ATTACHMENT B PRELIMINARY REPORT ON HHS - MAY 12, 1994 DISCLAIMER The following is a staff memorandum or other working document prepared for the members of the Advisory Committee on Human Radiation Experiments. It should not be construed as representing the final conclusions of fact or interpretation of the issues. All staff memoranda are subject to revision based on further information and analysis. For conclusions and recommendations of the Advisory Committee, readers are advised to consult the Final Report to be published in 1995. Preliminary Report on HHS - May 12, 1994 Attachment B Staff Analysis Letters reviewing HHS/PHS grant proposals could be an excellent source of documentation for the ethical and scientific criteria which were actually being applied at the time. Unfortunately, HHS has stated that it believes such letters are no longer in its files. However, an alternative source may have been found by one of the staff members of the Committee. In publicly available Department of Defense documents now held by the National Archives, Jim David, now of the Committee staff, had previously found copies of letters reviewing Public Health Service grants. Apparently, when projects were seeking multiple sources of funding, agencies obtained copies of documents from other agencies. Although HHS believes that the Public Health Service itself destroyed such review letters, the Department of Defense did not destroy its copies. One such letter reviewing a 1950 grant proposal by Eugene Saenger, MD, is attached as an example.The letter is a review of a 1950 proposal by Saenger to use iodine-131 as a tracer to measure blood circulation time in children. The reviewer, Dr. Myron Prinzmetal, M.D., opposes the proposal: "because of the possible unknown dangers of using radioactive substances on normal infants and children for purposes of Investigation when other methods which have been shown to be completely innocuous are available...', This example illustrates several important methodological points for the Committee to consider: First, the agencies are far from exhausting the possible avenues available for research. As HHS itself discovered in its own search, many projects were cc-funded. The discovery of this letter indicates that co-funding generated multiple copies of important documents. In instances in which the originating agency has routinely destroyed files, copies held by other agencies may be the only source available. Second, documents relating reasons for rejecting research proposals may be as crucial as documents approving proposals for determination of the ethical standards actually implemented at the time. Comparisons of rejections and acceptances may clarify the demarcation of ethical boundaries. (A more developed example of this is the article by staff member G. Whittemore on the rejection of human experimentation related to the development of a nuclear-powered bomber). 1 Third, such letters help determine when a medical procedure came to be regarded no longer as experimental but as routine. In this 1950 letter, the use of iodine-131 as a tracer is still regarded as a procedure with "unknown dangers." Fourth, such documents help uncover the history of the people and procedures used for reviewing research proposals. The letter provides a number of specific clues to aid in further research: - the name of the Public Health Service Section assigned the proposal (Physiology) - The name of the executive secretary of that section in 1950 (Scantlebury) - the name of the reviewer (Prinzmetal, although the use of the term "We" in the first sentence suggests others also contributed to the review) - the institution of the reviewer (Cedars of Lebanon Hospital) - the grant number. In addition to the single review letter just discussed, the file also contains a copy of the grant application itself and a letter of clarification from Saenger. These have also been included for the Committee. 