The US Food and Drug Administration (FDA) green-lighted the marketing of 53 therapeutic agents in 2019. This rate of approvals was consistent with the 5-year running average. Nonetheless, a few changes are worth noting. The rate of medicines first approved using an orphan drug designation declined from 56% in 2018 to 41% in 2019, which mirrored a comparable decline in the use of priority review.
A second notable feature was an uptick in industry consolidation. Twenty-five companies were lost, primarily because of mergers, leaving only 146 extant companies that have contributed to the research or development of an innovative FDA-approved medicine.
Published: Nov 2020The FDA approved 53 unique products in 2019, including new molecular entities (NMEs) given a green light from either the Center for Drug Evaluation and Research (CDER) or Center for Biologics Evaluation and Research (CBER). These medicines could be separated broadly into three categories: 11 biologics, 38 small molecules, and four biologicals (including gene and cell thera- pies) (Fig. 1).
To be clear, we define herein biologics reflecting products derived using re- combinant DNA technologies versus biologicals, which reflect products derived from primary animal or human sources. It is also important to point out that some products, such as Trifakta, contain multiple active ingredients.In such cases, we only consider an NME that was first approved in 2019. Although this rate of new approvals was lower than the 61 new molecules approved in 2018, the approval rate in 2019 exceeded the 5-year running average of 49.4 annual new medicine approvals.
The decline from 2018 reflects seven fewer biologics (18 in 2018 versus 11 in 2019), four fewer small molecules (42 in 2018 versus 38 in 2019), and one more biological (3 in 2018 versus 4 in 2019). The absolute and relative use of incentive regulatory mechanisms also declined. Twenty- one (or 40%) of medicines approved in 2019 utilized an orphan drug mechanism (Fig. 2), which is considerably lower than the highest- ever rate of 56% in 2018.
Nearly two-thirds (62%) gained an approval utilizing a priority review, again lower than the record rate of 71% set in 2018. However, these lower rates were more closely aligned with the 5-year running average of 46% for approved for an orphan indication and 59% reviewed on a priority basis. The FDA offers other mechanisms to expedite the approval of new medicines. Accelerated approvals are offered for indications, when a more easily obtained surrogate marker can be used in place of a longer-term clinical endpoint.
Our analyses revealed that accelerated approvals have increased steadily over the past 6 years, with eight NMEs approved in 2019 using this mechanism. Another mechanism invoked by FDA is break-through designation, which identified therapeu- tic options where preliminary information suggests a substantial improvement in clinical outcome. Fourteen NMEs were approved in 2019 with a breakthrough designation. When viewed over time, the rate of NMEs approved utilizing a breakthrough designation has generally increased, although the 14 NMEs approved utilizing a breakthrough designation in 2019 was somewhat lower than the 5-year running average of 16.7 NMEs awarded a breakthrough designation at the time of initial approval (Fig. 3).
As has been the case for most of the ongoing century, oncology applications continued to capture the largest number of new approvals (data not shown). Eleven new medicines were approved for the treatment of an oncology indication and one additional product was introduced for cancer diagnosis. All of these medicines were approved on a priority basis and six were initially approved for an orphan indication.
Whereas autoimmune diseases have generally reflected the next-most popular indication, this subset of diseases lagged considerably in 2018, with only four NMEs designated for the treatment of an autoimmune or inflammatory application. Eight new medicines targeted nervous system disorders, with two additional drugs targeting migraine-based pain and four other medicines approved for psychiatric indications.
There were other notable observations that distinguished 2019 from previous years. Infectious diseases in general and antibacterial agents in particular fared well, with six medicines approved for these diseases, all but one for a bacterial disease. According to our findings, 2019 was the first year since 1993 that lacked an approval for a treatment of vaccine for a viral disease.
By contrast, five different medicines were approved for dis- ease classes that are relatively uncommon, including non-oncological hematology indications (two for sickle cell disease, with one each for beta-thalassemia, erythropoietic protoporphyria, and thrombotic thrombocytopenic purpura) and three approvals were intended to remedy sleeping disorders (two for narcolepsy and one for insomnia).
Beyond evaluating the medicines themselves, we continued the practice of evaluating the organiza- tions responsible for the research and development activities necessary for FDA approval. This work updates our past studies to analyze the organizations responsible for the research and development of all types of medicine (and biologicals) between 1800 and the end of 2019 [1].
By the end of 2019, a total of 535 different private sector orga- nizations had contributed to the research or de- velopment of an FDA-approved or US-marketed medicine (the latter designation includes over-the- counter medicines) (Fig. 4a).
From this total set of private sector research companies, only 146, or just over a quarter, remained extant and committed to the research or development of a new medicine (Fig. 5a). Most of those lost had been subject to a merger or acquisition. In 2019 alone, 17 organizations that had contributed to the research or development of a new medicine were subject to a merger or acquisition.
Five additional organizations were deemed ‘defunct,’ meaning that there was no evidence that the company was still extant, and three others remained viable companies but did not convey any evidence of ongoing research and development towards new medicines. Looking further, the net loss of 25 organizations in 2019 was consistent with a larger trend. Whereas the net number of research and de- velopment companies had grown over the years, this peaked at 334 different institutions in 2004. In the intervening decade and a half, 188 of these companies are either no longer extant or not doing research.
2019 was rather unremarkable in many ways, The year witnessed a reversion to the mean from 2018, which had set records in terms of new drugs approved and a net gain in the overall number of companies that contributed to re- search and development. The maintenance of a level of approvals at the 5-year average is no mean feat given that the exceedingly high rate set in 2018 factors into this average. Nonetheless, issues raised by expert analysts and por- trayed broadly in the media suggest that the numbers posted in 2019 were somewhat enhanced.
Specifically, the FDA issued a spate of approvals late in the year, which in some cases came ahead of the scheduled deadline. Although viewed by some as a positive sign of regulatory efficiency, this trend could be troubling in light of a recent report that suggested that such ‘desk-clearing’ behaviors by regulators tend to increase the likelihood of approvals for medicines with increased toxicities[2]. The past year also gave rise to other trends or. more accurately, breaks in trends, that might ultimately prove interesting. For one thing, the year witnessed a rare downturn in the steady growth in the use of the provisions of the 1983 Orphan Drug Act [3]. Whereas 56% of medicines approved in 2018 took advantage of these incentives, far fewer, both in absolute and relative terms, did so in 2019 [4]. This might reflect a statistical hiccup but will be worth watching further.
A flurry of approvals late in the year induced conversation as to whether the FDA might be approving drugs too quickly, with questions being raised about declining stan- dards in assessing safety or efficacy [5,6]. Were such scrutiny to continue or a high-profile toxicity ensue, future years might see a more cautious regulator and the end to the record shattering rates seen in recent years.
Another significant change is the acceleration in mergers and acquisitions. Over the past 2 years, we had noted an easing in the decline associated with industry mergers and acquisitions. 2019 bucked this trend, witnessed a record number of companies subject to mergers and acquisitions. Importantly, the companies tracked herein reflect a privileged few organizations that have successfully contributed to the research or development of at least one approved medicine. Given the recent emphasis on new start-ups, this population of relatively ‘aged’ companies might not portend imminent disruptions in pharmaceutical pipelines.
Nonetheless, the reversion back to accelerating consolidation should be monitored further.
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Research reported in this publication was solely supported by Washington University in St Louis.