Animal
Safety Studies for Pantopaque I and II
September 7,
1967, Hazelton Laboratories completed an "Acute Intrathecal
Toxicity Study" Rabbits! involving 16 rabbits using Pantopaque
II that were followed for 14 days. The study data was submitted
to Lafayette Pharmacal, Inc. The summary of the study went as
followed:
"Pantopaque
II was evaluated for acute intrathecal toxicity by intraspinal
injection to 33 groups of adult albino rabbits (* 4 groups of
4 rabbits each) at graded dosage levels ranging from 0.562 to
316 g/kg of body weight. Partial mortality at the two lower levels
and total mortality at the two higher levels were produced. The
mortality pattern did not permit an accurate calculation of the
acute intrathecal LD50, but it is estimated to be in the order
of 0.5 g/kg of body weight.
Principal Toxic
Effects Observations noted during the 14-day period consisted
of the following:
· Slight
ataxia at the four-hour observation period only in all animals
at the lowest level and in two animals at the 1.0 g/kg level,
· rapid
respiration prior to death in one animal at the 1.78 g/kg level,
· limited
use of the hindquarters in two animals, and
· terminal
body weight loss in all animals at the lowest level;
· partial
mortality at the two lower levels and
· total
mortality at the two higher levels.
November 13,
1967 Hazelton Laboratories submitted "Acute Intrathecal Toxicity-
Dogs Pantopaque II"to Lafayette Pharmacal, Inc. The investigation
had been conducted from July 27, 1967 through September 6, 1967.
The summary of the data was as follows:
Single intraspinal
doses of the test material, Pantopaque II, were administered to
four groups of two dogs each, at levels of 0.316, 0.562, 1.00,
and 1.78 g/kg, respectively. The dogs were observed for 14 to
20 days after dosing and then sacrificed.
All dogs showed
signs of muscular weakness and incoordination following dose administration,
with particular loss of motor control of the hindlimbs. The degree
of this motor incoordination did not appear to be related to the
dose level.
All animals slowly
returned to normal or near normal appearance during the observation
period except one low level animal which died after two days,
apparently from an injury sustained during injection of the compound.
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Gross necropsies
after sacrifice revealed the presence of oily substance resembling
the test material in the cerebro-spinal fluid of all but two animals.
Connective tissue lesions in the area of the injection were present
in about half the animals.
The dog that
died had received the lowest Pantopaque II dose, Group No. 1,
(0.316 g/kg) and had appeared normal on the day of dosing. (*Two
dogs were used in each of the 4 dose groups.) On day 2, its behavior
became vicious and it was found dead on day 3. The other animal
in the low dose group appeared normal for several days following
dosing. However, on the day 4, the animal appeared uncoordinated
and became partially paralyzed in the hindlimbs. The dog’s
condition returned to normal by day 8, but it continued to lose
weight throughout the study until termination.
For the two dogs
in the next dose group, Group No. 2, (0.562 g/kg), both became
markedly uncoordinated with partial paralysis in the hindlimbs.
Their conditions gradually improved until sacrifice. (34)
Group No. 3 dogs
(1.00g/kg) both exhibited signs of muscular weakness and poor
coordination following dosing. Partial paralysis of the hindlimbs
was apparent in both and improved in one animal.
A similar picture
occurred in the highest dose group, Group No. 4, (1.78 g/kg),
with initial muscular weakness, lack of coordination and slow
improvement until time of sacrifice.
Histologically,
all animals in Groups No. 2 and 3 had connective tissue lesions
of varying severity found at the location of injection. The dog
in Group No. 1, the lowest dose group, that died had hemorrhagic
and purulent-appearing areas at the base of the medulla and between
the meninges and the spinal cord. The spleen of this animal was
enlarged to twice normal size. For all dogs, at autopsy, traces
of oily substance, varying in amount approximately proportional
to the administered dose level, were found within the cerebrospinal
fluid.”
