Pantopaque, FDA and New Drug Approval (NDA)
November 4, 1943,
Lafayette Pharmacal Company submitted NDA # 5-319 to FDA to obtain
the Agency’s premarketing approval of the imaging agent,
Pantopaque, intended for myelography in US population based on
the support of safety.
Prior to the
NDA submission there was an Agency memo of a telephone conversation
that had occurred between Dr. Walton VanWinkle, MD of FDA and
Dr. Strain of University of Rochester, Rochester, NY.
Dr. Van Winkle
had requested that Dr. Strain provide animal safety data that
could support the safety of Lafayette Pharmacal’s NDA.
Dr. Strain stated:
· that
he had received copies of our correspondence with the Lafayette
Pharmacal Company with reference to the new drug application for
"Pantopaque".
· that
he would furnish them with data relative to animal experiments
which he had performed.
· that
he did not have very good figures on the acute toxicity and felt
that the obtaining of any adequate data with regard to intrathecal
injection would be difficult.
He was told
· that
he should submit all the data which he could obtain and should
certainly give us some sort of reliable figure for at least the
intravenous toxicity.
· that
we would like to have some comparison between chemical meningitis
produced by Pantopaque and the reactions produced by lipiodol."
He stated that
he felt he had sufficient data on this to answer our questions.
(13)
Dr. Strain said
that Dr. Spurling was, ". publishing a resume of his experience
with this preparation in the August issue of the Army Medical
Bulletin. As soon as reprints are available copies will be sent
to us.".
Top
Apparently, trying
to obtain a response to the Agency’s request for animal data,
there followed a February 22, 1943 letter to Dr. Warren authored
by Dr. H. Hodge, Professor of Biochemistry and Pharmacology, University
of Rochester, regarding his acute toxicity studies of Pantopaque
conducted in the mouse model.
"I have
examined the acute toxicity of ethyl iodophenylundecylate (Pantopaque)
and have determined that the amount required to kill the average
mouse is in the order of 4.6.gms of Pantopaque per kilogram of
body weight of the mouse. The Pantopaque administered intraperitoneally.
These data indicate
that Pantopaque is only moderately toxic. It has about the same
order of toxicity as sodium chloride has. The appearance of hemorrhage
in the intestine is unusual and probably represents a specific
toxic action of Pantopaque. However, the doses given the mice
were relatively huge as compared to the doses which will be employed
clinically.”
Dr. Hodge’s
limited animal toxicity data had not developed a Lethal Dose 50
for intrathecal Pantopaque (i.e. the amount of drug that will
produce a 50% mortality in the animal species being examined.)
Dr. Hodge’s
data indicted his estimated amount of Pantopaque injected intraperitoneally
that would be "lethal" to the average mouse.
From later reports
by Dr. Strain, acute and chronic animal toxicity studies were
conducted using Pantopaque at the University of Rochester and
the data supplied to Lafayette Pharmacal to forward on to the
FDA in the NDA. In the mid 1960s FDA found these same animal studies
inadequate to support Pantopaque safety.
The documentation
I have available for NDA 5-319 contains a 5 page Statement of
Directions (* identified as revised -1944) for physicians. This
provides an initial example of Lafayette Pharmacal’s proposed
labeling for Pantopaque as the firm intended to marketed the imaging
agent to physicians in the U.S. in 1944.
Top
The Pharmacology
section stated that:
"Pantopaque
is absorbed in about 6 weeks from the peritoneal cavity of experimental
animals when injected at the level of 4 gms or less per kilogram,
and is absorbed in about 15 months from the subarachnoid space
of dogs when administered in a dose of 3 cc per animal. Because
the medium is absorbed, there is associated a moderate toxicity.
Thus the dosage
which causes death in 24 hours in 50 percent of experimental animals
(LD 50) has been found to be: 4.5 g/kg.
When injected
intraperitoneally in mice, 19 g/kg. When injected into rats, and
2.1 g/kg when administered orally to rats. Death in these lower
orders is accompanied by moderate fatty degeneration of the liver
and minor pathology of the kidney.
No toxic phenomena
have been observed, however, following intrathecal injection into
rabbits and dogs even when massive doses have been administered.
In agreement
with this, reports from several thousand myelograms in which 2-14.5
cc of the medium has been used show that Pantopaque is well tolerated
even when left in the spinal canal.
