- Email: [email protected]
New biopharmaceuticals in the USA: trends in development and marketing approvals 1995–1999
FEATURE By using angiotensin II and III loaded alternately into the 96 wells, Foret and co-workers demonstrated the completed acquisition of mass information from the entire plate within 8 min. This means that a sample from the plate was analysed every 5 s. Although they limited their study to proteins and peptides, this system could easily be adapted for a large variety of molecules. Speed, cost, integration and automation are important factors for viable, high-throughput screening
technologies. The system developed by Foret and co-workers clearly performs well in terms of speed (~5 s per analysis). In adddition, being fabricated in polymer lowers production costs and its automation seems straightforward. Furthermore, the 96-well-plate format of the fluidic device is compatible with other 96-well-plate technologies and so be readily integrated into various high-throughput platforms. High-throughput screening is increasingly being performed using
higher-density plate formats, and so increasing the density of their samplehandling plate will be an important challenge. This article illustrates a growing trend in biotechnology towards micro- and nanofabrication, which might help to transform highthroughput screening from ‘feasible’ to ‘affordable’. Daniel Figeys MDS-Ocata, 480 University Ave, Suite 401, Toronto, ON, Canada M5G 1V2. (E-mail: [email protected])
New biopharmaceuticals in the USA: trends in development and marketing approvals 1995–1999 Janice M. Reichert The Tufts Center for the Study of Drug Development has collected data on the clinical and approval phases of the 26 new biopharmaceuticals approved by the US Food and Drug Administration between 1980 and 1999. Here, the data for biopharmaceuticals approved between 1995 and 1999 are presented grouped by product category, review status, orphandrug designation and therapeutic indication, and the mean phase lengths are compared. They are also compared with the data for approvals during the periods 1982–1989, 1990–1994 and 1996–1998.
he Tufts Center for the Study of Drug Development (CSDD) has periodically surveyed companies for information about investigated and marketed biopharmaceutical products. These data are analysed in various ways to determine trends in the development and approval processes for these products. The first published report on marketed products covered biopharmaceuticals approved by the US Food and Drug Administration (FDA) between 1982 and 1994 (Ref. 1).This article examines trends in the development and approval process for biopharmaceuticals approved for marketing in the USA between 1995 and 1999. The biopharmaceutical industry in the USA has changed dramatically since the first recombinant protein was approved for marketing in 1982. Advances in science and technology now allow scientists routinely to clone genes, to express the corresponding protein in bacterial, insect or mammalian cells, and to purify the resulting product. Human monoclonal antibodies are even produced in mice. Specific biological proteins can
T
J.M. Reichert ([email protected]) is at the Tufts Center for the Study of Drug Development, 192 South Street, Suite 550, Boston, MA 02111, USA.
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be isolated from complex mixtures in commercially viable processes. Without a favorable regulatory environment, these advances alone would not have resulted in the wealth of new biopharmaceuticals currently on the market in the USA.The Prescription Drug User Fee Act of 1992 (Ref.2) and the renewal legislation,the Food and Drug Administration Modernization Act of 1997 (Ref. 3), include provisions designed to speed the FDA’s review of applications and also to encourage the mutual cooperation of industry and the FDA during the entire clinical development and approval process.The ultimate objective of both the biopharmaceutical industry and the FDA is the timely approval for marketing of safe and effective medical products. Description of the data The CSDD maintains a database of biopharmaceutical products that have entered human clinical trials since 1980.This database includes information on the development and regulatory review of products currently in development, terminated products and FDA-approved products. It currently includes records for over 900 products from more than 350 companies.
0167-7799/00/$ – see front matter © 2000 Elsevier Science Ltd. All rights reserved. PII: S0167-7799(00)01473-6
TIBTECH SEPTEMBER 2000 (Vol. 18)
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Information about biopharmaceutical products is collected from publicly accessible sources and documents available from the FDA (Refs 4–7) (http://www.fda. gov/ope/opehome.html) and by carrying out surveys. The 1999 biopharmaceutical survey was sent to 26 companies that developed biopharmaceutical products approved by the FDA between 1995 and 1999; 18 companies (69%) responded to the survey. A new biopharmaceutical was defined as the first unique therapeutic biopharmaceutical product approved for any indication; the 26 products identified as new were all approved between 1996 and 1999. Identical products approved subsequently were not included,with the exception of the first recombinant version of an approved non-recombinant protein. For example, the recombinant human growth hormone products approved by the FDA in 1995 were not included because a recombinant human growth hormone product was already approved and marketed in the USA. However,the first recombinant version of the Factor IX protein was included. Occasionally, the FDA approves identical or virtually identical products on the same day, as was the case with Follistim and Gonal-F. Both products were included in this study because no priority order could be established.Diagnostic monoclonal antibodies, vaccines (excluding recombinant vaccines) and biopharmaceutical products approved for supplemental indications were not included. The categories of biopharmaceutical product included in this study are: recombinant proteins; therapeutic monoclonal antibodies; polyclonal antibodies; purified, naturally occurring proteins (non-recombinant); and antisense oligonucleotides. Data for the selected products were segregated in various ways: by product category; by review status; by orphan designation; and by therapeutic indication. In all cases concerning confidential information, if the segregation resulted in a category containing only a single product, the values are not shown. For this study, the following