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Council on Pharmacy and Chemistry J- A- M- A- 958JU Dec. 9, 1944 COUNCIL ON PHARMACY AND CHEMISTRY REPORT OF THE COUNCIL The Council has authorized publication of the following report. The outline in this report is offered as an objective, a pattern and not a regulation. However, it has been adopted for publication with the belief that it will be of help to manufacturers and scientists who undertake the investigation of new drugs. Austin Smith, M.D., Secretary field have recently been described.1 Certain phases of LABORATORY AND CLINICAL the activities of the Food and Drug Administration APPRAISAL OF NEW which bear on this problem have also been published DRUGS or are in press.2 The Council on Pharmacy and Chemistry has pro- WALTON VAN WINKLE Jr., M.D. vided for almost forty years a set of rules to guide ROBERT P. HERWICK, Ph.D., M.D. manufacturers for the submission of articles for inclu- sion in New and Nonofficial Remedies. At HERBERT O. CALVERY, Ph.D. periodic intervals it has on these rules to Members of the Food and Drug Administration, enlarged provide Federal Security Agency criteria such as those found acceptable for the evalua- WASHINGTON, D. C. tion of skin disinfectants and contraceptives.3 Usually one AND the criteria have been concerned with special agent or The Federal and Cos- AUSTIN SMITH, .M.D. class of agents. Food, Drug metic Act that for new Secretary of the Council on Pharmacy and Chemistry provides applications drugs CHICAGO shall contain "full reports of investigations which have been made to show whether or not such drug is safe A new drug should pass through several phases of for use," and the Food and Drug Administration pro- investigation before it is declared suitable for distribu- vides a form in which are set forth suggestions con- tion in commerce. It should be studied in the labora- cerning the scope and character of these reports. the tory and in the clinic, details of the study depending If the'utmost of possible benefits with a minimum on the nature of the ingredients and the intended uses, of possible dangers is to result when a new drug is should a but all investigations follow general plan which introduced for experimental trial and later in commerce, will permit a thorough understanding of the usefulness it is necessary to develop methods of appraising the and toxic properties of the drug. therapeutic usefulness and potential harmfulness of In considering new drug applications in the enforce- new drugs and to organize these methods into a logical ment of the Federal Food, Drug and Cosmetic Act, the system which, if followed, will give reasonable assur- Food and Drug Administration is concerned primarily ance that the new preparation will not be offered to the with evidence of safety. The Council on Pharmacy medical profession or to the public before the extent and Chemistry is concerned not only with the evidence of its usefulness or the potentialities for harm are of safety but also the evidence adduced to support the understood. The present paper outlines the principles claims made for new drugs. Too frequently this evi- which have been helpful in making such an appraisal • dence is found inadequate and the sponsors of new of new drugs. if wish to the preparations, they provide missing data, PRELIMINARY OBSERVATIONS may find it necessary to repeat some of the more time The observations with a and and at other times preliminary experimental consuming expensive procedures new the clue to the field of useful- find it to new lines agent give possible advantageous proceed along entirely ness. In of If the manufacturer has facilities dealing with chemotherapeutic agents, these thought. adequate observations consist of tests of the for and clinical he can preliminary usually laboratory appraisal, usually of the in or some obtain the desired information within a reasonable efficacy agent combating preventing infections. In the case of that however such facilities are not experimental drugs might period. Frequently be termed the obser- available much effort must be in "symptomatic agents," preliminary immediately and spent vations should for channels for include tests of the possible pharmaco- searching appropriate investigation. actions of the These observations "set If a outline had first been and dynamic drug. comprehensive prepared the so to and indicate the course to then followed, loss of time and of sights," speak, be closely expenditure in more needless effort might have been avoided. pursued subsequent and detailed investigations. At the same time it is an advantage for physicians LABORATORY OBSERVATIONS and allied scientists to know by what standards a new Assuming that a new drug has shown promise in drug has been evaluated. When the physician is urged the preliminary tests, more