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Sat, 26 Jun 2004 01:18:10 -0000

[sSRI-Research] Pharma Efforts to Bar Placebo Responders from

Trials-WSJ

 

A clinical trial report in The Lancet debunks the value of Aricept, a

popular drug prescribed for Alzheimer's patients. The findings of a

three-year placebo controlled trial show that:

 

" Although the patients taking the drug did have slightly higher

scores on mental tests, after three years they did not differ from

the placebo group in their rates of being put in a nursing home or

becoming disabled. There were also no significant differences

between the groups in behavioral or psychological symptoms or in the

emotional well-being of the people taking care of the patients. "

See: British Study Sees Scant Value in Alzheimer's Drug Aricept, NY

Times, June 25, 2004, A-20.

 

-- http://www.nytimes.com/2004/06/25/health/25alzh.html

 

As disappointing as such findings are for patients whose hopes had

been raised about the drug's effectiveness, for those with financial

stakes in the marketing of new drugs, such set- backs cut profits.

Placebo-controlled clinical trials were declared " the gold standard "

by the FDA and pharmaceutical companies who were loath to test their

new drugs against existing ones, lest the (always cheaper) existing

drugs proved more effective than the new. But, as clinical trial

after clinical trial reveals, today's new drugs can't even perform

better than a sugar pill.

 

Since 1962, US law requires drug manufacturers to submit proof to the

FDA--not only of a drug's safety, but its effectiveness for specific

medical purposes, through " adequate and well-controlled " studies. But

recent revelations about clinical trials--specifically, concealed

drug hazards and failed efficacy--raise serious questions about the

credibility of trials that were submitted to the FDA to gain

marketing approval.

 

If FDA-approved drugs fail the placebo comparison in clinical trials

conducted by independent scientists, how valid are the claimed

findings from pre-approval trials?

 

Furthermore, one wonders how many of those enrolled in a clinical

trial who responded to placebo were included in the data analysis of

those trials?

 

Clearly, the FDA's drug approval process isn't identifying

ineffective drugs, and is approving such drugs in contradiction to

the US Food and Drug Administration Act.

 

The suit filed by NYS Attorney General, Eliot Spitzer, against

GlaxoSmithKline, charging fraudulent concealment of data, has sent

shivers down the spines of pharmaceutical CEOs.

 

See: -- http://www.ahrp.org/infomail/04/06/02.html

 

See: The Guardian. Glaxo changes tack after Spitzer assault, by

Heather Stewart, June 19, 2004,

-- http://www.guardian.co.uk/business/story/0,3604,1242494,00.html

 

See Glaxo internal memo, 1998 :

-- http://www.ahrp.org/risks/SSRI0204/GSKpaxil/pg1.html

 

Vera Sharav

 

 

Comments by AHRP board member, David Cohen, Ph.D., addressing the

placebo effect in psychotropic drug trials, are followed by an

article in The Wall Street Journal.

 

Leila Aboud reports in the Wall Street Journal (below) that Eli Lilly

and Pfizer plan to fund UCLA-based research using brain scans " to

identify patients who respond strongly to placebos, who could then be

excluded from clinical studies of new antidepressants. " Undoubtedly,

such research primarily serves commercial, not scientific or ethical

imperatives.

 

Placebo response has always been high, especially in trials of anti-

anxiety and anti-depressant drugs, where it regularly approaches 50%;

but it is substantial even in studies of patients with acute manic or

schizophrenic psychosis, where it averages around 25%.

 

The spin put on publications from investigators and trial sponsors

with a direct stake in the tested drug's performance, however, tended

to distract from this high placebo response. It also obscured the

large variability of drug response among individual patients and

study samples. It led government agencies, health care professionals,

and consumers to exaggerate the benefits of drugs and downplay their

harmful effects.

 

However, revelations and independent studies concerning " publication

bias " - the concealment of vital information from published reports

of clinical trials by sponsors, researchers, and authors - have

altered the landscape. It now looks like the major differences

between placebos and SSRIs - hugely profitable " specific medications

for specific disorders " - may amount to the following: SSRIs have

brand names, enjoy huge advertising support, and are more harmful.

 

In this light one can understand the jitters from drug makers. Now

that their control over reporting clinical trial results is beginning

to erode, they are attempting to modify clinical trials themselves in

their favor. The reason is that placebo responders " are the people

who ruin clinical trials for drug companies. " Steven Paul, the head

of research and development at Lilly is quoted as saying: " The

placebo response has plagued psychiatric clinical trials. "

 

Paul's quote aptly describes the point of a clinical trial in today's

interest-conflicted and profit-driven psychiatry: not a robust

scientific technique to establish whether a drug's healing effects

surpass those resulting from suggestion and expectation, but a hurdle

to gain FDA approval and reap multi-billion dollar profits.

