Herceptin and the rise of patient power

pharmafile | May 3, 2006 | Feature | Sales and Marketing |   

The controversy surrounding Herceptin and its use in patients with early stage breast cancer has become a graphic illustration of the conflicts which arise around prescribing innovative new drugs in new clinical settings.

With Herceptin, the stakes are high – in terms of both patient wellbeing and economic cost – but the evidence on which decisions would ideally be based is still being collated. This article offers a brief review of the Herceptin controversy so far, and looks at the conflicting responsibilities and priorities of different stakeholders.

The case has the potential to set precedents, and these might have a significant impact on rationing of care in the NHS  against a backdrop of organised patient lobbying and public sympathy.

The Herceptin case

Herceptin (trastuzumab) is a monoclonal antibody used to treat certain forms of breast cancer. It works by attaching itself to the HER2 protein. This prevents human epidermal growth factor attaching to the protein and thus blocks the division and growth of the tumour.  Around a fifth of breast cancer patients have high levels of the HER2 protein, and are thus most likely to benefit from Herceptin.

Herceptin gained UK marketing approval in 2000 for the treatment of advanced stage breast cancer and received NICE recommendation in 2002. Further trials published in 2005 suggested it could also be effective in treating early stage (HER2) breast cancer. The results gained significant press attention and were widely promoted by patient groups. As a result, doctors have faced pressure to prescribe Herceptin for this form of breast cancer, and health care bodies have also come under great pressure to fund its use.

This created a number of difficulties, because Herceptin is not yet licensed for use in early stage breast cancer, and at the time a licence application had not yet been made. Accordingly, it had not been reviewed by NICE to determine the effectiveness and cost-effectiveness of the treatment in early stage cancer patients. Doctors are allowed to prescribe a drug 'off-label', and health authorities are permitted to finance its use before a NICE review, but many PCTs have been reluctant to reimburse the drug in these circumstances. The cost of the drug, at almost 20,000 pounds for one year's treatment, is clearly likely to influence the views of PCTs on the subject.

Responses from stakeholders

Patient groups and individual patients have brought significant pressure to bear on NHS bodies to finance Herceptin for early stage breast cancer. A Panorama survey found that three quarters of oncologists were allowed to prescribe the drug in all or in certain cases, and BUPA has decided to reimburse Herceptin in early stage breast cancer patients.

Accessing Herceptin in the current environment depends on a doctor prescribing the drug off-label, after taking account of the risks and the benefits to an individual patient. However, it also depends on an NHS body, generally a PCT, being prepared to meet the cost. Difficulties in clearing the latter hurdle appear to have been more significant and certainly have attracted more debate.

Health Secretary Patricia Hewitt was drawn into the case, and announced on 5 October 2005: "From today all women diagnosed with early stage breast cancer will be tested for suitability for treatment with Herceptin. As soon as Herceptin receives a licence it will be fast-tracked for use throughout the NHS."

She also indicated that local health bodies will continue to decide whether to finance Herceptin for an individual patient – but also said access should not be denied on financial grounds alone.

When a patient of North Stoke Primary Care Trust threatened to take legal action after being refused Herceptin, Hewitt asked to see the evidence on which the decision had been made, noting that it was out of line with decisions made by other PCTs. The decision was subsequently reversed.

Ann Marie Rogers, a patient of Swindon Primary Care Trust, was refused access to Herceptin and took the trust to the High Court where the judge ruled that Swindon PCT had not acted unlawfully in refusing to pay for treatment.

The judge acknowledged differing opinions on the merits of supplying Herceptin in these circumstances, but stated that it was not for him to decide the best possibility, only to decide whether Swindons policy was arbitrary and irrational, and hence unlawful. He decided that it was not, but an appeal court has now overturned this decision (see our news pages for more).

Issues arising

The Herceptin case vividly illustrates how difficult decisions about the clinical and cost-effectiveness of medicines can be, especially when the evidence base is at a relatively early stage – but the consequences of delaying treatment are potentially serious.

This article doesn't seek to make firm conclusions on the appropriate role of Herceptin in the early stage breast cancer, but does seek to illustrate the pressures which can be imposed on the system.

Questions which need to be addressed include:

• What counts as evidence that a medicine is effective? Should efficacy be established beyond doubt in long-term trials and proved before regulators, or in difficult circumstances should prescribers judge risks and benefits based on the best evidence available to them?
• How is cost-effectiveness measured in medicines being prescribed off-label or before NICE appraisal, and how does this determine its availability?
• What does it mean to say that access to a medicine should not be withheld on financial grounds alone? How does NICEs review fit with this approach, and might the Herceptin debate affect the NICE appraisal process?

Judging effectiveness of new products

Herceptin has been widely described as a 'wonder drug', and patients who want access to it have been supported by patient groups and attracted sympathy in the popular press. These wonder drug claims are based on studies showing that over the short-term, Herceptin can significantly reduce the rate of recurrence of tumours. Interim results from the HERA study conducted by the Breast Cancer Group of international researchers compared two groups of 1,700 patients, one receiving Herceptin and the other simply being observed. Over one year in the observation group, recurrence occurred in 220 (13%) patients, with 34 deaths, while in the Herceptin group, recurrence occurred in 127 (7.5%) of patients, with 23 cancer-related deaths.

