FDA’s
Drug Efficacy Study Implementation (DESI) and Pantopaque
Uncertain about
the safety of America’s drug supply continued even after
the passage of the Kefauver-Harris Amendments. As a result,
Congress opened hearings in March 1964, chaired by Representative
L.H. Fountain, to investigate FDA’s efforts to promote
drug safety. But Fountain’s hearings took a comprehensive
look at the agency’s regulation of drugs, especially those
that were removed from the market.
To further
comply with the requirements of the drug amendments of 1962,
FDA contracted in 1966 with the National Academy of Sciences/National
Research Council (NAS-NRC) to study all drugs approved from
1938-1962 from the standpoint of efficacy. All drugs on the
U.S. market would have been reviewed for both "safety"and
"efficacy".
Following the
passage of the amendment, there was a legal time delay in enforcement
by the Agency while the courts determined whether demonstration
of "marketing success" met the requirements of valid
proof of product "efficacy" according to the FDA.
The courts in 1970s ruled that marketing success alone did not
constitute valid documentation of efficacy.
The review
process begun by the FDA was called the Drug Efficacy Study
Implementation(DESI). The Drug Amendments had required that
the DESI be completed within two years and that all labeling
recommendations be fully implemented by 1972. However, elements
of the DESI process still continues in 2002. DESI evaluated
over 3000 separate products and over 16,000 therapeutic claims.
The last NAS/NRC report was submitted in 1969, but the contract
extended through 1973 to cover ongoing issues. The initial agency
review of the NAS/NRC reports by the task force was completed
in November 1970.
One of the
early effects of the DESI study was the development of the Abbreviated
New Drug Application (ANDA). ANDAs were accepted for reviewed
products that required changes in existing labeling to be in
compliance. In September 1981 final regulatory action had been
taken for 90% of all DESI products. By 1984, final action had
been completed on 3,443 products; of these, 2,225 were found
to be effective, 1051 were found not to be effective, and 167
are still pending. (41)
In May 1972,
the DESI process was extended to cover over-the-counter (OTC)
products. Lafayette Pharmacal’s NDA 5-319 (Pantopaque I)
was a drug product to come under review of the NAS-NRC DESI
program as documented by Lafayette Pharmacal, Inc.s’ receipt
of the May 23, 1971 letter from FDA’s Director of DESI
Project Office, P. Bryan, M.D. The DESI letter echoes the earlier
1969 labeling requests from FDA.
During the
1970s, the FDA started two new forums to help increase drug
communication to the public. The Bureau of Drugs launched the
FDA Drug Bulletin in 1971. The National Drug Experience Reporting
System also was begun in 1971. The NAS had been studying the
problem of not only how to catalogue and store information about
adverse drug reactions, drug abuse, and drug interactions, but
also how that information could best made available to health
professionals. The study concluded that since the FDA had already
begun to collect the drug data, that they should take the lead
on creating and maintaining the adverse event reporting system.
In July 1979,
FDA also proposed a program to provide patients with additional
information about prescription drugs, including a description
of the drug’s uses, risks, and side effects. Under the
Agency’s proposal, all drug manufacturers would print the
information and the health provider would give the insert to
the patient. But, by September 1980, under the weight of well-organized
opposition to the program, the FDA was forced to drop the requirement
for a patient insert.
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Pantopaque
clinical literature had been reviewed by the NAS-NRC Panel on
Diagnostic Agents. The indication for the drug was for myelography,
and DESI advisory panel concluded that it was "effective"
for that labeled indication. The comments of the DESI review
summarized the information found in the published literature:
"Pantopaque
(ethyliodophenylundecylate with 30.5% iodine in oil) has been
widely used and is accepted as the current agent of choice in
myelography. Comparative studies are few, but one in cats showed
Pantopaque to be superior. Several groups have increased the
dose without untoward effects. Small volumes (2-3 cc) of Pantopaque
have been used also for positive-contrast ventriculography."
In terms of
the labeling review, the advisor panel reviewed Pantopaque labeling
that had been submitted and "cleared" by FDA in the
NDA for marketing of Pantopaque in the U.S., the general comments
by the members of the advisory panel for labeling of Pantopaque
were as follows:
"Additional
side effects should be mentioned:
Infrequently,
severe arachnoiditis has followed the intrathecal injection
of Pantopaque, producing headache, fever, meningimus, severe
back pains, pain in the lower extremities, and elevation of
the white cell count and protein content of the cerebrospinal
fluid. The incidence and severity of this arachnoiditis are
greatly increased when active subarachnoid bleeding has been
induced by the lumbar puncture. (42)
Rare instances
of lipoid granuloma, obstruction of the ventricular system,
and venous intravasation producing pulmonary embolization have
followed the intraspinal injection of Pantopaque. Diagnostic
tests of thyroid function involving the administration of radioactive
iodine may be invalidated for many years, following the intrathecal
injection of Pantopaque.