definitions were used. (1) The clinical phase was deemed to last from the date of the investigational new drug (IND) application filing to the date of submission of the biologics license application (BLA) or new drug application (NDA). (2) The approval phase was deemed to last from the date of BLA or NDA submission to FDA approval. (3) The total phase was deemed to last from the date of the IND filing to FDA approval (i.e. the sum of the clinical and approval phases). (4) The unit of time selected was months, with one month defined as 30.4 days. Most of the products selected for the study followed a USA-based development timeline.That is, the sponsoring company filed an IND with either of the two FDA centers that review biopharmaceutical product applications [the Center for Biologics Evaluation and Research (CBER),and the Center for Drug Evaluation and Research (CDER)], clinical trials of the product (Phases I, II and III or a combination of these) were done and then a BLA or NDA was submitted and subsequently approved. Eight of the products selected for the study did not follow this development timeline however.Alternate timelines were caused by three main factors: TIBTECH SEPTEMBER 2000 (Vol. 18)
(1) the initiation of development overseas, resulting in the start of clinical trials before an IND was filed; (2) the completion of clinical development overseas, so that either no IND was filed or there were no clinical trials done after the IND was filed; and (3) multiple INDs were filed because an initial IND was filed by an independent investigator and the sponsoring company required a subsequent IND filing to continue clinical trials of the product for the same indication. For these products, the clinical phase was calculated from the earliest development date available (earliest IND submission or clinical-phase start date) to the date of BLA or NDA submission. New biopharmaceuticals approved between 1995 and 1999 The new biopharmaceutical products included in our analysis are listed in Table 1. Of the 26 products, 15 were recombinant proteins, six were monoclonal antibodies, two were polyclonal antibodies, two were nonrecombinant proteins and one was an antisense oligonucleotide.Most of the products (58% of the total) were recombinant proteins. Eleven new products were approved in 1998, which is, to date, the largest number of biopharmaceutical products approved in one year.A total of 15 of the products were given priority review status. Orphan-drug designation was given to 12 of the products. The Center for Biologics Evaluation and Research approved 19 of the products for marketing, with the remaining seven being approved by the Center for Drug Evaluation and Research. Comparison of by product category The mean phase lengths for all of the 26 products and for the individual product categories are shown in Fig.1 (the result for the antisense-oligonucleotide category was excluded because there was only one product in the category). Polyclonal antibodies had the shortest mean clinical-phase length and the non-recombinant proteins had the longest. The mean clinical-phase length of the recombinant proteins and monoclonal antibodies were roughly equivalent, with a difference of only five months between the two product categories. There was a marked difference between the mean lengths of the approval phases when the products were compared by category. However, the difference was probably caused by the review status of the product (i.e. standard or priority) rather than the product category. The polyclonal-antibody products, both of which had standard review status, had the longest mean approval phase. By comparison, all of the monoclonal-antibody products had priority review status and also had the shortest mean approval phase. Between the two extremes were the non-recombinant proteins (50% priority products, mean approval phase 14.5 months) and the recombinant proteins (47% priority products,mean approval phase 16.7 months). The mean total phase for all 26 biopharmaceuticals was 73.3 months. Recombinant and non-recombinant proteins had longer mean total phase lengths than the overall average (78.3 and 84.1 months, respectively), longer than either the monoclonal or polyclonal antibody products. Despite having a shorter clinical phase,
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Table 1. New biopharmaceutical products approved by the FDA during 1995–1999 a Trade name
Generic name
Company
NDA Approval submission date date
Approval Review Rating phase center (mo.)
Orphan drug
Avonex Humalog Retavase Benefix Follistim Gonal-F Infergen Neumega Regranex Refludan
Interferon beta-1A Insulin Lispro Reteplase Factor IX Follitropin beta Follitropin alpha Interferon alphacon-1 Opreleukin Becaplermin Lepirudin
22/05/95 14/03/95 30/06/95 05/09/96 10/01/96 14/09/93 13/04/96 20/12/96 16/12/96 31/12/96
17/05/96 14/06/96 30/10/96 11/02/97 29/09/97 29/09/97 06/10/97 25/11/97 16/12/97 06/03/98
11.9 15.0 16.0 5.2 20.6 48.5 17.8 11.2 12.0 14.1
CBER CDER CBER CBER CDER CDER CBER CBER CBER CDER
P S S P S S S S S P
Y N N Y N N N Y N Y
Glucagen Enbrel Lymerix Ontak Novoseven
Glucagon Etanercept OSP-A Denileukin diftitox Factor VIIA
Biogen Eli Lilly Boeringher Mannheim Genetics Institute Organon Serono Amgen Genetics Institute R.W. Johnson Hoechst Marion Roussel Novo Nordisk Immunex SmithKline Beecham Seragen Novo Nordisk
18/09/97 08/05/98 15/09/97 09/12/97 10/05/96
22/06/98 02/11/98 21/12/98 05/02/99 25/03/99
9.1 5.8 15.2 13.9 34.5
CDER CBER CBER CBER CBER
P P S P P
N N N Y Y
Rituximab Dacliximab Basiliximab Palivizumab Infliximab Trastuzumab
Idec/Genentech Hoffman-La Roche Novartis Medimmune Centocor Genentech
28/02/97 10/06/97 12/11/97 19/12/97 30/12/97 04/05/98
26/11/97 10/12/97 12/05/98 19/06/98 24/08/98 25/09/98
8.9 6.0 6.0 6.0 7.8 4.7
CBER CBER CBER CBER CBER CBER
P P P P P P
Y Y Y N Y N
RSV immunoglobulin Medimmune Thymoglobulin Sangstat
17/02/93 17/01/97
18/01/96 30/12/98
35.0 23.4
CBER CBER
S S
Y N
Sacrosidase Interferon alpha-N1
Orphan Medical Glaxo Wellcome
06/05/97 30/09/97
09/04/98 25/03/99
11.1 17.8
CDER CBER
P S
Y N
Formivirsen
ISIS Pharmaceuticals 09/04/98
26/08/98
4.6
CDER
P
N
Recombinant proteins
Monoclonal antibodies Rituxan Zenapax Simulect Synagis Remicade Herceptin Polyclonal antibodies Respigam Thymoglobulin Non-recombinant proteins Sucraid Wellferon Antisense oligonucleotide Vitravene
aAbbreviations: CBER, Center for Biological Evaluation and Research; CDER, Center for Drug Biological Evaluation and Research; FDA, US Food and Drug administration; NDA, New drug application; N, no; P, priority review; S, standard review; Y, yes.
