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I. Qualifications

Since August 1995, I, Suzanne Parisian, M.D. have been President and founder of Medical Device Assistance, Inc., a regulatory and medical consulting firm specializing in matters involving the United States Food and Drug Administration's regulation of medical products. I received my Medical Degree (M.D) from the University of South Florida in 1978 and am Board Certified in Anatomic and Clinical Pathology. From 1991 to 1995, I served as a Commissioned Officer in the United States Public Health Service and achieved the rank of Commander. During this time period, I was primarily assigned to the Center for Devices and Radiological Health (CDRH) at the Food and Drug Administration (FDA). Concurrently, during l991 to l995, I was also assigned clinical responsibilities at the Armed Forces Institute of Pathology (AFIP), Office of the Medical Examiner for the Armed Forces, Washington, D.C.. From 1991 to 1993, I was a Medical Officer in the Office of Health Affairs (OHA) a staff office within the FDA. From

March 1993 to December 1993, I was a Medical Officer in the Office of Device Evaluation, (ODE), Division of Reproductive Abdominal, Ear, Nose and Throat, and Radiology, (DRAERD) at the FDA. From January 1994 through June 1995, I was Chief Medical Officer for DRAERD at the FDA. My most current curriculum vitae is provided in Attachment "1" (http://www.mdassist.com). ODE, FDA is the Office within CDRH responsible for the premarketing evaluation of product applications submitted by the manufacturer to market devices that are safe and effective within the United States. In ODE, I participated in the review of marketing applications as well as had the assigned responsibility of training new medical officers and scientific reviewers in application and labeling review at CDRH. I was an instructor in FDA’s Staff College for the instruction of CDRH reviewers in the design and evaluation of clinical data contained within 2 premarketing applications. While in OHA, I was a medical officer responsible for the review of mandatory adverse event reports submitted by a manufacturer, as well as the review of voluntary reports submitted by health care providers, patients and others. Within OHA, I was the primary clinician assigned responsibility to preside over 162 health risk assessments that were convened to advise FDA on the overall health risk of medical devices’ performance issues, identification of public health safety issues, and to make recommendations to FDA regarding the subsequent regulatory actions that should be undertaken by FDA, health care providers, users groups and manufacturers in order to help protect the public’s welfare. While in ODE, I performed an additional 100 health risk assessments and trained medical officers as to the procedure for conducting a health risk assessment. At FDA, I participated with FDA’s District Offices, Office of General Consul, and the Office of Compliance in the review of manufacturing records, product complaints and adverse event reports obtained by FDA. I was the primary clinician involved in several of FDA’s Major Corporate-Wide actions for which I received various citations and honors for my services from FDA, including Department of Health and Human Services and the Federal Government Employee of the Month. I was sent by FDA as official Agency representative to medical meetings and seminars to help monitor medical device manufacturers and distributors for deviations from regulations governing promotional activities. I was also required to provide guidance as to the FDA’s interpretation of Food and Drug Laws as they pertain to medical products and the role of manufacturers. After leaving FDA, and founding Medical Device Assistance, Inc., I have continued to provide information to individuals and organizations outside FDA regarding FDA’s requirements, Adverse Event Reporting, and labeling of medical products. I was requested by FDA to participate in a l997 panel of experts convened by FDA to comment on changes proposed in the requirements for medical device labeling. I continue to lecture at conferences and seminars regarding FDA, premarket clearance, design of clinical trials and product labeling. I am the author of FDA Inside and Out published May 2001 which is a book about the workings and history of the FDA.

My opinions are based upon my own personal experience and knowledge of activities developed while at the FDA, my review of FDA's records, my own professional activities, education and experience, and consulting activities after leaving FDA. I am familiar with the FDA's regulation of medical products, including radiological and imaging products, Adverse Event Reporting, health risk assessment, and labeling of FDA-regulated products that are intended to be marketed in the U.S. I have been responsible for the Agency’s review of biocompatibility and toxicity data including animal and clinical studies. I was Chief Medical Officer of ODE’s Division that reviewed radiologic products and was involved in the review and evaluation of contrast agents 3 and imaging devices. I am a Board Certified Anatomic and Clinical Pathologist. I have reviewed materials regarding Iophendylate, Pantopaque, Lafayette Pharmacal, Eastman Kodak Company, Alcon Laboratories, Inc. that have been provided to me for this litigation. I have conducted my own review of FDA’s database and the U.S. medical literature through the National Library of Medicine’s database to obtain documents pertaining to the use of iophendylate. I have reviewed all the Iophendylate, Pantopaque and Lafayette Pharmacal, Inc. and Alcon Laboratories, Inc. documents that were available to me within the public database. Finally, I have reviewed the March 20, 2002 Expert Witness Report of Charles V. Burton, M.D.

