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Evaluate medical advertising..

Evaluate efficacy of veterinary drugs marketed prior to 1962 (extramural review by NAS).

Evaluate efficacy of human drugs marketed prior to 1962 (extramural review by National Academy of Sciences).

+48

+506, 300

+568,000

+-67,000

Evaluate IND and NDA supplements..

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Provide medical support for legal actions.

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Expand extramural research program for oral contraceptive drugs..

Expand collection of drug-experience data to include material on outpatients in control group.

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One of the problems confronting the Agency for the past several years has been the existence of a large backlog of drug submissions from industry that have been awaiting evaluation and final action by FDA. This backlog developed and continued to grow because the drug amendments of 1962 required proof of efficacy as well as proof of safety in new drug applications. This additional data began to pour into the Agency before it was staffed to handle the increase in workload. Assembling a staff with the required expertise and developing the most efficient administrative procedures was a task that could not be accomplished immediately. However, this year FDA will have eliminated most of the backlog of NDAs that have remained within the Agency beyond the statutory time limit of 180 days. There are several factors underlying the Bureau of Medicine's improved efficiency in its handling of new drug submissions.

First, the Bureau was strengthened in 1966 by the addition of 63 medical officers and 29 pharmacists on two-year assignments from the Public Health Service. Second, the new-drug evaluation staff was organized into medicalscientific teams specializing in various drug categories. An Office of New Drugs was created, consisting of six divisions: cardiopulmonary and renal drugs, dental and surgical adjuncts, metabolism and endocrine drugs, neuropharmacological drugs, oncology and radiopharmaceuticals, and anti-infective drugs. To provide each division with a full complement of analytical capabilities, the pharmacological staff that formerly was part of the Bureau of Science was transferred to the Bureau of Medicine and individual members were assigned to evaluation teams in each of the six divisions. The creation of these specialized units, which now evaluate both INDs and NDAs, simplifies processing operations and focuses more expertise in a specific medical area on the drugs that are used in that area. Third, a new management tool was developed that will aid in the efficient management of NDA workload; this is the NDA Status Report, issued every two weeks, which informs management how many NDAs are under review and how long they have been in review status, what actions have been taken and what remains to be done, and whether workload patterns call for a shift of assignments from one area to another. This status report now provides a precise measurement of the current NDA workload and identifies submissions that require special attention; similar ways of measuring IND and supplement flow are being developed. Investigational new drugs (INDs)

An IND submission notifies FDA that a new drug will be clinically tested on humans for the first time. Since the clinical investigator may proceed with his tests immediately unless exception is taken by FDA, it is essential that these ap

plications (as well as related amendments and progress reports) be evaluated as soon as possible, However, the difficulties in completing the evaluation of INDs within 30-60 days presents one of the most critical problems currently facing the Bureau of Medicine. Each month, the Bureau receives an average of 57 IND and 960 amendments or progress reports. These are assigned to the medicalscientific team with the responsiblity for NDAs and INDs in a given area. All INDs are acknowledged by letter and are screened to determine whether the investigation warrants immediate FDA action to terminate or modify the plan for clinical testing, If an IND does not merit immediate action of this type, the cycle of evaluation begins. Each team is responsible for maintaining current review of many active INDs. The team must review all amendments and progress reports when submitted. At the present time, only about one fourth of the INDs received in any one month are completely reviewed within 90 days; if present trends continue, less than half of the INDs received in 1967 will be completely reviewed. Additional positions will be needed in 1968 to eliminate this delay. By the end of 1968, the objective is to completely review all INDs and related material within 60 days.

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The following workload table indicates that industry is submitting approximately twice as many NDAs in 1967 as it did in 1966. By concentrating its efforts on those submissions that exceed or approach the 180-day time limit, the Bureau plans to eliminate this particular backlog of overdue submissions by July 1967; however, additional positions will be needed in 1968 to keep pace with the larger volume of NDAs that is anticipated.

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A program increase of 48 positions and related costs in the amount of $506,300 is requested for the evaluation of INDs and NDAS. Both types of submission are processed by the Office of New Drugs. It is impossible at this time to predict what percentage of the new positions will be assigned to the review of NDAs or INDs. One of the advantages of combining these two functions is that the organizational structure is flexible enough to permit the diversion of review staff to the areas where workload is heaviest at any given time.

