Draft guidance from NICE does not recommend Avastin (bevacizumab) for treatment of recurrent advanced ovarian cancer.

NICE’s appraisal committee determined that the Roche drug, when used in combination with the chemotherapy drugs gemcitabine and carboplatin, did not represent good value for the NHS.

The main reason for the decision was that clinical data were unavailable for a third of clinical trial participants, for reasons unknown to NICE.

Recurrent advanced ovarian cancer, when the cancer has returned following initial treatment and has spread beyond the ovaries, is terminal. However, NICE did not accept that Avastin qualified as an end of life treatment.

Roche’s submission highlighted the fact that Avastin together with chemotherapy offers a median progression-free survival benefit of four months more than chemotherapy alone.

However, NICE stated that “the data from around 30 of the patients had been censored” and the impact of that on progression-free survival rates was “unclear”.

The committee further noted that Roche’s estimated ICER of £149,050 per QALY gained “was likely to be optimistic”.

In addition, it said, there was insufficient evidence of overall survival benefit, and there was no patient access scheme. The latter has become a key deal-breaker for NICE in recent years.

Ovarian cancer affects around 7,000 new patients in the UK each year, and Roche estimates that over 2,000 women would be eligible for treatment with Avastin if it were approved in this indication.

Avastin has received several NICE rejections in recent years, as it offers some progression-free survival benefit but is costly. Many UK patients currently receive it via the Cancer Drugs Fund, which is soon to be discontinued.

NICE has failed to recommend Pfizer’s Xalkori (crizotinib) for previously treated anaplastic-lymphoma-kinase-positive advanced non-small-cell lung cancer in new draft guidance.

An independent Appraisal Committee decided the drug did not meet NICE’s end-of-life treatment criteria so its cost exceeded the limit deemed cost-effective for NHS use.

Sir Andrew Dillon, NICE Chief Executive, said that although the clinical benefits of Xalkori had been recognised the high cost of the drug meant it could not be considered as a treatment option.

NICE usually recommends clinically effective treatments that cost up to at a maximum of up to £30,000 per quality adjusted life year (QALY) – the methodology current used to assess value.

If certain treatments meet the criteria to be considered under NICE’s supplementary advice for end-of-life treatments a higher cost per QALY may be accepted. The highest cost per QALY NICE has recommended has been around £50,000.

However, NICE’s Appraisal Committee concluded that the most plausible cost per QALY for Xalkori would be somewhere between £63,800 and £181,100 when compared with existing treatments and between £51,700 and £80,500 when compared with best supportive care.

“We have already recommended a number of treatments for the various stages of non-small-cell lung cancer,” said Sir Andrew Dillon. “However, although the independent committee that considered the evidence found crizotinib to be clinically effective treatment for ALK-positive non-small-cell lung cancer, even if the supplementary advice to the Committee for life-extending treatments had applied, crizotinib could not be considered a cost-effective use of NHS.”

NICE’s guidance is now open for consultation.

NICE draft guidance does not recommend Afinitor (everolimus), a treatment for advanced breast cancer that can increase progression-free survival by four months.

The Novartis drug, described by charity Breakthrough Breast Cancer as “one of the biggest advances in breast cancer treatment in many years”, does not meet NICE’s criteria for an ‘end of life treatment’.

The decision will heighten concern over NICE’s QALY metric for value, which the European Commission recently declared to be scientifically invalid.

Afinitor, an oral formulation of everolimus (which is already widely used as an immunosuppressant), is licensed for use in post-menopausal women with advanced HER-2 negative breast cancer, which will not respond to Herceptin.

The drug inhibits the division of tumour cells and the growth of blood vessels around a tumour, thereby inhibiting tumour growth and metastasis.

Clinical trial results published in September 2012 found that Afinitor could ‘stall’ advanced breast cancer by four to five months.

Dr Rachel Greig of Breakthrough Breast Cancer said: “Everolimus is one of the biggest advances in breast cancer treatment in many years.”

Though “by no means a cure,” she commented, “it could give patients several extra months of good quality of life with their families.”

Sir Andrew Dillon, NICE’s Chief Executive, explained: “While the independent Appraisal Committee acknowledged that everolimus may offer a step change in treatment by restoring sensitivity of the tumour to hormone therapy, the evidence highlighted uncertainty relating to how much the treatment extends overall survival.”

The failure to extend overall survival was only considered crucial because Afinitor did not meet NICE’s criteria for an ‘end of life drug’, since its target patients had a life expectancy slightly over two years.

Consultation on the draft guidance will remain open until 22 April 2013.

NICE will be responsible for assessing the value of medicines in the new value-based pricing (VBP) system to be implemented in 2014.