Almost two years
later, February 7, 1969, Hazelton Laboratories completed the study,
"15-Week Intrathecal Toxicity Study- Dogs" which was
a comparison of Pantopaque I and Pantopaque II.
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The data was
submitted to Kodak’s Distillation Products Industries, Rochester,
NY, not to Lafayette Pharmacal, Inc as had been done with the
earlier studies. (Why?)
The purpose of
the study was to evaluate the long-term effects of Pantopaque
II when compared to Pantopaque I after being left within the spinal
column of dogs. (The) Pantopaque I (used) was a lot that had been
received by Hazelton Laboratories from Lafayette Pharmacal on
November 27, 1967, Lot No. 129666, and (it) appears that it may
have been a production lot. The purity was "assumed"
to be 100%.
Pantopaque II
was identified as ethyl phenylundecyclate combined with 15% organically
bound iodine (Lots No 91347 and No. 91374), and appears that it
was an experimental product. It was received July 24, 1967 and
November 27, 1967 from Lafayette Pharmacal. The purity also was
"assumed" to be 100%.
The study used
24 purebred Walker hounds, divided into 2 dosage groups (0.014
ml/kg) or (0.14 ml/kg) of either Pantopaque I or II compounds,
for a total of 4 groups. The test material was administered by
a single injection into the cisterna magna, with all dogs observed
for 15 weeks. Full spine lateral x-rays were made for each dog
following injection and at regular intervals of 30 and 60 minutes,
3, 24, and 48 hours, and one to two weeks thereafter. Only the
brain and spinal cord were examined microscopically.
Five animals
that received Pantopaque II at 0.14 ml/kg showed a marked increase
in leukocyte counts at 24 hours. Five dogs had clotted blood present
at the base of the brain and anterior spinal cord - one Pantopaque
I and four Pantopaque II. Eight dogs had meninges visibly thickened,
three Pantopaque I and five Pantopaque II.
In two dogs,
both Pantopaque II dogs at 0.14 ml/kg, there were adhesions to
the floor of the vertebral column. In 6 dogs, oily material was
grossly seen in the meninges, three Pantopaque I and three Pantopaque
II. Two Pantopaque I dogs receiving 0.014 ml/kg (No. 12686) (No.
12705) (* the lowest dose) microscopically at autopsy had moderate
to severe granulomatous reaction surrounding large vacuoles in
the space under the meninges and surrounding some of the spinal
nerves. The granulomatous reaction involved spinal nerves.
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There was moderate
to severe fibrosis surrounding the spinal cord and scattered areas
of granulomatous reaction were present within the white matter
of the spinal cord. (35)
Most of the granulomatous
reaction was associated around large, clear empty (cystic) vacuoles.
The spinal cord was surrounded by moderate amounts of old blood
present under the meninges. A Pantopaque I dog that had received
the same dose (No.12694) had a similar microscopic picture of
granulomatous reaction and fibrosis with cystic spaces but had
a moderate amount of fresh hemorrhage under the meninges.
Pantopaque II
dogs receiving the lower dose level (0.014 ml/kg) appeared to
have gross acute bleeding at all levels of the spinal cord and
brain. Microscopically there was perivascular infiltration of
meningeal vessels and spinal cord involving macrophages and mononuclear
cells, and scattered clear cystic spaces.
Pantopaque II
dogs at the higher dose level (0.14 ml/kg) appeared to induce
a greater active inflammatory response component. The granulomatous
inflammatory reaction was moderate to severe infiltration of mononuclear
cells, macrophages, lymphocytes surrounding clear cyst-like areas,
moderate to severe adhesion of the arachnoid and dura mater to
the spinal cord.
Histologically,
sections of the spinal cords resembled areas of severe granulomatous
reaction seen with Pantopaque I. Severe granulomatous infiltration
extended down to the cauda equina, with moderate thickening of
the arachnoid, and areas of compression of the spinal cord.
