An accounting of all new entities approved by both the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) identified the approval of 44 new entities in the year 2022. Oncology-based drugs continued to be the most popular indication for these medicines. Likewise, orphan indications encompassed more than half of new drug approvals.
The number of new entities approved in 2022 declined from its peak after 5 years of more than 50 annual approvals. Likewise, the rate of consolidations slowed somewhat, among both new entries in the realm of clinical-stage developers and more established organizations.
Published: Feb 2023As part of an ongoing effort to assess drug development activities in 2022, we contin- ued an evaluation of the pharmaceutical and biotechnology industries. We included information gathered from both the CDER and CBER. All underlying data, as well as much more information pertain- ing to these active pharmaceutical ingredients (APIs), including previously approved and clinical-stage drugs (never or not yet approved), can be accessed on the public website www.cdek.liu.edu and was curated consistent with our previous analyses.1–6 Given an increasing breadth in the types of medicine, which include human and nonhuman cells, we refer to these new entries as ‘entities’ rather than the more conventional ‘new molecular entities.’
We compiled and curated information about all US Food and Drug Administration (FDA)-approved entities by aggregating and cross-matching relevant information from multiple sources, including the Duke University-led initiative, clinicaltrials.gov (https://aact.ctti-clinicaltrials.org),7 Drugs@FDA,8 the National Center for Advancing Translational Sciences’ (NCATS) Inxight Drugs,9 as well as the National Library of Medicine’s PubChem and Unified Medical Language System (UMLS).10
For example, we captured all trial design and outcomes data conveyed on clinicaltrials.gov, a web-based resource for patients, healthcare providers, and researchers, and compared the results with searches of PubMed (a product of the National Library of Medicine) and Google Scholar (a product of Alphabet). As we have reported previ- ously,6 clinicaltrials.gov has often proven to be ambiguous, with 20% of data inter- pretation confounded by typographic errors, alternative spellings, and characters derived from non-English languages, as well as other challenges that caused ambiguity in determining the identity of APIs, spon- sors, and/or clinical indications.
All ambiguities were resolved and standardized using a blend of machine-based and manual cura- tion to create a synonym list of key words to unambiguously identify all APIs, spon- sors, and intended clinical indications, all of which can be found on a public website: cdek.liu.edu.5
For each API, we catalogued the identi- fier(s) for the API, the sponsoring institution(s), target(s), and mechanism(s), as well as the maximum clinical trial status (i.e., Phase I, II, or III) and overall regulatory status (approved or experimental). Furthermore, an assessment of public disclosures by or about all identified sponsors, includ- ing press releases, news coverage, and 10- Q and 10-K documents from the Securities & Exchange Commission, was conducted to capture additional information not identified by these approaches.
Again, all information is publicly available on cdek. liu.edu. To standardize the mechanistic basis and target recognized by APIs, a manual approach identified targets for each anti- body product and categorized these based upon a modified approach based upon an established database of bioactive mole- cules (www.ebi.ac.uk/chembl/). The modi- fication was necessary because ChEMBL primarily focuses only upon small- molecule therapeutics and it was essential to include mechanisms unique to other therapeutic entities, including gene or cell-based therapies, recombinant proteins (including monoclonal antibodies), and biologicals
After a run of 5 years with an annual rate of approval exceeding 50 new entities, 44 new entities were approved by FDA in 2022. Thirty-seven new entities entered CDER’s Orange Book, while CBER’s Purple Book gained an additional seven entities. This level reflects a drop in the absolute rate of approvals since 2016 but is aligned with the 5-year rates of approval seen during most of the past decade and is higher than the 5-year running average for most of the 20th century (Figure 1a). These newly approved entities could be broadly divided based upon their composi- tion. These categories included 20 small molecules, 17 biologics, and seven other therapies (which included cell- and gene- based therapies).
