EU Accelerated Assessment – Hard To Get, Hard To Keep
Executive Summary
It’s hard enough in the first place for companies to persuade the European Medicines Agency that their planned marketing authorization application should be fast-tracked. Many are also finding that after accelerated assessment is granted, it is taken away during the actual review.
Many of the marketing authorization applications (MAAs) that until recently were being evaluated under the European Medicines Agency’s accelerated assessment mechanism have reverted to standard review timelines. The MAAs relate to products such as AveXis’s gene therapy, Zolgensma, and several other products that, like Zolgensma, have already been approved in the US.
Seven MAAs that were originally granted accelerated assessment and were initially being processed under this mechanism are no longer undergoing speedy review, according to the latest monthly list of products being reviewed under Europe’s centralized evaluation procedure at the EMA.
It appears that just four MAAs are currently being fast-tracked.
Fast-track review in the EU is reserved for products that are expected to be of major public health interest, particularly from the point of view of therapeutic innovation. The mechanism reduces the time it takes the EMA to evaluate an MAA from 210 days to 150 days (not counting clock stops when applicants have to provide additional information). Fast-track requests should be made at least two to three months before the MAA is submitted.
Around half the requests companies make to the EMA for accelerated assessment are rejected. In 2019 to date, just three out of the nine requests processed have been granted.
The seven MAAs that have reverted to standard review relate to the following products:
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Shionogi’s investigational antiobiotic agent, cefiderocol.
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Stemline Therapeutics’ tagraxofusp (Elzonris) for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare blood cancer.
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Onasemnogene abeparvovec/AVXS-101 (Zolgensma), the gene replacement therapy from Novartis/AveXis for the treatment of spinal muscular atrophy (SMA).
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Theratechnologies/TaiMed Biologics’ new HIV therapy, ibalizumab (Trogarzo).
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Daiichi Sankyo Europe’s acute myeloid leukemia (AML) therapy, quizartinib (Vanflyta).
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Karyopharm Therapeutics’ multiple myeloma drug, selinexor (Xpovio).
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The tissue-agnostic cancer treatment, larotrectinib (Vitrakvi), from Bayer/Loxo Oncology.
Some of the products have been approved elsewhere but there have often been problems along the way. One product – Daiichi Sankyo’s AML therapy, quizartinib – was approved in Japan but rejected in the US.
Importance Of Robust Data
Asked to comment on the high number of switches from accelerated to standard review, the EMA said it was important to note that marketing applications should be mature in terms of the data submitted at the start of the evaluation.
The agency further noted: “Requests for accelerated assessment are voluntarily made by the applicants and should be duly substantiated. In order to meet the short timelines of the assessment, applicants are strongly advised to enter [in timely manner] in a dialogue with the EMA to prepare for an evaluation under accelerated assessment.”
In at least three of the cases in hand, a scientific advisory group was or will be convened by EMA's reviewing committee, the CHMP, as part of the assessment of the MAA.
The Companies Explain
The Pink Sheet contacted all the companies involved for comment. Six replied, providing various levels of detail. Only Stemline did not respond.
AveXis And Zolgensma
With regard to Zolgensma, AveXis Inc. said that being on a standard approval timeline would “give the [EMA] the time they need to review the robust amount of data we are providing to answer their questions.”
It added that it continued to work closely with European regulators during their review of its product and that it was anticipating a potential approval in the second half of 2019.
According to Kacper Rucinski, a London-based executive board member of the nonprofit group SMA Europe, the EMA "has quite a significant number of questions for AveXis". He added: "My understanding is that the EMA wants to very thoroughly review the data and the scope of approval."
Zolgensma was approved in the US for all three types of SMA at the end of May. (Also see "Novartis CEO Calms Concerns Over Zolgensma launch " - Scrip, 18 Jul, 2019.) There is considerable interest over what is happening in Europe, where, even if Zolgensma is approved, there will be a struggle to get individual countries to agree to cover the $2m treatment.
Of the seven products whose accelerated review has reverted to standard timelines, Zolgensma is the only one receiving support under PRIME, the EMA’s priority medicines scheme. Products in PRIME are expected to undergo accelerated assessment.
Karyopharm And Selinexor
Karyopharm told the Pink Sheet that it submitted its MAA to the EMA in January requesting conditional approval for selinexor, in combination with dexamethasone, as a new treatment for patients based on the results of the Phase 2b STORM study in patients with triple class refractory multiple myeloma who were previously exposed to all five of the most commonly prescribed anti-myeloma therapies currently available.
The company said: “As a customary part of the marketing application review process, Karyopharm received the consolidated list of questions from EMA in early May 2019 and anticipates receiving additional feedback based on routine site audits and other activities. To provide adequate time to evaluate the application and allow Karyopharm to respond to questions and feedback, the EMA has switched from an accelerated review to a traditional review. We expect to receive a decision on the application by the end of 2019.”
Selinexor was approved as Xpovio in the US on 3 July with an accelerated approval, despite a Food and Drug Administration advisory panel having said that approval should be delayed until results of the randomized Phase III BOSTON trial were available. Full top-line results from BOSTON are not expected until the end of the year. (Also see "Karyopharm Selinexor Approval Likely Awaits BOSTON Trial, But US FDA Promises To Move Quickly" - Pink Sheet, 26 Feb, 2019.) (Also see "Keeping Track: US Approvals For Xpovio And Xembify Highlight Short Holiday Week" - Pink Sheet, 5 Jul, 2019.)
