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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.

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.

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!

CLT Update

Cytoluminescent Therapy (CLT) is a form of photodynamic therapy (PDT), in which a chlorophyll-based photosensitizer is administered to patients, followed by whole-body light treatment. Between November, 2002 and January, 2003, I took several trips to Ireland to investigate this method.

Nearly six weeks have elapsed since the completion of those sessions and I have now turned my attention to conducting an independent retrospective review of these patients' cases.

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 tumor shrinkages and improved quality of life, while others report 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 send 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.

I still believe that photodynamic therapy (PDT) in general holds great promise as a cancer treatment. But prospective patients must understand that for many indications 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 carefully, with the input of trusted doctors.

NOTE: Please be sure to read the Abstract of my December, 2003 scientific study on this topic. CLICK HERE

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.

--Ralph W. Moss, Ph.D.

References:

Horrobin DF. Are large clinical trials in rapidly lethal diseases usually unethical? Lancet 2003;361:695-7.

Expanded patient rights. International Herald-Tribune, February 19, 2003.

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IMPORTANT DISCLAIMER

The news and other items in this newsletter are intended for informational purposes only. Nothing in this newsletter is intended to be a substitute for professional medical advice.