A
New Phase of "Pantopaque" Development
Pantopaque
II or IND1-161 and NDA16-377
Strengthening
of the drug provisions of the 1938 Act had been the focus of Senate
hearings held in June 1960. These hearings chaired by Senator
Estes Kefauver of the Subcommittee on Antitrust and Monopoly of
the Committee on the Judiciary, resulted in S.3815.
This bill was
aimed to protect the public health by instituting certain manufacturing
practices, expanding antibiotic certification to all antibiotics,
and by other measures.
During the Kefauver
hearings, FDA had received an NDA for marketing of Kevadon, the
brand of thalidomide that the William Merrell Company wanted to
market in the U.S.
Despite ongoing
pressure by the firm, medical officer Frances Kelsey refused to
allow the NDA to become effective because of insufficient safety
data.
By 1962 thalidomide’s
horrifying effects on newborns had become known.
Even though Kevadon
was not approved for marketing, Merrell had been able to distribute
over two million tablets for "investigational use",
a use which the FDA’s regulations and laws had left unchecked.
For her efforts,
Dr. Kelsey received the President’s Distinguished Federal
Civilian Service Award in 1962, the highest civilian honor available
to a government employee. As a result of the narrowly avoided
tragedy, Senator Kefauver re-introduced his bill.
On October 10,
President Kennedy signed the Drug Amendments of 1962, also known
as the Kefauver-Harris Amendments. These amendments required drug
manufacturers to prove to the FDA that their products were both
safe and effective prior to marketing. They also gave FDA control
over prescription drug advertising.
The Drug Amendments
addressed the use of drugs in clinical trials, including requirement
for informed consent by subjects and obtaining an Investigational
New Drug (IND) exemption from FDA. FDA was now required to be
provided with full details (27) of drug clinical investigations,
including drug distribution, and IND clinical studies had to be
based on previous animal investigations that could assure "safety".
The FDA’s
National Center For Drug Analysis (NCDA) opened in St Louis, Missouri,
in July 1967 began to conduct large scale tests of drug products.
Prior to this, NCDA had been part of the Division of Pharmaceutical
Sciences in FDA’s Bureau of Science.
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In its first
year, the NCDA examined over 7,000 samples. Therefore, FDA, since
the approval of NDA5-319, had begun to develop the Agency’s
evaluation capabilities for examining of the quality of drug products
that were to be manufactured and sold in the US.
November 20,
1964 there was an interagency memo from Mr. Hagan, Division of
Toxicological Evaluation (DTE) to Medical Officer Dr. Frances
O Kelsy, Division of New Drugs (DND) regarding Lafayette Pharmacal
Inc.’s IND 1-161 (Investigational New Drug exemption) to
legally begin to conduct human clinical trials for support of
safety and efficacy for Pantopaque II to obtain the Agency’s
approval for marketing of a 15% (iodine content) Pantopaque (Pantopaque
II).
There was an
Agency memo that suggested Lafayette Pharmacal had begun interacting
with FDA prior to November 1964 to obtain future approval of "Pantopaque
II". The changes in the FDCA had greatly modified the route
for Pantopaque II to reach the U.S. market when compared to the
World War II 1944-era "Pantopaque I" approval based
only on "safety" and culled reports of positive physician
experience with military patients.
Mr. Hagan of
FDA’s DTE characterized that each 20 ml of Pantopaque II
product submitted to FDA for the IND contained "10 ml Iophendylate
and 10 ml Ethylphenylundecanoate", as an absorbable iodinized
fatty acid compound of low viscosity intended for myelography.
Lafayette Pharmacal
was now requesting to substitute a material yielding a "15%
iodine" content for the current "30% iodine" content
(of) Pantopaque I material. FDA’s reviewers were referred
by Lafayette Pharmacal back to the original NDA to review animal
toxicity data submitted for the Agency’s approval of "safety"
of Pantopaque in NDA 5-319.
Mr Hagan as part
of the Agency’s toxicological evaluation reviewed the animal
toxicity data for Pantopaque submitted in Lafayette Pharmacal’s
NDA 5-319.
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He wrote of his
major concerns regarding the production of " fever"
induced by injection during animal studies and how the fever appeared
to be related to the pyrogenicity of the product.