2 INSTITUTE FOR MEDICAL RESEARCH CEDARS OF LEBANON HOSPITAL 4751 Fountain Avenue Los Angeles 27, California November 17, 1950 Ronald E. Scantlebury, Ph.D. Executive Secretary Physiology Study Section Federal Security Agency Bethesda 14, Maryland when other methods which have been shown to be completely innocuous are available if a radioactive substance should be used in an infant, one would think a substance with a much shorter half life such as NA 24 would be preferable. Very truly yours, /a/ Myron Prinzmetal Myron Prinzmetal, M.D. UNIVERSITY OF CINCINNATI COLLEGE OF MEDICINE Mailing Address: Radioisotope Laboratory K-4 General Hospital Cincinnati 29, Ohio November 24, 1950 Dr. Ronald E. Scantlebury Executive Secretary Physiology Study Section National Institutes of Health Bethesda 14, Maryland Reference: Your H-925 Dear Dr. Scantlebury: The following information is submitted to cover the 3 points raised in your letter of November 15th, in regard to my application 11-925. "1. A letter from the Atomic Energy Commission that permission will be granted to use the isotopes requested (iodine-131 for the purpose indicated: l. In our original permit from the Atomic Energy Commission for the use of radioactive iodine-131, we are permitted to use iodine-131 for tracer studies in infants and children, giving one microcurie per kilogram of body weight. Our application and permit did not define whether such a dose would be given orally or intravenously, and no limitation was made by the Atomic Energy Commission as to the route of administration. At least 95% of this dose is absorbed into the blood. In developing this project further it now appears desirable to give the iodine-131 &5 radioactive di-iodofluorescein or as radioactive iodinated human serum albumin, since there will be a smaller uptake by the thyroid which will be chemically blocked before staking the test. Applications for such studies are now pending with the Atomic Energy Commission. I will notify you as to the outcome as soon as possible. In human adults approximately 35-50 microcuries of radioactive iodinated human serum albumin are used. Since radioactive di-iodofluorescein has a biological half life of 2 - 3 days as compared to a biological half life of 6.5 for radioactive sodium iodide, safe ranges for infants and children can be approached easily. "2. Have any studies been carried out on your animals, i.e. puppies, to get a preliminary indication of the dosage required for adequate detection with your equipment:" 2. No studies as yet have been carried out on animals, One of the chief purposes in requesting this grant is to develop detecting devices which ire more directional and more sensitive than the currently Dr. Scantlebury - 2 - ties for gamma radiation of 0.1 to 0.3; 0 all gam;'a photons, whereas scintillation counters have 30 - 40 times this sensitivity. It is planned to develop small Phosphors of 3 - 6 mm. in diameter which will be quite long in relation to their diameters, so that a highly directional probing counter will be obtained. Such detecting devices should permit the use of tracer doses of about 10% the present doses which are based in part on detection by Geiger counters. Preliminary studies of the method on puppies and dogs, approximating human infant size, will be done. "3. A question that arose, was, in what way will the proposed method be better than existing methods of measuring circulation tine in children. A statement from you on this point should be helpful:' 3. The measurement of circulation tines in children by present methods 15 adequate only if the child is well able to cooperate and is not crying or struggling. Such methods as decholin, cyanide and either times depend largely on subjective cooperation and hence are valueless in infants and children under the age of three years. The fluorescein method does not have a sharp end point, and also the end point is subjective to the observer and may vary with individual observers. It is our desire to develop a method of measuring circulation times which is completely objective. Also by using several detectors, several end points can be recorded simultaneously. In addition the blood volume can be determined. The problem of accurate diagnosis of congenital heart disease in infants and children under the age of three is, especially difficult, and this study will help to improve our diagnoses. We have available many patients with abnormal hearts at the children's hospital and our circulation time studies will be correlated with the findings of angio-cardiography, cardiac catheterization, surgery and autopsy. Respectfully Submitted, /s/ Eugene L. Saenger Eugene L. Saenger, M.D., Director Radioisotope Laboratory Asst. Professor of Radiology January 1960 Federal Security Agency Public Health Service APPLICATION FOR GRANT-IN-AID Rec. 6/2/50 C396(C3) No. S.S. Date May 1, 1950 Application is hereby made for a grant-in-aid in the amount of $1117.207 for the period from January 1, 1951 to December 31 1951, inclusive. Title of Project: Physiology of patients with cancer and experimental