In those cases
where the bulk of the contrast medium has been removed using the
technique of Kubik and Hampton, the small amount of material that
is left is usually absorbed within 2 months.
Where none of
the medium is removed the absorption proceeds at a variable rate
depending on conditions within the spinal canal, and may require
years.”
The Injection
of Pantopaque section indicated:
"A previously
prepared 5 cc. Syringe containing 2-5 cc. of Pantopaque is then
secured to the adaptor of the needle, and the medium is injected
slowly into the subarachnoid space....
When the Pantopaque
has been injected, the syringe is detached from the needle and
the stylet replaced. A sterile gauze dressing is then placed over
the adaptor of the needle and the patient is ready for the examination."
In the 1944 proposed
NDA draft labeling, Lafayette indicated to FDA that the proposed
dose of Pantopaque administered for myelography was " 2-5
cc". Removal of Pantopaque section stated:
It should be
possible to remove 80 percent to 90 percent of the injected Pantopaque
without much difficulty.......
Top
Side Effects
section stated:
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 puncture.
In 10- 30 percent
of such cases there may be transient asymptomatic reactions consisting
of slight temperature elevation and increase of symptoms referable
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 a minimum and to facilitate absorption of the medium,
the bulk of the Pantopaque should be removed by aspiration after
myelography.
The Limitations
section for the use of Pantopaque stated:
"Pantopaque
has not been studied adequately from a clinical stand point as
a contrast medium for body cavities other than the subarachnoid
space. The limitations and contraindications in other areas are
not known."
The NDA also
included information about a proposed dog study protocol, with
no population size provided. The protocol indicated that at least
5 dogs were to be injected in any one assay and at least 3 of
15 these 5 should not develop "fevers" greater than
1.5BC. lasting longer than 2 days.
Top
(* Appears to
represent the proposed assay method for ensuring the batch quality
of the manufactured material prior to release of the material
for sale by the University of Rochester, School of Medicine and
Dentistry, and prior to distribution by Lafayette Pharmacal.)
In the materials
I have reviewed from Lafayette Pharmacal, there is a November
15, 1943 Radiopaque Group Report generated by Dr. W. Strain regarding
the current status of the radiopaque compounds that he was investigating
at University of Rochester from August-November 1943. This information
was not apparently intended for submission to FDA within the NDA.
In terms of the agent Pantopaque and Dr. Strain’s update
report:
"The data
relating to the physiological properties of Pantopaque have been
submitted to the Lafayette Pharmacal Inc. This material has also
been discussed informally with the Food and Drug Administration."
Dr. Strain continued
his discussion regarding the new agent Atriopaque:
"Physiological
assays show that ATRIOPAQUE, a viscous liquid contrast medium,
has about the same toxicity as PANTOPAQUE and is absorbed at about
the same rate."
In his final
discussion he stated:
"During
the period August-November, 1943, emphasis has been on the physiological
study of the four products designated as Pantopaque, Atriopaque,
Cholopaque and Gastopaque III. This has been carried out at the
Medical School with the assistance of W.R. Chaleaxe, MD and Leon
Miller, Ph.D. both of whom have assisted on a part time basis.
In connection
with this work it has been necessary to have added supplies of
the radiopaque compounds, and these have been prepared either
by Dr. Creseman, working in Dr. Allan’s laboratory, or by
Dr. Hartman. The work has been seriously handicapped by an acute
shortage of rats and rabbits; steps are being taken to assure
a more satisfactory supply"..
Top
The material
relating to acute and chronic toxicity has been collected for
the Lafayette Pharmacal Inc. and submitted to them under the following
headings:
1. Provisional
Specifications for Ethyl Iodophenylundecylate (PANTOPAQUE)
2. Acute Toxicity
by Intraperitoneal Injection of Mice
3. Acute Toxicity
by Intraperitoneal Injection in Rats
4. Acute Toxicity
by Oral Administration in Rats
5. Acute Toxicity
by Intravenous Administration to Dogs and Rabbits
6. Acute Toxicity
by Intrapleural Injection in Dogs and Rabbits
7. Chronic Toxicity
by Intraperitoneal Injection in Various Species
8. Chronic Toxicity
by Intrathecal Injection in Dogs
9. Chronic Toxicity
by Intrathecal Injection in Rabbits
10. Chronic Toxicity
by Intra-Alveolar Injection in Dogs
11. Chronic Toxicity
by Intra-Uterine Injection in Rabbits. (16)
Copies of these
have been filed with Mr. Fuess together with the material relating
to the chemical preparation and the clinical testing of PANTOPQUE
which was submitted to the Lafayette Pharmacal during the spring.
