Animal & Veterinary
IMPLEMENTING THE ADAA - A SUMMARY OF CVM’S PROGRESS
by Daniel A. Benz, Ph.D., P.A.S.
FDA Veterinarian Newsletter November/December 1999 Volume XIV, No VI
On October 9, 1996, President Clinton signed into law the Animal Drug Availability Act of 1996 (ADAA), which amended the Federal Food, Drug, and Cosmetic Act (the Act). The purpose of the ADAA was to facilitate the approval and marketing of new animal drugs and medicated feeds. Further, the Food and Drug Administration (FDA) is to work with drug sponsors to identify the least burdensome appropriate means for demonstrating that a new animal drug is safe and effective.
The following is a brief discussion of each of the provisions of the ADAA and its status.
Feed Mill Licensing
The ADAA established a new regulatory system for licensing feed mills to manufacture medicated feeds. under the previous law, feed mills were required to obtain drug specific medicated feed applications (MFA’s; FD-1900’s) for each medicated feed they manufactured. Now, a single license is sufficient for all medicated feeds manufactured by a single facility. The requirement for the facility to submit a single license application has eliminated a substantial paperwork and administrative burden on the industry from filing multiple drug specific MFA’s. The underlying standards for the issuance of a license, and revocation of a license, do not differ substantively from the previous standards applicable to MFA’s. The principal criterion for the issuance of a feed mill license remains whether the establishment is operating within current good manufacturing practices. This is represented in the application and confirmed by FDA or State inspection prior to approval.
FDA has published proposed procedural regulations (july 30, 1997, Federal Register; (62 FR 40765) to provide for Medicated Feed Mill Licensing consistent with the ADAA. The proposed procedural regulations are in the process of being finalized and are expected to be published soon.
Veterinary Feed Directives (VFD’s)
The ADAA also created veterinary feed directive (VFD) drugs. VFD drugs are new animal drugs intended for use in or on animal feed which are limited to use under the professional supervision of a licensed veterinarian in the course of the veterinarian’s professional practice.
FDA has determined that certain animal drugs, not normally eligible for use in animal feed, but vital to animal health, should be approved for use in animal feed but only for use under a veterinarian’s order and supervision. For example, control of certain antimicrobials is critical to reducing unnecessary use of such drugs in animals and to slow or prevent the development of bacterial resistance. Safety concerns associated with the difficulty of diagnosing disease conditions, small margins of safety, or other reasons may also require that the use of drugs in animal feed be limited to use only under the order and supervision of a licensed veterinarian. A VFD drug is limited to use through a valid veterinarian-client-patient relationship where the veterinarian assumes the responsibility for the safe and effective use of the VFD drug and the client agrees to follow the instructions of the veterinarian.
Prior to the ADAA, an animal drug limited to use under the professional supervision of a licensed veterinarian was a prescription (and typically a dosage form) drug. Because the distribution system for medicated feeds is more complex than that for dosage form animal drugs, regulation of animal feeds under traditional prescription systems was not practical. Additionally, the occurrence of prescription drugs in animal feeds invoked State pharmacy laws that were impractical or impossible to meet. By declaring that VFD drugs and medicated feeds containing them are "not prescription" articles under any Federal or State law, the ADAA was able to sidestep this problem.
Under the ADAA, each person involved in the distribution, holding, or use of a VFD medicated feed, and the veterinarian issuing the VFD, is required to maintain a copy of the applicable feed directive. The only exception is that a person distributing the feed to another person for further distribution is required to maintain a copy of a written acknowledgement from the consignee stating that the VFD distribution limitations have been followed. FDA has authority to inspect and copy these VFD’s and written acknowledgements. Additionally, persons distributing VFD medicated feeds must provide a one-time notice to FDA.
The proposed regulations to implement VFD’s were published in the July 2, 1999, Federal Register (64 FR 35966) with comments being accepted until September 30, 1999. The first VFD drug, tilmicosin phosphate, was approved December 27, 1996. The VFD instructions were included on the label.
Combination New Animal Drugs
The Federal Food, Drug, and Cosmetic Act was amended to establish a streamlined approval process for certain combination new animal drugs. The purpose of this change was to reduce the burden on the drug sponsor to conduct additional effectiveness studies and to shorten the approval period for these combinations. The underlying assumptions for these combination new animal drugs are that: 1) the demonstration of each drug’s effectiveness and animal safety are contained in the previous separate approvals, and 2) each drug’s individual effectiveness and animal safety are maintained when combined if certain conditions are met.
