volume of prescription products is produced and marketed in the same atmosphere that produces a rapid turnover in automobile models and women's styles. Despite exceptions, premature and excessive promotion of drugs, inadequate investigation, and unnecessary, confusing duplication are common. It is difficult to assess how much responsibility for the failure of a large part of the clinical investigation of effectiveness to meet accepted scientific standards should be ascribed to the nature of the drug market. In this context, organized efforts to provide objective information about the newer drugs for the benefit of physicians and their patients are invaluable. Unfortunately, a large part of this activity must at present consist of warnings that prefabricated mixtures are undesirable, that the value of a given drug is unproven, that no advantages over its congeners have been established, or that it is too early to be certain about its complications. The effort of some medical journals to give close scrutiny to advertising material offered to them, strengthening of the FDA, and recent adverse publicity about marketing prac tices will undoubtedly help to control some of the worst abuses. These, though important, are essentially negative meas ures. The positive efforts of medical scientists to improve the standards of clinical investigation will likely lead. in the near futu, to the application of improved methods for clinical evaluation, to the availability of a larger body of qualified investigators, and to a more critical medical profession. It is doubtful, however, whether these efforts alone can succeed in reversing the process we have been describing. 't does not seem practical or desirable o suggest that educational or governmental bodies be asked to perform clinical evaluations of all new drugs produced. There are unlikely to be sufficient facilities, enough trained investigators, or even a large enough pool of patients to permit such a program. More important, it would be difficult to justify a program for the clinical evaluation of all drugs produced including those whose production is motivated largely by the hope of capturing a slice of someone else's market. In addition to ethical and financial objections to such a course, competent scientists will not be willing to devote a lifetime career to the unrewarding chore of performing difficult clinical trials to compare drugs with similar effects.41 If we are to see a general nation-wide adoption of a rational, scientific, and ethical program for the clinical evalua tion of drugs in patients and for their subsequent utilization in practice, the following requirement seems essential: that the development, production, and trial of new drugs be governed primarily by medical need and scientifically estab lished criteria. The evidence seems clear that the standards of the marketing experts and the use of sales and profits as predominant considerations are unde sirable guide lines for providing the best therapy for sick people. Many chemical problems involved in producing new drugs have been solved. We must find a way of guiding that production through the application of scientific medical methods so as to provide the maximum human benefit. Important progress in this direction will be possible only when evidence re garding the value of drugs is subjected to the rigorous criteria applied to other scientific problems. The general adoption of such standards depends not only on individual physicians who prescribe drugs but also on the organized efforts of hospital staffs and of medical care programs. Considerable experience has been gained in the preparation and use of formularies of approved drugs hy hospitals and medical care plans. Such organizations and individual physicians must demand convincing evidence in favor of a drug before they accept it. Widespread adoption of critical standards by which to judge proffered evidence of clinical value can result not only in financial savings but in an ap preciable and salubrious improvement in the standard of medical care given to the American people. REFERENCES 1. Stone, George B. The New Product Challenge. Am. J. Pharm. 131:327 (Sept.), 1959. 2. Pharmaceutical Manufacturers Association, Cost of Drugs-Questions and Answers. Washington, D. C. Undated. 3. Stiles, David D. More Drugs Die Younger As More People Live Longer. Am. J. Pharm. 131:407 (Nov.), 1959. 4. Kramer, Lucy M. Drugs and Medicines. Pub. Health Rep. 73:929 (Oct.), 1958. 5. Facts About Pharmacy and Pharmaceuticals. New York, N. Y.: Health News Institute, 1958. 6. de Haen, Paul. New Products Parade, 1959. Drug and Cosmetic Industry 86:161 (Feb.), 1960. 