Additional
contraindications should be mentioned:
The intrathecal
administration of Pantopaque should be deferred if active subarachnoid
bleeding is encountered in the performance of the lumbar puncture.
The administration of Pantopaque is contraindicated in patients
with known hypersensitivity to iodine or its compounds.
The following
phrase in the package insert is incorrect:
"The small
amount of material that is left is usually absorbed within two
months."
In fact, the
residual contrast medium in the subarachnoid space usually remains
for many years. This incorrect statement should be deleted.
It should be
specifically recommended that as much of the Pantopaque be removed
from the subarachnoid space as possible, after the examination
is completed. The amount of Pantopaque commonly used is 3-12
cc rather than that quoted in the brochure (3-5 cc).
The recommendation
in the package insert for the examiner to become "darkadapted"
before fluoroscopy is no longer applicable for many institutions
where image intensification is used.
Pantopaque
may be used in small volume (2-3 cc) for positive-contrast ventriculography
when conventional air ventriculography is unsuccessful."
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Marketing of
Pantopaque (30%) following withdrawal of Pantopaque II’s
NDA
April 18, 1969
letter from Frank Gollon, Eastman Kodak Legal Dept, Trademark
Section, to Mr. W.T. French, Patent Dept, Kodak Office:
"You have
requested information concerning our marketing of ethyl iodophenylundecylate
which is distributed by others as a contrast medium for radiography
under the trademark PANTOPAQUE.
I am advised
that this information is required in connection with an inquiry
received by Eastman Kodak Company from the United States Department
of Justice which has challenged certain restrictive provisions
in a patent license agreement relating to radiopaque (United
States v Sterling Drug, Inc. and E.R. Squibb & Sons, Inc.)(43)
I understand
that ethyl iodophenylundecylate is purchased from us by Lafayette
Pharmacal Inc. who packages(sic) it in dosage form or vials
for use as a contrast medium for radiography.
Lafayette in
turn sells the repackaged product to a number of distributors
including:
· General
Electric Company,
· Picker
X-Ray Corporation,
· Standard
X-Ray Company,
· E.M.
Parker Company,
· Kelley-Koett
Manufacturing Company.
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In order that
Lafayette may identify its product under our trademark PANTOPAQUE,
we licensed that company in 1943 to use our mark upon the product
sold by us to it under such trademark PANTOPAQUE. It is my understanding,
however, that our sales of the chemical to Lafayette have been
under the generic chemical name for many years now, probably
dating from before 1957.
Since PANTOPAQUE
would be distributed by such other companies as General Electric,
Picker, Standard, etc. in packages carrying neither the Lafayette
not the Eastman Kodak name, it was deemed advisable to protect
our proprietary interest in the mark, to also license these
other companies to use the mark.
Your copy of
the Department of Justice letter of inquiry addressed to this
company is returned herewith."
February 11,
1970, Eastman Kodak Company, finalized the development of a
process for manufacturing Ethyl Iodophenylundecylate (Pantopaque)
that found a substitute for benzene in the esterification process
to eliminate the health hazard associated with use of benzene.
The process was titled Manufacturing Controls for the Preparation
of Pantopaque and began:
"There
are no changes in the information previously submitted to the
Food and Drug Administration, except that iodic acid was indicated
as the iodinating agent.
Actually, iodine
is the iodinating agent and iodic acid is an oxidizing agent
for regenerating iodine from the hydrogen iodide that is liberated,
thus permitting complete use of the iodine. It is noted that
the instructions for items 6,7 and 8 of the current New Drug
Application Form (F.D. 356 H) apparently contemplate considerably
more detailed information than that which was originally required.
.....
The manufacture
and chemical purification of ethyl iodophenylundecylate is carried
out in the Synthetic Chemicals Division located in the Kodak
Park Division of Eastman Kodak Company in Rochester, NY. The
manufacturing operations are carried out by trained, experienced
chemical operators , chemical technicians and professional chemists
employed by the Synthetic Chemicals Division.
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Quality Control
operations are carried out by analytical technicians and professional
chemists assigned to three Kodak Park areas:
· Synthetic
Chemicals Division,
· Industrial
Laboratory, and
· Kodak
Research Laboratories."