 

The WSJ article states that drug " companies dismiss the criticism

that they will use the information [about placebo responders] to gain

approval of ineffective drugs. They say the techniques would be used

only in early trials, not for trials done for FDA approval. " But many

questionable strategies that help tested drugs look positive are now

used to gain FDA approval. Why wouldn't drug makers use new

strategies? Second, Drug makers already enjoy considerable design

latitude for early trials and rarely use strict placebo controls. The

issue of placebo response arises specifically in Phase III

randomized, controlled clinical trials submitted for FDA approval, as

the FDA requires at least two such trials.

 

The placebo effect remains crucial to understand any self-reported or

observed improvement in a drug trial, especially for disorders that

cannot be diagnosed with objective bodily markers. Much of what

appears as drug-induced improvements in symptom rating scales may be

part of the " placebo effect. " Because the nature of the placebo

effect has proven exceedingly difficult to identify, its benefits

have been easily claimed by others.

 

All efforts to understand the nature of placebo response should be

encouraged, though one can question the simplistic mindset of some

researchers attempting to distinguish placebo responders on the basis

of brain scans. There is no doubt that physiological responses

underlie placebo responses. However, as Charles Medawar and Anita

Hardon hint in their book, Medicines Out of Control? (London, 2004),

the placebo effect includes many factors that do not fit either in

the user-drug or doctor-patient relationship. These factors include

hope, faith, belief, susceptibility to influence from advertising, as

well as dependency on the power of organizations.

 

However, if the spotlight needs to shine on the chemistry of those

who improve their distress because of a complex response triggered by

ingesting a sugar pill, then we might entertain recruiting some other

study participants. Perhaps equal attention should be directed to

doctors as placebo responders, with brain scans of physicians used to

determine why such a high proportion of them continue to prescribe

drugs that research regularly shows to be only slightly more

effective than placebos.

 

 

