Fwd: THE MOSS REPORTS Newsletter (09/27/03)

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Sun, 28 Sep 2003 05:02:50 -0400 (EDT)

 

THE MOSS REPORTS Newsletter (09/27/03)

 

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

Newsletter #101 09/27/03

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DOES TRAVELING FOR TREATMENT INCREASE SURVIVAL? PART

TWO

 

 

Last week I reported on a study conducted by

researchers at Massachusetts General Hospital that

showed that the distance traveled by cancer patients

from home to a treatment center is itself an important

predictor of survival. The study, carried out by Dr.

Elizabeth B. Lamont and her Boston colleagues, was

published in last week's Journal of the National Cancer

Institute.

 

 

The patients in Dr Lamont's study all had head-and-neck

cancers and were all enrolled in Phase II clinical

trials at the University of Chicago Cancer Center. Dr.

Lamont reported that patients who lived further away

from the treatment center, and therefore had to travel

further to receive treatment, fared better in terms of

overall survival than those who lived closer and had

only local traveling to do. In fact, if they traveled

15 miles or more they had only one-third the risk of

dying as compared to those who lived closer to the

cancer center. This finding was particularly surprising

since the beneficial effect of travel remained

significant even when patients' age, stage of disease,

performance status and income level - all of which can

influence survival - were taken into account.

 

 

One is left with the inescapable conclusion that the

distance traveled for care - which is rarely reported in

the analysis of trials - is a potentially important

variable, which probably reflects some other more

fundamental but as-yet-unmeasured factor.

 

 

The study has profound implications for the way that

new cancer treatments are evaluated and approved.

According to Duke University biostatistician Dr.

Stephen George, writing in an accompanying JNCI

editorial, " this conclusion is unsettling because it

suggests that other unknown or unmeasured variables

have important prognostic impact. "

 

 

This is an important reminder, he says, of the degree

to which various known or even unknown selection

factors can influence the outcomes of clinical trials.

After all, if clinical trial enrollment is restricted

to patients who come from a distance, then the results

might turn out to be " impressively positive. " On the

other hand, if the trial is restricted just to local

patients, then the results - using exactly the same

protocol - might be " discouragingly negative. "

 

 

Here we have a prime example of what statisticians call

a " selection bias " (i.e., a testing error introduced by

the enrollment process itself), which, in Dr George's

words, " can seriously damage " the validity of a

trial's conclusions. The results from nonrandomized

trials in general, and Phase II trials in particular,

" depend heavily on the specific characteristics of

patients studied, including the known and unknown

variables. "

 

 

So, how does this insight affect our understanding of

the value of clinical trials? Simply put, says Dr.

George, patients enrolled in clinical trials " often

bear little resemblance to the larger population of

patients. " That is because people who take part in

clinical trials are not identical to the cross-section

of people in the general population who will ultimately

get the new treatment. They are different in many ways,

both known and as yet unknown - and how far they have

traveled to receive treatment may be one of the most

important factors ever to be routinely overlooked in

clinical trial design.

 

 

In fact, it is often the case with well-publicized new

treatments that highly motivated patients, who have

heard about the exciting new " breakthrough " from

friends, the media or the Internet, will move heaven

and earth - including traveling long distances - to

obtain the treatment. Perhaps due in no small part to

the fact that they have fought to enroll in the trial

and have traveled from afar to obtain the treatment,

they do well on it. The results of Phase II trials

involving such motivated patients end up looking so

promising that the treatment gains FDA approval on the

basis of this outcome, bypassing more stringent

testing. Once the treatment is approved, however, and

goes on to be prescribed to a wider and less selected

population, it no longer works so well, if at all. But

the world (or at least the USA) is now stuck with this

new treatment.

 

 

Rigorous randomized controlled trials (RCTs or Phase

III trials), performed by many hospitals together, used

to be required for new drug approvals, but more and

more these days, favorable and smaller Phase II trials

are being substituted, effectively circumventing this

requirement. As the Lamont study so eloquently

demonstrates, a Phase II trial may have a favorable

outcome not because the drug in question is

intrinsically better than previous treatments but

because the patients enrolled in the trial are

motivated 'distance travelers' whose will to live may

be the source of their prolonged survival.

