The Drug Efficacy Study, 1962-1970 by Paul A. Bryan, M.D. and Lawrence H. Stern When the Kefauver-Harris Amendments were enacted on October 10, 1962, few fully realized the impact their requirements for proof of effectiveness would have on the regulation of drugs in this country, or the magnitude of the task. Eight years later, the basic medical review of marketed drugs covered by this provision has just been completed and findings have been published for 870 of the products reviewed. FDA expects to publish findings for all the drugs by the end of this fiscal year, June 30, 1971. But this is really only the beginning of our task. For each of the drugs studied there are five or more times as many similar drugs on the market that are subject to the same requirements. It appears that virtually every one of these will require labeling revisions, further studies, or removal from the market. Our goal is consumer protection in this extensive area. We realize, however, that we must do the best possible job within the limitations of staff, budget, and scientific resources available. Dr. James L. Goddard, former Commissioner of Food and Drugs, realized this also. For this reason he contracted in 1966 with the National Academy of Sciences-National Research Council for that group to review the drug products marketed through the new drug and antibiotic clearance procedures from 1938 to October 10, 1962, and still remaining on the market. The Amendments exempted these pre-1962 drugs from the effectiveness requirement for a period of two years (until October 10, 1964) to allow the manufacturers time to obtain “substantial evidence" of effectiveness for the indications claimed on the labeling as required by the Amendments, if such evidence were not already available. Our review of the information in the New Drug Applications during this time revealed that much of the available information was inadequate to determine the effectiveness of many of these drugs. Therefore, the manufacturers were required to submit additional information: for the antibiotic drug preparations, by January 4, 1967; for other drug preparations still marketed, by September 6, 1966. The NAS/NRC was particularly equipped for the task because of the high esteem in which its membership is held throughout the medical and scientific communities and because of its ability to enlist the aid of many of the top scientific and medical experts in the country. The 30 panels of physicians and dentists, experts in their specialties and selected by the National Academy of Sciences-National Research Council Drug Efficacy Study Policy Advisory Committee, served without remuneration and performed a valuable service for all of us. Between October 11, 1967, and April 15, 1969, they forwarded to us 2,824 reports for 4,349 drug products. In early 1968 Agency implementation of these reports began. A plan for action and orderly procedure was announced by the Commissioner of Food and Drugs at a meeting held January 23, to which members of the regulated industry and other interested persons were invited. A task force consisting of two physicians, a regulation writer, a systems analyst, and a representative from our former Bureau of Regulatory Compliance was set up to establish procedures. Because the Academy reports needed interpretation and translation into action within the framework of the Act and regulations, it was decided by the Academy, FDA, and others at the beginning of the implementation program to keep the Academy reports confidential until the Agency conclusions on a drug were developed and published in the Federal Register and differences between Academy panels were resolved, sometimes by requesting more information from the Academy. This plan of operation also had the advantage of apprising all interested and affected persons simultaneously of the Agency's interpretation of the Academy reports and conclusions concerning a drug and of the procedures available to applicants to bring a drug into compliance with the Act. It was estimated that, notwithstanding the opinions of some that it was an impossible task, it would take two to three years to announce all the efficacy findings. Our goal, which we plan to meet, is to publish all the initial Federal Register Announcements by July 1, 1971. As of September 1, 1970, a total of 870 reports had been published, and 764 additional reports had been prepared for publication, but not yet finally approved. As of September 1, reports on approximately 350 of the drug products which the Academy and the Food and Drug Administration classified as having only "ineffective" claims have been published and the Academy reports released. Before an announcement is published the following steps must be taken: (1) The medical staff, in consultation with pharmacologists and chemists, considers the Academy Panel's evaluations and comments, not just in one Academy report but in all the reports pertaining to a given drug and to similar drugs. The staff also considers other information that may be in the Agency files or in the medical literature applicable to that drug. Academy classifications of "effective, but" and differences among panels must be resolved. (2) Each indication for a drug is classified by the medical staff as "effective," "probably effective,” “possibly effective," "ineffective," or "ineffective as a fixed combination." (The last two evaluations are interpreted as "lacking substantial evidence of effectiveness," not as positive evidence of ineffectiveness.) (3) Decisions must be made, if the drug is effective, as to whether an original New Drug Application or an abbreviated New Drug Application will be required of persons not now holding approved NDA's, whether bioavailability data will suffice in lieu of clinical studies of efficacy, and whether routine reports of experiences (usually required by regulation) may be waived. (4) Decisions must be made on the adequacy of the available methodology or the need to develop methodology to assure equivalent patient benefit from different brands of a drug and from batches of the same brand of a drug (bioavailability). (5) Initially, full labeling was written by the medical staff for publication when a drug was "effective" or "probably effective" for one or more uses. But the writing, reviewing, editing, and typing of full labeling was so