The following
was the summary of Hazelton Laboratories, William M. Busey, DVM,
Ph.D.’s findings:
"The intrathecal
administration of Pantopaque I and Pantopaque II to mature Walker
hounds produced varying degrees of granulomatous meningitis in
the brain and spinal cord. In the majority of instances, in the
animals possessing meningitis, the inflammatory reaction appeared
to be associated with empty vacuoles which could possibly have
been the experimental compounds.
In addition to
the granulomatous type of cellular infiltration, there were varying
degrees of fibrosis and thickening of the meninges of the both
the spinal cord and brain. In the group receiving Pantopaque I,
at a dosage level of 0.014 ml/kg, subdural granulomatous inflammation
was present to a moderate to severe degree in three animals......
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Only a slight
to moderate amount of granulomatous inflammation was seen in three
of the animals receiving Pantopaque II at 0.014 ml/kg. A slight
amount of granulomatous inflammation was present in the cervical
and thoracic regions of the spinal cord in Animal No. 12700. There
was, however, in this animal, a moderate degree of meningitis
in the brain which was associated primarily with two vacuoles
in the region of the medulla oblongata.....
There did not
appear to be any difference in the incidence or severity of granulomatous
meningitis between the animals receiving Pantopaque I at 0.14
ml/kg and those receiving Pantopaque II at 0.14 ml/kg. Severe
granulomatous meningitis was seen in the cervical regions of all
of the animals in these two test groups.
In addition to
the inflammatory cellular infiltration, there was severe fibrosis
in this region of the dura mater and arachnoid......
The majority
of the animals receiving Pantopaque I and Pantopaque II at 0.14
ml/kg also possessed some degree of meningitis of the brain......
In conclusion,
it can be stated that the intrathecal administration of Pantopaque
I and Pantopaque II at 0.014 ml/kg and 0.14 ml/kg stimulates a
granulomatous meningitis (*bold and italics added for emphasis)
in the areas where the compounds appear to localize. The majority
of the inflammatory reactions present in the animals on this study
were of a subacute to chronic nature. There was a definite difference
in the location and severity of the inflammatory reaction between
the two dose levels. The dosage level of 0.014 ml/kg of Pantopaque
I stimulated a granulomatous reaction in primarily the lumbar
region; whereas, the dosage level of 0.14 ml/kg of both Pantopaque
I and Pantopaque II produced severe reaction in the cervical and
thoracic cords. Granulomatous inflammation was also present in
the lumbar cord but to a slightly less degree of severity and
incidence." (36)
February 10,
1969, Hazelton Laboratories submitted the final report of the
"Teratology Study with Rabbits and Pantopaque II" to
Distillation Products, Rochester, NY.
The purpose of
the study had been to evaluate the potential of Pantopaque II
to produce embryotoxic and/or teratogenic effects in a study population
of albino rabbits.
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Peanut oil was
administered as a control injection to Group No. 1, Pantopaque
I to Group No. 2, and Pantopaque II to Group No. 3 rabbits. Each
experimental group, which consisted of 40 rabbits, was divided
into four subgroups of 10 animals each.
The first subgroups
received a single dose of the appropriate injection two days prior
to insemination; the second subgroups received a single dose of
the appropriate injection on Day 5 of gestation; and the third
and fourth subgroups were injected on Day 8 and Day 11 of gestation,
respectively. The study was begun on June 25, 1968, with sacrifice
of the last groups of females completed on September 6, 1968.
The final results
indicated that there were no meaningful differences between the
peanut oil, Pantopaque I and Pantopaque II groups in the number
and placement of implantation sites and live fetuses, in the weights
and lengths of the fetuses, or in the incubation survival.
Females with
implantation sites unaccounted for were found in the peanut oil
and Pantopaque I groups. The number of resorption sites and incidence
of females with resorption sites were high in both the Pantopaque
I and II females. The mean value of dead fetuses in the Pantopaque
I group was high; however, one female only was found with dead
fetuses, and the value for this parameter was within normal limits.
