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Paternalism no problem.

A sad episode in British cancer research recently drew to a low-key close in the setting of a parliamentary committee. The committee's investigation failed to throw any light, however, on why trials with doubtful ethics in the United Kingdom often concern breast cancer.

Evelyn Thomas was a physiologist with experience of conducting research on humans when she developed breast cancer in the early 1980s. In 1988 she wrote: "In retrospect, the first indication that I was in a trial came a few days after my mastectomy. The mastectomy patient in the next bed had been seen by a counsellor and given helpful information. The counsellor avoided me, to the extent that a breast prosthesis was given to me by a male fitter more used to fitting artificial limbs."[1]

It took her some years to get the London teaching hospital where she had been treated to admit that she had been in two randomized controlled trials. One compared postoperative counseling with no counseling; the other had four arms comparing cyclophosphamide, tamoxifen, both together, and placebo. Since Mrs. Thomas was never offered any alternative to mastectomy she later wondered whether that too had been chosen as part of a randomized trial.

With great persistence she worked her way through the National Health Service complaints procedure. She might have taken legal action - indeed, the only advice she received from the General Medical Council, which has the statutory duty to maintain professional standards of medical practice, was to do so. But she wanted to know what had happened to her, and to try to prevent it happening to other women, rather than to obtain financial compensation that she would probably have no time to enjoy.

She was met with delays and unhelpfulness that eventually became the subject of a further complaint to the parliamentary ombudsman. Along the way, however, she discovered that her personal medical data, in an identifiable form, had been entered into five separate computer systems. And her complaint about being used for research without her knowledge or consent was rejected at the final stage of the complaints procedure. That stage, called "independent professional review," is conducted by two specialists who are nominated by a national body, the Joint Consultants Committee, to review the complaint. Only later did Mrs. Thomas discover that one of the specialists was an author of the protocol of the chemotherapy trial, inclusion in which was the subject of her complaint. So much for "independent" review.

The ombudsman, or parliamentary commissioner, acts also as health service commissioner with powers to investigate maladministration in the NHS. He is not allowed to comment on clinical matters. A House of Commons select committee reviews some of his findings by summoning witnesses to be examined. At the beginning of last December, Mrs. Thomas's complaint was finally examined by that committee even though she had died more than two years earlier.[2]

During questioning, Kevin Zilkha, the physician chairman of the research ethics committee (REC, equivalent to an IRB) described how the chemotherapy trial had come to be performed without informed consent. Initially the REC had required informed consent, but the nurse counsellor who had to obtain it reported that it was distressing to patients to be asked for such consent within twenty-four hours of mastectomy. She had wished the timing to be changed, but instead the REC withdrew the requirement for consent altogether. Six months later they had to reimpose it under pressure from the United States, whence came some of the funds for the trial.

The latter information drew only one comment, from the chairman of the committee, Sir Antony Buck, MP: "It is rather surprising that people who are providing funds from abroad should be able to dictate your modus operandi, is it not?" There are some, such as this author, who would wish that more such dictation might take place. Dr. Zilkha and Michael Baum, the surgeon who put Mrs. Thomas into the trials, argued in the British Medical Journal in 1989 that informed consent was not needed if "the best medical care is randomisation into a trial."[3]

Professor Baum and others have been promoting another proposed trial recently, and complaining that it is being delayed by "ethical red tape." The proposal is to enter 15,000 women with a higher than normal risk of developing breast cancer into a five-year trial comparing the efficacy of tamoxifen in preventing breast cancer with that of a placebo. A variety of concerns have been raised,[4] some to do with information to be given to women and some, more fundamental, concerning the use of a drug to treat a risk.

One problem appears to be that tamoxifen has gained the reputation of being such a safe drug when used to treat breast cancer that women reporting side-effects are now likely to be told that they could not be caused by the drug. An example is the loss of one's singing voice: one very good amateur singer found that her voice dropped a whole octave, permanently, within a few days of starting tamoxifen. On inquiry she found in her own cancer support group in England half a dozen other women with the same problem. Yet lowering the pitch of the voice is not a recognized side-effect.

So there is concern as to whether women in the proposed trial - who will have a 4 per 1,000 risk or greater of developing breast cancer each year - will be given full information about side-effects. If they are given any information at all, that is. One well-known journalist found herself being pressured to join the pilot study already underway by a doctor who assured her that tamoxifen had no significant side-effects. And the latest draft of the proposed information sheet has a Flesch reading ease score of 39, suggesting that no more than a third of women will understand it.

Complaints by promoters of the trial about delays caused principally by the Medical Research Council raise another interesting point. Claims have been made that tamoxifen is likely to prevent about half the breast cancers that would otherwise have developed. If the trial promoters really believe that, how can they ethically run a trial against a placebo, when equipoise is obviously absent? Perhaps they would do better to look at the American evidence of a link between low levels of vitamin D and the development of breast cancer, and change the trial to a comparison of tamoxifen and vitamin D.

One other recent trial involving women with breast cancer is causing great concern. A cohort study comparing the outcomes for women who had or had not attended the Bristol Cancer Help Centre was reported in September 1990.[5] It purported to show that just attending the center, regardless of whether one participated in the treatment - diet, counselling - available there, made it 2.9 times more likely that a woman with breast cancer would relapse, and 1.8 times more likely that she would die than if she had not been there.

A group of women involved in the study as subjects thought this result rediculous, and started to make their own inquiries. They found that little attempt had been made to follow the original protocol approved by an REC, that the time scale suggested it was a pilot study that had been reported, and that the statistical analysis defied common sense.[6] Their request to know such basic information as how many women died in the control cohort remains unanswered. So far the researchers have resisted requests to retract the original paper - perhaps because it was released with maximum possible publicity and did the center great damage, both financially and to its reputation.

Were I a woman, perhaps I could comment there on the subtleties of what these three episodes say about the attitudes of researchers, predominantly male, to disordered - or potentially disordered - female breasts. But I am not sure that subtleties are needed. These incidents seem to me to arise from a lack of respect for research subjects. It is not just that many researchers remain thoroughly paternalistic toward their subjects. It is as if the prevailing view were that researchers own all the research they do, and that its subjects had no legitimate interest in the details of its conduct. The notion of research as an equal partnership between researcher and subject - as expressed by Margaret Mead twenty years ago[7] - seems totally absent.


[1.] "Research without Consent Continues in the U.K.," IME Bulletin (now Bulletin of Medical Ethics), no. 40 (July 1988), pp. 13-15. [2.] Select Committee on the Parliamentary Commissioner for Administration, Minutes of Evidence 4 December 1991 (London, HMSO: 1992). [3.] Michael Baum, Kevin Zilkha and Joan Houghton, "Ethics of Clinical Research: Lessons for the Future," British Medical Journal 299 (1989): 251-53. [4.] "MRC to Go Ahead with Controversial Tamoxifen Trial?" Bulletin of Medical Ethics, no. 72 (October 1991), pp. 3-5. [5.] F.S. Bagenal et al., "Survival of Patients with Breast Cancer Attending Bristol Cancer Help Centre," Lancet 336 (1990): 606-10. [6.] I. Bourke and H. Goodare, "Bristol Cancer Help Centre" (letter), Lancet 338 (1991): 1401. [7.] Margaret Mead, "Research with Human Beings: A Model Derived from Anthropological Field Practice," in Experimentation with Human Subjects, ed. P.A. Freund (London: George Allen and Unwin, 1972), pp. 152-77.
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Author:Nicholson, Richard H.
Publication:The Hastings Center Report
Date:Mar 1, 1992
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