An analysis 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 69 new entities in the year 2023, 50 % more than in the previous year. Oncology drugs tied with congenital and infectious diseases drugs for the most approvals.
Although orphan and priority approvals continued at a high pace, the rate of fast-track approvals continued to decline. The rate of industry consolidation also picked up again after decreasing slightly in 2022.
Published: May 2024As part of a long-standing effort to assess drug development activities, we continued an evaluation of the pharmaceutical and biotechnology industries.
We gathered data from the US Food and Drug Administration (FDA)’s Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER).
Given the increasing diversity in the types of medicines being approved, which now include human and non-human cells as well as gene therapies, we refer to the new entries as ‘entities’ rather than the more conventional ‘new molecular entities’.
All underlying data, as well as much more information pertaining to the active pharmaceutical ingredients (APIs), includ ing previously approved and clinical-stage drugs (those never or not yet approved), can be found at a public website (https:// www.cdek.liu.edu) and was curated consistent with our previous analyses.
We compiled and curated information about all FDA-approved entities by aggregating and cross-matching relevant data from multiple sources, including Duke University's initiative, clinicaltrials.gov (https://aact.ctti-clinical-trials.org), 7 Drugs@FDA, the National Center for Advancing Translational Sciences’ (NCATS) Inxight Drugs, as well as the National Library of Medicine's (NLM) PubChem and Unified Medical Language System (UMLS).
For example, we captured trial design and outcomes data from clinicaltrials.gov, a web-based resource for patients, healthcare providers, and researchers, and compared these results with those from searches on PubMed (a product of the NLM) and Google Scholar (a product of Alphabet). We reported that clinicaltrials.gov often proves to be ambiguous due to typographic errors, alternative spellings, and characters derived from non-English languages, causing challenges in determining API identities, sponsors, and clinical indications.
These ambiguities were resolved and standardized using a blend of machine-based and manual curation techniques to create a synonym list of key words that helped identify unambiguously all APIs, sponsors, and intended clinical indications found on cdek.liu.edu.
For each API, we catalogued its identifier(s), the sponsoring institution(s), target(s) and mechanism(s), maximum clinical trial status (phase I, II, or III), overall regulatory status (approved or experimental). Additionally, an assessment of public disclosures by or about all identified sponsors, including press releases, news coverage, and 10-Q and 10-K documents from the Securities & Exchange Commission, was conducted to capture extra information not found through these methods. This data is publicly available on cdek.liu.edu.
Many year-end reviews of FDA actions limit themselves to information in the Orange Book, which lists approvals granted by CDER. This approach overlooks contributions from biological products like gene therapies and vaccines approved by CBER. Consequently, we combined both sets of approvals for our analyses.
Fifty-five new molecular entities entered CDER’s Orange Book while CBER’s Purple Book gained an additional 14 entities (Figure 1A). This level reflects a substantial increase from the previous year, when 37 and seven new entries were recorded in the Orange and Purple books, respectively.
Beyond distinguishing between approvals granted by the CDER and CBER, we analyzed the character of these newly approved interventions in greater detail. These newly approved entities could be broadly divided on the basis of their composition. This parsing revealed 31 small molecules, 24 biologics (proteins produced using recombinant DNA technologies) and 14 other therapies (including vaccines, and cell- and gene-based therapies). The biologics were 12 monoclonal antibodies, six recombinant proteins and two nucleic acids (Figure 1B).
The biologicals were four vaccines, four gene therapies and four cell therapies. The 69 entities approved in 2023 exceeds 1996, which had previously had the highest rate of drug discovery ever recorded (Figure 1B). This surge in approvals is even more remarkable given that the burst in approvals in 1996 was artificially inflated as a consequence of the clearance of a backlog of new drug applications, which was enabled by the implementation of the Prescription Drug User Fee Act (PDUFA) in the early 1990s.
