nature publishing group
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`state art
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`Pharmaceutical Innovation in the 21st Century:
`New Drug approvals in the first Decade,
`2000–2009
`KI Kaitin1 and JA DiMasi1
`
`The first decade of the 21st century was a challenging period for the pharma sector and could prove to be a turning point
`in the evolution of the industry. We examine drug development performance metrics for new product approvals during
`2000–2009 and compare them with those of the prior two decades. The results indicate that, whereas total approvals
`are currently at a 25-year low, the percentage of priority products is nearly 50% of the total—a 30-year high. Following
`enactment of the prescription Drug use Fee act of 1992 (pDuFa), the mean duration of the approval phases of drug
`development declined by more than 1 year over the 30-year period—to a low of 1.2 years in 2005–2009—whereas
`the duration of the clinical phases increased. The longer clinical phases were due, in part, to a greater number of
`approved central nervous system (Cns) and antineoplastic agents, two therapeutic classes with relatively long average
`development times (8.1 and 6.9 years, respectively). The results provide the underpinnings of a fundamental shift in the
`structure of the research-based industry.
`
`Someday one might very well look back at the first decade of the
`21st century and conclude that it was a critical turning point in
`the evolution of the research-based pharmaceutical and biophar-
`maceutical industry. There were a number of seminal events over
`the 10-year period that have inexorably altered the landscape for
`bioinnovation. For example, the events of 11 September 2001
`and the subsequent anthrax scares heightened focus on bioter-
`ror countermeasures and led to passage in the United States
`of the Bioterrorism Preparedness and Response Act of 2002,1
`which directed resources to the creation of a rapid response to a
`bioterror attack. Moreover, global outbreaks of avian flu, SARS,
`and H1N1 during the decade led to increased efforts to develop
`new treatments for imminent threats posed by pandemics and
`other global health issues.
`In the early part of the decade, the National Institutes of
`Health (NIH) released its NIH Roadmap (http://nihroadmap.
`nih.gov/initiatives.asp). This was followed, in 2006, by the
`launch of the Clinical and Translational Science Award (CTSA)
`program.2 These initiatives expanded the definition of trans-
`lational medicine beyond bench-to-bedside and addressed
`the transfer of knowledge between basic science and clinical
`medicine, and from clinical researcher to medical practitioner
`to patient.3 Importantly, the NIH Roadmap and CTSA program
`substantially strengthened the role of academic institutions in
`
`bioinnovation.4 With 55 CTSAs awarded to date, and 60 planned
`by 2012, academic research centers in the United States are posi-
`tioned to become active partners with the private sector in medi-
`cal innovation.
`In 2004, the US Food and Drug Administration (FDA) intro-
`duced the Critical Path Initiative,5 the goal of which was to
`improve the translation of basic research findings into safe and
`effective medical treatments for patients. Similar in goal to the
`European Union’s Innovative Medicines Initiative,6 a public–
`private partnership established in 2007 between the European
`Federation of Pharmaceutical Industries and Associations and the
`European Community, the Critical Path Initiative fosters precom-
`petitive research by bringing together the respective capabilities of
`academia, industry, and government to identify new biomarkers
`and other tools to improve the selection of drug candidates and
`increase the likelihood of pipeline success.
`The decade also saw the ascension of pharmacogenomics and
`the development and approval of a new crop of targeted medi-
`cines for cancer and other life-threatening conditions. This new
`class of medicines is leading industry to increase its focus on
`companion diagnostics and other mechanisms to ensure that the
`right drug is delivered at the right dose to the right patient.
`The withdrawal from the market over the decade of
`several prominent prescription drugs for safety reasons also
`
`1Tufts Center for the Study of Drug Development, Tufts University, Boston, Massachusetts, USa. Correspondence: KI Kaitin (kenneth.kaitin@tufts.edu)
`Received 30 October 2010; accepted 31 October 2010; advance online publication 29 December 2010. doi:10.1038/clpt.2010.286
`
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`had a profound impact on the environment for bioinnovation.