A master copy has been retained in the Department of Radiology.
When all these
reports were available, they were discussed on October 20 with
Dr. Walton Van Winkle, Jr. at the Office of the Food and Drug
Administration.
Top
Dr. Van Winkle
expressed the opinion that the drug had been adequately studied
and that as soon as the reports had been officially submitted
to him, steps would be taken to consult with the investigators
who had used it.
Van Winkle revealed
however, that the Food and Drug Administration was short-handed
and that the investigation may take time. In the course of this
interview it developed that the Food and Drug Administration would
make no attempt to police the manufacture of PANTOPAQUE since
it will be made by one manufacturer and distributed through one
pharmaceutical house.
He further disclosed
that the Army and Navy acted independently of the Food and Drug
Administration and that any dealings with the services were free
of the restrictions which are imposed on new drugs for civilian
use."
November 18,
1943, Lafayette Pharmacal’s Mr. W.S. Bucke wrote to Dr. Van
Winkle, Jr. of FDA the following letter supplying the additional
data obtained from Dr. Strain:
"In reply
to your request of November 9, 1943, we are pleased to enclose
herewith data suggested for circular setting forth the indications,
dosage and contraindications for PANTOPQUE in addition to the
"Technique for Myelography with Pantopaque". With this
additional data we hope that the Department will be in a position
to act upon our application."
January 21, 1944,
Dr. Van Winkle of the FDA replying to Mr. W.S. Bucke. FDA had
the following concerns regarding approval of the Pantopaque premarketing
application:
"Further
consideration has been given to your application under section
505 of the Federal Food, Drug and Cosmetic Act for the preparation
of "Pantopaque".
From the description
of control procedures contained in the application, we are somewhat
in doubt as to the extent of the test to be made on each batch
of the drug.
In discussing
the preparation of the active ingredient, we note that certain
physical constants are mentioned and the drug is assayed biologically
in dogs. It also appears that a total iodide content determination
is made.
We assume that
these examinations are to be made either by the Eastman Kodak
Company or by the University of Rochester. It does not appear
that you exert any chemical control over the drug after you receive
the raw materials.
Top
In our opinion,
it will be highly desirable for some further check to be made
on the finished packaged product. We, of course, are not in the
position to state what sort of a test is most desirable, but we
feel that the manufacturer should assure himself that the product,
before distribution (17) in the channels of commerce, meets the
criteria for quality and purity as specified in this application.
It is also suggested
that in addition to the tests proposed in the application, a test
for free iodine is included. This is particularly desirable in
that no information has been furnished concerning the stability
of this product, other than the fact that the color changes on
exposure to light.
The clinical
reports which have been submitted leave one with the impression
that a rather large number of reactions of varying degrees of
severity have been observed, with the use of this material.
We are aware
that some of these reactions may be accounted for by the fact
that the investigators failed to remove the material following
examination of the patient. However, on the basis of the reports
contained in the application and without additional data, we hesitate
to permit this application to become effective on the basis of
safety for use.
It is suggested
that additional reports be obtained from some of the investigators
mentioned in the application to whom material has been sent but
who have not submitted reports.
We would be particularly
interested in having them state their opinion of the safety of
this preparation as compared to lipiodol and to discuss the nature
and severity of the reactions observed by them as compared to
those observed when lipiodol is used.
Top
In our opinion,
the proposed circular setting forth the indications and method
of administration of this product is not wholly satisfactory.
Because the severity
of reactions observed, in patients in (sic) whom the product is
not removed after injection, we feel that considerable stress
should be laid upon the necessity for removing this material on
completion of the radiologic examination. It might be well for
the label of the product to bear a caution calling this fact to
the physician’s attention.
The entire circular
creates the impression that reactions are infrequent and are of
a minor character. The reports which have been submitted do not
confirm this impression.
We suggest, therefore,
that a more thorough discussion of the side reactions and potential
toxicity be given in the circular and that it be stressed that
these reactions appear almost uniformly if the product is not
removed following examination of the patient.
It is also suggested
that the circular state that the product is not intended for use
in the bronchi or in the uterine cavity.
