Two decisions issued in as many days by the U.K.’s NICE risk cementing an already widely-held criticism amongst pharmaceutical manufacturers that the reimbursement watchdog cares more about cost-effectiveness than clinical effectiveness. NICE gave the nod on Feb. 26, to CTI BioPharma Corp.’s Pixuvri (pixantrone) for non-Hodgkin’s lymphoma, while panning an extended indication for Eli Lilly & Co.’s Alimta (pemetrexed) for non-small cell lung cancer the very next day.

NICE’s own statements on the drugs do nothing to dispel the negative assumptions of industry.

For Pixuvri, for example, NICE concluded that limited and non-robust evidence exists to show that pixantrone was more clinically effective than treatments currently used in clinical practice for treating multiply relapsed or refractory aggressive non-Hodgkin's B-cell lymphoma. It conceded that response rate, progression-free survival, and overall survival for Pixuvri all increased compared with treatment of physician's choice, but added that these results were not statistically significant.

In the case of Alimta monotherapy for the maintenance treatment of locally advanced or metastatic non-squamous NSCLC in patients − whose disease has not progressed immediately following induction therapy with pemetrexed and cisplatin − NICE acknowledged that the drug provides a statistically significant gain in progression-free survival and overall survival compared with placebo.

On the back of these statements it is difficult to immediately see why Pixuvri was recommended while Alimta was rejected. It may, though, have something to do with the fact that Pixuvri came with a patient access scheme – usually a discount agreed between the manufacturer and the Department of Health – which allowed the drug to generate a likely incremental cost-effectiveness ratio of £22,000 ($36,700) per quality-adjusted life-year gained. This is significantly below NICE’s traditional £30,000 (£50,000) threshold.

By contrast, the estimated most plausible ICER for Alimta as maintenance care was approximately £74,500 ($123,500) per QALY gained. What is slightly galling for Lilly is that this was the figure generated despite the fact that NICE took into account end-of-life considerations.

Qualified, But Costly

To qualify for these considerations, a drug must: be indicated for patients with a short life expectancy − normally less than 24 months; provide sufficient evidence that it offers an extension to life − normally of at least an additional 3 months, compared with current NHS treatment; and be licensed or otherwise indicated for small patient populations normally not exceeding a cumulative total of 7,000 for all licensed indications in England.

Alimta just about hit every target. Firstly, life expectancy of patients with advanced non-squamous NSCLC is normally less than 24 months.

Moreover, results from PARAMOUNT − an international, multicenter double-blind, phase III, randomized trial − showed a statistically significant increase in median overall survival of 2.85 months for Alimta, compared with best supportive care. NICE noted that this was less than the 3 months criteria required for end-of-life considerations, but was also aware that all of the modelled estimates provided by the manufacturer and its own expert review group were greater than 3 months.

Finally, NICE estimated that the total population size for which Alimta has a license was approximately 7,160 in England, and it agreed that this amount was close enough to the magic 7,000 criteria required by the end-of-life considerations. It was essentially persuaded by the fact that the benefit of Alimta had been demonstrated in all modelled estimates of mean overall survival, meaning that it offered a valuable therapy for a population for whom no other treatment options existed at this maintenance stage.

Lilly must be disappointed by NICE’s take on Alimta for maintenance therapy. After all, the U.K. cost watchdog knows the drug well, having recommended it for the treatment of malignant pleural mesothelioma in Jan. 2008 Also see "Lilly’s Alimta Gets UK Recommendation As Mesothelioma Therapy" - Pink Sheet, 24 January, 2008.. In June 2010, NICE even recommended Alimta for a slightly different indication as maintenance therapy in people with locally advanced or metastatic non-small-cell lung cancer other than predominantly squamous cell histology, if disease had not progressed immediately following platinum-based chemotherapy in combination with gemcitabine, paclitaxel or docetaxel Also see "U.K.'s Controversial NICE Suspends Publication Of Guidances Until After General Election" - Pink Sheet, 9 April, 2010..

At that time, NICE was persuaded that the most plausible ICER for Alimta compared with best supportive care was approximately £47,000 ($78,400) per QALY gained, below £50,000 ($83,400) per QALY, which it applied incorporating end-of-life considerations.

Lilly’s response to NICE rejection this time round has been very measured, pointing out that Alimta for maintenance therapy is already widely reimbursed across most European countries including Austria, Bulgaria, Denmark, Finland, France, Germany, Greece, Italy, Ireland, Iceland, the Netherlands, Norway, Romania, Spain, Sweden and Switzerland.

