. 2021 Aug 9;39(11):1243–1269. doi: 10.1007/s40273-021-01065-y

Table 1.

General characteristics and main estimates of the selected studies (costs in 2019 million US dollars), ordered by year of publication

Article^a	Publication year	Therapeutic class considered	Drug inclusion period	No. of drugs	No. of drugs considered to extract the sample	No. of companies	Clinical approval success rates	Average cash estimated per success drug^b		Clinical development time, years (PI+PII+PIII)	Real annual COC (rate)	Average capitalized costs estimated per successful drug^b
Article^a	Publication year	Therapeutic class considered	Drug inclusion period	No. of drugs	No. of drugs considered to extract the sample	No. of companies	Clinical approval success rates	Clinical phases	Total^c			Clinical phases (PI, PII and PIII)	Total^c
Wouters et al. [19]—All	2020	Mixed	FDA approval between 2009 and 2018	63 NCEs and NBEs	355 NCEs and NBEs	47	0.14	A.Included	A.Included^e	8.30^f	0.105	A.Included	1359.18
Wouters et al. [19]—High quality^d		Mixed		23 NCEs and NBEs	355 NCEs and NBEs		0.14			9.35^f			1163.22
Wouters et al. [19]—Oncology		Antineoplastic and immunomodulating agents		20 NCEs and NBEs	116 NCEs and NBEs		0.03			6.99^f			4538.93
Wouters et al. [19]—At and Me		Alimentary tract and metabolism		15 NCEs and NBEs	44 NCEs and NBEs		0.20			9.15^f			1455.22
Wouters et al. [19]—CNS		Nervous system		8 NCEs and NBEs	33 NCEs and NBEs		0.15			8.59^f			1095.66
Wouters et al. [19]—Abx		Anti-infectives for systemic use		5 NCEs and NBEs	40 NCEs and NBEs		0.25			8.02^f			1319.80
Jayasundara et al. [40]—Orphan	2019	Mixed	FDA approval between 2000 and 2015	100 orphan approved for a new indication	1163 trails with 602 orphan drugs	Not relevant	0.33	183.70	183.70	11.42	0.105	321.61	321.61
Jayasundara et al. [40]—non-orphan				100 non-orphan approved for a new indication	1163 trails with 561 non-orphan drugs		0.10	321.84	321.84	6.15	0.105	455.32	455.32
Jayasundara et al. [40]—Orphan (NME)				74 NME	As a scenario analysis, they identified, from the original selected sample, those that were NMEs		0.33	A.Included				267.18	267.18
Jayasundara et al. [40]—non-orphan (NME)				54 NME			0.10	A.Included				539.89	539.89
Årdal et al. [47]—Min	2018	Antibiotics	Not relevant	A hypothetical antibacterial project	Costs of finishing all of the expected clinical trials per phase for the antibacterial project	19 SMEs	Not considered	A.Included^e	A.Included^e	1.50^g	COC not considered	A.Not estimated
Årdal et al. [47]—Max	2018	Antibiotics	Not relevant	A hypothetical antibacterial project		19 SMEs	Not considered	A.Included^e	A.Included^e	6.00^g	COC not considered	A.Not estimated
Prasad and Mailankody [37]	2017	Oncological drugs	FDA approval between 2006 and 2015	10 NCEs and NBEs	13 NCEs and NBEs	10	Not considered	A.Included	750.18	7.30^f	0.070	A.Included	943.83
DiMasi et al. [17]	2016	Mixed	1995–2007	106 (86 NCEs, 19 NBEs)	1442 NCEs and NBEs	10	0.12	1065.50	1540.25	6.73	0.105	1611.32	2823.58
Chit et al. [45]	2014	Seasonal influenza vaccines	2000–2011	39 vaccines	Influenza vaccines that meet the inclusion criteria	24	0.20	70.16	70.16	7.33	0.090	243.81	522.42
Falconi et al. [50]	2014	Oncological drugs	Phase I–III trial took place between 1998 and 2012	199 NCEs and NBEs	199 NCEs and NBEs	Not relevant	0.11	A.Included		11.50	0.090	2086.68	2086.68
Sertkaya et al. [49]—Abx (Min—ABSSSI)	2014	Antibacterial drugs	Not relevant	A hypothetical new antibacterial drug for six indications	A hypothetical new antibacterial drug	Not relevant	0.09	58.58^h	84.47^h	2.75	0.110	A.Not estimated
Sertkaya et al. [49]—Abx (Max—HABP/VABP)		Antibacterial drugs		A hypothetical new antibacterial drug for six indications	A hypothetical new antibacterial drug		0.09	142.30^h	168.19^h	5.63	0.110
Sertkaya et al. [49]—Vaccines		Vaccines		A model based on a theoretical new vaccine in preventing ABOM	A hypothetical vaccine		0.39	230.24^h	315.47^h	6.70	0.110
Mestre-Ferrandiz et al. [48]	2012	Mixed	If one of the intervals was completed between 1998 and 2002: Intervals: (1) Pre-first toxicity dose; (2) first toxicity dose to first human dose; (3) first human dose to first patient dose; (4) first patient dose to first pivotal dose; (5) first pivotal dose to first core submission; (6) first core submission to first core launch	97 NMEs	209 NMEs	16	0.11	804.13	1029.34	5.90	0.110	1235.90	1724.12