At the time you
submit the additional data regarding controls and toxicity, you
should submit a draft of the proposed revised circular and labels."
February 5, 1944
Lafayette Pharmacal, Inc. sent a NDA Supplement to FDA including
physical and chemical testing properties, and the biological assay
method using dogs. The supplement included the animal studies
previously listed in the earlier Dr. Strain Radiopaque Group Report
summary.
The data included
the acute and chronic toxicity testing of injected (18) intraperitoneal
experimental batches of Pantopaque in rats, mice, rabbits and
dogs including intra-uterine injection in rabbits with comparison
to iodinized poppy seed oil; intrathecal injections of rabbits;
intra-alveolar injection of dogs, intrathecal injection of dogs.
In the dog studies,
histological sections of dog spinal column continued to demonstrate
encystation of the retained iodinized oil - whether the substance
was iodinized poppy seed oil or Pantopaque. The cysts of retained
iodinized poppy seed oil were generally larger than the multiple
small scattered cysts of Pantopaque. There were acute toxicity
studies with rats involving oral administration of Pantopaque.
Top
The supplemental
NDA information included a clinical report generated by Dr. W.
Hagman(?), Neurosurgery Dept., University of Rochester School
of Medicine. The clinical report involved his experience with
30 patients undergoing imaging of a suspected spinal cord space
displacing mass (*tumor). The report consisted of an abstract
that had been presented May 19, 1942 at the New York Meeting of
the Harvey Cushing Society. The abstract discussed the author’s
comparison of Pantopque to Lipiodol.
February 15,
1944 Lafayette Pharmacal Inc.’s, Mr.W.S. Bucke, President,
sent the following firm reply letter to Dr. Van Winkle’s
January 21, 1944 FDA letter requesting additional data regarding
Pantopaque.
"In reply
to your letter of January 21, we are pleased to enclose here with
what we believe to answer all of the questions.
Additional to
the data regarding controls and toxicity, we also submit a draft
of a proposed revised circular and labels.
The raw material
tests are to be conducted in the School of Medicine and Chemistry,
in the University of Rochester, both before and after packaging,
then arrangements entered into with Eastman Kodak Company and
Lafayette Pharmacal Inc. With this additional data, we trust that
the Department will be in a position to act upon our application
so that Pantopaque may be available to the civilian population."
Dr. Van Winkle
also received a February 16, 1944 letter sent from the Army Service
Forces, Seventh Service Command, Neurosurgical Section, O’Reilly
General Hospital, Major Francis Murphy, Chief Neurosurgical Section.
Dr. Murphy provided the Agency with his experiences using Pantopaque
compared to Lipiodol:
"At the
request of Lt. Col. R. Glen Spurling of Walter Reed General Hospital
and Dr. William H. Strain of the School of Medicine, University
of Rochester, Rochester, NY, I am writing you concerning my experience
with Pantopaque.
It is my belief
that this substance is considerably less toxic than Lipidol although
we have not done spinal fluid examinations following the myelograms
for the determination of the cell count in the spinal fluid. There
can be no doubt that it is (19) much more easily removed than
Lipiodol.
The average residual
amount in one series was one-tenth of 1 cc when 3 cc’s of
Pantopaque was used. Generally speaking it may be said that Pantopaque
is clinically less toxic and less irritating than Lipiodol and
that it is much more easily removed from the spinal subarachnoid
space than Lipiodol. It is our considered opinion that Pantopaque
should be approved by the Food and Drug Administration for use
in civilian life.
Top
Dr. Van Winkle
received a February 24, 1944 letter from Major Robert Robertson,
Chief of Neurosurgery, Brooke General Hospital, Fort Sam Houston,
Texas supplying FDA with his personal experience with use of Pantopaque:
“Dr. William
H. Strain, University of Rochester, School of Medicine and Dentistry,
has requested that a report be made to the Food and Drug Administration,
New Drug Section, regarding our experience in the use of Pantopaque.
Approximately 250 pantopaque myelograms have been done in the
Neurosurgical Section, Brooke General Hospital. 220 of this series
have been recently reviewed in detail:-
1. It is easily
injected. Usually it is readily recovered, almost, if not completely,
through an 18 gauge lumbar needle. As much as 0.7 to 0.8cc out
of 1cc have (sic) been demonstrated to be absorbed in the space
of one month to 6 weeks. It is hoped that some accurate figure
will be determined in further review of these films.
