Drug Discovery Today Volume 19, Number 9 September 2014
PERSPECTIVE
feature An analysis of FDA-approved drugs for infectious disease: antibacterial agents
Drugs targeting infectious diseases have greatly improved public health. A study to evaluate all US Food and Drug Administration (FDA)-approved new molecular entities (NMEs) reveals that the number of new agents targeting infectious disease peaked during the 1990s and declined rapidly thereafter. Molecules targeting bacterial pathogens represent the most common component of anti-infectives followed by antivirals and antifungals. Focusing on antibacterial agents, an increase in new NMEs predominated from the 1960s through to the 1990s, dropping sharply thereafter. Obsolescence and resistance has eliminated one-third of these drugs. Consequently, the arsenal of antibiotics peaked in 2000 and is declining. Likewise, the number of organizations awarded at least one NME for a bacterial indication has declined to a level not seen in more than a half century.
A brief history of anti-infectives Tuberculosis, influenza, and pneumonia were leading causes of morbidity and mortality in the USA for most of its history [1]. Beginning during the 1940s, the introduction, first of sulfa drugs and later antibiotics, provided new medical options that decreased the incidence and severity of infectious disease mortality. Today, deaths from the three aforementioned pulmonary infections are at all-time lows. Recently, the Yale Center for Molecular Discovery sought to develop a collection of all FDAapproved small molecules as a resource for screening to emphasize drug repurposing. As part of this global effort, we focused on the history of medicines targeting infectious diseases. As a brief history, the first anti-infective, sulfanilamide, was developed during the late 1930s [2]. The overarching need to combat bacterial infections led to an influx of myriad sulfa drugs within months. This
exuberance, coupled with inconsistent quality control, led to disaster in 1937, when more than 100 people, including many children, died from poisoning with a poorly formulated sulfa drug, Elixir Sulfanilamide [3]. The resulting public outrage prompted passage of the 1938 Federal Food, Drug and Cosmetic Act, ultimately giving rise to the FDA as the key regulator of drug safety in the USA. The total number of drugs targeting infectious diseases stands at 292 NMEs as of the end of 2013 (Fig. 1a). In 1939, FDA approved the first anti-infective, sulfapyridine. Thereafter, the annual rate of infectious disease-focused NMEs increased steadily from the 1930s through to the mid-1990s, peaking at a record annual number of 12 NMEs targeting infectious diseases in 1996 (Fig. 1b). Since then, the number of approvals has dropped precipitously. In the current decade, the annual average is down 75% from its peak.
1359-6446/06/$ - see front matter ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.drudis.2014.07.005
Infectious diseases encompass a broad spectrum of different pathogens (Fig. 1c). Antibacterial agents constitute most infectious disease NMEs (55.3%), followed by antivirals (22.3%). A smaller number of NMEs target pathogenic fungi (11.7%), parasites (7.8%), and insects (2.8%). Based on these findings, we focused our attention on the two major classes of infectious agent. Agents targeting bacterial pathogens are the focus of the present report and an evaluation of antiviral agents can be found in the accompanying article [4].
Analysis of antibacterials By the end of 2013, 155 antibacterial NMEs had been approved by FDA (Fig. 2a). Starting with the first approvals during the late 1930s, the number of antibacterial NMEs accelerated rapidly, reaching an annual average rate of 3.1 by the 1960s. When evaluated on a year-by-year basis, www.drugdiscoverytoday.com
1283
Features PERSPECTIVE
Michael S. Kinch, [email protected], [email protected], Eric Patridge, Mark Plummer and Denton Hoyer
PERSPECTIVE
Drug Discovery Today Volume 19, Number 9 September 2014
250
12
200 150 100
10 8 6 4 2
0
0 1930 1934 1938 1942 1946 1950 1954 1958 1962 1966 1970 1974 1978 1982 1986 1990 1994 1998 2002 2006 2010
50
(c)
Average annual NME rate
4
3
1930 1934 1938 1942 1946 1950 1954 1958 1962 1966 1970 1974 1978 1982 1986 1990 1994 1998 2002 2006 2010
Annual NME rate
(b) 14
Accumulated NMEs
(a) 300
Bacteria Virus Fungus Insect Parasite
2
1
0
Features PERSPECTIVE
1930s 1940s 1950s 1960s 1970s 1980s 1990s 2000s 2010s Drug Discovery Today
FIGURE 1
The growth and decline of anti-infective new molecular entities (NMEs). (a) The cumulative number of US Food and Drug Administration (FDA)-approved NMEs for infectious disease application is shown on an annual basis. Note that these numbers solely represent approvals and do not address drugs subsequently withdrawn. (b) The annual approval rate for NMEs targeting infectious diseases is shown. (c) The classification of infectious disease NMEs is separated into the type of pathogen targeted.
