Are Large Clinical Trials Ethical?

[Guest guest]

Are Large Clinical Trials Ethical?

 

 

http://www.cancerdecisions.com/030703.html

 

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

 

 

 

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.

 

 

Nearly six weeks have elapsed since the completion of those sessions

and I have now turned my attention to assisting in an independent

retrospective review of these patients' cases. I am in the process

of assembling 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 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. If this

interpretation is correct, it would suggest the need for debulking

of large tumors prior to treatment as well as a closely monitored

detoxification treatment program afterwards.

 

 

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, intends to

give CLT in a modulated way, with an emphasis on detoxification and

good follow-up care. I am pleased to know this, since Dr. Woeppel

has an excellent reputation, inside and outside Germany.

 

 

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 trusted doctors.

 

 

If you have questions about the suitability of this treatment for

your own situation, you may want to contact Dr. Woeppel directly.

His email address is wdrwoeppel I remain in close touch with

many of the CLT patients. However, we are not a clearinghouse for

information on this treatment. The email address of the CLT

organization is cltclinics

 

 

 

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.

 

 

Special Note: Because of an increasing number of commitments, I have

decided to produce this newsletter on a biweekly schedule for the

foreseeable future. The next issue will therefore appear during the

week of March 16-22.

 

 

 

 

 

 

 

 

 

--Ralph W. Moss, Ph.D.

 

 

 

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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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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.