The Government’s decision to make NICE central to VBP follows recommendations by the Health Select Committee (HSC).

It also follows a report by the European Commission stating that NICE’s QALY metric, the basis of its current value appraisals, is unfit for purpose.

The new role in VBP assessment will enable NICE to broaden the scope of its appraisals of the costs and benefits of drugs.

This will simplify the current routine of NICE declaring a drug too expensive in draft guidelines and then revising its verdict when the company offers a confidential patient access scheme.

Health Minister Lord Howe said: “We are delighted to announce the central role NICE will take in assessing the value of new medicines. This will allow us to draw on NICE’s world-leading expertise as we develop the Value-Based Pricing scheme.”

From April, NICE will be led by new Chairman David Haslam (pictured). It will have responsibility for social care as well as the NHS and public health, enabling it to play a major role in the integration of care.

The Government approved three other HSC recommendations: NICE should develop healthcare quality standards for patients with long-term conditions, co-morbidities or complex needs; NICE should promote better-integrated commissioning and care; and industry should be more transparent as regards clinical trial data.

Stephen Whitehead, Chief Executive of the ABPI, commented: “What will determine whether value-based pricing works for the pharmaceutical industry, the NHS and most importantly patients is not who does the assessment, but how it is done and what goes into it.

“NICE has an important role in supporting growth, which is often overlooked. NICE needs to be an enabler of innovation by the NHS and this is lacking from the Government’s response.

“We urge the Government to keep its foot on the pedal in spreading innovation through the NHS and ensuring that NICE helps to deliver its part of the growth agenda.”

NICE has issued preliminary guidance not recommending a drug for myelofibrosis, a rare blood cancer, which it says is clinically effective but too costly.

Jakavi (ruxolitinib) from Novartis is provisionally refused for NHS treatment of enlarged spleen caused by myelofibrosis.

Novartis has said it is encouraged by NICE’s acceptance of the drug’s clinical value and will work to reach agreement with the Institute on cost issues.

Myelofibrosis causes scarring of the bone marrow tissue, affecting their ability to produce blood cells. The spleen becomes enlarged to compensate, which has debilitating effects.

The NICE appraisal committee concluded that Jakavi offered a “step change” in treating the condition: it reduced spleen size and symptoms such as fatigue, pain and itching.

However, it did not consider the drug, which costs £43,200 per patient per year, more cost-effective than the next best alternative.

NICE’s value model – recently criticised by the European Commission – sets a threshold price of £30,000 per quality-adjusted life year (QALY) gained. Novartis claims a price per QALY of £74,000, but NICE claims the true figure is twice that.

Professor Carole Longson, Director of NICE’s Health Technology Evaluation Centre, said: “It is disappointing not to be able to recommend this new treatment in our preliminary recommendations, but in order to do this we have to be sure that the treatment is both clinically and cost effective.”

Consultant haematologist Professor Claire Harrison commented: “The lives of patients affected by myelofibrosis are improved with ruxolitinib therapy. In many cases this improvement is dramatic with long-lasting tangible benefits.”

“We are encouraged that the Committee considers ruxolitinib to be an innovative treatment and Novartis is committed to working alongside clinicians and patient groups in this area to address all queries raised by NICE,” said Panos Alexakos, Oncology General Manager, Novartis UK & Ireland.

Final guidance is expected in June 2013.

The Quality Adjusted Life Years (QALY) system for deciding which drugs should be available on the NHS is worthless, according to a European Commission report.

The three-year ECHOUTCOME project found that the key assumptions underlying NICE’s QALY evaluations are false, and decisions based on them are dangerously unreliable.

The report recommends that prescribing decisions be made relative to specific conditions and patient groups, rather than relying on a general algorithm.

NICE’s evaluation system is being considered by other European health technology assessment bodies, but ECHOUTCOME advises against its use.

The QALY system estimates the number of years of healthy life gained by the patient, with adjustments for the likely impact of the patient’s symptoms, to reach a figure for the number of Quality Adjusted Life Years (QALYs).

If the cost per QALY for each patient is estimated to be below £30,000, NICE will usually recommend the treatment.

But according to the European researchers, NICE is basing its quantitative assessments on factors that are both qualitative and ill-conceived.

The ECHOUTCOME study, conducted by six universities and several research agencies, analysed data from 1,300 respondents in Belgium, France, Italy and the UK and concluded that QALY cannot capture medical outcomes accurately.

QALY relies on four key assumptions: time and quality of life can be measured in consistent intervals; life years and quality of life are linked; patients have a neutral attitude towards risk; and willingness to sacrifice life years for quality of life is constant over time.