1971 was the most active year for new antibacterial agents, witnessing seven new medicines. This high rate of new antibacterial NMEs remained at high and steady levels from the 1950s through to the 1990s. Beginning with the onset of the new millennium, the number of new antibacterial NMEs plummeted. Only three NMEs have been approved in the current decade, a level not observed since the early 1940s. Compounding the issue, many NMEs have been rendered obsolescent or commercially unattractive because of drug resistance, toxicity, or newer-generation derivatives. In addition, some antibacterial drugs have been redirected towards applications such as animal feed supplements [5]. Thus, we assessed the number of antibacterial agents withdrawn from the market for human use. The loss of these products was unrelated to generic competition because we defined a withdrawal as the lack of availability of 1284
www.drugdiscoverytoday.com
an NME, regardless of whether it was available from the originator or a follow-on supplier. To assess this trend, we categorized all 155 antibacterial NMEs based on the year in which they were approved (defined as an ‘entry’) or the year of withdrawal (defined as an ‘exit’). These were plotted on an annual basis from the time of the first antibacterial approval (1939) through to the end of 2013 (Fig. 2b). The net number of antibacterial agents available for human use peaked during the late 1990s and is currently declining (Fig. 2c). Although a handful of antibacterial NMEs had been withdrawn from the marketplace as early as 1978, these were compensated by a continued high level of new antibacterial products in the years that followed. The pace of drug withdrawals increased during the late 1990s. In the 10-year period from 1999 to 2008, 34 antibiotics were withdrawn. Within this same time period,
17 NMEs were approved, thus translating into a 2:1 loss of antibacterial agents. The net effect of these changes is that the number of different antibacterial NMEs available for clinical application peaked at 113 NMEs in 2000. Since then, the number of antibacterial NMEs has declined to 96. Whereas 155 antibacterial agents have been approved since 1938, less than two-thirds (62%) remain available for clinical use today. The decrease in approvals for new antibacterial agents mimics an even more dramatic decrease in the number of biotechnology and pharmaceutical companies developing this class of drugs (Fig. 3a). To assess these changes, the number of companies that had gained approval for at least one NME was tracked over time. In total, 63 different companies have gained an approval for at least one antibacterial NME. The number of new entries into the field continued to increase from the late 1930s through to the
Drug Discovery Today Volume 19, Number 9 September 2014
PERSPECTIVE
140
140
120
120
Available NMEs
(c) 160
Cumulative NMEs approved
(a) 160
100 80 60
100 80 60
40
40
20
20
0 1939
1949
1959
1969
1979
(c)
1989
1999
2009
1949
1959
0 1939
1949
1959
1969
1979
1989
1999
2009
Entry
8 6 4 2 0
Exit
–2 –4
1939
1969
1979
1989
1999
2009 Drug Discovery Today
FIGURE 2
Recent collapse of antibacterial new molecular entities (NMEs). (a) The cumulative number of US Food and Drug Administration (FDA)-approved NMEs for antibacterial indications is shown on an annual basis. (b) The entry (blue) and exit (red; because of obsolescence or resistance) is indicated on an annual basis. (c) The net number of NMEs, reflecting changes resulting from new entries and exits, that are available for clinical use, is indicated over time.