the mean total phase for polyclonal antibodies was similar to that for monoclonal antibodies (63.5 and 63.1 months,respectively).This was caused by the much longer approval phase required for the polyclonal antibodies. The effects of orphan and priority classifications on phase lengths The data for all 26 of the biopharmaceuticals selected for study were sorted by review status and by orphandrug designation. Priority review products, as defined by both CBER and CDER, are those products that, if approved, would provide a significant improvement in the safety or effectiveness of the treatment, diagnosis or prevention of a serious or life-threatening disease. The definition is expanded by CDER to include products that, if approved, would provide a significant
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improvement in the safety or effectiveness of the treatment, diagnosis or prevention of a non-serious disease. Priority review status was expected to have an effect on the approval phase and, indeed, products with priority review status had a substantially shorter approval phase (53% shorter than standard products;Table 2).Nonetheless, because the mean clinical phase of the priority products was longer than that for the standard products, the mean total phase lengths were similar. Orphan-drug designation is given for diseases that are rare (less than 200 000 cases per annum in the USA). This designation alone was not associated with a marked effect on any phase of development (Table 3). There was no effect observed when the data were subanalysed by the major product categories: there was little difference in phase lengths when data for nonorphan and orphan recombinant proteins were compared, TIBTECH SEPTEMBER 2000 (Vol. 18)
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Products approved for specific therapeutic indications The 26 biopharmaceutical products were also sorted by therapeutic indication (Fig. 2). Of the 26 products, 23 could be put into a total of six groups containing a minimum of two products. The other three products had therapeutic indications that were unique for that product and were not included in the analysis. The mean clinical and approval phase lengths for the 23 products were 57.0 months and 15.3 months, respectively, which is similar to the mean clinical and approval phase lengths for all 26 products (58.6 months and 14.7 months, respectively). The six anti-infective agents had the shortest average clinical phase (just over 48 months) and the two gastrointestinal agents (with a mean time of 75.4 months) had the longest clinical phase. Compared with the mean clinical phase for all 23 products, the endocrine agents and immunologic agents required less time (1.9 and 5.2 months shorter,respectively),and the antineoplastic agents and hemostasis agents required more time (3.1 and 5.6 months longer, respectively). The variation observed in the approval phase lengths was most probably caused by the review status of the products and so was not a direct function of the therapeutic indication of the products.For example,the antineoplastic agents and the gastrointestinal agents (with mean approval phase lengths of 9.2 and 9.4 months, respectively) had priority review status. By contrast, the endocrine agents had standard reviewed status and required an average of 23.3 months for the approval process. The remaining three categories had mean approval phase lengths between the extremes; priority-reviewed products made up between onethird and two-thirds of the total number of products in each of these categories. In summary, getting through the clinical phase quickly did not guarantee speed to market because of the variation in approval phase length. For example, the anti-infective agents, despite having the fastest mean clinical phase, had a longer total phase than the immunologic agents.A similar reversal in phase-length order occurred between the antineoplastic agents and the endocrine agents: the endocrine agents, on average, completed the clinical phase five months faster than the TIBTECH SEPTEMBER 2000 (Vol. 18)
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All products (n = 26) rDNA (n = 15) Mab (n = 6) Pab (n = 2) Non-rDNA (n = 2)
84 Time (months)
nor when data for non-orphan and orphan monoclonal antibodies were compared.Review status was expected to have an effect on the approval phase and, indeed, orphan-designated products with priority reviews had approval phases about half as long as those of the orphan-designated products with standard reviews (11.9 months and 23.1 months, respectively). However, orphan-drug designation was associated with longer approval phases when the data were subanalysed specifically by priority review status.Thus,priority-reviewed, orphan-designated products had a mean approval phase that was nearly twice as long as that of the priority-reviewed, non-orphan products (11.9 months and 6.0 months, respectively). Similar subanalysis for the standard-reviewed products did not reveal a notable effect on the approval phase that was due to orphan designation. Neither subanalysis by review status revealed a notable effect on the clinical or total phase lengths.
72
69.6
84.1 78.3 73.3 63.1 63.5
61.5
60
58.6
56.5
48 36
34.3 29.2
24 14.7
16.7
12
14.5 6.6
0 Clinical phase
Approval phase Development phase
Total phase trends in Biotechnology
Figure 1 Mean phase lengths for biopharmaceutical product types approved 1995–1999. Abbreviations: Mab, monoclonal antibody; Pab, polyclonal antibody; rDNA, recombinant proteins.
antineoplastic agents but their mean total phase length was 9.1 months longer than that of the antineoplastic agents. Biopharmaceutical products approved between 1996 and 1998 The data was subanalysed by approval years 1996–1998 so that the results could be directly compared with similar results for new chemical entities (NCEs) recently reported by Kaitin and Healy8. For NCEs approved between 1996 and 1998,the mean total phase was 87.1 months. During the same period, the mean total phase for biopharmaceuticals was 70.8 months. Thus, even though the time required for clinical development and approval for biopharmaceutical products
Table 2. Comparison of mean phase lengths for standard and priority-reviewed biopharmaceutical products approved 1995–1999 Review status
Mean clinical phase (months)
Mean approval phase (months)
Mean total phase (months)
Standard (n 5 11)
52.7
21.1
73.8
Priority (n 5 15)
63.0
10.0
73.0
Table 3. Comparison of mean phase lengths for non-orphan and orphan-designated biopharmaceutical products approved 1995–1999 Orphan designation Clinical phase Approval phase Total phase (months) (months) (months) Non-orphan (n = 14) 58.7
15.5
74.2
Orphan (n = 12)
13.8
72.3
58.5
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96
Anti-infective (n = 6) Anti-neoplastic (n = 3) Endocrine (n = 4) Gastrointestinal (n = 2) Hemostasis (n = 5) Immunologic (n = 3)
84 Time (months)
75.4
72 62.6
60.1
60
84.8 78.8
78.4 69.3 64.4
63.6
55.1 51.8
48
48.4
36 23.3
24
16.2
16.0
12
9.2
9.4
11.8
0 Clinical phase
Approval phase Development phase
Total phase trends in Biotechnology
Figure 2 Comparison of biopharmaceutical products approved 1995–1999 for specific therapeutic indications.
has increased over the years, biopharmaceuticals still go through the process faster than conventional drugs. Priority-reviewed NCEs had a significantly shorter (38%) mean approval phase compared with standardreviewed NCEs (Ref. 8). A similar reduction of even greater magnitude (64%) was observed for the priorityreviewed biopharmaceuticals.NCEs with orphan-drug designation approved between 1996 and 1998 had longer mean clinical and approval phases than the average for all NCEs (Ref. 8) (by 23% and 42%, respectively). By contrast, the mean clinical and approval phases for all of the approved orphan-drug-designated biopharmaceuticals were slightly shorter (by 5% and 16%, respectively) than the average for all 26 products.The shorter mean approval phase was most probably caused by the priority review status of the products (80% of the orphan-drug products were priority reviewed). 96
rDNA 1982-1994 (n = 16) rDNA 1995-1999 (n = 15) Mab 1982-1994 (n = 2) Mab 1995-1999 (n = 6)
Time (months)
84
82.0 78.3
72 63.1
61.5 62.8
60
56.9
56.5
48 39.4
36 24
17.5 16.7
12
19.3
6.6
0 Clinical phase
Approval phase Development phase
Total phase trends in Biotechnology
Figure 3 Comparison of biopharmaceutical product categories approved during three time periods. Abbreviations: Mab, monoclonal antibody; rDNA, recombinant proteins.
