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tion were dealt with by the Food and Drug Administration during 1971. A few of these activities came to public attention but most went unnoticed. This report is intended to provide a more complete accounting of the Agency's drug activities.

Highest priority was again given to a long-range effort-FDA's program to ensure the effectiveness of the country's drug supply. Dealing mainly with prescription drugs introduced since 1938, some 1,100 official statements were published during the year to put drug manufacturers on notice that better evidence to support claims must be presented, or labeling changed, or the products withdrawn from the market.

The determinations on effectiveness are made by the best qualified medical experts in the country. Their knowledge is being focused on each drug, to carry out the mandate of the law that effectiveness be shown by "substantial evidence."

New policy on combination drugs-those containing two or more active ingredients-resulted from the reviews for effectiveness. Hazards of drug use are much increased when more than one drug is taken simultane

ously. The hazards can be balanced by rational combinations of drugs to deal with specific conditions. In brief, the new policy requires that each ingredient contribute to the claimed effect of the combination, and that the combination be safe and effective for a significant number of patients who require such concurrent therapy.

Probably the most far-reaching result of the drug effectiveness program will be, not the ineffective products taken off the market, but the lasting improvement of patient care through drugs that accomplish their intended purpose.

The public takes more doses of drugs for self-medication than by prescription. To require that prescription drugs meet high standards of effectiveness, but not those purchased for self-medication, leaves an obvious gap in consumer protection. Initial steps were taken to launch a comprehensive review of over-the-counter drugs to assure that they are safe and effective and that the labeling of these home remedies is true and clearly understandable to the user. Details on the scope and plans for this project were announced publicly by the Commissioner on January 4, 1972.

Some 16,000 physicians are presently testing investigational new drugs on about 60,000 patients each year. To safeguard such patients, notice of these investigations must be given to FDA. A new regulation requires a 30-day waiting period before administering the drugs to humans, giving time for FDA medical officers to review the proposed studies. Over 1,000 such reviews were completed in fiscal 1971.

Methadone, when used for heroin addiction, is an investigational drug. Approximately 300 physicians and clinics are testing it under FDA regulations. Six clinics were closed during fiscal 1971 when it became apparent that they were not controlling their studies to prevent abuse.

FDA's tally of drug lots recalled from the market totaled 1,543 in fiscal 1971, compared to 927 the previous year. Most of these were voluntary actions by the manufacturer, some not involving any law violation. A few were associated with serious medical emergencies. Recalls and seizures of Digoxin, Digitoxin, and digitalis were necessary when FDA analysis disclosed serious variations in potency. An industry-wide "voluntary certification" program was instituted, in which samples of all production batches were submitted for FDA testing and approval.

A total recall of Abbott Laboratories' intravenous solutions was undertaken because of bacterial contamination. Over 300 cases of septicemia and nine deaths of patients on IV therapy were reported by some 21 hospitals. More than 5.5 million bottles of 105 products were recovered and destroyed by the firm under FDA supervision (see "Drug Recalls").

Communicating the great volume of important new information to the medical profession is one of today's important public health problems. FDA is involved because of its responsibility to enforce the law on drug

labeling and prescription drug advertising. Required information has little value unless it reaches those who diagnose and prescribe. A new effort to close the drug information gap is the FDA Drug Bulletin, now reaching some 600,000 physicians and other health professionals in the United States and other countries. Particularly, it informs physicians concerning new, medically significant information requiring label changes to safeguard the patient.

This introduction covers only a few highlights of the year's work. Additional, more detailed information is presented in the sections that follow.

INVESTIGATIONAL NEW DRUG ACTIVITIES The Federal Food, Drug, and Cosmetic Act requires that before a sponsor of a new drug investigation may test the compound in human beings, he must first submit to FDA a Notice of Claimed Investigational Exemption for a "New Drug" (IND). In the past the sponsor was allowed to begin administering the new drug to humans immediately after filing the IND. To allow a reasonable time for review of research plans, a regulation was published requiring a delay of 30 days between IND submission and the beginning of studies. FDA may now prevent the exposure of human beings to investigational drugs where risks outweigh benefits, before that exposure takes place.

FDA medical officers completed 1,015 reviews of investigational drug studies during fiscal 1971. Some 938 original submissions were accepted and reviewed, but 366 submissions were not accepted due to deficiencies in the proposed studies.

Substantial progress was made in expediting the review of IND's. At the year's end only one IND was over 30 days old without safety review. This trend was due to the increasing familiarity of product managers with their new responsibilities.