Medical review

1967 estimate:

Positions 182

Amount $3,332,000

1968 estimate:

Positions 195

Amount $4,435,500

Increase or decrease:

Positions +13

Amount +$1,103,500

Efficacy of pre-1962 drugs

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In June 1966, FDA contracted with the National Academy of SciencesNational Research Council (NAS-NRC) to evaluate the efficacy of new drugs that were approved between 1938 and 1962 on the basis of safety alone. decision on their effectiveness had ever been required until the drug amendments of 1962 were enacted by Congress. Under the terms of the first NAS contract, this backlog of pre-1962 drugs that has burdened the Agency for the past several years will be screened by December 1967. This preliminary screening should substantiate the efficacy claims for a vast majority of the drugs under investigation, although many unfounded individual claims for drugs that are otherwise effective may have to be modified or retracted. Some other drugs will probably be found ineffective and withdrawn from the market without much difficulty. Still others, however, will be hard to classify. FDA intends to renew the NASNRC contract in order to analyze these questionable drugs in more detail, using additional data requested from manufacturers or prepared by NAS-NRC and FDA. The first contract was negotiated at $834,000 for an 18-month period beginning in 1966 and carrying through 1967. A total of $568,000 is requested to renew the contract for 12 months when it expires in December 1967. Current estimates are that this contract will have to be renewed once more, in December 1968, before evaluation of all the pre-1962 drugs is finally completed. The entire contract is expected to cost approximately $2,000,000 over a four-year period. Review of these drugs is an urgent matter. The Academy, with its unique ability to tap the best medical and scientific talent in the country, can provide FDA with expert and completely objective advice during the process of analyzing the efficacy of those drugs in the problem categories of "possibly" or "probably" ineffective. There is no alternate way of reviewing these drugs that is as quick and as economical as this method. More important, there is no other way in which FDA could obtain the depth and scope of talent that is available through the NAS-NRC. An identical contract is proposed for veterinary drugs and is discussed in that portion of the budget.

Medical regulatory support

An additional nine positions and related costs of $91,700 are requested to strengthen the Bureau's support of FDA enforcement programs. The Agency's legal workload is expected to increase significantly when FDA starts to implement the recommendations of the NAS-NRC panels that are evaluating the efficacy of pre-1962 drugs; it is likely that some manufacturers will go to court to resist changing claims for their products on the basis of NAS-NRC findings. The Bureau's case review branch provides regulatory support for FDA legal actions; this involves the selection of expert medical witnesses and the collection and evaluation of evidence, among other things. The regulatory support staff also is involved in many other enforcement actions.

One area that will receive more emphasis in 1967 and 1968 is the regulation of prescription-drug advertising. In the past, inadequate staff resources have limited FDA's review of such advertising. În 1967, however, 10 professional medical journals will be scanned on a routine basis by Bureau personnel, and extramural performers will scan three specialty journals under contract. With the increases proposed in this budget, the Bureau plans to review 25 general professional journals and 5 specialty journals on a continuous basis in 1968, and conduct in-depth analyses of 300 prescription-drug journal ads and 100 promotional labels. Supplement review and evaluation

The Office of Drug Surveillance reviews and acts upon supplements to NDA's submitted by industry. Each supplement outlines a change in a new drug, including all those currently on the market. In 1966, the number of supplements

received doubled from 418 to 922. Approximately 1,200 are anticipated in 1967 and 1,500 in 1968. This increase is directly related to the increase in the volume of NDAS. Another factor underlying this workload estimate is the increasing number of supplements that will be submitted in 1968 to cover changes recommended by the NAS-NRC in its review of pre-1962 drugs. Four additional positions and $41,000 in related costs are proposed for this area in 1968. Drug monitoring and epidemiology

The Bureau has budgeted $1,120,600 in 1967 contract funds for the collection of various types of drug experience data, including reports from hospitals, from international sources through the World Health Organization, and from the Kaiser-Permanente health plan, as well as abstracts of articles on drug experience that appear in the domestic and foreign medical literature. FDA is currently investigating the desirability of shifting emphasis in 1967 from the collection of adverse-reaction reports from hospitals throughout the country to a more systematic approach to the collection of drug experience data through the use of a controlled population available in the Kaiser-Permanente health plan in California. One advantage to this latter type of program is that statistics can be obtained that relate the extent to which a drug is used and the cases in which it is used to the frequency and relative seriousness of adverse reactions to that drug. Previously, it was extremely difficult to determine objectively whether 10 adversereaction reports for a specific drug meant that the drug was dangerous every time it was administered or in only one or two percent of the cases-or whether it affected the general population or only a specific minority of the population. There are enough people enrolled in the Kaiser-Permanente health plan to constitute a meaningful statistical sampling; the data collected is unique and valuable to FDA. In addition to the $728,500 budgeted for this project in 1967, a program increase of $365,000 is requested for 1968. This will allow expansion of the program to include data from out-patients as well as from those who are admitted to the hospitals participating in the plan.