FDA’s regulatory premarket oversight was officially extended over human drugs sold in the United States following the passage of the 1938 Food Drug and Cosmetic Act (FDCA) signed into law by President Franklin D. Roosevelt. Among the many provisions of the 1938 FDCA, was the requirement that all new drugs be required to be shown through FDA’s approval of a premarketing submission that they were "safe" before being legally allowed to be marketed in the U.S. The results of safety testing would be submitted to FDA in a New Drug Application (NDA) This revision of the earlier 1906 Act also had a provision that any drug which was marketed prior to June 25, 1938, could continue to be marketed without FDA’s approval provided no significant alterations in formulation or labeling had occurred since that time. That is, such a drug would not be considered a new drug (i.e. grandfather clause.) The law also required that drugs have adequate labeling for safe use. The monitoring of all drug advertising was assigned to the Federal Trade Commission.

The early 1940s saw three major additions to FDA’s responsibilities in terms of drugs. The Insulin Amendment, passed in 1941, required all batches of insulin to be tested for purity, strength, quality, and identity before marketing. Also starting in 1941, the Agency required prescriber labeling for all new drugs in concert with the adequate directions for use provision of the 1938 Act. The Penicillin Amendment was passed in 1945, modeled on the Insulin Amendment. The former required batch certification of drugs wholly or partially composed of penicillin. Subsequent amendments extended the certification requirement to other antibiotics. The FDCA and World War II greatly expanded the role of FDA’s overall regulatory oversight. Wartime demands stimulated the rapid development, availability and marketing of new "wonder drugs", especially antibiotics for treating war casualties. (* Pantopaque was approved for marketing 1944 through support of "safety.") 4

At the start of the 1950's, FDA’s resources were still viewed by Congress and the Agency as seriously deficient for the assigned tasks. FDA’s appropriations and staff in the 1950's, never considered as adequate by Congress, had remained approximately at the same levels as 1938 when Congress passed the FDCA. The 1951 Durham-Humphrey Amendment to the FDCA further defined U.S. drugs that could not be safely used without medical supervision and restricted the sale of these drugs to receipt of a prescription by a licensed health care provider. In 1955, FDA undertook a pigreat deal study on adverse drug reaction reporting. In cooperation with the American Society of Hospital Pharmacists, the American Medical Association, and others, the study was focused on reactions that could be reported by hospitals and pharmacists. Adverse reaction reporting was voluntary and reports were usually scarce. This study blossomed into a more ambitious effort in 1957 to test a large-scale system for voluntary reporting to assist with post-marketing evaluation of new drugs. By 1963 the study had evolved into a voluntary reporting system with almost 20 hospitals participating.

In Europe, there was a major safety uproar secondary to the disastrous introduction of the drug thalidomide, a new sleeping pill, and its subsequent association with a production of serious birth defects. However, the United States’s FDA was viewed in a positive light after the cautious actions of FDA’s Medical Office Dr. Frances Kelsey, that had kept the drug from approval for commercial entry onto the U.S. market. Despite lack of FDA approval, more than two million thalidomide tablets had been distributed in the U.S. as "investigational drugs." Investigational drug distribution had been largely unregulated in the US under FDCA. The FDA’s prudent actions to not approve thalidomide that appeared to have protected US public safety aroused a strong public support for FDA’s role in drug regulation and the need for stronger laws to ensure "drug safety." In partial response to the issue, FDA’s Commissioner George Larrick established an Advisory Committee on Teratology and Congress was able to obtain the necessary public support to pass the 1962 Kefauver-Harris Drug Amendment to ensure drug "safety and efficacy."

The 1962 Kefauver-Harris Drug Amendments or the Drug Amendments of 1962 to the FDCA continued to require that a "new drug" be required to demonstrate that it was both "safe" but also now that it was "effective" before being allowed commercially onto the U.S. market. As a result of the 1962 Amendment to the FDCA, FDA also retrospectively went back to reassess the "efficacy" of nearly 3,000 prescription drugs that FDA had already allowed to be introduced onto the U.S. market between 1938 and 1962. (*That review included Pantopaque.)

