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Drugs (Safety)
10.59 am
Dr. Jeremy Bray (Motherwell, South): The House has given a good deal of attention to the warning given by the Committee on Safety of Medicines on third generation oral contraceptives last October. The committee was right to hold the views and take the actions that it did, given the evidence available at that time. Certainly, there was, and is, a need to review the announcement procedure. Owing to the immediate public reaction, there was a deplorable jump in the number of unwanted pregnancies and abortions. Sadly, some women ignored the committee's advice that no one need stop taking oral contraceptives and that women taking the third generation pill should see their doctors.
This morning, I wish to talk about the lessons to be learnt about the general arrangements for monitoring the safety of drugs. The second generation pill, which was introduced from 1970, greatly reduced the risk of a blood clot forming in the veins of the legs and moving to the lungs--a pulmonary embolism--with sometimes fatal consequences. Second generation pills are still in use today and the Committee on Safety of Medicines' letter of 18 October reported even lower risks in their use than had previously been observed.
During the 1970s, there began to be concern about other circulatory side effects. Large cohort studies by the Royal College of General Practitioners and the Oxford Family Planning Association found a slightly increased mortality from heart attacks and strokes, and found factors in those cases that increased the risk of the pill. With appropriate prescribing and lower dosage, the incidence of circulatory side effects and mortality were reduced to very low levels.
There is a large--and what was a profitable--market for the pill in the United Kingdom, but the patents and trade agreements in the second generation pills held by Schering and Wyeth and by Janssen-Cilag and Syntex began to run out in the 1980s and 1990s. The search was on for new patentable products aimed at further reducing risks and side effects. The risks had become too low to be picked up by the public cohort studies and public funds were not available for a wider form of monitoring of a research standard.
Researchers began to pay more attention to surrogate or proxy bio-chemical markers to represent the side effects of the pill. At the same time, there was a great deal of research on fats and cholesterol, and their effects on the circulatory system. The relationship of those effects to the use of oral contraceptive pills is somewhat distant: it depends on a connection between the effect of the pill on cholesterol and the effect of cholesterol on arterial disease. Most of the studies of cholesterol changes have been on middle-aged and elderly men, not many of whom are on the pill.
Before they experience the menopause, women have a particularly low rate of coronary heart disease. Pharmaceutical companies came up with third generation pills with new progestogens that are claimed to protect women against coronary heart disease and strokes. The three firms that hold the third generation patents are Organon, Wyeth-with-Schering and Janssen-Cilag. The latter two had held second generation patents that were running out. Third generation pills were vigorously marketed and about
1.5 million women in the United Kingdom--out of a total of 3 million pill users in the country--were using them last October. Half the pill users were taking third generation pills.
It was against that background that the Committee on Safety of Medicines had to issue its warning on18 October last year that three independent new studies showed that the third generation pills, on a pooled estimate, doubled the risk of the old problem of blood clotting in the legs, leading to pulmonary embolism. It is a good idea to keep a sense of proportion and to bear the numbers in mind. The background risk of pulmonary embolism was five cases per 100,000 women per year not taking the pill, 15 cases per 100,000 women per year taking second generation pills and 30 cases per 100,000 women per year taking third generation pills. The 50 per cent. of young, pill-taking women, probably raising their families, using third generation pills, were therefore suffering 75 to 150 more thromboembolisms, and each year one to two more of them were dying.
It was not a major disaster by serious epidemic or public health disaster standards, but even those numbers should not be on the conscience of any firm or group of workers. Following the warning in October, sales of third generation pills have dropped drastically. One of the firms affected, Organon, has a factory in Newhouse next to my constituency, so I am acutely aware of the industrial effects. At the time of the announcement, the lay media did an excellent job of accurately reporting the relevant brands and passing on the committee's message that no one need stop taking oral contraceptives, but the scientific press made an ass of itself.
On 18 October, Schering, one of the three patent holders, flew over from Montreal Professor Spitzer, the author of one of the studies. He gave a press conference at Heathrow criticising the Committee on Safety of Medicines, based partly on his own work--possibly without knowing the other two study results.
Organon, another of the patent holders, paid for a conference in London for 400 family planning doctors in order to argue its case. Both the British Medical Journal and Nature managed to get their reporting of the facts wrong. For comic relief, the hon. Member for Southwark and Bermondsey (Mr. Hughes)--who I see is in his place and who is the Liberal Democrats' spokesperson on health--persisted in suggesting that the committee's announcement was a Government conspiracy to divert attention from the Home Secretary's troubles with Derek Lewis. I do not think that the Secretary of State for Health is that stupid, but the hon. Gentleman should not attack the independence and integrity of scientists doing their public duty.
The Committee on Safety of Medicines' announcement was not rushed: data for the two case control studies were collected between 1989 and 1993. The general nature of the results was known to those involved in the industry and in the regulatory agencies in advance of the announcement by the Committee on Safety of Medicines. Owing to the nature of its work, the committee has to base its findings on mostly unpublished work, and when the three studies were published, it was generally agreed on reflection that the committee was right to act as it did.