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The mean phases for products for three therapeutic indications could be compared directly. The clinical phases of anti-infective agents (not including AIDS antivirals), antineoplastic and endocrine agents were all longer for NCEs than for biopharmaceuticals. The approval phase for NCEs for only one indication (endocrine agents) was shorter than for the biopharmaceuticals. Overall, the NCEs required longer total phases for all three indications (24% longer for antiinfective agents, 40% longer for antineoplastic agents and 36% longer for endocrine agents) than did the biopharmaceuticals. Products approved between 1982 and 1994, and between 1995 and 1999 To assess the trends in biopharmaceutical product development over time, mean phase lengths of two categories of biopharmaceutical products approved between 1982 and 1994 were compared with the same product categories approved between 1995 and 1999 (Fig. 3). Recombinant proteins and therapeutic monoclonal antibodies were selected for this comparison because these products constituted the majority (21 of 26 products) of the products approved between 1995 and 1999. Recombinant proteins approved between 1995 and 1999 had a substantially longer (by 56%) mean clinical phase than recombinant proteins that were developed between 1982 and 1994. By contrast, the mean clinical phase length for therapeutic monoclonal-antibody products approved between 1995 and 1999 was 10% shorter than for products in the same category approved between 1982 and 1994.There was only a minor difference (~24 days) between the mean approval phase lengths for recombinant-protein products approved during the two time periods. Thus, the difference in the mean total phase remained relatively large (21.4 months). The therapeutic monoclonal-antibody products were approved very quickly betwen 1995 and 1999, with a mean approval phase length of only 6.6 months.The speed of the approval phase helped to increase the difference between the mean total phase lengths of the therapeutic monoclonal-antibody products approved during the two time periods. Several trends were apparent when the data for all new biopharmaceutical product approvals were compared in the three time periods 1982–1989 (Ref. 1), 1990–1994 (Ref. 1) and 1995–1999 (Table 4). First, the total number of approvals in each time period has increased dramatically. Second, the mean length of the approval phase has consistently decreased.Third,the mean length of the clinical and the total phases have consistently increased. Conclusions The biotechnology industry has grown substantially since the first recombinant protein was approved in 1982.Advances in chemistry and biology have yielded a wealth of information about human biological systems.This information has provided biotechnology companies with a vast number of potential new ways to intervene in disease states.As larger numbers of new biopharmaceuticals progress through the discovery and development phases, more are getting through the approval phase. Between 1995 and 1999, the FDA TIBTECH SEPTEMBER 2000 (Vol. 18)
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approved 26 new biopharmaceutical products,the most products approved in any five-year period to date. The two most notable trends evident from the data were: (1) the remarkable decrease in the mean length of the approval phase for the priority-reviewed products compared with the standard-reviewed products; and (2) the consistent increase in the total phase length for biopharmaceuticals over three time periods despite the consistent decreases in the mean approval phase length. The decrease observed in the mean length of the approval phases of the priority products was most probably due to the influence of the performance goals set in the relevant Acts2,3. Performance goals for the fiscal years 1997 and 1998 included for the first time a sixmonth review time for 90% of the initial priority NDAs and BLAs submitted (resubmissions are not included); 12 of the 15 NDAs and BLAs for priority-reviewed products included in this study were initially submitted during fiscal years 1997 and 1998. The performance goal for initial submissions for standard-review NDAs and BLAs for fiscal years 1997 and 1998 was a 12 month review time.The twofold difference between the goals for the review times is reflected in the observed difference between the mean approval times of priorityreview and standard-review products (10.0 months vs 21.1 months, respectively). Mean approval phase length as defined in this study included resubmission times and sponsor-response times, and so the observed phases are longer than those dictated by the performance goals. The mean length of the clinical phase for biopharmaceuticals, particularly recombinant proteins, has consistently increased over time and this could be caused by several factors.The technology currently used to manufacture and characterize biopharmaceutical products is more sophisticated than that used in the 1980s and early 1990s. In addition, biopharmaceuticals are being developed for therapeutic indications that are increasingly complex.The additional complexity of the disease interventions and the technology used to make biopharmaceuticals might have contributed to the observed clinical-phase-length increase for the biopharmaceutical products approved between 1995 and 1999 compared with the products approved between 1982 and 1994. As the biotechnology industry and the FDA gained experience with the unique development issues associated with biopharmaceuticals, higher standards for product characterization and the demonstration of safety and efficacy might have been applied to the newer products. In addition, companies might be taking time to prepare for launching products globally: 67% of the products selected for this study were also approved in the European Union between 1995 and 1999.These factors might also have contributed to the observed increase in the mean length of the clinical phase for the biopharmaceutical products. It remains to be seen whether the trends reported here will continue into the future. The significant reduction in the mean length of the approval phase for priority-reviewed products is encouraging but longer clinical phases are leading to longer total phases. The biopharmaceutical industry must work together with TIBTECH SEPTEMBER 2000 (Vol. 18)
Table 4. Number of new biopharmaceuticals approved by the FDA during three time periods and comparison of mean phase lengths for the products Time period
Total number of approvals
Clinical phase (months)
Approval phase (months)
Total phase (months)
1982–1989
14
32.7
24.0
53.2
1990–1994
15
46.5
21.3
67.8
1995–1999
26
58.6
14.7
73.3
the FDA to shorten the time required to complete clinical trials so that public access to effective biopharmaceutical medicines is provided in a timely manner. Supplementary material A table of the median values and ranges of the major categories (n .5) of biopharmaceuticals is available upon request. Acknowledgments I gratefully acknowledge the companies that provided data for this study and thank the people who completed the survey. Special thanks go to E. Healy for maintaining the biopharmaceuticals database and colleagues at CSDD for comments and suggestions on the manuscript. References 1 Gosse, M.E. and Manocchia, M. (1996) First biopharmaceuticals approved in the U.S.: 1980–1994. Drug Inf. J. 30, 991–1001 2 Prescription Drug User Fee Act of 1992. US Public Law 102-571 (1992 Oct 29); 21 USC 379; 106 Stat 4491 3 Food and Drug Administration Modernization Act of 1997. US Public Law 105-115 (1997 Nov 21); 21 USC 355a; 111 Stat 2296 4 Fourth Annual Performance Report: Prescription Drug User Fee Act of 1992. FY 1996 Performance Report to Congress (Dec 1996), US Food and Drug Administration, Rockville, MD, USA 5 Final Performance Report: Prescription Drug User Fee Act of 1992. Fiscal Year 1997 Report to Congress (Dec 1997), US Food and Drug Administration, Rockville, MD, USA 6 FY 1998 Performance Report to Congress for the Prescription Drug User Fee Act of 1992 as Amended by the Food and Drug Administration Modernization Act of 1997, US Food and Drug Administration, Rockville, MD, USA 7 FY 1999 Performance Report to Congress for the Prescription Drug User Fee Act of 1992 as Reauthorized and Amended by the Food and Drug Administration Modernization Act of 1997, US Food and Drug Administration, Rockville, MD, USA 8 Kaitin, K.I. and Healy, E.M. (2000) The new drug approvals of 1996, 1997 and 1998: drug development trends in the user fee era. Drug Inf. J. 34, 1–14
Letters to the Editor Trends in Biotechnology welcomes correspondence that are of interest to the biotechnology community. Please send letters to: [email protected]
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technologies. The system developed by Foret and co-workers clearly performs well in terms of speed (~5 s per analysis). In adddition, being fabricated in polymer lowers production costs and its automation seems straightforward. Furthermore, the 96-well-plate format of the fluidic device is compatible with other 96-well-plate technologies and so be readily integrated into various high-throughput platforms. High-throughput screening is increasingly being performed using
higher-density plate formats, and so increasing the density of their samplehandling plate will be an important challenge. This article illustrates a growing trend in biotechnology towards micro- and nanofabrication, which might help to transform highthroughput screening from ‘feasible’ to ‘affordable’. Daniel Figeys MDS-Ocata, 480 University Ave, Suite 401, Toronto, ON, Canada M5G 1V2. (E-mail: [email protected])
New biopharmaceuticals in the USA: trends in development and marketing approvals 1995–1999 Janice M. Reichert The Tufts Center for the Study of Drug Development has collected data on the clinical and approval phases of the 26 new biopharmaceuticals approved by the US Food and Drug Administration between 1980 and 1999. Here, the data for biopharmaceuticals approved between 1995 and 1999 are presented grouped by product category, review status, orphandrug designation and therapeutic indication, and the mean phase lengths are compared. They are also compared with the data for approvals during the periods 1982–1989, 1990–1994 and 1996–1998.