The FDA responded to this large retrospective review task given to it by Congress by seeking external advice or assistance through a contract with the National Academy of Sciences- National Research Council (NAS-NRC). NAS-NRC membership were required to review previously marketed prescription drugs and made recommendations to FDA regarding safety, efficacy, and 5 labeling. The FDA’s retrospective efficacy review program was called the " Drug Efficacy Study Implementation Review" or "DESI."

As a result of DESI, in the years following 1962, literally thousands of previously "approved" drugs were removed from the U.S. market by FDA because it was determined that they lacked evidence in the medical literature to support "efficacy." DESI evaluated 3000 separate drug products and over 16,000 therapeutic claims. By 1984, FDA had completed final action on 3,443 products; of these, 2,225 were found to be effective; 1,051 were found to not be effective, and 167 the decision was still pending.

FDA also required manufacturers to update their product labeling to reflect the known medical facts regarding drug safety and efficacy determined by DESI and to bring drug labeling into compliance with FDA’s requirements for prescription labeling. Drug prescription labeling was revised to be more uniform and come into compliance with FDA’s prescription labeling requirements of the FDCA and labeling for other similar products. To expedite developing drug prescription labeling for similar types of products, FDA turned to the regulated industry itself for models of the "best" designed labeling for each type of product.

The 1966 Fair Packaging and Labeling Act required all consumer products sold in interstate commerce to be honestly and informatively labeled. FDA became officially responsible for enforcement of labeling provisions for foods, drugs, cosmetics and medical devices.

(*Pantopaque had been approved with "safety" data in 1944, and was included in the FDA’s retrospective drug review (DESI) of the medical literature by NAS-NRC for support of both safety and efficacy. FDA required labeling changes that coincided with NAS-NRC medical literature review and labeling of similar products.

In 1963 FDA had required the sponsors of Pantopaque to submit a new NDA for gaining approval of a new strength (15% iodine) Pantopaque, or Pantopaque II. The product for the new NDA would be required to meet the Agency’s new requirements for animal safety testing to assure safety, scientific support of both human safety and efficacy, requirements further developed by FDA since the initial World War II era NDA for Pantopaque I (30% iodine). The new Pantopaque NDA was subsequently left uncompleted and withdrawn by Lafayette Pharmacal in 1969.)

In Upjohn v. Finch, 1970, the Court of Appeals upheld enforcement of the 1962 Drug Efficacy Amendments by ruling that commercial success alone did not constitute substantial evidence of drug safety and efficacy. FDA’s review actions of drugs for "efficacy" had been curtailed while the Agency waited to learn the final decision of the Courts as to legality of the Agency’s enforcement actions for "efficacy" requirements.

A 1977 Intercenter FDA Task Force established a Bioresearch Monitoring Program for FDA. The need for such a program to monitor clinical trials became evident from a survey of the 6 "conductance of clinical studies" involving FDA-regulated products by FDA’s field inspection operation team between 1972 and 1974. Following a further review of the agency’s inspectional findings, Congress mandated that FDA immediately develop and implement a new agency-wide program for monitoring the conductance of bioresearch and clinical activities.

1980's

In 1982, the Bureau of Biologics and the Bureau of Drugs were merged into a Center for Drugs and Biologics, with Biologics products regulated through the Office of Biologics. In 1987 the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) officially were divided into two separate and independent FDA review and evaluation Centers.

As a result of the U.S. push to obtain cheaper generic drugs and the FDA’s Generic Drug Scandal of the 1990's, (*i.e. manufacturers had supplied FDA with fraudulent data regarding the production of generic drugs), the FDA instituted product-specific, pre-approval inspection of manufacturing sites listed within a sponsor’s marketing applications would extend to generic drug applications. During pre-marketing approval inspection, FDA was required to review the step-by-step manufacturing process of each product under review. All drug applications were reviewed for their scientific content and for manufacturing procedures as well as validation methods, raw material specifications and container and closure systems used.

By Federal Register, September 10, 1991, FDA’s Notice 56 FR 46191- Fraud, Untrue Statements of Material Facts, Bribery, and Illegal Gratuities; Final Policy, the agency announced its final policy that set forth FDA’s approach regarding applicants that sought to subvert the agency’s review and approval process of premarketing applications.