time-consuming that in February 1970 this procedure was discontinued except in certain instances, and only acceptably worded indications are included in the publication. (6) Because the implementation of the reports will affect not only those drugs referred to the National Academy of Sciences for review but many other similar marketed drugs (an estimated five products for every one reviewed), a list of all other approved NDA's or antibiotics was prepared. Preparation of this list has been deferred until after publication to expedite implementation. (7) After the medical decisions are made, a proposed Federal Register notice is drafted to announce: the effectiveness classification; the appropriately worded indications to be used in the labeling (if the drug has effective or probably effective indications); the period of time that will be allowed for substantiating claims evaluated less than effective, i.e., 12 months for "probably effective"; 6 months for "possibly effective"; 30 days for "ineffective"; and the conditions for continued marketing, if any. This must then be approved by responsible officials of the Agency and the Office of the General Counsel, DHEW. (8) Prior to publication but after the Commissioner of Food and Drugs has approved and signed a document, a letter is sent to each firm whose product is named in the document, informing the firm that publication is imminent and furnishing a copy of the NAS/NRC report. (9) When a document is published, other firms holding approved NDA's for the same or similar drug products are notified that their products may be subject to the implementation proceedings. Shortly after Agency implementation began, the responsibility for preparing the Federal Register notices was assigned to the Regulations and Policy Office of the former Bureau of Medicine. Top level decisions on policies and procedures for implementation were slowly worked out during 1968 and action did not get well under way until nearly 1969. During fiscal 1970, the Bureau of Medicine (now Bureau of Drugs) alone expended over 50 man-years of medical, scientific, and administrative effort in the implementation of this project. To speed up implementation the FDA is establishing the Drug Efficacy Study Implementation Task Force as an office within the Office of the Director, Bureau of Drugs. It is being staffed with approximately 50 professionals and support personnel, including the Federal Register writers. Under this new organization and with changes in internal procedure, it is expected that all reports will be released and FDA's and the Academy's findings published by June 30, 1971. This will permit orderly implementation of the Act in a reasonable time, considering the magnitude of the task: 2,824 reports, 4,349 preparations, and more than 10,000 claims (plus the estimated five times as many similar products not studied); the publication of all reports for drugs marketed with the same labeling and flatly classified as "ineffective"; the fact that announcements have been published for products regarded as presenting a medically significant safety problem; budgetary and staffing constraints; and other obligations. Follow-up publications are needed in those cases where the initial announcement classified drug products as ineffective or possibly or probably effective. Any data submitted to support these claims must be reviewed and a conclusion made as to whether the drug is effective or ineffective for the claims. If it is ineffective with no effective claims, action is required to withdraw approval or repeal the regulations. Follow-up procedures are initiated as soon as possible upon the expiration of the allotted time and do not now generally exceed 20 days. In the case of drugs evaluated as ineffective for all conditions, interested parties are allowed 30 days following publication of the implementation notice to submit data not previously submitted to substantiate claims. Submissions are reviewed by the medical officer, in consultation with the chemist and pharmacology staffs when necessary. If the review indicates that the submission does not provide substantial evidence of effectiveness, the interested party is notified and is solicited to submit a voluntary request for withdrawal. If the party agrees to such a request, a proposed final order withdrawing approval of the New Drug Application is prepared, to become effective upon signature by the Commissioner. If the party disagrees, a notice of opportunity for hearing is initiated giving him and other interested parties 30 days to avail themselves of the opportunity for hearing. If no response is received in 30 days, a final order is prepared for the Commissioner's signature to withdraw approval of the New Drug Application. Many firms use this 30-day period to notify FDA that they waive any hearing. This makes publication of a formal notice of opportunity for a hearing unnecessary. If a firm has in fact developed pertinent evidence between 1966 and the present, the FDA should have it for review before the hearing begins. Such data may alter the initial conclusions concerning efficacy and may also alter the kind of evidence needed by FDA if a hearing is held. If a drug is evaluated as either "effective," "probably effective," or "possibly effective," but with an "ineffective" claim, the NDA holder has 60 days to submit a supplemental NDA revising labeling to delete the "ineffective" claim; six months to provide substantial evidence of effectiveness for the "possibly effective" claims; and a year to provide substantial evidence of effectiveness for the "probably effective" claims. Submissions are reviewed by the medical officers, the chemists, and pharmacology staffs of the appropriate division. At the termination of the six-month or one-year periods, further follow-up is similar to that for drugs classified as lacking substantial evidence of effectiveness for all claims. The amount of time spent in review of a submission will vary depending on the quantity, quality, and organization of the submission. Reviews are completed within relatively short times, some as short as two weeks, but occasionally as long as three months. Administrative action on the basis of these reviews is generally initiated promptly upon receipt of the review. As each of these actions is taken, the Office of Compliance in the Bureau of