The Rise and Fall of Modern Medicine (59 page)

Perhaps predictably, successive sets of guidelines forced the level of a ‘normal' cholesterol ever downwards, resulting in 2001 in a quantum leap in those eligible for treatment with statins in the United States – up from 13 million to 30 million.
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Two years later a further revision would increase that figure to 40 million. This generated some controversy when it was pointed out that the relevant panel of experts had failed to report any potential ‘conflicts of interest' – for good reason, as it subsequently transpired that six of the nine experts on the panel had received research grants or consultancy fees from at least three of the drug companies involved in manufacturing statins.
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In Britain comparable guidelines required that those dropping in to see their family doctor for any reason, and irrespective of their age, would have their cholesterol checked and commence treatment where it was deemed ‘appropriate'. This was perhaps a step too far, as when statins are routinely prescribed to the fit and healthy and things ‘go wrong', it is easy to make the connection. Those previously accustomed to taking regular daily exercise were struck down by muscular aches and pains, reducing them to a state of decrepitude. Meanwhile the mentally alert suffered memory lapses, loss of concentration and depressed mood of such severity as to suggest they might be developing incipient dementia.
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Then once the penny dropped and the statins were discontinued, within a few weeks the decrepit regained their mobility and the incipiently demented their minds.

The dramatic accounts implicating statins in this pattern of sudden physical or mental decline and seemingly miraculous recovery attracted a lot of attention, raising the question of how many of the chronic and insidious symptoms experienced by
those on long-term statins might similarly be attributed to this class of drug.
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Curiously or not, there is scarcely a hint of such problems in the findings of the clinical trials, where less than 1 per cent of the participants report nerve or muscle complaints. This would seem to be a considerable underestimate and would be contradicted by the subsequent finding of, for example, a twenty-six-fold increased risk of nerve damage (polyneuropathy) in those treated with statins for two or more years.
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And so the bottom line beckons. Two decades have elapsed since the launch of lovastatin, so what is the payback for that annual $26 billion expenditure on statins? There are strong theoretical grounds for supposing that the statins are not nearly as effective as portrayed, not least because the pattern of the rise and fall of heart disease over the past fifty years is strongly suggestive of an underlying (and as yet unknown) biological cause. For the vast majority of those taking statins, the 75 per cent who are otherwise healthy but designated as ‘high risk' because of their ‘raised' cholesterol levels or associated risk factors, the largest ever review, examining the results of eleven controlled trials, published in 2010, concludes perhaps surprisingly that statins do not prolong life; that is, they have no effect on ‘all-cause mortality'.
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So whatever small advantage there might be in reducing the chances of a heart attack is offset by the increased risk of dying from other causes. This verdict is unlikely to be reversed. By contrast, for men aged less than seventy who have a previous history of heart problems, then the most favourable of the clinical trials reveal that statins do indeed ‘save lives', reducing the risk of dying by almost a third. Put another, less dramatic way, for one hundred of those in this category taking statins, ninety-two will still be alive five years later, compared to eighty-eight of those in a control group taking a placebo.
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Currently the prospects of the pharmaceutical industry could scarcely seem rosier, with the prodigious wealth generated by the blockbuster phenomenon providing the financial muscle – and influence – to shape the priorities of medicine to its own advantage. And there is no reason, one would suppose, why that situation should not prevail for the foreseeable future. But that is certainly not how it appears to those who must take a realistic view of the industry's prospects in the long term – its potential investors. So while those annual revenues have soared ever upwards over the past ten years, simultaneously and paradoxically share prices have halved, slashing $850 billion from the stock market value of the top fifteen companies.

The most important of the several reasons for this pessimistic interpretation of Big Pharma's future is that some of its most profitable blockbusters are set to ‘fall off a cliff' over the next few years as they come off patent and are replaced by generic equivalents. This could result, it is estimated, in the drug companies losing a quarter of their annual revenue, $200 billion worth, with no further statin-type blockbusters in the pipeline to plug the gap.
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Then there is the undesirable combination of escalating research costs and declining (or static) drug innovation. So while the collective investment in research and development (R&D) across the industry of $2 billion spent in 1980 had risen to $43 billion by 2006, the number of new drugs approved by the regulatory authorities remains roughly the same, at around twenty a year – most of which are me-toos, with less than one-fifth designated as new molecular entities (i.e. genuinely novel compounds).

This ever widening discrepancy between the scale of R&D and its ‘returns' is due to the same combination of factors as outlined in ‘The Dearth of New Drugs'. These include the
‘low-hanging fruit problem', where the easy therapeutic advances have already been made; and the ‘better than the Beatles problem', where it is difficult to improve on the efficacy of those drugs already discovered; and the ‘cautious regulator problem', where the regulatory authorities, in the aftermath of the thalidomide tragedy and similar more recent episodes, have imposed ever stricter (and more costly) criteria for drug approval.
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Thus in retrospect it appears that the blockbuster era, for all the phenomenal revenues it generated, could offer only a temporary reprieve from these deep-seated structural issues. Or, as a senior researcher at Eli Lilly observed in 2010; ‘We may be moving closer to a pharmaceutical “ice age” and the potential extinction of the industry, at least as it exists today.'
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Nonetheless there is no reason in principle why the potential of medicinal chemistry should be exhausted and, contrary to such gloomy predictions, Big Pharma has recently found a way to circumvent the implications of the falling-off-the-cliff of those patent-expiring blockbusters. The calculation is simple and the implications for its future are profound: rather than creating a market for relatively costly drugs (such as Lipitor at £35 for a month's treatment) that will be taken by millions, switch to producing very expensive drugs (at £20,000 for a course of treatment) that will be taken by tens of thousands.

