Pink Sheet - Antipsychotic Trials Biased Towards Sponsor's Drug

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[sSRI-Research] Pink Sheet - Antipsychotic Trials Biased

Towards Sponsor's Drug

 

 

 

ALLIANCE FOR HUMAN RESEARCH PROTECTION

Promoting Openness, Full Disclosure, and Accountability

www.ahrp.org

 

FYI

 

 

An independent review by a team of German analysts published in the

American Journal of Psychiatry confirms that corporate bias is

ubiquitous in clinical trials. The credibility of company sponsored

tests of the so-called 'atypical' antipsychotic drugs (neuroleptics)

including Johnson & Johnson subsidiary Janssen's Risperdal

(risperidone), Lilly's Zyprexa (olanzapine), Novartis' Clozaril

(clozapine), Pfizer's Geodon (ziprasidone) and Sanofi-Aventis' Solian

(amisulpride) is totally undermined by corporate bias at every step of

the process--from design, subject selection, data analysis, and

journal reports.

 

 

Dr. Stephan Heres and colleagues (Technical University, Munich) found

that 90% of company-sponsored clinical studies found the company's

drug more favorable than its competitors. " Different trials comparing

the same two drugs have had contradictory conclusions, " the study

notes. The reported results seem to be much like partisan

politics-the drug favored depended upon who paid for the trial.

 

A total of 42 clinical trial reports were identified. Of these, 32

were (fully or partially) funded by pharmaceutical companies.

 

" The blinded review included 30 abstracts and found that the overall

outcome was positive for the sponsor's drug in 27 cases. Looking at

peer-reviewed studies only did not significantly alter the results:

only three of 21 cases did not favor the sponsor's drug. "

 

The authors note that all reports-regardless of peer review-favored

the sponsoring company's drug. Although the report does not venture to

explain why this might be so-analysts must open their eyes to

industry's overall influence on ALL drug safety and efficacy reports

because the academics conducting them are not necessarily as objective

as some had previously supposed.

 

" Pair-wise comparisons revealed contrasting outcomes, depending on the

sponsor of the study, although the outcomes were derived from trials

involving the same drugs, " Heres et al. noted.

 

" On the basis of these contrasting findings in head-to-head trials, it

appears that whichever company sponsors the trial produces the better

antipsychotic drug. "

 

The authors list a number of possible sources of bias-including

selection criteria, dosing, statistics and methods, reporting and

" wording of results. "

 

They outline " relatively simple measures " to overcome potential bias

in industry-sponsored studies.

The authors note: " A complete disclosure of all results of the

head-to-head comparison would appear to be mandatory but is not always

provided. Furthermore, reporting of adverse events seems to be selective. "

 

The authors rightly emphasize that peer reviewers for scientific

journals whose responsibility is to demand balanced reporting of the

results is not exercised. They cite a recent study by William Honer

(University of British Columbia) et al., published in the Feb. 2, 2006

issue of the New England Journal of Medicine that seems to confirm

Heres' analysis of bias in head-to-head studies of antipsychotics. The

NEJM study found no beneficial effects of risperidone augmentation in

schizophrenic patients not responding to clozapine.

 

Perhaps demonstrating the failure of peer review to catch false claims

about benefits unspoorted by the data, an editorial by Dr. John Davis

(University of Illinois at Chicago) accompanying the Honer study

claimed that two previous trials, which were industry-funded, showed

a clear benefit for risperidone augmentation. "

 

When challenged by Bloomberg News reporter, Rob Waters, with the fact

that the two previous trials Dr. Davis cited came to opposite

conclusions, he acknowledged that he misspoke- " a bad mistake " .

 

However, the " bad mistake " continues to be disseminated--as neither

the NEJM or Dr. Davis have retracted the false statement, thus

physicians, the press, and the public continue to be misled.

