Early Development

(In) approximately 1918, following a proposal by Dandy, visualization of the spinal cord radiographically was done by injection of air into the spinal column to enhance anatomic structure imaging.(7)

In 1922, iodinized poppy seed oil, which had been commercially available since 1901 for injection into the epidural space, began to be used for intrathecal injection for enhanced imaging of the spinal cord. Usually less than 5 cc of poppy seed oil was introduced into the intrathecal space and it was recommended that it be removed following imaging.

A 1932 opinion statement of the American Medical Association had discouraged the introduction of any foreign oily material, such as iodinized poppy seed oil, into the spinal cord unless the potential benefit of the procedure could justify the potential long-term risk to the patient.

The investigation of the use of the medical imaging agent ethyl iodophenylundecylate, which would eventually be called Pantopaque, began in 1936 at the University of Rochester, School of Medicine and Dentistry, Rochester, NY with initial animal work done by William Strain, Ph.D. and Stafford Warren, MD.

The investigators were reportedly seeking a more effective and safer medical imaging agent for imaging the spinal cord then iodinized poppy seed oil. They also wanted to develop a radiopaque substance that would be nontoxic when injected into the spinal canal, that would disappear from the body within several weeks, more rapidly than the iodinized poppy seed oil, and also improve the overall quality of radiological imaging of the spinal cord.

They began working with several different oily iodinated compounds. During animal studies in 1937-1938, Warren and Strain began referring to one of their new oily iodinized non water-soluble medical imaging agents as ethyl iodophenylundecylate, iophendylate, or "Pantopaque".

Their animal studies indicated that the oily imaging compound was not absorbed by the body and, just as with the already available oily non water soluble iodinized poppy seed oil, would remain permanently encysted within the spinal column as a foreign body capable of triggering a moderate inflammatory reaction with production of fibrosis.

The June 1941 doctoral thesis of T.B. Steinhausen, also at the University of Rochester and who was working with Strain and Warren, a study funded for the Radiopaque Group by Eastman Kodak Company, was entitled "An Experimental Study of Iodinated Compounds for Intrathecal Use". His work involved the use of rat and dog animal studies and a series of iodinated imaging compounds. The potential contrast media of his thesis, Pantopaque, had been a product synthesized by Plati in 1940.

Steinhausen began his thesis work by looking at the intrathecal injection effects of the already available iodinized poppy seed oil (or Lipiodol) in animal systems. It was his opinion that since there had been no histological tissue information available, with very little experimental studies done regarding the nature of the foreign body reaction stimulated by the material, when injected into the human's subarachnoid space, that it (iodinized poppy seed oil – Lipiodol) should not be considered as a suitable product for human use.

He reviewed cat studies that demonstrated there was no absorption of the iodinized poppy seed oil over time and that one of the cats had died following injection. He commented that those researchers appeared to have used too much oil in that cat and that there was no way that iodinized poppy seed oil should ever be considered as safe for human injection.

Steinhausen cited an earlier 1925 rabbit study using 17 rabbits with intrathecal Lipiodol injection that had a 47% mortality with pathological changes seen at autopsy.

He referred to a 1938 study by Mettier and Leake that had reported numerous untoward reactions secondary to the (8) introduction of iodinized poppy seed oil into the intrathecal space. For this reason, Steinhausen stated that those authors had recommended that the oily iodinized poppy seed agent be used very carefully and that every effort should be made to remove as much of the substance as possible immediately from the intrathecal space following an imaging procedure.

He cited that in 1939, Brison had developed a technique that would aid in removal of iodinized poppy seed oil from the subarachnoid space in order to help decrease the potential meningeal irritation. This was a procedure that was similar to a procedure used at the Mayo Clinic.

A 1941 study by Brown and Carr, following a 6 month instillation of retained intrathecal injection of poppy seed oil, had found the oil emeshed or encysted within fibrous adhesions in the spinal column amongst a thickened dura with chronic inflammation. The authors also had indicated that there was a significant danger in injection of iodinated poppy seed oil within the spinal canal for imaging.