The most obvious situation in which it might be possible to contemplate this quantum leap in drug pricing is for the treatment of cancer. Here there is, as noted, a marked discrepancy in the efficacy of chemotherapy, with very impressive cure rates of around 90 per cent in childhood cancer and some forms of leukaemia and lymphoma, and a much more modest improvement in survival rates of around 10 per cent in those with the much commoner age-determined ‘solid' tumours of the breast,
lung, gut and so on. In this latter group in particular progress in understanding cancer at the most fundamental level of the workings of the cell has suggested the potentially fruitful approach of identifying the proteins on the outer surface of cancer cells or those involved in the proliferation of blood vessels. These can then be targeted and their action blocked.
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This approach has always been the Holy Grail of cancer treatment, being so much more selective in targeting cancer cells than the blunderbuss of standard chemotherapy, which indiscriminately destroys both normal and malignant cells. But it only became a viable proposition with the development of a process that involves transferring human ‘immunity' genes into mice that are then vaccinated against the relevant cancer-related protein to produce what are known as ‘monoclonal antibodies'. These then need to be modified to ‘look like' human antibodies, and transferred to the patient, whose immune system is thereby stimulated to destroy the cancer cells.

The drug Herceptin illustrates the possibilities for those women with an aggressive form of breast cancer due to the ‘overexpression' in the cancer cells of a receptor for the protein epidermal growth factor (EGF). Herceptin blocks the action of this protein, and when combined with conventional chemotherapy reduces the incidence of subsequent recurrence of the disease by almost a half.
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Similarly, Avastin, used in the treatment of cancer of the colon, blocks the protein vascular endothelial growth factor (VEGF) involved in promoting the growth of the blood vessels that provide oxygen and nutrients to rapidly growing cancers.
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These ‘biological therapies', as they are known (to distinguish them from the cytotoxic chemicals of conventional chemotherapy), represent the most important conceptual advance in cancer treatment for the past thirty years. The stumbling block
is their cost, and that for the most part they are not ‘curative' but rather improve survival from several months to years. Here the ‘price tag of progress' in the treatment of advanced cancer of the colon that has already spread or metastasised elsewhere is as follows: the average survival for those opting for no treatment is eight months; that rises to twelve months with conventional standard chemotherapy which costs $63. The addition of three further ‘chemo' drugs increases the survival time to twenty-one months, but pushes the cost up to $11,000. With Avastin that rises to $30,000. Put another way, the doubling of survival from one to two years has been accompanied by a 340-fold increase in the cost of treatment, which in the United States would come to an extra $1.2 billion a year for this cancer alone. Multiply that by the several hundred thousand new cases of cancer a year and the additional expense becomes truly ‘astronomical', where the cost for each additional year of life gained is in the region of $100,000.
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Such astronomical costs are not restricted to cancer treatment. Thus Avastin-type drugs, it was found by chance, are also effective in inhibiting the proliferation of blood vessels from the retina at the back of the eye impairing the vision of those with the common Age-related Macular Degeneration. This discovery, which requires three monthly injections of the drug directly into the eye, though obviously of great importance, is staggeringly expensive, with each injection carrying the hefty price tag of £800. And for those with severe rheumatoid arthritis who fail to respond to standard ‘disease modifying drugs' there is now the option of the regular infusion of a monoclonal antibody that inhibits the enzyme Tissue Necrosis Factor involved in causing inflammation of the joints – but this too carries a similar price tag for each treatment.

These ‘biological' drugs have proved immensely successful,
with three now in the top-ten list of blockbusters. But the dilemma is obvious. Cancer is an emotive illness; the pressure to prescribe these drugs even for a modest improvement in prognosis is immense. But when, as is estimated, 80 per cent of the expense of anti-cancer therapies is incurred in the last three months of life, the cost to the health services of the Western world might soon become unsustainable.
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The only recourse would be for governments to legislate to compel the drug companies to drastically reduce their pricing structure – but that in turn would undermine the viability of the companies that depend on their revenues to ensure their continuing profitability.

F
or all that has happened in the last decade, the everyday practice of medicine is not noticeably different – except in its scale. It would be most surprising if it were, for its major preoccupations have not changed: ameliorating with drugs and surgery the effects of the chronic diseases associated with ageing. And so it will be ten years hence, by which time those now in their fifties and sixties will need their arthritic hips replacing, their cataracts removing, their arteries replumbing, their blood pressure lowering and their diabetes treating. It is possible that the biological therapies just considered might further improve the prognosis in the common age-determined cancers of the breast, lung, gut and so on. But that, as suggested, will pose a substantial financial strain on the health services of the Western world. Similar considerations apply to the more distant and yet unfulfilled promises of ‘regenerative medicine' with the prospect that customised stem cells from foetal tissue or bone marrow might repair, for example, damaged nerve cells to become a viable treatment for multiple sclerosis or brain disorders such as Parkinson's and Alzheimer's.