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.

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 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 was 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. (Why?)

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. (The) Pantopaque I (used) was a lot that had been received by Hazelton Laboratories from Lafayette Pharmacal on November 27, 1967, Lot No. 129666, and (it) appears that it may have been a production lot. The purity was "assumed" to be 100%.

Pantopaque II was identified as ethyl phenylundecyclate combined with 15% organically bound iodine (Lots 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 clotted 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 white matter of the spinal cord. (35)

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 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." (36)

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; 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 (later involved in the Generic Medicine Scandal of the 1980's) 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:













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.

Please submit the reports and let us know your proposal to the above recommendations within ten days of the receipt of this letter."

Lafayette Pharmacal's Withdrawal of NDA 16-377 for Approval of Pantopaque II

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 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 submitted in lieu of the annual progress reports. (39)

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 not support the "safety" of Pantopaque I.

June 27, 1969, Memo of a Telephone Conversation of another conversation held between Dr. Grigsby and Dr. Kunz, and after the writing of Lafayette's withdrawal letters by Mr. Bucke.

"Dr. Kunz stated that he had collected all data in their possession and that their annual progress report is due within one or two months. He referred to this new drug application as one pending with FDA for approval but they have found the Pentopaque (sic) 30% produces no better visualization than 15% and in fact in some instances it is worse.

He stated that he will be in the District of Columbia within the next few days and will leave an amendment to the IND discontinuing clinical studies. He was told that he may cross reference the information on clinical studies reported in the NDA to serve as a progress report for the IND. He was also advised to state the reasons for discontinuing the study and to inform us as to the final disposition of the drug and notification of all clinical investigators. He thanked me for the information and terminated the conversation."

Technically, the Hazelton Laboratories data had not sent the more damaging conclusions of their animal studies obtained in 1969 directly to Lafayette Pharmacal but rather had sent them to Kodak, Distillation Products Industries Division, Rochester, NY.

Therefore, it is "unclear" whether the most unfavorable Hazelton Laboratories animal safety data for both Pantopaque I and II sent to Kodak would have been in Dr. Kunz's "physical possession" at Lafayette Pharmacal when he spoke with Dr. Grigsby. (40)

It is also unclear whether the performance animal data obtained with both "approved" Pantopaque I and "investigational" Pantopaque II were ever shared with FDA within the three volumes of submitted "clinical data" for withdrawal of the NDA.

Dr. Grigsby documented in his memo that he clearly was indicating to Dr. Kunz that the firm was to be forthright and honest with the agency regarding providing all known product information and all reasons for withdrawal of the Pantopaque II marketing application.

It would have been assumed that Lafayette management would have known to be honest, forthright and complete with FDA in all information regarding NDA 5-319 (*Pantopaque I), and, that it was a crime for any sponsor to make fraudulent and/or misleading statements to FDA about a product marketed in the US.

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