Contact Person
Food & Drug Administration
Lisa Helmanis (301) 443-3480

the Regulation of

Animal Drugs

President Bill Clinton
Vice President Al Gore

May 1996



One of the Food and Drug Administrationís (FDAís) many responsibilities is assuring that drugs used to treat animals are safe and effective. The agency has worked hard to ensure the expeditious and predictable review of animal drugs and other related therapeutic products. However, the overall process of developing a new drug is complex, and a significant period exists between the first introduction of the drug into animals and formal submission to FDA, completion of review by FDA, and approval of the drug for marketing. The reforms in this proposal address both the process undertaken by the sponsor before the application is submitted to FDA, as well as the review by FDA after the agency has received the application.

Faster Approvals: the New Animal Drug Reinvention Initiative

To speed up the drug approval process, FDA is implementing a set of policies that will enable faster approval of new animal drugs. The new animal drug reinvention initiative will introduce numerous new process changes and programs to create a more streamlined new animal drug application review and approval process. Although the reforms that comprise this initiative are relatively new, they have been positively received by sponsors. FDA proposes to re-write the new animal drug application (NADA) regulations to provide timeframe incentives for each step of the new process and thereby further encourage participation. The reform proposal is detailed below.

FDA'S Proposal for Reform

Re-engineering the New Animal Drug Approval Process

Background: Historically, FDA has reviewed new animal drug applications using a process that has emphasized centralized coordination of the applicationís review throughout a project. FDA has also required the submission of a single application package that included data and other information necessary to address all possible efficacy, human food safety, animal safety, and drug manufacturing questions. While this system had some advantages -- it ensured a single location for administrative processing and quality control -- it also resulted in delays in application processing. For example, because the project manager was solely responsible for communication with the sponsor, delays could occur in communicating to the sponsor the results of technical review of a portion of a new animal drug application (NADA). In addition, even though important scientific issues concerning safety or efficacy were often identified by FDA experts, such discoveries and new-data requests were too often spread out over an extended period, unnecessarily prolonged the total review time. Furthermore, FDA had no centralized means of tracking all applications under review in the Center, and therefore, no way of monitoring overall review performance and progress.

Proposal and Justification: Under this initiative, FDA has begun to introduce numerous new process changes and programs that will enable a more streamlined animal drug application review and approval process, and which would result in less regulatory burden upon industry.

Implementation of pre-submission conferences: In a change from past practice, FDA is now encouraging sponsors of new animal drug applications to participate in pre-submission conferences during which FDA and the sponsor discuss in detail what studies are necessary to demonstrate the safety and effectiveness of the drug for its intended indications and conditions of use. The purpose of holding pre-submission conferences is to get agreement between FDA and the sponsor on the studies necessary to obtain approval for the desired drug claims. To date, these conferences have decreased instances where sponsors conduct studies, but after review, FDA determines that the information is not pivotal in making the final decision on approvability. This process will eliminate unnecessary studies, save drug companies significant resources, and contribute substantially to more expeditious marketing of new products.

Implementation of protocol reviews: FDA has begun to encourage sponsors to submit review protocols for the studies to be conducted in support of a NADA. Once FDA agrees to a protocol, it is committed to no "moving targets" unless significant, new scientific issues arise. These commitments enable FDA reviewers to evaluate studies in a more timely manner, and sponsors to embark on a development plan with a more certain understanding of FDAís requirements. FDA will propose regulations mandating a timeframe for the agencyís completion of its protocol review.

New Program of "phased review" of data submissions: During pre-submission conferences, sponsors are being encouraged by FDA to identify the critical studies and timeframes in their drug-development plans. FDA will commit to review these studies individually in the sequence most advantageous to the sponsor. For example, FDA will review a dose-determination study prior to the sponsor conducting trials for efficacy and target animal safety, thus allowing the sponsor to ensure that subsequent research is conducted with the formulations and doses that have been confirmed to be effective.

Direct review of sponsorsí technical submissions: FDA has begun to implement a new approach to submission review in which review responsibilities are decentralized. Under this approach, each individual conducting a technical review on the submission is responsible for the scientific evaluation and administrative processing of a particular section of a submission, and communication with the sponsor on that particular technical review. Under the previous system, each animal drug application had a single project manager, who was responsible for parceling out work assignments to technical reviewers and communicating with the sponsor. The new decentralized system encourages more expeditious reviews and more direct communication between appropriate FDA reviewers and drug sponsors by eliminating the "middle man," which means that the appropriate FDA technical reviewers will now speak directly to the sponsorís technical experts. Although CVM (Center for Veterinary Medicine) senior review managers will maintain oversight of the process, with the assistance of STARS (see below), the resolution of technical questions on one part of the submission will no longer be likely to interfere with the review process for other parts of the submission.