Adams and Brantner [51]	2010	Mixed	1989–2001	All NCEs that fulfil the selection criteria	2245 observations (firm/year)	183	0.24	702.08	702.08	6.20	0.110	1,785.85	1,785.85
Paul et al. [52]	2010	Mixed	2000–2007	No clear number of NCEs and NBEs	No info	13	0.12	652.96	1,040.21	6.50	0.110	1,079.53	2,118.55
DiMasi and Grabowski [53]	2007	Therapeutic recombinant proteins and mAbs	1990–2003	17 NBEs (4 from DiMasi et al. [18], 13 from a Biotech firm)	522 NBEs	4 (3 companies from DiMasi et al. [18] and 1 Biotech firm)	0.30	463.39	717.75	6.81	0.115	803.18	1591.65
Adams and Brantner [54]	2006	Mixed	1989–2002	Same selected sample as DiMasi et al. [18]: 68 NCEs	3181 NCEs	Cash expense costs from DiMasi et al. [18] (10 companies). Developing times and success rates sample based on Pharmaprojects	0.24	446.05	637.42	6.58	0.110	700.73	1248.94
DiMasi et al. [55]—All	2004	Mixed	1983–1994	68 NCEs	All compounds in the Tufts CSDD database that met the inclusion criteria	10	0.22	405.48	405.48	6.01	0.110	670.51	670.51
DiMasi et al. [55]—Anes		Analgesic/anesthetic		10 of the 68 NCEs and NBEs			0.25	359.36	359.36	3.87		539.58	539.58
DiMasi et al. [55]—Abx		Anti-infective		9 of the 68 NCEs and NBEs			0.25	517.77	517.77	4.21		707.92	707.92
DiMasi et al. [55]—CV		Cardiovascular		12 of the 68 NCEs and NBEs			0.18	401.75	401.75	5.08		661.88	661.88
DiMasi et al. [55]—CNS		CNS		13 of the 68 NCEs and NBEs			0.18	394.10	394.10	7.71		758.28	758.28
DiMasi et al. [18]	2003	Mixed	1983–1994	68 (61 NCEs, 7 NBEs)	583 NCEs and NBEs	10	0.22	405.50	579.60	6.01	0.110	671.64	1153.66
Global Alliance for TB Drug Development [56]—Min	2001	Tuberculosis	Not relevant	One hypothetical project to develop a new TB drug	One hypothetical project to develop a new TB drug	Not relevant	0.10	A. Included		6.58	0.100	109.35	166.91
Global Alliance for TB Drug Development [56]—Max	2001	Tuberculosis	Not relevant	One hypothetical project to develop a new TB drug	One hypothetical project to develop a new TB drug	Not relevant	0.10	A. Included		9.30	0.120	165.47	345.33
Young and Surrusco [24]—Min	2001	Mixed	FDA approval between 1990 and 1996	Base results based on 207 NCEs. R&D costs based on all approved drugs were also estimated	563 new drugs	Not relevant	Not considered	A.Included	247.97	Estimations were based on the average (per year) R&D spending over a 7-year period divided by the average (per year) number of drugs approved during the previous 7 years	COC not considered	A.Not estimated
Young and Surrusco [24]—Max	2001	Mixed	FDA approval between 1994 and 2000	234 NCEs. R&D costs based on all approved drugs were also estimated	667 new drugs	Not relevant	Not considered	A.Included	326.65		COC not considered	A.Not estimated
DiMasi et al. [57]—Small firms	1995	Mixed	1970–1982	23 of the 93 NCEs	The selected data correspond to 19% of all NCEs in the database	5 of 12	0.24	78.52	291.89	4.66	0.090	132.68	674.68
DiMasi et al. [57]—Medium firms				33 of the 93 NCEs		4 of 12	0.17	139.26	277.16	6.13		221.36	545.58
DiMasi et al. [57]—Large firms				37 of the 93 NCEs		3 of 12	0.28	97.16	235.23	5.72		143.59	451.18
DiMasi et al. [58]—All	1995	Mixed	1970–1982	93 NCEs	All drugs in the CSDD database that meet the inclusion criteria	12	0.23	97.10	230.11	No information for clinical phases only. 8.24 years reported for the clinical and submission period	0.090	152.38	472.77
DiMasi et al. [58]—NSAID		Non-steroidal anti-inflammatory		8 of the 93 NCEs			0.22	162.27	162.27	8.29		265.07	265.07
DiMasi et al. [58]—CV		Cardiovascular		21 of the 93 NCEs			0.26	101.41	101.41	7.63		160.52	160.52
DiMasi et al. [58]—Abx		Anti-infective		15 of the 93 NCEs (one outlier was excluded)			0.30	79.88	246.15	5.03		114.43	393.17
DiMasi et al. [58]—Neuro		Neuropharmacological		18 of the 93 NCEs			0.20	97.16	97.16	6.53		167.82	167.82
DiMasi et al. [16]	1991	Mixed	1970–1982	93 NCEs	The selected data correspond to 19% of all NCEs in the database	12	0.23	94.57	223.56	5.72	0.090	148.10	454.53
Wiggins [59]	1987	Mixed	FDA approval between 1970 and 1985	223 NCEs	324 NCEs	No information	Not considered	A.Not estimated	131.17	Not considered	0.080	252.25	252.25
Hansen [60]	1979	Mixed	1963–1975	Around 100 NCEs	Sample corresponds to around 15% of the NCEs taken into human testing by the 25 firms surveyed during the study conducted by Hansen [61]	14	0.13	48.79	105.93	4.58	0.080	68.74	176.15