7. Edelstein, S. G.; Flescher, R.; Morrison, R. S.; Sheps, M. C.; Howard, F. A.; and Chalmers, T. C. A Controlled Double-Blind Evaluation of Hydroflumethiazide and Hydrochlorothiazide. New England J. Med. 264:207 (Feb. 2), 1961. 8. Symposium-New Diuretics and Antihypertensive Current Therap. Research 2:237 (June), Agents. Thiazide Diuretics. New England J. Med. 263:296 (Aug. 11), and 504 (Sept. 8), 1960. 11. Julian, D. G. Drugs in the Treatment of Hypertension. Brit. M. J. 2:660 (Aug. 27), 1960. 12. Rosenbloom, Stanley E.: Shapera, R. P.; Goldbloom, R. S.; Pincus, J.; and Shapiro, A. P. Technique of Controlled Drug Assay: II. Comparison of Chlorothiazide, Hydrochlorothiazide, and Placebo in the Hypertensive Patient. New England J. Med. 264:164 (Jan. 26), 1961. 13. Fox, T. F. The Ethics of Clinical Trials in Laurence, D. R. (Ed.). Quantitative Methods in Human Pharmacology and Therapeutics. New York, N. Y.: Pergamon Press, 1959. 14. Waife, S. O., and Shapiro, A. P. (Eds.). Clinical Investigation of New Drugs. New York, N. Y.: Hoeber, 1959. 15. Leake, Chauncey D. The Pharmacologic Evaluation of New Drugs. J.A.M.A. 93:1632 (Nov. 23), 1929. 16. Van Winkle, W., Jr.; Herwick, R. P.; Calvery, H. O.; and Smith, A. E. Appraisal of New Drugs. Report of the Council on Pharmacy and Chemistry. Ibid. 126:958 (Dec. 9). 1944. 17. Marshall, E. K., and Merrell, M. Clinical Therapeutic Trial of a New Drug. Bull. Johns Hopkins Hosp. 85:221 (Sept.), 1949. 18. Dowling, Harry F. Twixt the Cup and the Lip. J.A.M.A. 165:657 (Oct. 12), 1957. 19. Modell, Walter. Recent Contributions to Diuretic Therapy. Am. J. M. Sc. 231:564 (May), 1956. 20. Smyth, Charley, J. A Method of Drug Evaluation in Rheumatoid Arthritis: Results with Phenylbutazone, Oxyphenylbutazone, Cortisone and Prednisone. Ann. New York Acad. Sc. 86:292 (Mar. 30), 1960. 21. Irons, Ernest E. The Clinical Evaluation of Drugs. J.A.M.A. 93:1523 (Nov. 16), 1929. 22. Puckner, W. A., and Leech, P. N. The Introduction of New Drugs. Ibid. 93:1627 (Nov. 23), 1929. 23. Modell, W., and Houde, R. W. Factors Influencing Clinical Evaluation of Drugs. Ibid. 167:2190 (Aug. 30), 1958. 24. Mainland, Donald. The Clinical Trial-Some Difficulties and Suggestions. J. Chronic Dis. 11:484 (May), 1960. 25. Hobson, Lawrence B. Clinical Evaluation of a New Drug. (Talk given to NPC Pharmacy Education Industry Forum) E. R. Squibb and Sons. Processed. 26. Sheps, Mindel C. Unpublished data. 27. Ross, O. B., Jr. Use of Controls in Medical Research. J.A.M.A. 145:72 (Jan. 13), 1951. 28. Laties, V. G., and Weiss B. A Critical Review of the Efficacy of Meprobamate (Miltown) in the Treatment of Anxiety. J. Chronic Dis. 7:500 (June), 1958. 29. Foulds, G. A. Clinical Research in Psychiatry. J. Mental Sc. 104:259 (Apr.), 1958. 30. Hofmann, W. D. Criteria for Research. Am. J. Psychiat. 117:166 (Aug.), 1960. 31. Chalmers, Thomas C. Pathogenesis and Treatment of Liver Failure. New England J. Med. 263:77 (July 14), 1960. 32. Beckman, Harry. Yearbook of Drug Therapy 1957-58. Chicago, Ill.: Yearbook Publishers, 1958. 33. Committee on Advertising. New England J. Med. Drug Terminology and the Urgent Need for Reform. New England J. Med. 263:21 (July 7), 1960. 34. United States Senate. Hearings Before the committee on Antitrust and Monopoly of the Committee on the Judiciary, Administered Prices. Washington, D. C.: Gov. Ptg. Office, 1960. Sub 35. Kessenich, William H. Safe New Drugs and Their Control Under Law. Clin. Pharmacol. & Therap. 1:53 (Jan.-Feb.), 1960. 36. Committee on Government Operations (U. S. House of Representatives). False and Misleading Adver tising (Prescription Tranquillizing Drugs). House Report No. 2668. Washington, D. C.: Gov. Ptg. Office (Aug. 18), 1958. 37. Department of Health, Education, and Welfare, Food and Drug nistration. Enforcement Reg. Drugs and Devices, New Drugs. Notice of Proposal to Amend Labeling Requirements. Federal Register (July 22), 1960. 38. AMA Council on Pharmacy and Chemistry. New Program of Operation for Evaluation of Drugs. J.A.M.A. 158:1170 (July 30), 1955. 39. Smith, Austin E. The Council on Pharmacy and Chemistry. Ibid. 124:433 (Feb. 12), 1944. 40. Modell, Walter (Ed.). Drugs of Choice 1960-61. St. Louis, Mo.: Mosby, 1960. 41. Smith, Jackson A., and Wittson, C. A. Hazards of Drug Evaluation: Trials of 84 Non-Approved Drugs. Am. J. Psychiat. 117:118 (Aug.), 1960. 