 

 

Even RCTs are not immune from selection bias, says Dr.

George, but at least " they have the strong advantage

that the treatment comparisons are unbiased because of

the randomization. " Large multi-center trials have been

very good at cutting exaggerated claims down to

size...which is one reason that far fewer drugs were

approved when RCTs were required.

 

 

In nonrandomized Phase II trials, such as Dr. Lamont

analyzed, a relatively small number of patients are

given a new treatment but there is no mechanism for

randomly assigning those patients to receive either the

treatment in question or some competitive approach

(such as either state-of-the-art therapy or the best

supportive care currently available).

 

 

The FDA now approves a growing number of cancer drugs

in this way, using its so-called " accelerated approval "

process. This mechanism was first used in 1995 and

allowed approval based on what was called a " surrogate

endpoint. " A surrogate endpoint is a change in the

patient's condition that may be of minimal clinical

significance, but which is considered reasonably likely

to predict ultimate patient benefit, such as increased

survival (Hirschfeld 2002). For instance, the temporary

shrinkage of a tumor by 50 percent or more, for a month

or more, is a commonly used " surrogate " that has been

accepted as a substitute for actual proof of life

prolongation. In actuality, however, a temporary tumor

shrinkage (called a " response " ) does not necessarily

correlate with increased survival.

 

 

Notice that accelerated approval requires no clear

evidence that patients actually benefit from a new

treatment. Approval is based on evidence that is by its

very nature " less than sufficient to grant full

approval, " says Dr. George. Yet " [t]he majority of the

more than 20 accelerated approvals granted to date have

been based on the results of Phase II trials. "

 

 

The rationale for accelerated approval is " to provide

rapid access to potentially effective agents in serious

or life-threatening diseases when no other effective

therapies exist. " Although this altruistic-sounding

rationale understandably pleases some patient

advocates, and certainly pleases the drug's sponsors,

the truth is that many of the treatments that are

approved by the accelerated process are toxic and

dangerous. When the FDA lowers its own standards in

this way the risk of it approving " toxic placebos " is

greatly increased. For all we know, patients' lives may

actually be shortened, rather than lengthened, by

taking these inadequately studied treatments.

 

 

These developments in oncology are part of a trend at

the FDA in recent years. A December, 2000,

investigative series on this subject by the Los Angeles

Times staff points to at least seven instances in which

FDA laxity has led to harm or even to the death of

patients. " Once a wary watchdog, " said the L.A. Times

report, " the Food and Drug Administration set out to

become a 'partner' of the pharmaceutical industry. "

This report makes for very scary, but still timely,

reading.

 

 

To view the Los Angeles Times articles click or go to:

http://www.latimes.com/features/health/la-health-fda.storygallery

 

 

Technically, FDA's accelerated approval regulations

require the completion of more definitive studies that

either confirm or deny actual patient benefit, and

don't just rely on such arbitrary, stand-in endpoints.

There is also the possibility of the FDA rescinding its

approval if the sponsor (usually a big pharmaceutical

company) fails to swiftly complete these confirmatory

studies with 'due diligence', or if the subsequent

results do not live up to the initial promise. However,

as Dr. George notes, " to date, no accelerated approval

in oncology has been withdrawn.... "

 

 

 

Hasty Approval of Iressa

 

 

A case in point was the accelerated approval of the

drug Iressa (gefitinib) in May 2003 as a treatment for

advanced non-small-cell lung cancer (NSCLC).

 

 

My previous discussion of Iressa can be found by

clicking or going to:

http://www.cancerdecisions.com/060603_page.html

 

 

The basis for this approval was a Phase II study

involving 139 lung cancer patients who no longer

responded to conventional chemotherapy. The overall

" response rate " in this trial was about 10 percent.

