Clinical Trial Disclosure Is Incomplete: Study
6 CommentsBy Ed Silverman // November 26th, 2008 // 7:55 am
In an observational study published in PLoS Medicine, researchers tested the hypothesis that not all trial results in New Drug Applications for new drugs submitted to the FDA are published in medical journals. They examined efficacy trials between 2001 and 2002, and searched for discrepancies between trial data included in NDAs and in published articles between July 2006 and June 2007.
What did they find? They reported that “only three-quarters of the efficacy trials in the NDAs were published; trials with favorable outcomes were nearly five times as likely to be published as those without favorable outcomes. Although 155 primary outcomes were in both the papers and NDAs, 41 outcomes were only in the NDAs.
“Conversely, 17 outcomes were only in the papers; 15 of these favored the test drug. Of the 43 primary outcomes reported in the NDAs that showed no statistically significant benefit for the test drug, only half were included in the papers; for five of the reported primary outcomes, the statistical significance differed between the NDA and the paper and generally favored the test drug in the papers. Finally, nine out of 99 conclusions differed between the NDAs and the papers; each time, the published conclusion favored the test drug.
“These findings indicate that the results of many trials of new drugs are not published 5 years after FDA approval of the drug. Furthermore, unexplained discrepancies between the data and conclusions in NDAs and in medical journals are common and tend to paint a more favorable picture of the new drug in the scientific literature than in the NDAs…Thus, the information that is readily available in the scientific literature to health care professionals is incomplete and potentially biased…
However, their may be room for optimism: “The recent introduction in the US and elsewhere of mandatory registration of all clinical trials before they start and of mandatory publication in trial registers of the full results of all the predefined primary outcomes should reduce publication bias over the next few years and should allow clinicians and patients to make fully informed treatment decisions,” the researchers from the University of California, San Francisco, conclude.
In an accompanying editorial, An-Wen Chan, who previously worked as a scientist with the World Health Organization’s International Clinical Trials Registry Platform and is now at the Mayo Clinic, writes that “much remains to be done - not only to establish reliable, comprehensive registration and results disclosure processes worldwide, but also to start heeding the calls for increased access to full protocols and regulatory agency submissions…Misreporting of trials can be difficult to detect without access to detailed documents beyond what is currently available on registries and results databases. Only with full transparency can the validity of a randomized trial be judged.”
Former Marketing Exec
There are some physician organizations that are now making it mandatory for all P.I’s involved in the clinical trials to review all the raw data. This would help considerably in ensuring that the data being published matches the data in the NDA’s.
Former Marketing Exec
There are a few physicians associations who are mandating that the P.I.’s for clinical trials have access to the raw data.
In many cases now, the P.I.’s do not always get access to this data, they get access only to the trial data from their site, which provides an incomplete picture if it is a multiple trial site.
Excerpt from recent paper with source sited below….
THE PROBLEM
Research contracts between a company and a clinical
trial investigator often contain “non-disclosure” clauses,
drawn up to protect the company against the investigator
divulging proprietary information or information about the
company’s business operations. Yet the research contracts
that today’s investigators are asked to sign before partici-
pating in an industry-supported clinical research trial often
contain broadly worded clauses that can be used to restrict
their rights to access, analyze, and report trial data. Typi-
cally, they demand confidentiality by restricting the dissem-
ination of “confidential information,” but in doing so may,
for example, include in the definition of confidential infor-
mation “data developed or generated in whole or part by
the investigator during the research investigation.” Some
clauses prohibit “publication of the results of the research
unless agreed to by the Company in writing.” The latter
restriction may be either without time limits or allowed
under contract only after an inappropriately long period of
time after completion of the research or trial. Such clausessummaries and statistical analyses performed by the com-
pany. There may be a lack of investigator input into the data
included in or excluded from the summary data set and thus
from publication, with no recourse under the terms of the
contract. Delays or failure to report adverse events or to
report negative trials may result, and the company’s role in
causing these may be justified or defended by the restrictive
terms of many contracts.
Tactics that have been reported as delaying or discour-
aging publication of negative or unfavorable clinical re-
search trials include withholding company approval of a
manuscript submission (based on terms stipulated in the
contract) and dragging out the company review of the
manuscript (which is required by contract), prolonging a
dispute over company-suggested revisions and/or having
another version submitted by other authors in the interim.6
Companies have also withheld raw data needed as back-
ground for a published report……2,10 Other tactics have been
reported, not necessarily based on contract restrictions.10
From the Department of Surgery, Vascular Surgery Section, University of Colorado Health Sciences Center,a and the Department of Surgery,
Toronto General Hospital, University of Toronto.b
Reprint requests: K. Wayne Johnston, MD, Editorial Office, Toronto General Hospital, 5 Eaton, Room 312, 200 Elizabeth St, Toronto, Ontario,
M5G 2C4, Canada.
J Vasc Surg 2002;35:1036-40.
Copyright © 2002 by The Society for Vascular Surgery and The American
Association for Vascular Surgery.