(From a document
in my possession this was Van Winkle’s concern too. MF)
He was also under
the impression from sources outside Lafayette Pharmacal that the
iophenydylate(30%) intrathecal dosage for myelography was 6-12
cc. Mr Hagan determined that Pantopaque 30% had produced a significant
fever rise during the NDA’s when injected into humans during
the original clinical studies.
To better characterize
the deficiencies in Pantopaque’s animal toxicity data in
the NDA#5-319 and what would now be required in the NDA, he wrote:
"Despite
the 20-years history of use of this drug, we should have acute
toxicity data in perhaps dogs or rabbits in which the 15% material
is administered by intrathecal administration. Effort should be
made to relate the use levels to that causing death in toxicity
studies.
Directions contraindicate
repeat of dosage within 10 days. We suggest a repeat of 3 times
a therapeutic intrathecal dose in animals after a 10-day 28 interval.
If effects result then a repeat of the foregoing procedure should
be made at a lower dosage."
January 26, 1966,
attorney Bradshaw Mintener wrote Mr. J. Hauser, FDA, Bureau of
Medicine, regarding IND#1-161 submitted by his client Lafayette
Pharmacal. He indicated that Lafayette Pharmacal had previously
filed IND#1-161 on June 6, 1963 to market Pantopaque with 15%
iodine.
He referenced
the NDA that had approved Pantopaque (30%) in 1944, the comparison
of the new Pantopaque product, and the firm’s desire to now
withdraw IND1-161 and submit the marketing application as a supplement
to NDA5-319:
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"In the
course of years, because of the trend toward using greater volumes
of Pantopaque, and because (of) the great density, even within
the usual amounts of Pantopaque, 30% may obscure the more subtle
shades of the spectrum of density which one uses to detect the
presence of compressive lesions involving the subarachnoid space.
Many neurosurgeons
and radiologists have requested a less dense material. Accordingly,
the iodination of ethyl phenyl undecanoate was decreased to give
a 15% iodinated Pantopaque. This gives a corresponding decrease
in specific gravity to 1.09, as compared to 1.25 for the standard
30%.
An IND application-#1161
and dated June 6, 1963 was filed with the Food and Drug Administration
covering the 15% product and supplemental information was subsequently
submitted to the Department, as well as reports of clinical studies.
In view of the
fact that the 15% product is the same as the 30%, save for the
iodinization producing a product with less iodine content, Lafayette
Pharmacal would like to submit this supplemental application to
their NDA 5319 and recall their IND application 1161, if this
is necessary"
Pantopaque is
distributed by seven major x-ray companies as well as Lafayette
Pharmacal Inc. and enclosed you will find labeling for all distributors.
The study performed at the Neurological Institute was exhibited
in the scientific section of the American Neurological Association
Meeting, held June 14-16, 1965 in Atlantic City."
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March 17, 1966
Mr. W, S, Bucke, President of Lafayette Pharmacal, Inc. wrote
to Dr. Frances O. Kelsey, Chief of Investigational Drug Branch,
Division of New Drugs regarding the status of IND 1161:
"Thank you
very much for the courtisies extended during my recent visit to
your office and this will confirm our discussion relative to your
letter of February 17, 1966. (29)
The error in
the IND number occurred in the office of Mr. Bradshaw Mintener
in his letter of January 26, 1966 addressed to Mr. Julius Hauser.
Referring to
paragraph #3 of your letter of February 17, 1966, we do not wish
to discontinue our study under Exemption (IND 1161), our reason
being that on the suggestion of Mr. Julius Hauser, Bureau of Medicine,
we have filed a supplemental application. This was filed by us
by Mr. Bradshaw Mintener and we are awaiting your opinion on this
supplemental application.”
FDA did not accept
the proposal of Lafayette to submit Pantopaque II as a supplement
to NDA 5-319 and withdraw IND 1161 for obtaining clinical data
for inclusion in a new NDA. Dr. Kelsey and her staff had determined
that FDA’s marketing approval of Pantopaque II was to require
the submission of a separate new NDA to FDA by Lafayette Pharmacal.
FDA’s reviewer
Elton Herman, MD prepared a 4/29/1966 (29 April 1966) summary
of NDA 16-377 sponsored by Lafayette Pharmacal, Inc. regarding
the approval of Pantopaque II (Iophendylate Injection).