Four different vaccines were approved in 2023, two for RSV, one for bacterial meningitis and one targeting Chikungunya virus. Approvals of interventions that modify gene expression or function continued in 2023; this category included four new entities, three genemodified cell therapies and two short-interfering RNA (siRNA)-based therapeutics. Another notable new entity was a new bacterial cell-based therapy for gut reconstitution following C. difficile infection in the form of donor fecal microbiota.
Beyond the clinical indications them- selves, we assessed trends in the approval mechanisms utilized by the FDA. The predominance of orphan indications continued (Figure 3). Thirty seven new entities targeted an orphan indications, continuing the strong utilization of the incentives offered by the 1983 Orphan Drug Act (ODA). More than half of newly approved drugs have received an orphan designation for at least five years running. 13
The fraction of approved new entities that used a priority review route also remained at a high level in 2023, although we did note a relative and absolute drop in the number of approvals using an accelerated approval pathway.
Our analyses also considered the organiza tions that contributed to the research and/or received approvals for an entity approved in 2023. Pfizer led by obtaining eight approvals in one year. These included four small molecules, two vaccines, a monoclonal antibody, and a recombinant protein. GlaxoSmithKline, Chiesi, and UCB each recorded three approvals, with Eli Lilly, Sarepta Therapeutics, Leo Pharma, Bausch Health, and AstraZeneca each receiving two approvals in 2023. Consistent with our activities over more than a decade, we calculated the number of ‘successful’ companies, which we define as private sector organizations that have contributed to the development of at least one FDA-approved entity.
Looking over the history of the modern pharmaceutical industry, a total of 455 different companies have contributed to the research and development of at least one new therapeutic entity approved by the FDA since 1980. Of these 455 successful organizations, 295 had been acquired, gone defunct or halted research into unapproved experimental medicines as of December 31, 2023 (Figure 4A).
In 2023, ten additional companies were subject to mergers or acquisitions, and two were no longer involved in developing new entities (Figure 4B). Consequently, by the end of 2023, the total number of ‘successful’ companies still contributing to the develop ment of new drugs stood at 160 companies that were still actively engaged in drug discovery.
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 (including countries in the European Union, Japan, China, Aus tralia, and many developed and developing world nations). We further cross-referenced this information to identify mergers, acquisitions and other business decisions that might impact the continued activity of companies in drug development.
Our review identified all companies that have ever contributed to the development 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 4,031 private sector organizations with prior experience in drug development as of 31 December, 2023. We then analyzed the impact of industry consolidation and other business decisions on the number of companies still participating in pharmaceutical research and development. One company was formed in 2023 that subsequently filed an investigative new drug application (IND) in that same year. Yet, 59 companies were lost due to mergers and acquisitions in 2023.
From the list of the remaining companies, we sought out evidence of whether the organization was still extant and if so, whether it was still performing research on new entities. This outcome was determined using searches of business records and websites. This action identified an additional 19 companies that were lost in the year 2023. We identified 86 extant organizations (i.e., companies that could still be verified using business records and active websites) that were removed from the list of drug developers because they had not participated in a clinical trial for at least five years, based upon a review of information compiled from clinicaltri als.gov and reviews of their press releases.
As of 31 December, 2023, the total number of companies that were participating in at least clinical-stage biopharmaceu- tical development stood at 1,928. Stated another way, fewer than half of companies that have ever participated in clinical-stage development (1,928 of 4,031) were still active and engaged in clinical-stage development of new entities as of 31 December, 2023. If this population of organizations is reduced only to those that have previously been successful in developing an entity that was approved by the FDA, the fraction of extant organizations that are still developing new entities stands at just over one- third (160 of 455).
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 as they do not reflect organiza- tions that will eventually, but have not yet, contributed to the development of at least one clinical-stage novel entity. In general, our dataset suggests that an average of five years elapses between the foundation of a company and the initiation of clinical-stage investigation. Consequently, the identified trends are quite dynamic.
The past decade has witnessed historically high levels of FDA approvals, exceeding 50 new approvals in seven of the past eleven years. The 69 approvals in 2023 reflect an upwards reversion to the mean after a lower-than-average number of approvals in 2022. Two other continuing trends are worth watching.