CDER 06/19/00 release of the Guidance for Industry- Developing Medical Imaging Drugs and Biological Products. This guidance was prepared by the Division of Medical Imaging and Radiopharmaceutical Drug Products in CDER and the Office of Therapeutics Research and Review in CBER, FDA, with comment from Office of Device Evaluation, Radiological Branch, CDRH. The guidance was to represent the Agency’s current thinking on the development of medical imaging drugs and biologics (medical imaging agents).

A. Early Development

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 7 structure imaging. 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 then 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 Lipidol) 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 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 Lipidol 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 9 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. 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.

Despite the documentation by Steinhausen of the similarities and risks of Pantopaque when compared to Lipidol 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 no 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 10 improve imaging quality. He also indicated that he felt that the material was extremely difficult to remove. 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 lipidol, 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 demonstrated 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 lipidol, but he was quite unsuccessful. I am sending you illustrations of two cases, one done with lipidol 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 lipidol, 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 lipidol (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, FDA 11 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. 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,(*Underlining added for emphasis.), 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, December 1, 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 12 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:

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. (*Bold added for emphasis)

B. Pantopaque, FDA and New Drug Approval (NDA)

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." He stated that he would furnish them with data relative to animal experiments which he had performed. He stated 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. He was also told that we would like to have some comparison between chemical meningitis produced by pantopaque and the reactions produced by lipidol. 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 (* bold added for emphasis) in which 2- 14 5 cc (* bold added for emphasis) of the medium has been used show that Pantopaque is well tolerated even when left (* bold added for emphasis) in the spinal canal. In those cases where the bulk of the contrast medium has been removed using the technique of Kubik and Hampton(* bold added for emphasis) , 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.(* bold added for emphasis) 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 (* bold added for emphasis) 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,(* 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.). 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. ).

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 (* underlining added for emphasis) 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 wrote back 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 (* Bold and underlining added for emphasis.), 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 (* Bold and underlining added for emphasis). 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 lipidol and to discuss the nature and severity of the reactions observed by them as compared to those observed when lipidol is used.

In our opinion, the proposed circular setting forth the indications and method of administration of this product is not wholly satisfactory (* Bold and underlining added for emphasis). Because the severity of reactions (* Bold and underlining added for emphasis) observed in patients in whom the product is not removed after injection, we feel that considerable stress (* bold for emphasis) 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.(* Bold and underlining for emphasis) 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 (* Bold and underlining for emphasis) 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.(* Bold and underlining for emphasis).

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 Lipidol.

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 Lipidol:

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 Lipidol. 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 Lipidol and that it is much more easily removed from the spinal subarachnoid space than Lipidol. 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 a .7 to .8 cc out of 1 cc have 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 pigreat deal, developed moderate headache which occurred after flying a few days following the Pantopaque study....The other eight cases had no symptoms.

2. In one case in this series who had a Pantopaque study and operation for a herniated nucleus pulposus, there developed an adhesive arachnoiditis (* bold added for emphasis) 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.

3. The material shows good opacity and interpretations of the films are as simple as that done with other opaque media.

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 inclusiong(sic) 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 letter 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,(* bold added for emphasis), 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 (* bold added for emphasis) 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.(* Bold added for emphasis)

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 , authored by Lt. Col. Spurling and Cpt. George Wyatt, Pantopaque, Notes on Absorption following Myelography, described intrathecal injection of a Pantopaque dose of 3.5 ccs, began:

Pantopaque has replaced Lipidol and the gases as the contrast medium for myelography in the Army Medical Corps. The chief reason for the preference to lipidol is that Pantopaque is absorbed (* bold added for emphasis) instead of remaining as a persistent foreign substance in the subarachnoid space. Experience has shown it to be nontoxic and no more irritating than lipidol, and its sharp radiographic contrast and consequent clear delineation of pathologic anatomy affords 22 a definite superiority over the gases as does lipidol. In contrast to lipidol, 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.(* bold added for emphasis)

November 12, 1945, Lafayette Pharmacal, Inc. sent a coverletter to Dr. Merrick of FDA requesting to amended 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,(* bold added for emphasis), 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.(* Bold added for emphasis.). 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 (* bold added for emphasis) of ethyl iodophenylundecylate in some six centers. The logical application of the medium appears to be bronchoscopy, (* bold added for emphasis) 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 a 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 (* bold added for emphasis) 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, 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 great deals of pantopaque,(*bold and italics emphasis added), 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% (* bold emphasis added). 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. (* bold added for emphasis) 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) 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 aboveindicated 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.

