It is a full ten years since the Lancet paper from Steve Johnson and many others (you will find my name in the small print at the end of the article) demonstrated that fludarabine produced a higher response rate and a longer progression-free survival than CAP, a combination of alkylating agent, anthracycline and prednisolone, when used as first-line treatment for CLL. This CAP combination had been shown previously to be equivalent to chlorambucil in effect. It is 6 years since Kanti Rai's CALGB trial reported that fludarabine was superior to chlorambucil in the New England Journal. In America hardly anyone still uses chlorambucil. John Gribben joshes me when I mention it. He thinks he came across a History of Medicine paper that mentioned it once. Why is it then that chlorambucil is still the only drug that is licensed for the first-line treatment of CLL in the UK?
I was privileged to be asked to take part in the NICE review of fludarabine which took place this autumn. The National Institute for Clinical Excellence goes by the acronym NICE and there have been continual cracks about it being more nasty than nice. The job it has is to look at new and existing treatments for various diseases and make a recommendation as to whether they should be available on the National Health Service.
There are three 'E's when it comes to providing health care.
Equality is what the Government is most concerned about. This is supposed to be a National Health Service. They can't abide what is known as post-code prescribing: the idea that you can get a drug in Dover but not in Darlington or that you have to wait 3 months for your hip replacement in Bournemouth but 24 months in Birmingham. They won't listen to the argument that if there was a true market everyone could get it next week; markets in health care are an anathema to the British public. Markets would, of course, mean that you could buy different standards of care for different prices, and even New Labor shrinks at the idea that rich people should get better care than poor people. So regulation is necessary to hold back the convoy to the speed of the slowest ship.
Effectiveness is what the patient is concerned about and also the concern of most doctors. We want the best result for the patient in front of us. If treatment A cures 70% of patients at a cost of £100,000 a cure while treatment B cures 50% of patients at a cost of £1000 a cure, we would still want treatment A for all our patients.
Efficiency is what the health economists want. In a way you can see what's behind their thinking. Supposing there is a limited health care budget, you would want to see it spent in the most effective way. You would want everybody to get the most effective treatment. You wouldn't want money wasted on treatments that didn't work. You wouldn't want speculative spending at the expense of proven treatments. If there was a doubt about whether a treatment worked, you would want the treatment tested so that you knew for sure whether it worked. When new, expensive drugs were introduced, you would want to know whether they produce value for money, especially in days when the market is being flooded with new products, all very expensive.
In order to compare different treatments, they have hit upon QALYs. This stands for Quality Added Life Years. It boils down to, "How much does it cost to add one extra year of high quality life?"
This approach has inherent dangers. The most cost effective treatments turn out to be ones that reduce infant mortality. Allowing a baby to live who would otherwise die adds 80 or so QALYs. Helping an 80 year old live an extra 6 months doesn't score very highly. The policy is therefore Ageist. It is also misleading to suggest that there is a limited health care budget. America is now spending approaching 20% of GDP on health. In France and Germany it is 12+%. In the UK it is 7% - still comparatively very low despite the government massively increasing what it was pre-1997. Taxpayers will only stand so much taxation. Gordon Brown has proved a master in introducing stealth taxes that people have not noticed, but if that button is pressed to often the electorate will vote for the other lot.
The rest of government spending is not subject to the same stringency. Take Transport. Installing crash barriers between opposing lanes on motorways saves lives. It may well have saved my daughter's life last week. But the cost of each life saved is £1 million. For the automatic train warning system, a system that stops railway trains passing red signals, the cost is £3 million for every life saved. On the other hand if a new drug costs more than £25,000 per QALY it will not be recommended.
The Royal Air Force has just taken delivery of the new Eurofighter. These are superb airplanes. Probably they outperform anything the Russians or Americans have produced. If either America or Russia invades us we will be able to defend ourselves. Meantime, we are still using 'snatch' Land Rovers in Iraq and Afghanistan where they are susceptible to roadside bombs and RPGs because we can't afford better.
I could give examples across government spending. Educational policies are introduced at the whim of an advisor without objective evidence of improved effectiveness. An Identity Card is about to be introduced without evidence that it will help anything. Huge amounts (equivalent to 1% of the world GDP) have been committed to fight global warming when a fraction of the amount would wipe out malaria from the planet and as a consequence raise world GDP by 3%. Prisons policy, road building, housing policy; whatever are you look at government spending is in a spiral of out of control increase. Yet because it can be measured the cost of new effective drugs is 'controlled'.
However, this is the system we've got and we have to live with it.
The NICE examination was mainly informed by the recent LRF CLL4 trial that compared chlorambucil with fludarabine with fludarabine plus cyclophosphamide as first line treatment for CLL. The important difference from other trials was that chlorambucil was given in a bigger dose than previously. The dose in the CALGB trial was 40 mg per sq meter per month; in CLL4 the dose was 70 mg sq meter per month. Even at this dose it was less toxic than was the fludarabine arm. CLL4 showed that although there was a slightly higher response rate with fludarabine, this was not statistically significant. This was a large trial with nearly 800 participants. It was powered to detect quite small differences between the treatments. There was no difference between these two drugs in terms of progression-free survival or overall survival. The combination of fludarabine and cyclophosphamide (FC), however, proved superior to both chlorambucil and fludarabine as single agents in terms of the response rate, the complete response rate and the length of remission. The differences were statistically significant. However, there was no difference in overall survival between any of the treatment groups. In fact at 5 years follow-up the chlorambucil group was doing slightly better, though the differences were not statistically significant. Patients who failed to respond to the FC had a very poor survival indeed with most failing to live 2 years. On the other hand non-responders to either chlorambucil or fludarabine could be rescued by salvage therapy.
It is likely that this is the last word in chlorambucil trials. A recent Cochrane review, which performed a meta-analysis of all the trials comparing fludarabine and chlorambucil has failed to find a difference in overall survival. The most likely reason for this is that patients who fail treatment can be salvaged by other treatments so that it does not matter much which treatment is given first.
Is that the end of the story? Are all those people in the world who have avoided chlorambucil and gone straight to fludarabine combinations wrong? Don’t miss the next exciting episode of this story.