Another study compared taking Herceptin together with Taxol, compared to Taxol alone and found that adding Herceptin reduced risk of recurrence by a half and death by a third. It is easy to see why such results are regarded as highly promising and have attracted such interest. The New England Journal of Medicine, in which one of the studies was published, carried an editorial suggesting the results were 'simply stunning'.

However, not everybody is convinced by the currently available evidence. In particular an editorial in the Lancet cautioned that: "The best that can be said about Herceptin's efficacy and safety for the treatment of early breast cancer is that the available evidence is insufficient to make reliable judgments." Particular issues which need to be considered in assessing the clinical data include:

• The status of the studies, which the Lancet describes as "interim efficacy studies," suggesting it should be viewed with caution.
• The timeframe of the data, and the reliance which it is appropriate to place on interim measures such as recurrence, rates over a relatively short timeframe. It has been noted that HER2 positive tumours often recur over 18 months to two years, so it will be important to monitor data over this time period and longer. However there is currently no long-term survival data in early breast cancer, and Ian Smith, the lead investigator of the HERA trials in the UK has acknowledged that evidence relating to this is currently only marginal.
• Prevalence of side effects, notably cardio-toxicity, which can cause severe heart failure in some patients.

Obviously there are no easy answers to the question of how to trade off these risks. In general, the approach of the regulatory system is not to license a product until the case in favour has been proven. The rigour of this process is clearly important, and it should be noted that, even when the process is carried out at length, subsequent product withdrawals do occur. Vioxx has been a recent high profile example.

However, it should also be acknowledged that in some cases doing nothing does not represent a risk-free option – particularly where there are no other therapies currently available. In these circumstances, it appears appropriate that the risks of doing nothing, as well as the risks of side effects, are traded against the possibility of benefits from a medicine. The off-label prescribing route may be suitable for this purpose, although it must be ensured these considered individual decisions do not become routine.

Cost-effectiveness of a new medicine

The cost-effectiveness of medicines is assessed by NICE following regulatory approval. There are ongoing concerns about the length of this process, and in particular, concern about 'NICE blight'; where local NHS bodies will not fund new products until NICE publishes its review. The government and NICE have moved to respond to concerns about this phenomenon through initiatives such as fast track review.

In principle, the suggestion above as regards clinical effectiveness – that in circumstances of uncertainty, 'do nothing' should not automatically be the default option – also applies here. However, this raises further questions including:

• Can local health bodies realistically take an informed view on the likely cost-effectiveness of a product given the complex technical nature of the question, and the fact it takes an expert body a substantial amount of time to provide an answer?
• Is this not a route back to postcode prescribing, the avoidance of which was  a key driver for the establishment of NICE?
• What happens if a product is made available locally, pending a NICE review, which does not recommend reimbursing the product?

Clearly these issues raise important practical barriers to accessing medicines pre-NICE approval. In practice, this may especially be true when prices are high, although it may also be argued that when larger amounts of resources are at stake greater attention to decision-making is appropriate.

Unlike less high profile products, many localities have seen these barriers broken down by public pressure in the case of Herceptin. If Herceptin can gain funding without being subject to tests applied to less high profile technologies, the risk of misallocating resources has to be real. Once made, decisions to allow a technology to be made available are hard to reverse, particularly for existing patients, and there is a risk of any such misallocation persisting for a substantial period.

Withholding approval on grounds of cost

Hewitt's view that Herceptin use should not be withheld on grounds of cost alone is highly significant, particularly in light of the current financial pressures on the NHS. Firstly, one needs to distinguish 'cost alone' from 'cost-effectiveness'.

Clearly, health economists will support any move towards re-allocating resources based on cost-effectiveness rather than cost alone. However, a product proven to be marginally effective at high cost might be refused NICE recommendation on ground of cost-effectiveness.

Thus if NICE's role in ensuring the effective allocation of NHS resources is to be maintained, a clear definition of 'cost alone' needs to be agreed. This is clearly an important issue in light of the emotional debate about a drug that could have potential to save or prolong life, against an otherwise harsh prognosis, even given the uncertainties involved.

NICE's clinical director, Peter Littlejohn commented on the HERA results in an article for Lancet Oncology. In it he suggests 18 patients would need to be treated with Herceptin to save one life, and that: "For every 100 suitable patients prescribed trastuzumab (Herceptin), 94 will have been exposed to the side effects without any benefit, at a cost of 400,000 pounds per recurrence prevented."

Clearly detailed analysis and modelling is necessary, ideally based on robust clinical data, but these data suggest Herceptin won't escape the scrutiny of economic regulators such as NICE.

Yet given the public clamour for the product, the support from the Health Secretary and Herceptin's established use in later stages of the disease, a rejection on value for money grounds would create huge controversy. If NICE did rule against Herceptin in early stage breast cancer, the stage would be set for a huge debate about the role of cost in making rationing decisions. It would also raise questions once again about the power of NICE to ration treatment in the face of public opinion and organised patient lobbying.

David Lewis is a senior consultant with NERA Economic Consulting