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This subactivity includes programs for medical and scientific research, industry coordination, NAS NRC coordination, professional development, and assistance from advisory committees. The addition of 92 Public Health Service officers has necessitated some increase in the amount of time allocated to training; however, increases in other areas of the budget take into consideration the time and resources needed for professional development of the entire staff, so no position increases are requested for this subactivity.

A total of $416,000 is budgeted for extramural research projects in this subactivity in 1967. A number of these projects will be designed during the course of the year to answer specific questions about drugs under consideration by FDA; $110,000 is budgeted for that type of regulatory clinical study in 1967, and no increase is requested in 1968. Also, arrangements have been made with the Georgetown University medical school to provide clinical and pharmacological research resources for "quick-response" investigations on short notice, as well as for training and similar professional development activities; that project will continue in 1968 at its current level. The balance of the research contract funds is devoted to studies of a more general nature, such as research into the reactions of monkeys to drugs that may have side effects on the reproductive system. The Bureau's most important research plans involve studies of possible long-term effects of the oral contraceptive drugs. These drugs are used today by more than five million American women. While they are not considered unsafe at this time on the basis of extensive pre-market testing and the considered opinion of the FDA Advisory Committee on the Oral Contraceptives-the consensus is that possible rare side effects, if present at all, may not become apparent for a considerable length of time. Preliminary studies are being conducted in this area in 1967 at a cost of $82,000; an additional $502,000 is proposed for 1968 as the first step in a long-range research program in this critical area.

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This activity encompasses only the Bureau of Medicine; support functions for the Bureau of Veterinary Medicine are included in the latter subactivity. Half of the administrative resources are devoted to abstracting and coding of drug experience data. The balance constitutes the administrative support group for the Bureau, including secretarial services and document control. The effectiveness of these units can best be measured in the progress that has been made in vital areas of drug review: streamlining the work process and improving systems for administrative handling of workload. Many of these projects are initiated or carried out by members of the supporting administrative staff included in this budget category.

1967 estimate:

Positions

Amount

1968 estimate:

Positions

Amount..

Increase or decrease:

Positions

Amount.

Veterinary medicine

153 $1,695, 300

153

$1,877, 500

+$182, 200

Formerly a division within the Bureau of Medicine, the new Bureau of Veterinary Medicine was established on November 7, 1965, to focus separate attention and special talents on veterinary drug problems. The programs in this subactivity parallel those of the Bureau of Medicine in most respects. Veterinary medical review

This function provides for the surveillance of marketed veterinary drugs and devices, as well as support for FDA's regulatory activities whene ver veterinary expertise is needed. In June 1966, FDA contracted with the National Academy of Sciences-National Research Council (NAS-NRC) to evaluate the efficacy of new veterinary drugs that were approved between 1938 and 1962 on the basis of safety alone. That preliminary screening by NAS will determine which drugs are obviously effective and which are not. A second contract is proposed to finance NAS-NRC assistance in analyzing drugs in problem categories of "possibly" or "probably" ineffective. The first contract was negotiated at $100,000 in 1966 to cover costs for 18 months; no funds were necessary in 1967. A program increase of $67,000 is requested to renew the contract for 12 months when it expires in December 1967. The problem of reviewing pre-1962 drugs is the most critical one facing the Bureau of Veterinary Medicine at this time; with its relatively small staff, the Bureau would not be able to eliminate this backlog for many years without the cooperation of NAS-NRC, nor would it be able to employ such expert and objective talents for the task.

Surveillance and control of marketed drugs is accomplished in two ways: First, medicated feed and dosage form drug applications from manufacturers are reviewed to ensure that product composition labeling, and manufacturing controls meet current standards; second, drug experience data is submitted by industry to inform FDA of any adverse reactions to drugs or of any other happenings that may have a bearing on the NDA as originally approved. Indications are that many firms do not submit as many drug-experience reports as the law requires; when violative firms have been identified and warned, the workload in this area will increase. The Bureau is currently investigating the feasibility of establishing an adverse-reactions reporting network as a third arm to its surveillance program. Arrangements have been made with the American Veterinary Medical Association to encourage individual practitioners to send in reports through its Council on Biological and Therapeutic Agents. Furthermore, the Bureau hopes to enlist the cooperation of leading veterinary colleges, which will furnish adverse-reaction reports on a regular basis in exchange for summary information that FDA would

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