1980s, reaching a peak of 32 active and independent companies in 1988. Thereafter, the number of commercial organizations awarded an NME for an antibacterial agent decreased. Using the same entry/exit approach as utilized above, the average number of companies entering the antibacterial space peaked during the 1960s, declining thereafter (Fig. 1b). Starting during the 1990s, the net number of companies that had gained FDA approval for at least one antibacterial agent entered negative territory. This negative growth continues. The current decade is experiencing an average loss of two companies per year. Consequently, the current number of organizations that have gained at least one NME approval for an antibacterial now stands at 11, the lowest number seen since 1961. The declining number of companies with antibacterial experience in part arises as a result of consolidation through mergers and acquisitions. Of the 63 companies that have been
awarded at least one NME for an antibacterial agent, 35 have been acquired or merged into a new organization. We considered that a merger of two organizations into a new and larger single organization might concentrate, and not necessarily eliminate, the expertise necessary for development of future antibiotics. Thus, a separate analysis asked the fate of organizations that had gained an approval for at least one antibacterial agent. A web-based search asked whether the resulting company continued work in antibacterial agents as evidenced by an assessment of their pipelines, public presentations, and press releases. Of the 28 active and independent organizations remaining after consolidation, at least 17 have made strategic decisions to leave the field. Of the top ten most successful companies (in terms of the number of NMEs awarded), four continue to demonstrate active research into NMEs.
As an additional assessment of the capacity to develop new antibacterial drugs, we related the number of NMEs awarded to the 11 organizations with active programs relative to the total number of antibacterial NMEs. These analyses revealed that more than 75% of the experience, as represented by awarded NMEs, has left the field a result of consolidations, bankruptcies, and strategic reprioritization. We recently compared the relative contribution of biotechnology and pharmaceutical companies to NMEs approvals and, thus, performed a similar analysis focused on antibacterial drugs. Seven of 82 (8.5%) NMEs since 1980 were awarded to biotechnology companies. The relative input from biotechnology is trending upwards because two of ten NMEs from the first decade of the new millennium were awarded to biotechnology companies. Remarkably, six of the seven (85.7%) biotechnology companies awarded an NME for an antibacterial agent www.drugdiscoverytoday.com
1285
Features PERSPECTIVE
–6
PERSPECTIVE
(a)
Drug Discovery Today Volume 19, Number 9 September 2014
(c)
Organizations with active anti-bacterial programs
35 30 25 20
Abbvie
15
Roche
10 Bayer 5 Merck 0 1939
1949
1959
1969
1979
1989
1999
2009
Johnson & Johnson Sanofi Aventis
(b) Entry
4
Bristol-Myers Squibb
2 Eli Lilly 0 GlaxoSmithKline
Exit
–2 Pfizer –4 0
–6
10
20
30
40
–8 1939
1949
1959
1969
1979
1989
1999
2009 Drug Discovery Today
Features PERSPECTIVE
FIGURE 3
Organizations contributing to antibacterial new molecular entities (NMEs). (a) The net number of organizations that had obtained at least one NME for a bacterial disease and which remain active in the field is shown over time. (b) The entry and exit of organizations is indicated. (c) The leading ten organizations, in terms of directly or indirectly acquiring NMEs for antibacterial agents, are shown. Organizations with active programs in new antibiotics are indicated in blue.
remain active and independent. This contrasts with the general trend in which fewer than half (49.2%) of all biotechnology companies that have been awarded an NME remain active an independent as of writing. Such findings suggest that biotechnology companies that develop antibacterial agents are less attractive as takeover targets compared with those addressing other therapeutic areas.
Concluding remarks and implications Although public health has benefitted greatly from past successes in the development of new drugs to treat infectious diseases, we now stand at a point where the number of drugs available in the antibiotics arsenal is shrinking. In parallel, the number and breadth of organizations with demonstrated abilities to gain FDA approval for a new antibacterial agent is now at a level not seen since at least the early 1960s. It is important to point out that some organizations are less transparent and we are not able to exclude that 1286
www.drugdiscoverytoday.com
NME research continues at some of these organizations. Recent reports have focused attention on the combination of declining approvals coupled with increasing drug resistance [6,7]. To the best of our knowledge, the present report is unique in evaluating this subject from the global perspective of NME approvals and withdrawals of both NMEs and the organizations that developed them. Many high-visibility organizations have made strategic decisions to leave the field of antibacterial agents, including some of the most successful and historically innovative pharmaceutical companies (i.e., Pfizer, Eli Lilly, AstraZeneca, and Bristol–Myers Squibb). These decisions were rational and considered the financial reality of a relatively poor return on investment that is associated with antibacterial drugs. Antibiotic treatment is generally low cost and acute, whereas treatments for other indications (e.g., cancer or autoimmune diseases) can be more chronic and
have higher profit margins. Such facts have prompted many organizations to leave the field. Despite being fiscally sound, the retreat from development of antibacterial agents has long-term public health ramifications [8]. Much recent attention has focused on the implications of a shrinking antibacterial arsenal in the face of increasing drug resistance [9,10]. A related concern is the potential for irreplaceable loss of expertise. Given that many organizations with a successful track record have abandoned anti-infectives, the institutional knowledge is lost as experienced personnel are generally furloughed or reassigned. There are some promising signs that the trend might be changing. The average cost of new antibacterial NMEs has been increasing, with the most recent prices of approximately US$3000 per course of treatment [11,12]. This presents challenges for payer organizations (most notably, insurers, governments, and public health systems in the emerging world), but might be effective in creating new attraction for a field,
Drug Discovery Today Volume 19, Number 9 September 2014
and active engagement coupled with productive discussion and the participation of public and private organizations is urgently required. 7
Acknowledgments This work was conducted as part of a project at the Yale Center for Molecular Discovery to develop a collection of all FDA-approved small molecules as a resource for screening to emphasize drug repurposing. Please contact the corresponding author if you or your organization would be interested in potential participation in this project.
