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With the reorganization and resulting centralization of four separate mail, file, and control functions, responsibility for receipt, jacketing, maintenance, and control of all documents was centralized in one branch in the Director's office. No new positions are requested for the Office of the Medical Director in fiscal year 1967. An increase of $65,000 for space rental to accommodate the 163 new positions requested for the Bureau in fiscal year 1967 has been prorated among the various activities.

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New veterinary drugs must now be evaluated and approved by FDA or virtually the same basis as human drugs. In addition to evaluating veterinary IND's and NDA's, conducting research, and maintaining surveillance over drugs subject to approval, the Bureau must also grant its imprimatur before animals that have been administered test drugs may be slaughtered for human consumption. A new Bureau of Veterinary Medicine was formed in October 1965 in recognition of the growing importance of veterinary products and medicated feeds, and their effect on animals consumed as food.

During fiscal year 1965, approximately 1,500 records and reports were submitted to FDA in accordance with provisions of the new drug regulations that require these reports for drugs that had been previously approved. The Bureau was able to process about a thousand of these reports by diverting personnel from their customary duties primarily from regulatory support work. In fiscal year 1966, the staff increase authorized should permit FDA to eliminate backlogs in this area and keep pace with the day-to-day workload.

In fiscal year 1967, an increase in the number of submissions is anticipated. With each publication of a food additive regulation involving a veterinary NDA, for example, past experience indicates that FDA can expect several thousand submissions from feed mills in the months following. Another important responsibility in this area is the evaluation of veterinary IND's. In fiscal year 1965, about 3 man-years were devoted to the processing of some 600 items. primary function of this staff is to approve the slaughter of animals that have been administered investigational drugs. In fiscal year 1967, over a thousand IND's are anticipated. To keep pace with this influx of IND's and NDA's, an additional eight positions are requested.

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FDA also proposes to strengthen its veterinary research capabilities in fiscal year 1967 with the addition of two positions. More tests of human products on animals are needed, as well as studies to determine tissue residues of marketed drugs and to assist in the design of investigations to determine the safety of new animal growth-promoting agents and other veterinary drugs. An increase of $10,000 is proposed to purchase experimental animals for these tests.

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The Bureau of Scientific Research (BSR) was established as an integral organization within FDA in January 1964. This budget is the first program plan specifically designed to meet the research needs of the Bureau as disclosed by operational experience. The disciplines represented in this program cover the entire spectrum of the sciences, from bacteriology and botany to zoology. Of the total of approximately 600 positions in this program in fiscal year 1967, over 350 (about three-fifths of the total) will be filled by professional personnel with 1 or more college degrees in the various fields of science.

One of the fetures of this presentation worthy of special note is the expansion of the extramural research program from $330,000 in fiscal year 1966 to $580,000 in 1967: an increase of $250,000, or about 70 percent.

The requirements of a vital and progressive research program must inevitably exceed the availability of personnel and facilities to meet these requirements. An extramural program makes it possible to secure the professional support required for the program but unavailable within FDA's own ranks. Often, the use of outside talent-particularly for specific research problems-is more effective and more economical than hiring and training personnel and purchasing equipment for the same tasks. Furthermore, the various advisory committees that have examined FDA operations in the past have consistently recommended that the agency strengthen the ties between its professional personnel and leading non-Government investigators.

A second noteworthy feature of the proposed fiscal year 1967 budget is the inclusion of "research breakthrough funds" under research support. These are envisioned as unrestricted funds that may be used to support promising research for which the requirements were not anticipated in the preparation of the annual budget some 18 months before the actual initiation of the research program. The need for funds of this type was clearly defined in a report to President Kennedy by a high-level committee assigned to discover improved mechanisms for supporting and encouraging Government research. This device has been employed with success by the Defense Department in some of its research laboratories for several years. The total funding requirements for this purpose cannot be predicted accurately, since there is no past FDA experience as a basis for comparison. A reasonable level, based upon past experience in the Defense Department, appears to be about 1 percent of the total in-house research budget for the Bureau: a total of $75,000. This amount is included in the amount available for extramural research in the Bureau support program and will be administered by the Bureau Director.

Another feature of this budget presentation is the identification of new approaches to the solution of research problems. It is a fundamental obligation of a research program to explore the unknown and to probe continually beyond the present limits of applied science in the certain knowledge that the routine scientific tools of the future will emerge from present-day hypotheses and speculative experimentation. Many of the techniques currently employed in areas of research outside of FDA can undoubtedly be used with good results in Agency investigations. Many new instruments, such as the mass spectrometer, have been used successfully in the field of organic chemistry and can be used with equal success to separate, identify, and examine chemicals found in food, drugs, cosmetics, and hazardous substances. About a fifth of the new positions requested by BSR in fiscal year 1967 are intended for inclusion in this area of new research approaches.

