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THE MOSS REPORTS Newsletter (12/31/02)

 

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

Newsletter #67 12/31/02

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No Glee Over Gleevec

 

 

 

In late December 2002, the Food and Drug

Administration (FDA) approved the drug Gleevec (also

called imatinib mesylate or STI571) as a first-line

treatment for patients with chronic myeloid leukemia

(CML). CML afflicts about 40,000 people in the US. It

is an unusual form of cancer in that its genetic origin

is well defined. The genetic fault occurs when

fragments of two different chromosomes break off and

trade places, reattaching on the opposite chromosome.

This results in the formation of a characteristically

shortened chromosome -- the so-called " Philadelphia

chromosome " -- which is unique to CML. This

translocation of chromosomes leads to a certain blood

cell enzyme, tyrosine kinase, being " turned on " all the

time. As a result, white blood cells proliferate

rapidly in the blood and bone marrow, eventually

becoming life threatening. Gleevec was designed to turn

off white cell tyrosine kinase.

 

 

In May 2001, the FDA rapidly approved Gleevec as a

treatment for the advanced stages of CML. It was later

approved as a second-line treatment for patients in the

earliest stage of CML (called the chronic phase) after

they no longer responded to standard interferon-alpha

therapy. It has now been approved for virtually all CML

patients. (It has also been approved as a treatment for

a rare form of stomach cancer, gastrointestinal stromal

tumor, or GIST.)

 

 

Back in 2001, the FDA said that further studies were

needed to evaluate whether the drug provided a clinical

benefit in CML, since there was no direct proof that

Gleevec actually helps patients by alleviating their

symptoms or extending their lives. As the manufacturer,

Novartis Pharmaceutical Corporation, readily admitted:

 

 

" Accelerated approval of Gleevec was based on time to

progression as the primary surrogate endpoint. Approval

under these regulations requires further adequate and

well-controlled studies to verify and describe clinical

benefit. There are no controlled trials demonstrating a

clinical benefit, such as improvement in

disease-related symptoms or increased survival. "

 

 

In his December 2002 announcement, FDA Commissioner

Mark B. McClellan, MD, PhD, said, " Today's approval

represents continued efforts by government and industry

to provide patients suffering from CML with additional

therapies that have proven safe and effective through

ongoing research and clinical trials. With this new use

even more patients will have access to this product

earlier on in their fight against cancer. "

 

 

Commissioner McClellan's statement certainly sounds

like good news for patients with CML. But how accurate

is it? Has Gleevec in fact been proven " safe and

effective, " as the FDA commissioner claims? If so, how

safe? And effective to do what?

 

 

 

Improved Markers Versus Patient Benefit

 

 

 

In assessing the safety and effectiveness of cancer

treatments, it seems self-evident that one should use a

yardstick that measures patient benefit. Patients don't

necessarily care whether a certain blood marker goes up

or down. They want to be cured, or at the very least to

obtain a meaningful extension of their life. And they

almost always want to preserve or enhance their quality

of life.

 

 

Yet the FDA's recent approval of Gleevec was based

entirely on a clinical trial that measured improvement

in " surrogate markers. " These are not direct measures

of patient benefit but simply test results that are

supposed to correlate with patient benefit. The full

data on this trial were disclosed on May 20, 2002, at

the annual American Society of Clinical Oncology (ASCO)

meeting in Orlando, Florida. It thus represents

non-peer-reviewed data since, to my knowledge, it has

not yet been published in a medical journal.

 

 

In this clinical trial of 1,106 patients with newly

diagnosed CML, half of the patients were treated with

Gleevec and the other half with what has been the

standard CML therapy, a combination of the older drugs

interferon and cytarabine. Those treated with Gleevec

after one year had significantly fewer cancerous cells

in their blood and bone marrow. The rate of disease

progression was also decreased.

 

 

" The remarkable results from this trial show that

Gleevec is ten times more effective than standard

interferon therapy, " enthused Brian Druker, MD, of the

Oregon Health Science University, Portland, Oregon, and

lead author of the study. The patients on Gleevec had a

major (75 percent) or complete (54 percent) cytogenetic

response (i.e., a reduction in the number of cancer

cells in the bone marrow), while the patients on the

standard two-drug combination showed only a 15 percent

major response and a 3 percent complete response.

