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AstraZeneca Paying for Genetic Testing Services for UK Lung Cancer Patients Receiving Iressa

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By Turna Ray

Ahead of a cost-effectiveness appraisal
by the UK's National Institute of Health and Clinical Excellence of its non-small cell lung cancer drug Iressa, AstraZeneca is paying for EGFR mutation analysis to help predict which lung cancer patients will benefit from the drug.

"EGFR mutation testing is not a common practice in the UK," an AstraZeneca spokesperson told Pharmacogenomics Reporter this week via e-mail. "However, capabilities are available for this type of genetic testing either via commercial and/or National Health Service laboratories."

As a result, while it awaits the NICE appraisal for Iressa (gefitinib), which is slated for June, "AstraZeneca UK has decided to fund testing as a service to medicine," according to the spokesperson, who added that the company expects "that the overall cost-effective price of Iressa to be appraised by NICE will include the cost of testing, which means there will be no additional cost to the NHS to carry out EGFR testing."

Due to a study showing Iressa to have low efficacy in the general NSCLC population, AstraZeneca in 2005 withdrew its application in the EU. The company reapplied for marketing approval in 2008 with efficacy data in EGFR-positive patients, and last year the drug was approved for marketing in Europe as a treatment for locally advanced or metastatic NSCLC patients whose tumors have EGFR mutations.

According to a preliminary review by NICE of AstraZeneca's Iressa marketing application, the company has proposed to make gefitinib available to the patients in the NHS through a patient access scheme, or PAS, ahead of NICE's appraisal. Under the PAS, AstraZeneca is charging the NHS a single fixed price for each patient treated with Iressa.

This fee, which was not disclosed in the NICE review, "will include the entire cost of a course of treatment of Iressa until disease progression, irrespective of treatment duration, and will be reviewed after three years in line with the Pharmaceutical Price Regulation Scheme," NICE said in the review.

Under the PAS, AstraZeneca is also offering EGFR mutation tests to all UK patients newly diagnosed with advanced NSCLC until June, when NICE is slated to issue its final guidance to NHS on the use of gefitinib.

In the UK, AstraZeneca has received approval of its marketing application for Iressa from the Medicines and Healthcare Products Regulatory Agency, a body under the UK's Department of Health that clears medical drugs and devices for marketing based on their safety and efficacy. However, the NHS, another agency under the Department of Health, decides which medical products to reimburse based on cost-effectiveness recommendations from NICE.

If NICE deems Iressa to be cost-effective, and NHS subsequently reimburses for the drug and companion test, then AstraZeneca will no longer need to pay for genetic testing as it is doing now. However, if NICE deems the drug not cost-effective, it will remain available under the PAS, with AstraZeneca paying for genetic testing.

Of course, there is no guarantee where NICE's final appraisal will fall, but its initial review issued in November 2009 offers some insight into the agency's thinking. In its evaluation of the clinical and cost-effectiveness data submitted by AstraZeneca, NICE's evidence review group identified several weak points.

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The main study data submitted from a trial called IPASS "is the only published relevant head-to-head randomized-controlled trial with sufficient data available to compare the use of gefitinib with chemotherapy in chemotherapy-naïve patients with adenocarcinoma histology who are EGFR mutation positive," the evidence review group wrote in its review, adding that it "considers the clinical evidence to support the use of gefitinib for patients with NSCLC in England and Wales to be weak."

Furthermore, AstraZeneca provided the evidence review group with an incremental cost-effectiveness ratio of £20,744 ($31,623) per quality-adjusted life year, or QALY, for Iressa treatment in the UK population. However, the review group notes that the probabilistic sensitivity analysis in AstraZeneca's marketing submission "illustrates that for patients who are EGFR mutation positive, gefitinib compared with doublet chemotherapy is not likely to be cost-effective at what would usually be considered standard levels of willingness to pay (WTP) for an additional QALY."

According to the review group, the mean incremental cost-effectiveness ratio for gefitinib treatment in EGFR mutation positive patients versus doublet chemotherapy in this subset of patients is £35,700 ($54,423) per QALY.

"It would have been useful if the manufacturer had also updated its economic evaluation and compared the cost effectiveness of gefitinib with pemetrexed and docetaxel for EGFR mutation positive patients," the review groups said, adding that it considers the lack of this data "a major weakness" of AstraZeneca's marketing application.

In the area of cancer treatments, NICE has recommended against covering certain drugs it has deemed too expensive. Cancer drugs that have fallen in NICE's not cost-effective category, and are therefore not provided by NHS, include renal cell cancer drugs Avastin (bevacizumab), Nexavar (sorafenib), Sutent (sunitinib), and Torisel (temsirolimus). Last year, based on NICE reviews, NHS decided not to pay for Nexavar for liver cancer and Avastin for metastatic colorectal cancer.