One of the new iodinated compounds that was studied by Steinhausen in his thesis included ethyl iophenylundecylate ("Plati's iophendylate" or "Pantopaque"). This compound was reportedly chosen by Steinhausen because it would break down more slowly than the other iodinized agents that he examined. That property was one that he thought would help facilitate better radiographic imaging.

In a series using 3 dogs, Steinhausen's Pantopaque produced meningeal irritation symptoms that ranged from slight to severe. In another series of 15 dogs all injected intrathecally with 4 cc Pantopaque:

· 27% were clinically free of meningeal irritation symptoms,

· 46% had symptoms of slight meningeal irritation at 2-9 days,

· 20% had moderate symptoms at 3-9 days,

· 7% had severe meningeal irritation symptoms beginning at day 4 and lasting 12 days, with

· 1 dog dying on the 24th day post-injection from a gangrenous terminal ileum.

In the dog studies, despite a lack of overt acute clinical symptoms, at time of termination of the study and autopsy, the histological and gross meningeal changes were more severe in nature then had been clinically suggested.

Such significant changes included:

· granulomatous foreign body reactions with acute inflammation, polymorphonucleocytes (PMNs),

· phagocytes,

· and fibroblasts with fibrous adhesions involving the nerve roots.

The typical meningeal histological changes seen at dog sacrifice at 1½ months post intrathecal injection included clear cystic areas, dispersed throughout the spinal column, consistent with the presence of pockets of retained oily injected material, surrounded by fibrosis, scattered macrophages and acute inflammation.

One of Steinhausen's 15 Pantopaque dogs following injection had a persistent generalized weakness of the legs with an inability to walk. This was the first time that this type of generalized neurological reaction with lower limb paralysis had been reported by Steinhausen associated with the use of any of the oily imaging compounds that he was testing.

For the purpose of comparison and using his model, Steinhausen injected a series of 9 dogs with iodinized poppy seed oil. One dog died 24 hours after injection, with symptoms of moderate meningeal irritation and subarachnoid hemorrhage.

80% of the dogs appeared to recover clinically without remaining neurological symptoms. However, histologically, at time of termination and autopsy, the histological and gross changes were similar to the changes that had been seen with injections of ethyl iophenylundecyalate (Pantopaque) and the findings were more severe than would have been suggested clinically. (9)

"The primary difference for the iodinized poppy seed oil, when compared to Pantopaque in the dog model, was that the iodinized poppy seed oil appeared to produce greater number of clinical symptoms referable to the immediate mechanical trauma of the injection. Histologically, the iodinized poppy seed oil resembled the changes produced by Pantopaque, including moderate meningeal irritation with areas of oil floating within the cord as encysted clusters, acute inflammation, fibroblasts, fibrous adhesions and nerve root involvement."

Steinhausen's research in dogs foreshadowed both the significant acute and long-term adverse events that were reported in human patients following the intrathecal injection of Pantopaque for myelography.

In terms of the body of Steinhausen's research, it is unclear why, in lieu of the significant and severe animal safety findings produced by intrathecal administration of Pantopaque, and the similarity to the harmful effects of iodinized poppy seed oil, that he would have made the following 4 thesis conclusions regarding the apparent imaging "utility" of Pantopaque for injection into humans for myelography:

1. Of the 26 ethyl esters of various iodinated organic acids, only ethyl iodophenylundecylate seemed suitable for myelography.

2. Ethyl iodophenylundecylate appeared to be absorbed and as long as any of the ester was present there was some pathological reaction about the compound.

3. Comparative tests with the standard iodized poppy seed oil showed a definite but different pathological response which persisted indefinitely, since the compound was very slowly absorbed.

4. Ethyl-w-(4-iodophenyl)-o-valerate, although not suitable for myelography, had found clinical application as a contrast medium."