42. Editorial. New York Hospital Formulary. J.A.M.A. 174:67 (Sept. 3), 1960. Dr. Sheps is associate research professor of biostatistics, Graduate School of Public Health, and associate research professor of preventive medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pa. This paper was presented before the Medical Care Section of the American Public Health Association at the Eighty-Eighth Annual Meeting in San Francisco, Calif., October 31, 1960. EXHIBIT 54 (Published in Federal Register July 22, 1960) DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE FOOD AND DRUG ADMINISTRATION [21 CFR PARTS 1, 130] ENFORCEMENT REGULATIONS DRUGS AND DEVICES, NEW DRUGS NOTICE OF PROPOSAL TO AMEND LABELING REQUIREMENTS The Commissioner of Food and Drugs, pursuant to the provisions of the Federal Food, Drug, and Cosmetic Act (sec. 701(a), 52 Stat. 1055; 21 U.S.C. 371(a)) and under the authority delegated to him by the Secretary of Health, Education, and Welfare (22 F.R. 1045, 23 F.R. 9500, 25 F.R. 5611) proposes to amend the regulations for the enforcement of the drug and device sections and the new-drug section (21 CFR 1.106, 130.4, 130.5, 130.9, 130.13) as hereinafter set forth. The Commissioner hereby offers an opportunity to all interested persons to submit their views in writing with reference to this proposal to the Hearing Clerk, Department of Health, Education, and Welfare, Room 5440, 330 Independence Avenue SW., Washington 25, D.C., within 60 days from the date of publication of this notice in the FEDERAL REGISTER. Views and comments should be submitted in quintuplicate. 1. a. It is proposed to amend § 1.106 in the following respects: By changing paragraphs (b), (c), and (d) to read as follows: (b) Exemption for prescription drugs. A drug subject to the requirements of section 503 (b)(1) of the act shall be exempt from section 502(f)(1) if all the following conditions are met: (1) The drug is: (1) (a) In the possession of a person (or his agents or employees) regularly and lawfully engaged in the manufacture, transportation, storage, or wholesale distribution of prescription drugs; or (b) In the possession of a retail, hospital, or clinic pharmacy, or a public health agency, regularly and lawfully engaged in dispensing prescription drugs; or (c) In the possession of a practitioner licensed by law to administer or prescribe such drugs; and (ii) It is to be dispensed in accordance with section 503(b), (1) The statement "Caution: Federal law prohibite dispensing without prescription"; and (ii) The recommended or usual dosage; and (111) The route of administration, if it is not for oral use; and (iv) If it is fabricated from two or more ingredients and is not designated solely by a name recognized in an official compendium, the quantity or proportion of each active ingredient, as well as the informa tion required by section 502(d) and (e); and C 1 (v) If it is intended for opthalmic use or for administration by parenteral injection, the quantity or proportion of all inactive ingredients; and (vi) An identifying lot or control number from which it is possible to determine the complete manufacturing history of the package of the drug; Provided, however, That in the case of containers too small or otherwise unable to accommodate a label with sufficient space to bear all such information, but which are packaged within an outer container from which they are removed for dispensing or use, the information required by subdivisions (ii), (iii), and (v) of this subparagraph may be contained in other labeling on or within the package from which it is to be dispensed, and the information referred to in subdivision (1) of this subparagraph may be placed on such outer container only. (3) Labeling ad or within the package from which the drug is to be dispensed bears adequate information for its use, including indications, effects, dosages, routes, methods, and frequency and duration of administration, and any relevant hazards, contraindications, side effects, and precautions under which practitioners licensed by law to administer the drug can use the drug safely and for the purposes for which it is intended, including all purposes for which it is advertised or represented; and, if the article is subject to section 505, 506 507 of the act, the labeling bearing such information is the labeling authorized by the effective newdrug application or required as a condition for the certification or the exemption from certification requirements applicable to preparations of insulin or antibiotic drugs; Provided, however, That in the case of drugs not subject to section 505, 506, or 507, such information may be omitted from the dispensing package if, but only if, the article is a drug for which directions, hazards, warnings, and use information are commonly known to the ordinary practitioner. Upon written request, stating reasonable grounds therefor, the Commissioner will offer an opinion on a proposal to omit such information from the dispensing package under this proviso. (4) Any labeling, whether or not it