The US first-approver advantage over the European Union remains stark, with eight of ten novel agents first cleared by the US Food and Drug Administration, according to a Pink Sheet analysis of recent novel approvals by the FDA and European Medicines Agency.
Key Takeaways
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The FDA and European Union’s novel approvals in 2023 through April 2024 included 48 drugs cleared in both regions and 37 approved by the FDA first.
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At least 21 of the 90 novel FDA approvals are under European Medicines Agency review.
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FDA complete response letters and COVID-19-related inspection delays helped the EU-first approval total.
During 2023 and through April 2024, 108 novel products received approval from at least one of the US or European Union’s central regulators, with 48 receiving approval as a new active drug substance, new molecular entity or novel biologic from both the US FDA and EMA, data from the suite of Pink Sheet regulatory performance trackers show.
Thirty-seven of those 48 drugs (77%) were approved by the FDA first, with a median of 5.1 months before EU approval was received. Only 11 new active substances were cleared in Europe first (20%), but with a longer median time advantage of 11.1 months before FDA approval. (For more details, see box below with links to the other stories in this series.)
The January 2023-April 2024 data is consistent with a Pink Sheet comparative analysis in 2021, which found that 90% of the FDA’s first half 2021 novel approvals had been cleared in the US first. (Also see "US And EU Approvals In First Half 2021 Underscore US-First Orientation Of Novel Drug Development" - Pink Sheet, 30 August, 2021.)
In some major therapy areas, notably oncology and central nervous system therapies, the FDA was even more likely to approve drugs before the EMA.
Individual corporate priorities and ground-level economic conditions guide many drug development decisions, but differences in reimbursement opportunities and regulatory predictability likely contribute to the FDA clearing drugs before the EMA.
The FDA’s first-mover advantage extends globally as well. Over the decade from 2014-2023, 70% of the new molecular entities and novel biologics that cleared the FDA’s largest review center, the Center for Drug Evaluation and Research, were first approved in the US, according to CDER’s annual novel drug summaries.
A 2023 global analysis by the industry trade group Pharmaceutical Research and Manufacturers of America (PhRMA) found that 57% of the 460 new medicines launched from 2012-2021 were first introduced in the US, while 23% were first launched in Europe and 13% in Japan.
Few Decisions Are Truly Divergent
The US FDA approved 90 NMEs and novel biologics in 2023 and the first four months of 2024, nearly 50% more than the 46 new active substances cleared by the European Commission.
US approval came first for 74 of its 90 approvals. A majority of those products, 49, had not been approved in the EU by the end of April.
However, at least 21 of those products have pending MAAs in Europe. The EMA and the US FDA follow different procedures for evaluating applications with notable differences, including no European equivalent for the US Prescription Drug User Fee Act structure of goal dates for regulatory action. (See sidebar below explaining the different review schemes.)
Only five drugs approved by the EU in the 2023-April 2024 period have not been approved by the FDA. One, the COVID-19 booster vaccine Bimervax from Spanish company HIPRA, is not being developed for the US. The FDA regulator identified problems with the other four:
- Merck & Co.’s Lyfnua (gefapixant) for chronic cough has received two complete response letters saying effectiveness had not been established, in particular citing the cough counting system used to assess efficacy. The first CRL came in January 2022, well before the 15 September 2023 EU approval. (Also see "FDA Panel Rejects Merck’s Gefapixant For Chronic Cough, Calls For Better Endpoints" - Pink Sheet, 18 November, 2023.)
- Eli Lilly and Company’s Ebglyss (lebrikizumab) has only received one CRL, spurred by a multi-sponsor inspection of a third-party contract manufacturer. The CRL was announced a month before the 16 November 2023 EU approval.
- FDA turned down Immedica AB/Aeglea BioTherapeutics, Inc.’s Loargys (pegzilarginase) earlier in the process with a mid-2022 refuse to file letter. The EU cleared the drug more than a year later, on 15 December 2023.
- Ascendis Pharma A/S’ palopegteriparatide, approved as Yorvipath in Europe and known as TransCon PTH in the US, is on its second FDA review cycle. The FDA issued a CRL citing manufacturing control strategy problems, including the variability of the delivered dose, in April 2023, seven months before EU exceptional circumstances authorization on 17 November 2023. Ascendis’ resubmitted NDA has a 14 August goal date in the US.
The FDA and the EC concluded that GSK plc’s Jesduvroq (daprodustat) was only suitable for the dialysis-dependent component of the broad requested indication for anemia in chronic kidney disease patients.