The approval last year of L-dopa for Parkinson's disease contained a unique condition that studies of the drug be continued after marketing. This was done to allow the benefits of the product to reach those in greatest need, while making further evaluations of the hazards of the drug. Anticipating other similar situations, FDA published a proposal this year to require a fourth phase of clinical studies for certain drugs and to provide for provisional marketing of such drugs.

CLINICAL INVESTIGATION MONITORING

Reviewing the clinical investigations of new drugs under the 3,252 IND's which were active at the end of fiscal 1971 is a major workload.

Systematic surveillance of clinical research studies was carried out in 13 investigations of individuals and 19 inspections of facilities. These led to 49 drug manufacturing and laboratory inspections to follow up on problems uncovered. Seven investigations and inspections resulted in recommendations for action.

Drug integrity: Operator cleaning residual drug material from a tablet press after completion of a tableting run.

In the fall of 1969, visits by medical officers and District inspectors to pharmaceutical firms were instituted to observe how they monitor their clinical investigations. In February 1970, the on-site program was expanded to include laboratory visits by pharmacologists from the Bureau of Drugs to evaluate performance in that area. This year (August 1970), visits by District inspectors to drug company research directors were begun to evaluate their compliance with the investigational drug regulations.

Many drug studies, especially in their early stages, are carried on in establishments such as nursing homes, hospitals, mental institutions, and prisons. When instances of poorly conducted research came to FDA's attention, it was concluded that additional protection was needed for the persons taking part in these studies. A regulation was issued requiring that all human drug studies on such patients be approved and supervised by a committee appointed by the institution. Duties and responsibilities of such committees are similar to those required under research contracts and grants from the Department of Health, Education, and Welfare. The FDA regulations, however, require at least one member of each committee to be a nonphysician.

Methadone, widely used for maintenance treatment of heroin addiction, has not been approved by FDA as safe and effective for this use. Approximately 300 physicians and clinics have submitted investigational drug applications to FDA for this use of methadone and have initiated studies. When it became apparent that not all investigators were controlling their studies to prevent abuse, FDA issued instructions to all sponsors regarding compliance with the general new drug regulations. Six clinics have since been closed, as a result of FDA investigations. FDA works closely in this program with State and local authorities and with the Federal Bureau of Narcotics and Dangerous Drugs.

NEW DRUG APPLICATIONS

Applications for approval of new drugs received in fiscal 1971 totaled 229, of which 99 had not previously been submitted. Twelve submissions were rejected as inadequate. Completed reviews increased in fiscal 1971 to 256 as compared to 193 in 1970. Applications for 26 drugs were approved, eight of which are considered as new single chemical entities: Lysodren Tabs (mitotane), for treatment of inoperable adrenal cortical carcinoma of both functional and nonfunctional type; Efudex and Fluoroplex Topical Solution (fluorouracil) for actinic or solar keratoses; Dexon Polyglycolic Acid Sutures (absorbable surgical sutures); Rubratrope-57 and Rubratrope-60 (cyanocobalamin) capsules for diagnosis of addisonian (pernicious) anemia and a diagnostic adjunct in other defects of intestinal vitamin B12 absorption; FUDR (fluoxuridine) for palliative management of carcinoma; and Narcan (naloxone hydrochloride), a narcotic antagonist for reversal of narcotic depression.

The pace of NDA reviews accelerated despite diversion of manpower to other programs such as investigational drug review, and at the end of the year, 91 NDA's were under review, only nine of which were over 180 days old-down from 118 under review at the beginning of the year, 16 of which were over 180 days old. This indicates that the Bureau of Drugs has been able to more rapidly review and reach decisions on the safety and efficacy of new drugs proposed for marketing. Of 109 NDA's the Bureau found not approvable, major deficiencies were found in data relating to manufacturing (74 percent), clinical efficacy (63 percent), and labeling (62 percent).

After approval of an NDA, the manufacturer is required to submit records and reports on any new significant information learned during marketing, such as

new adverse reactions to the drug. During the 1971 fiscal year, 3,282 reports were received containing such information. To reduce administrative workloads and obtain a clearer picture of the products on the market with approved NDA's, 2,752 inactive NDA's were iden

tified and withdrawn with the manufacturers' concurrence. Most of these were for products no longer manufactured or which had not been manufactured. This mass withdrawal also reduced the workload associated with evaluating the efficacy of drugs marketed between 1938 and 1962. These actions left approximately 5,300 original approved NDA's on FDA's books, of which about 4,700 are still subject to review for effectiveness. In order to ensure the continuing safety and efficacy of products with approved NDA's after marketing, the Bureau of Drugs evaluates changes in formulation, manufacturing procedure, and other modifications to NDA's in the form of supplements. This workload increased from 2,109 supplements received in fiscal 1970

to 2,253 in fiscal 1971.