he Tufts Center for the Study of Drug Development (CSDD) has periodically surveyed companies for information about investigated and marketed biopharmaceutical products. These data are analysed in various ways to determine trends in the development and approval processes for these products. The first published report on marketed products covered biopharmaceuticals approved by the US Food and Drug Administration (FDA) between 1982 and 1994 (Ref. 1).This article examines trends in the development and approval process for biopharmaceuticals approved for marketing in the USA between 1995 and 1999. The biopharmaceutical industry in the USA has changed dramatically since the first recombinant protein was approved for marketing in 1982. Advances in science and technology now allow scientists routinely to clone genes, to express the corresponding protein in bacterial, insect or mammalian cells, and to purify the resulting product. Human monoclonal antibodies are even produced in mice. Specific biological proteins can
T
J.M. Reichert ([email protected]) is at the Tufts Center for the Study of Drug Development, 192 South Street, Suite 550, Boston, MA 02111, USA.
364
be isolated from complex mixtures in commercially viable processes. Without a favorable regulatory environment, these advances alone would not have resulted in the wealth of new biopharmaceuticals currently on the market in the USA.The Prescription Drug User Fee Act of 1992 (Ref.2) and the renewal legislation,the Food and Drug Administration Modernization Act of 1997 (Ref. 3), include provisions designed to speed the FDA’s review of applications and also to encourage the mutual cooperation of industry and the FDA during the entire clinical development and approval process.The ultimate objective of both the biopharmaceutical industry and the FDA is the timely approval for marketing of safe and effective medical products. Description of the data The CSDD maintains a database of biopharmaceutical products that have entered human clinical trials since 1980.This database includes information on the development and regulatory review of products currently in development, terminated products and FDA-approved products. It currently includes records for over 900 products from more than 350 companies.
0167-7799/00/$ – see front matter © 2000 Elsevier Science Ltd. All rights reserved. PII: S0167-7799(00)01473-6
TIBTECH SEPTEMBER 2000 (Vol. 18)
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Information about biopharmaceutical products is collected from publicly accessible sources and documents available from the FDA (Refs 4–7) (http://www.fda. gov/ope/opehome.html) and by carrying out surveys. The 1999 biopharmaceutical survey was sent to 26 companies that developed biopharmaceutical products approved by the FDA between 1995 and 1999; 18 companies (69%) responded to the survey. A new biopharmaceutical was defined as the first unique therapeutic biopharmaceutical product approved for any indication; the 26 products identified as new were all approved between 1996 and 1999. Identical products approved subsequently were not included,with the exception of the first recombinant version of an approved non-recombinant protein. For example, the recombinant human growth hormone products approved by the FDA in 1995 were not included because a recombinant human growth hormone product was already approved and marketed in the USA. However,the first recombinant version of the Factor IX protein was included. Occasionally, the FDA approves identical or virtually identical products on the same day, as was the case with Follistim and Gonal-F. Both products were included in this study because no priority order could be established.Diagnostic monoclonal antibodies, vaccines (excluding recombinant vaccines) and biopharmaceutical products approved for supplemental indications were not included. The categories of biopharmaceutical product included in this study are: recombinant proteins; therapeutic monoclonal antibodies; polyclonal antibodies; purified, naturally occurring proteins (non-recombinant); and antisense oligonucleotides. Data for the selected products were segregated in various ways: by product category; by review status; by orphan designation; and by therapeutic indication. In all cases concerning confidential information, if the segregation resulted in a category containing only a single product, the values are not shown. For this study, the following definitions were used. (1) The clinical phase was deemed to last from the date of the investigational new drug (IND) application filing to the date of submission of the biologics license application (BLA) or new drug application (NDA). (2) The approval phase was deemed to last from the date of BLA or NDA submission to FDA approval. (3) The total phase was deemed to last from the date of the IND filing to FDA approval (i.e. the sum of the clinical and approval phases). (4) The unit of time selected was months, with one month defined as 30.4 days. Most of the products selected for the study followed a USA-based development timeline.That is, the sponsoring company filed an IND with either of the two FDA centers that review biopharmaceutical product applications [the Center for Biologics Evaluation and Research (CBER),and the Center for Drug Evaluation and Research (CDER)], clinical trials of the product (Phases I, II and III or a combination of these) were done and then a BLA or NDA was submitted and subsequently approved. Eight of the products selected for the study did not follow this development timeline however.Alternate timelines were caused by three main factors: TIBTECH SEPTEMBER 2000 (Vol. 18)