Additional information can be found in electronic supplementary information 2.

Source: Authors’ elaboration

A.Not estimated assumed to be NOT estimated (the analysis of the article suggests that this particular calculation of R&D costs was NOT estimated), A.Included assumed to be included (the value is not reported; however, our analysis suggests that the R&D costs for that particular phase are reflected in the TOTAL R&D reported), All estimation includes all the observations in the sample, ABOM acute bacterial otitis media, ABSSSI acute bacterial skin and skin structure infections, Abx anti-infectives, Anes analgesics/anesthetic, CNS central nervous system, COC cost of capital, CSDD Center for the Study of Drug Development, CV cardiovascular, HABP/VABP hospital-acquired/ventilator-associated bacterial pneumonia, mAbs monoclonal antibodies, Max maximum reported value, Min minimum reported value, NBE new biological entity, NCE new chemical entity, Neuro neuropharmacological, NME new molecular entity, NPV net present value, NSAID nonsteroidal anti-inflammatory drug, R&D research and development, SMEs small and medium enterprises, TB tuberculosis

^aEach row corresponds to the information related to one main R&D estimate. When more than one R&D cost estimate is reported, we refer to each by including the reference of the corresponding article and a keyword that describes the main characteristic of the R&D cost estimate

^bMillion US dollars—2019 prices

^cConsiders failures and includes all estimated phases (when animal testing has been estimated separately, it is also included here)

^dConsistency and completeness of company reporting in the US Securities and Exchange Commission (SEC) filings vary. Therefore, Wouters et al. [19] categorized each selected data point as high, medium, or low quality, depending on the availability and consistency of reported data

^eThe authors reported only the average cash estimated per investigational compound (cash spent in R&D, not considering failures). Values are presented in electronic supplementary information 2

^fAuthors collected information by drug candidate, starting from the year in which the company began reporting costs for that particular drug in their financial statements until approval. This period could include 1 or more years of preclinical costs. The development time reported by the authors is based on the average time of all drugs included in the analysis. This means that, for some of these drugs, time also includes a few years of preclinical trials

^gÅrdal et al. [47] considered only phase I and phase II

^hWe assumed that Sertkaya et al. [49] considered the risk of failure. They used a decision tree model to estimate the costs. There is a decision node in each trial phase with the success rate to transit to the next phase, and the terminal nodes represent the NPV of each outcome (failure or success at each phase). The final figure, the expected NPV of a successful antibiotic, was obtained by working backward from each terminal node to the beginning of the R&D process