Are Large Clinical Trials Ethical?
In the February 22, 2003 issue of the Lancet, distinguished scientist 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.
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 one of the world's leading medical journals.
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 discrete 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
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
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 the antifungal clotrimazole; a polyunsaturated fatty acid,
eicosapentaenoate and the antidiabetic thiazolidinediones. (He does not give
dosages in the article.) At the time he wrote, he had 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!
Editor’s Comment: At press time
we sadly learn that Dr. David Horrobin has died from his cancer.
We will post an obituary in the next issue.
Last fall, I wrote about a new cancer treatment in Ireland called Cytoluminescent
Therapy (CLT). This is a form of photodynamic therapy (PDT), in which a chlorophyll-based
photosensitizer is administered to patients, followed by whole-body light
treatment. I was excited by the preliminary results of this treatment and
took several trips to Ireland to investigate further. I also presented educational
seminars for patients who received the treatment in four sessions between
November, 2002 and January, 2003.
Since the completion of those sessions, I have turned my attention to assisting
in an independent retrospective review of these patients' cases. I have assembled
a team of professionals to carry out this necessary initial evaluation.
The anecdotal reports I have received so far paint a far more complex picture
than was indicated by the initial data I reviewed. Some patients feel the treatment
is responsible for an improvement in their condition, while others have reported
distressing symptoms, such as flu-like fatigue, persistent coughs, and inflammation
or necrosis around known or suspected sites of tumor. This has sometimes been
accompanied by significant pain. The extent of these reports surprised me,
since none of the past patients I interviewed in September described anything
but tolerable side effects. I had some early intimations of this problem late
in the fall, but only became fully cognizant of the extent of the problem after
I sent a circular letter to patients in February. I hope that a careful analysis
of the patients' outcomes will explain the clinical significance of these effects.
Proponents of CLT feel that these "after effects" result from the
destruction of cancer or the toxic buildup of dead cancer cells in a patient
after treatment, particularly in those patients who had a large "tumor
load" or widespread or advanced disease.
The treatment is no longer given in Ireland. However, it is presently available
at the Hufeland Klinik in Bad Mergentheim, Germany. Wolfgang Woeppel, MD, director
of that clinic, has said he intends to give CLT in a modulated way, with an
emphasis on detoxification and good follow-up care.
I still believe that photodynamic therapy in general, and CLT in particular,
hold great promise as a cancer treatment. But prospective CLT patients must
understand that the treatment is new and experimental and that, by definition,
an experimental treatment's potential risks and benefits are less predictable
and understood than those of more established therapies. Patients must make
all treatment decisions, before and after CLT, carefully, with the input of
Expansion of Patients' Rights
In mid-February, a major US court expanded patients' rights to receive experimental
treatments, by ruling that consumers could sue a health insurance company
for injuries resulting from the company's refusal to authorize such treatments
when their doctors deem them necessary.
This ruling, issued by the 2d US Circuit Court of Appeals in New York, said
that health maintenance organizations (HMOs) and their directors could be sued
for medical malpractice if they made incorrect decisions about the treatment
of their customers. In the past, courts usually rejected such claims. But old
precedents were no longer binding because the Supreme Court changed the basis
for analyzing such issues in a 2000 case.
According to David Trueman, the attorney who filed the case, "This ruling
means that there's now no barrier for anyone in New York, Connecticut or Vermont
to sue" an HMO "when the health plan denies treatment recommended
by a doctor." Of course, that comprises a broad spectrum of treatments,
since some doctors recommend treatments that others consider unorthodox.
The case in question concerned a man with a form of leukemia, whose oncologist
recommended high-dose chemotherapy as well as a double infusion of the patient's
own stem cells. But in 1998 the HMO's medical director denied the claim, stating
the treatment was experimental and therefore not a covered benefit. After an
appeal, the company approved a different treatment, but the patient died that
year. His widow then sued, claiming that he might have survived if the company
had approved the recommended treatment.
While this case concerns academic medicine, it opens the door to non-conventional
treatments, as well. It will make it less possible for insurance companies
(at least in the Northeast US) to deny payment for treatments simply because
they are deemed "experimental." In fact, in a disease for which there
is no certain cure, the "experimental" category includes nearly all
possible therapies that a patient may wish to take.