`For example, the withdrawal of the COX-2 analgesic Vioxx
`(rofecoxib) in 2004 catalyzed critics of both the FDA and the
`drug industry regarding standards used by the agency to assess
`premarket safety of prescription drugs, the industry’s conduct
`of phase IV studies required at the time of product approval, the
`agency’s ability to monitor the use of pharmaceutical products in
`the marketplace, and its authority to require sponsors to conduct
`new studies when necessary to evaluate drug risks. With the
`passage of the Food and Drug Administration Amendments
`Act of 2007,7 the agency was given sweeping new authority to
`demand submission of risk evaluation and mitigation strate-
`gies to accompany submission for regulatory approval, require
`postmarket clinical studies of approved products if safety ques-
`tions arise, mandate changes to a drug’s approved labeling, and
`impose new restrictions on distribution and use of marketed
`drugs where warranted. The full impact of these new areas of
`authority was highlighted recently in the agency’s decision to
`allow the antidiabetic drug Avandia (rosiglitazone) to remain
`on the market despite concerns about associated cardiovascular
`risk, albeit with significant restrictions on its use.
`Finally, the global economic crisis at the end of the decade,
`and the resultant frozen asset markets, severely restricted access
`to capital for many small and medium-sized pharmaceutical
`companies and start-ups. The result was a restructuring of the
`small pharma sector of the life science industry, as many of the
`smaller companies were either acquired by wealthier, cash-rich
`larger companies, or were liquidated as they ran out of cash.
`Over the past 10 years, drug developers have been buffeted
`by a host of formidable threats, including patent expirations
`for a large number of top-selling products, growing reimburse-
`ment pressures, increasing regulatory demands, intense market
`competition, loss of public confidence, and the relentless rise
`in research and development (R&D) costs. These represent the
`litany of challenges facing drug developers today.
`At the heart of the problem for the research-based indus-
`try, however, is the fact that, despite several decades of effort
`to improve R&D efficiency and performance, the process for
`bringing a new pharmaceutical or biopharmaceutical product
`to market remains an extraordinarily expensive, time-consum-
`ing, and risky proposition,8,9 and the rate of new drug introduc-
`tions has remained flat.10 Some have concluded that the extant
`model of bioinnovation itself is no longer sustainable11 and
`that, in the future, new pharmaceutical products will emanate
`from a network of innovation stakeholders—including large
`and small pharmaceutical and biotechnology companies, aca-
`demic research centers, contract research organizations, public–
`private partnerships, and patient groups—who will share in
`both the risks and the rewards of innovation.12,13 There is
`already evidence of industry’s realignment into these new
`innovation models, sometimes referred to as “fully integrated
`pharmaceutical networks,” or FIPNets.14–16
`In this study, we examined current performance metrics for
`the research-based industry during the first decade of the 21st
`century. Our goals were to assess how companies fared against
`the myriad economic and political challenges facing the industry
`
`and to create a benchmark against which to measure industry’s
`future success in bringing new pharmaceutical and biopharma-
`ceutical products to market.
`
`New drug and biological approvals
`We analyzed approval rates, clinical development durations,
`and regulatory approval phase durations for new drugs and
`biologics approved in the United States from 1980 through
`2009. Because our focus was on the development and approval
`processes for therapeutics, we excluded diagnostics and mol-
`ecules indicated for preventive purposes. We also excluded
`approvals of new salts or esters, new formulations, and new
`indications. Specifically, the unit of analysis is a therapeutic
`new molecular entity (NME) approved through an original
`new drug application (NDA) by the FDA’s Center for Drug
`Evaluation and Research or a significant new biologic approved
`through a Biologics License Application (BLA) by either the
`Center for Drug Evaluation and Research or the FDA’s Center
`for Biologics Evaluation and Research.
`
`Therapeutic ratings
`We examined approval rates, clinical development times, and
`regulatory approval times by the therapeutic significance rat-
`ing assigned by the FDA at marketing approval. From the late
`1970s through the early 1990s, the FDA utilized a three-tier rat-
`ing system designed to prioritize its reviews of applications for
`marketing approval. NMEs thought to represent a significant
`gain over existing therapy, a modest gain over existing therapy,
`or little or no gain over existing therapy were given an A, B, or C
`rating, respectively. In late 1992, the FDA compressed its rating
`system into two categories: P (priority) and S (standard).