(This last statement is a direct contradiction of itself! But for real shock horror read the next paragraph which I have split up for easy reading. M.F.)

Despite the documentation by Steinhausen of the similarities and risks of Pantopaque when compared to Lipiodol in animal studies,

despite the 1932 warning of the AMA regarding the permanent long-term risks for introduction of foreign oily compounds into the spinal cord for imaging, and

despite the FDCA's 1938 requirements for obtaining FDA's premarketing approval through demonstration of "safety" to the FDA before introducing an imaging agent for use in U.S. patients,

Dr. Warren took it upon himself to begin sending Pantopaque to U.S. physicians to obtain their clinical input from imaging their own patients.

The 1938 FDCA, as seen with the later distribution in the U.S. of two million of investigational tablets of thalidomide in the early 1960s, did not address the legal responsibility of a manufacturer to control the distribution of "investigational drugs", nor did it require obtaining informed patient consent or obtaining an Investigational New Drug (IND) exemption from FDA.

On June 26, 1942, Dr. Rigler, University of Minnesota Hospitals, Minneapolis, MN, wrote to Dr. Warren reporting his facility's negative clinical experience with Pantopaque for imaging their patients. Dr. Rigler did not provide "favorable" information to Dr. Warren regarding the performance of Pantopaque in human patients.

Dr. Rigler indicated that it was his opinion, as well as his staff's opinion, that the material mixed too readily with the spinal fluid and did not improve imaging quality. He also indicated that he felt that the material was extremely difficult to remove. (10)

Dr. Rigler wrote to Dr. Warren of the experiences of his staff with Pantopaque:

"We have completed some myelographies with your Pantopaque which you were so kind to send me, but for our purposes we have found it somewhat unsatisfactory.

Doctor Peterson, who has been doing this work here for some time and has had a considerable experience with both air and lipiodol, feels that the material mixes much too readily with the spinal fluid so that a clear cut picture cannot be obtained.

Obviously, in a case of a block of any degree, it would be entirely satisfactory, but if you are trying to demonstrate herniated disc or tumor without complete block or arachnoiditis, the normal miscibility of the material would be most confusing."

Furthermore, he found it extremely difficult to remove.

"Large quantities of spinal fluid were removed by the usual methods that we use in removing lipiodol, but he(sic) was quite unsuccessful.

I am sending you illustrations of two cases, one done with lipiodol and the other with Pantopaque, to give you some idea of the contrast, both the original films and the amount of opaque material left after attempts at removal.

You will note that in the case of lipiodol, using the maneuver of Kubik and Hampton, all except a very few droplets were successfully removed whereas in the case of the Pantopaque most of it all remained."

From other documentation, Dr. Warren had also sent Pantopaque to physicians based at military hospitals to encourage their use of the product for imaging military patients.

Major R.G. Spurling, Walter Reed Hospital, Washington, D.C., September 5, 1942, wrote to Dr. Warren in 1942 indicating that Pantopaque produced, "as many irritative symptoms as lipiodol (poppy seed oil) but it was absorbed more rapidly."

When removed immediately post procedure, there had been no more evidence of meningeal irritation than after a plain lumbar puncture. Major Spurling felt 90-95% of the Pantopaque could be removed, with the remainder absorbed in two to four weeks.

Major Spurling had observed a patient of his that he had injected a 5cc dose of Dr. Warren's Pantopaque material intrathecally and concluded that approximately 50% (*2.5cc) had been absorbed at the end of 7 months by serial x-ray. He also wrote:

When Pantopaque is removed immediately following the myelogram, there is no more evidence of meningeal reaction than after plain lumbar puncture studies.

Furthermore, with ordinary care, it is possible in all cases to remove 90 to 95% of the Pantopaque from the subarachnoid space. A few drops remaining cause no demonstrable clinical signs and these droplets are absorbed within two to four weeks.

I have used Pantopaque in approximately one hundred clinical cases and I consider it to be the most nearly ideal myelographic medium yet available."