8
9
10 11
References 1 Jones, D.S. et al. (2012) The burden of disease and the changing task of medicine. N. Engl. J. Med. 366, 2333–2338 2 Schnitker, M.A. (1938) Sulfanilamide: a review. N. Engl. J. Med. 218, 503–511 3 Ballentine, C. (1981) Taste of raspberries, taste of death: the 1937 elixir sulfanilamide incident. FDA Consum. Mag. June, 15 4 Kinch, M.S. and Patridge, E. (2014) An analysis of FDAapproved drugs for infectious disease: HIV/AIDS drugs. Drug Discov Today (in press) 5 Solomons, I. (1978) Antibiotics in animal feeds: human and animal safety issues. J. Anim. Sci. 46, 1360–1368 6 Shlaes, D.M. et al. (1997) Society for Healthcare Epidemiology of America and Infectious Diseases
12
Society of America Joint Committee on the Prevention of Antimicrobial Resistance: guidelines for the prevention of antimicrobial resistance in hospitals. Clin. Infect. Dis. 25, 584–599 D’Costa, V.M. et al. (2006) Sampling the antibiotic resistome. Science 311, 374–377 Infectious Diseases Society of America (2011) Combating antimicrobial resistance: policy recommendations to save lives. Clin. Infect. Dis. 52, S397–S428 Spellberg, B. et al. (2008) The epidemic of antibioticresistant infections: a call to action for the medical community from the Infectious Diseases Society of America. Clin. Infect. Dis. 46, 155–164 Lewis, K. (2013) Platforms for antibiotic discovery. Nat. Rev. Drug Discov. 12, 371–387 Sclar, D.A. et al. (2012) Fidaxomicin for Clostridium difficile-associated diarrhoea. Clin. Drug Invest. 32, e17–e24 Laohavaleeson, S. et al. (2008) Effectiveness of telavancin versus vancomycin for treatment of complicated skin and skin structure infections. Pharmacotherapy 28, 1471–1482
Michael S. Kinch, Eric Patridge, Mark Plummer, Denton Hoyer Yale Center for Molecular Discovery, Yale University, 600 West Campus Drive, West Haven, CT 06516, USA
Features PERSPECTIVE
whose very existence is threatened. Indeed, a recent decision by Roche to re-enter the field might signal a re-emergence for antibacterial research and development. In light of the aforementioned loss of institutional knowledge and talent, the retooling of infectious disease research would take considerable time and resources. Furthermore, the biopharmaceutical industry remains in a risksensitive mode that emphasizes ‘derisking’ and other strategies to avoid high-profile and costly clinical failures. Thus, in the short term, there might be a need for governmental and/or nongovernmental support to recreate the foundations needed for renewed engagement. These incentives could include governmental incentives in the form of tax advantages, clear guidance on trials required for approval, or intellectual property considerations for companies entering or re-entering the field. In addition, both governmental and nongovernmental organizations could identify ways of engaging scientists formerly engaged in anti-infectives research, many of whom have landed in academic or public research institutions. To avoid a risk that increasing drug resistance will cause a reemergence of trends not seen since the beginning of the 20th century, creative
PERSPECTIVE
www.drugdiscoverytoday.com
1287
PERSPECTIVE
feature An analysis of FDA-approved drugs for infectious disease: antibacterial agents
Drugs targeting infectious diseases have greatly improved public health. A study to evaluate all US Food and Drug Administration (FDA)-approved new molecular entities (NMEs) reveals that the number of new agents targeting infectious disease peaked during the 1990s and declined rapidly thereafter. Molecules targeting bacterial pathogens represent the most common component of anti-infectives followed by antivirals and antifungals. Focusing on antibacterial agents, an increase in new NMEs predominated from the 1960s through to the 1990s, dropping sharply thereafter. Obsolescence and resistance has eliminated one-third of these drugs. Consequently, the arsenal of antibiotics peaked in 2000 and is declining. Likewise, the number of organizations awarded at least one NME for a bacterial indication has declined to a level not seen in more than a half century.