`We grouped the approved NMEs that had received an A or B
`rating with those that had received a P rating to form the “priority-
`rated” category for analysis. Similarly, we grouped NMEs that had
`been assigned a C rating by the FDA with NMEs that had been
`assigned an S rating to form the “standard-rated” category.
`
`Clinical development and approval phases
`We examined the estimated average clinical development and
`approval phase durations for new drugs and biologics. We
`defined the “clinical phase” as the time from the filing of the
`first investigational new drug (IND) application to the first
`NDA/BLA submission. Developers must file INDs with the
`FDA before they can begin testing a new molecule in humans
`in the United States. Therefore, the IND filing date approximates
`the start of clinical testing in the United States, and the clinical
`phase approximates the length of the clinical testing period in
`the United States for molecules approved for marketing.
`The “approval phase” is defined as the time from first NDA
`submission to NDA/BLA approval. This period can include the
`time during which the sponsor is gathering requested additional
`data about the molecule or is correcting other deficiencies in the
`application. The “total phase” is defined as the sum of the clinical
`and the approval phases (IND filing to NDA/BLA approval).
`In addition to providing descriptive statistics on development
`and approval phase times for new molecules in general over time,
`
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`37.6
`
`Total
`
`30.0
`
`22.4
`
`Standard
`
`15.2
`
`17.6
`
`11.8
`
`Priority
`
`20.2
`
`10.4
`
`9.8
`
`25.8
`
`12.2
`
`11.6
`
`22.6
`
`10.8
`
`9.0
`
`40
`
`30
`
`20
`
`18.2
`
`10.4
`
`7.6
`
`10
`
`0
`
`Number of approvals
`
`1980–1984
`
`1985–1989
`
`1990–1994
`1995–1999
`Year of approval
`
`2000–2004
`
`2005–2009
`
`Figure 1 average annual number of approved priority, standard, and total
`new molecular entities and significant biologicals, 1980–2009, in 5-year
`periods.
`
`5.7
`
`5.8
`
`6.4
`
`6.5
`
`6.6
`
`6.4
`
`2.8
`
`2.7
`
`2.4
`
`1.4
`
`1.5
`
`1.2
`
`8
`
`Years
`
`0
`
`1980–1984
`
`1985–1989
`
`1990–1994
`
`1995–1999
`
`2000–2004
`
`2005–2009
`
`Approval phase
`
`Clinical phase
`
`Figure 2 Mean clinical phase times (IND filing to NDa/BLa submission)
`and approval phase times (NDa/BLa submission to approval) for new
`molecular entities and significant biologicals approved by the US food and
`Drug administration, 1980–2009, in 5-year periods. BLa, biological license
`application; IND, investigational new drug; NDa, new drug application.
`
`Priority: 2000–2004
`(n = 59)
`
`Priority: 2005–2009
`(n = 49)
`
`Standard: 2000–2004
`(n = 88)
`
`Standard: 2005–2009
`(n = 52)
`
`7.7
`
`1.0
`
`8.7
`
`6.3
`
`0.8
`
`7.1
`
`5.9
`
`6.5
`
`1.8
`
`7.7
`
`1.6
`
`8.1
`
`0
`
`Years
`
`10
`
`Clinical phase
`
`Approval phase
`
`Figure 3 Mean clinical and approval phase times for approved priority and
`standard new molecular entities and significant biologicals, 2000–2009, in
`5-year intervals.
`
`relative to nonpriority drugs. This is because the mean clinical
`phase duration for priority drugs decreased by 1.4 years dur-
`ing the 2005–2009 period, whereas clinical phase durations for
`standard drugs were 0.6 years longer, on average, in the later
`period. The changes in the duration of the clinical phase (by
`therapeutic rating) for the two periods may be explained, at least
`in part, by shifts in the distribution of drugs by therapeutic class,
`
`we also analyzed trends in these metrics by therapeutic class and
`orphan drug status (for the original approved indication). The
`Tufts Center for the Study of Drug Development (CSDD) groups
`newly approved molecules into a number of therapeutic classes
`on the basis of their originally approved indications.