2. Reactions
of neural tissue and/or meninges have been rare to minimal. In
several cases there has been some transient nuchal rigidity of
2 to 4 days duration. Nine cases, due to marked position changes,
are known to have had the material enter the cranial cavity. Of
these nine known cases, one, an airplane pilot, developed moderate
headache which occurred after flying a few days following the
Pantopaque study. The other eight cases had no symptoms.
3. In one case
in this series who had a Pantopaque study and operation for a
herniated nucleus pulposus, there developed an adhesive arachnoiditis
in the lumbar region, the cause for which was undetermined. It
is our opinion that Pantopaque was not the primary cause of this
reaction but it cannot be definitely shown.
4. The material
shows good opacity and interpretations of the films are as simple
as that done with other opaque media.
Top
March 24, 1944,
Mr. Fuess of Eastman Kodak Company, Chemical Sales Staff, wrote
to Mr. Bucke of Lafayette Pharmacal Inc, regarding Kodak’s
opinions for the proposed revisions of the Pantopaque labeling.
Lafayette Pharmacal
had been revising the labeling at the request of FDA to meet the
Agency’s recommendations. Eastman Kodak continued to hold
the Pantopaque 20 trademark and Lafayette Pharmacal was legally
required to obtain Kodak’s prior approval of Pantopaque product
labeling:
"I am returning
the copies of the labels for Pantopaque which you forwarded to
use for approval in accordance with our agreement.
As pointed out
in my previous letter, the chemical name is incorrectly spelled
in both places where it appears. As noted on the copy an "l"
should be inserted between the "y" and the "u".
Our Patent Department has approved these labels with this change.
We also forwarded
the labels to the University for their approval. Dr. Ramsey makes
the following statement: "In general I feel that the labels
are satisfactory but I dislike the inclusion of the phrase "After
Myelography, remove as much as possible" as part of the label.
This gives undue emphasis to the removal, an emphasis that I do
not believe is necessary beyond other points in the technique."
Dr. Strain repeats
this with a further comment as follows:
"The labels
are satisfactory in every respect except for the typographical
errors that you noted, and the inclusion of the phrase "After
Myelography, remove as much as possible.: I feel that the latter
should not be on the label. In any event "Myelography"
should not be capitalized."
My comment on
these statements is that my interpretation of the statements from
the Food and Drug Administration is that they feel that the inclusion
of the phrase in question is essential. Upon correction of the
typographical errors we approve the labels as submitted.
April 14, 1944
Pantopaque’s NDA application was approved for marketing in
the U.S. by FDA for the intended use for myelography. The product
approval appears to have occurred without resolution of Dr. Van
Winkle’s concerns regarding the "safety" of the
product.
Top
April-July,1944,
Dr. Strain’s periodic report on Radiopaque Compounds began:
"Pantopaque:
The several x-ray houses are offering Pantopaque for sale to physicians
in civilian life. To coordinate with the sales effort, an exhibit
on Pantopaque myelography has been prepared and a number of papers
on Pantopaque Myelography have been submitted for publication......"
During the period
April-July, 1944, the final phase of marketing Pantopaque was
completed. Assays were conducted for Lafayette Pharmacal, both
in April and June, 21 and the product was announced in June at
the annual meeting of the American Medical Association in Chicago.
"The problem
of the policy of the University in marketing new products has
received consideration during this period......."
Prior to initiating
the final steps for an agreement with Squibb, a discussion was
held at the Medical School on the general policy of the University.
Those participating in this discussion were: Dr. Whipple, Col.
Warren, Mr. Thompson, Mr. Kappelman, Dr. Strain.
The issue was
whether the University should send out material for corroborative
clinical testing. The argument in favor of such a policy was presented
by Strain, who reasoned that the corroborative testing was the
most important part of the development of any new product and
that it is desirable to keep this in the hands of the University.
The other four
members of the group felt that the risks of potential liability
of this policy were so great that it could not be considered,
nevertheless they agreed that any new products should be tested
within the Medical School of the University of Rochester.
"Since this
conference, arrangements have progressed further with Squibb so
it is probable that an agreement will be made to submit Pantopaque
emulsion to clinical trial through this organization."
