Uncertain about the safety of America's drug supply continued even after the passage of the Kefauver-Harris Amendments. As a result, Congress opened hearings in March 1964, chaired by Representative L.H. Fountain, to investigate FDA's efforts to promote drug safety. But Fountain's hearings took a comprehensive look at the agency's regulation of drugs, especially those that were removed from the market.

To further comply with the requirements of the drug amendments of 1962, FDA contracted in 1966 with the National Academy of Sciences/National Research Council (NAS-NRC) to study all drugs approved from 1938-1962 from the standpoint of efficacy. All drugs on the U.S. market would have been reviewed for both "safety"and "efficacy".

Following the passage of the amendment, there was a legal time delay in enforcement by the Agency while the courts determined whether demonstration of "marketing success" met the requirements of valid proof of product "efficacy" according to the FDA. The courts in 1970s ruled that marketing success alone did not constitute valid documentation of efficacy.

The review process begun by the FDA was called the Drug Efficacy Study Implementation(DESI). The Drug Amendments had required that the DESI be completed within two years and that all labeling recommendations be fully implemented by 1972. However, elements of the DESI process still continues in 2002. DESI evaluated over 3000 separate products and over 16,000 therapeutic claims. The last NAS/NRC report was submitted in 1969, but the contract extended through 1973 to cover ongoing issues. The initial agency review of the NAS/NRC reports by the task force was completed in November 1970.

One of the early effects of the DESI study was the development of the Abbreviated New Drug Application (ANDA). ANDAs were accepted for reviewed products that required changes in existing labeling to be in compliance. In September 1981 final regulatory action had been taken for 90% of all DESI products. By 1984, final action had been completed on 3,443 products; of these, 2,225 were found to be effective, 1051 were found not to be effective, and 167 are still pending. (41)

In May 1972, the DESI process was extended to cover over-the-counter (OTC) products. Lafayette Pharmacal's NDA 5-319 (Pantopaque I) was a drug product to come under review of the NAS-NRC DESI program as documented by Lafayette Pharmacal, Inc.s' receipt of the May 23, 1971 letter from FDA's Director of DESI Project Office, P. Bryan, M.D. The DESI letter echoes the earlier 1969 labeling requests from FDA.

During the 1970s, the FDA started two new forums to help increase drug communication to the public. The Bureau of Drugs launched the FDA Drug Bulletin in 1971. The National Drug Experience Reporting System also was begun in 1971. The NAS had been studying the problem of not only how to catalogue and store information about adverse drug reactions, drug abuse, and drug interactions, but also how that information could best made available to health professionals. The study concluded that since the FDA had already begun to collect the drug data, that they should take the lead on creating and maintaining the adverse event reporting system.

In July 1979, FDA also proposed a program to provide patients with additional information about prescription drugs, including a description of the drug's uses, risks, and side effects. Under the Agency's proposal, all drug manufacturers would print the information and the health provider would give the insert to the patient. But, by September 1980, under the weight of well-organized opposition to the program, the FDA was forced to drop the requirement for a patient insert.

Pantopaque clinical literature had been reviewed by the NAS-NRC Panel on Diagnostic Agents. The indication for the drug was for myelography, and DESI advisory panel concluded that it was "effective" for that labeled indication. The comments of the DESI review summarized the information found in the published literature:

"Pantopaque (ethyliodophenylundecylate with 30.5% iodine in oil) has been widely used and is accepted as the current agent of choice in myelography. Comparative studies are few, but one in cats showed Pantopaque to be superior. Several groups have increased the dose without untoward effects. Small volumes (2-3 cc) of Pantopaque have been used also for positive-contrast ventriculography."

In terms of the labeling review, the advisor panel reviewed Pantopaque labeling that had been submitted and "cleared" by FDA in the NDA for marketing of Pantopaque in the U.S., the general comments by the members of the advisory panel for labeling of Pantopaque were as follows:

"Additional side effects should be mentioned:

Infrequently, severe arachnoiditis has followed the intrathecal injection of Pantopaque, producing headache, fever, meningimus, severe back pains, pain in the lower extremities, and elevation of the white cell count and protein content of the cerebrospinal fluid. The incidence and severity of this arachnoiditis are greatly increased when active subarachnoid bleeding has been induced by the lumbar puncture. (42)

Rare instances of lipoid granuloma, obstruction of the ventricular system, and venous intravasation producing pulmonary embolization have followed the intraspinal injection of Pantopaque. Diagnostic tests of thyroid function involving the administration of radioactive iodine may be invalidated for many years, following the intrathecal injection of Pantopaque.