Drugs maintains an awareness of the activity and is responsible for assuring that all manufacturers of similar products comply on a voluntary or a regulatory Paul A. Bryan, M.D., director, Drug Efficacy Study Implementation Project Office (DESI), Bureau of Drugs, joined FDA at Washington in 1963 as a medical officer. basis. Our procedures for implementation were challenged on October 13, 1969, by the Upjohn Company in the Panalba case. An appellate court decision was made in FDA's favor on February 27, 1970, which states in essence that we have the right to require substantial evidence of effectiveness of drugs marketed prior to 1962 and the right to refuse an administrative hearing in certain circumstances. During the time the issues in the Panalba case were under litigation, we were enjoined from acting upon regulations that were issued on September 19, 1969, under a court order obtained by the Pharmaceutical Manufacturers Association in Wilmington, Delaware. Thus we could not move ahead with implementation of the NAS/NRC Drug Efficacy Study except by scheduling for a public hearing every case in which a drug company objected to our action on an NAS/NRC report. We would have been required to litigate, in each case, the scientific question: what constitutes an adequate and well-controlled study? These hearings would have tied the matter up for protracted periods of time, making it impossible for us to require withdrawal of drugs from the market or to require relabeling until after hearings. The Commissioner of Food and Drugs chose to establish regulations defining what is meant by an adequate and well-controlled clinical investigation against which to measure the adequacy of the clinical data offered in support of a company's request for hearing, and to provide a mechanism for summary disposition of any request that failed to establish legally sufficient grounds for a hearing. This, we believe, will enable us to get this important job done in the most expeditious way in the interest of patient care. We hope there will not be further resistance from the drug companies to our action to remove from the market any drugs evaluated as ineffective, even though they may be economically important to the companies. We are requesting their assistance in this task and we will require strict adherence to the principles we have set forth in our regulations describing appropriate clinical trials. Most companies are cooperating with us once a final determination has been made. The summary procedure to eliminate hearings when no real issue of fact exists should significantly expedite the process. We certainly expect that it will. Lawrence H. Stern, deputy director, Division of Management Systems, Office of the Assistant Commissioner for Administration, was detailed as assistant director for project management, DESI, during JulyAugust. He joined FDA as an inspector in 1959 at Cincinnati. Dallas Does Something About Celia The Food and Drug Administration doesn't do anything about the weather, but does something about the disasters and the attendant threat to public health that come in the wake of hurricanes and other excesses of Nature. Take FDA's Dallas District and Hurricane Celia. Celia, after a three-day buildup in the Caribbean, struck the Corpus Christi area of the Texas Gulf Coast late in the day on Monday August 3. Dallas District, which has seen other hurricane disasters, went into action the next morning. During the hurricane, winds from 120 to 184 miles per hour had been measured at various locations in the stricken area. Rainfall ranged from 6 to 8 inches and tides from the freakish minus 14.5 feet at Corpus Christi to plus 14 feet at Aransas Pass. On Tuesday morning Dallas District Director Louis Weiss, following a general pattern developed from previous experience with hurricanes in that and other FDA Districts, directed three resident inspectors from Houston and one each from San Antonio and Brownsville to survey specific areas where the hurricane had struck. They were then to meet in Corpus Christi on Wednesday with a contingent from the Dallas headquarters consisting of two inspectors and Supervisory Inspector John A. Krakosky, who was designated by Chief Inspector James E. Anderson as FDA coordinator for the operation. On arrival at Corpus Christi, the eight (eventually 11) FDA men set up headquarters at the Civil Defense Center where other State and Federal health officials were headquartered, and met Wednesday morning with these and city officials. Forrest Stokes, U. S. Public Health Service, DHEW Region VII, presided at this meeting, which consisted of a brief assessment of the emergency problem and which ended with Mr. Stokes' charge: "You people know your jobs, so go out and do them!" After this meeting, Mr. Krakosky met with Lenwood L. Scholtz, supervisory inspector of the Food and Drug Division of the Texas State Health Department, and Dr. W. R. Metzger, director of the Corpus ChristiNueces County Health Department. Dr. Metzger told the State and FDA representatives that his department had its hands full and suggested they work out their own plan of operation. Messrs. Scholtz and Krakosky then convened with the four State and seven FDA inspectors on the scene and after a discussion decided it would be necessary to cover all food and drug establishments affected by the hurricane in a joint operation, with FDA issuing all work assignments. From the survey reports submitted by the FDA inspectors, the situation was assessed this way: • Virtually no damage at George West, Three Rivers, and Alice. • Some water damage at Banquete and Aqua Dulce. • Heavy damage from wind and possibly rain at Corpus Christi, Aransas Pass, Aransas, Rockport, Ingleside, Portland, Taft, Sinton, Mathis, Robstown, and Port Aransas. Electric power was off in most areas except for such emergency centers as hospitals and police stations. Only some sections of Corpus Christi had drinking water. Other areas had none. The surveys indicated there were some 500 food and drug establishments, including retail places, that required immediate coverage. Assignments were issued to the State and FDA inspectors. Three were to visit all food and drug warehouses and all pertinent manufacturing plants in Corpus Christi. Three others were to cover all food and drug retail stores in the city, by areas (lists of |