`The information in the Tufts CSDD data sets permits us to
`track trends in the output of new drugs by the pharmaceutical
`and biopharmaceutical industries overall, and also by various
`clinical and regulatory characteristics. In this review, we exam-
`ine trends regarding approval for new therapeutic drugs in the
`United States from 1980 to 2009, with a particular emphasis on
`the results for the past decade (for ease of reference, we include
`new biologicals under the category of new drugs).
`
`Trends in approvals for new drugs
`Figure 1 shows averages of the annual numbers of NME and
`significant biological approvals for 5-year periods from 1980 to
`2009. The chart shows an upward trend up to the mid-1990s,
`followed by a downward trend thereafter. However, the spike
`in new drug approvals from 1995 to 1999 was likely impacted
`significantly by the initial implementation of the Prescription
`Drug Use Fee Act of 1992 (PDUFA). The number of therapeutics
`approved in 1996 is particularly high (49), and such a high rate
`has not been recorded either before or after in the modern drug
`development era (post-1962).
`The number of standard and priority new drugs generally
`followed the same pattern as the number of approvals overall
`through the first half of the 2000s. The share of approvals that
`received priority ratings for the 5-year periods through 2000–
`2004 varied from 39% for 2000–2004 to 45% for 1990–1994.
`However, the priority share did increase to nearly half (49%) for
`the most recent 5-year period.
`
`Clinical development and approval times by period,
`therapeutic significance, and therapeutic class
`Figure 2 shows mean durations of the clinical and approval
`phases for new drugs by 5-year periods from 1980 to 2009. The
`most recent three periods demonstrate the impact that PDUFA
`has had on approval phase duration. The average time from
`initial submission of an NDA or BLA to eventual marketing
`approval is more than a year shorter for the PDUFA period.
`The durations of the clinical development phases increased, on
`average, during the 1980s but remained stable during the 1990s
`and the 2000s. However, the average time to approval from the
`start of clinical testing in the United States declined from 8.8
`years for 1990–1994 to ~8 years thereafter. These results were
`driven by the declines in approval times during the PDUFA
`period.
`Figure 3 shows development and approval times for new
`drugs that were approved 2000–2009, categorized according to
`therapeutic rating. As expected, approval phase durations were
`shorter for priority drugs than for standard drugs. The mean
`approval phase time was 0.8 years shorter for priority drugs in
`each of the two 5-year subperiods than for nonpriority drugs.
`The duration of the clinical phase was 1.8 years longer for pri-
`ority drugs in 2000–2004 but 0.2 years shorter in 2005–2009,
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`Table 1 Median clinical and approval phase times and (range) for
`new molecular entities and significant biologics by therapeutic
`class, 2005–2009
`
`median (range)
`clinical phasea
`3.6 (2.8–8.1)
`6.1 (1.1–9.0)
`
`median (range)
`approval phasea
`0.5 (0.5–0.6)
`0.8 (0.5–1.2)
`
`5.4 (1.8–9.2)
`6.2 (0.3–16.0)
`5.8 (3.2–15.5)
`6.4 (1.7–26.7)
`
`0.8 (0.5–2.8)
`0.5 (0.5–1.5)
`1.0 (0.5–3.6)
`1.9 (0.5–3.0)
`
`N
`5
`8
`
`12
`21
`18
`12
`
`aIDS antivirals
`anesthetic/
`analgesic
`anti-infectiveb
`antineoplastic
`Cardiovascular
`Central nervous
`system
`0.8 (0.5–4.3)
`5.4 (2.6–15.6)
`12
`Endocrine
`1.1 (0.8–5.0)
`5.3 (2.2–10.7)
`5
`Gastrointestinal
`0.8 (0.6–1.8)
`7.0 (1.9–9.8)
`4
`Immunologic
`aPhase times given in years. bExcludes aIDS antivirals.