(1) the initiation of development overseas, resulting in the start of clinical trials before an IND was filed; (2) the completion of clinical development overseas, so that either no IND was filed or there were no clinical trials done after the IND was filed; and (3) multiple INDs were filed because an initial IND was filed by an independent investigator and the sponsoring company required a subsequent IND filing to continue clinical trials of the product for the same indication. For these products, the clinical phase was calculated from the earliest development date available (earliest IND submission or clinical-phase start date) to the date of BLA or NDA submission. New biopharmaceuticals approved between 1995 and 1999 The new biopharmaceutical products included in our analysis are listed in Table 1. Of the 26 products, 15 were recombinant proteins, six were monoclonal antibodies, two were polyclonal antibodies, two were nonrecombinant proteins and one was an antisense oligonucleotide.Most of the products (58% of the total) were recombinant proteins. Eleven new products were approved in 1998, which is, to date, the largest number of biopharmaceutical products approved in one year.A total of 15 of the products were given priority review status. Orphan-drug designation was given to 12 of the products. The Center for Biologics Evaluation and Research approved 19 of the products for marketing, with the remaining seven being approved by the Center for Drug Evaluation and Research. Comparison of by product category The mean phase lengths for all of the 26 products and for the individual product categories are shown in Fig.1 (the result for the antisense-oligonucleotide category was excluded because there was only one product in the category). Polyclonal antibodies had the shortest mean clinical-phase length and the non-recombinant proteins had the longest. The mean clinical-phase length of the recombinant proteins and monoclonal antibodies were roughly equivalent, with a difference of only five months between the two product categories. There was a marked difference between the mean lengths of the approval phases when the products were compared by category. However, the difference was probably caused by the review status of the product (i.e. standard or priority) rather than the product category. The polyclonal-antibody products, both of which had standard review status, had the longest mean approval phase. By comparison, all of the monoclonal-antibody products had priority review status and also had the shortest mean approval phase. Between the two extremes were the non-recombinant proteins (50% priority products, mean approval phase 14.5 months) and the recombinant proteins (47% priority products,mean approval phase 16.7 months). The mean total phase for all 26 biopharmaceuticals was 73.3 months. Recombinant and non-recombinant proteins had longer mean total phase lengths than the overall average (78.3 and 84.1 months, respectively), longer than either the monoclonal or polyclonal antibody products. Despite having a shorter clinical phase,
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FEATURE
Table 1. New biopharmaceutical products approved by the FDA during 1995–1999 a Trade name
Generic name
Company
NDA Approval submission date date
Approval Review Rating phase center (mo.)
Orphan drug
Avonex Humalog Retavase Benefix Follistim Gonal-F Infergen Neumega Regranex Refludan
Interferon beta-1A Insulin Lispro Reteplase Factor IX Follitropin beta Follitropin alpha Interferon alphacon-1 Opreleukin Becaplermin Lepirudin
22/05/95 14/03/95 30/06/95 05/09/96 10/01/96 14/09/93 13/04/96 20/12/96 16/12/96 31/12/96
17/05/96 14/06/96 30/10/96 11/02/97 29/09/97 29/09/97 06/10/97 25/11/97 16/12/97 06/03/98
11.9 15.0 16.0 5.2 20.6 48.5 17.8 11.2 12.0 14.1
CBER CDER CBER CBER CDER CDER CBER CBER CBER CDER
P S S P S S S S S P
Y N N Y N N N Y N Y
Glucagen Enbrel Lymerix Ontak Novoseven
Glucagon Etanercept OSP-A Denileukin diftitox Factor VIIA
Biogen Eli Lilly Boeringher Mannheim Genetics Institute Organon Serono Amgen Genetics Institute R.W. Johnson Hoechst Marion Roussel Novo Nordisk Immunex SmithKline Beecham Seragen Novo Nordisk
18/09/97 08/05/98 15/09/97 09/12/97 10/05/96
22/06/98 02/11/98 21/12/98 05/02/99 25/03/99
9.1 5.8 15.2 13.9 34.5
CDER CBER CBER CBER CBER
P P S P P
N N N Y Y
Rituximab Dacliximab Basiliximab Palivizumab Infliximab Trastuzumab
Idec/Genentech Hoffman-La Roche Novartis Medimmune Centocor Genentech
28/02/97 10/06/97 12/11/97 19/12/97 30/12/97 04/05/98
26/11/97 10/12/97 12/05/98 19/06/98 24/08/98 25/09/98
8.9 6.0 6.0 6.0 7.8 4.7
CBER CBER CBER CBER CBER CBER
P P P P P P
Y Y Y N Y N
RSV immunoglobulin Medimmune Thymoglobulin Sangstat
17/02/93 17/01/97
18/01/96 30/12/98
35.0 23.4
CBER CBER
S S
Y N
Sacrosidase Interferon alpha-N1
Orphan Medical Glaxo Wellcome
06/05/97 30/09/97
09/04/98 25/03/99
11.1 17.8
CDER CBER
P S
Y N
Formivirsen
ISIS Pharmaceuticals 09/04/98
26/08/98
4.6
CDER
P
N
Recombinant proteins
Monoclonal antibodies Rituxan Zenapax Simulect Synagis Remicade Herceptin Polyclonal antibodies Respigam Thymoglobulin Non-recombinant proteins Sucraid Wellferon Antisense oligonucleotide Vitravene
aAbbreviations: CBER, Center for Biological Evaluation and Research; CDER, Center for Drug Biological Evaluation and Research; FDA, US Food and Drug administration; NDA, New drug application; N, no; P, priority review; S, standard review; Y, yes.
