Ralph W. Moss, Ph.D. Weekly CancerDecisions.com
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
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
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."
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
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.
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
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.
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.
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
"[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
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
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
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
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
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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