Are Large Clinical Trials Ethical

Ralph W. Moss, Ph.D. Weekly Newsletter #76 03/07/03

Are Large Clinical Trials Ethical?

In the February 22 issue of the Lancet, distinguished scientist Dr. David F. Horrobin argues that enrolling cancer patients in large clinical trials is generally unethical.

Dr. Horrobin has been involved in biomedical research for many decades. He has medical and doctorate degrees from Oxford University and has taught at the Universities of Oxford, London, Nairobi, Newcastle, and Montreal. He edits two biomedical journals, "Medical Hypotheses" and "Prostaglandins, Leukotrienes, and Essential Fatty Acids," and is the author or co-author of 500 papers.

He founded the biotech company, Scotia Holdings PLC, in 1979, and is currently Executive Chairman of Laxdale Ltd., a company that specializes in the development of new drugs for psychiatric and neurological disorders.

As he writes in the Lancet, "I am thoroughly acquainted with the many important ethical and statistical issues that impinge on clinical trials." Yet these long-standing intellectual concerns became palpable for him when, two years ago, he was diagnosed with mantle cell lymphoma. Because of the severity of his disease, he was told that he had just six months to live.

"And so," he wrote, "I entered a universe parallel to the one in which I had lived for 30 years." Suddenly, he was a cancer patient with a "terminal" diagnosis and he could see everything "from the other side." Much of his time was spent talking to other lymphoma patients, scouring medical databases, and surfing the Internet.

Much of his discussion of clinical trials centers on "effect sizes." It is a basic principle of statistics that the more effective the treatment, the smaller the trial that is needed to prove its value. "I looked at effect sizes and power calculations in a wholly new way," he wrote.

For example, the drug cisplatin was approved for testicular cancer after a study in just half a dozen cases, because its effect in that disease is huge. Some spectacularly effective treatments do not even need clinical trials at all. "To my dismay," Horrobin wrote, "I soon learned that in oncology, with few exceptions, effect sizes were very small."

In other words, few cancer treatments have a demonstrably big effect on the various forms of the disease.

As Horrobin points out, there is a divergence between what patients and scientists expect of treatments. Patients first confronting cancer want to live, and in order to live, they need to find the best possible treatments.

It is only much later, if no effective treatment is forthcoming, that they may begin to think in altruistic terms, volunteering for clinical trials that may possibly add to scientific knowledge that will help future generations of patients. Yet the medical literature is filled with glib talk about patients' altruism as a basis for joining clinical trials.

"The idea that altruism is an important consideration for most patients with cancer is a figment of the ethicist's and statistician's imagination," Horrobin writes, forcefully. In fact, it is "nonsense."

"I believe that patients who are asked to volunteer for large trials in cancer and other rapidly lethal diseases are being misled," he says. "Most such trials cannot be justified on ethical grounds." He gives four reasons.

First, "patients entering large clinical trials have little chance of benefit." His emphasis is on the size of the trial. If a trial needs to be large (recruiting, say, over 100 patients) then you can be sure that the "effect size" will be correspondingly small. What that means, in practice, is that "most patients entering the trial have little or no chance of receiving benefit." In fact, given the toxicity of many treatments, there "may be a substantial chance of harm."

Pulling no punches, Dr. Horrobin concludes that "[a]lmost all patients volunteering for most trials in oncology are doomed….At best they can expect little benefit. They are not usually being properly told about this low expectation."

I have been saying such things in my writings for many years, but it is astounding to hear these sentiments from a distinguished scientist writing in the one of the world's leading medical journals. (Ralph Moss)

Second, large clinical trials are supposed to speed the acceptance of new treatments. Yet, in Dr. Horrobin's view, they actually delay the entry of most new treatments because of their cost and complexity. Even a small clinical trial costs around $160,000.

A large multi-center trial can cost millions. The expense associated with clinical trials is a major reason that a new drug today costs on average $802 million, according to an authoritative Tufts University survey. There is an inherent conflict of interest for the institutions that administer such trials.

Clinical trials "have become major sources of revenue for many institutions," he writes. These institutions are financially dependent on payments ultimately derived from drug companies for carrying out such trials. Most patients, says Horrobin, are unaware of this.

Such trials "take forever" and "cost the earth," said Horrobin, who, before he got sick, was involved in establishing many trials. For that reason, "most patients entering most oncology trials will be dead before the results are known."

The high cost of conducting clinical trials means that they can realistically be done only on patent-protected agents. Yet there are so many "vested and competing interests" in medicine that the entry even of patented items is endlessly delayed.

"[O]nly commercial interests can afford to pay for the trial," says Horrobin. And since commercial considerations rule, only those new agents with a remaining patent life of 10 or, preferably, 15 years have even a chance of being developed. The majority of useful treatments do not fall into this category, however, and are never heard from again.

"Cancer patients are, of course, not told that such a small part of potential therapies is open to them. Nor are they told that researchers in most institutions, when considering which trials to take part in, are heavily influenced by the size of the financial contribution from the commercial sponsor. There is distressingly little altruism there," he writes.

Third, the number of patients willing and able to participate in clinical trials of any disease is small. Therefore, an "over-powered" trial that recruits more patients than it actually needs "will considerably reduce the number of discreet therapies that can be tested."

In fact, according to Dr. Horrobin, some companies cold-bloodedly sabotage the efforts of their competitors by deliberately "over-powering" their own clinical trials. This is a way of keeping competitors out of the marketplace, by using as many prospective patients for one's own trial and leaving as few as possible for a competitor's trial.

Finally, Dr. Horrobin has discovered that for most cancers "there are many potential treatments, many of which are not toxic. Contrary to general orthodox medical opinion, most such potential treatments are neither fringe nor irrational. They are based on solid biochemical in-vitro work, on reliable work with animals, and occasionally on a few well documented case histories." (My book, Cancer Therapy, discusses 102 such treatments.) Most of these treatments "have not been adequately tested in well designed trials, and most of them never will be."

Dr. Horrobin believes that their lack of progress in the world has nothing to do with their scientific rationale or the strength of the evidence. "It is simply that they are unpatentable or difficult to patent," he writes. "Without patent protection, in the present climate, such potential remedies will never be tested."

In his own case, drawing on the existing medical literature, Dr. Horrobin discovered that a substance called cyclin D1 rises dramatically in patients with mantle cell lymphoma. He therefore devised a regimen of substances that reduce cyclin D1. These include an antifungal agent, an antidiabetic drug and a polyunsaturated fatty acid. He has already outsurvived his six-month prognosis by a year and a half. This is great for him, but how many other patients have the knowledge and medical connections to devise and implement an innovative regimen? Most are shunted off for radiation or chemotherapy and, if these treatments don't work, they are pressured into joining clinical trials.

Horrobin's conclusions about the war on cancer are damning. "[D]espite huge expenditures, success has largely eluded us," he writes. "The few outstanding successes in rare cancers cannot hide the overall failure." In fact, there is something fundamentally wrong with the direction of the conventional approaches.

Our best hope of changing the situation is to test as many different approaches and compounds as possible, looking for substantial effects. But the almost universal belief in large, multi-center trials for the purpose of detecting tiny benefits "has effectively killed this possibility."

"Most people are more interested in the remote chance of a cure," Horrobin concludes, "than in the certainty of toxicity and the near certainty of no useful response."

Who can argue with that? I wish Dr. Horrobin the best in his struggle against mantle cell lymphoma. He has made yet another great contribution to medicine. May he continue to raise his powerful voice for many years to come!

Ralph Moss sent this summary of the Lance, 2/03 article.

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