“On the basis that (NICE’s Appraisal) Committee has recognized that pemetrexed met NICE’s supplementary advice on end-of-life treatments, we will continue to work with NICE and the clinical community to try and enable access to this important medicine through the NHS,” a spokesperson for the manufacturer said.

Of course, the company’s best bet would be to offer a PAS, but Lilly is remaining tight-lipped about this possibility at present.

Case For Pixuvri

NICE has not issued the same glowing statements about Pixuvri as it did with Alimta.

The point is, though, NICE’s seemingly non-committal nod to CTI’s drug is not about Pixuvri being a weak therapy, but rather that the U.K. cost watchdog doesn’t seem to have seen huge added value in the product. Indeed, it rejected the drug in April 2013. Just for good measure it did so again in October that year, that time despite a discount from CTI Also see "CTI Finds Pixuvri’s Conditional Authorization Is Not Enough To Win NICE Approval" - Pink Sheet, 11 April, 2013..

The drug also had a torrid time in Germany where the senior HTA body, the G-BA, said in May 2013 that it could find no added benefit in the drug ([A#14130520001]). Still, CTI did reach an agreement on Pixuvri’s reimbursement price in Germany with the Statutory Health Insurance Funds in December that year.

This time around NICE appears to have given Pixuvri, an aza-anthracenedione analogue and inhibitor of topoisomerase II, the benefit of its considerable doubt.

These doubts were manifest throughout the guidance, with NICE commenting early on that PIX301 trial − a randomized, controlled, open-label phase III study conducted in 66 centers, including the U.S. and Europe − was underpowered because it had failed to recruit the planned number of patients.

It conceded that PIX301 included a high proportion of patients who would be eligible for treatment under the terms of the marketing authorization, but added that the intention-to-treat population was not appropriate for evaluation and decision-making. Expressing fundamental concerns about the design of PIX301, NICE said there was considerable uncertainty in the validity and robustness of its results.

Going in to further detail, NICE noted that just over half of patients in the PIX301 trial had previously received rituximab (Roche’s MabThera). The cost watchdog expressed surprise at the low proportion because clinical specialists advised it that rituximab is an integral part of standard first-line treatment in the publicly-funded National Health Service, and is also often used as a second-line treatment.

To be fair, though, the European Medicines Agency has only granted Pixuvri a conditional marketing authorization, requiring CTI to undertake a trial to confirm the clinical benefit of the drug in patients who have previously received rituximab.

The confirmatory study is a randomized trial of pixantrone-rituximab versus gemcitabine-rituximab for patients with aggressive B-cell NHL who relapse after receiving CHOP-R therapy or an equivalent regimen and are ineligible for stem cell transplant. The primary endpoint is progression free survival and secondary endpoints are complete remission, overall response rate and overall survival. “We are in the process of opening additional sites in the EU, which we expect will help increase patient enrolment and also increase the visibility of pixantrone among EU thought leaders,” a spokesperson for the company said. She added that enrollment should be completed by mid-2015, with final results to follow months later, after database close and analysis.

NICE may have given a lukewarm reception to Pixuvri, but CTI is supremely confident about the value its drug has to offer.

At the European Hematology Association meeting in June 2013, new analyses were presented evaluating the efficacy of single-agent Pixuvri in 3rd and 4th line salvage setting with or without prior rituximab. Compared to physicians’ choice of other agents given as monotherapy, single-agent Pixuvri resulted in 30% of patients who had previously received rituximab achieving a complete or unconfirmed durable complete response lasting on average 9.5 months with 67% of patients surviving at 2 years, the spokesperson said. “In contrast, only 5.6% of patients in the comparator arm achieved an unconfirmed complete response,” she added.

CTI also pointed out that patients on rituximab − current standard first-line treatment in the U.K. − will relapse. Moreover, the anthracycline drugs that are used in combination with rituximab are toxic and difficult for patients to tolerate. By contrast, toxicity of Pixuvri is predictable and manageable. “Pixuvri is the only option for patients who have failed second line treatment. It has a strong product profile in a disease where there is no standard,” the spokesperson said.

The drug has also found some support from Cancer Research U.K., whose chief clinician Professor Peter Johnson said: "This decision by NICE to approve Pixuvri for advanced non-Hodgkin's B-cell lymphoma will give doctors an extra treatment option for patients whose disease has returned or become resistant to chemotherapy and rituximab."

NICE On Alimta, Pixuvri Ups Concerns It Prefers Cost Over Clinical Efficacy

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