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Sat, 8 Mar 2003 19:37:14 -0500 (EST)

 

 

THE MOSS REPORTS Newsletter (03/07/03)

 

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

Newsletter #76 03/07/03

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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.

 

 

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.

 

 

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, PhD

 

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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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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.

 

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