`
`median (range)
`total phasea
`4.2 (3.3–8.6)
`7.3 (1.6–9.5)
`
`6.6 (2.6–9.9)
`7.2 (1.0–16.5)
`6.7 (3.7–18.6)
`7.6 (2.9–29.5)
`
`6.3 (3.3–16.1)
`6.9 (6.0–14.6)
`8.3 (2.7–10.5)
`
`
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`state artstate art
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`CNS
`
`Antineoplastic
`
`Endocrine
`
`Cardiovascular
`
`Immunologic
`
`Gastrointestinal
`
`Anti-infective
`
`Anesthetic/analgesic
`
`AIDS antivirals
`
`0
`
`6.9
`
`6.5
`
`6.5
`
`6.4
`
`5.8
`
`5.4
`
`5.3
`
`4.6
`
`8.1
`
`1.9
`
`10.0
`
`0.7
`
`7.6
`
`1.2
`
`1.3
`
`1.0
`
`2.4
`
`7.7
`
`7.8
`
`7.4
`
`8.2
`
`1.2
`
`6.6
`
`0.8
`
`6.1
`
`0.5
`
`5.1
`
`Years
`
`11
`
`Clinical phase
`
`Approval phase
`
`Figure 4 Mean clinical and approval phase times for approved new
`molecular entities and significant biologicals, 2005–2009, grouped by
`therapeutic class. Note that the anti-infective group does not include aIDS
`antivirals. CNS, central nervous system.
`
`for both priority drugs and standard drugs. Drugs belonging to
`certain therapeutic classes tend to require longer clinical devel-
`opment times than others. It is important to note that, with
`respect to priority drugs, proportionately more of the priority
`drugs approved in the later period were for AIDS antivirals and
`anesthetics/analgesics. With regard to standard drugs, for the
`period 2005–2009, proportionately fewer of the approvals were
`for analgesics/anesthetics, whereas proportionately more were
`for antineoplastic drugs and drugs for central nervous system
`(CNS)-related conditions.
`We examined in detail development and approval phase times
`for new drugs approved in the past 5 years, categorized by thera-
`peutic class. Figure 4 shows the mean durations of the clinical
`and approval phases for each of nine therapeutic classes. The
`data show substantial variability in these mean durations. The
`mean clinical phase time was 76% longer for the drug class that
`moved most slowly in the pipeline (CNS) as compared with the
`one that moved most quickly (AIDS antivirals). The total time to
`market (inclusive of approval phase durations) was, on average,
`approximately twice as long for CNS drugs as for AIDS antivi-
`rals. Table 1 gives the medians and ranges by therapeutic class
`for this period for the approval, clinical, and total phases. The
`rankings of classes by medians is somewhat different, although,
`even by this measure, AIDS antivirals were still the fastest to
`reach the market, and CNS drugs took a relatively long time
`to get to market. To provide a historical perspective on clinical
`development and approval times by therapeutic class, we show,
`in Table 2, the means and medians by class for each of the three
`previous decades.
`
`Trends in approval rates for various therapeutic
`classes of drugs
`Numerous factors can affect the decisions that determine the
`extent to which firms pursue and succeed in the development of
`drugs in various therapeutic classes. These factors include poten-
`tial development and approval times, but they also include esti-
`mates of the likelihood of approval, development-related costs,
`and potential market sizes. A full examination of these factors
`and the separate assessments of their impact on development
`
`decisions is beyond the scope of this work, but we can docu-
`ment the trends in output by therapeutic class. Figure 5 shows
`the number of drugs approved, categorized by class, in each of
`the three previous decades.
`The results show clear monotonic trends for antineoplastics and
`anti-infectives (exclusive of AIDS antivirals). The number of anti-
`neoplastics reaching the marketplace has increased substantially
`over time, with nearly five times as many approvals obtained in the
`past decade as compared with the 1980s. Conversely, the number
`of approvals for anti-infectives has steadily declined over the past
`three decades. The results are more mixed for other classes. For
`example, approvals peaked substantially for cardiovascular drugs
`during the 1990s and to a lesser extent for CNS drugs. The average
`annual rate of endocrine drug approvals was nearly constant dur-
`ing the 1990s and the 2000s; however, this represents a substantial
`increase relative to the rate during the 1980s.
