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Defining and quantifying the use of personalized medicines Despite the great attention given to personalized medicines, the pace at which they are being added to the pharmacopaeia and adopted into clinical practice has been limited. Quantifying the use of personalized medicines in multiple geographical regions over time would help monitor the extent to which different policies and health care systems might support their adoption. Here, we propose a definition for personalized medicines and provide — to our knowledge — the first replicable, objective and longitudinal quantification of worldwide use of personalized medicines, which could serve as a baseline from which to measure their future uptake. To establish a reliable baseline, a standardized definition of personalized medicines is necessary. Here, we define a personalized medicine on the basis of it meeting one of the following two criteria: • A medicine that has a US Food and Drug Administration (FDA) or a European Medicines Agency label stating that its
choice as a treatment must be governed by results from a companion diagnostic test. • A medicine that has a label that recommends (but does not require) the companion diagnostic, and at least one authoritative professional organization also recommends use of the test to guide treatment. We excluded medicines for which the companion diagnostic is used primarily to help titrate their dosage. In the future, autologous biologically modified treatments tailored to individual patients would also fall within our definition of personalized medicines; none were approved by the end of our study period in 2009, but sipuleucel-T (Provenge; Dendreon) became the first such treatment to be approved in 2010. For the period 1998–2009, we identified all personalized medicines that met this definition, and characterized their regulatory history, safety, utilization and sales (see Supplementary information S1 (box) for
b Biologic personalized medicines per 1,000 capita utilization
4.0
12
United States EU5 Japan Rest of world
3.5 3.0 2.5
Standard unit per capita (SU/1,000 capita)
Standard units (million units)
a Biologic personalized medicines SU level
2.0 1.5 1.0 0.5 0
2,500 2,000 1,500 1,000 500 0
6 3
1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
5
United States EU5 Japan Rest of world
Standard unit per capita (SU/capita)
3,000
United States EU5 Japan
d Small-molecule personalized medicines per capita utilization
4,000 3,500
9
0
1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
c Small-molecule personalized medicines SU level Standard units (million units)
methods and databases used in this study). A total of 27 unique personalized medicines were identified (Supplementary information S2 (table)). Of these, 22 personalized medicines were used in oncology indications, 2 were used in virology indications, and 1 each was used in metabolic, central nervous system and immunological conditions. In 2009, these personalized medicines had combined total sales of US$19.72 billion ($8.65 billion for the eight biologics and $11.07 billion for the 19 small molecules), and accounted for 3% of global pharmaceutical expenditures. Oncology personalized medicines represented 88% of total personalized medicine sales (Supplementary information S3 (figure)). Worldwide utilization of biologic personalized medicines grew from 0.13 million to 9.65 million standard units (SUs; see Supplementary information S1 (box) for definition) from 1998 to 2009, with an average annual growth rate (AAGR) of 48% (FIG. 1a). Although the per capita utilization of biologic personalized medicines was initially greatest in the United States, by 2007 per capita utilization in the five major EU markets (EU5; France, Germany, Italy, Spain and the United Kingdom) exceeded the United States, and by 2009 Japan also surpassed the United States and nearly converged with the EU5 markets (FIG. 1b). Worldwide utilization of small-molecule personalized medicines grew from 713 million SUs to 6,245 million SUs from 1998 to 2009, an AAGR of 22% (FIG. 1c); this
1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
Figure 1 | Standard unit level and per capita utilization of personalized medicines: 1998–2009. a | Standard unit (SU) level for biologics. b | Per 1,000 capita utilization of biologics. c | Standard unit level for small
4
United States EU5 Japan
3 2 1 0
1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
molecules. d | Per capita utilization of small molecules. EU5, France, Germany, Italy, Spain and the United Kingdom; ROW, rest of world (outside the United States, the EU5 andNature Japan).Reviews | Drug Discovery
896 | DECEMBER 2013 | VOLUME 12
www.nature.com/reviews/drugdisc © 2013 Macmillan Publishers Limited. All rights reserved
