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

NEW DRUGS AND THE COSMETIC CHEMIST 463 some detail is omitted, such as the quantitative declaration of a perfume, which you may consider of no importance but which the law requires. In addition to the formula for the dosage form, a representative batch formula is required. This serves as a check on the quantitative composition and should disclose overages which are used in the manufacturing procedure. I will not attempt to discuss in detail all the requirements in Part Four of the new drug application, which deals with manufacturing procedures and controls. The new drug application form contains a detailed outline which is largely self-explanatory. Such procedures and controls are neces- sary in establishing the safety of a drug. They offer assurance that the product marketed will meet adequate and uniform standards. There are certain omissions and misunderstanding of our requirements which frequently occur. These merit some attention. The chemistry involved in the synthesis of new drugs, the use of outside manufacturers and laboratories in the preparation of a drug dosage form, the checking of specifications of raw materials, information derived from assay procedures and product stability studies are necessary information in a new drug application. Omissions or'inadequacies in these areas be- come the causes of delay in the handling of an application. When the specifications and controls of a new drug are inadequate in themselves to determine its identity, strength, quality and purity, the methods used in synthesis, extraction, isolation and purification must be described in detail. The method of preparation may be one of the most important points in establishing the identity of the product. Less detail is usually required in a description of the synthesis of a compound of known structure which has clearly defined specifications. Frequently the applicant does not perform all of the manufacturing pro- cedures himself. Some operations may be done by another firm. When such is the case, a signed description of all procedures conducted by the second firm should be submitted to the Administration, either directly or through the applicant, to be included in the application. Similarly, de- scriptions of control procedures performed by a consulting laboratory for an applicant should be prepared and signed by that laboratory. We be- lieve it is desirable for the applicant to check independently compliance of an article manufactured for him with its specifications. When this is the, case, it should be described in the application. Raw material control is an essential part of an over-all control program that is capable of maintaining the integrity of the product. In the Divi-. sion of New Drugs we adopt the view that adequate control must include defined standards for each raw material used in a drug and the use of appro- priate methods to insure compliance with the standards. Standards and methods adequate to determine the identity, strength, quality and purity of each raw material, and therefore its safety, are as important for any raw material, whether an active or inert substance.