A brief history of anti-infectives Tuberculosis, influenza, and pneumonia were leading causes of morbidity and mortality in the USA for most of its history [1]. Beginning during the 1940s, the introduction, first of sulfa drugs and later antibiotics, provided new medical options that decreased the incidence and severity of infectious disease mortality. Today, deaths from the three aforementioned pulmonary infections are at all-time lows. Recently, the Yale Center for Molecular Discovery sought to develop a collection of all FDAapproved small molecules as a resource for screening to emphasize drug repurposing. As part of this global effort, we focused on the history of medicines targeting infectious diseases. As a brief history, the first anti-infective, sulfanilamide, was developed during the late 1930s [2]. The overarching need to combat bacterial infections led to an influx of myriad sulfa drugs within months. This
exuberance, coupled with inconsistent quality control, led to disaster in 1937, when more than 100 people, including many children, died from poisoning with a poorly formulated sulfa drug, Elixir Sulfanilamide [3]. The resulting public outrage prompted passage of the 1938 Federal Food, Drug and Cosmetic Act, ultimately giving rise to the FDA as the key regulator of drug safety in the USA. The total number of drugs targeting infectious diseases stands at 292 NMEs as of the end of 2013 (Fig. 1a). In 1939, FDA approved the first anti-infective, sulfapyridine. Thereafter, the annual rate of infectious disease-focused NMEs increased steadily from the 1930s through to the mid-1990s, peaking at a record annual number of 12 NMEs targeting infectious diseases in 1996 (Fig. 1b). Since then, the number of approvals has dropped precipitously. In the current decade, the annual average is down 75% from its peak.
1359-6446/06/$ - see front matter ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.drudis.2014.07.005
Infectious diseases encompass a broad spectrum of different pathogens (Fig. 1c). Antibacterial agents constitute most infectious disease NMEs (55.3%), followed by antivirals (22.3%). A smaller number of NMEs target pathogenic fungi (11.7%), parasites (7.8%), and insects (2.8%). Based on these findings, we focused our attention on the two major classes of infectious agent. Agents targeting bacterial pathogens are the focus of the present report and an evaluation of antiviral agents can be found in the accompanying article [4].
Analysis of antibacterials By the end of 2013, 155 antibacterial NMEs had been approved by FDA (Fig. 2a). Starting with the first approvals during the late 1930s, the number of antibacterial NMEs accelerated rapidly, reaching an annual average rate of 3.1 by the 1960s. When evaluated on a year-by-year basis, www.drugdiscoverytoday.com
1283
Features PERSPECTIVE
Michael S. Kinch, [email protected], [email protected], Eric Patridge, Mark Plummer and Denton Hoyer
PERSPECTIVE
Drug Discovery Today Volume 19, Number 9 September 2014
250
12
200 150 100
10 8 6 4 2
0
0 1930 1934 1938 1942 1946 1950 1954 1958 1962 1966 1970 1974 1978 1982 1986 1990 1994 1998 2002 2006 2010
50
(c)
Average annual NME rate
4
3
1930 1934 1938 1942 1946 1950 1954 1958 1962 1966 1970 1974 1978 1982 1986 1990 1994 1998 2002 2006 2010
Annual NME rate
(b) 14
Accumulated NMEs
(a) 300
Bacteria Virus Fungus Insect Parasite
2
1
0
Features PERSPECTIVE
1930s 1940s 1950s 1960s 1970s 1980s 1990s 2000s 2010s Drug Discovery Today
FIGURE 1
The growth and decline of anti-infective new molecular entities (NMEs). (a) The cumulative number of US Food and Drug Administration (FDA)-approved NMEs for infectious disease application is shown on an annual basis. Note that these numbers solely represent approvals and do not address drugs subsequently withdrawn. (b) The annual approval rate for NMEs targeting infectious diseases is shown. (c) The classification of infectious disease NMEs is separated into the type of pathogen targeted.