What was particularly disturbing about this approval

was that it went forward despite the fact that the

results of two larger Phase III trials using Iressa in

combination with standard chemotherapy were strongly

negative (FDA 2002).

 

 

However, for the reasons discussed in Dr. Lamont's

study, even this minimally positive response rate may

have depended heavily on the characteristics of the

patients enrolled, " in ways that cannot be adequately

assessed, " says Dr. George. The Iressa trial was well

publicized and attracted a highly motivated population

of patients, many of whom undoubtedly traveled to

receive this treatment. We now know that this probably

introduced a serious bias in favor of survival. But no

analysis by distance traveled to the treatment center

is available for the study.

 

 

Since this Iressa study was a Phase II trial, there was

no comparison group and no assessment of overall

survival, time to progression, or toxicity compared to

other therapies or best supportive care. Also, I would

point out (as I did in my book Questioning

Chemotherapy) that there is no proof that tumor

shrinkages ('responses') correlate well with actual

life prolongation.

 

 

Nevertheless, the FDA and its advisory panel were

persuaded that this meager 10 percent response rate in

patients was " reasonably likely " to predict patient

ultimate benefit. So they approved it and now Iressa is

being aggressively marketed, without reliable evidence

of its actual effectiveness.

 

 

I wholly agree with and applaud Dr. George's

conclusions:

 

 

" These considerations suggest that the results of Phase

II trials need to be interpreted with great caution and

that their use in the regulatory process can be

especially problematic. "

 

 

RCTs are difficult, time-consuming and expensive.

However, they provide " the best protection against the

risks of erroneous conclusions inherent in Phase II

trials, especially for regulatory decisions.

Accelerated approval may provide earlier access to

potentially beneficial agents, but the evidence

required for granting it should not come solely from

Phase II trials. "

 

 

To those of us who have long championed the cause of

complementary and alternative medicine (CAM), this

accelerated approval process is filled with bitter

irony. I know of no CAM treatments that have been given

accelerated approval. It is Big Pharma that reaps the

benefit of this relaxed stance, while the FDA

gatekeepers remain vigilant against CAM advocates and

practitioners. CAM is still held to the high standards

of Phase III RCTs....which, let's face it, are nearly

impossible for " the little person " to finance or

arrange. And so a great many potentially useful

treatments are excluded from mainstream medicine by the

same regulators who admit dubious pharmaceutical

treatments on the basis of flawed and abbreviated

clinical trials.

 

 

Whatever happened to that " level playing field " that

government officials promised CAM advocates a dozen

years ago? The undisguised bias of the FDA towards Big

Pharma breeds cynicism, bitterness and paranoia in the

public. Ironically, it also opens the door to health

frauds, since it lends credibility to the often-heard

claim that the US government is not seriously

interested in evaluating treatments that do not emerge

from Big Pharma. If Phase II trials are sufficient for

proof, then let all treatments benefit from these

relaxed regulations. Conversely, if RCTs are still

required, let everyone be held to this high standard.

 

 

 

LOUIS LASAGNA, MD, 1923-2003

 

 

I note with sadness the passing, last month, of Dr.

Louis Lasagna, Dean Emeritus, Sackler School of

Graduate Biomedical Sciences and founder, in 1976, of

the Tufts Center for the Study of Drug Development. He

died of lymphoma on August 6, 2003, at the age of 80.

 

 

To view a picture of Dr. Lasagna click or go to:

http://www.cancerdecisions.com/images/lasagna.gif

 

 

His career in medicine spanned five decades and he was

the author of nearly 250 PubMed-listed journal articles

on a wide range of topics relating to new drugs. He was

a pioneer in understanding the placebo effect and

helped expose the ineffectiveness of many supposedly

active drugs. In 1954, Lasagna published his classic

paper, " A study of the placebo response, " in the

American Journal of Medicine.

 

 

In the late 1970s our paths crossed in a very

unexpected way. I had recently been fired from Memorial

Sloan-Kettering Cancer Center (MKSCC) for my public

dissent over the hospital's handling of the testing of

amygdalin (laetrile). To say that I was persona non

grata in conventional medical circles would be an

understatement. I was out of a job and working on a

book that no one seemed to want to publish.