David Cohen, PhD, Secretary

AHRP

Contact: cohenda

~~~~~~~~~~~~~~~~~~~

 

 

THE WALL STREET JOUNRAL

Drug Makers Seek to Bar

'Placebo Responders' From Trials

 

By LEILA ABBOUD

June 18, 2004; Page B1

 

They are the people who ruin clinical trials for drug companies:

placebo responders, who get better on sugar pills. Drug makers want

to get rid of them, especially in trials of depression drugs, where

placebos can have a particularly powerful effect. The problem: Nobody

knows who they are.

 

Now drug companies are looking for ways to identify patients who

respond strongly to placebos, who could then be excluded from

clinical studies of new antidepressants.

 

With funding from Eli Lilly & Co. and Pfizer Inc., scientists at the

University of California, Los Angeles, are beginning to unravel the

mysteries of the placebo effect in depressed patients. Armed with

brain-imaging technology, these researchers believe that placebo

responders share the despairing mood that other depressed people

feel. But the responders may not have the physical symptoms often

accompanying severe depression, including disruptions of sleep and

thinking. In a way, they may not be as severely depressed -- and it

may be possible to spot them ahead of time.

 

Another technique for finding placebo responders is being tried by

Pfizer, which has found that such people have different DNA in key

areas of the genome that are linked to depression. So Pfizer is

exploring whether genomics could also one day be used to pick out

placebo responders.

 

The placebo effect has existed since snake oil and bloodletting.

Scientists noticed that big placebo pills worked better than small

ones, brightly colored ones were more potent than dull and sham

surgeries -- entailing anesthesia and an incision but no actual

repair -- were the most powerful of all.

 

Many antidepressant trials fail because the placebo effect can be so

powerful and highly variable. Somewhere between 30% to 50% of

patients in depression trials get better when given fake pills, and

that number has increased and become more volatile over time, making

it more difficult to prove that a drug works. In comparison, only

about half of patients taking antidepressants find their symptoms

relieved by 50% or better.

 

" The placebo response has plagued psychiatric clinical trials, " says

Steven Paul, head of research and development at Lilly. If drug

companies could sort out the placebo responders, it " would greatly

help us in the short term in drug development. "

 

Psychiatric medicines are huge sellers. Antidepressants racked up

more than $17 billion in world-wide sales in 2003 and were the third-

largest class of drugs by sales.

 

To get permission from the Food and Drug Administration to market a

new drug, its maker must show that it works better than a placebo in

at least two large, controlled studies. The drug companies say that

weeding out placebo responders would allow them to do much smaller,

quicker, cheaper trials to find out if an experimental antidepressant

actually worked.

 

" It would tell us early on in development whether we have an

effective agent or not, " Lilly's Dr. Paul says. Such quick answers

would prevent the industry from spending years researching new kinds

of antidepressants that turn out to be ineffective.

 

FEELING BETTER?

 

Many clinical trials have found that placebos are almost as effective

as the actual antidepressants:

 

Drug Brand Name Number of Trials Response* to Drug Response* to

Placebo

Fluoxetine Prozac 5................ 8.3 ...............7.34

Paroxetine Paxil 12................ 9.88.............. 6.67

Sertraline Zoloft 3................ 9.96 .............. 7.93

Venlafaxine Effexor 6............... 11.54 .............. 8.38

Citalopram Celexa 4................ 9.69 .............. 7.71

 

*Participants' average improvement, measured in points on a standard

scale used to quantify the severity of depression

 

Source: Prevention & Treatment

 

 

 

The cost of failure can be immense. After a decade of study, Merck

last year abandoned its effort to develop a new type of

antidepressant when it couldn't do better than a placebo in tests;

Merck didn't reveal how much the effort cost.

 

But some clinical-trial experts worry that excluding placebo

responders to facilitate drug development could lead to the approval

of ineffective drugs. Kay Dickersin, a Brown University professor who

teaches courses on clinical trials, says such winnowing " allows bias

to enter in " and constitutes " a subtle manipulation " of trial results.

 

The companies dismiss the criticism that they will use the

information to gain approval of ineffective drugs. They say the

techniques would be used only in early trials, not for trials done

for FDA approval.

 

It's too early for the FDA to have weighed in on the issue.

 

New York State Attorney General Eliot Spitzer recently threw a

spotlight on antidepressants when he sued GlaxoSmithKline PLC,

charging that the company hid clinical trials from the public in

which its antidepressant Paxil worked no better than placebos in

children and adolescents. Glaxo has asserted it didn't hide the trial

results.

 

Why are placebos so potent in depression trials? Some blame technical

flaws in the way clinical trials are done, such as including people

who are not clinically depressed and using inexact ratings to measure

complicated feelings. Scientists speculate that human factors may

also play a role: Patients who like the researcher or nurse doing the

study may get better even without actual medication.

 

The biggest complication may turn out to be intrinsic to

antidepressant trials. Study subjects are divided into two groups.

One gets the drug and regular meetings with researchers to track

their progress, while the placebo group gets sugar pills as well as

the regular meetings.

 

There's the rub: People in the placebo group are actually getting

treatment of a kind. They still have the doctors' visits with someone

paying attention to their distress and trying to address it. That

medical interaction, and the hope engendered by simply being in a

study, may be responsible for their improvement even when on a fake

antidepressant.

 

Pfizer and Lilly, unlikely allies, are together ponying up more than

$1 million to fund the research at UCLA. Psychiatrist Andrew

Leuchter, vice chairman of the university's Department of Psychiatry

and Biobehavioral Sciences, will lead a study aimed at developing

tools to spot people who seem to get better without drugs. The 11-

week study will examine 60 patients, mapping their brain waves four

times, recording their sleep patterns, and checking their mental

agility at solving puzzles.

 

" The placebo responders look just the same as the drug responders, "

Dr. Leuchter says. " But in some subtle ways they may be different. "

 

Dr. Leuchter believes that placebo responders, although they appear

just as sad and down as other depressed patients, actually have less

severe physical symptoms. That's why tests related to sleep and

mental agility may be able to pick them out, he says.

 

Some doctors worry that making the trials more restrictive would make

the test subjects even more unlike the depressed people who actually

show up in their offices seeking treatment. " If you exclude a whole

bunch of placebo responders, " says Duke University psychiatrist P.

Murali Doraiswamy, " the results won't apply to the patients I see in

my practice. "

 

Write to Leila Abboud at leila.abboud

 

 

 

 

FAIR USE NOTICE: This may contain copyrighted (C ) material the use

of which has not always been specifically authorized by the copyright

owner. Such material is made available for educational purposes, to

advance understanding of human rights, democracy, scientific, moral,

ethical, and social justice issues, etc. It is believed that this

constitutes a 'fair use' of any such copyrighted material as provided

for in Title 17 U.S.C. section 107 of the US Copyright Law. This

material is distributed without profit.

 

 

SSRI-Research/

 

 

 

 

 

 

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