Additional contraindications should be mentioned:

The intrathecal administration of Pantopaque should be deferred if active subarachnoid bleeding is encountered in the performance of the lumbar puncture. The administration of Pantopaque is contraindicated in patients with known hypersensitivity to iodine or its compounds.

The following phrase in the package insert is incorrect:

"The small amount of material that is left is usually absorbed within two months."

In fact, the residual contrast medium in the subarachnoid space usually remains for many years. This incorrect statement should be deleted.

It should be specifically recommended that as much of the Pantopaque be removed from the subarachnoid space as possible, after the examination is completed. The amount of Pantopaque commonly used is 3-12 cc rather than that quoted in the brochure (3-5 cc).

The recommendation in the package insert for the examiner to become "darkadapted" before fluoroscopy is no longer applicable for many institutions where image intensification is used.

Pantopaque may be used in small volume (2-3 cc) for positive-contrast ventriculography when conventional air ventriculography is unsuccessful."

Marketing of Pantopaque (30%) following withdrawal of Pantopaque II's NDA

April 18, 1969 letter from Frank Gollon, Eastman Kodak Legal Dept, Trademark Section, to Mr. W.T. French, Patent Dept, Kodak Office:

"You have requested information concerning our marketing of ethyl iodophenylundecylate which is distributed by others as a contrast medium for radiography under the trademark PANTOPAQUE.

I am advised that this information is required in connection with an inquiry received by Eastman Kodak Company from the United States Department of Justice which has challenged certain restrictive provisions in a patent license agreement relating to radiopaque (United States v Sterling Drug, Inc. and E.R. Squibb & Sons, Inc.)(43)

I understand that ethyl iodophenylundecylate is purchased from us by Lafayette Pharmacal Inc. who packages(sic) it in dosage form or vials for use as a contrast medium for radiography.

Lafayette in turn sells the repackaged product to a number of distributors including:

· General Electric Company,

· Picker X-Ray Corporation,

· Standard X-Ray Company,

· E.M. Parker Company,

· Kelley-Koett Manufacturing Company.

In order that Lafayette may identify its product under our trademark PANTOPAQUE, we licensed that company in 1943 to use our mark upon the product sold by us to it under such trademark PANTOPAQUE. It is my understanding, however, that our sales of the chemical to Lafayette have been under the generic chemical name for many years now, probably dating from before 1957.

Since PANTOPAQUE would be distributed by such other companies as General Electric, Picker, Standard, etc. in packages carrying neither the Lafayette not the Eastman Kodak name, it was deemed advisable to protect our proprietary interest in the mark, to also license these other companies to use the mark.

Your copy of the Department of Justice letter of inquiry addressed to this company is returned herewith."

February 11, 1970, Eastman Kodak Company, finalized the development of a process for manufacturing Ethyl Iodophenylundecylate (Pantopaque) that found a substitute for benzene in the esterification process to eliminate the health hazard associated with use of benzene. The process was titled Manufacturing Controls for the Preparation of Pantopaque and began:

"There are no changes in the information previously submitted to the Food and Drug Administration, except that iodic acid was indicated as the iodinating agent.

Actually, iodine is the iodinating agent and iodic acid is an oxidizing agent for regenerating iodine from the hydrogen iodide that is liberated, thus permitting complete use of the iodine. It is noted that the instructions for items 6,7 and 8 of the current New Drug Application Form (F.D. 356 H) apparently contemplate considerably more detailed information than that which was originally required. .....

The manufacture and chemical purification of ethyl iodophenylundecylate is carried out in the Synthetic Chemicals Division located in the Kodak Park Division of Eastman Kodak Company in Rochester, NY. The manufacturing operations are carried out by trained, experienced chemical operators , chemical technicians and professional chemists employed by the Synthetic Chemicals Division.

Quality Control operations are carried out by analytical technicians and professional chemists assigned to three Kodak Park areas:

· Synthetic Chemicals Division,

· Industrial Laboratory, and

· Kodak Research Laboratories."

