Managers & Medicine

The pressure on health authorities to fund expensive drugs for multiple sclerosis is becoming almost irresistible, with a third brand of interferon now on the market, a fourth product in the pipeline and news that treatment may work in progressive as well as relapsing-remitting disease. Yet a significant number of commissioners - and some neurologists - continue to doubt the value of these MS therapies and are refusing to recommend treatment or foot the bill.

Avon HA is the latest to dig its heels in, despite direct pleading from consultants, patients and the local MP.

It says there is not enough evidence that interferon can make a significant difference to MS patients. But as the neurology journals fill up with papers reporting statistically significant reductions in relapses and slowing of progression and disability associated with beta interferons 1a and 1b and the novel polypeptide mixture, copolymer 1, why are some experts convinced by the data while others remain so sceptical?

'The majority of British neurologists do not doubt the data on beta interferons but are concerned about its interpretation. We're convinced that treatment does have an effect on MS but a question-mark still hangs over the magnitude of the effect, ' explains Colin Mumford, consultant neurologist at the Western General Hospital, Edinburgh.

'If the effect is small, we have to consider whether it is appropriate to commit patients to frequent injections without being certain that they are going to get a useful benefit, ' he adds.

In contrast, Professor Richard Hughes, head of neurology at Guy's Hospital, London, described a 'breakthrough in the treatment of multiple sclerosis' in the publicity for drug company Serono's newest brand of interferon, Rebif.

'I spent two to three years trying to damp down people's enthusiasm because I felt there was insufficient evidence to use these drugs as standard treatment. But the results from the latest study are so convincing I have changed my mind and I hope health authorities will do the same, ' he explains.

The as-yet unpublished study - called PRISM (Prevention of Relapses and Disability by Interferon-beta 1a, Rebif, subcutaneously in MS) - reports exacerbation rates down by a third and overall disability reduced by 83 per cent during the course of the two-year trial. The 560 patients in the study had relapsing-remitting MS - the most common form of the disease - and those on active treatment were given higher doses of interferon than in previous trials.

So why haven't all neurologists and health authorities been converted? At the root of the problem is the way disability has been monitored in all the trials. Researchers have used the Kurtzke Expanded Disability Status Scale (EDSS), which measures dysfunction in several neurological systems on a scale of 0 (normal) to 10 (dead) to generate a measure of disability.

The problem is that, despite its 'gold standard' status, everyone agrees that EDSS is not good at allowing for the unpredictable course of MS. Its scale is not linear, so a change in score from 1 to 2 is not equal to a change from 5 to 6, and it places more emphasis on changes in lower limb rather than upper limb or cognitive function.

'It's terribly difficult to know what results mean for an individual patient because there are so many ups and downs in the disease, ' explains Dr Mumford .

Quite bluntly, neurologists need a simple measure that will allow them to compare the effects of different drugs on the number of patients who will end up in a wheelchair, 10 years down the line. And they don't have one. Drug trials to date only give two and three-year EDSS data.

Professor Hughes agrees that EDSS is less than ideal. Indeed, he and his colleagues have devised the Guy's Disability Scale as an alternative, and this is undergoing validation tests. But he is convinced that the EDSS figures obtained in PRISM are so striking they cannot be ignored.

There is growing concern among support groups such as the MS Society that some specialists are getting so caught up in the minutiae of the data that they are failing to see the individuals behind the numbers.

'When consultants say that the reduction in number of relapses is not good enough they are just looking at averages. Some people who take interferon do get very little effect, but others see a huge reduction in their relapse rate and the severity of their symptoms, which has an enormous impact on their ability to work, look after their family and lead a normal life, ' explains Peter Cardy, chief executive of the MS Society.

He is not seeking a major expansion of the current criteria for prescribing beta interferon, he simply wants more patients who fulfil the current prescribing guidance for the drugs to be given the option of treatment. That is, patients with relapsing-remitting disease who have had at least two attacks in the preceding three years, without evidence of progression between relapses.

A survey, sponsored by Serono carried out last year by the Association for Quality in Healthcare, reported that fewer than 5 per cent of 83 health authorities that responded had any specific strategy for MS provision.

In most cases, it fell within the overall needs of those with physical disability, neurology or other complex healthcare requirements.

Three-quarters had no plans to spend more on MS this year.

Any argument for greater spending will not have been helped by a recent cost-utility analysis of interferon beta 1b commissioned by the NHS Executive's Health Technology Assessment programme.

This concluded that treatment produces small gains in quality-adjusted life years, at large additional cost.

Newcastle researchers estimated cost effectiveness over five years was£28,700 per relapse avoided, giving a cost-utility ratio of£809,900 per QALY gained. When possible effects on progression over five and 10 years were accounted for, the cost per QALY fell to£328,300 and£228,300 respectively, with a 'best-case' estimate as low as£74,500 per QALY gained.