`
`Development and approval times for orphan drugs
`We also examined the durations of the clinical development and
`approval phases for orphan drugs (Table 3). The mean approval
`phase time in the past decade was one half-year shorter for
`orphan drugs than for non-orphan drugs. This is to be expected,
`however, because a much higher proportion of applications for
`approval of orphan drugs obtain a priority rating from the FDA
`as compared with other categories. Eighty percent of the orphan
`drug approvals in the past decade had a priority rating, whereas
`slightly less than one-third of the non-orphan drug approvals
`had a priority rating.
`Although approval phase times tend to be shorter for orphan
`drugs, clinical phase durations are often comparable to or longer
`than those for non-orphan drugs. For the entire decade, the
`mean duration of the clinical phase was 0.8 years longer for
`orphan drugs than for non-orphan drugs. However, the picture
`is notably different for the first half of the decade as compared
`with the second half. The mean duration of the clinical phase
`was 2 years longer for orphan drugs in 2000–2004 but 0.7 years
`shorter in 2005–2009, relative to non-orphan drugs.
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`Table 2 Mean and (median) clinical and approval phase times for new molecular entities and significant biologics by therapeutic
`class, 1980–2009 by decade
`mean (median) clinical phasea
`1980–1989
`1990–1999
`2000–2009
`2.3 (2.0)
`3.9 (3.7)
`5.0 (4.5)
`aIDS antivirals
`6.2 (4.9)
`6.6 (4.8)
`4.9 (4.1)
`anesthetic/analgesic
`anti-infectiveb
`4.2 (3.5)
`5.4 (4.5)
`6.6 (5.3)
`7.4 (6.7)
`7.8 (6.2)
`7.4 (6.6)
`antineoplastic
`6.1 (4.9)
`5.8 (4.8)
`5.3 (4.5)
`Cardiovascular
`7.9 (7.3)
`7.0 (6.3)
`8.6 (7.0)
`Central nervous system
`5.6 (4.8)
`8.0 (6.7)
`6.1 (4.9)
`Endocrine
`4.9 (4.4)
`7.5 (7.5)
`6.2 (5.7)
`Gastrointestinal
`5.2 (4.0)
`8.3 (6.6)
`5.8 (6.3)
`Immunologic
`6.5 (4.8)
`7.2 (4.2)
`6.5 (7.2)
`Respiratory
`aPhase times given in years. bExcludes aIDS antivirals.
`
`mean (median) approval phasea
`1980–1989
`1990–1999
`2000–2009
`1.8 (2.1)
`0.6 (0.5)
`0.5 (0.5)
`3.0 (2.2)
`1.9 (1.2)
`1.4 (1.0)
`2.0 (1.8)
`1.8 (1.5)
`1.4 (0.9)
`2.8 (1.7)
`1.5 (1.2)
`1.0 (0.6)
`2.8 (2.6)
`2.3 (1.7)
`1.5 (1.1)
`4.3 (3.8)
`2.0 (1.7)
`1.9 (1.8)
`4.9 (3.0)
`1.1 (1.0)
`1.4 (0.9)
`2.1 (1.8)
`1.5 (1.4)
`2.0 (1.4)
`2.5 (2.2)
`1.1 (0.9)
`1.4 (1.2)
`3.5 (3.4)
`2.8 (1.9)
`1.9 (2.1)
`
`mean (median) total phasea
`1980–1989
`1990–1999
`2000–2009
`4.2 (4.7)
`4.5 (4.4)
`5.6 (5.0)
`9.2 (8.0)
`8.5 (5.9)
`6.3 (6.6)
`6.1 (5.4)
`7.2 (6.4)
`7.9 (6.9)
`10.3 (8.4)
`9.3 (7.8)
`8.3 (7.3)
`8.9 (7.8)
`8.2 (7.3)
`6.7 (6.1)
`12.2 (11.8)
`9.0 (8.6)
`10.5 (9.4)
`10.6 (12.6)
`9.1 (7.8)
`7.5 (5.8)
`7.0 (6.2)
`9.1 (8.8)
`8.2 (7.2)
`7.8 (6.3)
`9.4 (7.4)
`7.3 (7.8)
`10.0 (10.4)
`10.1 (9.2)
`8.7 (9.4)
`
`Table 3 Orphan and non-orphan approvals, 2000–2009: clinical
`and approval phase times by 5-year periods
`mean
`mean
`mean
`(median)
`(median)
`(median)
`N
`clinical
`total
`approval
`(priority/
`phasea
`phasea
`phasea
`standard)
`8.1 (6.3)
`1.0 (0.8)
`7.1 (5.2)
`60 (48/12)
`2000–2009: Orphans
`7.8 (7.0)
`1.5 (1.1)
`2000–2009: Non-orphans 191 (60/128) 6.3 (5.5)
`9.5 (7.3)
`1.3 (1.2)
`2000–2004: Orphans
`32 (24/8)
`8.2 (5.8)
`2000–2004: Non-orphans 118 (35/80)b
`7.8 (6.9)
