Pfizer Loses Fight To Persuade NICE Of Xalkori’s Cost-Effectiveness

Pfizer says that it won’t challenge NICE’s final rejection of Xalkori on cost-effectiveness and survival uncertainty grounds.

Pharmaceutical manufacturers hoping to propel life-extending drugs through the NICE evaluation process need to brace themselves for a price hit; particularly where uncertainty surrounds their survival data. The UK cost-watchdog’s rejection of Pfizer Inc.’s lung cancer therapy Xalkori (crizotinib) is a case in point.

At Odds With Others

In a Final Appraisal Determination published on Aug.16, 2013, the National Institute for Health and Care Excellence turned down Xalkori in its EU approved indication for the treatment of adults with previously treated anaplastic-lymphoma-kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC). NICE also rejected the drug in April, citing survival issues (Also see "Xalkori And Inlyta: NICE Pans Two Pfizer Oncology Drugs In Two Days" - Pink Sheet, 28 Mar, 2013.).

This puts the British HTA decision at odds with that of its counterparts in Germany, where Xalkori was initially rejected by the Institute for Quality and Efficiency in Healthcare (IQWiG), but eventually saved by the senior reimbursement watchdog, the G-BA (Also see "Germany’s IQWiG Pans Pfizer’s Xalkori On Study Results, Side Effects" - Pink Sheet, 20 Feb, 2013.). Xalkori has in fact already made a name for itself across the globe, clearing the FDA in August 2011 in less than five months, based on early stage evidence (Also see "Pfizer’s Crizotinib Eases Past FDA With Targeted Population" - Pink Sheet, 29 Aug, 2011.).

The drug is clearly clinically effective, in NICE’s view. What’s more, it should have been well-positioned for uptake into the NHS. For instance, clinical specialists and patient experts told NICE that there are limited treatment options for people with non-small-cell lung cancer whose disease has failed chemotherapy. They also noted that people with ALK-positive non-small-cell lung cancer would particularly value the availability of an effective targeted therapy and the convenience of an oral formulation.

Docetaxel (Sanofi’s Taxotere and generics), one of the comparators selected by NICE, has neither of these beneficial attributes. The other relevant comparator was “best supportive care”.

In fact, NICE had initially selected three comparators, the two already mentioned plus Roche’s Tarceva (erlotinib).

Still, Pfizer said a comparison with Tarceva would not be valid because Tarceva acts as an epidermal growth factor receptor (EGFR) inhibitor and EGFR mutation does not tend to occur with anaplastic lymphoma kinase (ALK) translocation. NICE conceded this point and Pfizer undoubtedly saved both time and money by avoiding an unnecessary trial. The main message however is that had the manufacturer not been so proactive, an additional, yet superfluous, study may have been carried out.

Another Case For Staggered Reimbursement

Evidence for Xalkori came from one main multi-center, randomized phase III efficacy and safety study in patients with advanced or metastatic previously treated ALK-positive non-small-cell lung cancer (PROFILE 1007). Three hundred fourty-seven trial patients were randomized to receive either crizotinib 250 mg twice daily or chemotherapy. The chemotherapy consisted of pemetrexed 500 mg/m2 [58%], or docetaxel 75 mg/m2 [42%] if the patients had already received treatment with pemetrexed earlier in their treatment pathway and met eligibility criteria for liver function and peripheral neuropathy.

The primary outcome in PROFILE 1007 was progression-free survival and, following disease progression, crossover was allowed in both directions. Secondary outcomes from the trial included overall survival, objective response rate, response duration and disease control rate, medication-related adverse events and health-related quality of life (lung cancer-specific symptoms as well as general health status).

NICE acknowledged that, based on the PROFILE 1007 data concerning progression-free survival and response rate, Xalkori was undoubtedly clinically effective for the treatment of ALK-positive non-small-cell lung cancer, compared with chemotherapy.

Still, on the progression-free survival front, Pfizer is clearly onto a winner.

NICE noted that the median gain in PFS of 5.1 months with Xalkori compared with docetaxel from the PROFILE 1007 study represented an impressive extension.

The cost watchdog also accepted that Xalkori was likely to offer an overall survival gain compared with docetaxel, but exactly what the extent of this gain might be is uncertain due to the immaturity of the PROFILE 1007 data. A high rate of crossover from chemotherapy to Xalkori in the study has also muddied the waters.

The irony is that Pfizer informed NICE that more mature and therefore more reliable overall survival data would be available for PROFILE 1007 in the future. But the U.S. drug maker conceded that this would not be within the timeframe of this appraisal. “Pfizer submitted data to NICE based on three trials, all of which are ongoing and relevant,” a spokesperson for the company said.

When the additional data will be available is unclear. “For the PROFILE 1007 trial, more data will be available when the final analysis is undertaken. Given this is designed to measure overall survival, it is not possible to provide timings,” the spokesperson said.

The debate over the immaturity of data is ongoing and is possibly the best argument for a more staggered reimbursement process the likes of which have already been tested in Italy (Also see "Europe Transparency Initiatives May Aid Progress Toward Adaptive Licensing Systems" - Pink Sheet, 18 Mar, 2013.). This would speed patient access, while also offering the manufacturer a restricted return on investment until definitive effectiveness and safety profiles can be made.

No Challenge

But companies will still need to prove a certain level of cost effectiveness, something that eluded Pfizer in this Xalkori case. NICE calculated that even with the patient access scheme agreed between Pfizer and the Department of Health – an undisclosed discount – Xalkori would not be cost effective.

Compared with best supportive care, the incremental cost-effectiveness ratio per quality-adjusted life-year gained would be in excess of £50,000 ($78,000). NICE said this ICER was associated with a substantial amount of uncertainty which it was not possible to quantify due to the lack of a robust mixed treatment comparison between Xalkori and best supportive care.

Pfizer’s spokesperson said, “Pfizer did undertake a mixed treatment comparison using the best available data, which we consider to be robust.”

A comparison with docetaxel resulted in an eye-watering figure of more than £100,000 ($156,500) per QALY gained. Both of the ICERs are well beyond the traditional £30,000 ($46,900) threshold at which NICE considers a drug to be cost effective.

Pfizer has taken issue with NICE’s suggestion that Xalkori might be overpriced, though. “Pfizer considers crizotinib to be a cost effective use of NHS resources and so we do not consider these ICERs to be plausible,” the spokesperson said.

Despite this clash, Pfizer will not take the submission any further.

“We have made the decision not to appeal, as we believe this would not achieve the reform to the current HTA system that is required to ensure innovative medicines such as crizotinib are recommended for use in England and Wales,” the spokesperson said.

Pfizer argues that the current NICE process does not accommodate the levels of uncertainty that are inherent in the assessment of oncology medicines similar to Xalkori. “New approaches are required to deal with issues such as cross-over in trials to ensure HTA assessments align with those of regulatory bodies,” the spokesperson said.