extensive inquiry must now to use this agent, he should have available such evi- be made into the mechanisms of its action and its dence as will his and satisfy questions concerning safety 1. Smith, Austin: Membership, Activities, Method of Operation, efficacy. Attainments of the Council, J. A. M. A. 124: 433 (Feb. 12) 1944. The activities of the Council on and 2. Woodard, Geoffrey, and Calvery, Herbert O.: Acute and Chronic Pharmacy Toxicity, Industrial Med., January 1943. Calvery.4 Van Winkle.6 Draize, Chemistry of the American Medical Association in this Woodard and Calvery.5 3. Contraceptive Agents, Report of Council on Pharmacy and Chem- The authors wish to express their appreciation of the helpful comments istry, J. A. M. A. 123: 1043 (Dec. 18) 1943; Criteria for Evaluation of offered by Dr. Torald Sollmann, Dr. P. J. Hanzlik and Dr. A. L. Tatum. Skin Disinfectants, ibid. 121: 593 (Feb. 20) 1943. Downloaded From: http://jama.jamanetwork.com/ by a NHS Oxford Radcliffe Hospitals User on 07/17/2015 toxicity. In order for the clinician to use a drug (A) Acute Toxicity.—Dosage response curves in three or intelligently he must know the manner in which its more species; objective symptoms; statistical calculations for effects are brought about. The plan of procedure and comparative studies ; simultaneous comparative determinations the details of the tests to be employed should be formu- of other substances ; variations in toxicity with method of lated in accordance with the type of agent to be inves- administration. tigated, e. g. single chemical entity, complex extract, (B) Subacute Toxicity.—Large daily doses to one or more hormone, serum or vaccine. The conditions in which species for six to twelve weeks ; microscopic pathology. the drug is thought to be useful and the observations (C) Chronic Toxicity.—Three or more species ; at least one made in the preliminary testing will also modify the species for the life of the animal ; several dosage levels gradu- plan of investigation and the details of the test pro- ated to produce from no effect up to pronounced lesions, and cedures. Nevertheless we feel that the following gen- possibly shortening life span ; microscopic pathology ; effects eral types of study should prove to be applicable to on voluntary activity, e. g. running or other performance as evidence of more subtle functional most new drugs, keeping in mind that these are sug- changes. gestive and not necessarily exhaustive : (D) Local Effects.—Sensitization ; skin irritation ; mucous membrane irritation ; photosensitization. (A) Biochemistry.—General properties of drug, including sol- distribution and ubility, stability ; studies of absorption, reabsorption, fate, dis- (E) Special Studies.—Reproduction ; storage ; effect of effect of and liver function tribution and excretion of the drug ; quantitative data on these diet; environment; kidney tests. points where possible ; mode of detoxification (excreted acetylated?) ; effect on enzymes, unchanged, oxidized, reduced, In animals for of new it blood and tissues ; chemistry of body fluids and tissues ; produc- selecting investigation drugs is to use several distinct since it is tion of toxic products during course of metabolism. important species, well known that qualitative as well as quantitative (B) Pharmacodynanties.—Local : Tests of irritation on skin, differences exist between animal species in their reac- eye, alimentary canal ; intradermal irritation, sensitivity or anes- tions to Some species are wholly unsuited for thesia ; tests of protoplasmic depression or toxicity, and reversi- drugs. demonstration of certain effects ; e. g. bility of effects on cilia, nerve trunks, mucosa; hemolysis, methemoglobin not in rodents and if the is antihemolysis and blood pigment changes. is readily produced drug suspected of causing this reaction rats, rabbits and Systemic : Action on blood pressure, respiration, muscles, guinea pigs are not suitable test animals. Rabbits are nervous cardiac temperature, vol- system, functions, secretions, not animals for blood untary activity, organ perfusion, isolated tissues ; effects of usually satisfactory pressure studies and often react e. histamine vasomotor agents, proteins, fats, metals, solvents and other atypically; g. pro- duces a rise of instead of a fall. Emetics agents on the actions of the drug ; cumulative effects ; develop- pressure not ment of tachyphylaxis ; quantitative and qualitative differences cannot be tested in rodents, since vomiting does in action in different species of animals. occur in these species. Many other examples could be but these suffice to demonstrate the need for (C) Experimental Functional Pathology.—Effects in experi- cited, careful selection of suitable test animals. mentally induced pathologic states,
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