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REVIEW OF THE VETERINARY DRUG APPROVAL PROCESS by Linda A. Burgos, D.V.M. The following article is provided for those readers interested in the approval process for veterinary drugs. The term "new animal drug" means any drug intended for use for animals other than man, including drugs intended for use in animal feed. The approval of a new animal drug is a multi-stage process. The first stage involves the accumulation of the data that will support the safety and efficacy of the product. This phase, where pertinent preliminary and supportive studies are conducted, is developed as an Investigational New Animal Drug (INAD). Once investigational studies have been completed and a data base has been established that addresses both the safety and efficacy of the product, this information may be submitted in a new animal drug application (NADA) along with the other items discussed under 21 CFR 514.1 (such as the manufacturing and environmental information and labeling). If the NADA is complete and the information satisfactory, the NADA is approved and the drug may be legally marketed. INAD Stage Sponsor's responsibilities: A drug company or other sponsor pursuing approval of a new animal drug must first establish an INAD with CVM so that they may legally ship their new animal drug to investigators to conduct studies. Often a sponsor will request a meeting with CVM to discuss their developmental plan for their product and get initial feedback and guidance from CVM. CVM encourages these "pre-INAD" meetings, especially for innovative drugs. Studies demonstrating the safety and efficacy of the new animal drug are required to support approval of the product. According to the regulations (21 CFR 514.111), at least two well-controlled efficacy studies, including a clinical field trial, are needed to provide substantial evidence that the drug is effective for the purpose(s) indicated on the labeling. The types of studies generally done to demonstrate efficacy are dose determination, dose confirmation, and clinical field trial. The dose determination study is conducted to determine an effective dose that does not cause toxicity. The dose confirmation study is done to confirm that the therapeutic dose (determined from the dose determination study) is effective. Both of these studies are typically conducted on laboratory animals. The clinical field trial is performed to demonstrate that the drug is effective under conditions of actual use, i.e., using client-owned animals. Important safety data is also collected from this trial. The types of studies needed to demonstrate the safety of the new animal drug include drug tolerance test, margin of safety, and reproductive safety. The drug tolerance test characterizes the target animal's response to a toxic dose(s) (usually up to 10 times the maximum proposed dose for the proposed maximum duration of use or up to 21 days). The study is done to determine what a potential overdose would cause clinically and what organ systems are affected. The margin of safety study is usually conducted at 0, 1x, 3x, and 5x the proposed therapeutic dose for at least 3 times the recommended duration of treatment. Reproductive safety studies are performed on both sexes to evaluate possible drug effects in the target species on general reproductive performance (i.e., fertility), teratogenesis, and postnatal factors. A sponsor may opt for a label disclaimer in lieu of conducting reproductive studies. CVM's responsibilities: CVM's responsibilities during the INAD stage include being available for pre-INAD meetings with sponsors and explaining the requirements for obtaining approval of their product. This involves input from the applicable drug evaluation division, the division of chemistry (regarding manufacturing requirements), the environmental staff, and possibly the division of toxicology (regarding human safety issues). During the study development phase, CVM is often requested by the sponsor to review their study protocols. CVM strongly encourages this practice to prevent firms from conducting inadequate studies which waste time, money, and animal lives. Once studies are completed, CVM has the responsibility of reviewing all of the raw data generated from each study and deciding if the data truly demonstrate what they were supposed to. This review of data usually involves the expertise of several people. Safety and efficacy data are primarily reviewed by a veterinary medical reviewer. At the veterinary medical reviewer's discretion, selected data may be reviewed by specialists in other divisions in the form of "consulting reviews." For example, statisticians may be requested to review the statistical analyses of the data or a toxicologist may be asked to review histopathologic data. (CVM mathematicians, toxicologists, immunologists, pharmacologists, etc. may be consulted during the review of study protocols as well.) Another important responsibility of CVM and FDA is to evaluate the integrity of the raw data. Specifically, FDA