Comparative estimates carried out for beta interferon 1a and 1b and copolymer 1 over two years showed comparable costs per QALY gained of£354,900,£327,300 and£433,900 respectively. But the substantial indirect costs of MS - social services, carers' costs, loss of earnings - weren't accounted for.

But despite this debate, there is quite good agreement about which MS patients are likely to benefit. Practical experience is showing that patients with relapsing-remitting disease with frequent, serious relapses tend to get most out of beta interferon. Their quality of life is improved and their self-confidence is restored. Some can go back to work. For them, there is no doubt that the£10,000 price tag for their treatment is money well spent.

Box 1: What is MS?

Multiple sclerosis is the most common cause of severe disability in young British adults and affects about 8,500 people in the UK, in a ratio of three women to two men.

Although it is more common in the north than the south of Britain, an average health district of 250,000 people is likely to have 10 to 20 new cases of MS a year and a total of between 250 and 425 patients on its books.

The most common symptoms are muscle weakness, visual disturbance, balance and co-ordination problems, tingling, numbness or burning feeling, and slurred speech.

There are four types of MS.

Benign: a small number of mild attacks with no permanent disability.

Relapsing-remitting: symptomatic attacks lasting at least 24-48 hours, followed by complete or partial recovery over a few weeks, with no progression between attacks.

Primary-progressive: steadily worsening symptoms and progressive disability, with occasional plateaux but no permanent recovery.

Secondary-progressive: initial relapsing-remitting disease developing into progressive deterioration and increasing disability with few if any remissions.

Standard therapy, until the arrival of the interferons, consisted of short courses of high doses of corticosteroids to damp down inflammation and shorten the duration of relapses. But these drugs have no effect on the course of MS and once the disease has started to progress, treatment is targeted at relief of symptoms and aids to daily living.

Box 2: Novel MS treatments Three brands of beta interferon are now available in the UK. A fourth drug, copolymer 1 (Copaxone), developed by Teva, is being considered for a licence by the Medicines Control Agency.

Interferon beta-1b (Betaferon): the first brand, introduced in 1996, by Schering Healthcare.

Interferon beta-1a (Avonex): launched in 1997 by Biogen.

Interferon beta-1a (Rebif ): launched in May 1998 by Serono.

The interferons and how they work

The differences between the three are small, particularly Avonex and Rebif. Each manufacturer has learned from its rivals. The latest brand, Rebif, is administered three times a week under the skin in much larger doses than once-weekly Avonex, which is injected into the muscle. All the interferons can cause flu-like side-effects, which can be minimised by judicious use of paracetamol.

The precise mechanism of action of beta interferon remains uncertain but laboratory studies show it inhibits the activation, proliferation and many of the functions of T-lymphocytes. These white blood cells, an essential component of the body's immune system, appear to be key players in MS.

When a person has MS, the white blood cells, instead of patrolling the blood system fighting bacteria and viral infection, stray across the blood-brain barrier and release substances that are toxic to nerve cells. They trigger inflammatory reactions that damage the protective myelin coating on nerves. In the early stages of MS, the body's repair systems replace some of the damaged myelin. But as the disease progresses, there is permanent nerve-tissue scarring.

New drug up for licence

Copaxone is different from the interferons. It is a mixture of synthetic polypeptides, composed of four different amino acids, and is thought to work by interfering with the way activated T-lymphocytes that have crossed the blood-brain barrier bind to recognition sites on nerve cells before inflicting inflammation and nerve damage. It is injected daily, under the skin.

Body of evidence

All four MS drugs have a major trial in relapsing remitting disease.

In 1993, the relapse rate in 327 patients taking Betaferon at 8 MIU (million international units) a week for three years was shown to be about 30 per cent lower than with a placebo.

3Twenty-seven per cent of the Betaferon group had worsening disability compared with 39 per cent of the placebo group, and they needed significantly less time in hospital. But the disability and hospitalisation figures were so-called 'secondary endpoints' and carried less weight than the 'primary endpoint' of relapse rate. In February 1996, the Drug and Therapeutics Bulletin concluded that Betaferon was expensive and the evidence in its favour was weak. It advised that patients should be treated only as part of a clinical trial or detailed clinical audit.

The key Avonex trial compared the effects of a 6 MIU dose per week with a placebo in 301 patients, this time with progression of disability as the primary endpoint.

The study was scheduled to continue for two years but was halted early, on the grounds of clear-cut effectiveness, when 56 per cent of patients had completed treatment.

Results showed sustained progression of their disease in one in five patients in the Avonex group compared with one in three taking the placebo. The exacerbation rate was about a third lower in the Avonex than in the placebo group.

