The European Union’s authorization of CTI BioPharma Corp.’ Pixuvri (pixantrone) for the treatment of non-Hodgkin B-cell lymphomas is perhaps paving the way towards a greater acceptance of the conditional and, potentially in the future, staggered approval entry systems.

The Commission’s confirmation of the European Medicines Agency’s conditional approval of Pixuvri on Feb. 16 must come as a welcome relief to Cell Therapeutics, given that the company felt obliged to withdraw its NDA for the drug in the US in January this year Also see "Saving Face? Cell Therapeutics Withdraws Pixantrone NDA Ahead Of Advisory Committee Review" - Pink Sheet, 30 January, 2012..

An Annual Review On Safety Grounds

The EU authorization allows CTI to market Pixuvri in all 27 EU Member States, as well as Iceland, Liechtenstein and Norway, but a full marketing authorization will only be granted on the provision of positive results from the PIX306 randomized, controlled, Phase III clinical trial, which should be available by June 2015. In the meantime, the company will have to renew the authorization on an annual basis until the EMA is satisfied with the PIX306 trial data.

“Currently, there are over 100 sites in the study in North America that are open for enrolment [for the PIX306 trial] and we’re hoping to open an additional 22 sites in Western Europe over the course of this year,” a spokesperson for the company said.

Until the results are published, Pixuvri will be available as monotherapy for the treatment of adult patients with multiply relapsed or refractory aggressive non-Hodgkin B-cell lymphomas (NHL). The EMA’s Committee for Medicinal Products for Human Use, the agency’s senior scientific body, said the product’s benefits outweighed its risks and that there was a greater response to the drug than with comparator chemotherapy (20% v. 6%).

And the company is making strides towards expanding the role of the drug to the pediatric sector. CTI submitted an updated Pediatric Investigation Plan to the EMA’s Pediatric Committee (PDCO) in July 2010 after recommendation that CTI expand the original PIP to include pixantrone’s potential clinical benefit of reducing long-term cardiotoxicity associated with current curative therapies in children. The pediatric program studies pixantrone in pediatric patients age 6 months to 18 years with the goal of determining the comparative safety and effectiveness of pixantrone compared to doxorubicin in pediatric lymphoid cancers.

The PDCO began reviewing the expanded PIP in August 2010 and approved it in November that year. But the PDCO also recommended deferral of the initiation of the clinical studies until after the drug receives EMA approval.

CTI, meanwhile, has other major battles ahead as it seeks to navigate the myriad of European health technology assessment systems in order to qualify Pixuvri for reimbursement. And with Germany tightening its data requirements – a fact to which the latest decision from the Institute for Quality and Efficiency in Healthcare can attest – it will have its work cut out Also see "European HTA Highlights: Discounts Soften NICE Approach But Germany’s IQWiG Shows Its Teeth" - Pink Sheet, 16 April, 2012.. But the company knows the product’s “unmet medical need” designation will play in its favor. “CTI is currently working with national payers on developing a dossier to support reimbursement,” the spokesperson said.

The Rise Of The Conditional And Staggered Approval

EU’s conditional approval, like its staggered approval, has a clear aim: to speed access, while maintaining a high level of safety. Also, in both cases, additional information would be required further down the line in the form of study results or real-life data. At the same time, the two are legally distinct from each other and apply to different types of drugs.

In order to qualify for conditional approval status, a drug must fulfill an unmet medical need. This is laid down in a definitive regulation and guideline. The drug should be aimed at treating a seriously debilitating or life-threatening disease, be designed for use in emergency situations, or be developed as an orphan medicinal product for the treatment of a rare disease.

But use of the conditional approval system, since its introduction in 2007, is relatively rare. By the end of February this year, the process had only been used 15 times. Two products were withdrawn before completion: GlaxoSmithKline Inc.’s H1N1 Vaccine Arepanrix and Sanofi’s H1N1 vaccine Humenza; both contained split influenza virus, inactivated, containing antigen: A/California/7/2009 (H1N1)v like strain (X-179A.

Of the remaining 13, eight are still approved as conditional and for five the authorization has been transformed into a full marketing authorization. Interesting products that have been through the process include Biogen Inc.’s MS drug Fampyra (fampridine), GlaxoSmithKline Inc.’s breast cancer treatment Tyverb (lapatinib) and AstraZeneca PLC’s Caprelsa (vandetanib) for medullary thyroid cancer.

The staggered approval system – also called adaptive/progressive licensing – could kick in where a medicine simply does not qualify for conditional approval and where the focus is on a broad patient population. “The main difference right now is that the conditional marketing authorization exists; adaptive licensing – not quite,” a spokesperson for EMA said.

EMA is set to launch pilot projects by the end of the year to evaluate the staggered approval process, which industry hopes should speed up entry for more complex molecules.

Pixuvri’s Conditional EU Approval Could Herald The Rise Of Staggered Approval

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