therapy of cancer Title of Principal Investigator: Dean of the Medical School and Professor of Pediatrics Name of Principal Investigator: Dr. Francis Scott Smyth Address of Principal Investigator: University of California, School of Medicine, Medical Center, San Francisco 22, California. Title of Financial Officer: Vice-President - Business Affairs Name of Financial Officer: Mr. James H. Corley Address of Financial Officer: 250 Administration Building, University of California, Berkeley 4, California Name of Institution: University of California School of Medicine. (Name and title of official authorized to sign for institution) Robert G. Sproul, President of the University Page 1 C 396(C3) No. S.S. Budget proposed for the year 1/1/51 through 12/31/51 this date to be the same as those given on page 1 Item Funds requested Funds from the public from health service other sources PERSONNEL (itemize all positions, give names, of professional ?) See attached breakdown $65,223.90 $5,940.00 PERMANENT EQUIPMENT NEEDED (Itemize) None --- ---- Consumable Supplies Needed (Itemize) See attached breakdown 17,854.00 7,060.00 Travel None -- --- (Another category) Materials, for bed space: Reimburse Laguna Honda Home 15 patients @ $4.10 per day, 365 days 2,447.50 --- Subtotal 105,525.40 xxxxxx Overhead (Not to exceed 4% of subtotal) 5,662.83 - xxxxxxxx Total for the year 117,207.43 $15,000.00 (b) Estimate of future requirements" First additional year $115,000.00 Second additional year $120,000.00 Third additional year $120,000.00 Fourth additional year $120,000.00 Instructions: Remove last copy and carbon only, and replace ? sheet between (carbon and paperplate before returning to Public Health Service.) Page 2 APPLICATION FOR GRANT-IN-AID C-396(C2) C 396(C3) No. S.S. Budget proposed for the year 1/1/51 through 12/31/51 PERSONNEL (1(a) cont.) Per Mo. Per Annum Total Ward nurses: Day Duty (4) 220.00 2,640.00 10,560.00 Night Duty (4) 230.00 2,760.00 11,040.00 Dietician (1) 260.00 3,120.00 3,120.00 Ward Helpers (3) 175.00 2,100.00 6,300.00 Orderlies (4) 190.00 2,280.00 9,120.00 Kitchen Helpers (3) 173.50 2,082.00 6,246.00 Secretary (1) 200.00 2,400.00 2,400.00 Janitor (1) 185.00 2,220.00 2,220.00 (51,006.00) The above represents the actual number of people on our personnel rolls. The per annum figure represents the entrance salary for a beginning employee. No Professional (M.D. or Ph.D.) personnel are employed on these funds. ______________________________________________________ Allowance for yearly honor merit increase for personnel: Nurses 1,800.00 Dietician 120.00 Ward Helpers 720.00 Orderlies 840.00 Kitchen Helpers 720.00 Secretary 360.00 Janitor 240.00 This figure represents increases already in effect and for (4,800.00) increases anticipated for the period of this budget. ___________________________________________________________ General Assistance: Relief Dietician (1) (yearly basis) @ $1.269 hr. 960.00 Dietician, relief (1 mo. period) @ $1.269 hr. 220.00 Kitchen Helper, relief (3 mo. period) @ $1.001 hr. 520.50 Ward Helper, relief (3 mo. period) @ $1.010 hr. 525.00 Orderly, relief (3 mo. period) @ $1.096 hr. 570.00 Allowance for accumulated vacation leave for personnel on permanent status (based o 1 month period): Nurses (8) 1/800.00 Dietician (1) 270.00 Ward Helpers (3) 585.00 Orderlies (4) 820.00 Kitchen Helpers (3) 581.00 Secretary (1) 230.00 Janitor (1) 205.00 (7,286.50) Matching contributions to the State Employee Retirement System 5,047.40 at 8% of total gross non-academic salaries, plus a $4.00 service charge for each participant. 4.00 (5,131.40) TOTAL 68,223.90 Page 2a APPLICATION FOR GRANT-IN-AID C-396(C2) C 396(C3) No. S.S. Budget proposed for the year 1/1/51 through 12/31/51 CONSUMABLE SUPPLIES NEEDED (1(a) cont.) Total Supplemental food for diets 15 patients @ $0.65 per day, 365 days 3,599.00 Drugs, including fluids, antibiotics, heparin 5,219.00 Surgical Dressings 1,278.00 Kitchen Equipment, expendable 230.00 Glassware, syringes, surgical supplies, catheters 1,526.00 Surgical Instruments, enamelware, replacement items for permanent equipment on hand 841.00 X-ray film, photographic supplies 552.00 Linen replacements 774.00 Household supplies (soap, paper towels, lysol, etc.)627.00 Minor repairs and maintenance of equipment 248.00 Total $17,854.00 These items are based on actual expenses incurred during past full year of operation. No additional permanent equipment is requested. Many items not covered by this request for the operation of the research ward are to be referred by the anticipated grant from the University of California of $16,000. Page 2b APPLICATION FOR GRANT-IN-AID C-396(C2) C 396(C3) No. S.S. Budget proposed for the year 1/1/51 through 12/31/51 BUDGET SUMMARY COMPARISON SINCE ESTABLISHMENT OF RESEARCH WARD Personnel 35,150.56 54,111.00 60,732.00 68,223.90 Permanent Equipment 14,196.00 2,877.50 --- --- Consumable Supplies 5,500.00 14,495.00 12,743.00 17,854.00 Contractual-Bed space 15,246.50 18,450.65 20,422.00 22,447.50 Other expenses 400.00 --- --- --- TOTAL $79,372.50 $97,128.88 $101,408.76 $117,207.43 1/ The research ward was actually opened on July 6, 1948. 