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.

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.

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."

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."

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)

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.

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?"

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).

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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