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 then had been provided to FDA in NDA 5-319 (i.e. 2-5 cc) with the availability of "multiple size" ampules. The labeling stated:

(*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 1-3 cc of Pantopaque.) 26

The labeling also had the following information regarding product utility:

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 (* bold added for emphasis), 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 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. 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:

In the course of years, because of the trend toward using greater volumes (* bold and italics added for emphasis) of Pantopaque, and because 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....(* bold and italics added for emphasis) 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, 1996 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 (* bold added for emphasis) 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 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 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 30 concentrated than it, "it was felt that no further laboratory work need be done."

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 8/1/63 and 5/31/64; of these, approximately half received 15% or 221/2% ( 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.

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.

The application is incomplete (* underlining added for emphasis) 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 5/4/66: Should pharmacologic work be complete before any further human tests? Is there an IND? Reviewer E. Herman wrote a reply dated 5/5: There is an IND with reports as stated above. There was then an FDA Intra-Administrative Referral issued 5/5/66 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 11/20/64 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. Iophenylate 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 (*bold added for emphasis) with hydrocephalus one year after cervical myelography using iophenylate. Whether the response was a direct result of 32 chemical irritation or a form of hypersensitivity could not be ascertained. In its review (11/20/64) of IND 1161, Pantopaque 15%, DTE recommended that acute toxicity tests be performed in either the rabbit or dog using single administration of iophenylate or the 1:1 mixture have been performed by workers at the Neurological Institute (New York). 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 indicted 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.

September 7, 1967, Hazelton Laboratories completed an Acute Intrathecal Toxicity Study-Rabbits involving 16 rabbits using Pantopaque II that were followed for 14 days. The study data was submitted to Lafayette Pharmacal, Inc. The summary of the study went as followed: Pantopaque II was evaluated for acute intrathecal toxicity by intraspinal injection to 33 groups of adult albino rabbits (* 4 groups of 4 rabbits each) at graded dosage levels ranging from 0.562 to 316 g/kg of body weight. Partial mortality at the two lower levels and total mortality at the two higher levels were produced. The mortality pattern did not permit an accurate calculation of the acute intrathecal LD50, but it is estimated to be in the order of 0.5 g/kg of body weight. Principal Toxic Effects Observations noted during the 14-day period consisted of the following: Slight ataxia at the four-hour observation period only in all animals at the lowest level and in two animals at the 1.0 g/kg level, rapid respiration prior to death in one animal at the 1.78 g/kg level, limited use of the hindquarters in two animals, and terminal body weight loss in all animals at the lowest level; partial mortality at the two lower levels and total mortality at the two higher levels.

November 13, 1967 Hazelton Laboratories submitted Acute Intrathecal Toxicity- Dogs Pantopaque II to Lafayette Pharmacal, Inc. The investigation had been conducted from July 27, 1967 through September 6, 1967. The summary of the data was as follows: Single intraspinal doses of the test material, Pantopaque II, were administered to four groups of two dogs each, at levels of 0.316, 0.562, 1.00, and 1.78 g/kg, respectively. The dogs were observed for 14 to 20 days after dosing and then sacrificed. All dogs showed signs of muscular weakness and incoordination following dose administration, with particular loss of motor control of the hindlimbs. The degree of this motor incoordination did not appear to be related to the dose level.(* underlinging added for emphasis) All animals slowly returned to normal or near normal appearance during the observation period except one low level animal which died after two days, apparently from an injury sustained during injection of the compound. Gross necropsies after sacrifice revealed the presence of oily substance resembling the test material in the cerebro-spinal fluid of all but two animals. Connective tissue lesions in the area of the injection were present in about half the animals.

The dog that died had received the lowest dose Pantopaque II dose, Group No. 1, (0.316 g/kg) and had appeared normal on the day of dosing. (*Two dogs were used in each of the 4 dose groups.) On day 2, its behavior became vicious and it was found dead on day 3. The other animal in the low dose group appeared normal for several days following dosing. However, on the day 4, the animal appeared uncoordinated and became partially paralyzed in the hindlimbs. The dog’s condition returned to normal by day 8, but it continued to lose weight throughout the study until termination. For the two dogs in the next dose group, Group No. 2, (0.562 g/kg), both became markedly uncoordinated with partial paralysis in the hindlimbs. Their conditions gradually improved until sacrifice. 34 Group No. 3 dogs (1.00g/kg) both exhibited signs of muscular weakness and poor coordination following dosing. Partial paralysis of the hindlimbs were apparent in both and improved in one animal. A similar picture occurred in the highest dose group, Group No. 4, (1.78 g/kg), with initial muscular weakness, lack of coordination and slow improvement until time of sacrifice. Histologically, all animals in Groups No. 2 and 3 had connective tissue lesions of varying severity found at the location of injection. The dog in Group No. 1, the lowest dose group, that died had hemorrhagic and purulent-appearing areas at the base of the medulla and between the meninges and the spinal cord. The spleen of this animal was enlarged to twice normal size. For all dogs, at autopsy, traces of oily substance, varying in amount approximately proportional to the administered dose level, were found within the cerebrospinal fluid.

