Do No Harm: Stories of Life, Death and Brain Surgery (21 page)

The following day we went to visit Tanya’s grave in the local cemetery. It was some miles away from Katya’s house, standing on its own beside a wood. The road to it wound along country lanes, lined with bare winter trees, passing through battered and dishevelled villages, each with a pond, frozen over with blue-grey ice, with geese and ducks standing at the edges. Orthodox cemeteries are wonderful places. The graves are decorated with dozens of brilliantly coloured artificial flowers and the gravestones all have photographs behind glass or portraits etched in stone of the deceased. Everything was in perfect order and in marked contrast to the dilapidated houses in the villages of the living which we had passed through on our way to the cemetery.

Tanya’s grave had a six-foot-high headstone from which her carved face appeared – odd, perhaps to western eyes, but beautiful. The sun was shining, the artificial flowers glittered and shook in a light wind and in the distance I could hear the chickens in the local village. The snow had melted and only a little was left, showing up as white lines in the furrows of the ploughed field which we had crossed to reach the cemetery. There was birdsong everywhere. As the film crew set up their equipment I wandered round the cemetery, looking at the gravestones and their portraits. Most of the people buried here would have lived through the most terrible times – the Civil War of the 1920s, the famine of the 1930s (though it had been worst in central Ukraine), Stalin’s despotism and the unspeakable horrors of the Second World War. At least a quarter of the population of Ukraine died violently in the twentieth century. I wanted to ask these dead faces what they had done during those years, and what compromises they must have made to survive, but it seemed to me that they looked back at me as though to say: ‘We are dead. You are still alive. And what are
you
doing with the time that you have left?’

The film about Igor and me was a great success. It has been shown all over the world and won many awards. At the end of the film I was shown standing in front of Tanya’s grave. I was looking sad not just because of Tanya’s death but because next to her grave, and unbeknown to any viewers, was her father’s grave. He had gone to Poland a few months earlier to make some money as an agricultural labourer since he and Katya were desperately poor. He had managed to earn a thousand dollars and was about to set out for home for Christmas when he was found murdered. The money had gone. I had wanted to see Katya not just because of Tanya but also because of her father’s death. Life in Ukraine is not easy.

23

TYROSINE KINASE

n.
an enzyme that acts as an on/off switch in many cellular functions. Drugs to reduce its activity, known as tyrosine kinase inhibitors or
TKIs
, are used in the treatment of many cancers.

‘Are we quorate?’ the chairman asked. A rapid head count showed that we were, so the meeting began.

The chairman, after making a few brief jokes, got to the business of the meeting.

‘We have patient representatives from the Support Group for the technology we are discussing today,’ he said, looking towards three elderly grey-haired men who sat on one side of the hollow square of tables around which the Technology Appraisal Committee was seated. ‘Welcome!’ he said, with an encouraging smile. ‘We have our clinical experts,’ – he pointed to two grave-looking men next to the patient representatives – ‘and we have representatives from the company whose drug for this cancer we are considering,’ he continued, in a slightly more formal voice, looking towards two anonymous-looking men in dark suits with large box-files on the floor in front of them. They sat a few feet behind us, away from the tables.

‘Mr Marsh is the Clinical Lead and will tell us about the evidence for the effectiveness of the drug, but I thought we might first start with statements from the patient representatives.’

The first of the three elderly men cleared his throat a little nervously and, with a sad and resigned expression, delivered his statement.

‘I was diagnosed with the cancer two years ago,’ he began, ‘and at the moment am in remission. I have been told that it’s bound to start growing sooner or later and the only possible treatment when that happens will be this new drug you are considering today . . .’

As he spoke, the committee listened in complete silence. It was difficult not to admire his bravery in talking to a room full of strangers in this way. He went on to explain that he had started a support group for patients with this particular disease.

‘There were thirty-six of us to begin with but now there are only nineteen of us left. I would ask you to remember when you consider this drug,’ he added, with a slight note of despair as he finished, ‘that life is precious, that every day counts . . .’

The next elderly man spoke of how his wife had died from the cancer, and he told of us of her suffering and the misery of her final months. The third elderly man opened the briefcase in front of him and pulled out a sheaf of papers. He looked very determined.

‘I am only here,’ he began, ‘in my opinion, because of this drug. I was first diagnosed twelve years ago – and as you all know most people die from it in less than five years. The doctors here had nothing to offer me so I read up about it and went to America and was enrolled in various drug trials. The last drug was the one you are looking at today – I started it eight years ago. The
NHS
would not give it to me. It has cost me three hundred thousand pounds of my own money so far. Gentlemen . . .’ he looked around the room at us all, ‘I hope you will not consider me to be a statistical outlier.’

