FROM C. G. Aulisio, Ph.D., Biologics Product Inspector SUBJECT CCA Test Inspection Notes 1. On 11 April 1972 while officially inspecting the biologic 2. I bring this to your immediate attention because these observations I feel, are of importance and interest to you and to the Division. Calvin 1. Calvin Calvin G. Aulisio, Ph.D. THROMBIN, TOPICAL (BOVINE ORIGIN) PARKE-DAVIS THROMBIN, TOPICAL MUST NOT BE INJECTEDI APPLY ON THE SURFACE OF BLEEDING TISSUE AS A SOLUTION OR POWDER. DESCRIPTION Thrombin, Topical (Bovine Origin) is produced through a conversion reaction in which prothrombin is activated by thrombokinase in the presence of calcium chloride. Following standardization of potency (by dilution), the Thrombin solution is sterilized by filtration, filled into vials, dried from the frozen state and sealed under aseptic conditions. Also contained in this preparation are calcium chloride, sodium chloride, aminoacetic acid (glycine) and Phemerol (benzethonium chloride, Parke Davis). Glycine is included to make the dried product friable and more readily soluble, and benzethonium chloride as a preservative as follows: 0.4 mg, per 1000 unit vial, 0.1 mg per 5000 unit vial and 0.2 mg. per 10,000 unit vial, This product is prepared under rigid assay control. A National Institutes of Health (N.I.H.) unit is defined as the amount required to clot 1 cc. of standardized fibrinogen solution in 15 seconds. Approximately 2 N.I.H. units are required to clot 1 cc. of oxalated human plasma in the same period of time." ACTION Thrombin requires no intermediate physiological agent for its action. It clots the fibrinogen of the blood directly. Failure to clot blood results in the rare case where the primary clotting defect is the absence of fibrinogen itself. The speed with which thrombin clots blood is dependent upon its concentration. For example, the contents of a 5000 N.I.H. unit vial of Thrombin, Topical dissolved in 5 cc. of saline diluent is capable of clotting an equal volume of blood in less than a second, or 1000 cc. in less than a minute. INDICATIONS Wherever oozing blood from capillaries and small venules is accessible, bleed. ing can be checked promptly wil bin. Topical. It is particularly useful where there is bleeding from pachymatous tissues, cancellous bone, dental sockets, laryngeal and nasal s gery, and plastic surgery and skin grafting procedures. It may also be ed orally controhemorrhage of the upper gastrointestinal tract. WARNING BECAUSE OF ITS ACTION IN THE CLOTTING MECHANISM, THROMBIN, TOPICAL MUST NOT BE INVECTED INTRAVENOUSLY OR OTHERWISE ALLOWED JOUR LASSE:OLOKET VESSELS. EXTENSIVE INTRAVAS GK CULAR CLOTTING AND EVEN DEATH MAY RESULT. THROMBIN IS AN ANTIGENIC SUBSTANCE AND HAS CAUSED SENSITIVITY AND ALLERGIC REACTIONS WHEN INJECTED INTO ANIMALS ALTHOUGH NO SUCH EFFECT HAS BEEN REPORTED WHEN IT IS USED IN MAN FOR LOCAL HEMOSTASIS THROUGH TOPICAL APPLICATION AS RECOMMENDED.' ADMINISTRATION AND DOSAGE Solutions of Thrombin, Topical may be prepared in sterile distilled water or isotonic saline. The intended use determines the strength of the solution to prepare. For general use in plastic surgery, dental extractions, skin grafting, neurosurgery, etc., solutions containing approximately 100 units per cc. are frequently used. For this, 10 cc. of diluent added to the 1000 unit package (Bio. 2077) is suitable. Where bleeding is profuse, as from cut surfaces of liver and spleen, concentrations as high as 1000 to 2000 units per cc. may be required. For this the 5000 unit vial (Bio. 2073) dissolved in 5 cc. or 2.5 cc. respectively, of the diluent supplied in the package is convenient. Intermediate strengths to suit the needs of the case may be prepared by selecting the proper strength package and dissolving the contents in an appropriate volume of diluent. In many situations, it may be advantageous to use Thrombin, Topical in dry form on oozing surfaces. Caution: Solutions should be used the day they are prepared, If several hours are to elapse, the solution should be refrigerated, preferably frozen, and not used after 48 hours. Dilute acid, alkalies, saits of heavy metals and heat are detrimental to Thrombin activity, therefore, stomach acids must be neutralized prior to oral administration of Thrombin. The following techniques are suggested for the topical application of thrombin: 1. The recipient surface should be sponged (not wiped) free of blood before. thrombin is applied. 2. A spray may be used or the surface may be flooded using a sterile syringe and small gauge needle. The most effective hemostasis results when the thrombin mixes freely with the blood as soon as it reaches the surface. 3. In cases where a tourniquet is employed, it is well to release the constrictor temporarily, ligate large vessels and apply thrombin solution to oozing surfaces. 4. In instances where thrombin in dry form is needed, the vial is opened by removing the metal ring by grasping the edge where it is scored and tearing, using sterile pliers. The rubber-diaphragm cap may be easily removed and the dried thrombin is then broken up into a powder by means of sterile. glass rod or other suitable sterile instrument. 5. Sponging of treated surfaces should avoided in order that the clot remain securely in place. Eurombin, Joniçal max ba admin)sinjas primador Ventment of upper gastroIntestinal tract bleeding using either the followin methode METHOD 1: 1. Give two ounces of milk to neutralize the stomach acid. 2. After five minutes, administer two ounces of milk containing 10,000 to 20,000 N.I.H. units of Thrombin, Topical. 