No dead fetuses were found in the Pantopaque II group. No unusual
findings were noted in the external appearance or gross visceral
anatomy of any of the fetuses. The development and skeletal structure
of the Pantopaque I and Pantopaque II fetuses were comparable
to that the peanut oil (control) fetuses. Therefore, the response
for Pantopaque II was essentially the same as for Pantopaque I.
(37)
April 14, 1969,
FDA’s Associate Director for Marketed Drugs, Marvin Seife,
MD (later involved in the Generic Medicine Scandal of the 1980’s)
issued Lafayette Pharmacal, Inc. a letter regarding the status
of NDA 5-319.
"Our records
indicate that you have not submitted any annual reports as required
by the provisions of regulations 130.13 and section 505(j) of
the Federal Food, Drug and Cosmetic Act.
The failure to
maintain the required records and make the reports pursuant to
the authority under section 505(j) of the Act may result in withdrawal
of the approval of the new drug application, and is prohibited.
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In addition for
the sake of uniformity and the convenience of the physician, it
is recommended that the labeling of your product and those of
your distributors, be revised to contain sections in the following
order:
NAME OF THE DRUG
DESCRIPTION
ACTIONS
INDICATIONS
CONTRAINDICATIONS
WARNINGS
PRECAUTIONS
ADVERSE REACTIONS
DOSAGE AND ADMINISTRATION
OVERDOSAGE
HOW SUPPLIED
REFERENCES
Further we recommend
the following:
1. Delete the
statement "The small amount of material left in the subarachnoid
space is usually absorbed in two months."
2. In the INDICATIONS
section state the substance of the following: "Pantopaque
is indicated for the performance of myelography."
3. In the ADVERSE
REACTIONS section include the following:
a. Severe arachnoiditis
producing headache, fever, meningismus, pain in the back and extremities
and elevations in the white blood count and the protein count
of the cerebrospinal fluid.
b. The incidence
and severity of arachnoiditis are generally increased when active
subarachnoid bleeding has been induced by the lumbar 38 puncture.
c. Rare instances
of the development of lipoid granulomas, obstruction of the ventricular
system and venous intravasation producing pulmonary emboli.
4. In the CONTRAINDICATIONS
section include the substance of the following:
"The administration
of Pantopaque is contraindicated in patients with known hypersensitivity
to iodine or its compounds. Intrathecal administration should
be deferred if bleeding is encountered in the performance of the
lumbar puncture."
5. In the PRECAUTIONS
section, note that diagnostic tests of thyroid function involving
measurements of iodine may be invalidated for several years following
intrathecal injection of Pantopaque.
6. In the DOSAGE
AND ADMINISTRATION section the amount commonly use as 3 to 12
ml.
Please submit
the reports and let us know your proposal to the above recommendations
within ten days of the receipt of this letter."
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Lafayette Pharmacal’s
Withdrawal of NDA 16-377 for Approval of Pantopaque II
June 25, 1969
Lafayette Pharmacal’s President W. S. Bucke wrote to Dr.
Grigsby of FDA to request to withdraw NDA 16-377 for marketing
approval of Pantopaque II. The reason that was given to FDA for
withdrawal of the NDA was as followed:
"Based on
the summaries of the three principal investigators who studied
203 cases (91% of total), it is concluded that Pantopaque II containing
15% organically bound iodine has no real improvement over conventional
Pantopaque (Iophendylate Injection, U.S.P.) containing 30% iodine.
Supplies of Pantopaque
II sent to clinical investigators have been recalled and inventories
have been balanced with the amount shipped and returned. Case
reports from investigators have been summarized and are included
in Volume III. The information submitted with this letter has
been compiled according to the form described in regulation 130.4(e)
and represents the complete data on the subject. It is presented
as three volumes, in triplicate."