 

 

Out of the blue, I received an invitation from Dr.

Lasagna, then chairman of Pharmacology and Toxicology

at the University of Rochester School of Medicine and

Dentistry, to contribute a chapter to a medical

textbook that he was editing! The book was called

" Controversies in Therapeutics, " and its unique format

was to present arguments for and against various

disputed questions.

 

 

My contribution was called " In Defense of Laetrile. "

The book appeared in 1980 and was published by W.B.

Saunders, a major medical publisher. This essay later

found its way, in a modified form, into The Cancer

Industry (which was published, as The Cancer Syndrome,

by Grove Press in that same year).

 

 

This essay may have been the sole instance of a serious

defense of amygdalin being published in the

peer-reviewed literature during all those years of

controversy. Although I was far from being a " laetrile

advocate, " I did feel that its use should be a matter

of scientific discussion, and I was appalled by the

crude mudslinging that often took the place of rational

discussion on the subject. I also drew on the knowledge

of my colleagues Robert G. Houston, Ernst T. Krebs,

Jr., and Michael Schachter, MD, to put together a

credible defense of the theory behind its use.

 

 

Most other academics had flat-footedly taken their

stance against this " fraudulent " therapy. But Dr.

Lasagna saw it as an open controversy. He stated his

belief that " a perverse characteristic of the human

race is its preference for spurious simplicity as

opposed to truthful complexity. " Nothing better

described the politicized atmosphere in medicine at the

time.

 

 

It was also a great experience for me personally to

suddenly find myself in the company of more than 60

distinguished scholars in the field of medicine. It

restored my faith in the possibility of a fair hearing

for controversial alternative treatments. As I scanned

the list of contributors I was stunned to realize that

I was the only one without an academic, governmental or

drug company affiliation. Most were medical school

professors. I was listed simply as " Editor, Second

Opinion, " i.e., the underground cancer newsletter that

I had edited in my Sloan-Kettering days!

 

 

Much has changed since 1980, but many of the questions

that Dr. Lasagna posed in his book are still open. This

includes the ultimate value (and mechanism of action)

of amygdalin in cancer and, I would say, the more

philosophical questions of how to decide whether any

new treatment is really effective and worth taking.

 

 

Robert Temple, MD, an associate director of the Food

and Drug Administration, has said that Dr. Lasagna was

a leader among those clinical pharmacologists who,

during the late 1950s and early 1960s, " started to

point out that our data to support the efficacy of

drugs was utter [rubbish]. "

 

 

Although he didn't use the term, Lasagna was in fact an

early advocate of the " friendly skepticism " that I

think is the proper attitude to take towards any new or

controversial treatment. A person of such intelligence

and integrity as Lou Lasagna comes along only rarely.

His probing and courageous examination of contemporary

medical practice will be sorely missed.

 

 

 

--Ralph W. Moss, PhD

 

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References

 

Lasagna obituary:

http://www.biomedcentral.com/news/20030908/02

 

FDA: U.S. Food and Drug Administration. Oncologic Drugs

Advisory Committee Briefing Document. September 24, 2002. At:

http://www.fda.gov/ohrms/dockets/ac/02/briefing/3894b1.htm

 

George, S. L. (2003). Selection Bias, Phase II Trials,

and the FDA Accelerated Approval Process. J Natl Cancer

Inst 95:1351-1352.

http://jncicancerspectrum.oupjournals.org/cgi/content/full/jnci;95/18/1351

 

Hirschfeld S, Pazdur R. Oncology drug development: United

States Food and Drug Administration perspective. Crit Rev

Oncol Hematol 2002;42:137-43.

 

Lamont EB, Hayreh D, Pickett KE, Dignam JJ, List MA, Stenson KM,

et al. Is patient travel distance associated with survival on Phase

II clinical trials in oncology? J Natl Cancer Inst 2003;95:1370-5

 

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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.

 

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