 

See: http://www.ahrp.org/cms/content/view/64/80/

 

 

 

Contact: Vera Hassner Sharav

212-595-8974

veracare

 

 

 

 

http://www.thepinksheet.com/NR/FDC/images/pinksheet/print_masthead.gif

 

" THE PINK SHEET "

February 06, 2006

Volume 68 | Number 006 | page 9

 

Antipsychotic Trials Biased Towards Sponsor's Drug, Study Suggests

 

Clinical trial protocols for head-to-head comparisons of antipsychotic

drugs should be reviewed by regulatory authorities like FDA to

eliminate potential sources of bias, according to a recent analysis

published in the American Journal of Psychiatry.

 

In a February 2006 article reviewing head-to-head studies of

second-generation antipsychotics that were funded by pharmaceutical

companies, 90.0% of studies found favorable results for the sponsor's

drug (p<0.001). " Different trials comparing the same two drugs have

had contradictory conclusions, " the study notes. " This effect may not

be totally unrelated to the funding sources of the trials. "

 

Various sources of bias - including elements of clinical trial design

- were identified in the analysis. Review of trial protocols by FDA or

other regulators was suggested as one way to control for potential bias.

 

" Responsible agencies such as the U.S. Food and Drug Administration

(FDA) or the European Medicines Agency (EMEA) might be given the

chance to look at the protocol before the study is begun in order to

allow the correction of obvious flaws, " Stephan Heres (Technical

University of Munich) et al. recommend.

 

The study examined 33 head-to-head studies sponsored by a

pharmaceutical company that were identified through a MEDLINE search

from 1966 to September 2003. Additional studies were selected from

conference proceedings for the period from 1999 to February 2004.

 

The study looked at head-to-head studies involving several commonly

prescribed second-generation antipsychotics, including Johnson &

Johnson subsidiary Janssen's Risperdal (risperidone), Lilly's Zyprexa

(olanzapine), Novartis' Clozaril (clozapine), Pfizer's Geodon

(ziprasidone) and Sanofi-Aventis' Solian (amisulpride).

 

Of the 42 reports identified, 32 were fully or partially funded by

pharmaceutical companies. The blinded review included 30 abstracts and

found that the overall outcome was positive for the sponsor's drug in

27 cases. Looking at peer-reviewed studies only did not significantly

alter the results: only three of 21 cases did not favor the sponsor's

drug.

 

In addition to the overall pattern of positive findings, the analysis

also found that studies by different sponsors had contradictory

results (see chart: " 1Home Court Advantage? " ).

 

" Pair-wise comparisons revealed contrasting outcomes, depending on the

sponsor of the study, although the outcomes were derived from trials

involving the same drugs, " Heres et al. noted.

 

" On the basis of these contrasting findings in head-to-head trials, it

appears that whichever company sponsors the trial produces the better

antipsychotic drug. "

 

Dosing was identified as a possible source of bias, although the

authors also found problems with entry criteria and study population,

statistics and methods, and reporting and wording of results.

 

" Dose ranges and dose escalation are crucial factors that potentially

influence trial outcome, " the study states. " In numerous trials, dose

ranges are scheduled according to the manufacturer's package insert,

which is problematic with antipsychotic drugs. "

 

For example, in Risperdal trials sponsored by J & J, a dose range of 2

mg to 6 mg per day was used, and even lower doses were used in elderly

patients. Competitors, however, used higher doses that are associated

with greater side effects but not greater efficacy.

 

In trials involving Zyprexa, the upper dose range limit is often set

at 15 mg/day, thus excluding the most effective 20 mg/day dose, the

study says. " Use of this limited dose range possibly reduces

olanzapine's efficacy and may result in a misleading conclusion of the

competitor's therapeutic superiority or equality. "

 

" Finding the optimum dose escalation schedules for both compounds in a

study is difficult and may be another source of bias. In some cases,

the bias may derive from the fact that titration is mandatory for some

drugs (risperidone, clozapine, sertindole), while the comparator (for

example, olanzapine) does not require a stepwise dose escalation, " the

article states.