September 16, 1942, eleven days after Dr. Spurling's letter had been written to Dr. Warren, (the) FDA responded to an earlier (September 4, 1942) letter received from Mr. J.T.Fuess of Chemical Sales Division, Eastman Kodak Company, Rochester, NY, regarding the issue of Eastman Kodak's reported interstate deliveries of Pantopaque. (11) The letter was written by the Assistant Commissioner of the FDA, P.B. Dunbar.

This refers again to your letter of September 4 in reference to Pantopaque. With the understanding that deliveries of this drug will be restricted exclusively to the military forces, this Administration will not insist on compliance with the requirements of section 505 of the Act dealing with new drugs.

Should you contemplate at any time entering into the ordinary commercial distribution of Pantopaque, it will be expected that the precise requirements of section 505 of the Act will be met. This will require the filing of a formal application with proof of the safety of the drug.

If in lieu of filing of a formal application you elect to take advantage of section 505(i) and distribute the drug solely for investigational use by qualified civilian experts, it will be expected that the requirements of section 505(i), together with the regulations thereunder, will be met, including the labeling of the product with the statement:

"Caution: New drug - Limited by Federal law to investigational use.

Up to the present time we have had inquiries regarding the use of Pantopaque only from the Office of the Surgeon General of the War Department. Should a similar request be received from medical authorities of the Navy our decision would be identical.

However, in apparent violation of the "military-only restrictions" stated in the FDA's letter for legal distribution of the drug to military facilities, of December 1st 1942, Dr's; Steinhausen, Plati, Furst, Dungan, Smith, Strain and Warren presented the results of their:

"Experimental and Clinical Myeolography with Ethyl Iodophenylundecylate (Pantopaque)"

at the 28th Meeting of the Radiological Society of North America, a "civilian medical association".

The data began with a presentation of results of intrathecal injection of 3-5cc in dogs. However, the presentation concluded with an open "off label clinical discussion" of the use of their "unapproved" contrast agent in three unusual clinical cases, with no mention of FDA's restriction to military-only use.

There was no mention within the written abstract that product availability had been "restricted" by FDA to military medical facilities, nor was there a discussion that the "safety" for human use had never been submitted, nor demonstrated, to the FDA for support of marketing the product for use in a US human population.

In terms of the sponsors' Pantopaque presentation, in the abstract, it also appeared that the authors did not wish to accurately reflect the earlier Steinhausen dog data, nor actual clinical experience described in the 1942 letter from Dr. Rigler in terms of his facility's "unfavorable" clinical experience.

There appears to have been a conscious decision in 1942 by the authors

· to disregard Dr. Rigler's clinical findings,

· an intentional disregard of the requirements that had been detailed by the FDA,

· an intentional disregard of clinical ethical conduct, and

· failure to provide physicians with complete and accurate, and truthful outcomes documented for Pantopaque through both human and animal experience.

The abstract misrepresents the scientific facts for Pantopaque as known by the authors in 1942 by containing "misleading" statements about the long-term effects of Pantopaque in the dog studies (as follows):-

· The new medium is more fluid than the iodinized oils and may be injected with ease. With dogs intrathecal injection of 3-5 cc causes a transitory pleocytosis with cell counts of 200 to 700 (mostly polys).

· Histological sections taken during or after this transient reaction period show collection of the medium under the meninges with a localized foreign body response around the small droplets.

· Consecutive radiographs demonstrate that the preparation is rapidly absorbed at first, but more slowly as the medium becomes fixed in position.

· Nevertheless, amounts of 3-5 cc are absorbed nearly completely in the course of a year with little or no evidence of residual reaction.

· Parallel experiments with iodized poppy seed oil in dogs show somewhat more extensive pathology with little evidence of absorption.

· Clinically, the new medium has been found to facilitate greatly myelographic examination.

· In addition to ease of injection, the preparation flows readily immediately after injection and may be removed without difficulty

· The entire examination, including injection and removal, can be completed in fifteen minutes."

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