Almost two years later, February 7, 1969, Hazelton Laboratories completed the study 15-Week Intrathecal Toxicity Study- Dogs which was a comparison of Pantopaque I and Pantopaque II. The data was submitted to Kodak’s Distillation Products Industries, Rochester, NY, not to Lafayette Pharmacal, Inc as had been done with the earlier studies. The purpose of the study was to evaluate the long-term effects of Pantopaque II when compared to Pantopaque I after being left within the spinal column of dogs. Pantopaque I was a great deal that had been received by Hazelton Laboratories from Lafayette Pharmacal on November 27, 1967, great deal No. 129666, and appears that it may have been a production great deal. The purity was "assumed" to be 100%.

Pantopaque II was identified as ethyl phenylundecyclate combined with 15% organically bound iodine ( great deals No 91347 and No. 91374), and appears that it was an experimental product. It was received July 24, 1967 and November 27, 1967 from Lafayette Pharmacal. The purity also was "assumed" to be 100%.

The study used 24 purebred Walker hounds, divided into 2 dosage groups (0.014 ml/kg) or (0.14 ml/kg) of either Pantopaque I or II compounds, for a total of 4 groups. The test material was administered by a single injection into the cisterna magna, with all dogs observed for 15 weeks. Full spine lateral x-rays were made for each dog following injection and at regular intervals of 30 and 60 minutes, 3, 24, and 48 hours, and one to two weeks thereafter. Only the brain and spinal cord were examined microscopically.

Five animals that received Pantopaque II at 0.14 ml/kg showed a marked increase in leukocyte counts at 24 hours. Five dogs had cgreat dealted blood present at the base of the brain and anterior spinal cord - one Pantopaque I and four Pantopaque II. Eight dogs had meninges visibly thickened three Pantopaque I and five Pantopaque II. In two dogs, both Pantopaque II dogs at 0.14 ml/kg, there were adhesions to the floor of the vertebral column. In 6 dogs, oily material was grossly seen in the meninges- three Pantopaque I and three Pantopaque II. Two Pantopaque I dogs receiving 0.014 ml/kg (No. 12686) (No. 12705) (* the lowest dose) microscopically at autopsy had moderate to severe granulomatous reaction surrounding large vacuoles in the space under the meninges and surrounding some of the spinal nerves. The granulomatous reaction involved spinal nerves. There was moderate to severe fibrosis surrounding the spinal cord and scattered areas of granulomatous reaction were present within the 35 white matter of the spinal cord. Most of the granulomatous reaction was associated around large, clear empty (cystic) vacuoles. The spinal cord was surrounded by moderate amounts of old blood present under the meninges. A Pantopaque I dog that had received the same dose (No.12694) had a similar microscopic picture of granulomatous reaction and fibrosis with cystic spaces but had a moderate amount of fresh hemorrhage under the meninges. Pantopaque II dogs receiving the lower dose level (0.014 ml/kg) appeared to have gross acute bleeding at all levels of the spinal cord and brain. Microscopically there was perivascular infiltration of meningeal vessels and spinal cord involving macrophages and mononuclear cells, and scattered clear cystic spaces.

Pantopaque II dogs at the higher dose level (0.14 ml/kg) appeared to induce a greater active inflammatory response component. The granulomatous inflammatory reaction was moderate to severe infiltration of mononuclear cells, macrophages, lymphocytes surrounding clear cyst-like areas, moderate to severe adhesion of the arachnoid and dura mater to the spinal cord. Histologically, sections of the spinal cords resembled areas of severe granulomatous reaction seen with Pantopaque I. Severe granulomatous infiltration extended down to the cauda equina, with moderate thickening of the arachnoid, and areas of compression of the spinal cord.