On May 9, 1944,
U.S. Patent 2,348,231, covering Pantopaque and Gavitrast was issued
to Strain, Plati and Warren
July-October,
1944 Radiopaque Group Compound Report of Dr. Strain indicted that
the exploitation of the civilian market for use of Pantopaque
was well under way.
"An agreement
in early August had been concluded with E.R. Squibb & Son
for them to study the "emulsion" formulation of Pantopaque,
but no progress had been made at that time due to the lack of
suitable equipment.
Top
An initial 8000
ampules of Pantopaque for civilian use had been sold during the
period July 1- August 18, with backorder of 4000 ampules. As other
applications of the medium develop the business will increase.
The initial skepticism of the x-ray houses on the size of the
market have now changed to optimism."
October 1944
, "Surgery" published a paper authored by Lt. Col. Spurling
and Cpt. George Wyatt, "Pantopaque, Notes on Absorption following
Myelography", (which) described intrathecal injection of
a Pantopaque dose of 3.5 ccs, (and) began:
"Pantopaque
has replaced Lipiodol and the gases as the contrast medium for
myelography in the Army Medical Corps. The chief reason for the
preference to Lipiodol is that Pantopaque is absorbed instead
of remaining as a persistent foreign substance in the subarachnoid
space. Experience has shown it to be nontoxic and no more irritating
than Lipiodol, and its sharp radiographic contrast and consequent
clear delineation of pathologic anatomy affords (22) a definite
superiority over the gases as does Lipiodol. In contrast to Lipiodol,
Pantopaque is more fluid than viscous and therefore fills out
the smaller spaces such as dural nerve sheaths. It also is more
easily removed following examination."
November 12,
1945, Lafayette Pharmacal, Inc. sent a cover letter to Dr. Merrick
of FDA requesting to amended (sic) the batch specifications for
Pantopaque in their NDA 5-319.
Top
In the original
provisional specifications for Pantopaque and ethyl iodophenylundecylate,
the manufacturing control of the quality of the product had been
verified by measurement of physical constants, chemical analyses,
and an intrathecal biological assay using injection of dogs.
All these controls
for manufacturing had been at the recommendations given to Lafayette
Pharmacal from Dr. William H. Strain and his associates in Radiology,
School of Medicine and Dentistry, University of Rochester, Rochester,
New York, who had been responsible for the development and production
of the product. Lafayette’s letter to the NDA contained the
following new information:
"We have
been advised by Dr. Strain that in his opinion, the intrathecal
assay in dogs is meaningless "procedure" and does not
give critical information for the control of the quality of the
product..
Accordingly,
in submitting the amended specifications, the intrathecal assay
has been eliminated, and, to compensate for this, the range of
each physical and chemical constant has been narrowed. We understand
from Dr. Strain that the proposed changes have been discussed
with Dr. Walton Van Winkle, Jr., of your staff......"
April-October
1946 Report on Radiopaque Compounds by Dr. Strain, under his discussion
of Pantopaque, Dr. Strain indicated that "they" were
still working through Lafayette Pharmacal, with some progress
made in promotion of clinical indications for Pantopaque beyond
myelography.
A number of clinical
investigators had been supplied with Pantopaque by Lafayette Pharmacal
to conduct their own clinical investigations of indications other
than myelography. For example, studies were underway at the University
of Pennsylvania for injecting Pantopaque into facial sinuses for
radiological visualization, as well as utero-tubography, and nerve
delineation. Pantopaque was also being investigated for uterotubography
imaging at University of California Hospital, and Michael Reese
Hospital in Chicago.
Top
Dr. Strain also
wrote regarding the new formulation, "Emulsion" of Ethyl
Iodophenylundecylate":
"Through
correspondence with a number of surgeons and radiologists it was
possible to arouse interest in the emulsion of ethyl iodophenylundecylate
in some six centers.
The logical application
of the medium appears to be bronchoscopy, and, because of this,
the program for the study of the emulsion overlaps that for the
study of new fields for Pantopaque. With either there is a problem
of developing new techniques for the (23) visualization of the
bronchial passages, and currently conditions are not too favorable
for such studies; most of the centers of thoracic surgery are
in a state of flux as a result of the return of veterans.....
The most progressive
results have been obtained at the University of Cincinnati School
of Medicine where Dr. Francis McGrath has had very satisfactory
results in the visualization of empyema cavities, and some progress
in applying the medium to bronchoscopy. As a result of correspondence
and discussion with Dr. McGrath the technique of the bronchogram
in dogs has been revised carefully, and a procedure using a 90%
emulsion worked out. The results obtained with the more concentrated
and more viscous medium are uniformly good.