1971 was the most active year for new antibacterial agents, witnessing seven new medicines. This high rate of new antibacterial NMEs remained at high and steady levels from the 1950s through to the 1990s. Beginning with the onset of the new millennium, the number of new antibacterial NMEs plummeted. Only three NMEs have been approved in the current decade, a level not observed since the early 1940s. Compounding the issue, many NMEs have been rendered obsolescent or commercially unattractive because of drug resistance, toxicity, or newer-generation derivatives. In addition, some antibacterial drugs have been redirected towards applications such as animal feed supplements [5]. Thus, we assessed the number of antibacterial agents withdrawn from the market for human use. The loss of these products was unrelated to generic competition because we defined a withdrawal as the lack of availability of 1284
www.drugdiscoverytoday.com
an NME, regardless of whether it was available from the originator or a follow-on supplier. To assess this trend, we categorized all 155 antibacterial NMEs based on the year in which they were approved (defined as an ‘entry’) or the year of withdrawal (defined as an ‘exit’). These were plotted on an annual basis from the time of the first antibacterial approval (1939) through to the end of 2013 (Fig. 2b). The net number of antibacterial agents available for human use peaked during the late 1990s and is currently declining (Fig. 2c). Although a handful of antibacterial NMEs had been withdrawn from the marketplace as early as 1978, these were compensated by a continued high level of new antibacterial products in the years that followed. The pace of drug withdrawals increased during the late 1990s. In the 10-year period from 1999 to 2008, 34 antibiotics were withdrawn. Within this same time period,
17 NMEs were approved, thus translating into a 2:1 loss of antibacterial agents. The net effect of these changes is that the number of different antibacterial NMEs available for clinical application peaked at 113 NMEs in 2000. Since then, the number of antibacterial NMEs has declined to 96. Whereas 155 antibacterial agents have been approved since 1938, less than two-thirds (62%) remain available for clinical use today. The decrease in approvals for new antibacterial agents mimics an even more dramatic decrease in the number of biotechnology and pharmaceutical companies developing this class of drugs (Fig. 3a). To assess these changes, the number of companies that had gained approval for at least one NME was tracked over time. In total, 63 different companies have gained an approval for at least one antibacterial NME. The number of new entries into the field continued to increase from the late 1930s through to the
Drug Discovery Today Volume 19, Number 9 September 2014
PERSPECTIVE
140
140
120
120
Available NMEs
(c) 160
Cumulative NMEs approved
(a) 160
100 80 60
100 80 60
40
40
20
20
0 1939
1949
1959
1969
1979
(c)
1989
1999
2009
1949
1959
0 1939
1949
1959
1969
1979
1989
1999
2009
Entry
8 6 4 2 0
Exit
–2 –4
1939
1969
1979
1989
1999
2009 Drug Discovery Today
FIGURE 2
Recent collapse of antibacterial new molecular entities (NMEs). (a) The cumulative number of US Food and Drug Administration (FDA)-approved NMEs for antibacterial indications is shown on an annual basis. (b) The entry (blue) and exit (red; because of obsolescence or resistance) is indicated on an annual basis. (c) The net number of NMEs, reflecting changes resulting from new entries and exits, that are available for clinical use, is indicated over time.