 

" This difference plays a major role in studies evaluating efficacy

over a brief period of time. "

Heres et al. acknowledge that there may be other sources of bias their

analysis did not articulate. " Other readers may have different

opinions, especially about the more subtle potential sources of bias. "

 

The authors included several disclaimers about their research. Heres

cautioned that the study is not a review or meta-analysis examining

efficacy or tolerability, but rather " an exploratory approach to

clarifying partly contradictory study results in the field of

schizophrenia treatment. "

 

The authors also added a statement that they were not implying that

the bias was intentional on the part of sponsors: " Most of the

identified factors were indeed rather subtle and did not reflect an

attempt by the drug trial sponsors to intentionally misinterpret their

findings or to willfully mislead readers. "

 

" Although at least some of the biases we identified seemed very

obvious, our analysis remains speculative, and there is no proof that

the factors we identified really influenced the results. "

 

Despite concerns regarding industry-sponsored trials, the authors

acknowledge they are vital for clinical research and often surpassed

non-industry sponsored trials in the quality of research methods.

" Industry-independent studies are not necessarily free of bias and are

often too underpowered to find clinically significant differences to

allow any generalization, " the study notes.

 

The article outlines " relatively simple measures " to overcome

potential bias in industry-sponsored studies.

For problems with dosing, the study suggests study initiators solicit

suggested dose ranges and titration schedules from the manufacturers,

" as the manufacturer of a drug knows its properties best. "

 

Defining a valid study population is critical in patients with

treatment-resistant conditions that focus on antipsychotic

effectiveness, the study adds. Previous treatment discontinuation

elements, such as medication intolerance, shouldn't be used as

alternative inclusion criteria. " Otherwise, it is unclear which aspect

is related to the superiority of a compound, " the authors said.

 

Peer reviewers also have a responsibility, Heres et al. suggest, since

the wording and phrasing of study results are " surely the most

debatable sources of bias. "

 

" A complete disclosure of all results of the head-to-head comparison

would appear to be mandatory but is not always provided, " the study

states. " Furthermore, reporting of adverse events seems to be selective. "

 

" It is again the responsibility of peer reviewers for scientific

journals to demand balanced reporting of the results, " Heres et al.

concluded.

 

A study appearing in the Feb. 2, 2006 issue of the New England Journal

of Medicine appears to confirm Heres' analysis of bias in head-to-head

studies of antipsychotics. The study, supported by the Stanley Medical

Research Institute and authored by William Honer (University of

British Columbia) et al., found no beneficial effects of risperidone

augmentation in schizophrenic patients not responding to clozapine.

 

" In contrast, two previous trials, which were industry-funded, showed

a clear benefit for risperidone augmentation, " John Davis (University

of Illinois at Chicago) pointed out in an accompanying editorial.

 

The discrepancies may be due to a lower average dose than what

investigators in the two industry-sponsored studies utilized, Davis

suggested. In addition, the trial " may have focused on patients who

were too sick for augmentation to make a difference. Nonetheless, the

Honer trial was carefully conducted, and its negative findings

introduce palpable doubt about the efficacy of augmentation therapy in

refractory schizophrenia. "

 

Davis added that previous studies evaluating the primary

antipsychotics used to treat schizophrenia also had inconsistent

results. He included among his citations the NIMH-sponsored Clinical

Antipsychotic Trials of Intervention Effectiveness (CATIE) (2 " The

Pink Sheet " Sept. 26, 2005, p. 4).

 

[Editor's note: Coverage of a related AJP study appeared in the " The

Pink Sheet " DAILY Feb. 1. To read the article and sign up for a free

trial, visit our website, www.ThePinkSheetDAILY.com.]

 

Contents copyrighted © F-D-C Reports, Inc. 2006; protected by U.S.

Copyright Law.

 

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