The Drug and Therapeutics Bulletin was still not impressed. In January this year, it bemoaned the fact that the study had stopped early and concluded the evidence 'does not support the manufacturer's claim that the drug slows the progression of disability over a two-year period'.

For once, being late to market was an advantage for Serono. For its pivotal Rebif trial (PRISM), it chose much higher doses - 6 and 12 MIU three times a week for two years - than its rivals. It also did more fancy analyses of its progression data, calculating the total amount of disability that patients had to put up with during the study, not just disability scores at the beginning and end of the trial.

Reductions in relapse rates with the two doses of Rebif were similar to those seen with the earlier brands of interferon - about a third. But the time to confirmed progression in the high-dose Rebif group was double that seen in the placebo group, and the median reduction in accumulated disability throughout the trial compared with the placebo was 88 per cent. Researchers also reported that MRI scans showed significant reductions in active nerve lesions.

Like the interferon manufacturers, Teva had its pivotal study with Copaxone, with comparable results. The annual relapse rate over three years was down by 32 per cent and worsened disability was half that seen with a placebo.

As with Rebif, there was a significant impact on the amount of time patients were disabled during the study, down by 93 per cent compared with the placebo. MRI scans confirmed fewer active lesions. Experience in the US, where Copaxone is licensed, suggests it may have fewer side-effects than the interferons.

'I have to find£800 a month myself ' When Avon health authority recently decided against providing funds for beta interferon treatment for its MS patients, part-time classroom assistant Barbara James tried not to take it personally. At the authority's monthly meeting, she and her consultant neurologist had the opportunity to plead their case, face to face with the purse-holders, and explain why Ms James should get the drug on the NHS. They failed.

'The community health council had told me not to be too optimistic and I wasn't really surprised that they said no. But I still wasn't prepared for the disappointment. I was the human face of MS and I didn't really achieve any thing by going to tell my story, ' she explains.

As a result of the decision, Ms James will continue to find£800 per month for her treatment - just as she has since the beginning of December last year.

'We are not rich, we're just an ordinary family.

There won't be any holidays this year but as long as I can go on working, we should be able to pay for my treatment, ' she explains.

Ms James' MS has run an almost textbook course.

Diagnosed in 1990 as a result of numbness in her left arm, she coped with her gradually increasing relapses with courses of steroids prescribed by her GP until 1996. But when the effectiveness of the steroids began to diminish, she was referred to a neurologist, who agreed that she was a perfect candidate for beta interferon treatment. The only problem was that there was no room in clinical trials and Avon HA would not pay for treatment.

'My lowest point was in June 1997. I fell down in the street when I was out with the children. My walking became so bad that I couldn't work and I could hardly get out of the house, ' Ms James recalls. She and her family opted to pay for beta interferon on private prescription and Ms James waited impatiently for the previous course of steroids to work its way out of her system before starting the new treatment.

She was shown by a nurse how to inject the drug into her thigh muscle, a procedure she has to go through once a week. 'I do one leg one week, and the other leg the next, ' she says.

She found it difficult at first. 'The needle has to go in a long way.' Her husband helps by filling the syringes for her and leaving them in the fridge. 'I've got it down to five minutes now before I can pluck up the courage to do it, ' says Ms James.

But she has been back at work since Christmas and has had no relapses since starting interferon treatment.

Her balance is better and she can walk more quickly.

She can cross and uncross her legs, get dressed more easily, and get in and out of a car with fewer problems.

'I still get tired and I can't walk very far but my gait is more normal. I know it's not a cure, but I would have expected a relapse by half-term or at Easter, and I didn't have one.'

Side-effects have been minimal. At first Ms James had headaches and flu-like symptoms, but these didn't last. 'I have days when my legs feel very heavy, but I can still walk about. I just can't keep going for very long.'

After her failure to get Avon to reconsider its policy, Ms James is considering taking her case to judicial review. She understands the dilemma facing HAs, but has to consider herself and her family. 'I'm not unsympathetic to the health authority problems and I'd hate to think that, because I was getting treatment on the NHS, some old lady wasn't getting a hip replacement or a baby was going without something.

But I know that each time I have a relapse I'm being left with more problems and I want to try to stop that.'

REFERENCES

1 Association for Quality in Healthcare. Report of a survey of multiple sclerosis service provision in the UK in 1997-1998. Nov 1997.

2 Parkin D, Miller P, McNamee P et al . A cost-utility analysis of interferon beta for multiple sclerosis. Health Technology Assessment 1998. 3 The beta Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. Neurology 1993; 43(4): 655-66.

4 Jacobs L, Cookfair D, Rudick R et al. Intramuscular interferon beta-1a for disease progression in relapsingremitting multiple sclerosis. Ann Neurol 1996; 39(3): 285-94.

5 Johnson K, Brooks B, Cohen J et al. Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Neurology 1998; 50(3): 701-08.