Despite this comparatively slow pace, the 5-year average rate of approvals remains near its historic high- est level, suggesting continued robustness of drug development (Figure 1b). To identify the disease areas targeted by NMEs approved in 2022, we relied upon Medical Subject Headings (MeSH), a con- trolled vocabulary developed by the National Institutes of Health (NIH) for indexing articles for PubMed. 11 For indications not readily defined using MeSH headings, we used ICD-10 guidelines for coding and reporting, as compiled by the Centers for Medicare and Medicaid Ser- vices (CMS). 12
An evaluation of the clinical applica- tions addressed by these newly approved medicines revealed a continue predominance of oncology indications. Cancer applications captured nearly one-third of new approvals, extending a decade long trend. Oncology was followed by eight new entities approved for autoimmune or inflammatory diseases.
These autoimmune/inflammatory disease approvals were an increase relative to 2021, which witnessed no new entities approved for this subset of indications. Two of the 44 approvals were for diagnostic agents. A growth of interventions that modify gene expression or function was reflected by five new entities, which encompassed two gene therapies (nadofaragene firaden- ovec and etranacogene dezaparvovec), two gene-modified cell therapies (ciltacabtagene autoleucel and betibeglogene autotemcel), and a single small interfering (si)RNA- based therapeutic (vutrisiran).
Another notable new entity was the first new bacte- rial cell-based therapy for gut reconstitution following Clostridium difficile infection in the form of donor fecal microbiota.
Beyond the clinical indications themselves, we assessed trends in the approval mechanisms utilized by FDA. The predom- inance of orphan indications continued in 2022. The 23 new entities targeting an orphan indication reveal the continued utilization of the incentives offered by the 1983 Orphan Drug Act (ODA). 13 The relative fraction of new entities approved using a priority, accelerated, or fast-track approval process remained at roughly their 5-year historical levels (Figure 2), as did the nearly one-third of drugs approved with a breakthrough designation (data not shown).
Ten of the 14 oncology drugs were approved for an orphan indication. This large fraction is consistent with concerns about the use, and potential overuse, of the incentives. Specifically, the concerns are that an orphan indication is merely a loophole used to obtain the lucrative financial incentives conveyed upon orphan drugs. Such worries further pre- sume that many of these oncology drugs will have comparable utility against much larger, non-orphan, markets. Looking fur- ther, we note that these ten oncology approvals reflect fewer than half of the 23 approvals that utilized the ODA process. This is a promising trend, which could indicate that the actions of drug develop- ers are aligning with the original intentions of the ODA (Figure 3).
Consistent with our activities over more than a decade, we calculated the number of ‘successful’ companies, which we define herein as private sector organizations that have contributed to the develop- ment of at least one FDA-approved entity. A total of 393 different companies contributed to the research and development of at least one new therapeutic entity that was approved by the FDA.
Of these 393 organizations, 265 had been acquired, gone defunct, or halted research into unapproved experimental medicines as of December 31, 2021, leaving a total of 128 companies that were still actively engaged in drug discovery (Figure 4a). In 2022, three additional compa- nies were subject to mergers or acquisitions. We also analyzed the impact of industry consolidation and other busi- ness decisions and found that an additional three companies demonstrated no evidence of continued development of new entities for at least 5 years (remaining focused instead on the marketing or distri- bution of products previously approved).
Consequently, by the end of 2022, the total number of ‘successful’ companies still contributing to the development of new drugs stood at 122. To put this in perspec- tive, the number of companies still active in drug development last reached this level in 1983, when our records indicate that a total of 124 ‘successful’ companies were engaged in drug development.
Taking a wider view, we also evaluated companies that were participating in clinical-stage drug development (including those that have not yet, or ever, received an FDA approval).2 These data were compiled by analyzing historic information about clinical-stage entities and their sponsors, as listed in ClinicalTrials.gov and its international equivalents.
Our data analysis included both US and ex-US data from participating countries that make their data publicly available (which includes the European Union, Japan, China, Australia, and many other high and low–middle income nations). We further cross-referenced this information to identify those subject to mergers, acquisi- tions, and other business decisions that might impact their continuation of drug development. This review identified all companies that have ever contributed to the develop- ment of at least one clinical-stage entity.
This analysis was intended to identify organizations that were still devoted to the development of new drugs (as opposed to extending applications or reformula- tions of existing medicines). Our analyses identified 3319 private sector organizations with prior experience in drug devel- opment, of which 1779 were still active in drug development as of December 31, 2021.