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Research in this area has been directed largely toward the nutritional aspects of food components and toward the chemical characteristics of animal fats, vegetable oils, and the manufactured fat-like materials used in food and in feeds. Studies will continue on the relationship between diet and body functions like tissue changes and growth, and on the nutritional role of various diet components, such as vitamins and minerals. Other studies will deal with the effects of obesityinducing drugs and the possible connection between diet and diseases of the arteries.

New or expanded projects in fiscal year 1967 call for an increase of seven positions. In order to evaluate manufacturers' claims for various dietary supplements, FDA needs more information on the relation of hormone balance, antibiotics, and environmental influences to the availability of mineral nutrients, and the effects of changes in temperature and humidity on nutritional requirements. Another project will be aimed at methods for determining vitamins and other nutrients in foods and dietary preparations. In addition, preliminary findings have convinced FDA that it must investigate in more depth the effects on fats and oils of prolonged heating and of storage at various temperatures.

An increase of $45,000 is requested for extramural cooperative studies: bringing the total to $70,000 in this area. Recent clinical evidence has created certain doubts about the wholesale, unqualified use of vitamin preparations. Extramural studies are proposed to determine if a surplus of one or more specific vitamins in the diet may have a harmful effect-particularly on children. Two other studies are proposed: one on the effects of diet on the chemical composition of the unborn child and one on the role of certain trace elements like zinc and selenium in nutrition.

Natural Contaminants of Food

Research in this area has centered around four major sources of contamination: microbial organisms, radioactive material, filth, and mycotoxins that are derived from molds. This last problem is relatively new for FDA scientists. Mycotoxins are known to be extremely harmful to certain animal species, but their effect on man is not yet fully understood. Molds which may grow on bread, grapes, peanuts, corn, peaches, and cocoa beans produce a group of closely related chemical substances know as aflatoxins. The discovery that molds can produce several different types of this toxin, as well as others not yet clearly characterized, has suggested the need for more research in this entire areaparticularly on methods for separating the various known aflatoxins, on determining the different molds and fungi that can produce toxins, on analysis of conditions affecting mold growth, and on investigations of the effects of these toxins on animals, humans, and tissue cells.

Another problem that demands immediate FDA attention is the relation of foodborne viruses to human illness. Anticipating future requirements to evaluate the efficacy of antiviral drug preparations, FDA plans a study in this area. Also, work should be expanded on the effects of various methods of food preservation (such as freeze-drying, the use of antibiotics, and ionizing radiation) on decomposition. Five positions are requested to expand ongoing projects and initiate new work in these areas.

Four studies totaling $78,000 are proposed in this area, an increase of $23,000 over fiscal year 1966. One of these is a pharmacological study of the effects of controlled amounts of aflatoxin as part of the cooperative research program already underway at the medical college outlined in the pesticides section of this budget, on page 30. These experiments are aimed at the detection of subtle microscopic changes in human tissue and organs that occur long before a person is seriously harmed; the safety of the procedures used in these tests is fully guaranteed by adequate advance animal experimentation. The other studies relate to microbiological contamination of food: Two are on botulism and represent extensions

of current projects, and the third will be on the significance of food-borne viruses as a source of disease.

Food additives

The major portion of BSR's research program in this area has been based upon exposure of animals to food additives in short-term (acute) or long-term (chronic) studies. Even the acute tests are quite time consuming; many tests take anywhere from 2 to 7 years to complete. Emphasis in food-additive research will continue to be placed on the search for more subtle "early warning" signs of toxicity that will reveal harmful effects more quickly than current methods do.

Four additional positions are requested in this area: Three are for comprehensive studies on the effects of selected additives on experimental animals, including swine, that are fed these substances on a controlled basis. Some of the results of these studies can be applied to pathological research programs in other areas, such as drugs or pesticides. The other position is for a project on the development of multiple detection procedures for antioxidant food additives that will be expanded to identify and determine alteration and reaction products of these chemicals in foods.

Two extramural studies totaling $60,000 are proposed, an increase of $35,000 over fiscal year 1966. One is for the synthesis of certain food additives that may cause cancer, to be used in developing methods to detect substances of this type in foods. The other will utilize the facilities and techniques of the medical college previously mentioned for research on the effects of food additives on man. New approaches in food research

The need for a “speculative” research program that will seek novel approaches to the solution of scientific problems has been explained in the introduction to BSR's request. Five additional positions are needed to determine if the multiple detection procedures that have been developed to analyze pesticides can be applied as successfully in other areas-to analyze mycotoxins, food additives, and toxic inorganic elements, for example. Three other new positions are needed for studies in a new area: "gnotobiotics." This is the field of nutrition in germ-free animals, and FDA scientists hope to obtain valuable data on the role that intestinal organisms play in making nutrients available to their host. It appears that many of these intestinal flora are vital to the processes of food metabolism. One other position is requested to support a search for microbiological methods to determine the hazards associated with the use of new food-processing techniques, such as gaseous sterilization, dehydro-freezing, and hermetically sealed containers.