The first is the continued and outsized emphasis upon orphan indications, which once again exceeded the 50% level in 2023. This response to the incentives conveyed by the Orphan Drug Act has continued to be a source of controversy. 14–16 In practice, many organizations have taken advantage of the orphan drug amendment incentives to identify patient subsets (of a larger disease) that meet this requirement.
A rise in the approval of entities that can intervene against truly rare and under-served indications would be welcome by many, and our data suggest that the development of such medicines may be starting given the strong performance of entities meant to treat congenital disease in 2023.
Thus, we will be interested to see whether approvals for indications other than oncology will continue to increase in future years. A second and still lingering question surrounds the impact of industry consolidation. We have previously reported that most of the consolidation activity that has taken place over the past 20 years has involved the acquisition of small-tomedium sized biotechnology companies by more established and well-capitalized companies.2,3 Such trends have encouraged academic organizations to favor innovation.
Although such outcomes are promising, it is unclear whether the rate of new company foundation will be sufficient to meet the need for start-ups in the future. 3 To investigate this possibility, our team is beginning to analyze the lifecycle of drug introduction into the clinic and the likelihood of progressing from early safety analyses through to approvals. Our research over the past decade, including observations described in this review, suggests that a combination of consolidation and business decisionmaking has reduced the number of organizations actively participating in drug development.2,6
It will also be important to analyze the rate of new start-ups in the future. Anecdotal information suggests that rising interest rates have negatively impacted investor sentiment for high-risk activities such as investment in biotech startups. 17
However, the collection of evidence to confirm such outcomes will require more watchful waiting.
The past decade has witnessed historically high levels of FDA approvals, exceeding 50 new approvals in seven of the past eleven years. The 69 approvals in 2023 reflect an upwards reversion to the mean after a lower-than-average number of approvals in 2022. Two other continuing trends are worth watching.
The first is the continued and outsized emphasis upon orphan indications, which once again exceeded the 50% level in 2023. This response to the incentives conveyed by the Orphan Drug Act has continued to be a source of controversy.14–16 In practice, many organizations have taken advantage of the orphan drug amendment incentives to identify patient subsets (of a larger disease) that meet this requirement.
A rise in the approval of entities that can intervene against truly rare and under-served indications would be welcome by many, and our data suggest that the development of such medicines may be starting given the strong performance of entities meant to treat congenital disease in 2023.
Thus, we will be interested to see whether approvals for indications other than oncology will continue to increase in future years. A second and still lingering question surrounds the impact of industry consolidation. We have previously reported that most of the consolidation activity that has taken place over the past 20 years has involved the acquisition of small-tomedium sized biotechnology companies by more established and well-capitalized companies.2,3 Such trends have encouraged academic organizations to favor innovation.
Although such outcomes are promising, it is unclear whether the rate of new company foundation will be sufficient to meet the need for start-ups in the future. 3 To investigate this possibility, our team is beginning to analyze the lifecycle of drug introduction into the clinic and the likelihood of progressing from early safety analyses through to approvals.
Our research over the past decade, including observations described in this review, suggests that a combination of consolidation and business decisionmaking has reduced the number of organizations actively participating in drug development.2,6 It will also be important to analyze the rate of new start-ups in the future. Anecdotal information suggests that rising interest rates have negatively impacted investor sentiment for high-risk activities such as investment in biotech startups. 17 However, the collection of evidence to confirm such outcomes will require more watchful waiting.
Acknowledgements
This work was generously supported by Arnold Ventures.
Conflicting interests
Michael S Kinch is an employee of Long Island University and has performed consulting work for Resonance Pharma and Analysis Group. His wife is an employee of Pfizer.
Credit authorship contribution statement
Data availability
I am happy to share the spreadsheet
with the data. I direct readers to cdek.liu.edu
Acknowledgements
This work was generously supported by Arnold Ventures.