determines if the data have been collected in conformance with the Good Laboratory Practices Regulations for safety studies and acceptable standards for the conduct of clinical investigations in animals. This is done by performing an inspection of the study. Each pivotal study in support of drug approval may be inspected. Trained FDA field investigators go to the study site and conduct a routine inspection of the study including the facility, investigator(s) and study records. When possible, the veterinary medical reviewer may also participate in the inspection. Results of the inspection (Establishment Inspection Report) are submitted to the primary reviewer, who reviews the inspection results and draws conclusions about the integrity of the data. NADA Stage Sponsor's responsibilities: When a sponsor has collected data that adequately demonstrate the safety and efficacy of their new animal drug and has the other information needed to support NADA approval, they file a New Animal Drug Application, or NADA. An original NADA consists of the following: Form FDA 356V, identification of the drug, table of contents and summary, labeling, components and composition of the drug, manufacturing methods, facilities and controls, samples (if requested by CVM), analytical methods for residues, evidence to establish safety and effectiveness, environmental assessment, and Freedom of Information Summary. CVM's responsibilities: According to the Regulations, if a NADA is determined not to be acceptable for filing, the sponsor must be notified within 30 days of receipt of the application. However, if the application is found to be acceptable for filing, CVM has up to 180 days to review the NADA. For the primary veterinary medical reviewer, usually the safety and efficacy data have already been reviewed under the INAD stage. At the NADA stage, the labeling may be reviewed since all of the data used to write the label have been completed and reviewed. Components which correspond to divisions outside of the primary review branch are reviewed by the respective division, i.e., the environmental assessment is reviewed by the Environmental Sciences Staff. If the application is complete and satisfactory, the NADA is approved and a regulation regarding the approval is published in the Federal Register and subsequently in the Code of Federal Regulations. If the NADA is not satisfactory, either an incomplete letter is issued to the sponsor, or, if the unsatisfactory items are minor, the issues may be resolved over the telephone with the sponsor. Special Requests for Use of Unapproved Substances CVM occasionally receives requests from private practitioners, zoo veterinarians, etc. to obtain investigational drugs, unapproved drugs, or chemical substances for use in treating animals in special situations. These requests are resolved on a case-by-case basis. If the situation is urgent in that the patient's condition is life-threatening, then the INAD request is handled with special priority as an Expedited Compassionate Investigational New Animal Drug Exemption. If the situation is not an emergency, the exemption should be requested in writing. The category of Expedited Compassionate Investigational New Animal Drug (ECINAD) Exemption (with respect to non-food animals) is reserved for treatment of life-threatening conditions in which there is no animal or human drug approved in the U.S. When a request is restricted to a single occurrence for emergency treatment to save an animal's life, the Center may allow shipment under the following specified conditions: 1. The sponsor submits to FDA a Notice of Claimed Investigational Exemption for a New Animal Drug and a copy of the appropriate investigational labeling. The shipper (drug supplier) must keep a record of the shipment and the practitioner a record of receipt and disposition of the drug for two years and make the record available for FDA inspection. 2. For requests involving exotic animals in zoos where a drug may be needed but the situation may not be life-threatening, permission may be considered for multiple shipments, if indicated, under the same controls, i.e., submissions to FDA and retention of records. 3. The sponsor provides additional information. If the above issues are satisfactorily addressed, an INAD file is established and an Investigational Exemption is granted. Emergency INAD requests are generally taken by telephone. The CVM employee records the information requested on the ECINAD form and then a decision to grant the exemption or not is made by CVM. If the exemption is granted, the CVM employee notifies the practitioner and gives him/her an INAD number. Two copies of the ECINAD form are then mailed to the practitioner--one to be signed by the practitioner and returned to CVM, and the other for the practitioner to keep for his/her records. The completed and signed ECINAD form serves as the Notice of Claimed Investigational Exemption.
prev | next Source: May/June 1996 FDA Veterinarian Newsletter |
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