W.S. Bucke
, Lafayette Pharmacal, Inc. wrote Mr. J. Robinson, Legal Department,
Eastman 44 Kodak Company on February 18, 1971 the following:
"Pursuant
to our conversation, I wish to advise that your company Kodak,
Distillation Products Industries Division is responsible for
meeting the U.S.P. requirements for Iophendylate Injection."
A proof of
an advertisement for George Banta Company, Inc. intended for
the “Journal of Neurosurgery”, August 1969 for marketing
of Pantopaque. The advertisement discussed the use of Pantopaque
contrast medium for the visualization of a large neurofibroma
(*tumor) at the level of the third cervical vertebra (as follows):
"Side
Effects:
Clinical reports
indicate that the incidence and the severity of the side effects
following Pantopaque myelography with aspiration of the medium
is but slightly greater than with ordinary lumbar punctures.
In 10-30 percent
of such cases there may be transient symptomatic reactions consisting
of slight temporary elevation and increase of symptoms referrable
to a back condition. When the medium is not removed, similar
transient side effects occur with a slight elevation of temperature
in a greater percent of patients.
To reduce the
reactions to minimum and to facilitate the absorption of the
medium, the bulk of the Pantopaque should be removed by aspiration
after myelography.
The implication
from the advertisement is that for a physician to reduce the
risk of transient fever following myelography, they should attempt
to remove the bulk of Pantopaque. But, that if the agent is
left in the spinal cord similar transient side effect(s) may
occur in a greater percentage of patients.
This labeling
does not:-
· reflect
the results of long-term animal testing for Pantopaque when
the contrast medium is left in the spinal column,
· nor
the occurrence of permanent long term complications such as
"obliterative arachnoiditis" in patients that has
been reported within the medical literature,
· nor
does it reflect the concerns that had been expressed by the
FDA.
This labeling
also implies the Pantopaque has been cleared by FDA for visualization
of a tumor in the cervical spine.”
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The letter
from October 3, 1972 John Potts, of Eastman Kodak to Mr. Strawbridge,
Picker Corporation, demonstrated just how closely Eastman Kodak
monitored the Pantopaque trademark.
(Picker is
one of the companies listed above who were supplied with Pantopaque
by Lafayette Pharmacal – MF)
It is unfortunate
that Kodak did not monitor the "accuracy and truthfulness"
of the contents of the labeling in terms of patient safety.
Regarding the license to use the trademark Pantopaque, Mr. Potts
wrote:
"Our attention
has recently been directed to the sales carton you are currently
using to merchandize the Picker Myelogram Tray.
Although this
is a most attractive carton, we are somewhat concerned that
the treatment afforded our PANTOPAQUE mark is not in compliance
with the terms of our license agreement dated August 24, 1943....
In the first
instance, the legend "Trademark PANTOPAQUE Licensed by
Proprietor", does not appear thereon. We believe such a
legend is imperative to avoid any misunderstanding as to the
ownership of the PANTOPAQUE mark, and request that it be added
as soon as possible to the main face panel of the carton–preferably,
immediately beneath the most prominent impression of the mark.
Secondly, although
the mark PANTOPAQUE appears some eight times on the carton,
the proper generic terminology appears only once.....
Finally, it
is noted that the carton in question does not contain one of
the accepted legal notices of trademark registration as required
by the license......
We realize,
of course, that your company would not intentionally do anything
to jeopardize our rights in the PANTOPAQUE mark and know that
you will take prompt action to correct the packaging in question.
(45)
In terms of
demonstrating the working role and oversight of Eastman Kodak
over Lafayette Pharmacal’s product and product labeling,
there was a January 31, 1973 letter from Eastman Kodak Company’s
Executive Vice President, International Photographic Division,
written for the approval of Mr. Bucke of Lafayette Pharmacal:
"It is
our understanding that your firm wishes to distribute and sell
in Mexico, packages and vials of contrast medium for radiography
under our registered trademark PANTOPAQUE (Mexican Reg. No.
163,727).
Accordingly,
by this letter, we hereby grant to you a nonexclusive, nonassignable
license to use said trademark in Mexico subject to the following
terms and conditions which are necessary to protect our rights
in and to said trademark PANTOPAQUE and the good will associated
therewith:
1. Said trademark
PANTOPAQUE will be used by you only on radiographic contrast
media manufactured and sold by us to you;
2. all such
product to conform to standards of quality and sterility prescribed
and approved by us.
3. We shall
have the right of approval of all such product, packages and
labels and you agree to furnish to us upon request, production
samples of same for our inspection.
4. You, at
all times, will acknowledge our ownership of an rights in and
to the trademark PANTOPAQUE as applied to radiographic contrast
media and similar goods."
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