After a brief pause the Chairman turned to me. ‘Mr Marsh will now tell us about the clinical effectiveness of the drug in question.’ He pushed the laptop in front of him towards me.

I had volunteered my services to
NICE
, the National Institute of Clinical Excellence, two years earlier. I had seen an advertisement in one of the medical journals for a consultant surgeon to join one of the
NICE
Technology Appraisal Committees. I thought the word ‘technology’ would mean interesting things like microscopes and operating instruments but it turned out, to my dismay, to mean drugs. The only exam I ever failed in my prolonged academic career was in pharmacology. The popular press often accuses
NICE
of being an organization of callous bureaucrats – in America right-wing politicians refer to it as a ‘Death Panel’. These are wholly unfair accusations and as I have become familiar with the process by which new drugs are appraised by the committee, and a decision made as to whether the
NHS
should use them or not, I have become increasingly fascinated. Once a month I will take the train to Manchester, where the all-day meeting is held in the
NICE
head office. The members take it in turns to present the evidence about the drugs being considered. On this occasion it was my turn.

The slides for my presentation were projected, one by one, on three of the room’s four walls as I spoke. They were rather dull slides, plain blue letters on a white background, with facts and figures and the long unpronounceable names of chemotherapy drugs, over which I stumbled as I read. I had prepared the slides in a frantic rush with the help of the
NICE
staff over the preceding few days. The meetings are open to the public and there can be none of the jokes and pictures trawled off Google Images with which I usually decorate my medical lectures. My presentation took about ten minutes.

‘The conclusion,’ I said as I finished, ‘is that this
TKI
works for this particular cancer in the sense that it significantly reduces the size of the patient’s spleens but this is only a surrogate outcome. It is not clear from the trials whether patients lived longer or had a better quality of life. Many of the patients were lost to follow-up and the quality of life data is largely missing.’

There was then a ten-minute break for coffee. I found myself standing next to the chairman. I told him that I had been in Ukraine two weeks earlier and had been told that drug trials there are a good little money-spinner. Many of the hospitals are involved in trials for the big drug companies and I was told that the same patient might be put into several different trials since the doctors get paid for every patient they enter. If that is true, I said, the results are therefore meaningless. The chairman chose not to comment.

The next presentation was by a health statistician and dealt with the cost-effectiveness of the drug – in other words the question of whether the benefits for patients dying from the cancer are worth the drug’s cost. He had the hesitant delivery of an academic and he stumbled and hesitated as he went through his complex slides. His presentation was a series of graphs and tables and acronyms, using the various models that health economists have developed in recent years to analyse this question. I quickly became lost and furtively looked around me, trying to guess if the other committee members understood his presentation any better than I did. They were not giving anything away and were all watching the projection screens with expressionless faces.

In this kind of economic evaluation the extra life that patients may, or may not, get from a drug is adjusted to make allowances for the fact that the extra time might, or might not, be of only poor quality. Most patients dying from lung cancer, for instance, will be in poor health – short of breath, coughing blood, in pain, in fear of death. If they were to live an extra year (which is unlikely with that particular cancer once it has spread) and were in good health, that extra year would be given the value of one year. If they were in poor health, that value would be correspondingly reduced. This value is called a Quality Adjusted Life Year and it is calculated using ‘utilities’. In theory this involves asking dying patients how they feel about the quality of their life, but it has proved very difficult to do this in practice since it often involves openly confronting dying patients with their imminent death. Not surprisingly this is something from which both doctors and patients shy away. Instead, healthy people are asked to imagine that they are dying, that they are coughing blood or in pain, and then asked how much they feel this would reduce the quality of their life. Their replies are used to calculate the quality of the extra life gained by using the new cancer drug. There are various ways of doing this – one is based on a technique from game theory called the ‘standard gamble’. It was invented by the great mathematician von Neumann who – it is perhaps worth pointing out – also recommended on the basis of game theory a pre-emptive nuclear strike against the Soviet Union in the days of the Cold War. Some might conclude that the standard gamble is not necessarily the best basis for human decision-making.