Guidelines for Research Sponsors and Investigators To speed the development of new drugs so their benefits reach the consumer as quickly as possible, it is important that the industry and research community understand the nature and extent of scientific evidence required to judge safety and efficacy. Much effort was given during fiscal 1971 to development of clinical guidelines for drug manufacturers and investigators. With improved understanding, there should be fewer hazards to those exposed to investigational drugs and higher quality data to support New Drug Applications. The clinical testing guidelines are being sent to specialty medical societies for comment. Initial responses have been favorable, and the guidelines should be completed during fiscal 1972.

DRUG EFFECTIVENESS

The FDA Drug Efficacy Study Implementation program (DESI) continued to have top priority during 1971. Through "DESI" the Agency is evaluating the efficacy of several thousand drugs marketed before the passage of the 1962 Drug Amendments. Previously the law required premarketing approval for safety only. The initial efficacy evaluations were made by expert committees of the National Academy of Sciences-National Research Council, which submitted 2,824 reports covering over 4,300 drug formulations.

Numerous law suits filed by prescription drug manufacturers challenged FDA's implementation of the study, but strong court decisions have upheld FDA's actions. In the most recent of these, the U.S. Court for the District of Delaware held that the Commissioner

may require that a genuine and substantial issue of fact be raised as a condition for granting a hearing on a drug affected by the study implementation. A request by the Pharmaceutical Manufacturers Association for a preliminary injunction against FDA action was denied (see "Decisions of the Courts").

To expedite the program a DESI Project Office was organized in the Office of the Bureau Director to manage the complex reviews, evaluations, and publications concerning the NAS/NRC reports, a large undertaking.

The Project Office completed FDA review of all the submitted reports by November 1, 1970. Efforts were directed toward removing drugs from the market or removing claims and indications from the labeling when evidence of effectiveness was lacking. Administrative steps to remove the following drugs from the market were completed: penicillin-streptomycin combinations, penicillin-sulfonamide combinations, tetracycline-oleandomycin (or troliandomycin) combinations, parenteral

Drug integrity: Plant control chemist tests a drug during the manufacturing process.

nations.

The labeling of many marketed drugs has been revised to narrow the scope of recommended use to only those claims for which safety and efficacy have been shown. Among these were sodium heparin, chlorpromazine, anti-depressants, and curare-type drugs.

During fiscal 1971, Federal Register notices were published concerning drugs involved in 1,163 of the NAS/NRC reports, bringing the total of 1,715 published reports, and completing 62 percent of the initial implementation. A total of 159 NDA approvals were withdrawn, removing ineffective products from the market. Industry responses are increasing, generating additional data to justify continued marketing of products not found effective.

When the NAS/NRC efficacy review shows a drug to be both safe and effective, manufacturers of like products not covered by an effective NDA may submit an abbreviated NDA (ANDA) if there are no unusual manufacturing problems associated with the drug. An abbreviated NDA need not contain the detailed clinical data normally required for approval. ANDA receipts have kept pace with implementation publications, from three received in fiscal 1969 to 543 in 1971. Increasing manpower has been devoted to the review of these applications to allow the continued marketing of effective products.

Further litigation with the drug industry is expected, and extensive market surveillance and compliance activities will be needed to assure the public that all effective drugs covered by the Study are properly labeled and that all ineffective drugs are removed from the market. The Study generated a massive workload. Perhaps its

deficiencies in scientific data and to improve claims of effectiveness for the wide spectrum of drugs which remain after the ineffective drugs are eliminated.

As the FDA moves to evaluate remaining claims and to bring labeling into line, the program will directly affect drug advertising (annual investment by drug companies in drug promotion estimated at $800 million). Indirectly, consumer payments for drugs may be affected through the removal of expensive proprietary products and greater use of lower cost generic products. A further benefit should be improved patient care through the improvement of drug use. The impact of DESI on the drug industry, the physician, the patient, and the FDA will be direct, long-lasting, and unprecedented.

Over-the-Counter Drug Products Evaluation

Late in fiscal 1971, the FDA Commissioner testified

before the Senate Select Committee on Small Business that FDA plans to review the composition and the promotion of over-the-counter (OTC) drugs to assure that they are safe and effective and that their labeling is understandable to the lay public. This extensive prolarge majority of drug dosages consumed by the public gram should benefit nearly every American since the are sold over-the-counter. Formal planning was started and the review began in fiscal 1972. Overall philosophy of the project will be developed by an FDA National Advisory Drug Committee. The goal is to modernize the entire field of home remedies-ensure that they are safe and effective in the light of present knowledge, and described fairly and adequately with labeling in everyday language so the consumer can make an intelligent choice and use of the many such drugs on the market.