the mean total phase for polyclonal antibodies was similar to that for monoclonal antibodies (63.5 and 63.1 months,respectively).This was caused by the much longer approval phase required for the polyclonal antibodies. The effects of orphan and priority classifications on phase lengths The data for all 26 of the biopharmaceuticals selected for study were sorted by review status and by orphandrug designation. Priority review products, as defined by both CBER and CDER, are those products that, if approved, would provide a significant improvement in the safety or effectiveness of the treatment, diagnosis or prevention of a serious or life-threatening disease. The definition is expanded by CDER to include products that, if approved, would provide a significant
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improvement in the safety or effectiveness of the treatment, diagnosis or prevention of a non-serious disease. Priority review status was expected to have an effect on the approval phase and, indeed, products with priority review status had a substantially shorter approval phase (53% shorter than standard products;Table 2).Nonetheless, because the mean clinical phase of the priority products was longer than that for the standard products, the mean total phase lengths were similar. Orphan-drug designation is given for diseases that are rare (less than 200 000 cases per annum in the USA). This designation alone was not associated with a marked effect on any phase of development (Table 3). There was no effect observed when the data were subanalysed by the major product categories: there was little difference in phase lengths when data for nonorphan and orphan recombinant proteins were compared, TIBTECH SEPTEMBER 2000 (Vol. 18)
FEATURE
Products approved for specific therapeutic indications The 26 biopharmaceutical products were also sorted by therapeutic indication (Fig. 2). Of the 26 products, 23 could be put into a total of six groups containing a minimum of two products. The other three products had therapeutic indications that were unique for that product and were not included in the analysis. The mean clinical and approval phase lengths for the 23 products were 57.0 months and 15.3 months, respectively, which is similar to the mean clinical and approval phase lengths for all 26 products (58.6 months and 14.7 months, respectively). The six anti-infective agents had the shortest average clinical phase (just over 48 months) and the two gastrointestinal agents (with a mean time of 75.4 months) had the longest clinical phase. Compared with the mean clinical phase for all 23 products, the endocrine agents and immunologic agents required less time (1.9 and 5.2 months shorter,respectively),and the antineoplastic agents and hemostasis agents required more time (3.1 and 5.6 months longer, respectively). The variation observed in the approval phase lengths was most probably caused by the review status of the products and so was not a direct function of the therapeutic indication of the products.For example,the antineoplastic agents and the gastrointestinal agents (with mean approval phase lengths of 9.2 and 9.4 months, respectively) had priority review status. By contrast, the endocrine agents had standard reviewed status and required an average of 23.3 months for the approval process. The remaining three categories had mean approval phase lengths between the extremes; priority-reviewed products made up between onethird and two-thirds of the total number of products in each of these categories. In summary, getting through the clinical phase quickly did not guarantee speed to market because of the variation in approval phase length. For example, the anti-infective agents, despite having the fastest mean clinical phase, had a longer total phase than the immunologic agents.A similar reversal in phase-length order occurred between the antineoplastic agents and the endocrine agents: the endocrine agents, on average, completed the clinical phase five months faster than the TIBTECH SEPTEMBER 2000 (Vol. 18)
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All products (n = 26) rDNA (n = 15) Mab (n = 6) Pab (n = 2) Non-rDNA (n = 2)
84 Time (months)
nor when data for non-orphan and orphan monoclonal antibodies were compared.Review status was expected to have an effect on the approval phase and, indeed, orphan-designated products with priority reviews had approval phases about half as long as those of the orphan-designated products with standard reviews (11.9 months and 23.1 months, respectively). However, orphan-drug designation was associated with longer approval phases when the data were subanalysed specifically by priority review status.Thus,priority-reviewed, orphan-designated products had a mean approval phase that was nearly twice as long as that of the priority-reviewed, non-orphan products (11.9 months and 6.0 months, respectively). Similar subanalysis for the standard-reviewed products did not reveal a notable effect on the approval phase that was due to orphan designation. Neither subanalysis by review status revealed a notable effect on the clinical or total phase lengths.
72
69.6
84.1 78.3 73.3 63.1 63.5
61.5
60
58.6
56.5
48 36
34.3 29.2
24 14.7
16.7
12
14.5 6.6
0 Clinical phase
Approval phase Development phase
Total phase trends in Biotechnology
Figure 1 Mean phase lengths for biopharmaceutical product types approved 1995–1999. Abbreviations: Mab, monoclonal antibody; Pab, polyclonal antibody; rDNA, recombinant proteins.
antineoplastic agents but their mean total phase length was 9.1 months longer than that of the antineoplastic agents. Biopharmaceutical products approved between 1996 and 1998 The data was subanalysed by approval years 1996–1998 so that the results could be directly compared with similar results for new chemical entities (NCEs) recently reported by Kaitin and Healy8. For NCEs approved between 1996 and 1998,the mean total phase was 87.1 months. During the same period, the mean total phase for biopharmaceuticals was 70.8 months. Thus, even though the time required for clinical development and approval for biopharmaceutical products
Table 2. Comparison of mean phase lengths for standard and priority-reviewed biopharmaceutical products approved 1995–1999 Review status
Mean clinical phase (months)
Mean approval phase (months)
Mean total phase (months)
Standard (n 5 11)
52.7
21.1
73.8
Priority (n 5 15)
63.0
10.0
73.0
Table 3. Comparison of mean phase lengths for non-orphan and orphan-designated biopharmaceutical products approved 1995–1999 Orphan designation Clinical phase Approval phase Total phase (months) (months) (months) Non-orphan (n = 14) 58.7
15.5
74.2
Orphan (n = 12)
13.8
72.3
58.5
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Anti-infective (n = 6) Anti-neoplastic (n = 3) Endocrine (n = 4) Gastrointestinal (n = 2) Hemostasis (n = 5) Immunologic (n = 3)
84 Time (months)
75.4
72 62.6
60.1
60
84.8 78.8
78.4 69.3 64.4
63.6
55.1 51.8
48
48.4
36 23.3
24
16.2
16.0
12
9.2
9.4
11.8
0 Clinical phase
Approval phase Development phase
Total phase trends in Biotechnology
Figure 2 Comparison of biopharmaceutical products approved 1995–1999 for specific therapeutic indications.
has increased over the years, biopharmaceuticals still go through the process faster than conventional drugs. Priority-reviewed NCEs had a significantly shorter (38%) mean approval phase compared with standardreviewed NCEs (Ref. 8). A similar reduction of even greater magnitude (64%) was observed for the priorityreviewed biopharmaceuticals.NCEs with orphan-drug designation approved between 1996 and 1998 had longer mean clinical and approval phases than the average for all NCEs (Ref. 8) (by 23% and 42%, respectively). By contrast, the mean clinical and approval phases for all of the approved orphan-drug-designated biopharmaceuticals were slightly shorter (by 5% and 16%, respectively) than the average for all 26 products.The shorter mean approval phase was most probably caused by the priority review status of the products (80% of the orphan-drug products were priority reviewed). 96
rDNA 1982-1994 (n = 16) rDNA 1995-1999 (n = 15) Mab 1982-1994 (n = 2) Mab 1995-1999 (n = 6)
Time (months)
84
82.0 78.3
72 63.1
61.5 62.8
60
56.9
56.5
48 39.4
36 24
17.5 16.7
12
19.3
6.6
0 Clinical phase
Approval phase Development phase
Total phase trends in Biotechnology
Figure 3 Comparison of biopharmaceutical product categories approved during three time periods. Abbreviations: Mab, monoclonal antibody; rDNA, recombinant proteins.