The degree of uncertainty that surrounds all these calculations must also be measured, which makes matters even more complicated. At the end of all this, a final figure is generated – the Incremental Cost Effectiveness Ratio, which is the cost of one extra quality-adjusted life year which the new treatment achieves when compared to the best current alternative. If this is more than £30,000
NICE
will not approve the use of the drug by the
NHS
, although exceptions will sometimes be made for patients dying from rare cancers. Whenever
NICE
refuses to approve a drug there is an inevitable outcry from patient groups and the drug companies. Patients dying from various distressing diseases will appear on the television news accusing the
NHS
and
NICE
of abandoning them.
NICE
will be accused of being a Death Panel.

The health economist, who looked more like a harmless drudge than a sinister death panellist, trudged through his complex slides. The talk seemed to consist of nothing but acronyms and I constantly had to ask the friendly analyst next to me what they meant. Once he had finished, the chairman of the committee asked the visiting experts for their opinion and the committee members then questioned them.

‘How can we judge the value of the drug if the trials don’t really tell us how the patients were doing and only how long they lived?’ I asked.

There was a grave and bearded professor of oncology attending the meeting as an expert witness.

‘If you look at the Manufacturer’s Submission,’ he said in a very soft voice, which I could scarcely hear, ‘you will see that the quality of life data wasn’t collected because the clinicians running the trial felt it would be bad for the patient’s welfare. It’s a standard problem with cancer chemotherapy trials – it’s difficult to get dying patients to complete questionnaires. One has to use standard utilities instead. But it’s one of the few chemotherapy agents we have for this cancer that has very few side effects,’ he added.

He spoke movingly of the difficulties of treating dying patients, and the fact that he had so few effective treatments.

‘We would very much like to have the choice of using this drug,’ he concluded.

‘At any cost?’ the chairman asked, delivering the coup de grace. The expert had no answer to this terrible question. Once the discussion had ended the patient representatives and experts and outside observers were then ushered out of the room and the second part of the meeting – where a decision is made whether to allow the
NHS
to use the drug or not, but in camera – started.

‘Surely,’ I wanted to say to the hard-nosed health economists and public health doctors around me, but did not dare, ‘the real utility of the drug is to give dying patients hope? The hope that they might be statistical outliers and live longer than average? How do you measure the utility of hope?’

I could have delivered an impassioned lecture on the subject. I have spent much time talking to people whose life was coming to an end. Healthy people, I have concluded, including myself, do not understand how everything changes once you have been diagnosed with a fatal illness. How you cling to hope, however false, however slight, and how reluctant most doctors are to deprive patients of that fragile beam of light in so much darkness. Indeed, many people develop what psychiatrists call ‘dissociation’ and a doctor can find himself talking to two people – they know that they are dying and yet still hope that they will live. I had noticed the same phenomenon with my mother during the last few days of her life. When faced by people who are dying you are no longer dealing with the rational consumers assumed by economic model-builders, if they ever existed in the first place.

Hope is beyond price and the pharmaceutical companies, which are run by businessmen not altruists, price their products accordingly.

The admirable purpose of
NICE’s
technology appraisal (which is only one part of
NICE’s
work) is to try to provide a countervailing force to the pharmaceutical companies’ pricing policies. The methodology used for the drug in question was unrealistic, verging on the absurd, and I wondered how many of the people sitting round the hollow square understood the difficulties and deceptions involved in treating patients who are dying, where the real value of a drug such as this one is hope, and not the statistical probability of living, possibly in great pain, for an average of an extra five months.

I kept my doubts to myself since I firmly believe that the pricing policies of the great drug companies must be resisted and that healthcare costs, like greenhouse gases, must be curbed. The abstract discussion continued.

‘But the
MS
doesn’t even involve a
PSA
!’ a young health economist was saying with deep indignation. ‘And if you want my opinion we should toss this application out . . .’

‘Surely not Prostate Specific Antigen?’ I asked my neighbour, unable to resist a silly joke.

‘No,’ he said. ‘Probabilistic Sensitivity Analysis.’

‘Well, I have some problems with
PSAs
,’ the chairman said, ‘but the assumptions about the
haq
slope are important and the lowest possible
icer
is £150,000 so even though
EOL
applies there is no way this drug will pass. At a cost of £40,000 per year for treatment per patient there was never any chance it could be cost-effective.’

This last one at least was an acronym I knew – End of Life was a compromise
NICE
had recently been forced to make to allow the use of expensive drugs in small groups of patients dying from rare cancers.

The discussion went on interminably. Half of my fellow committee members spoke and argued in the arcane language of cost-effectiveness analysis with passion and assurance, while the other half nodded wisely.