2/ As seen from the budget, the increase of $15,738.67 is due to three major factors: (a) merit and other increases in salaries, as authorized by the University, plus the State Employment Retirement System contributions, as agreed by the United States Public Health Service and the Secretary of the Regents of the University of California, (b) increases cost of reimbursement for beds to Laguna Honda Home from $3.72 to $4.10 per day per bed, and, (a), an additional $5,000.00 is requested for drugs such as antibiotics, fluids, etc., which were underestimated last year, such as antibiotics, fluids, etc., which were underestimated last year. Page 2c C-396(C2) C 396(C3) No. S.S. [deleted] all support, including that from own institution, on this related research projects from sources other than Public Health Service. Budget proposed for the year 1/1/51 through 12/31/51. TITLE OF PROJECT PREVIOUS Laboratory Univ. of California 5,000.00 1/47 - 6/30/47 School of Medicine Research Ward Univ. of California State funds 15,000.00 11/47 - 6/30/48 Laboratory Univ. of California 3,000.00 7/1/47 - 6/30/48 Research Ward - Univ. of California Isotope Unit State Funds 7,000.00 11/47 - 6/30/48 Research Ward Univ. of California Pathology Unit State Funds 10,000.00 11/47 - 6/30/48 Research Ward Univ. of California Pathology Unit State Funds 12,500.00 7/1/48 - 6/30/48 Laboratory Ditto 4,500.00 7/1/48 - 6/30/48 Research Ward Ditto 9,500.00 7/1/48 - 6/30/48 Isotope Unit Research Ward Ditto 7,200.00 7/1/48 - 6/30/48 Pathology Unit CURRENT Research Ward and Univ of California Laboratory State Funds 15,000.00 7/1/49 - 6/30/50 Research Ward - Isotope Unit Ditto 7,400.00 7/1/49 - 6/30/50 Research Ward - Pathology Unit Ditto 11,000.00 7/1/49 - 6/30/50 Research Ward Demon Program Fellowship 500.00 7/1/49 - 6/30/50 PENDING Research Ward and Univ of California Laboratory State Funds 16,000.00 7/1/50 - 6/30/51 Research Ward - Isotope Unit Ditto 7,400.00 7/1/50 - 6/30/51 Research Ward - Pathology Unit Ditto 11,000.00 7/1/50 - 6/30/51 Page 3 (note from typist: First column (Grant Number) deleted by improper copying) Cancer Inst. Direct Allocation - Laboratory 51,500.00 1/1/47 - 6/30/47 Cancer Inst. Direct Allocation - Laboratory 54,544.58 7/1/47 - 6/30/48 Research Ward 73,372.50 3/1/48 - 12/31/48 Cancer Inst. Direct Allocation - Laboratory 117,525.00 7/1/48 - 6/30/49 Research Ward 83,064.20 1/1/49 -12/31/49 Research Ward 12/064.65 1/1/49 - 12/31/49 Cancer Inst. Direct Allocation - Laboratory 114,000.00 7/1/49 - 6/30/50 Research Ward 101,408.76 1/1/50 - 12/31/50 Current shown includes 8% overhead Proposed Plan: Specific aims of project. Method of procedure. Relationship of anticipated results to general problems in field. Facilities available including list of major items of permanent equipment. Previous work done on this or closely related projects by the investigatorial. Most important publications of investigator(s) pertaining to this problem. Results bearing on this project obtained by other investigators. Publications of other investigators related to this proposed project. Page 4 Application for Grant in Aid 4. Proposed Plan (Continued Sheet) Number: C 396 (C3) No S.S. 4(a). Specific aims of Project: The specific aim of the project is clinical research in cancer. With the cancer patient as the focal point of the investigations, the work is oriented along four ----- approaches: (1) Experimental therapy, providing clinical material for other studies as well as permitting evaluation of such procedures on neoplastic diseases; and (2) Physiology, particularly cardiovascular and respiratory physiology of patients with neoplastic diseases; (3) Biochemistry, including metabolic studies on cancer patients, and investigations of specific biochemical reactions; and (4) The study of protein fractions of cancer and normal tissues of human and animal origins, utilizing physicochemical and immunochemical techniques. 