"The current
intrathecal dose recommendation listed was still the 2-5 cc dose
injected into the subarachnoid space of NDA5-319. The general
category of the drug was intended as a diagnostic agent for myelography,
indicated to be particularly satisfactory for study of the lumbar
region. The structural formula was of a mixture of isomeric ethyl
esters.
Pharmacology
information included a report dated January 19, 1962 of a study
conducted at Hazleton Laboratories regarding acute intraperitoneal
injection in 8 rats and acute intramuscular irritation study in
2 rabbits."
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He concluded:
"DTE review
of 11/20/64 (20 November 1964) requested "acute toxicity
data in perhaps dogs or rabbits in which the 15% material is administered
by intrathecal administration," as well as repeat dosage
after 10 days using 3 x the therapeutic dosage; apparently none
of these were ever performed and no further explanation is provided."
One of the investigators,
reported under clinical studies, performed preliminary dog work
with one control dog given 30% Pantopaque intrathecally and two
given 15%; amount given is not stated but it was apparently sufficient
to perform an adequate myelogram.
Baseline CSF
studies were done and repeated after 6 weeks (Pantopaque was left
in the subarachnoid space during this period), and the dogs were
sacrificed and autopsied. Examination of one of the 15% dogs could
not be performed as there was "an interval between sacrifice
and post-mortem in which major autolysis took place."
Both 15% dogs,
on the 6-week post-myelographic CSF test, showed " modest
protein elevation" and "slight inflammatory response
with increase in WBC, similar to the response of the original
dog work" utilizing 30%.
Histology report
on the 30% dog is reported as "O.K. No histologic abnormality"
and on the 15% dog as "Histology normal." It is stated
that evaluations were "comparable; if anything, the 15% Pantopaque
dog showed less inflammatory response in the form of lymphocytic
and polymorphonuclear cell infiltration." As the original
30% product is commercially available and the new preparation
is less concentrated than it, "it was felt that no further
laboratory work need be done." (30)
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Clinical studies:
No case reports
are included from any investigator in either the NDA or IND. IND
1161 filed for this product contains statements of investigation
and brief protocols for study from 5 investigators or groups,
all of whom appear to have good credentials; for 3 of these, there
is no follow-up, report, summary, or result of any type given.
Of a fourth investigator, it was later said in a letter from the
firm that he, "Due to pressing duties,....did not enter into
any investigational work."
The fifth group
of investigators, Drs. E. Ralph Heinz, Ray A. Brinker, and Juan
M. Taveras, from the Neurological Institute, New York (the same
group which performed the above-described pharmacologic 3-dog
study), have also not submitted any case reports but they have
sent in a brief summary of 117 patients studies between 1 August
1963 and 31 May 1964; of these, approximately half received 15%
or 22.5% ( equal volumes of 15% and 30%) Pantopaque and were compared
to the remainder in whom only 30% was used.
The first 20
patients were "checked clinically for signs of meningeal
irritation, fever, or other untoward effect following instillation
of the lesser concentration, and no abnormality was found. Subsequently,
additional patients have been added without any detectable objective
or subjective abnormality...."
The authors conclude
that they "have been better able to visualize the spinal
cord utilizing the less concentrated contrast, as well as visualize
small differences in density when external compression of the
subarachnoid space is present."
The authors feel
that this less concentrated Pantopaque offers definite advantages
over the conventional 30% Pantopaque. However, they offer no objective
confirmation of these claims, no individual case reports, and
no criteria by which they measure "better" visualization
or "small differences" in density.
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Labeling:
Discussion seems
completely superfluous at this point, except to state that, save
for omission of a section describing "Technique for Large
Volume Dynamic Myelography" and the obvious changes in the
portion dealing with chemical and physical characteristics so
as to describe the 15% preparation, the labeling exactly reproduces
that last approved in 1960 for 30% Pantopaque.
Conclusions:
The application
is incomplete under section 505(b)(1), in regard to clinical studies,
because of failure to report in full investigations that have
been made to show whether or not the drug is safe for use and
effective in use, failure to include adequate case reports concerning
each subject given the drug or employed as a control, and failure
to include substantial evidence consisting of adequate and well-controlled
investigations. Final comment on labeling will be reserved until
the application is complete in its other respects." (31)
At the bottom
of the reviewer’s report there is also a handwritten note
from A. Ruskin dated 4 May 1966:
"Should
pharmacologic work be complete before any further human tests?