Utilization of sponsor-monitored methods trials: In order for a new animal drug to be approved, there must be a practical analytical method available that is capable of detecting residues of the drug in tissue of food-producing animals. In the past, FDA and sponsor companies had been dependent on government laboratories for evaluation of analytical methods, which often have higher priorities than evaluation of animal drug analytical methods. FDA now allows sponsors to contract with private laboratories to conduct methods trials. FDA evaluates the results of the trials and determines the acceptability of the method.

New requirements for data quality assurance: FDA has undertaken a program designed to improve the quality of the data contained in animal drug applications. This program has two parts: (1) a major effort to improve guidance to the animal drug industry regarding quality assurance for data collection, analysis, and reporting and (2) an effort to have sponsors assume greater responsibility for data quality assurance. In order to implement this program, FDA plans to propose regulations requiring that sponsors certify that NADA data have been subjected to a quality assurance audit.

Implementation of the Submission Tracking and Reporting Systems (STARS): In November 1992, FDA started using a new computer system. This system enables FDA to set prioritized time frames for each submission based on the purpose of the submission and the amount and complexity of the submissionís data. STARS is critical to FDAís ability to monitor the status of pending applications and other files. Furthermore, STARS enables FDA to much more efficiently coordinate scientific reviews among individual reviewers and reviewing divisions as the reviews move forward in an interactive process among reviewers and the sponsor. FDA will propose regulations committing to these prioritized timeframes.

Updated regulations and guidance documents: Largely due to declining resources, FDA had for some years been unable to review and update existing regulations and guidance documents or to prepare new ones. Recognizing the value of such documents, especially in the drug development process, FDA has renewed its commitments in this area. FDA will soon propose regulations for the investigational and new animal drug application processes, as well as guidance regarding responsibilities of clinical investigators, and manufacturing chemistry issues. Several more documents are in development, including guidance on efficacy studies for production drugs intended to change carcass quality/leanness, efficacy and target animal safety requirements for anticoccidial, anthelmintic, and mastitis drugs.

Impact: These new initiatives will streamline the NADA approval process. For example, pre-submission conferences are essentially eliminating what sponsors and others in the animal health industry have referred to as the "moving target," in which FDA specifies the studies necessary for approval in an interative fashion over a protracted period. Phased review has removed a common bottleneck caused by the fact a sponsor had to wait until all technical sections were reviewed before FDA would render an opinion on the sufficiency of an application. As a result, the technical section in the application that required the longest review could stymie progress on other sections. Under phased review, however, sponsors can coordinate submission of each technical section as the work for that section is completed. In addition, the direct review program, when linked with phased review, has resulted in significantly improved and more interactive communication between sponsor and reviewer, enabling a more efficient and logical review process.

These changes, while relatively new, have been positively received by sponsors. Because the reform initiative is presently being implemented, very few applications have been completely reviewed under the initiativeís reformed procedures. However, it is clear from FDAís experience with those applications that have had the final stages of review take place under the reformed procedures, that fewer iterations occur in which FDA must ask for additional data and the sponsor must go back to produce the data. Elimination of each iteration represents a time savings. Although only a few NADA approvals have been reviewed under these procedures, the average total time for their review was less than that for applications reviewed the traditional way. The most recent animal drug approval under this program was issued 22 days after filing -- all of the substantive review having already taken place while the drug was still in testing.

While drug sponsors are pleased with the added efficiency of the program, they have expressed concern over the lack of statutory timeframes for review. Therefore, FDA will propose new regulations for animal drug applications and testing that will provide FDAís commitment to prioritized review timeframes -- all of which will be shorter than the current statutory timeframe of 180 days.

Implementation and Timeline: All of these program changes are being implemented now by FDA. Proposed regulations describing the administrative process and FDAís commitment to application-review timeframes will publish in 1997. Guidelines for study protocol development, clinical investigator guidelines (which include data quality assurance guidelines), and manufacturing chemistry guidelines are expected in late 1997, after publication of the regulations. Guidelines for efficacy studies for production drugs intended to change carcass quality/leanness are expected before the end of 1997, and guidelines for efficacy and target animal safety requirements for anticoccidial, anthelmintic, and mastitis drugs will be produced in early 1998.

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