4(b). Method of Procedure. Patients for investigation are selected through the Consultative Tumor Board of the University of California School of Medicine, by referral of physicians of the Bay Area. Such patients as are not applicable for curative therapy by surgery or irradiation are evaluated for their applicability to experimental procedures. For admission to the research ward, each patient signs a release which indicates that the patient understands that he will be used for experimental work and that he agrees to this and to a ------ (see attached Balance Form). The patient receives a full clinical and pathology work-up, an observation period, and is then applied toward one or another of the investigations on patients is reviewed by the Cancer board of the University of California School of Medicine for its clinical safety. 4(c). Relationship of Anticipated Results to General Problems in the Field. The results of the investigations, since they are of work being done on patients, is directly applicable of the clinical management of patients with cancer. The chief interests of the Laboratory, however, are the study of the biology, physiology and biochemistry of human cancer, with particular emphasis on how the presence of ----- neoplastic diseases affects the human host. 4(d). Facilities Available. The Laboratory and its research ward occupy two floors of a wing of the Laguna Hond Hote. This space was made available by arrangement between the University of California and the San Francisco Department of Public Health; the Laboratory will move to its new quarters at the Medical Center toward the end of 1952. Two-thirds of the area is occupied by laboratories, including clinical biochemical laboratories, 1 hematology laboratory, 1 protein chemistry and immunochemistry laboratory, 1 clinical isotope laboratory, 1 biochemical isotope laboratory, 1 physiology laboratory and an animal room. The pathology laboratory (supported by University of California funds) is in another area. All these laboratories and the research ward are fully equipped for their designated work. Special equipment includes: electrophoresis (Amino), preparatory ------ (Spinco), microchemical assembly (Kirk), and a full clinical physiology complement of strain-gage indicators, recording oximeters, oscillographs, electroenosphalographs, Page 5 Application for Grant-in-aid C 396 (C3) Proposed Plan (continued sheet) No S.S. 5(a) Previous Work Done on This (or closely related) Project. The Laboratory of Experimental Oncology was initiated in January 1947 and the research ward, which was supported by Grant C-396, was opened on July 6, 1948. The attached project report indicates the lines of investigation being undertaken and the publications ----- the segments of work which have been pursued to the point of publication. 5(b). Personal Publications Pertaining to this Problem. The list of 19 publications which have appeared or have been submitted during the past year are give in the regress report. Five additional papers are in the process of preparation. At least 40 copies of reprints of all publications have been submitted to the National Tumor Institute and National Institutes of Health and additional reprint copies are being submitted with this application at this time. 6(a). Results Bearing on This Project Obtained by Others. The wide program being undertaken at the Laboratory of Experimental Oncology would refer to such an extensive review of previous literature in cancer research that it is considered inappropriate to include this here. The paper entitled, "Experimental chemotherapy in neoplastic diseases" by Shirking and Bierman (Radiology, 53, 518-529, October, 1949), for example, lists 64 references on this segment of the program alone. It is believed that some specific investigations were first initiated at this laboratory. These include: (1) the effects of virus infections on clinical cancer, which is now also being studied at the Memorial Hospital in New York, (2) intra-arterial, ---- including the use of chemotherapeutic agents by this route (3) ----- upon the exploration of cardiovascular affects of cancer. 6(b). Publications by Others on Related Work. Refer to 6(a). The listing of references from the literature for this wide program would be too extensive to justify inclusion here. References to publications by others on similar or related work are, of course, always indicated in the publications. Page 6