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Pharma Funding May Bias Safety Findings

By Crystal Phend, Staff Writer, MedPage Today
Reviewed by Zalman S. Agus, MD; Emeritus Professor at the University
of Pennsylvania School of Medicine.
October 22, 2007

VALENCIA, Spain, Oct. 22 -- Industry-funded trials may downplay the
side effects of corticosteroids both through study design and
interpretation of findings, researchers said.
Funded studies were about half as likely to find a significant
difference in adverse events between corticosteroid and control groups
compared with nonfunded studies, according to a meta-analysis in the
Oct. 22 issue of the Archives of Internal Medicine.

Among the studies that found a difference, researchers were 3.68 times
more likely to deem corticosteroids "safe" if they had received
pharmaceutical company money, reported Angel Mazon, M.D., Ph.D., of
Children's Hospital La Fe here, and colleagues.

"These results, together with the many studies that gave no
information on safety, further support calls for the systematic
reporting of adverse effects in current standards for the publication
of results of clinical trials and of observational studies of
therapeutic interventions," they wrote.

Although inhaled corticosteroids are the cornerstone in treatment of
inflammatory respiratory diseases, especially asthma, "they are not
free of adverse effects, and concerns have been raised about long-term
treatment courses in milder cases of disease or in young children,"
the researchers wrote.

Previous studies have shown that industry funding is associated with
better study outcomes. So to see if the same was true for safety
outcomes, Dr. Mazon and colleagues conducted a meta-analysis of
inhaled corticosteroid trials with explicit reporting of adverse
events.

The researchers abstracted adverse events and conclusions of 275
funded and 229 nonfunded studies after masking authors, affiliation,
funding sources, and acknowledgments.

Notably, 39.6% of corticosteroid studies could not be included in the
meta-analysis because they did not report adverse events. A third of
those were industry-funded, "a figure astonishingly high considering
that this represents omitting data on the safety of a therapeutic
intervention," the researchers said.

Among the studies that were included, 34.5% of those with drug company
funding versus 65.1% of those without industry funding reported
statistically significant differences in adverse events between the
corticosteroid arms and the control arms (prevalence ratio 0.53, 95%
confidence interval 0.44 to 0.64).

The difference was even more substantial between studies with funding
exclusively from industry and those that reported funding from both
pharmaceutical companies and other organizations (26.5% versus
71.4%).

But, there was little difference between those with funding from
nonprofit organizations and those that declared no funding at all
(73.0% versus 61.3%).

Funded studies were also more likely to conclude that the drug was
safe overall, even if there was a statistically significant increase
in adverse events with inhaled corticosteroids (41.8% funded versus
11.4% nonfunded, PR 3.68, 95% CI 2.14 to 6.33).

The reason for the differences between industry-funded and nonfunded
studies appeared to have been primarily because of study design, the
researchers said.

Funded studies were more likely to report only general and nonspecific
clinical and laboratory data (PR 2.82, 95% CI 1.93 to 4.15) and less
likely to look at growth retardation (PR 0.47, 95% CI 0.30 to 0.76) or
bone metabolism (PR 0.28, 95% CI 0.18 to 0.45).

The funded trials were also more frequently randomized, multicentric,
parallel designed, and with a primary focus on efficacy. They used
lower medication doses, had larger sample sizes, shorter follow-up,
and were less likely to study adults and patients with asthma.

When these factors associated with lower likelihood of finding
significant adverse event differences were included in a multivariate
analysis, funded trials were no longer less likely to report an
adverse safety profile for inhaled corticosteroids compared with non-
industry funded studies (PR 0.94, 95% CI 0.77 to 1.15).

"This suggests that these differences in design are part of the
mechanism explaining the association (i.e., they are part of the
reason why the frequency of finding adverse effects varies according
to the funding source)," the researchers wrote.

However, whether pharmaceutical company-funded studies were "too
benevolent" or nonfunded studies "too cautious" is unclear, they
noted.

Nevertheless, the results "probably will be applicable to many other
drugs and therapeutic interventions" and "support maintaining or even
strengthening medical journals' full disclosure policies regarding
funding source," they said.

"In addition, the introduction of a new conflict of interest field in
the MEDLINE database (that could be searched and displayed like all
the other fields) should also be considered," they said.

The researchers reported no financial conflicts of interest.

*  *  *

Adverse Effects of Inhaled Corticosteroids in Funded and Nonfunded
Studies

Antonio Nieto, MD, PhD; Angel Mazon, MD, PhD; Rafael Pamies, MD; Juan
J. Linana, MD; Amparo Lanuza, MD, PhD; Fernando Oliver Jiménez, MD;
Alejandra Medina-Hernandez, MD; F. Javier Nieto, MD, PhD

Arch Intern Med. 2007;167:2047-2053.

Background  Evidence regarding the safety profile of drugs may vary
depending on study sponsorship. We aimed to evaluate differences
between studies funded by the pharmaceutical manufacturer of the drug
(PF) and those with no pharmaceutical funding (NoPF) regarding the
finding and interpretation of adverse effects of inhaled
corticosteroids.

Methods  We assessed the safety reporting of inhaled corticosteroids
in 275 PF and 229 NoPF studies identified by a MEDLINE search using
prespecified criteria.

Results  Overall, the finding of statistically significant differences
for adverse effects was significantly less frequent in PF (34.5%) than
in NoPF (65.1%) studies (prevalence ratio, 0.53; 95% confidence
interval, 0.44-0.64). This association became nonsignificant
(prevalence ratio, 0.94; 95% confidence interval, 0.77-1.15) after
controlling for design features (such as dose or use of parallel
groups) that tended to be associated with less frequent finding of
adverse effects and were more common in PF studies. Among studies
finding a statistically significant increase in adverse effects
associated with the study drug, the authors of PF articles concluded
that the drug was "safe" more frequently than the authors of NoPF
studies (prevalence ratio, 3.68; 95% confidence interval, 2.14-6.33).

Conclusions  The type of funding may have determinant effects on the
design of studies and on the interpretation of findings: funding by
the industry is associated with design features less likely to lead to
finding statistically significant adverse effects and with a more
favorable clinical interpretation of such findings. Disclosure of
conflicts of interest should be strengthened for a more balanced
opinion on the safety of drugs.

Author Affiliations: Pediatric Allergy Units, Children's Hospital La
Fe, Valencia, Spain (Drs A. Nieto, Mazon, Pamies, Linana, Lanuza, and
Jiménez), and Hospital de Queretaro, Queretaro, Mexico (Dr Medina-
Hernandez); and Department of Population Health Sciences, University
of Wisconsin School of Medicine and Public Health, Madison (Dr J.
Nieto).