0741-5214/2002/$35.00
Marketing Exec
Excerpt from a recent paper from the journal of vascular surgery.
THE PROBLEM
Research contracts between a company and a clinical
trial investigator often contain “non-disclosure” clauses,
drawn up to protect the company against the investigator
divulging proprietary information or information about the
company’s business operations. Yet the research contracts
that today’s investigators are asked to sign before partici-
pating in an industry-supported clinical research trial often
contain broadly worded clauses that can be used to restrict
their rights to access, analyze, and report trial data. Typi-
cally, they demand confidentiality by restricting the dissem-
ination of “confidential information,” but in doing so may,
for example, include in the definition of confidential infor-
mation “data developed or generated in whole or part by
the investigator during the research investigation.” Some
clauses prohibit “publication of the results of the research
unless agreed to by the Company in writing.” The latter
restriction may be either without time limits or allowed
under contract only after an inappropriately long period of
time after completion of the research or trial. Such clausessummaries and statistical analyses performed by the com-
pany. There may be a lack of investigator input into the data
included in or excluded from the summary data set and thus
from publication, with no recourse under the terms of the
contract. Delays or failure to report adverse events or to
report negative trials may result, and the company’s role in
causing these may be justified or defended by the restrictive
terms of many contracts.
Tactics that have been reported as delaying or discour-
aging publication of negative or unfavorable clinical re-
search trials include withholding company approval of a
manuscript submission (based on terms stipulated in the
contract) and dragging out the company review of the
manuscript (which is required by contract), prolonging a
dispute over company-suggested revisions and/or having
another version submitted by other authors in the interim.6
Companies have also withheld raw data needed as back-
ground for a published report.2,10 Other tactics have been
reported, not necessarily based on contract restrictions.10
Former Marketing Exec
Excerpt from a recent paper:
Protecting the rights of investigators in industry-
supported clinical research
Robert B. Rutherford, MD,a and K. Wayne Johnston, MD,b Silverthorne, Colo; and Toronto, Canada
Journal of Vascular Surgery
THE PROBLEM
Research contracts between a company and a clinical
trial investigator often contain “non-disclosure” clauses,
drawn up to protect the company against the investigator
divulging proprietary information or information about the
company’s business operations. Yet the research contracts
that today’s investigators are asked to sign before partici-
pating in an industry-supported clinical research trial often
contain broadly worded clauses that can be used to restrict
their rights to access, analyze, and report trial data. Typi-
cally, they demand confidentiality by restricting the dissem-
ination of “confidential information,” but in doing so may,
for example, include in the definition of confidential infor-
mation “data developed or generated in whole or part by
the investigator during the research investigation.” Some
clauses prohibit “publication of the results of the research
unless agreed to by the Company in writing.” The latter
restriction may be either without time limits or allowed
under contract only after an inappropriately long period of
time after completion of the research or trial. Such clauses
can create and have created problems for investigators,
probably only a small portion of which has been reported by
summaries and statistical analyses performed by the com-
pany. There may be a lack of investigator input into the data
included in or excluded from the summary data set and thus
from publication, with no recourse under the terms of the
contract. Delays or failure to report adverse events or to
report negative trials may result, and the company’s role in
causing these may be justified or defended by the restrictive
terms of many contracts.
Tactics that have been reported as delaying or discour-
aging publication of negative or unfavorable clinical re-
search trials include withholding company approval of a
manuscript submission (based on terms stipulated in the
contract) and dragging out the company review of the
manuscript (which is required by contract), prolonging a
dispute over company-suggested revisions and/or having
another version submitted by other authors in the interim.6
Companies have also withheld raw data needed as back-
ground for a published report.2,10 Other tactics have been
reported, not necessarily based on contract restrictions.10
Such tactics may include requesting investigators/authors
to withhold publication of the trial data until after an
additional ….
Doc
Why would this selective publication be surprising when it is marketing departments that often decide what trials to do on products. Why marketing? Because the “science” is particularly valid if it reinforces greater use of a product. Nice to know you have al those bright MBAs deciding what science to pursue.
Former Marketing Exec
That is exactly my the point I was making in my posts, that went a bit haywire, I must say…
It is inappropriate for those decisions to be made purely on marketing reasons, but it is the way it goes.
The company researchers and executives approach marketing to determine who, what, where and when a drug will fit in the market and how will it generate the best ROI for the organization. Whatever market research is discovered goes into the marketing mix, and marketing then influences the direction of the clinical research.
It is quite crazy when you think that Medical doctors and researchers who have dedicated years to their education and perfecting their skills are actually being “undermined” and in some cases compromised by the decisions being made in the marketing department. Some marketing directors have MBA’s some do not. Medical, regulatory should drive the process. When I was working in Pharma, I insisted and usually got what I wanted, because it worked. We increased our credibility with our KOL’s who then found ways to give us more time, this worked to our competitive advantage.
Big Pharma does have some very good people working inside, very smart PhD and MD’s, they need to listen to these people much more than just thinking about the marketing, that is what is killing them and causing the problems and great distrust.
Hope the right people read this and think about thinking out side of the box for a change….