According to the study, these assumptions are all false, and so QALY has no valid empirical basis.

Gerard Duru, Emeritus Research Director in Mathematics at the French National Centre of Scientific Research, commented: “The underlying assumptions of the QALY outcome are very theoretical and are not verified in a real population. It is impossible to know what we are measuring, and therefore impossible to base a formula upon it.”

According to ECHOUTCOME’s Project Leader, Ariel Beresniak, a different approach is needed: “Each case is different and each should use adequate evaluation tools. There should be a list of adequate validated tools to make these decisions with guidance on when to use each.”

For example, the report recommends using a cost per remission approach to evaluate drugs treating rheumatoid arthritis, and a cost-benefit approach to evaluate drugs for wide-scale vaccinations.

The Scottish Medicines Consortium (SMC) has approved the use of an ocular drug to protect diabetic patients against macular oedema (MO) after cataract surgery.

Nevanac (nepafenac), an eye drop medication from Alcon, is the only non-steroidal anti-inflammatory drug (NSAID) licensed in the UK for this indication.

The approval follows a clinical trial in more than 200 diabetic patients that showed the drug’s effectiveness (in combination with a steroid) in reducing the risk of MO and maintaining visual acuity.

In addition, Alcon submitted health economic analysis stating a cost improvement per quality adjusted life year (QALY) of £4,181 for Nevanac plus steroid compared with the steroid alone.

People with diabetes are at highest risk of developing MO, which causes visual impairment, following cataract surgery.

Roger Lopez, General Manager of Alcon UK, commented: “MO is difficult to treat, requiring additional eye care for a prolonged time, which can lead to increased healthcare costs.”

Based in Texas, Alcon is a leading global eye care company and the second largest division of the Novartis Group.

What priorities does Andrew Lansley’s draft mandate for the NHS Commissioning Board reveal?

The draft mandate for the NHS Commissioning Board (NHSCB), published on 5 July 2012, is a manifesto for the new NHS: the first clear public statement of the anticipated course of NHS reform since the Health and Social Care Act became law. It offers a snapshot of the emerging structure for local commissioning, and highlights the Government’s key priorities for an NHS reform that is now a reality.

Introducing Our NHS Care Objectives: A Draft Mandate to the NHS Commissioning Board to Parliament, Health Secretary Andrew Lansley said: “Today we will be laying the foundations of the new, more independent NHS.” By this, he explained, he meant an NHS “free from constant political interference” and “tasked with continuously improving the care that patients receive”.

Transfer of powers
A key background document to the draft mandate is Lansley’s letter to the new Chair of the NHS Commissioning Board Authority, Malcolm Grant, in April. The letter stated his primary objective as being
“to design the Board so it transfers power to local organisations”. Other priorities included integrating health and social care and promoting patient choice.

Another important background document is the NHS Outcomes Framework, published in December 2010 and updated a year later. This defines the patient outcomes the NHS has to work towards – a counterpart to the business processes defined by the reform agenda.

The draft mandate has been issued for consultation. The final NHSCB mandate will be published in October and will guide the Board when it assumes its full statutory authority in April 2013.

Improving healthcare outcomes
The draft mandate begins by setting the context: the NHS is facing “one of the tightest funding settlements in its history”, while elderly care, long-term conditions and mental health are growing priorities. It outlines 22 objectives for the NHSCB for the two years from April 2013, as well as ‘ambitions’ for the coming decade.

The first major section lists 11 objectives for improving outcomes. The first six relate to the NHS Outcomes Framework – one for each of the five domains and one for the whole – setting concrete targets in QALY and similar terms, but leaving the actual numbers to the final version.

While there are no objectives for specific conditions, this section refers to dementia and mental illness and notes the need for better integration of general healthcare with treatment of these conditions. The NHS should work towards treating mental health as “on a par with physical health,” it states. There are objectives for reducing health inequalities, including life expectancy at birth. However, the reference to “greater improvement in more disadvantaged communities” should be seen in the context of the planned shift of public health funding from the NHS to local government. Finally, there are objectives relating to service performance standards and support for patient self-care.

Patient choice and local control
While the first 11 outcomes are related to the agenda for NHS improvement defined by Lord Darzi in 2008, the last 11 belong wholly to the new reform agenda. One crucial objective relates to patient choice. The Board must ensure that people are “involved in decisions about their care and treatment”; that personal health budgets are available “to anyone who might benefit”; and that a patient who has waited 18 weeks for treatment is entitled to choose another provider.

The Board is required to develop integrated care through joint commissioning and other methods, particularly for “people with dementia or other complex long-term needs”. It should also improve the quality of NHS information, using IT to make the NHS “transparent” to patients and carers.