1980s, reaching a peak of 32 active and independent companies in 1988. Thereafter, the number of commercial organizations awarded an NME for an antibacterial agent decreased. Using the same entry/exit approach as utilized above, the average number of companies entering the antibacterial space peaked during the 1960s, declining thereafter (Fig. 1b). Starting during the 1990s, the net number of companies that had gained FDA approval for at least one antibacterial agent entered negative territory. This negative growth continues. The current decade is experiencing an average loss of two companies per year. Consequently, the current number of organizations that have gained at least one NME approval for an antibacterial now stands at 11, the lowest number seen since 1961. The declining number of companies with antibacterial experience in part arises as a result of consolidation through mergers and acquisitions. Of the 63 companies that have been
awarded at least one NME for an antibacterial agent, 35 have been acquired or merged into a new organization. We considered that a merger of two organizations into a new and larger single organization might concentrate, and not necessarily eliminate, the expertise necessary for development of future antibiotics. Thus, a separate analysis asked the fate of organizations that had gained an approval for at least one antibacterial agent. A web-based search asked whether the resulting company continued work in antibacterial agents as evidenced by an assessment of their pipelines, public presentations, and press releases. Of the 28 active and independent organizations remaining after consolidation, at least 17 have made strategic decisions to leave the field. Of the top ten most successful companies (in terms of the number of NMEs awarded), four continue to demonstrate active research into NMEs.
As an additional assessment of the capacity to develop new antibacterial drugs, we related the number of NMEs awarded to the 11 organizations with active programs relative to the total number of antibacterial NMEs. These analyses revealed that more than 75% of the experience, as represented by awarded NMEs, has left the field a result of consolidations, bankruptcies, and strategic reprioritization. We recently compared the relative contribution of biotechnology and pharmaceutical companies to NMEs approvals and, thus, performed a similar analysis focused on antibacterial drugs. Seven of 82 (8.5%) NMEs since 1980 were awarded to biotechnology companies. The relative input from biotechnology is trending upwards because two of ten NMEs from the first decade of the new millennium were awarded to biotechnology companies. Remarkably, six of the seven (85.7%) biotechnology companies awarded an NME for an antibacterial agent www.drugdiscoverytoday.com
1285
Features PERSPECTIVE
–6
PERSPECTIVE
(a)
Drug Discovery Today Volume 19, Number 9 September 2014
(c)
Organizations with active anti-bacterial programs
35 30 25 20
Abbvie
15
Roche
10 Bayer 5 Merck 0 1939
1949
1959
1969
1979
1989
1999
2009
Johnson & Johnson Sanofi Aventis
(b) Entry
4
Bristol-Myers Squibb
2 Eli Lilly 0 GlaxoSmithKline
Exit
–2 Pfizer –4 0
–6
10
20
30
40
–8 1939
1949
1959
1969
1979
1989
1999
2009 Drug Discovery Today
Features PERSPECTIVE
FIGURE 3
Organizations contributing to antibacterial new molecular entities (NMEs). (a) The net number of organizations that had obtained at least one NME for a bacterial disease and which remain active in the field is shown over time. (b) The entry and exit of organizations is indicated. (c) The leading ten organizations, in terms of directly or indirectly acquiring NMEs for antibacterial agents, are shown. Organizations with active programs in new antibiotics are indicated in blue.
remain active and independent. This contrasts with the general trend in which fewer than half (49.2%) of all biotechnology companies that have been awarded an NME remain active an independent as of writing. Such findings suggest that biotechnology companies that develop antibacterial agents are less attractive as takeover targets compared with those addressing other therapeutic areas.
Concluding remarks and implications Although public health has benefitted greatly from past successes in the development of new drugs to treat infectious diseases, we now stand at a point where the number of drugs available in the antibiotics arsenal is shrinking. In parallel, the number and breadth of organizations with demonstrated abilities to gain FDA approval for a new antibacterial agent is now at a level not seen since at least the early 1960s. It is important to point out that some organizations are less transparent and we are not able to exclude that 1286
www.drugdiscoverytoday.com
NME research continues at some of these organizations. Recent reports have focused attention on the combination of declining approvals coupled with increasing drug resistance [6,7]. To the best of our knowledge, the present report is unique in evaluating this subject from the global perspective of NME approvals and withdrawals of both NMEs and the organizations that developed them. Many high-visibility organizations have made strategic decisions to leave the field of antibacterial agents, including some of the most successful and historically innovative pharmaceutical companies (i.e., Pfizer, Eli Lilly, AstraZeneca, and Bristol–Myers Squibb). These decisions were rational and considered the financial reality of a relatively poor return on investment that is associated with antibacterial drugs. Antibiotic treatment is generally low cost and acute, whereas treatments for other indications (e.g., cancer or autoimmune diseases) can be more chronic and
have higher profit margins. Such facts have prompted many organizations to leave the field. Despite being fiscally sound, the retreat from development of antibacterial agents has long-term public health ramifications [8]. Much recent attention has focused on the implications of a shrinking antibacterial arsenal in the face of increasing drug resistance [9,10]. A related concern is the potential for irreplaceable loss of expertise. Given that many organizations with a successful track record have abandoned anti-infectives, the institutional knowledge is lost as experienced personnel are generally furloughed or reassigned. There are some promising signs that the trend might be changing. The average cost of new antibacterial NMEs has been increasing, with the most recent prices of approximately US$3000 per course of treatment [11,12]. This presents challenges for payer organizations (most notably, insurers, governments, and public health systems in the emerging world), but might be effective in creating new attraction for a field,
Drug Discovery Today Volume 19, Number 9 September 2014
and active engagement coupled with productive discussion and the participation of public and private organizations is urgently required. 7
Acknowledgments This work was conducted as part of a project at the Yale Center for Molecular Discovery to develop a collection of all FDA-approved small molecules as a resource for screening to emphasize drug repurposing. Please contact the corresponding author if you or your organization would be interested in potential participation in this project.