`1.6 (1.2)
`6.2 (5.2)
`6.6 (5.6)
`0.8 (0.7)
`2005–2009: Orphans
`28 (24/4)
`5.9 (4.9)
`8.0 (7.3)
`1.4 (1.0)
`2005–2009: Non-orphans
`73 (25/48)
`6.6 (6.0)
`aPhase times given in years. bThree non-orphan approvals in 2000–2004 did not have
`therapeutic ratings.
`
`the numbers approved in previous years, with the exception of
`the mid-1990s, one may conclude that the overriding concern
`for the industry is not depressed productivity but rather an
`extant business model that is not well calibrated to today’s mar-
`ket economy. This reality will undoubtedly be a driver of change
`within the pharma sector for many years to come.
`Since the enactment of PDUFA in 1992, average approval
`phase times have generally declined, reaching their lowest 5-year
`average (1.2 years) in 2005–2009. Clinical phase times, in con-
`trast, increased in the 1990s and have remained stable at 6.4–6.6
`years through the 2000s. The results suggest that much of the
`benefit of PDUFA, in terms of faster FDA approvals, has been
`offset by longer durations of clinical development phases. On
`the other hand, the lengthening of the clinical phases in the lat-
`ter two decades can be explained by the general increase in the
`development of products in therapeutic classes that are intrinsi-
`cally associated with very long clinical development times. For
`example, as shown in Figure 5, there has been a marked increase
`in the number of CNS and antineoplastic drugs approved in the
`1990s and 2000s relative to the 1980s. These therapeutic classes
`represent the two areas requiring the longest clinical phase times
`(Figure 4). In contrast, the number of anti-infectives approved
`in each of the three decades has steadily declined. Because
`
`74
`
`52
`
`49
`
`47
`
`80
`
`60
`
`40
`
`20
`
`0
`
`1980–1989
`1990–1999
`2000–2009
`
`35
`
`25
`
`23
`
`20
`
`10
`
`4
`
`51
`
`41
`
`38
`
`30
`
`11
`
`35
`
`20
`
`27
`
`25
`
`26
`
`7
`
`11
`
`10
`
`9
`
`10 12
`
`3
`
`3
`
`18
`
`7
`
`Respiratory
`Im m unologic
`G astrointestinal
`Endocrine
`C N S
`Cardiovascular
`Antineoplastic
`Anti-infective
`Anesthetic/analgesic
`AID S antivirals
`
`Figure 5 Number of approved new molecular entities and significant
`biologicals by decade, 1980–2009, grouped by therapeutic class. CNS, central
`nervous system.
`
`State of the research-based industry and future trends
`Despite the many dire assessments about the state of the phar-
`maceutical industry in this country and of biopharmaceutical
`innovation in general, the results presented here provide rea-
`son for guarded optimism. For example, despite a decline in the
`numbers of recent approvals for new drugs relative to the mid-
`1990s, our results show that the high number of approvals in the
`mid-1990s was more of an aberration than are the lower num-
`bers now. In fact, many of the approvals of the former period
`were the result of the FDA’s cleaning out its formidable backlog
`of unapproved NDAs, as mandated by PDUFA,17 rather than
`evidence of a highly productive period in the research-based
`industry. Moreover, whereas the average number of approved
`priority products in the most recent 5-year period is similar to
`levels seen prior to 1995–1999, the number as a percentage of
`total approvals has grown to nearly 50%—the highest level seen
`over the 30-year study period.