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The mean phases for products for three therapeutic indications could be compared directly. The clinical phases of anti-infective agents (not including AIDS antivirals), antineoplastic and endocrine agents were all longer for NCEs than for biopharmaceuticals. The approval phase for NCEs for only one indication (endocrine agents) was shorter than for the biopharmaceuticals. Overall, the NCEs required longer total phases for all three indications (24% longer for antiinfective agents, 40% longer for antineoplastic agents and 36% longer for endocrine agents) than did the biopharmaceuticals. Products approved between 1982 and 1994, and between 1995 and 1999 To assess the trends in biopharmaceutical product development over time, mean phase lengths of two categories of biopharmaceutical products approved between 1982 and 1994 were compared with the same product categories approved between 1995 and 1999 (Fig. 3). Recombinant proteins and therapeutic monoclonal antibodies were selected for this comparison because these products constituted the majority (21 of 26 products) of the products approved between 1995 and 1999. Recombinant proteins approved between 1995 and 1999 had a substantially longer (by 56%) mean clinical phase than recombinant proteins that were developed between 1982 and 1994. By contrast, the mean clinical phase length for therapeutic monoclonal-antibody products approved between 1995 and 1999 was 10% shorter than for products in the same category approved between 1982 and 1994.There was only a minor difference (~24 days) between the mean approval phase lengths for recombinant-protein products approved during the two time periods. Thus, the difference in the mean total phase remained relatively large (21.4 months). The therapeutic monoclonal-antibody products were approved very quickly betwen 1995 and 1999, with a mean approval phase length of only 6.6 months.The speed of the approval phase helped to increase the difference between the mean total phase lengths of the therapeutic monoclonal-antibody products approved during the two time periods. Several trends were apparent when the data for all new biopharmaceutical product approvals were compared in the three time periods 1982–1989 (Ref. 1), 1990–1994 (Ref. 1) and 1995–1999 (Table 4). First, the total number of approvals in each time period has increased dramatically. Second, the mean length of the approval phase has consistently decreased.Third,the mean length of the clinical and the total phases have consistently increased. Conclusions The biotechnology industry has grown substantially since the first recombinant protein was approved in 1982.Advances in chemistry and biology have yielded a wealth of information about human biological systems.This information has provided biotechnology companies with a vast number of potential new ways to intervene in disease states.As larger numbers of new biopharmaceuticals progress through the discovery and development phases, more are getting through the approval phase. Between 1995 and 1999, the FDA TIBTECH SEPTEMBER 2000 (Vol. 18)
FEATURE
approved 26 new biopharmaceutical products,the most products approved in any five-year period to date. The two most notable trends evident from the data were: (1) the remarkable decrease in the mean length of the approval phase for the priority-reviewed products compared with the standard-reviewed products; and (2) the consistent increase in the total phase length for biopharmaceuticals over three time periods despite the consistent decreases in the mean approval phase length. The decrease observed in the mean length of the approval phases of the priority products was most probably due to the influence of the performance goals set in the relevant Acts2,3. Performance goals for the fiscal years 1997 and 1998 included for the first time a sixmonth review time for 90% of the initial priority NDAs and BLAs submitted (resubmissions are not included); 12 of the 15 NDAs and BLAs for priority-reviewed products included in this study were initially submitted during fiscal years 1997 and 1998. The performance goal for initial submissions for standard-review NDAs and BLAs for fiscal years 1997 and 1998 was a 12 month review time.The twofold difference between the goals for the review times is reflected in the observed difference between the mean approval times of priorityreview and standard-review products (10.0 months vs 21.1 months, respectively). Mean approval phase length as defined in this study included resubmission times and sponsor-response times, and so the observed phases are longer than those dictated by the performance goals. The mean length of the clinical phase for biopharmaceuticals, particularly recombinant proteins, has consistently increased over time and this could be caused by several factors.The technology currently used to manufacture and characterize biopharmaceutical products is more sophisticated than that used in the 1980s and early 1990s. In addition, biopharmaceuticals are being developed for therapeutic indications that are increasingly complex.The additional complexity of the disease interventions and the technology used to make biopharmaceuticals might have contributed to the observed clinical-phase-length increase for the biopharmaceutical products approved between 1995 and 1999 compared with the products approved between 1982 and 1994. As the biotechnology industry and the FDA gained experience with the unique development issues associated with biopharmaceuticals, higher standards for product characterization and the demonstration of safety and efficacy might have been applied to the newer products. In addition, companies might be taking time to prepare for launching products globally: 67% of the products selected for this study were also approved in the European Union between 1995 and 1999.These factors might also have contributed to the observed increase in the mean length of the clinical phase for the biopharmaceutical products. It remains to be seen whether the trends reported here will continue into the future. The significant reduction in the mean length of the approval phase for priority-reviewed products is encouraging but longer clinical phases are leading to longer total phases. The biopharmaceutical industry must work together with TIBTECH SEPTEMBER 2000 (Vol. 18)
Table 4. Number of new biopharmaceuticals approved by the FDA during three time periods and comparison of mean phase lengths for the products Time period
Total number of approvals
Clinical phase (months)
Approval phase (months)
Total phase (months)
1982–1989
14
32.7
24.0
53.2
1990–1994
15
46.5
21.3
67.8
1995–1999
26
58.6
14.7
73.3
the FDA to shorten the time required to complete clinical trials so that public access to effective biopharmaceutical medicines is provided in a timely manner. Supplementary material A table of the median values and ranges of the major categories (n .5) of biopharmaceuticals is available upon request. Acknowledgments I gratefully acknowledge the companies that provided data for this study and thank the people who completed the survey. Special thanks go to E. Healy for maintaining the biopharmaceuticals database and colleagues at CSDD for comments and suggestions on the manuscript. References 1 Gosse, M.E. and Manocchia, M. (1996) First biopharmaceuticals approved in the U.S.: 1980–1994. Drug Inf. J. 30, 991–1001 2 Prescription Drug User Fee Act of 1992. US Public Law 102-571 (1992 Oct 29); 21 USC 379; 106 Stat 4491 3 Food and Drug Administration Modernization Act of 1997. US Public Law 105-115 (1997 Nov 21); 21 USC 355a; 111 Stat 2296 4 Fourth Annual Performance Report: Prescription Drug User Fee Act of 1992. FY 1996 Performance Report to Congress (Dec 1996), US Food and Drug Administration, Rockville, MD, USA 5 Final Performance Report: Prescription Drug User Fee Act of 1992. Fiscal Year 1997 Report to Congress (Dec 1997), US Food and Drug Administration, Rockville, MD, USA 6 FY 1998 Performance Report to Congress for the Prescription Drug User Fee Act of 1992 as Amended by the Food and Drug Administration Modernization Act of 1997, US Food and Drug Administration, Rockville, MD, USA 7 FY 1999 Performance Report to Congress for the Prescription Drug User Fee Act of 1992 as Reauthorized and Amended by the Food and Drug Administration Modernization Act of 1997, US Food and Drug Administration, Rockville, MD, USA 8 Kaitin, K.I. and Healy, E.M. (2000) The new drug approvals of 1996, 1997 and 1998: drug development trends in the user fee era. Drug Inf. J. 34, 1–14
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