In one way, the episode has demonstrated the effectiveness of modern pharmaceutical research and monitoring. Yet, and yet, and yet--was it necessary for that decade of commercial research to be wasted on the blind alley of the third generation pills? More fundamental medical research might have come up with real advances in contraception, but instead contraceptive research was run down by the Medical Research Council. Had the United Kingdom publicly funded cohort studies been extended and had new research methods been adopted, could not the epidemiology of pulmonary thromboses, cholesterol levels, heart attacks and strokes have been properly measured in women at a much earlier stage and at much reduced cost?
What about the use of the United Kingdom general practice research database? American drug companies often say that the United Kingdom is a good place to do pharmaceutical research, because the national health service provides such a coherent and well-ordered source of data. The general practice research database is a good case in point. It is a computerised record by general practitioners of all the medical events affecting some3 million or 4 million people and accumulating in the past five or six years. It is a record that could not have been built up in the United States without a general practitioner system. It is a development of the VAMP--value added medical products--system which this privatising Tory Government nationalised absentmindedly when Reuters decided that it could not afford to develop it. It is now run by the Office of Population Censuses and Surveys which has now been merged into the new Office of National Statistics. The software is archaic and the only person who seems to be able to wring real results out of the database is Hershel Jick, an American in Boston who is 70 years old and operates on his own with half a dozen assistants. It was to him that the Committee on Safety of Medicines had to go for a database study on third generation pills.
Open access to the general practitioner research database costs £250,000 a year, which puts it out of the reach of academic researchers. It is a neglected gem of a resource. There are two United Kingdom efforts at exploitation of the database. One is by Dr. Alan Dean, the remarkable medical practitioner who pioneered the database. The other, which is apparently inadequately resourced, is by the Office of Population Censuses and Surveys. Contrast that with the sophistication of the human genome databases. Three independent versions are emerging, two of them with free access and two of them privately financed.
Let us suppose that the Committee on Safety of Medicines wanted a pharmaceutical company to carry out a study on a licensed drug, as it could have done using the general practitioner research database. The Committee on Safety of Medicines has no powers to require a pharmaceutical company to do that. In the trials before licensing, the CSM has the obvious sanction of refusing the licence until the study is done, but afterwards it has no sanction. It could withdraw the licence, but often that is not desirable because there may be cases in which the drugs are useful, as with third generation pills for older women who persist in smoking while taking the pill. The CSM can ask for new studies on a licensed product, but only if it has new evidence rather than a new judgment on existing evidence.
The Medicines Control Agency, the CSM, the Royal College of General Practitioners, the British Medical Association and the Association of the British Pharmaceutical Industry have issued agreed guidelines for company-sponsored safety assessment of marketed medicines. That is an admirable example of the way in which progress is made by agreement in the United Kingdom, but the so-called SAMM guidelines do not cover database methods, nor does the CSM have powers to require such studies. Drug companies can be recalcitrant and tough, as the third generation pill affair showed. Could not the CSM have powers to require companies to carry out specified studies on licensed drugs or pay for others to do so?
In discussing these issues, members and staff from all the organisations concerned, pharmaceutical companies included, have been very helpful, especially John McEwan, a consultant at King's College hospital who alerted me to the broader issues; Michael Rawlins, the chairman of the CSM; Susan Wood, a director of the Medicines Control Agency; and Frances Charlesworth, a director of the Association of the British Pharmaceutical Industry. The views that I have expressed and any mistakes that I have made are, of course, entirely my own.
I think that the practice in the United Kingdom of seeking informal agreement is more healthy and productive than the lawyer and litigation-ridden world in the United States and the regulated, directive-laden world of the European Union, but we have to live with those worlds and they have great strengths, including the enterprise of the American and the thoroughness of the European. We go too far in our passion for informality and agreement if we let things slip.
Safety is not the only aspect of medicines that has to be considered. Important issues arise in patenting, research and pricing. Safety must not be compromised by those or any other considerations, yet there are interactions. An enhanced pharmaco-vigilance system would increase the price of medicines. Firms will not do research that does not offer the prospect of a commercial return, yet the prospect of a valuable patent can unlock resources for research quite beyond the reach of the basic research funding bodies, whether charitable or public. The CSM and the Medicines Control Agency must not be diverted by interesting research questions, by difficult patent issues, by tough commercial pressure or by political pressures. They must have the uncompromising support of Parliament in discharging their responsibilities for safety, but Parliament must likewise provide other ways in which the interactions can be explored and reviewed.
Medicines have a long history. The existence of the overarching Medicines Commission was a factor that led the Select Committee on Science and Technology recently to recommend the setting up of a human genetics commission to keep an overview on that rapidly developing field. The Government seem about to accept the principle of that recommendation. A similar breadth of view needs to be, and could be, taken for medicines generally by the existing Medicines Commission without in any way compromising the independence and integrity of the CSM and the Medicines Control Agency.
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