The following was the summary of Hazelton Laboratories, William M. Busey, DVM, Ph.D.’s findings:

The intrathecal administration of Pantopaque I and Pantopaque II to mature Walker hounds produced varying degrees of granulomatous meningitis in the brain and spinal cord. In the majority of instances, in the animals possessing meningitis, the inflammatory reaction appeared to be associated with empty vacuoles which could possibly have been the experimental compounds. In addition to the granulomatous type of cellular infiltration, there were varying degrees of fibrosis and thickening of the meninges of the both the spinal cord and brain. In the group receiving Pantopaque I, at a dosage level of 0.014 ml/kg, subdural granulomatous inflammation was present to a moderate to severe degree in three animals...... Only a slight to moderate amount of granulomatous inflammation was seen in three of the animals receiving Pantopaque II at 0.014 ml/kg. A slight amount of granulomatous inflammation was present in the cervical and thoracic regions of the spinal cord in Animal No. 12700. There was, however, in this animal, a moderate degree of meningitis in the brain which was associated primarily with two vacuoles in the region of the medulla oblongata..... There did not appear to be any difference in the incidence or severity of granulomatous meningitis between the animals receiving Pantopaque I at 0.14 ml/kg and those receiving Pantopaque II at 0.14 ml/kg. Severe granulomatous meningitis was seen in the cervical regions of all of the animals in these two test groups. In 36 addition to the inflammatory cellular infiltration, there was severe fibrosis in this region of the dura mater and arachnoid...... The majority of the animals receiving Pantopaque I and Pantopaque II at 0.14 ml/kg also possessed some degree of meningitis of the brain......

In conclusion, it can be stated that the intrathecal administration of Pantopaque I and Pantopaque II at 0.014 ml/kg and 0.14 ml/kg stimulates a granulomatous meningitis (*bold and italics added for emphasis) in the areas where the compounds appear to localize. The majority of the inflammatory reactions present in the animals on this study were of a subacute to chronic nature. There was a definite difference in the location and severity of the inflammatory reaction between the two dose levels. The dosage level of 0.014 ml/kg of Pantopaque I stimulated a granulomatous reaction in primarily the lumbar region; whereas, the dosage level of 0.14 ml/kg of both Pantopaque I and Pantopaque II produced severe reaction in the cervical and thoracic cords. Granulomatous inflammation was also present in the lumbar cord but to a slightly less degree of severity and incidence.

February 10, 1969, Hazelton Laboratories submitted the final report of the Teratology Study with Rabbits and Pantopaque II to Distillation Products, Rochester, NY. The purpose of the study had been to evaluate the potential of Pantopaque II to produce embryotoxic and/or teratogenic effects in a study population of albino rabbits. Peanut oil was administered as a control injection to Group No. 1, Pantopaque I to Group No. 2, and Pantopaque II to Group No. 3 rabbits. Each experimental group, which consisted of 40 rabbits, was divided into four subgroups of 10 animals each. The first subgroups received a single dose of the appropriate injection two days prior to insemination; the second subgroups received a single dose of the appropriate injection on Day 5 of gestation; and the third and fourth subgroups were injected on Day 8 and Day 11 of gestation, respectively. The study was begun on June 25, 1968, with sacrifice of the last groups of females completed on September 6, 1968.

The final results indicated that there were no meaningful differences between the peanut oil, Pantopaque I and Pantopaque II groups in the number and placement of implantation sites and live fetuses, in the weights and lengths of the fetuses, or in the incubation survival. Females with implantation sites unaccounted for were found in the peanut oil and Pantopaque I groups. The number of resorption sites and incidence of females with resorption sites were high in both the Pantopaque I and II females. The mean value of dead fetuses in the Pantopaque I group was high; (* bold added for emphasis) however, one female only was found with dead fetuses, and the value for this parameter was within normal limits. No dead fetuses were found in the Pantopaque II group. No unusual findings were noted in the external appearance or gross visceral anatomy of any of the fetuses. The development and skeletal structure of the Pantopaque I and Pantopaque II fetuses were comparable to that the peanut oil (control) fetuses. Therefore, the response for Pantopaque II was essentially the same as for Pantopaque I 37

April 14, 1969, FDA’s Associate Director for Marketed Drugs, Marvin Seife, MD issued Lafayette Pharmacal, Inc. a letter regarding the status of NDA 5-319. Our records indicate that you have not submitted any annual reports as required by the provisions of regulations 130.13 and section 505(j) of the Federal Food, Drug and Cosmetic Act.

