 127 according to the Academic Drug Discovery Consortium (http://addconsortium.org). Most of the prolific institutions (Table 1) already have small molecule-screening facilities. These centers represent a valuable opportunity for academia to increase their drug discovery efforts, perhaps significantly, because they are already responsible for introducing more than half of all NMEs. It is also important to consider that both public and private funding resources will be crucial for insuring the success of academic screening facilities. References 1 Drews J. (2000) Drug discovery: a historical perspective. Science 287, 1960–1964 2 Newman, D.J. and Cragg, G.M. (2012) Natural products as sources of new drugs over the 30 years from 1981 to 2010. J. Nat. Prod. 75, 311– 335 3 Munos B. (2009) Lessons from 60 years of pharmaceutical innovation. Nat. Rev. Drug. Discov. 8, 959–968 4 Kaitin, K.I. and DiMasi, J.A. (2011) Pharmaceutical innovation in the 21st century: new drug approvals in the first decade, 2000–2009. Clin. Pharmacol. Ther. 89, 183–188 5 Kinch, M.S. et al. (2014) An overview of FDA-approved new molecular entities: 1827–2013. Drug Discov. Today 19, 1033–9 6 Patridge, E. et al. (2015) An analysis of FDA-approved drugs: natural products and their derivatives. Drug Discov. Today. Published online January 21,2015. http://dx.doi.org/10.1016/j.drudis.2015.01.009
Page 4 of 8
19 20 21 22 23 24 25 26 27 28 29 30
ip t
16 17 18
cr
11 12 13 14 15
us
10
Boerhaave, H. (1727) Process 98: the native salt of urine. In Elementa Chemiae (2nd edn) (Boerhaave, H., ed.), pp. 317–318, Caspar Fritsch Barger, G. and Ewins, A.J. (1910) CCXXXVII. Some phenolic derivatives of β-phenylethylamine. J. Chem. Soc. Trans. 97, 2253–2261 Pina, A.S. et al. (2010) An historical overview of drug discovery. In Ligand–Macromolecular Interactions in Drug Discovery (editor details), [LM2]pp. 3–12, Springer Martin, Y.C. (1995) Accomplishments and challenges in integrating software for computer-aided ligand design in drug discovery. Perspect. Drug Discov. Design 3, 139–150 Kinch, M.S. (2014) The rise (and decline?) of biotechnology. Drug Discov. Today 19, 1686–1690 Runge, F.F. (1820) Neueste phytochemische Entdeckungen zur Begründung einer wissenschaftlichen Phytochemie, Reimer Tralau-Stewart, C.J. et al. (2009) Drug discovery: new models for industry–academic partnerships. Drug Discov. Today 14, 95–101 Kozikowski, A.P. et al. (2006) Why academic drug discovery makes sense. Science 313, 1235–1236 Rai, A.K. et al. (2008) Pathways across the valley of death: novel intellectual property strategies for accelerated drug discovery. Yale J. Health Policy Law Ethics 8, 53–89 Hamburg, M.A. and Collins, F.S. (2010) The path to personalized medicine. N. Engl. J. Med. 363, 301–304 Butler, D. (2008) Translational research: crossing the valley of death. Nat. News 453, 840–842 Melese, T. et al. (2009) Open innovation networks between academia and industry: an imperative for breakthrough therapies. Nat. Med. 15, 502–507 Edwards, A. (2008) Open-source science to enable drug discovery. Drug Discov. Today 13, 731–733 Lombardino, J.G. and Lowe, J.A. (2004) The role of the medicinal chemist in drug discovery: then and now. Nat. Rev. Drug. Discov. 3, 853– 862 Scannell, J.W. et al. (2012) Diagnosing the decline in pharmaceutical R&D efficiency. Nat. Rev. Drug. Discov. 11, 191–200 Ekins, S. et al. (2013) Four disruptive strategies for removing drug discovery bottlenecks. Drug Discov. Today 18, 265–271 Frearson, J.A. and Collie, I.T. (2009) HTS and hit finding in academia: from chemical genomics to drug discovery. Drug Discov. Today 14, 1150–1158 Slusher, B.S. et al. (2013) Bringing together the academic drug discovery community. Nat. Rev. Drug. Discov. 12, 811–812 Frye, S. et al. (2011) US academic drug discovery. Nat. Rev. Drug. Discov. 10, 409–410 Oprea, T.I. et al. (2009) A crowdsourcing evaluation of the NIH chemical probes. Nat. Chem. Biol. 5, 441–447 Tralau-Stewart, C.J. et al. (2009) Drug discovery: new models for industry–academic partnerships. Drug Discov. Today 14, 95–101 Kirkegaard, H.S. and Valentin, F. (2014) Academic drug discovery centres: the economic and organisational sustainability of an emerging model. Drug Discov. Today 19, 1699–1710 Peter, R. and Roy, A. (2011) A roadmap for achieving self-sustainability of academic high throughput screening core facilities. Drug Discov. 12, 59 Jorgensen, W.L. (2012) Challenges for academic drug discovery. Angew. Chem. Int. Ed. 51, 11680–11684
an
7 8 9
M
Figure 1. Roles of pharma and academia in the overall discovery and approval of new molecular entities (NMEs). (A) The origin of the 1453 US Food and Drug Administration (FDA)-approved NMEs is shown for each sector, charted by the year of each first publication. (B) The gap in approval, from first publication to FDA approval is shown for all NMEs, over time, aggregated into the fraction of NMEs brought to FDA approval in: 3 years or less, 4–9 years, 10–50 years, and greater than 50 years. (C) The gap in approval, from first publication to FDA approval is shown for all NMEs, over time, aggregated into the average number of years and reported by sector.