N E W S & A N A LY S I S growth was driven mostly by the conversion of carbamazepine into a personalized medicine in 2007. By 2009, the per capita utilization in the EU5 markets was 25% greater than in United States, followed by Japan (FIG. 1d). Several findings of this study merit discussion (see also Supplementary information S1 (box)). First, in terms of characteristics, oncology agents dominate personalized medicine utilization, and disproportionately address unmet medical needs as revealed by priority, accelerated, and orphan disease FDA designations. Second, older drugs that have become personalized medicines post-launch have had a significant impact on the growth of small-molecule personalized medicines; however, the translation from label to clinical practice remains uncertain. Third, per capita usage of personalized medicines in the EU5 markets is greater than in the United States, with usage rates in Japan and the rest of the world
growing rapidly (FIG. 1b,d), suggesting further investigation to identify the underlying drivers of the utilization of personalized medicines is merited. Fourth, the pace of emergence of personalized medicines has been slow, with them still constituting a small portion of the ~30 new drugs approved annually by the FDA in the period studied. Responding to the small numbers and modest utilization of personalized medicines in the United States, officials from the FDA and the US National Institutes of Health have stated their intention “to help make personalized medicine a reality” through “substantial investments in infrastructure and standards” (N. Engl. J. Med. 363, 301–304; 2010). Nevertheless, only 8 out of 69 new molecular entities approved by the FDA in 2011 and 2012 were personalized medicines. More rapid progress may require increased public funding for translational research, greater use of electronic medical records to
NATURE REVIEWS | DRUG DISCOVERY
better access patients’ test information, and incentives for developers to personalize both approved and investigational therapeutics. Sean X. Hu is at BioStrat Advisory LLC, 521 Topping Hill Road, Westfield, New Jersey 07090, USA. Murray L. Aitken is at the IMS Institute for Healthcare Informatics, 11 Waterview Boulevard, Parsippany, New Jersey 07054, USA. Arnold M. Epstein is at the Harvard School of Public Health, 677 Huntington Avenue, Boston, Massachusetts 02115, USA. Mark R. Trusheim and Ernst R. Berndt are at the Massachusetts Institute of Technology, Alfred P. Sloan School of Management, 100 Main Street, E62-518, Cambridge, Massachusetts 02142, USA. Correspondence to S.X.H. and M.R.T. e-mails: [email protected]; [email protected] Competing interests statement The authors declare competing interests: see Web version for details.
SUPPLEMENTARY INFORMATION See online article: S1 (box) | S2 (table) | S3 (figure) ALL LINKS ARE ACTIVE IN THE ONLINE PDF
VOLUME 12 | DECEMBER 2013 | 897 © 2013 Macmillan Publishers Limited. All rights reserved
Defining and quantifying the use of personalized medicines Despite the great attention given to personalized medicines, the pace at which they are being added to the pharmacopaeia and adopted into clinical practice has been limited. Quantifying the use of personalized medicines in multiple geographical regions over time would help monitor the extent to which different policies and health care systems might support their adoption. Here, we propose a definition for personalized medicines and provide — to our knowledge — the first replicable, objective and longitudinal quantification of worldwide use of personalized medicines, which could serve as a baseline from which to measure their future uptake. To establish a reliable baseline, a standardized definition of personalized medicines is necessary. Here, we define a personalized medicine on the basis of it meeting one of the following two criteria: • A medicine that has a US Food and Drug Administration (FDA) or a European Medicines Agency label stating that its
choice as a treatment must be governed by results from a companion diagnostic test. • A medicine that has a label that recommends (but does not require) the companion diagnostic, and at least one authoritative professional organization also recommends use of the test to guide treatment. We excluded medicines for which the companion diagnostic is used primarily to help titrate their dosage. In the future, autologous biologically modified treatments tailored to individual patients would also fall within our definition of personalized medicines; none were approved by the end of our study period in 2009, but sipuleucel-T (Provenge; Dendreon) became the first such treatment to be approved in 2010. For the period 1998–2009, we identified all personalized medicines that met this definition, and characterized their regulatory history, safety, utilization and sales (see Supplementary information S1 (box) for
b Biologic personalized medicines per 1,000 capita utilization
4.0
12
United States EU5 Japan Rest of world
3.5 3.0 2.5
Standard unit per capita (SU/1,000 capita)
Standard units (million units)
a Biologic personalized medicines SU level
2.0 1.5 1.0 0.5 0
2,500 2,000 1,500 1,000 500 0
6 3
1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
5
United States EU5 Japan Rest of world
Standard unit per capita (SU/capita)
3,000
United States EU5 Japan
d Small-molecule personalized medicines per capita utilization
4,000 3,500
9
0
1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
c Small-molecule personalized medicines SU level Standard units (million units)