Top
Applications
of the emulsion other than to problems of thoracic surgery have
not been as favorable.
In uretero-tubography
there seems to be a high incidence of transient low-grade discomfort,
and in the visualization of the renal bladder there does not seem
to be much interest."
During the early
part of June (that year), Dr. Strain had a visit to the Montreal
Neurological Institute to discuss a number of "problems"
that had occurred relating to their utilization of Pantopaque.
Later in June, he made a trip to E.R. Squibb & Sons to discuss
the possibility of transferring the Radiopaque Project to their
Institute of Medical Research.
From abroad,
Dr. Strain had learned that Pantopaque was being manufactured
in England by Glaxo and sold under the name "Myodil".
As a counter measure to this, a Swedish physician delegation studying
medical education in the U.S. had been furnished by him with a
moderate supply of US produced Pantopaque to distribute when back
in Sweden.
December 21,
1950, an untitled memo(?) was issued by Kodak’s Color Control
Department regarding control of the manufacturing of Pantopaque
(000190):
"Because
of complaints on certain lots of pantopaque, it was decided that
a more thorough investigation of the compound should be made,
aided by the infared spectrophotometer, to see if the cause of
the trouble can be found.
The "trouble"
with the pantopaque was identified to be the presence of 5% odophenylundecanoic
acid rather than 0.9%. A method was then developed using titration
with alcoholic potassium hydroxide to determine the percent of
iodophenylundecanoic acid."
In terms of the
active "off-label" conductance of clinical research
for a new emulsion formulation by Lafayette Pharmacal, March 20,
1950 G.C. Mees, Vice President, Distillation Products Industries,
a Kodak Company, wrote to W.S. Bucke, President, Lafayette Pharmacal,
the following regarding their business relationship:
"We are
writing to confirm the understanding reached at our recent meeting
with respect to an arrangement for conducting further work in
the preparation and testing of emulsions of Ethyl Iodophenylundecylate
in the drug and pharmaceutical field. (24)
Top
As you know,
some work along this line has been done under previous arrangements
with the University of Rochester and with E.R. Squibb and Sons
but these arrangements are no longer active. We are both desirous
that such work shall not be dropped but rather shall be continued
on the following basis.
We will supply
to you information available to us pertaining to this problem
and which shall have been supplied to us by the University of
Rochester and E.R. Squibb and Sons under the previous arrangements
hereinabove mentioned.
We will furnish
to you, on a no-charge basis, such amounts (not to exceed a total
of 25 kilon(sic)) of Ethyl Iodophenylundecylate as you shall require
for carrying on the work contemplated by this letter.
You will prepare
emulsions of such Ethyl Iodophenylundecylate in any way you may
see fit and supply such emulsions to one of your experts, qualified
by scientific training and experience, to investigate their safety
as drugs, and you will arrange with such experts to conduct clinical
work necessary to establish whether or not such emulsions are
suitable for use, and useful, as drugs, all in accordance with
the pertinent provisions of the Federal Food, Drug, and Cosmetic
Act and regulations promulgated thereunder.
In the event
such work shows satisfactory results, you will prepare a "New
Drug Application", or other appropriate application, for
submission to the Federal Food and Drug Administration in accordance
with the New Drug provisions of the Federal Food, Drug, and Cosmetic
Act and seek, by proper means, to secure the approval of such
application.
We are advised
by you that a "New Drug Application" has been submitted
with reference to Ethyl Iodophenylundecylate as such, and that
this New Drug Application has become effective, but that another
"New Drug Application", or perhaps an amendment to the
earlier application, may be required in connection with the emulsions
of Ethyl Iodophenylundecylate which you will prepare.
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You accordingly
agree that such emulsions will not be introduced or delivered
for introduction into commerce by you except in accordance with
the pertinent provisions of the Federal, Food, Drug and Cosmetic
Act relating to new drugs, to wit, Section 505 and the regulation
promulgated thereunder.
It is further
understood and agreed that our company assumes no responsibility
whatsoever with respect to this arrangement except to supply you
with the above indicated amounts of Ethyl Iodophenylundecylate.
