For the past decade, looming patent expirations, increasing research and development (R&D) costs, and forecasts of dwindling drug approvals have posed significant challenges for the pharmaceutical industry.(1−5) A 2009 report estimated that more than $209B in annual sales would be at risk between 2010 and 2014 due to patent expirations.(2) These patent expirations included the blockbuster small molecule drugs atorvastatin (peak year sales of $13B in 2006), which lost exclusivity in 2011, as well as clopidogrel (peak year sales of $7.1B) and montelukast (peak year sales of $5.5B in 2012), both of which lost exclusivity in 2012.(6) The introduction of the Biologics Price Competition and Innovation Act (BPCIA) of 2009 similarly encouraged generic competition for biologics by creating a regulatory licensing path for biosimilars.(7) A biosimilar is defined by the U.S. Food and Drug Administration (FDA) as “highly similar reference product... [with] no clinically meaningful differences from a reference product.”(8) The first biosimilar approved by the FDA was filgrastim-sndz, a granulocyte colony-stimulating factor agent, in 2015.(9) Adalimumab, the number one selling prescription drug (peak year sales of $19.9B in 2018), faces no fewer than four biosimilar competitors, all approved in the past 4 years.(10)

A total of 289 NMEs, 89 biological license applications (BLA), and 27 biosimilars were approved from 2010 to 2019 (Figure 1).(11−13) Over the decade, the median number of NME and BLA approvals per year was 40, with a low of 21 in 2010 and a high of 59 in 2018. This compares to a median of 25 drugs approved per year for the decade from 2000 to 2009, with a high of 36 in 2004 and a low of 18 in 2007.(14) The proportion of BLA approvals did not change over the past decade (Figure 1), with an average of 23% of all new drug approvals (excluding biosimilars). The lowest percentage of BLAs was approved in 2013, with 8% compared to a high of 32% in 2015. The number of biosimilar approvals has steadily increased since the first approval granted by the FDA in 2015.(9)

The time from filing of the investigational new drug (IND) application to final new drug application (NDA) approval was compared for 268 new drugs from 2010 to 2019 (Figure 2). This data was obtained either within FDA regulatory documents,(15) or where the IND application date could not be found in FDA documents, the IND filing date was ascertained from the patent restoration (Drug Price Competition and Patent Restoration Act of 1984) documentation on the Federal Register.(16)

The average time from IND filing to NDA approval was 8.7 years (±3.8), and the median was 8.1 years (range 2.2–23.2). The shortest time frame from IND filing to NDA approval was 2.2 years for osimertinib 1 (Figure 3), which was approved alongside a companion diagnostic for metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive nonsmall cell lung cell cancer (NSCLC).(17) This was followed closely by deflazacort 2 (2.3 years), approved for Duchenne muscular dystrophy (DMD).(18) On the other extreme, some examples with long IND to NDA approval times are ibalizumab and flibanserin 3, which took ∼16 and ∼18 years from IND filing to NDA approval, respectively. Ibalizumab, a CD4 antibody that blocks entry of human immunodeficiency virus (HIV) into CD4+ T-cells, is the first novel treatment for HIV in >10 years as well as the first monoclonal antibody approved for HIV.(19−21) Flibanserin 3 was approved for the treatment of women with hypoactive sexual desire disorder.(22)

Previous studies of timelines from IND filing to NDA approval have been reported (Table 1).(23,24) Between 1987 and 1989, the median total time for IND to NDA approval was 7.7 years, with a median time of 4.2 years in development and 2.5 years regulatory time.(23) This remained relatively constant between 1990 and 1992 (median of 7.8 years total time for IND to NDA approval, median of 4.9 years in clinical development and median of 2.0 years in regulatory review).(24) Between 1992 and 2002, the median time from IND filing to NDA approval decreased to 6.4 years, with median times of 5.1 years for clinical trials and 1.2 years for regulatory review (Table 1).(25) The dramatic acceleration of regulatory approval was attributed to the Prescription Drug User Fee Act of 1992 (PDUFA) which utilized user fees as a mechanism to fund regulatory review and reduce review times.(26) Today, a number of expedited review designations can help to decrease regulatory review time, including Fast-track (instituted in 1988), Priority Review and Accelerated Approval (1992), and Breakthrough (2012) (Figure 4).(27,28) As a result, from 2012 to 2016, the median time from IND to NDA was 8.0 years for nonexpedited programs, while drugs with Breakthrough therapy designation received the fastest approvals, with a median of 4.8 years.(29) According to current FDA data, approval times have remained consistent since the mid-1990s, with the median time for priority reviews in 2016 of ∼8 months versus ∼10 months for standard review applications.(30) Consistent with this data, our analysis of 268 drugs from 2010 to 2019 demonstrated a median regulatory approval time of 0.8 years (range 0.2–9.4 years) (Table 1, entry 5).

To expedite the market entry of drugs for life-threatening or serious diseases, the FDA has instituted four expedited programs: Priority Review, Fast Track, Breakthrough, and Accelerated Approval (Figure 4). These categories are not mutually exclusive, meaning a drug can be granted expedited review status in more than one of these programs. Figure 5 illustrates the breakdown of expedited review designations for FDA-approved drugs from 2010 to 2019. For example, in 2019, of the 48 drugs approved, 17 were Fast Track (35%), 13 were Breakthrough (27%), 28 were Priority (58%), and 9 were Accelerated (19%). Priority Review designations make up the majority in the expedited review categories, with more than half of all drug approvals each year in this category since 2014 (Figure 5). The percentage of FDA-approved drugs with the Fast Track designation remained relatively constant over the decade (with the exception of 2010), with ∼35% of approved drugs on average. Since the introduction of the Breakthrough category in 2012, an increasing number of drugs has been awarded this designation and now makes up ∼25% of approved drugs. The most stringent category isAccelerated Approval, with an average of ∼13% of new drugs approved with this designation. The Accelerated Approval designation grants early approval of a drug, with the requirement that further clinical studies will be performed to confirm efficacy, and as such it is used sparingly. For example, only nine compounds in 2019 were given accelerated approval: erdafitinib 4, zanubrutinib 5, fam-trastuzumab deruxtecan-nxki, enfortumab vedotin-ejfv, polatuzumab vedotin-piiq, entrectinib 6, and selinexor 7 were approved for oncology indications; voxelotor 8 was approved for sickle cell disease, and golodirsen was approved for DMD (Figure 6).(34) Three of these drugs are antibody-directed conjugates (ADCs) (fam-trastuzumab deruxtecan-nxk, enfortumab vedotin-ejfv, and polatuzumab vedotin-piiq) which we will discuss in more detail in the section on other modalities. Similar to 2019, the majority (3 out of 4) of accelerated approvals in 2018 were for oncology (larotrectinib 9, duvelisib 10, and lorlatinib 11) while migalastat 12 was approved for the treatment of Fabry disease.(35) Drugs may have more than one designation; for example, of the 2018 accelerated approvals, larotrectinib 9 was given both Breakthrough and Priority review designation, duvelisib 10 was awarded Fast Track and Priority review, lorlatinib 11 was given Breakthrough and Priority review, and migalastat 12 was given Fast Track and Priority review.