 

 

Does this mean that Gleevec was shown to increase

survival in patients with CML? The answer is no.

Although you might think that a decrease in cancer

cells would necessarily lead to a meaningful increase

in overall survival, this is not necessarily true. In

cancer, all too often surrogate markers fail to

correlate with any actual increase in survival.

 

 

So, why not just measure life prolongation? According

to the FDA, since patients with CML often live for up

to 10 years with their disease, the 14-month follow-up

was simply " too short to measure long-term clinical

benefits such as improved survival. " While it may be

true for those in the early, chronic phase of CML,

there are more advanced phases of CML that could

readily show whether or not the drug is effective at

prolonging life.

 

 

To explain: CML occurs in three different phases:

chronic, accelerated and blastic. In the chronic phase,

there are less than 5 percent immature " blasts " in the

peripheral blood and bone marrow. As the FDA correctly

states, the severe form of the disease takes a long

time to develop and survival in such cases would be

difficult to measure. However, in the accelerated

phase, there are between 5 and 30 percent immature

blasts in both the peripheral blood and bone marrow,

and in the blastic phase there are greater than 30

percent blasts in the peripheral blood and bone marrow.

The " blastic phase " is a rapidly progressing form of

the disease, and would be very amenable to tests of

survival. Patients in a " blast crisis " generally do not

live an average of 10 years. When the patient has entered

a blast crisis, says the National Cancer Institute (NCI),

survival is on the order of only a few months. Thus, the

blastic phase of CML would be well suited to demonstrate

the survival advantage of any new treatment, such as

Gleevec.

 

 

In fact, according to the NCI, this question was

addressed in an earlier phase I trial of Gleevec. In

that study, just four out of 38 patients in a blast

crisis had a complete hematologic remission while 17

had a decrease in blasts in the marrow to 15 percent or

less. " Unfortunately, " the NCI summarizes, " these

responses have not been durable. " In other words,

cancer cells often develop resistance to this drug, as

they commonly do to chemotherapy. Given its lack of

durability, Gleevec cannot be deemed " effective " in the

advanced phase of the disease, and there is no reason

at this moment to conclude that Gleevec increases

survival in CML.

 

 

 

A Safe Drug?

 

 

 

FDA Commissioner Mark McClellan implied that Gleevec

has been proven safe. But safe is a relative term.

Interferon has punishing side effects and so Gleevec

might appear mild in comparison. However, it is

not without serious adverse reactions. As the

manufacturer's website states: " The majority of

patients who received Gleevec in clinical studies did

experience side effects. " The most common were nausea

(up to 71 percent of patients treated for CML), fluid

retention (73 percent), muscle cramps (55 percent),

diarrhea (55 percent), hemorrhage (52 percent), skin

rash (44 percent), joint pain (36 percent), headache

(34 percent), and indigestion (24 percent). Other side

effects included fatigue, muscle and bone pain,

vomiting and shortness of breath.

 

 

Serious and severe side effects were also reported with

Gleevec, including liver problems and low levels of

certain blood cells. According to a company document,

64 percent of those in the blast crisis experienced

neutropenia, a serious or severe deficiency in white

blood cells called neutrophils; 63 percent had another

kind of white blood cell destruction, thrombocytopenia;

and 52 percent developed anemia of the red blood cells.

Gleevec was discontinued due to side effects in 5

percent of those in blast crisis. The company also

states that " there are no long-term safety data for

Gleevec available. "

 

 

FDA approval was a generous Christmas present for

Novartis. Online pharmacies have " discounted " each

100-milligram capsule to around $17. At a dose of 600

mg per day, this works out to $100 per day, or around

$36,500 per year. If every CML patient in the US were

to take the drug, this would represent around $1.46

billion in Gleevec sales for Novartis. Not bad for a

drug whose effects on survival remain unproven.

 

 

 

Double Standard

 

 

 

Some readers have written to me with enthusiastic

anecdotes about their responses to Gleevec. The drug

has given a lot of hope and perhaps will eventually be

shown to be life extending. I certainly would not want

to deny even a glimmer of hope to any cancer patient.

