EU Authorization Before US? Biologics Manufacturing Is Likely To Blame

Contract manufacturing of biologics is one of the few weak points in the typically overwhelming advantage the US holds over Europe in bestowing the first approval for new drug products, a Pink Sheet analysis of approvals by the US FDA and European Commission showed.

Biologics dominate the list of new products approved in the European Union before US approval. Only four new molecular entities appear on the list of 22 EU-first products identified in the 2024 and 2025 approval cohorts by the Pink Sheet. (See chart below.)

The US historically has been the overwhelming first choice of market for new drugs and biologics. The trend is holding in 2025 despite upheaval at the US FDA.

A total of 37 new drugs and biologics have received approval by the US Food and Drug Administration, the European Commission or both. European approval came first for only 10 products.

In the US, the 2025 novel agent count reached 17 with the 16 May approval of Novavax‘s COVID-19 vaccine Nuvavoxid, a COVID-19 vaccine that received European Commission clearance on 20 December 2021. The EC approval also came before Nuvaxovid’s 13 July 2022 emergency use authorization (EUA) in the US.

Only one other novel 2025 approval by the FDA lagged behind the EU: medac GmbH and Medexus’ Grafapex (treosulfan). The FDA also issued a January 2025 complete response letter to one novel biologic that had received EU clearance, Atara Biotherapeutics‘ cell therapy Ebvallo (tabelecleucel), citing manufacturing concerns.

Eight of 22 new approvals by the European Commission in 2025 came before US action. Three of the eight address COVID-19: Arcturus Therapeutics’ Kostaive (zapomeran), the first self-amplifying mRNA COVID-19 vaccine, AstraZeneca‘s long-acting antibody Kavigale (sipavibart) for pre-exposure prophylaxis in immunocompromised adults and adolescents, and InflaRx‘s Gohibic (vilobelimab) to treat COVID-19-induced acute respiratory distress syndrome.

Gohibic is available in the US under a 4 April 2023 EUA, but has never gained full biologics license application approval. On 12 May, Arcturus predicted a BLA filing for Kostaive in the third quarter of 2025, but delays and a limited indication for Novavax’s Nuvavoxid may dampen enthusiasm for the US market, especially if Moderna‘s next-generation mRNA COVID-19 vaccine candidate faces similar challenges as its 31 May user fee goal approaches.

The previous year, almost 80 separate new products were approved in the US and/or the EU. The European Commission authorized 37 new active substance-containing products in 2024, while the US FDA approved 61 novel agents.

More than 30% of medicines approved in the US were not available in Europe after two years, the CEOs of Novartis and Sanofi noted in an April letter to the Financial Times. The executives argued European price controls and austerity measures “reduce the attractiveness of its markets.”

Asia is overtaking Europe as the source of previously approved novel agents moving to the US. The FDA Center for Drug Evaluation and Research calculated that 68% of its 2024 novel approvals were first in the world. The Center for Biologics Evaluation and Research found 64% of its novel approvals were first in approved in the US.

Europe was the site of the first approval for only six of the 20 novel agents that were approved outside the US prior to 2024 clearance. Many of the products held decentralized approvals in specific countries in Europe.

The story continues after the chart …

Of the 22 products out of the combined 2024-2025 group that cleared the EU first, nine also followed up with FDA approval. Five applications are currently under FDA review, and the sponsors of two others are assessing complete response letters from the FDA.

Quality: Biologics’ Achilles Heel

The concentration of biologics in the EU-first products reflects the FDA’s stringent biologics quality review.

Complex manufacturing requirements are a growing source of multi-cycle reviews of biologics at the FDA. Facilities issues were the largest and fastest growing topic area in a 2014-2024 FDA analysis of complete response letters for biologics regulated by the FDA’s CDER, which is responsible for most therapeutic biologics aside from regenerative medicine and vaccines.

Contract manufacturing operations were half of all facility deficiencies, the CDER study found. Third-party contract manufacturing accounted for five of eight quality-related CRLs issued by the FDA to products in the EU-first cohort, more than any other single topic.

A multi-sponsor inspection of a third-party contract manufacturing organization spurred the FDA’s CRL for Lilly‘s Ebglyss (lebrikizumab). Lilly had planned for simultaneous review of the BLA and the MAA, which were submitted within days of each other, but the company received the CRL on 28 September 2023. The European Commission approved Ebglyss on 16 November 2023.

The lebrikizumab CRL described concerns about the reliability of data supporting the comparability of commercial and clinical materials. The FDA also advised the sponsor to hire a third party to conduct a comprehensive assessment of data reliability.

The FDA eventually approved Lilly’s resubmitted Ebglyss BLA on 13 September 2024, almost 10 months after EU approval.

Regeneron‘s Lynozyfic (linvoseltamab) also was submitted at about the same time in the US and EU. The FDA acted first, issuing a CRL in August 2024, but the EC beat the FDA to approval, authorizing Lynozyfic on 23 April. Regeneron responded to the CRL, and has a 10 July user fee goal for linvoseltamab in the US.