Is there an IND?"
Reviewer E. Herman
wrote a reply dated 5 May:
"There is
an IND with reports as stated above."
There was then
an FDA Intra-Administrative Referral issued 5 May 1966 to Investigational
Drug Branch (IDB), Division of Toxicological Evaluation (DTE)
from E. Herman, MD of the Medical Evaluation Branch:
"This NDA
will be incomplete by letters that should issue within several
weeks. In accordance with question raised by Dr. Ruskin, do you
feel pharmacologic work should be completed before any further
human tests?"
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DTE’s response:
"DTE review
of 20 November 1964 did request "acute toxicity data in perhaps
dogs or rabbits," but apparently never performed."
A.R. Casola,
Ph.D., FDA’s Manufacturing Control Branch (MCB) authored
a June 15 1966 draft of controls portion of letter intended for
Lafayette Pharmacal regarding NDA 16-377. The reviewer determined
that the application was "incomplete". The NDA failed,
among many other things, to provide adequate information regarding
the qualifications, educational background and experience of the
technical and professional personnel responsible for assuring
that the drug had the safety, quality and purity it purported.
The applicant
was also requested to submit information regarding the facilities
and personnel for Taylor Pharmacal Co., Distillation Products
Industries and for Analytical Chemists.
The applicant
had not submitted to FDA the required samples for agency evaluation
and had not submitted the draft labeling required for all distributors.
October 3, 1966,
FDA’s reviewer James E.Wilson, Ph.D., wrote the agency’s
pharmacological review that also found the NDA incomplete pharmacologically.
The new drug name was Pantopaque II and the recommended injection
dose for myelography was "2-5 cc". The following was
his evaluation of the NDA:
"Pantopaque
II is a 1:1 (v/v) mixture of iophenylate (Pantopaque) and ethyl
phenylundecanote. Iophendylate has been on the market for twenty
years but deaths have been attributed to its use.
Recently, Swartz
(New England J. Med. 272, 898- 902, 1965) cites a case report
of a 61 year old woman who died of obliterative arachnoiditis
with hydrocephalus one year after cervical myelography using iophenylate.
Whether the response was a direct result of chemical irritation
or a form of hypersensitivity could not be ascertained (32).
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In its review
(20 November 1964) of IND 1161, Pantopaque 15%, DTE recommended
that acute toxicity tests be performed in either the rabbit or
dog using single administration of iophendylate or the 1:1 mixture
have been performed by workers at the Neurological Institute (New
York). (sic) These investigators examined the cerebrospinal fluid
and histologic sections of the cerebrospinal axis.
"The test
however, needs repeating since the dosage level (approximated
at 0.1 ml. or gm/kg) was within the human therapeutic range (2-5
ml)(*bold added for emphasis) and did not approach toxicity or
lethality. Further, the number of animals used (only 2 autopsies)
was too small for a valid evaluation. Some attention should be
devoted by the applicant to the development of a hypersensitivity
towards the drug. A suggested test is the intrathecal administration
of the drug to dogs with a subsequent challenge 2-3 weeks later.
The application
is considered incomplete."
October 21, 1964,
from a memo to the NDA record by W. Gyarfas, MD.
"Mr. Mintener,
without an appointment, visited the FDA offices to inquire about
the status of NDA 16-377 and to resubmit information from the
Neurological Toxicity Studies (*information that had been previously
submitted by Lafayette within both the IND and the NDA). He also
inquired of Dr. Gyarfas what would be required for Lafayette to
answer the agency’s letter of October 11, 1966 that had again
requested the submission of an over-due progress report of the
status of the clinical studies.
The inadequacies
of the NDA were reviewed with Mr. Mintener, who seemed unprepared
to discuss the issues, and Mr. Mintener kept making references
to "Julius" and "old timers". Mr. Mintener
indicated that he would inform his client Lafayette Pharmacal
how to bring their IND up-to-date and recommend that they complete
their NDA."
May 4, 1967,
Dr. Gyarfas again recorded that he was visited, but this time
by Mr. Bucke of Lafayette, who also visited the FDA offices without
an appointment to ask questions regarding the application. Mr
Bucke inquired about the ability to use foreign clinical investigators.
He was informed that foreign investigators would also be required
to sign FD Form 1573 and that their data would also be carefully
evaluated by FDA.
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