8
9
10 11
References 1 Jones, D.S. et al. (2012) The burden of disease and the changing task of medicine. N. Engl. J. Med. 366, 2333–2338 2 Schnitker, M.A. (1938) Sulfanilamide: a review. N. Engl. J. Med. 218, 503–511 3 Ballentine, C. (1981) Taste of raspberries, taste of death: the 1937 elixir sulfanilamide incident. FDA Consum. Mag. June, 15 4 Kinch, M.S. and Patridge, E. (2014) An analysis of FDAapproved drugs for infectious disease: HIV/AIDS drugs. Drug Discov Today (in press) 5 Solomons, I. (1978) Antibiotics in animal feeds: human and animal safety issues. J. Anim. Sci. 46, 1360–1368 6 Shlaes, D.M. et al. (1997) Society for Healthcare Epidemiology of America and Infectious Diseases
12
Society of America Joint Committee on the Prevention of Antimicrobial Resistance: guidelines for the prevention of antimicrobial resistance in hospitals. Clin. Infect. Dis. 25, 584–599 D’Costa, V.M. et al. (2006) Sampling the antibiotic resistome. Science 311, 374–377 Infectious Diseases Society of America (2011) Combating antimicrobial resistance: policy recommendations to save lives. Clin. Infect. Dis. 52, S397–S428 Spellberg, B. et al. (2008) The epidemic of antibioticresistant infections: a call to action for the medical community from the Infectious Diseases Society of America. Clin. Infect. Dis. 46, 155–164 Lewis, K. (2013) Platforms for antibiotic discovery. Nat. Rev. Drug Discov. 12, 371–387 Sclar, D.A. et al. (2012) Fidaxomicin for Clostridium difficile-associated diarrhoea. Clin. Drug Invest. 32, e17–e24 Laohavaleeson, S. et al. (2008) Effectiveness of telavancin versus vancomycin for treatment of complicated skin and skin structure infections. Pharmacotherapy 28, 1471–1482
Michael S. Kinch, Eric Patridge, Mark Plummer, Denton Hoyer Yale Center for Molecular Discovery, Yale University, 600 West Campus Drive, West Haven, CT 06516, USA
Features PERSPECTIVE
whose very existence is threatened. Indeed, a recent decision by Roche to re-enter the field might signal a re-emergence for antibacterial research and development. In light of the aforementioned loss of institutional knowledge and talent, the retooling of infectious disease research would take considerable time and resources. Furthermore, the biopharmaceutical industry remains in a risksensitive mode that emphasizes ‘derisking’ and other strategies to avoid high-profile and costly clinical failures. Thus, in the short term, there might be a need for governmental and/or nongovernmental support to recreate the foundations needed for renewed engagement. These incentives could include governmental incentives in the form of tax advantages, clear guidance on trials required for approval, or intellectual property considerations for companies entering or re-entering the field. In addition, both governmental and nongovernmental organizations could identify ways of engaging scientists formerly engaged in anti-infectives research, many of whom have landed in academic or public research institutions. To avoid a risk that increasing drug resistance will cause a reemergence of trends not seen since the beginning of the 20th century, creative
PERSPECTIVE
www.drugdiscoverytoday.com
1287