d
Figure 2. Geography of productivity and outcomes. The research origin of US Food and Drug Administration (FDA)-approved new molecular entities (NMEs) is shown by region and year of FDA approval, for (A) NMEs produced in North America, Europe and/or Russia, and Asia; and (B) the most prolific cities in each region: New York, London, and Tokyo. (C) The origin of all FDA-approved NMEs is charted for the most prolific 12 cities, with NMEs aggregated into their academic and pharma origins.
te
*A new molecular entity (NME) is a drug that contains an active moiety that has never been approved by FDA or marketed in the USA [LM3]. †Each one of the FDA-approved NMEs from Russia (n = 7) originated in Moscow or Kazan; therefore, we grouped these with Europe. For our convention of geographic divisions, we divided Europe from Asia along the Bosphorus, the Dardanelles, the Caucasus, and the Urals; we divided Africa from Asia at the Isthmus of Suez; and we divided North and South America at the Isthmus of Panama.[LM4]
Ac ce p
Table 1. Most proliferative academic institutions accounting for all author contributions to first publications No. of NMEs
Institution
20 19 19 18 16 12 11 11 8 8 8 8 8
University of Michigan National Institutes of Health University of Wisconsin Harvard University Columbia University Johns Hopkins University Yale University University of Berlin University of California, Los Angeles University of California, San Francisco University of London Oxford University University of Pennsylvania
Table 2. Summary of all 21 NMEs controlled by academic institutions at the time of IND applicationa NME
Original publication
Filed IND application
Alemtuzumab Algluceraseb Azacitidineb Cladribine Collagenase clostridium histolycumb Decitabine
Cambridge University NIH Czech. Academy of Sciences University of Hokkaido Syracuse University The Ohio State University
Cambridge University NIH NCI (NIH) Scripps Clinic Stony Brook University NCI (NIH)
Page 5 of 8
Brown University NCI (NIH) Georgia State University University of Texas Royal Alexandra Hospital University of Texas Research Triangle Institute Viz Principe Eugenio SRI International University of Palermo University of Michigan University of Vermont Southwest Foundation for Biomedical Research Detroit Institute of Cancer Research Yale University
NCI (NIH) Brigham Women's Hospital WRAIR Duke University NICHD (NIH) NCI (NIH) NCI (NIH) US Army Memorial Sloan Kettering NCI (NIH) University of Michigan NIH NICHD (NIH) NCI (NIH) NCI (NIH)
ip t
Didanosine L-Glutamine Mefloquineb Nelarabine Nitric oxided Omacetaxine Paclitaxelb Perfluoropolymethylisopropyl ether; poly tetrafluoroethylenec,d Pralatrexate Teniposide Tositumomab Trimetrexate Ulipristalb Zalcitabineb Zidovudine
NCI, National Cancer Institute; NICHD, National Institute of Child Health and Human Development; NWRAIR, Walter Reed Army Institute of Research.
b
NMEs where academic institutions were key participants at EoP2 Meeting (n = 7)
The one NME for which an academic institution was granted FDA approval.
d
M
an
us
The two NME synthetic compounds for which an academic institution was granted FDA approval.
te
d
Ac ce p
c
cr
a
Page 6 of 8
Academic
Industry
(B)
Biotech
<=3
100%
4 to 9
10 to 50
>50
Percentage of NMEs
us
100%
75%
M an
75% 50% 25%
0%
50% 25%
ce pt
Year of first manuscript
ed
0%
Year of FDA approval
(C)
Academic
Industry
Biotech
Average number of years
50
Ac
Percentage of NMEs
cr
(A)
i
Figures for main article
40 30 20 10
0
Page 7 of 8
Year of FDA approval
Europe/Russia
cr
(B) North America
New York
Asia
London
Tokyo
60
Number of NMEs
us
100%
50 40
M an
75% 50% 25%
30
20 10
ce pt
Year of FDA approval
0
ed
0%
Year of FDA approval
(C)
Academia
Industry
Biotech
Number of NMEs
150
Ac
Percent of NMEs
i
(A)
125 100
75 50 25 0
Page 8 of 8