Theratechnologies/TaiMed And Ibalizumab
Theratechnologies said that the MAA for it and TaiMed's ibalizumab was switched to a standard procedure when the CHMP requested a scientific advisory group for its application. This “delayed the review slightly,” Theratechnologies Inc. added.
The CHMP aimed to convene its scientific advisory group for HIV/viral diseases in early April. Theratechnologies said in a statement in late May that it had requested and obtained from the EMA an additional month to address new questions it had received in regard to the establishment of a post-approval registry to gather long-term data on patients taking ibalizumab in Europe.
The company said at that time that it would submit responses to the EMA by the end of June, after which the CHMP would then have 30 days to provide a recommendation on whether ibalizumab should be approved in Europe. “Assuming a positive CHMP opinion, our plans to launch in Germany before the end of the year remain unchanged,” it said. The timelines cited by Theratechnologies suggest that ibalizumab should be among the MAAs up for an opinion from the CHMP at its next monthly meeting, which takes place on 23-25 July.
Approved in the US in early 2018, ibalizumab/Trogarzo was the first HIV therapy with a new mechanism of action to reach the market in 10 years.
Daiichi Sankyo’s Quizartinib
Daiichi Sankyo confirmed that the CHMP had determined that the standard review period would be required to review the MAA for quizartinib. It added that it was “not uncommon” for MAAs to revert to the standard review timeline during the EMA’s review process.
In the US, the FDA issued Daiichi Sankyo with a complete response letter for quizartinib in June this year, just days after it secured its first approval - in Japan, as Vanflyta. An FDA advisory committee had voted 8-3 against an approval in mid-May, after questions over persuasive evidence of efficacy. (Also see "Keeping Track: FDA OKs AMAG's Vyleesi, But Bronchitol And Quizartinib Draw CRLs" - Pink Sheet, 21 Jun, 2019.) (Also see "AML Contender Quizartinib Gains First Approval, In Japan " - Scrip, 20 Jun, 2019.)
Bayer/Loxo And Larotrectinib
Regarding the status of the MAA at the EMA for Loxo Oncology and Bayer AG’s larotrectinib, Bayer said only that it was currently in discussions with the regulatory authorities, that it could not share details from those discussions, and that it would provide updates as they became available.
Bayer and Loxo (now owned by Eli Lilly) are jointly developing larotrectinib. They are seeking approval in the treatment of adult and pediatric patients with locally advanced or metastatic solid tumors (excluding primary central nervous system tumors) with a neurotrophic tyrosine receptor kinase (NTRK) gene fusion after prior standard therapy or as initial therapy when there is no adequate treatment option.
In November 2018, larotrectinib was approved in the US, where it is marketed as Vitrakvi. (Also see "Vitrakvi, Daurismo Approvals Put US FDA On Brink Of Another Record " - Pink Sheet, 27 Nov, 2018.)
Shionogi And Cefiderocol
Like Daiichi Sankyo, Shionogi chose to point out that it was not unusual for accelerated assessments to revert back to standard review. "This is reflective of the complexity within this treatment area and may explain why no antibacterials to date have been approved through this route," it told the Pink Sheet. "Shionogi wish to allow enough time to thoroughly complete the review process in order to bring cefiderocol to market as quickly as possible so all suitable patients can receive this treatment," it added.
Shionogi was granted accelerated assessment for two separate planned MAAs involving cefiderocol. One covered the treatment of infections caused by carbapenem-resistant gram-negative bacteria in adults with limited treatment options and the other covered treatment of infections caused by aerobic gram-negative bacteria in adults with limited treatment options.
The MAA under review is for the latter indication, which, Shionogi pointed out, is "the more extensive of the two". This label incorporates the other indication, it said.
Cefiderocol has yet to be approved in any market, according to Informa's Biomedtracker.
Stemline And Tagraxofusp
Stemline Therapeutics is seeking approval of its CD123-directed cytotoxin tagraxofusp for the treatment of adult and pediatric patients, two years or older, with BPDCN.
The company noted earlier this month that the tagraxofusp MAA review would proceed on a standard timeline and that it expected the CHMP to issue an opinion later this year on whether the product should be approved for marketing in the EU. A scientific advisory group meeting is planned for September as part of the review.
If its MAA is successful, Stemline is targeting a commercial launch in Europe in the first quarter of 2020. In the meantime, the company continues “to build out a European commercial infrastructure in advance of potential approval.
Tagraxofusp was approved in the US in December 2018, achieving one of the fastest novel product review times of the year, at exactly six months. (Also see "Keeping Track Of The US FDA's Final Approvals Of 2018" - Pink Sheet, 2 Jan, 2019.) Marketed as Elzonris, it was the first drug to be approved for BPDCN in the US, where it has the following black box warning: “Capillary Leak Syndrome (CLS), which may be life threatening or fatal if not properly managed, can occur in patients receiving Elzonris.”
Trackers
The EMA told the Pink Sheet that it only began proactively identifying products no longer being reviewed under the accelerated assessment program in June. The aim is to increase transparency and clarity about the procedure, it said.
The status of all MAAs granted accelerated assessment since the beginning of 2018 is recorded in the table below. For details of the outcome of all fast-track requests made in 2018 and in 2019 to date, see the latest edition of the Pink Sheet’s EU Accelerated Assessment Tracker.
This article and the table below were updated on 24 July to reflect the fact that Alnylam has filed for EU approval of givosiran.