E-drug: Controlling Publication of Clinical Trials
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Dear Colleagues:
Ciprian Jauca's October 21, 1999 posting notes that clinical trials of the
new nonsteroidal anti-inflammatory drug (NSAID) celecoxib (Celebrex) have
not been published making it impossible to conduct an independent assessment
of this drug. Manufacturers who selectively make the results of clinical
trials of new drugs available only as abstracts, or in meeting
presentations, rather than publishing full length journal articles should
be condemned. However, it is their data and the release of some results
may have a negative impact on sales. Another problem not addressed by
Ciprian is the blurring of the boundaries between science (peer reviewed
journal articles) and promotion.
A partial solution to these problems, at least for drugs approved in the
US, lies in the transparency of the US drug approval process. The Freedom
of Information Act (FOIA) provides public access to the reviews done by the
Food and Drug Administration (FDA) of the clinical trials and other data
submitted by manufactures as part of a new drug application (NDA). These
reviews are referred to as approval packages and are available for many
drugs approved since 1997 on the FDA's web site at
http://www.fda.gov/cder/foi/nda/index.htm.
This includes the approval package for celecoxib.
Approval packages typically contain pharmacology/toxicology,
biopharmaceutics/pharmacokinetics, and statistical reviews of the data
submitted in an NDA. In addition, the FDA Medical Officer will write an
overall review of a drug's safety and efficacy based the above mentioned
reviews and the clinical trials submitted in the NDA.
Celecoxib was approved in the US in December 1998 and the approval package
was available on the Internet in early 1999. Searle submitted 15 studies
of celecoxib in patients with osteo- or rheumatoid arthritis and 7 studies
of the drug used in postsurgical analgesia. Celecoxib was approved for
osteo-and rheumatoid arthritis but failed to show efficacy for the
treatment of acute pain.
Transcripts of FDA Advisory Committees are another valuable source of
information that can reveal the concerns of committee members regarding the
safety and efficacy of a drug under discussion. Advisory committee members
are outside experts selected by the FDA and make recommendations to the
agency about a drug's approval that are not always followed. Advisory
committee meetings are conducted under the Federal Advisory Committee Act
(FACA) to ensure that the public has access to the workings of the
government. Transcripts are found at http://www.fda.gov/foi/electrr.htm on
the FDA's web site by the name of the advisory committee and the date of the
advisory committee meeting. For example, celecoxib was reviewed by the
Arthritis Drugs Advisory Committee on 12/1/98. Note, not all drugs go
before FDA advisory committees.
Copies of approval packages and advisory committee transcripts for drugs
approved prior to 1997 can be obtained from the FDA through an FOIA request.
These older approval packages are usually provided on microfiche and
require a microfiche reader-printer to produce a hard copy. Access to these
documents is not limited to US citizens. US non-profit organizations are
granted a fee waiver when the requested information is shared with the
public. The procedures for making a FOIA request can be found at
http://www.fda.gov/opacom/backgrounders/foiahand.html on the agency's web
site.
Examination of FDA approval packages is now particularly important as
reliable independent assessments of new drugs using the medical literature
may no longer be possible even when studies are published. The new flu drug
zanamivir (Relenza) is an example. A major clinical trial, conducted in the
Southern Hemisphere, showing a benefit with zanamivir treatment, is the
only one that has been published. However, Glaxo Wellcome submitted three
major trials to the FDA in zanamivir's NDA. The other two were conducted
in
Europe and North American and have only been presented as abstracts.
The North American trial, almost twice as large as the other two combined,
found no statistical difference between zanamivir and placebo, while the
European trial, the smallest of the three, showed the greatest treatment
effect. The Antiviral Drugs Advisory Committee voted 13 to 4 against
recommending zanamivir's approval on efficacy grounds. The transcript of
this meeting and other documents posted on the FDA's web site at the end of
August give a very different picture of zanamivir's efficacy, or lack of
efficacy, than the published results of the Southern Hemisphere trial.
These documents can be found at
www.fda.gov/ohrms/dockets/ac/cder99t.htm#Antiviral and
www.fda.gov/cder/news/relenza/default.htm. The complete approval package
for zanamivir is not available at this time.
The FDA, in the past, has interpreted provisions of FOIA and FACA to mean
that approval packages can not be made available to the public until after a
drug is approved. This can be several months after an advisory committee
meeting as is the case with zanamivir. The FACA provides for public access
to materials that will be discussed at federal advisory committee meetings
without having to make a FOIA request. Public Citizen challenged the FDA's
interpretation of the law and sued in December 1998. Beginning in January
2000, FDA reviews of new drugs will be made available to the public at or
before advisory committee meetings. Other aspects of our law suit remain
with the court, for example, if safety and efficacy data can be considered
confidential commercial information that is exempt from public disclosure
under FOIA until a drug is approved.
The selective publication of clinical trials by manufacturers can influence
the perception of a new drug's therapeutic value by limiting the evidence
available for interpretation to that which is most favorable to the drug.
It now appears necessary to wait until a drug's approval package is publicly
available from the FDA before independent recommendations or formulary
decisions can be made about new drugs. Controlled access to published
clinical trial results by manufacturers and the lack of transparency in the
drug approval process in other countries remain problems.
Those who have difficulty in navigating the FDA's web site can contact me
at the E-Mail address given below.
Best regards,
Larry
Larry D. Sasich, Pharm.D., M.P.H., FASHP
Research Analyst
Public Citizen Health Research Group
1600 20th Street, NW
Washington, DC, 20009
USA
Phone: 202-588-7782
FAX: 202-588-7796
Web Site: www.citizen.org/hrg
Larry Sasich <lsasich@citizen.org>
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