3. Repeat three times daily for four to five days or until bleeding is controlled. METHOD II: If preferred, a phosphate buffer solution may be used to control stomach acidity as follows: 1. By means of a Levine tube, introduce buffer solution into the stomach and aspirate contents. 2. Administer, through the Levine tube, two ounces of the phosphate buffer. 3. After five minutes follow with an additional two ounces of buffer containing 10,000 N.I.H. units of Thrombin, Topical. 4. Clamp tube for thirty minutes. At the end of that time aspirate very gently. 5. If no fresh blood is apparent, carry patient on buffer for 48 hours, administering one ounce every half hour. 6. If bleeding was not controlled, repeat steps 1 through 4. 7. If bleeding is still uncontrolled, other methods of therapy are indicated. *One-seventh molar phosphate buffer, pH 7.8 prepared as follows: 0.41 Gm, KH PO; 4.41 Gm, NasHPO (anhydrous) and MO, q.a. to make 8 ounces. PACKAGE INFORMATION Thrombin, Topical is supplied as Bio. 2073-Package contains one 5000 N.I.H. unit vial of Thrombin, Topical and one 5 cc. vial of Isotonic Saline Diluent with 1:50,000 Phemerol as a Preservative. Bio. 2076-Package contains one 10,000 N.J.H. unit vial of Thrombin, Topical. Bio. 2077-Package contains one 1000 N.I.H. unit vial of Thrombin, Topical REFERENCES 1. Tidrick, R.T., Seegers, W.H. and Warner, E.D.: Clinical Experience With Thrombin as Hemostal Agent. Surgery, 14-193, 1943. 2. Daly, B.M., Johnston, C.G, and Penberthy, G.C. The Management of Patients With Bleeding From The Upper Gastro-intestinal Tract With Butter and Thrombin Solution. Ann. Surg. 12.12. 1949. 3. Seegers, W.H. and Sharp, E.A.: Hemostatic Agents, Charles C. Thomas. Springfield, Minois, 198 4. Seegers, W.H. and Smith, H.P.: Factors Which influence the Activity of Purified Thrombin, Amer. Jour. Physiol. 137:348, 1942. EXHIBIT 59 WASHINGTON, D.C. Dr. ROBERT Q. MARSTON, DEAR DR. MARSTON: Your meager plan to shift DBS regulatory activities to FDA, and your inaccurate and incomplete response to the suggestion that the scientific work of DBS is not what it should be, indicate that you are willing, in fact desire, to take responsibility for the public health problems that result from reliance on the discredited CCA test for determination of influenza vaccine potency. This suggests that once again all of the relevant information has not reached your office. The DBS inspector of two companies producing influenza vaccine recently reported in writing to the DBS director that the CCA test is not giving satisfactory results. Variance in multiple test results of a single lot of influenza vaccine exceeded 100%. The companies, according to the written reports of the investigator, are routinely excluding the highest set of results to give a better picture of the test's accuracy than actually exists. A recent meeting of company and DBS officials held in the DBS established that even with careful attention to the large number of variables in the test the results achieved by different operators varied far in excess of the claimed 15% error. All of this practical experience supports the conclusions contained in the scientific literature that, in the words of Dr. Kilbourne, one of the members of the Benenson Committee, the CCA test is "archaic and unsatisfactory." That the people in your office who prepared your latest defense of science at DBS can see no contradiction between this statement about the CCA test and the assertion that the CCA test "appears to be a satisfactory procedure for estimating the content of the major influenza virus antigens in a vaccine" reveals a kind of myopia that explains much of the NIH inability to respond reasonably to questions about its scientific competence. Other equally inaccurate assertions clutter the latest defense of DBS science. For some reason, the inclusion of the ship study concerned with influenza is quoted for exactly the opposite points made by the data and the author. The reference to the polio situation does not take into consideration the 1968 position of Dr. James Shannon that the polio decision was arrived at in too much secrecy; that in 1954, Sven Gard, of the Swedish vaccine control authority, warned the American officials that the formaldehyde system they were relying on could not be expected to kill live polio virus contained in the vaccine; or that from witnesses who were at the meeting-Dr. Workman objected to proceeding with the polio vaccine licensing. Nor does the NIH defense explain how test methods, which they had great faith in, could be effective in detecting live polio virus contamination when many lots were released to the public without testing. There are a number of other assertions, mis-statements, or over-sights contained in the "comments on" and "staff analysis of" the suggestions of scientific problems at DBS which I helped to raise. Hopefully, this is not a document that the NIH intends to rely on for scientific purposes. I am curious to know the reason that one version of this document was presented to the Senate Appropriations Committee and another version was presented to the press. To me, this handling of the document supports the impression of its contents that it was not intended to