methods and databases used in this study). A total of 27 unique personalized medicines were identified (Supplementary information S2 (table)). Of these, 22 personalized medicines were used in oncology indications, 2 were used in virology indications, and 1 each was used in metabolic, central nervous system and immunological conditions. In 2009, these personalized medicines had combined total sales of US$19.72 billion ($8.65 billion for the eight biologics and $11.07 billion for the 19 small molecules), and accounted for 3% of global pharmaceutical expenditures. Oncology personalized medicines represented 88% of total personalized medicine sales (Supplementary information S3 (figure)). Worldwide utilization of biologic personalized medicines grew from 0.13 million to 9.65 million standard units (SUs; see Supplementary information S1 (box) for definition) from 1998 to 2009, with an average annual growth rate (AAGR) of 48% (FIG. 1a). Although the per capita utilization of biologic personalized medicines was initially greatest in the United States, by 2007 per capita utilization in the five major EU markets (EU5; France, Germany, Italy, Spain and the United Kingdom) exceeded the United States, and by 2009 Japan also surpassed the United States and nearly converged with the EU5 markets (FIG. 1b). Worldwide utilization of small-molecule personalized medicines grew from 713 million SUs to 6,245 million SUs from 1998 to 2009, an AAGR of 22% (FIG. 1c); this
1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
Figure 1 | Standard unit level and per capita utilization of personalized medicines: 1998–2009. a | Standard unit (SU) level for biologics. b | Per 1,000 capita utilization of biologics. c | Standard unit level for small
4
United States EU5 Japan
3 2 1 0
1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
molecules. d | Per capita utilization of small molecules. EU5, France, Germany, Italy, Spain and the United Kingdom; ROW, rest of world (outside the United States, the EU5 andNature Japan).Reviews | Drug Discovery
896 | DECEMBER 2013 | VOLUME 12
www.nature.com/reviews/drugdisc © 2013 Macmillan Publishers Limited. All rights reserved
N E W S & A N A LY S I S growth was driven mostly by the conversion of carbamazepine into a personalized medicine in 2007. By 2009, the per capita utilization in the EU5 markets was 25% greater than in United States, followed by Japan (FIG. 1d). Several findings of this study merit discussion (see also Supplementary information S1 (box)). First, in terms of characteristics, oncology agents dominate personalized medicine utilization, and disproportionately address unmet medical needs as revealed by priority, accelerated, and orphan disease FDA designations. Second, older drugs that have become personalized medicines post-launch have had a significant impact on the growth of small-molecule personalized medicines; however, the translation from label to clinical practice remains uncertain. Third, per capita usage of personalized medicines in the EU5 markets is greater than in the United States, with usage rates in Japan and the rest of the world
growing rapidly (FIG. 1b,d), suggesting further investigation to identify the underlying drivers of the utilization of personalized medicines is merited. Fourth, the pace of emergence of personalized medicines has been slow, with them still constituting a small portion of the ~30 new drugs approved annually by the FDA in the period studied. Responding to the small numbers and modest utilization of personalized medicines in the United States, officials from the FDA and the US National Institutes of Health have stated their intention “to help make personalized medicine a reality” through “substantial investments in infrastructure and standards” (N. Engl. J. Med. 363, 301–304; 2010). Nevertheless, only 8 out of 69 new molecular entities approved by the FDA in 2011 and 2012 were personalized medicines. More rapid progress may require increased public funding for translational research, greater use of electronic medical records to
NATURE REVIEWS | DRUG DISCOVERY
better access patients’ test information, and incentives for developers to personalize both approved and investigational therapeutics. Sean X. Hu is at BioStrat Advisory LLC, 521 Topping Hill Road, Westfield, New Jersey 07090, USA. Murray L. Aitken is at the IMS Institute for Healthcare Informatics, 11 Waterview Boulevard, Parsippany, New Jersey 07054, USA. Arnold M. Epstein is at the Harvard School of Public Health, 677 Huntington Avenue, Boston, Massachusetts 02115, USA. Mark R. Trusheim and Ernst R. Berndt are at the Massachusetts Institute of Technology, Alfred P. Sloan School of Management, 100 Main Street, E62-518, Cambridge, Massachusetts 02142, USA. Correspondence to S.X.H. and M.R.T. e-mails: [email protected]; [email protected] Competing interests statement The authors declare competing interests: see Web version for details.
SUPPLEMENTARY INFORMATION See online article: S1 (box) | S2 (table) | S3 (figure) ALL LINKS ARE ACTIVE IN THE ONLINE PDF
VOLUME 12 | DECEMBER 2013 | 897 © 2013 Macmillan Publishers Limited. All rights reserved