June 25, 1969,
Mr. Bucke also wrote to FDA to withdraw IND #1161 for Pantopaque
II. The letter indicated that the case reports of IND 1161 were
included in NDA 16-377, and were being submitted in lieu of the
annual progress reports. (39)
June 26, 1969,
Memorandum of a Telephone Conversation, was written by F. Grigsby,
MD of his discussion with Dr. Kunz of Lafayette Pharmacal, Inc.
Dr. Kunz had called Dr. Grigsby to inform FDA that Lafayette was
officially going to withdraw NDA 16-377 for marketing of Pantopaque
II (15%).
"Dr. Kunz
indicated that the firm’s reason for withdrawal of their
Pantopaque II marketing application was that the firm had found
that the 15 % Pantopaque was no more effective, and frequently
less effective, then the currently marketed 30% preparation."
Dr. Kunz was
informed by Dr. Grigsby that if no further clinical studies were
contemplated for the 15% Pantopaque II that IND 1161 should also
be discontinued by Lafayette’s submission of an amendment
to the IND with a reference to the clinical studies that have
or will be submitted to the NDA before its official withdrawal.
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The "Notice"
reference may serve in lieu of the annual progress report. In
addition the amendment to the IND should include information respective
to notification to all clinical investigators of their action
and to the disposition of the remaining drug.
From the memo,
and the letter to FDA to withdraw the IND and NDA for Pantopaque,
there appears to have been no mention by either Mr. Bucke or Dr.
Kunz of the adverse findings of the animal safety studies done
by Hazelton Laboratories relative to the equivalent poor safety
performance of both Pantopaque I, the approved product, and Pantopaque
II, the investigational product. Therefore, FDA was not informed
that the animal toxicity studies did not support the "safety"
of Pantopaque I.
June 27, 1969,
Memo of a Telephone Conversation of another conversation held
between Dr. Grigsby and Dr. Kunz, and after the writing of Lafayette’s
withdrawal letters by Mr. Bucke.
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"Dr. Kunz
stated that he had collected all data in their possession and
that their annual progress report is due within one or two months.
He referred to this new drug application as one pending with FDA
for approval but they have found the Pentopaque (sic) 30% produces
no better visualization than 15% and in fact in some instances
it is worse.
He stated that
he will be in the District of Columbia within the next few days
and will leave an amendment to the IND discontinuing clinical
studies. He was told that he may cross reference the information
on clinical studies reported in the NDA to serve as a progress
report for the IND. He was also advised to state the reasons for
discontinuing the study and to inform us as to the final disposition
of the drug and notification of all clinical investigators. He
thanked me for the information and terminated the conversation."
Technically,
the Hazelton Laboratories data had not sent the more damaging
conclusions of their animal studies obtained in 1969 directly
to Lafayette Pharmacal but rather had sent them to Kodak, Distillation
Products Industries Division, Rochester, NY.
Therefore, it
is "unclear" whether the most unfavorable Hazelton Laboratories
animal safety data for both Pantopaque I and II sent to Kodak
would have been in Dr. Kunz’s "physical possession"
at Lafayette Pharmacal when he spoke with Dr. Grigsby. (40)
It is also unclear
whether the performance animal data obtained with both "approved"
Pantopaque I and "investigational" Pantopaque II were
ever shared with FDA within the three volumes of submitted "clinical
data" for withdrawal of the NDA.
Dr. Grigsby documented
in his memo that he clearly was indicating to Dr. Kunz that the
firm was to be forthright and honest with the agency regarding
providing all known product information and all reasons for withdrawal
of the Pantopaque II marketing application.
It would have
been assumed that Lafayette management would have known to be
honest, forthright and complete with FDA in all information regarding
NDA 5-319 (*Pantopaque I), and, that it was a crime for any sponsor
to make fraudulent and/or misleading statements to FDA about a
product marketed in the US.
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