The failure to maintain the required records and make the reports pursuant to the

authority under section 505(j) of the Act may result in withdrawal of the approval of

the new drug application, and is prohibited.

In addition for the sake of uniformity and the convenience of the physician, it is

recommended that the labeling of your product and those of your distributors, be

revised to contain sections in the following order:

NAME OF THE DRUG

DESCRIPTION

ACTIONS

INDICATIONS

CONTRAINDICATIONS

WARNINGS

PRECAUTIONS

ADVERSE REACTIONS

DOSAGE AND ADMINISTRATION

OVERDOSAGE

HOW SUPPLIED

REFERENCES

Further we recommend the following:

1. Delete the statement "The small amount of material left in the subarachnoid space is usually absorbed in two months."

2. In the INDICATIONS section state the substance of the following: "Pantopaque is indicated for the performance of myelography."

3. In the ADVERSE REACTIONS section include the following: a. Severe arachnoiditis producing headache, fever, meningismus, pain in the back and extremities and elevations in the white blood count and the protein count of the cerebrospinal fluid. b. The incidence and severity of arachnoiditis are generally increased when active subarachnoid bleeding has been induced by the lumbar 38 puncture. c. Rare instances of the development of lipoid granulomas, obstruction of the ventricular system and venous intravasation producing pulmonary emboli.

4. In the CONTRAINDICATIONS section include the substance of the following:

"The administration of Pantopaque is contraindicated in patients with known hypersensitivity to iodine or its compounds. Intrathecal administration should be deferred if bleeding is encountered in the performance of the lumbar puncture." 5. In the PRECAUTIONS section, note that diagnostic tests of thyroid function involving measurements of iodine may be invalidated for several years following intrathecal injection of Pantopaque.

6. In the DOSAGE AND ADMINISTRATION section the amount commonly use as 3 to 12 ml. (* Bold added for emphasis) Please submit the reports and let us know your proposal to the above recommendations within ten days of the receipt of this letter.

June 25, 1969 Lafayette Pharmacal’s President W. S. Bucke wrote to Dr. Grigsby of FDA to request to withdraw NDA 16-377 for marketing approval of Pantopaque II. The reason that was given to FDA for withdrawal of the NDA was as followed: Based on the summaries of the three principal investigators who studied 203 cases (91% of total), it is concluded that Pantopaque II containing 15% organically bound iodine has no real improvement (* underlining added for emphasis) over conventional Pantopaque (Iophendylate Injection, U.S.P.) containing 30% iodine. Supplies of Pantopaque II sent to clinical investigators have been recalled and inventories have been balanced with the amount shipped and returned. Case reports from investigators have been summarized and are included in Volume III. The information submitted with this letter has been compiled according to the form described in regulation 130.4(e) and represents the complete data on the subject. It is presented as three volumes, in triplicate. June 25, 1969, Mr. Bucke also wrote to FDA to withdraw IND #1161 for Pantopaque II. The letter indicated that the case reports of IND 1161 were included in NDA 16-377, and were being 39 submitted in lieu of the annual progress reports. June 26, 1969, Memorandum of a Telephone Conversation, was written by F. Grigsby, MD of his discussion with Dr. Kunz of Lafayette Pharmacal, Inc.. Dr. Kunz had called Dr. Grigsby to inform FDA that Lafayette was officially going to withdraw NDA 16-377 for marketing of Pantopaque II (15%). Dr. Kunz indicated that the firm’s reason for withdrawal of their Pantopaque II marketing application was that the firm had found that the 15 % Pantopaque was no more effective, and frequently less effective, then the currently marketed 30% preparation.

Dr. Kunz was informed by Dr. Grigsby that if no further clinical studies were contemplated for the 15% Pantopaque II that IND 1161 should also be discontinued by Lafayette’s submission of an amendment to the IND with a reference to the clinical studies that have or will be submitted to the NDA before its official withdrawal. The "Notice" reference may serve in lieu of the annual progress report. In addition the amendment to the IND should include information respective to notification to all clinical investigators of their action and to the disposition of the remaining drug.

From the memo, and the letter to FDA to withdraw the IND and NDA for Pantopaque, there appears to have been no mention by either Mr. Bucke or Dr. Kunz of the adverse findings of the animal safety studies done by Hazelton Laboratories relative to the equivalent poor safety performance of both Pantopaque I, the approved product, and Pantopaque II, the investigational product. Therefore, FDA was not informed that the animal toxicity studies did