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.".

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.

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.......

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.

(* 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"..

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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)

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.

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.

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.

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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