You agree that
the "Ethyl Iodophenylundecylate" will be referred to
and described only by that name and that no trade-mark of our
company will be used in any way in connection with your activities
under the arrangement, except with the express (25) written consent
of our company.”
(It
has occurred to this reader that this letter assures Kodak of
a "baled out" excuse, i.e. we did warn them that they
had to insure their product did not injure people. It also occurs
to me that if Kodak felt that they were at risk in the US, they
would certainly insure that their legal responsibilities in the
UK were similarly covered. So where is the letter to Glaxo?)
This letter serves
to document that the University of Rochester, School of Medicine
and Dentistry and Dr. Strain were no longer actively involved
with the manufacturing, investigation and promotion of Pantopaque
in the U.S..
Significantly,
the change in testing site was a potential significant "alteration"
in the batch release criteria that had been specified within the
NDA for manufacturing product control and quality oversight.
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Such a change
could potentially have been viewed by FDA, if they were not informed,
as having a potential impact on the "safety" of the
product sold by Lafayette Pharmacal, Inc. and approved for marketing
under NDA#5-319.
Also, Lafayette
Pharmacal and Kodak’s Distillation Products Industries (DPI)
demonstrated in the letter that they had an awareness of need
to appear to meet the requirements of the FDCA for conducting
clinical research as well as the need to obtain clearance from
FDA for the legal marketing of the Ethyl Iodophenylundecylate
emulsion formulation.
In the 1950 letter,
Mr. Mees of Kodak’s Distillation Products Industries attempted
to assign all responsibility for compliance, manufacturing and
fulfillment of FDCA’s requirements onto Lafayette Pharmacal.
The intent of Kodak’s letter appeared to create "legal
distance"for Kodak and Kodak’s Distillation Products
Industries from any potentially illegal ramifications for actions
that may result from Lafayette’s distribution of the emulsion
formulation within the U.S. However, Mr. Mees also indicated that
his firm wished to take steps to facilitate future marketing,
investigation and development of the product.
1953 Lafayette
Pharmacal Inc.’s Pantopaque labeling as it appeared in The
American Journal of Roentgenology, Radium Therapy and Nuclear
Medicine, December 3, 1953, indicated a usual Pantopaque myelographic
study employed injection of 6 or 9 cc of contrast media.
(The 1944 draft
labeling and all information provided to FDA in the NDA for Pantopaque
recommended a myelography dose of "2-5" cc. ).
Lafayette Pharmacal’s
labeling continued to make no reference to potential serious acute
or longterm consequences associated with intrathecal injection
of Pantopaque which had been the expressed concern of FDA’s
reviewer, Dr. Van Winkle, for injection of a dose of 2-5 cc, nor
did the labeling appear to emphasize the need to remove all the
material following imaging.
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The labeling
emphasized injecting a larger dose of Pantopaque for imaging of
the spinal column than had been provided to FDA in NDA 5-319 (i.e.
2-5 cc) with the availability of "multiple size" ampules.
The labeling stated:
"The contrast
medium of choice now available in 3 sizes. (3 cc, 6cc, 12cc)."
Note: In terms
of the favorable reported clinical experience in the military
imaging populations, Major Spurling’s study that appeared
in Surgery October 1944 had indicated an injected Pantopaque dose
of 3.5 cc; Major Murphy reported positive results with an injected
dose of 1 to 3 cc of Pantopaque. (26)
The labeling
also had the following information regarding product utility:
"Dynamic
Myelography
These two radiographs
of the same patient demonstrate the bulging of the annulus fibrosous
during hyperextension and flexion, respectively, of the vertebral
column. 30 cc of Pantopaque contrast medium was used. Note how
this technique permits visualization of the posterior surface
of the vertebral canal.
"PANTOPAQUE"
is the registered trademark under which all leading x-ray dealers
supply the compound ethyl iodophenylundecylate, which is synthesized
by the Research Laboratories of Eastman Kodak Company and prepared
as the myelographic contrast medium Iophendylate Injection, U.S.P.,
by Lafayette Pharmacal Inc. The trademark serves to indicate to
the radiologist continuity of experience in the manufacture of
this medium. (A-0000352)."
(So
the amount to be used increases, what had started out as a 2-5cc
dose now leaps to 30cc and the company is providing it in ampules
much larger than before. The temptation to use a whole ampoule
is hardly resistable, especially given the positive results described
above " MF)
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