`Nonetheless, there is justifiable concern that the number of
`products currently reaching the marketplace is too low to gen-
`erate sufficient revenue to drive innovation in an era of rapidly
`rising R&D costs.18 It is important to consider, however, that
`because the recent number of product approvals is in line with
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`
`
`
`state artstate art
`
` anti-infectives as a class require relatively short clinical develop-
`ment times, the decrease in anti-infectives in the overall sample
`tended to raise the mean length of the clinical phase.
`
`impetus of that shift in the bioinnovation landscape. Going for-
`ward, our findings will serve as a benchmark for assessing future
`performance by the research-based industry.
`
`Portfolio decision-making: drivers and impact
`How do companies decide what types of products to develop,
`and in which therapeutic areas? A variety of factors drive portfo-
`lio decisions and R&D strategy within firms. Basically, these fall
`into three categories: market opportunity, including competi-
`tive landscape and reimbursement environment; exploitable sci-
`ence and new targets; and development challenges. For example,
`treatments for neuropsychiatric disorders and cancer represent
`large and growing worldwide markets. However, in both these
`therapeutic classes, lengthy development times and high attri-
`tion rates serve as disincentives to pharmaceutical developers.
`In oncology, an explosion of scientific knowledge about cancer
`mechanisms and the relatively favorable reimbursement envi-
`ronment tend to offset the negative development challenges,
`but in the neuropsychiatric area, these offsetting factors do not
`exist. As in the cardiovascular and anti-infective drug areas,
`CNS drugs tend to enter crowded markets in which there is
`significant reimbursement pressure and generic competition.
`This explains, in part, the declining developmental activity and
`drop in new drug approvals in these therapeutic areas over the
`past decade.
`To be sure, industry portfolio decisions have clear medical and
`societal ramifications. Neuropsychiatric disorders—including
`schizophrenia, depression, and Alzheimer’s disease—and infec-
`tious diseases—in particular, those caused by antibiotic-resistant
`strains of bacteria—are areas of enormous medical need.19,20
`For example, neuropsychiatric diseases are the leading cause
`of disability in North America and Europe and constitute 40%
`of all years lost to disability.21 The cost in lost earnings attribut-
`able to psychiatric disease in the United States is estimated to
`be $200 billion per year. Yet, despite the clear and compelling
`need for newer and better medications to treat these diseases,
`there is a paucity of innovation in this area. From a developmen-
`tal standpoint, psychiatric diseases typically represent complex
`syndromes with multiple etiologies, and it is often difficult to
`measure end points. Preclinical screens are poor, and because
`the products are often used chronically, clinical studies are large
`and protocols are costly and complex.22 These are significant
`obstacles to bringing new medicines to market.
`
`Industry outlook
`The pharma industry is undergoing a seismic shift in struc-
`ture and in the strategy it uses to bring new drugs to market.
`Consolidation and partnerships, functional outsourcing rela-
`tionships, innovation networks, global drug development strate-
`gies, expansion into emerging markets, lateral integration into
`orphan and specialty pharma products, and academic alliances
`reflect new thinking aimed at achieving higher R&D efficiency
`and greater return on investment. The results presented here,
`demonstrating flat productivity, long development cycles, and
`declining investment in drugs for critical disease areas, are the
`
`CONFlICT OF INTereST
`K.I.K. is Director of the Tufts Center for the Study of Drug Development
`(Tufts CSDD) and Research Professor at Tufts University School of Medicine.
`J.a.D. is Director of Economic analysis at Tufts CSDD. Tufts CSDD is a
`nonprofit academic research center at Tufts University, Boston, Ma. Tufts
`CSDD is funded in part by unrestricted grants from pharmaceutical and
`biotechnology firms, as well as companies that provide related services (e.g.,
`contract research, consulting, and technology firms) to the research-based
`industry. The authors report no other potential conflicts of interest relevant
`to this article.
`
`© 2011 american Society for Clinical Pharmacology and Therapeutics
`
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