We then analyzed the impact of indus- try consolidation and other business deci- sions on the number of companies still participating in pharmaceutical research and development. Unsurprisingly, we did not identify any companies that were formed in 2022 that subsequently filed an investigative new drug application (IND) in that same year. Yet, 44 companies were lost as a result of mergers and acquisi- tions that year. From the list of the remaining companies, we sought out evidence of whether the organization was still extant, based upon searches of business records and websites.
This action identified an additional 15 companies that were lost in the year 2022. In addition, we identified 62 extant organizations (i.e., companies that could still be verified using business records and active websites), which were removed from the list of drug developers because they had not participated in a clinical trial based upon a review of informa- tion compiled from clinicaltrials.gov and other relevant data sources. We then subtracted the number of organizations that had been subsumed by a merger or acquisition, had been deemed defunct, or with no evidence of continued development of novel drugs.
As of December 31, 2022, 1666 companies had demonstrated evidence of clinical-stage drug development in support of at least one new entity over the past 5 years. It must be appreciated that these assess- ments of companies contributing to drug development are lagging indicators of the overall health of the drug development enterprise because they do not reflect organizations that will eventually, but have not yet, contributed to the development of at least one clinical-stage novel entity.
In general, our data set suggests that an average of 5 years elapses between the foundation of a company and the initia- tion of clinical-stage investigation (data not shown). Consequently, the trends identified in Figure 4b are dynamic.
The past decade has witnessed historically high levels of FDA approvals, exceeding 50 new approvals in 6 of the past 10 years.
The 44 approvals in 2022 might simply reflect a reversion to the mean. Two other continuing trends bear watching. The first is the continued and outsized emphasis upon orphan indica- tions, which again exceeded the 50% level in 2022. This response to the incentives conveyed by the ODA has continued to be a source of controversy and has inspired calls for legislative action to redress what is seen by many as an abuse of a law that has been in place for 40 years. 14–16
The year 2022 witnessed a relative decline in orphan drugs for oncology indications, which have dominated orphan approvals since pas- sage of this critical legislation during the 1980s. The ODA was passed to create incentives for unmet diseases, which afflict fewer than 200 000 Americans.17 In practice, many organizations have taken advantage of these requirements to identify patient subsets (of a larger disease) that meet this requirement. This practice has been decried as disingenu- ous because the intended population for many of these oncology drugs is for a population that would not qualify for orphan drug status.14
An increase in drugs meant to intervene against truly rare and under-served indications would be welcome by many. Thus, we will be interested to see whether indications other than oncology will continue to increase in future years. A second and still lingering question surrounds the impact of industry consolidation. The continued erosion in the num- ber of companies participating in research and development is a topic of possible concern.
Although some acquisitions rep- resent a combination of large organiza- tions, we have previously reported that most of the consolidation activity over the past 20 years has involved the acquisi- tion of a small-to-medium-sized biotech- nology company by a more established and well-capitalized company.2,3 Such trends have encouraged academic organi- zations to favor innovation. Although such outcomes are promising, it appears unlikely that the rate of new company foundation will be sufficient to meet the need for start-ups in the future.3
A decline in the number can be viewed in a negative sense as limiting the breadth of participation in development activities and, therefore, might portend a slowdown in an aging enterprise, with massive eco- nomic and public health implications.18 Indeed, our research over the past decade, including observations herein, suggest that a combination of consolidation and business decision-making has reduced the number of organizations actively participating in drug development.2,6 Recent trends are also consistent with a Wall Street Journal article published a decade ago with the headline, ‘In Drug Mergers, There’s One Sure Bet: The Layoffs’.19
Recent evidence confirms that layoffs in the biotechnology sector have been grow- ing, impacting both established and startup companies.20 Biotechnology com- panies faced a particularly challenging year in 2022 as declining initial public offerings decreased interest by investors in drug development. 21 Although the comparatively high number of product approvals since 2013 has been promising (e.g., Figure 1), the sustainability of this momentum is uncertain.
Data will be made available on request. Declaration of Competing Interest 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.
This work was generously supported by Arnold Ventures.