NEW DRUGS AND THE COSMETIC CHEMIST 461 trols used for the manufacture, processing and packing of the drug are inadequate to preserve its identity, strength, quality and purity or (4) there is insufficieat information to determine whether the drug is safe for use under the conditions prescribed, recommended or suggested in the pro- posed labeling. This authority to refuse an application also gives the Food and Drug Administration the responsibility to refuse any application until it has been adequately demonstrated that the drug is safe according to the criteria out- lined above. Based upon our experience with cosmetic firms entering the new drug field, we believe that many pitfalls encountered are those which can be attributed to lack of background with respect to new drug application re- quirements. Therefore a few of the more common obstacles to obtaining an effective new drug application should be covered. Let us consider more specifically the contents of an application for a new drug. A new drug application form is available on request from the Food and Drug Administration. It furnishes a detailed outline which should be followed in assembling the data for the application, which must be submitted in duplicate. The investigations of the safety of the drug should include adequate tests by all methods reasonably applicable. The reports should contain detailed data derived from animal and clinical studies in which the methods used and the results obtained are clearly set forth. This usually means pharmacologic studies in animals and subsequent clinical investigations. The kind and the amount of information required will depend on several factors, such as the nature of the drug and its indications, and must be determined individually for each new drug. Cosmetic-type drugs may be employed daily or several times daily and during the greater portion of the individual's lifetime, that is, by the young, by the old and even by individuals in varying conditions of health. Al- though the risk of adverse effects is justified to seek the benefits of a life- saving drug, no significant risks should be tolerated from the administration of a product for essentially cosmetic purposes. A dogmatic statement cannot be mkde of•the requi'rements with respect to animal toxicity studies since such will vary with the drug and the nature of its use. If the intended use includes prolonged or continuous adminis- tration, then chronic experiments of from six months to a year or more are probably indicated. A useful guide in this c6nnection is a booklet, "Ap- praisal of the Safety of Chemicals in Foods, Drugs and Cosmetics," pre- pared by the staff of our Division of Pharma•c•logy and published in 1959 by the Association of Food and Drug Officials of the United States. Of particular interest in connection with 6osmetic-type preparations intended for external application is the chapter on "Dermal'Toxicity."

462 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS Perhaps it is appropriate to make a few points in connection with clinical studies. Before undertaking the investigation of a new drug, prepare a program for it. Do not send the product to a number of investigators haphazardly and wait hopefully for what you can get. After six months or a year, you will examine the reports and begin to realize that most of the questions have not been answered. If you have not had experience in planning a study, get help. Consult a competent investigator. Food and Drug Administration scientists cannot reasonably make an advance commitment that a specified group of studies will be sufficient to establish the safety of a given article but will furnish comment on proposed plans of study before or during the course of investigations. It is difficult to predict how much clinical investigation will answer the question of safety of a new drug. It is impossible to state simply how many patients must be studied. To a large extent the quality of the study means more than purely volume. The most meaningful information is derived from a well-performed clinical evaluation reporting detailed inform- ation on each individual case, such as age, sex, conditions treated, dosage, frequency and duration of administration of the drug results of clinical and laboratory examinations made and a full statement of any adverse effects and therapeutic results observed. Since investigators, clinical facilities, and patient material will vary, one can hardly expect to achieve all of the needed information on a new drug from one or even two clinical studies. Choose investigators who are experts in the field appropriate for the drug A dermatologist is usually best trained to evaluate a preparation for application to the skin. For such products you might also include an allergist. In a review of the clinical reports in applications we are often confronted with the necessity of making difficult decisions on their adequacy to demon- strate the safety of the product. In most instances this could be avoided by an understanding of the requirements. The deficiency may be one of inadequate reporting. The second part of a new drug application requires a complete listing of the components of the drug. This includes not only the ingredients of the final product but all substances used in the synthesis or other method of preparation of any new drug substance. This may alert us to the possi- bility of contamination of the final product with such components. It may suggest the necessity of control procedures or specifications to insure their absence from the final product or their presence only in a limited con- centration. Omissions in this connection result in additional correspon- dence and loss of time. The full statement of the composition of the drug should offer no diffi- culty and is usually presented in a satisfactory manner. Occasionally