These controversial coverage denials have put pressure on drug makers to prove the efficacy of their treatments in order to gain access to the UK market, bringing about risk-sharing strategies in which the state payor has agreed to fork up the cost for expensive treatments only when they work, with the drug maker picking up the balance. Examples of risk-sharing schemes in the UK include Janssen's Velcade Response Scheme for its multiple myeloma drug Velcade; Merck-Serono's cost-sharing program for Erbitux (cetuximab) in metastatic colorectal cancer; and Roche's rebate program for its non-small cell lung cancer drug Tarceva.

AstraZeneca would not say it was considering such risk-sharing schemes with the NHS. However, the fixed price structure for the drug and the company's payment of genetic testing under the PAS can be interpreted as a risk-sharing effort of a kind. And, the fact that under the arrangement, the NHS will review the fixed price for the drug after three years in line with the Pharmaceutical Price Regulation Scheme, leaves open the possibility of a risk-sharing agreement in the future.

The UK Department of Health's Pharmaceutical Price Regulation Scheme, a five-year voluntary program that begun on January 1, 2009, facilitates voluntary agreements between the UK government and pharmaceutical companies to make drug treatments available at a "fair price" to the NHS. The new scheme allows more flexible pricing arrangements and the promulgation schemes to improve patient access to drugs and ensure that the cost of drugs reflect their value.

According to the AstraZeneca, it initiated the PAS for Iressa ahead of NICE's review under the PPRS, in order to enable the NHS to predict budgetary impact accurately; to allow access to Iressa in the UK; to ensue NHS gets "value for money;" and to provide transparency around its assessment of cost.

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The AstraZeneca spokesperson said the company is gathering data generated by its testing partners to improve understanding of EGFR mutation rates in UK patients. "This will help us improve the effectiveness of providers in identifying patients and thereby giving the patient a tailored treatment to maximize outcomes and improve the cost-effectiveness of lung cancer treatments," the spokesperson said.

EGFR testing for Iressa is currently available through an Rx/Dx partnership with Qiagen subsidiary DxS (PGx Reporter 08/05/10), and through several other laboratories. Last week, AstraZeneca announced a partnership with Source Bioscience to conduct EGFR testing for not just Iressa, but all its tyrosine kinase inhibiting drugs in its pipeline.

Ultimately, if NICE issues a favorable appraisal for Iressa in EGFR mutation-positive NSCLC patients, then AstraZeneca will have a leg up against competitors in a market where NICE hasn't been so nice to other lung cancer drugs.

For example, NICE in 2008 did not recommend the use of Bristol-Myer's Squibb's Avastin in addition to platinum-based chemotherapy for the first-line treatment of patients with unresectable advanced, metastatic or recurrent NSCLC.

According to NICE's website, the appraisal for Merck KGaA's Erbitux in NSCLC was "suspended" as of December 2007 due to ongoing regulatory discussions at the European Medicines Agency. However, in July 2009, the EMEA issued a negative opinion, refusing a marketing application to Merck for Erbitux as a first-line treatment of EGFR-expressing advanced or metastatic NSCLC in combination with platinum-based chemotherapy.

NICE is currently conducting a cost-effectiveness appraisal for OSI/Genentech's Tarceva for NSCLC and is slated to issue a determination in August.

For AstraZeneca, gathering PGx-guided outcomes data in the UK is also a step toward collecting necessary evidence for the company to begin marketing the drug in the US again.

In 2004, around the time AstraZeneca withdrew its initial application for Iressa in the EU, the company also informed the US Food and Drug Administration that a large randomized study, called ISEL, failed to demonstrate a survival advantage for Iressa in NSCLC patients. Based on these findings, the FDA did not take the drug off the market but restricted any new patients from taking Iressa.

"There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival," Iressa's label states. The company provides the drug in the US through an access program. Now, with EU approval for Iressa in the EGFR-expressing NSCLC population, the company still hasn't announced any plans to relaunch the drug in the US.

Source Bioscience estimates the global market for cancer diagnostics during 2010 to be in the region of $6 billion due to the increasing requirement for molecular diagnostics based on genetic analysis. "If we are able to provide better diagnostic information for clinicians, this will help ensure that treatment pathways are managed more effectively, positively impacting the clinical outcome and cost effectiveness of therapy," Source Bioscience said in a statement.

Once EGFR testing becomes common practice in the UK, AstraZeneca estimates that the cost will be around £200 ($304) per test.

In an effort to spur utilization of EGFR testing, not only is AstraZeneca paying for testing for the time being, but the company has also launched a website on EGFR testing. The website tells patients to contact AstraZeneca if they want to find out about EGFR-testing laboratories.

Additionally, AstraZeneca offers guidelines to physicians on this website about EGFR testing. For instance, if EGFR testing reveals patients have deletions in exon 19, or L858R mutations, constituting around 90 percent of EGFR mutations, then they are candidates for Iressa, the website informs. NSCLC patients with double mutations, such as T790M mutations and exon 19 deletions, have limited response to Iressa, studies have shown. Finally, patients with the exon 20 point mutation T790M or the exon 20 insertions, comprising around 3 percent of EGFR TK mutations, are unlikely to benefit from Iressa, the company informs doctors.

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