The decision by the National Institute for Health and Clinical Excellence (NICE) in May, after a provisional refusal in February, to recommend abaritarone acetate for metastatic castration resistant prostate cancer in adult men whose disease has progressed on or after a docetaxel-based chemotherapy regimen has been hailed by most of the news media as a defeat for NICE. Was it? What went on?
Prostate cancer growth is stimulated by androgens (male sex hormones, such as testosterone). In England and Wales, there were over 33,000 men newly diagnosed with prostate cancer and over 9,100 deaths from prostate cancer in 2008.
It is estimated that 55% to 65% of men with prostate cancer will go on to develop metastatic disease. More than 90% of men with metastatic prostate cancer initially respond to hormonal therapy. However, the disease will eventually become resistant to standard hormonal therapy and therefore alternative treatment strategies are required. This clinical condition is known variously as castration-resistant prostate cancer, androgen-independent prostate cancer, or hormone-refractory prostate cancer. Castration-resistant prostate cancer has become the preferred term within the clinical community.
The NICE technology appraisal no. 101 recommends docetaxel as a treatment option for men with hormone-refractory prostate cancer who have a Karnofsky performance status score of 60% or more. For men with metastatic hormone refractory prostate cancer that has progressed during or after a docetaxel-based treatment, patients may receive a combination of palliative treatments. Management options include mitoxantrone with or without steroids such as prednisolone.
Abiraterone from Janssen, a subsidiary of Johnson & Johnson, is a selective androgen biosynthesis inhibitor. Abiraterone blocks cytochrome P17 (an enzyme thought to play a role in the production of testosterone), thereby stopping the testes and other tissues in the body from making testosterone. It is administered orally.
Abiraterone has a UK marketing authorisation for use “with prednisone or prednisolone for the treatment of metastatic castration resistant prostate cancer in adult men whose disease has progressed on or after a docetaxel-based chemotherapy regimen.”
Abiraterone has a different history (provenence) from many recent cancer drugs in that it was developed from research funded by the charity Cancer Research UK, which took it through its earlier trials before selling it to a company now owned by Johnson & Johnson. Cancer Research UK have a deal which means it would receive a share of the profits, hence its vested interest in the NICE decision. The company submission went as far as claiming that the increased research spending by CRUK should be taken into account by the NICE appraisal committee. Abiraterone costs just under £100 per day. Trial evidence shows abiratorone extending median survival from 11 to 15 months. On that basis, abiraterone would cost on average around £46 000 per patient treated (details were kept commercial in confidence).
NICE initially rejected the drug in February 2012 on the basis of its high incremental cost per quality adjusted life year (QALY) of £60 000. It also judged that the drug failed to meet NICE’s end of life criteria and noted that even if it did, £60 000 per QALY would still be too high. By May, the company had offered a discount which reduced the cost per QALY to just under £50k. If it qualified as an end of life therapy, for which precedent has established a threshold of £50k, NICE could say yes.
Those end of Life criteria, outlined in 2009 required that:
“The treatment is indicated for patients with a short life expectancy, normally less than 24 months and;
a) There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared to current NHS treatment, and;
b) No alternative treatment with comparable benefits is available through the NHS, and;
c) The treatment is licensed or otherwise indicated, for small patient populations.”
As abiraterone was considered by NICE to meet conditions a) and b) the debate hinged on c) the small patient population.
Here is what NICE said on the size of the patient population in February:
“The committee understood from the estimates provided by the manufacturer that approximately 4300 people with metastatic castration resistant prostate cancer were receiving docetaxel in England and Wales in 2011, and that approximately 75% of these (n = 3300) would be eligible for abiraterone. The committee also noted that the manufacturer estimated that the number of people with castration-resistant metastatic prostate cancer receiving docetaxel in England and Wales would rise to approximately 5500 in 2013. The committee heard from the commissioning expert that these were underestimates of the number of patients who would receive abiraterone in clinical practice.”
And in May:
“The committee understood from estimates obtained from the appraisal of cabazitaxel that approximately 3500 people with hormone refractory metastatic prostate cancer received docetaxel in England and Wales in 2011, and that, according to estimates provided by the manufacturer, approximately 70% of these (n = 2500) would be able to receive second-line abiraterone treatment in line with the marketing authorisation.”
The threshold for qualifying as a small patient group seems to be between 2,500 and 5,500. NICE rather than Jannson reduced the estimate of the number who might receive abiraterone, based on a different appraisal it had conducted. The last sentence in the February consultation to do with commissioning expert predicting that this was an underestimate was dropped.
The threshold for small population has been contentious. Originally set at 7,000 by NICE on the basis of capping the cost to the NHS, the rationale was to prevent the major cancers qualifying— NICE Chair, Mike Rawlins is on record to the House of Commons health committee as follows: “NICE has defined the size of the population of patients suffering from terminal illnesses who would benefit from its new guidance as “small patient populations.”
For cancer, this means that the four most common types of cancers in the UK (affecting the colon, breast, prostate, and lung) would not benefit from the guidance. Professor Rawlins argued that it was important to place clear limits on the numbers of patients who would benefit from the new guidance because “we cannot do this for common lethal conditions. It would cost the health service hundreds of millions of pounds a year.”
The House of Commons health committee concluded: “We believe that the definition of subgroups of patients suffering from rarer cancers as ‘small populations’ is too woolly and needs more clarity.”
NICE’s advice to its appraisal committees did not specify the number required to qualify as a small patient group.
The size of the patient population for castration resistant prostate cancer is small compared to the population who might benefit from abiraterrone—NICE is scheduled to appraise the drug for the wider group of first line castration resistant patients by July 2013, in England and Wales. Having recommended it for this more severe sub-group will make it harder to refuse it to the bigger group next year.
What of the argument that increased sales would lead to increased income to Cancer Research UK, which in turn would lead to more research in the UK? This argument was dismissed by the appraisal committee on the grounds that “although health benefits were likely to accrue from this research, these did not contribute to the health related quality of life within the ‘Guide to methods of technology appraisal.'” (Para 4.19) . This guide restricts the relevant quality of life gains to the technology under consideration.
Who backed down? It seems that both NICE and the company made concessions, the company by reducing the price in a patient access scheme and NICE by judging that it would apply to a sufficiently small patient group to qualify for the End of Life premium.
Who gave up most is harder to judge. NICE’s February statement that noted that at the then current price, abiraterone could not be recommended even if it met the End of Life criteria, can be seen as a strong urge towards a price cut. However, the price reduction to reduce the cost per QALY from £60 000 to just under £50 000 is not likely to have been very large. Abiraterone provides an instance of a drug being priced via the discount up to the £50 000 per QALY limit allowed by the End of Life criteria.
The background of value based pricing may also be important in understanding NICE’s readiness to change its mind. Under value based pricing, to be in place from the end of 2013, price negotiation will play a bigger role. It can only be beneficial for NICE to be able to show that it can help negotiate a lower price.
James Raftery is a health economist with several decades experience of the NHS. He is Professor of Health Technology Assessment at Southampton University. A keen ‘NICE-watcher’, he has provided economic input to technical assessment reports for NICE but has never been a member of any of its committees. The opinions expressed here are his personal views.