Two cooperative studies totaling $60,000 are proposed: an increase of $60,000 over fiscal year 1966. These will involve investigation of two potentially more rapid and more accurate multiple-detection procedures for the analysis of pesticides. Since the instruments used in these studies are quite expensive and still in the experimental stage as far as FDA use is concerned, it is more economical to contract for the equipment and scientific skills needed in their use until the Bureau has enough information to determine if it can apply these new methods to its own research and enforcement programs.

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Research in this area has been directed toward three major problems: improvement of methodology, studies of pesticide metabolism, and toxicological studies. Improved methods, beyond those used in industry tests, are needed to insure that pesticide residues in foods are within the tolerances established by law. FDA must also determine whether the original pesticide chemical has been transformed within a plant or animal into a different compound (called a metabolite) that may be more harmful, or whether exposure of the pesticide to light and air has produced harmful changes. Finally, tests must be conducted to measure the toxic effects of these substances on animals and, to the extent feasible, on man— particularly over a long period of time.

The six additional positions requested in this area will be used on two new projects. One will involve a study of the chemical and biological behavior of pesticides after they are assimilated into an animal's body. Of particular interest is the possibility that altered pesticide chemicals exist in milk. The other project will involve the exploration of the possible advantages of miniature swine otver other animal species used in pesticide tests, since there is reason to believe hat in many instances the pigs' responses more nearly resemble those of man.

A total of $170,000 is requested for cooperative research: an increase of $20,000 over fiscal year 1966. The most significant of these projects is a continuing contract with a medical college, where unique and important work is being performed. Very low levels of the pesticide parathion have been fed under careful medical supervision to human volunteers. Chemical and electron microscopic examination of their blood and tissue has failed to reveal any significant abnormal effects, even though the parathion level in their diets was considerably higher than that established for this chemical in human food. This study provides FDA with its only means of obtaining first hand information on the direct effect of toxic chemicals on man. In fiscal years 1966 and 1967, this program will be expanded to include food additives and aflatoxins, as well as the pesticide chemicals TDE, Captan, and Dalapon.

Two other cooperative studies will involve a literature search in the pesticide field and a study of the effects of food processing on pesticide residues.

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To insure the purity, potency, and efficacy of drugs, FDA must continually improve its capability to detect and measure drug components, even in microscopic quantities. Methods to detect and isolate various adulterants must also be developed. In addition to research on the composition and strength of drugs, more emphasis will be placed on research to determine their efficacy, so that FDA can judge whether or not manufacturers' claims are presented truthfully and fairly. Seven new positions are requested for drug research.

Among the new techniques for identification and determination of drug substances to be investigated in fiscal year 1967 are vapor phase and reflectance infrared spectroscopy and the analysis of fluorescence spectra. More sensitive methods must also be devised to assay single tablets and capsules, since recent experience has shown that the potency of individual tablets varies significantly within a lot that appears to be satisfactory on the average. Such extremes in the potency of powerful drugs like digitoxin or thyroxin present a serious hazard to users. Other new projects for fiscal year 1967 include the examination of cardiovascular, antiviral, and anticancer drugs, as well as experiments to design systems for predicting the storage stability of drugs. A $15,000 study is proposed to apply new techniques to analyze drugs that contain fluorine.

Another important aspect of drug research is the study of drug mechanisms. Methods are sought to disclose early signs of toxic reaction to drugs. Three additional positions are requested in fiscal year 1967 to examine tissues and cells in hormone and enzyme systems for these warning signs. In addition, a position is needed for an expansion of the program to investigate skin sensitization caused by drugs. Guinea pigs injected with sensitizing substances will be observed for manifestations of shock, and their blood, skin, thymus, and lymph nodes will be examined to detect any subtle enzyme or biochemical changes.

New approaches in drug research

Six new positions are requested to support an investigation of the possible application to drug analysis of complex approaches which enable the scientist to detect, isolate, and measure microscopic amounts of drug components. Tissue culture techniques for the assay of anticancer and antiviral drugs, and for the detection of toxic reactions to drugs will also be explored. Two studies totaling $55,000 will involve the application of new or advanced analytical

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