While the FDA approved Jesduvroq for dialysis-dependent CKD only and issued a CRL for non-dialysis dependent patients, the CHMP returned a negative recommendation that convinced GSK to withdraw the MAA. (Also see "GSK Pulls EU Filing For Jesduvroq In CKD Anemia After Label Narrowed" - Pink Sheet, 18 July, 2023.)
As of the end of April, the CHMP had cleared four of the MAAs pending for drugs approved by the FDA in 2023-April 2024. Two of them went on to EC approval in May. Biogen’s Qalsody (tofersen) earned exceptional circumstances approval on 29 May, while Novartis’s Fabhalta (iptacopan) got the nod on 17 May.
Still pending after the April CHMP meeting returned two more positive opinions for pending new active substances already approved in the US are Sanofi’s Altuviiio/Altuvoct (antihemophilic factor, recombinant, Fc-VWF-XTEN fusion protein) and Takeda/HUTCHMED (China) Limited’s Fruzaqla (fruquintinib).
COVID-19’s Long Tail
Fruzaqla illustrates the path taken by many drugs originating with companies based in Asia. Fruzaqla was developed in China, where it was approved in 2018, five years before the FDA cleared the colorectal cancer drug. The agency’s need for clinical trial data in patients representative of the US and its standard medical practice helps prolong the time between approval in China, Japan or South Korea and approval in the West.
The COVID-19 pandemic placed more hurdles for the burgeoning Chinese pharma sector’s worldwide expansion plans. The country was slow to remove strict travel restrictions, keeping inspectors away from manufacturing and clinical sites in China.
Like Fruzaqla, BeiGene’s Tevimbra (tislelizumab) has been approved since December 2019 in China. The company says it is “the leading PD-1 inhibitor in the country” with 11 indications. Tevimbra was approved by the EMA in September 2023, the same month Novartis dropped out of a collaboration.
FDA approval came six months after the EU, and 20 months after the agency’s own user fee goal date. (Also see "BeiGene’s Tevimbra And The End Of The COVID Inspection Era" - Pink Sheet, 16 March, 2024.)
Six of the FDA’s 2023-April 2024 approvals came after their user fee goal date because COVID-19 delayed inspections, mostly in China.
Of those, Amicus Therapeutics’s Pombiliti (cipaglucosidase alfa), like Tevimbra, received EU clearance before the US. Evive Biotech/Acrotech Biopharma’s Ryzneuta (efbemalenograstim alfa) was approved by the FDA almost 20 months after its user fee goal date, but waited another four months for eventual EU approval. Coherus/Junshi Biosciences’s Loqtorzi (toripalimab) was approved by the FDA in October 2023, but European evaluation has been ongoing since December 2022.
UCB’s NDA for Bimzelx was initially delayed by COVID-19, then by inspection findings and a safety signal, before finally receiving approval 17 October 2023. The EU, in contrast, had approved Bimzelx on 21 August 2021.
The FDA’s user fee goal, 15 October 2021, was only a few months later than the EU approval date, but was missed while COVID-19 prevented an FDA inspection of UCB’s manufacturing operations in Belgium.
When travel was possible, the findings led to a May 2022 complete response letter. The FDA prolonged its review of the resubmission so the agency could evaluate new concerns about suicidal ideation and behavior. (Also see "US FDA’s Missed User Fee Goals Spiked In 2023 – And Not Just Because Of COVID-19" - Pink Sheet, 16 January, 2024.)
Alternate Routes To The European Market
Six of the 90 FDA-approved drugs were available in Europe first, but not through the centralized EMA pathway for new active substances.
Three of the products classified as NMEs by the FDA were not seen as new drugs by the EMA. Bausch + Lomb Inc./Novaliq GmbH’s dry eye therapy Miebo (perfluorohexyloctane) received CE Mark clearance as a class IIa device almost 10 years prior to FDA approval as an NME. The product is currently marketed in Europe by URSAPHARM Arzneimittel as EvoTears.
EU Drug Approval Procedures
The EU has three drug approval procedures for seeking marketing authorization in more than one member state. It also offers the possibility of a purely national procedure for seeking approval in a single country.
The Centralized Procedure (CP): This is compulsory for new drugs derived from biotechnology processes such as genetic engineering, for advanced therapies such as gene therapy, somatic cell therapy and tissue engineered products, and for biosimilar medicines. It is also mandatory for new drugs in certain therapeutic areas, such as AIDS, cancer, neurodegenerative disorders, diabetes, autoimmune diseases and viral diseases, and for drugs with an orphan designation. It can also be used for generic versions of centrally authorized medicines.