is on or within a package from which the drug is to be dispensed, distributed by or on behalf of the manufacturer, packer, or distributor of the drug, that furnishes or purports to furnish information for use or which prescribes, recommends, or suggests a dosage for the use of the drug contains: (1) Adequate information for its use, including indications, effects, dosages, routes, methods, and frequency and duration of administration and any relevant hazards, contraindications, side effects, and precautions, under which practitioners licensed by law to administer the drug can use the drug safely and for the purposes for which it is intended, including all conditions for which it is advertised or represented; and if the article is subject to section 505, 506, or 507 of the act, the labeling providing such information is the labeling authorized by the effective newdrug application or required as a condition for its certification or exemption from certification; and (11) The same information concerning the ingredients of the drug as appears on the label and labeling on or within the package from which the drug is to be dispensed. (5) All labeling bearing information for use of the drug also bears the date of the issuance of such labeling. (c) Exemption for veterinary drugs. A drug intended solely for veterinary use which, because of toxicity or other potentiality for harmful effect, or the method of its use, is not safe for animal use except under the supervision of a licensed veterinarian, and hence for which "adequate directions for use" cannot be prepared, shall be exempt from section 502(f)(1) of the act if all the following conditions are met: (1) The drug is: (1) In the possession of a person (or his agents or employees) regularly and lawfully engaged in the manufacture, transportation, storage, or wholesale or retail distribution of veterinary drugs and is to be sold only to or on the prescription or other order of a licensed veterinarian for use in the course of his professional practice; or (ii) In the possession of a licensed veterinarian for use in the course of his professional practice. (2) The label of the drug bears: (1) The statement "Caution: Federal law restricts this drug to sale by or on the order of a licensed veterinarian"; and (ii) The recommended or usual dosage; and (iii) The route of administration, if it is not for oral use; and designated solely by a name recognized in an official compendium, the quantity or proportion of each active ingredient as well as the information required by section 502(e) of the act; and (v) If it is intended for ophthalmic use or for administration by parenteral injection, the quantity or proportion of all inactive ingredients; and (vi) An identifying lot or control number from which it is possible to determine the complete manufacturing history of the package of the drug Provided, however, That in the case of containers too small or otherwise unable to accommodate a label with sufficient space to bear all such infor mation, but which are packaged within an outer container from which they are removed for dispensing or use, the information required by subdivisions (ii), (iii), and (v) of this subparagraph may be contained in other labeling on or within the package from which it is to be so dispensed, and the information referred to in subdivision (i) of this subparagraph may be placed on such outer container only. (3) Labeling on or within the package from which the drug is to be dispensed bears adequate information for its use, including indications, effects, dosages, routes, methods, and frequency and duration of administration, and any relevant hazards, contraindications, side effects, and precautions under which veterinarians licensed by law to administer the drug can use the drug safely and for the purposes for which it is intended, including all purposes for which it is advertised or represented; and if the article is subject to section 505 or 507 of the act, the labeling bearing such information is the labeling authorized by the effective newdrug application, or required as a condition for the certification or the exemption from certification requirements applicable to preparations of antibiotic drugs; Provided, however, That in the case of drugs not subject to section 505 or 507, such information may be omitted from the dispensing package if, but only if, the article is a drug for which directions, hazards, warnings, and other information are commonly known to the ordinary veterinarian. Upon written request, stating reasonable grounds therefor, the Commissioner will offer an opinion on a proposal to omit such information from the dispensing package under this proviso. |