What irks me is not so much the hype surrounding

Gleevec, but what its swift approval reveals about the

double standard in the appraisal of new cancer

treatments.

 

 

Drugs that are sponsored by big pharmaceutical

companies are given first consideration and accelerated

approval, then are praised to the skies by an alliance

of company publicists, enthusiastic scientists,

government officials and compliant media. (Gleevec has

been featured on the cover of Time.) But when it comes

to treatments that originate from individual

entrepreneurs or small companies, suspicion reigns.

Innovators are often ignored or harassed, and this is

especially so if they happen to come from the field of

complementary and alternative medicine (CAM).

 

 

Novartis's website for Gleevec contains patient

anecdotes, but no data showing that the drug extends

life. Yet the standard comeback to therapeutic claims

coming from entrepreneurs is, " All you are presenting

are anecdotes. Where are your randomized controlled

trials proving the safety and efficacy of your alleged

treatment? "

 

 

Unlike " Big Pharma, " the entrepreneur is expected to

perform to impossibly high standards. If these

innovators have the temerity to submit their cases to

the government, and they are accepted for review, they

will be gone over with a fine-toothed comb. The

slightest imperfection suffices to nullify the validity

of the claim.

 

 

It is no wonder that neither the NCI nor the FDA has

ever validated or approved an alternative, or nontoxic,

method of treating cancer. Yet, at the same time, we

have the bizarre spectacle of huge companies being

allowed to market toxic drugs in the complete absence

of any proof of life extension!

 

 

The cost of developing a new drug has escalated in

recent years, which further keeps entrepreneurs from

competing with " Big Pharma. " To develop a new drug cost

$54 million in 1979 and $231 million in 1991. Today,

according to the Tufts Center for the Study of Drug

Development, the average cost has skyrocketed to $802

million per drug. Those who cannot ante up this kind of

money are relegated to the sphere of nutritional

supplements and alternative medicine.

 

 

Our civilization is supposed to be based on equal

justice under the law. But where is the equality, when

independent inventors are held to impossible standards,

while " Big Pharma " gets by with a wink and a nod? This

situation makes a mockery of equality. Or, as Anatole

France said many years ago, " The law, in its majestic

equality, forbids the rich, as well as the poor, to

sleep under the bridges, to beg in the streets, and to

steal bread. "

 

 

 

Best wishes to you and yours for a Happy New Year!

 

 

 

--Ralph W. Moss, Ph.D.

 

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References

 

 

Gleevec pilot study: Druker BJ et al. Activity of a specific

inhibitor of the BCR-ABL tyrosine kinase in the blast crisis

of chronic myeloid leukemia and acute lymphoblastic leukemia

with the Philadelphia chromosome. N Engl J Med

2001;344:1038-42.

 

 

Gleevec randomized trial: Druker BJ. STI571 (Gleevec/Glivec,

imatinib) versus interferon (IFN) + cytarabine as initial

therapy for patients with CML: results of a randomized

study. Abstract #1 presented at the 38th Annual Meeting of

the American Society of Clinical Oncology (ASCO), May 20,

2002.

http://www.asco.org/ac/1,1003,_12-002324-00_29-00A-00_18-002002-00_19-001,00.asp

 

 

Gleevec approved for first line treatment of chronic myeloid

leukemia (CML). Food and Drug Administration press release,

December 20, 2002.

http://www.fda.gov/bbs/topics/NEWS/2002/NEW00860.html

 

 

Gleevec confirmed as superior over conventional

treatment for CML. National Cancer Institute, May 20, 2002.

http://www.nci.nih.gov/clinicaltrials/results/gleevec-superior-for-cml0502

 

 

Chronic myelogenous leukemia stage information. National

Cancer Institute.

http://www.nci.nih.gov/cancerinfo/pdq/treatment/CML/healthprofessional/#Section2\

..1

 

 

Tufts Center for the Study of Drug Development pegs cost of

a new prescription medicine at $802 million. Tufts Center

for the Study of Drug Development, November 30, 2001.

http://csdd.tufts.edu/NewsEvents/RecentNews.asp?newsid=6

 

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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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