Use of the CP is optional for medicines containing new active substances for disorders other than those stated above, that represent a significant therapeutic, scientific or technical innovation, or whose authorization would be in the interest of public health at EU level.
The Decentralized Procedure: This is used to apply for marketing authorization in more than one EU member state at the same time. It can be used for medicines that do not need to be authorized via the CP and have not already been approved in any EU country. The reference member state (RMS) evaluates the marketing authorization application (MAA) and produces an assessment report (AR) that is circulated to the other concerned member states (CMS). The RMS and CMS then make their national approval decisions based on the AR.
The Mutual Recognition Procedure: This is used to gain national approvals when an RMS has already issued a marketing authorization. The assessment report produced by the RMS forms the basis for further MAAs in the other concerned member states.
Companies can also choose to take the national marketing authorization route, for example where approval in only one member state is needed.
Botanical wound healing drug Filsuvez (birch triterpenes gel) and enzyme replacement therapy Elfabrio (pegunigalsidase), both now at Chiesi, were not considered new active substances in the EU. Elfabrio was okayed in Europe only a few days before its FDA approval, while Filsuvez was cleared in Europe more than a year before the US.
The EU’s decentralized pathway brought two therapies to at least some patients in Europe long before the US FDA approved them. Octapharma’s Balfaxar (prothrombin complex concentrate, human), first known as Octaplex, has been used under Norway’s national plasma fractionation project since 1997, and went on to its first official approval in Germany in 2003.
Ceftobiprole, the antibiotic approved by the FDA as Switzerland-based Basilea Pharmaceutica’s Zevtera on 3 April, has a long and convoluted history, including European clearance as Janssen/Cilag’s Zeftera from 2008 until its withdrawal in 2010.
In the US, an equivalent Zevtera NDA originally submitted in 2007 went on to receive three complete response letters, and Basilea discontinued the program in 2014. But in Europe, Zeftera returned under decentralized procedures in 2013 for a new set of indications. Almost 11 years later, the FDA approved a new NDA for an even broader range of claims.
The Zevtera/Zeftera saga touches many of the factors making antibiotics difficult products to develop and sell. Regulatory expectations and endpoints differ between the regulators while evolving internally. Basilea has become one of the more established independent specialty players in the not exactly crowded antibiotics field, capable of sponsoring programs on both sides of the Atlantic.
The other novel antibiotic product on the 2023-2024 list followed a quicker path to market. The FDA and centralized EU approvals of Exbiflep (cefepime/enmetazobactam) were only a month apart.
However, the indications and sponsors differed. Allecra licensed European development and commercialization rights to ADVANZ PHARMA in early 2022.
The FDA cleared Allecra’s NDA on 22 February for complicated urinary tract infection. Advanz saw the EC approve Exbiflep on 21 March for cUTI, as well as hospital- and ventilator-associated pneumonia and associated bacteremia.
Coming Attractions
US-first approvals dominated the lineup of 1 January 2023-30 April 2024 novel approvals by the FDA and the EC, but that does not appear to portend a future full of US-only approvals.
Of 90 US FDA approvals, 49 went to products that were not approved under any pathway in Europe. Less than half of those drugs (43%) had MAAs under review. Four of the 21 MAAs have received a positive opinion from the EMA’s Committee on Human Medicinal Products, a key step before European Commission approval.
The pending MAAs moving towards the EMA’s CHMP includes a large cohort of rare disease therapies. Of the 17 candidates, nine were designated orphan drugs by the FDA.
Four of the 17 are oncologics, including three that qualified for the FDA’s marquee expedited development status, the breakthrough therapy designation: Bristol Myers Squibb’s Augtyro (repotrectinib), SpringWorks Therapeutics’s Ogsiveo (nirogacestat), and Loqtorzi.
Nine of the 17 pending MAAs held breakthrough therapy designations in the US, and two held the newer biologics-focused regenerative medicine advanced therapy (RMAT) designation, including Beqvez, which held breakthrough and RMAT designations.
At least four more have projected MAA filings over the coming year, all in orphan diseases: Elevidys, Amtagvi, X4 Pharmaceuticals’s Xolremdi (mavorixafor) and Acadia’s Daybue (trofinetide).
Patients in the US may get the first look at these drugs, but the European Union will catch up.
This analysis drew on the Pink Sheet’s suite of regulatory tracking tools, including the US FDA Performance Tracker’s Novel CDER Approvals, Novel CBER Approvals and User Fee Goal Dates charts and the European Performance Tracker’s EU Approvals and EU CHMP Opinions & MAA Updates charts.
