Pharmaceutical manufacturers who gain a conditional marketing authorization from the European Union should tread cautiously when seeking U.K reimbursement for the product, an April 11 NICE decision on CTI BioPharma Corp.’s Pixuvri underscores.

The National Institute for Health and Care Excellence gave an unfavorable review to Pixruvi in its authorized indication on the basis that the data used for conditional authorization is not sufficient for the agency’s approval. And the agency has previously shown it will be ready to pull a positive recommendation should a conditionally authorized drug falter. (NICE amended its name at the start of April to reflect its new responsibilities in the area of social care.)

The agency refused to recommend Pixuvri (pixantrone) for treating multiply relapsed or refractory aggressive non-Hodgkin's lymphoma on the grounds that there is insufficient evidence to show that the drug is more effective than current British National Health Service treatments and is not cost-effective. “Unfortunately in this case, the clinical trial evidence submitted to the Appraisal Committee highlighted a number of uncertainties that called into question the true benefit people might receive from this treatment,” said NICE Chief Executive Sir Andrew Dillon. The agency also criticized CTI’s study as underpowered as well as the company’s choice of endpoints.

The recommendation is part of an appraisal consultation determination and there is a long way to go before NICE issues a final decision.

The EU granted the drug a conditional marketing authorization in May 2012 as monotherapy for the treatment of adult patients with multiply relapsed or refractory aggressive non-Hodgkin B-cell lymphomas (NHL). For CTI to gain a full marketing authorization, it must undertake a study to further investigate the effects of using Pixuvri in patients who had received prior treatment with Roche’s MabThera (rituximab). Full marketing authorization will depend on positive results from the Phase III PIX306 trial, a randomized trial investigating pixantrone plus rituximab versus gemcitabine plus rituximab in patients with relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma who have previously received a rituximab-containing regimen.

“This trial is due to be completed in 2015 and is intended to support the conversion of our EU conditional approval to a full approval,” CTI said in a written statement.

The short-term challenge for CTI is that rituximab is given as part of standard first-line treatment in the U.K. The main evidence for the conditional authorization comes from PIX301, a randomized, controlled, open-label Phase III study conducted in 66 centers, including sites in the U.S. and Europe. NICE noted that a large proportion of trial subjects were recruited from outside the UK/EU and of these 37.2% had previously received rituximab because it was not available in all participating countries.

The company remains optimistic about Pixuvri’s U.K. prospects, saying that it does have evidence available to demonstrate the cost effectiveness of pixantrone in this indication. “NICE chose to focus its review on a retrospectively determined subset of the study population across all lines of therapy, rather than on the population of patients for whom the drug has been licensed -- third or fourth line therapy. This is where benefit was established irrespective of whether patients previously received rituximab as first or second line treatment,” the statement said.

NICE has reviewed other drugs granted a conditional marketing authorization. In 2008, the agency published guidance on the use of Sanofi’s Accomplia (rimonabant) for the treatment of overweight and obese patients, but then withdrew it after the European Medicines Agency’s October 2008 suspension of the product’s marketing authorization due to increased risk of psychiatric disorders Also see "Sanofi’s Rimonabant Off The European Market; CHMP Finds Risk Management Plan Does Not Adequately Address Depression" - Pink Sheet, 23 October, 2008..

NICE also published a 2006 clinical guideline on the prevention, identification, assessment and management of overweight and obesity in adult and children which included recommendations for treatment with Abbott Laboratories Inc.’s Reductil (sibutramine). The drug’s marketing authorization was suspended in 2010 after the EMA found that the cardiovascular risks of sibutramine outweigh its benefits. NICE subsequently withdrew its recommendations.

Potentially Well Positioned To Fill A Gap

Pixuvri is an aza-anthracenedione analogue and inhibitor of topoisomerase with a new mechanism of action that is associated with lower cardiotoxicity compared with related drugs, including anthracyclines. The lower cardiotoxicity could be an overall advantage for the drug, but the initial scope of NICE’s review does not include any anthracyclines as comparators

Pixuvri would be well placed to fill a treatment gap in the U.K., because current therapy options for patients in the NHS range from participating in clinical trials (depending on eligibility and willingness to participate) to receiving palliative care. However, it has come up against some formidable hurdles at NICE.

The cost watchdog was unconvinced about the PIX301 trial’s design, considering it to be underpowered because it had failed to recruit the planned number of patients. FDA also critiqued the trial design back in March 2010 Also see "Cell Therapeutics Should Consider Different Trial Design For Pixuvri, FDA's Pazdur Says" - Pink Sheet, 22 March, 2010.. Cell Therapeutics withdrew its NDA for the drug prior to an FDA advisory committee review.

NICE also noted that European regulators generally prefer a primary end point of overall survival or progression-free survival for clinical trials of anticancer drugs, but the primary end point for PIX301 was complete or unconfirmed complete response.

NICE noted that few patients from the U.K. were enrolled in PIX301 and that patients from Western Europe tended to be more heavily pretreated than the anticipated population in England and Wales. More worrying was that just over half of patients in the PIX301 trial with aggressive B-cell lymphoma confirmed by central independent pathological review had previously received rituximab, which is an integral part of standard first-line treatment in the NHS and is also often used in second-line treatment. NICE said that such a difference generated considerable uncertainty in determining Pixuvri’s likely clinical effectiveness in U.K. clinical practice.

Implications For Cost Effectiveness

Unfortunately for CTI, the rituximab issue impacted the cost-effectiveness analysis as well. NICE decided that there was considerable uncertainty regarding the cost-effectiveness estimates for Pixuvri in patients previously treated with rituximab, who would be the main population when treating multiply relapsed or refractory aggressive non-Hodgkin’s lymphoma in England and Wales.

CTI proposed an incremental cost-effectiveness ration of £32,700 per quality-adjusted life-year gained – nominally above NICE’s traditional threshold of £30,000. However, NICE’s expert review group – an independent academic center commissioned to technically review the evidence submission and prepare a report – proposed an ICER of £60,200 per QALY gained.

NICE concluded that the most plausible cost-effectiveness estimate, based on available evidence, would lie between these two values. However, NICE said that this was based on the data from the PIX301trial, where a sizeable proportion had not previously received rituximab, so the ICER could in fact be much higher for the current UK patient group, where rituximab is given as part of standard first-line care for aggressive B-cell non-Hodgkin’s lymphoma.

If more European reimbursement bodies were ready to consider a staggered approval process – as is being developed in much of Italy – whereby they would reimburse a certain proportion of costs until further evidence were available, drugs such as Pixuvri would stand a better chance of qualifying Also see "Pixuvri’s Conditional EU Approval Could Herald The Rise Of Staggered Approval" - Pink Sheet, 15 May, 2012..

Meanwhile, CTI is unsurprisingly determined to pursue its case with Pixuvri at NICE, but it is hard to see a breakthrough without the additional rituximab-related evidence. “We will resubmit additional requested analyses and meet with the panel in May to discuss the cost effectiveness of the labeled patient population. We look forward to working with NICE and are cautiously optimistic we will arrive at a price that NICE will agree is cost effective,” the written statement said.

In the meantime, CTI says that Pixuvri is currently being reimbursed in the U.K. (through private hospitals), the Netherlands, Nordic countries, Austria and Germany, where there is free market access until either reimbursement decisions are made, or for 12 months. “Pixantrone is being reviewed in the five major market countries,” CTI added.

CTI Finds Pixuvri’s Conditional Authorization Is Not Enough To Win NICE Approval

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