The CRL cited findings from a pre-approval inspection at a third-party fill/finish manufacturer for another company’s product candidate, which would be filled on the same manufacturing line as linvoseltamab, the company said.

“The kinds of issues that have come up are reflecting, in my view, an increased scrutiny by the FDA post-COVID on contract manufacturers performing a variety of functions,” Regeneron CEO Len Schleifer told a first quarter earnings call. “The FDA has recognized that third-party suppliers were woefully behind the times during COVID.”

Third-party supplier issues also were cited in CRLs for line extensions of Regeneron’s Eylea.

Astellas’ Vyloy (zolbetuximab-clzb) only had a one month lag between EU approval and US approval, although the US BLA was submitted about three weeks before the MAA. After a pre-license inspection of a third-party manufacturing facility, the FDA issued a 4 January 2024 CRL citing deficiencies and advising modifications to drug product release. The letter also suggested additional validation of a test used in drug product stability testing.

For Atara’s off-the-shelf T-cell immunotherapy Ebvallo (tabelecleucel), third-party manufacturer issues drove a January CRL, as well as a clinical hold on trials of tab-cel and another Atara cell therapy.

In Europe, Atara’s partner Pierre Fabre began a country-by-country launch for Ebvallo in early 2023 after receiving EC marketing authorization under the “exceptional circumstances” regulatory pathway in December 2022. Atara did not move in the US until BLA submission in May 2024.

“The clinical hold is directly linked to inadequately addressed Good Manufacturing Practices (GMP) compliance issues referenced in the response letter,” the company said in its annual SEC filing. “We are currently undertaking efforts to support this third-party manufacturer.”

Atara completed transfer of all worldwide manufacturing and supply responsibility to Pierre Fabre in March. On 15 May, Atara announced the FDA lifted the clinical holds. A second quarter date is upcoming for a Type A meeting to address the CRL.

FDA Concerns, From Toxicity …

Liver safety proved a sticking point for FDA approval of Akebia Therapeutics’ Vafseo (vadadustat). The oral drug was authorized by the EC on 24 April 2023, beating the US approval by 11 months despite the European filing coming seven months after the NDA.

Foreign data turned out to be important to resolving FDA concerns about hepatoxicity, but the data came from Japan, where vadadustat has been available since August 2020. After an unsuccessful formal dispute resolution bid to challenge the March 2022 CRL, Akebia also agreed to narrow Vafseo’s indication.

… To Data Integrity …

Medexus Pharmaceuticals and medac GmbH’s alkylating agent treosulfan claimed the longest gap between EU authorization and subsequent US approval in the 2024-2025 class: 67.1 months.

The extent of foreign experience was less persuasive to the FDA for treosulfan, which was introduced in some individual European countries as an oral formulation in 1973 and an IV formulation in 1996 for palliative treatment of ovarian cancer. Medac obtained centralized EU authorization in June 2019 as conditioning therapy prior to allogeneic hematopoietic stem cell transplantation under the name Trecondi.

In the US, treosulfan was approved 21 January as Grafapex. The companies initially submitted an NDA in 2020, which drew a CRL in July 2021 stating the FDA could not confirm the event-free survival primary endpoint because “all complete blood cell (CBC) and bone marrow results were not submitted to support adjudication of the endpoint,” FDA review documents state.

The FDA said the first two attempts made by the sponsors to respond to the CRL were incomplete, citing continued inconsistencies and missing assessments. At a December 2022 Type A meeting, the FDA said, “we have no confidence in the marrow data submitted in the datasets.”

Ultimately, the third CRL response was accepted in April 2024, which included a “systematic review of all source documentation of bone marrow evaluations,” the FDA said.

… Comparability …

PTC Therapeutics’ gene therapy Kebilidi (eladocagene exuparvovec) was submitted in the US four years after the EU application was filed. Even with a single-cycle approval, Kebilidi’s 14 November 2024 FDA clearance came more than two years after European authorization as Upstaza.

One key factor driving the lag was the comparability assessment between the clinical trial and commercial drug product.

Upstaza’s EU approval was based on two open-label studies conducted in Taiwan, but the FDA determined the manufacturing process for the Taiwan studies was not comparable to the product to be marketed in the US. Another study was required.

… And Confirmatory Evidence

In March 2024, Regeneron’s Ordspono (odronextamab) received what the company called the first CRL for a product seeking accelerated approval because of the confirmatory trial status. The CRL relied on authority granted under the 2022 Food and Drug Omnibus Reform Act (FDORA) to require confirmatory trials be underway at the time of accelerated approval.

Regeneron submitted Ordspono applications for the EU and US in late summer 2023, emerging 13 months later with European authorization, the first odronextamab approval in the world.

The FDA wanted the confirmatory portion of the Phase III OLYMPIA trial to be underway, not just the dose-finding portion.

Regeneron resubmitted odronextamab in the US, and expects FDA action by its 30 July user fee goal. However, the product was resubmitted only for one of the two indications originally sought, relapsed or refractory follicular lymphoma, while the EC authorized for the FL and diffuse large B-cell lymphoma indications.