W.S. Bucke , Lafayette Pharmacal, Inc. wrote Mr. J. Robinson, Legal Department, Eastman 44 Kodak Company on February 18, 1971 the following:

"Pursuant to our conversation, I wish to advise that your company Kodak, Distillation Products Industries Division is responsible for meeting the U.S.P. requirements for Iophendylate Injection."

A proof of an advertisement for George Banta Company, Inc. intended for the "Journal of Neurosurgery", August 1969 for marketing of Pantopaque. The advertisement discussed the use of Pantopaque contrast medium for the visualization of a large neurofibroma (*tumor) at the level of the third cervical vertebra (as follows):

"Side Effects:

Clinical reports indicate that the incidence and the severity of the side effects following Pantopaque myelography with aspiration of the medium is but slightly greater than with ordinary lumbar punctures.

In 10-30 percent of such cases there may be transient symptomatic reactions consisting of slight temporary elevation and increase of symptoms referrable to a back condition. When the medium is not removed, similar transient side effects occur with a slight elevation of temperature in a greater percent of patients.

To reduce the reactions to minimum and to facilitate the absorption of the medium, the bulk of the Pantopaque should be removed by aspiration after myelography.

The implication from the advertisement is that for a physician to reduce the risk of transient fever following myelography, they should attempt to remove the bulk of Pantopaque. But, that if the agent is left in the spinal cord similar transient side effect(s) may occur in a greater percentage of patients.

This labeling does not:-

· reflect the results of long-term animal testing for Pantopaque when the contrast medium is left in the spinal column,

· nor the occurrence of permanent long term complications such as "obliterative arachnoiditis" in patients that has been reported within the medical literature,

· nor does it reflect the concerns that had been expressed by the FDA.

This labeling also implies the Pantopaque has been cleared by FDA for visualization of a tumor in the cervical spine."

The letter from October 3, 1972 John Potts, of Eastman Kodak to Mr. Strawbridge, Picker Corporation, demonstrated just how closely Eastman Kodak monitored the Pantopaque trademark.

(Picker is one of the companies listed above who were supplied with Pantopaque by Lafayette Pharmacal – MF)

It is unfortunate that Kodak did not monitor the "accuracy and truthfulness" of the contents of the labeling in terms of patient safety. Regarding the license to use the trademark Pantopaque, Mr. Potts wrote:

"Our attention has recently been directed to the sales carton you are currently using to merchandize the Picker Myelogram Tray.

Although this is a most attractive carton, we are somewhat concerned that the treatment afforded our PANTOPAQUE mark is not in compliance with the terms of our license agreement dated August 24, 1943....

In the first instance, the legend "Trademark PANTOPAQUE Licensed by Proprietor", does not appear thereon. We believe such a legend is imperative to avoid any misunderstanding as to the ownership of the PANTOPAQUE mark, and request that it be added as soon as possible to the main face panel of the carton–preferably, immediately beneath the most prominent impression of the mark.

Secondly, although the mark PANTOPAQUE appears some eight times on the carton, the proper generic terminology appears only once.....

Finally, it is noted that the carton in question does not contain one of the accepted legal notices of trademark registration as required by the license......

We realize, of course, that your company would not intentionally do anything to jeopardize our rights in the PANTOPAQUE mark and know that you will take prompt action to correct the packaging in question. (45)

In terms of demonstrating the working role and oversight of Eastman Kodak over Lafayette Pharmacal's product and product labeling, there was a January 31, 1973 letter from Eastman Kodak Company's Executive Vice President, International Photographic Division, written for the approval of Mr. Bucke of Lafayette Pharmacal:

"It is our understanding that your firm wishes to distribute and sell in Mexico, packages and vials of contrast medium for radiography under our registered trademark PANTOPAQUE (Mexican Reg. No. 163,727).

Accordingly, by this letter, we hereby grant to you a nonexclusive, nonassignable license to use said trademark in Mexico subject to the following terms and conditions which are necessary to protect our rights in and to said trademark PANTOPAQUE and the good will associated therewith:

1. Said trademark PANTOPAQUE will be used by you only on radiographic contrast media manufactured and sold by us to you;

2. all such product to conform to standards of quality and sterility prescribed and approved by us.

3. We shall have the right of approval of all such product, packages and labels and you agree to furnish to us upon request, production samples of same for our inspection.

4. You, at all times, will acknowledge our ownership of an rights in and to the trademark PANTOPAQUE as applied to radiographic contrast media and similar goods."

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