be scientific. I sincerely hope that neither document represents the standard of science that is acceptable in the Director's office of the NIH. Unfortunately, an exchange of letters between Dr. B. G. Young and the Director's office suggests otherwise. Specifically, Dr. Young wrote to you asking for the reasons that Dr. J. Anthony Morris was barred from speaking at a seminar conducted in the Department of Microbiology at the University of Maryland where Dr. Young is the chairman. The answer given, in both its substance and the authority it distortingly quotes, suggests that the quality of scientific thinking at NIH has slipped greatly since the days when NIH was one of the world's foremost research institutions. Specifically, the response to Dr. Young's inquiry states that scientists are only allowed to raise controversial scientific issues within the "republic of science." It cites Alvin Weinberg in a way that suggests that he supports this idea. The letter also argues that the presentation of the views of "dissident scientists" outside the republic of science "is only likely to mislead and alarm an already underinformed and unsophisticated public * * *." Both of these ideas are directly counter to the growing belief of many individuals inside and outside of scientific circles that the general public must be more widely included in scientific debates. No more effective and eloquent a spokesman of this point of view exists than the Alvin Weinberg whose name is used in your office's response to lend prestige to the opposite point of view. In his book, Reflections on Big Science, Dr. Weinberg makes two points relevant to the inaccurate impression given by the use of his name in a letter justifying the restriction of scientists to speak on "Science, Law and Public Policy." He says, "In the long run, how much our society is going to spend on basic science depends upon the extent to which nonscientists develop the intellectual power and taste to appreciate, if not discover, science." Restricting the presentation of a scientist like Dr. Morris because his audience in this case a group of microbiology graduate students and their professors-is too "underinformed or unsophisticated" to understand and make judgments about what he has to say is surely not the way to develop the sunport for science that Dr. Weinberg sees as necessary. To use Dr. Weinberg's ideas as if they support such an action suggests not only that NIH does not feel public support is necessary but also has difficulty in understanding the point of the Weinberg argument. Dr. Weinberg also says, "In this age of big money for big science, it is harder than in earlier days to find the scientists dedicated solely to the truth * * *." I must say that my experience with the DBS and the NIH for the past two years suggests that an ever increasing consideration is given to other than scientific truth. Emphasis appears to be given to cost benefit analysis, risk-benefit ratio, personality consideration, and the expenditure of tremendous amounts of energy and money in an effort to support a position erroneously taken seem more important to the NIH leadership than arriving at scientific answers. You have a copy of the speech that Dr. Weinberg made at NIH. It makes a number of very important points about the nature of the scientific debate. Most importantly, it points out that the Republic of Science is a place where the credibility of scientists is tested. The Republic of Transscience is where policy debates to which some scientists might have some input takes place. The debates in the Republic of Transscience are public debates. In it is that kind of debate which is being conducted now about vaccine regulation. I hope that this letter has helped to put into context the policy issues which I am attempting to draw to your attention. Most specifically, whatever you may think about the Weinberg arguments, you must take some steps to insure that the currently indefensible state of influenza vaccine potency testing by the CCA method be investigated and corrected. As I have always made clear, I would be more than happy to discuss these issues with you at any time. I have found useful, and enjoyed, by various conversations with other NIH officials with whom I have spent time discussing the DBS situation over the past month. I hope to hear from you about these points. Sincerely yours, JAMES C. TURNER. EXHIBIT 60 DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE-PUBLIC HEALTH SERVICEBACTERIAL VACCINES AND BACTERIAL ANTIGENES REVIEW OF EFFECTIVENESS [Federal Register, Vol. 37, No. 51, Mar. 15, 1972] In accordance with the delegation of authority (37 F.R. 4004-4005) authorizing the Director, National Institutes of Health to administer the provisions of the Federal Food, Drug and Cosmetic Act with respect to those human drugs that are biologicals subject to section 351 of the Public Health Service Act (42 U.S.C. 262), the Division of Biologics Standards is undertaking a review of the effectiveness of all licensed biologicals. The first categories of licensed products to be reviewed for this purpose will be those bacterial vaccines and bacterial antigens whose labels are required by 42 CFR 73.001 (r) to state "No U.S. standard of potency." A licensed manufacturer of such bacterial vaccines or antigens who wishes to continue manufacturing and marketing such products shall advise the Division |