The Government’s innovation agenda is highlighted by an objective requiring the Board to “promote access to clinically appropriate drugs and technologies recommended by NICE”, as well as supporting the participation of NHS clinicians and patients in life science research.

The section on commissioning states that the Board should fully authorise “as many CCGs as are willing and able” by April 2013, and allow the CCGs “full control over where they source their commissioning support”. The new clinical senates and networks will provide advice, with CCGs “free to make their own arrangements”.

The Board must have a “transparent, principle-based system” for managing “poor performance” or “financial risk” by CCGs. It must “support a fair playing field between providers” and “ensure that financial incentives for commissioners and providers support better outcomes and value for money”. The latter objective includes the controversial Quality Premium, a bonus payment rewarding CCGs who achieve a surplus on their annual budget. This will be funded from within “the overall administration costs” available to CCGs.

Crucially for industry, there is an objective to support “changes in services that lead to improved outcomes for patients”. These must meet four criteria: support from clinical commissioners; strong patient engagement; a clear clinical evidence base; and consistency with patient choice.

On the critical issue of cost savings, the mandate says only that the Board must ensure that QIPP savings are made “in a sustainable manner” as dictated by the Treasury, but without reducing service quality.

Between the lines
Responses to the draft mandate have focused on its open-ended nature. Mike Farrar, Chief Executive of the NHS Confederation, commented: “Unlike documents that have gone before it, the mandate does not seek to develop an ever-growing ‘wish list’ of objectives. It rightly encourages commissioners to exercise their knowledge of the needs of their local communities to plan and deliver the best care.”

Shadow Health Secretary Andy Burnham argued that Lansley had missed an important opportunity to highlight the issue of healthcare rationing – which the Health Secretary had recently stated to be
“unacceptable”. The delegation of control to local commissioners, Burnham argued, was “a mandate for privatisation.”

Dr Richard Vautrey, Deputy Chairman of the BMA’s GP Committee, praised the mandate for not placing too many restrictions on GP-led commissioning. However, he was strongly critical of the Quality Premium, which he claimed would encourage rationing and increase health inequalities.

Whatever the consultation period delivers, the draft mandate for the NHSCB is a clear statement of the NHS reform agenda: to deliver improved patient outcomes through CCG autonomy and provider competition.

NICE has failed to recommend the use of Sanofi’s Jevtana (cabazitaxel) in final guidance in combination with prednisone or prednisolone as a second line treatment for prostate cancer.

Concerns were raised by NICE’s Appraisal Committee over the cost of the treatment and its side-effects, including haematological adverse events and diarrhoea.

Sir Andrew Dillon, Chief Executive of NICE, said the Committee queried the “nature of the health-related quality of life information” provided by Sanofi.

Sanofi had appealed the decision not to recommend the treatment however, this was dismissed on all points.

NICE recognised that Jevtana resulted in a mean improvement of greater than three months in mean overall survival. But the Committee considered that its cost per QALY gained would exceed £87,500 – considerably higher than the most expensive treatment it has recommended at £50,000.

Additionally, the numerous side-effects, such as fatigue, nausea, vomiting and constipation, associated with Jevtana raised concerns with the Appraisal Committee.

“We need to be sure that new treatments provide sufficient benefits to patients to justify the significant resources the NHS would need to make available,” said Sir Andrew.

“Although cabazitaxel can extend life for some patients, its price remains well above what the independent Committee appraising this drug considered acceptable, given the benefits it offers.”

NICE has failed to recommend GSK’s Tyverb (lapatinib) or Roche’s Herceptin (trastuzumab) with aromatase inhibitors as a first line treatment for a particular type of breast cancer in final draft guidance.

The decision is based on uncertainties over the overall survival benefits compared to existing treatments of both medicines and the high cost of the treatments.

Sir Andrew Dillon, Chief Executive of NICE, said that while the two have been shown to reduce the growth and spread of breast cancer the extent of overall survival extension “appears to be small or difficult to quantify”.

Final guidance on the appraisal is now expected in June.

The guidance only advises the use of the drugs alongside aromatase inhibitors as a first line treatment option to delay the growth of advanced breast cancer that has spread and reacts with oestrogen or progesterone and has high levels of HER2.

Alongside the clinical benefits, NICE also raised concerns around the cost effectiveness of both products. GSK estimates that the most plausible incremental cost effectiveness ratio (ICER) for Tyverb is likely to be around £74,400 per QALY gained. Roche estimates the most plausible ICER for Herceptin to be around £51,000 per QALY gained – both far in excess of the £20,000-£30,000 NICE typically deems to be a cost effective use of NHS resources.