The criteria to permit the streamlined approval process for combination new animal drugs differ between those for feed and/or drinking water combinations and dosage form combinations (excluding drinking water). The exact criteria are identified in the implementing regulations [published in the Federal Register on July 28, 1999 (64 FR 40746)] for combination new animal drugs that occurred as part of those for substantial evidence.
Those combination new animal drugs, which meet the appropriate criteria, have no additional effectiveness requirements. Other combination new animal drugs that do not meet the exemptions will require traditional effectiveness studies.
Adequate and Well-Controlled
The ADAA required FDA to publish a final rule to further define "adequate and well-controlled" to require that field studies be designed and conducted in a scientifically sound manner. As part of this regulation, FDA was to take into account practical conditions in the field and the differences between field and laboratory conditions.
To meet this directive, a final rule further defining "adequate and well-controlled" was published in the Federal Register on March 5, 1998 (63 FR 10765). This final rule defined the essential characteristics of adequate and well-controlled studies and explicitly addressed differences between field and laboratory studies.
The ADAA amended the definition of "substantial evidence" of effectiveness permitting greater flexibility in studies required to demonstrate a new animal drug’s effectiveness. Prior to the enactment of the ADAA, the Act required that a sponsor conduct at least two studies, at least one of which must have been a field study, to demonstrate the effectiveness of the new animal drug. The ADAA has eliminated the requirement that at least one field study is required for approval of each new animal drug, but FDA continues to have the authority to require field studies when needed. A field study remains an important element of many new animal drug approvals because a field study assesses the effectiveness of a new animal drug under conditions that approximate actual use. FDA will not require a field study for the purposes of demonstrating effectiveness in those instances in which a field study would yield no more useful information with regard to the new animal drug’s effectiveness than can be obtained through laboratory studies.
With the elimination of the requirement to use no more new animal drug than is necessary to achieve the intended effect to minimize drug residues, the ADAA does not require adequate and well-controlled dose titration studies as part of the demonstration of substantial evidence that the new animal drug is effective at the dose or over the dose range suggested in the proposed labeling. However, dose characterization is required.
In addition to making changes to the definition of substantial evidence, the ADAA requires FDA to further define the term "substantial evidence" in a manner that encourages the submission of new animal drug applications (NADAs) and supplemental NADAs.
To meet this directive, a final rule was published in the Federal Register on July 28, 1999 (64 FR 40746). This final rule defined the term "substantial evidence" and encouraged the submission of new animal drug applications (NADAs) and supplemental NADAs for single ingredient and combination new animal drugs. The final rule also encouraged dose range labeling.
Minor Use and Minor Species
The ADAA requires the announcement for proposals for legislative and regulatory changes to facilitate the approval of new animal drugs intended for minor species (e.g., sheep, fish) and for minor uses (e.g., conditions that are rare or occur in limited geographic areas). The purpose of these changes is to identify more practical approaches in approving drugs for use in minor species or for minor uses, because the traditional safety and effectiveness studies were often difficult to design and conduct. These alternate approaches should also improve the economic incentives for a sponsor to conduct such studies in light of the potential market for the product.
FDA published a request for comments on the development of options to encourage animal drug approvals for minor species and for minor uses in the June 23, 1997, Federal Register (62 FR 33781). Also, a Discussion Draft of proposals for legislative or regulatory change was posted on CVM’s Internet Home Page on December 19, 1997. A notice of the availability of FDA’s "Proposals to Increase the Legal Availability of Animal Drugs for Minor Species and Minor Uses" was published in the October 29, 1998, Federal Register (63 FR 58056). Additionally, FDA announced in the August 25, 1999, Federal Register (64 FR 46400), the availability of a draft Compliance Policy Guide (CPG) entitled "Use of Medicated Feeds for Minor Species.'' The purpose of the draft CPG, if finalized, would be to provide guidance to FDA's field offices concerning the Agency's exercise of regulatory discretion with regard to the extra-label use of medicated feeds for minor species.
The ADAA amended the Act to provide that applicants are entitled, at their discretion, to one or more presubmission conferences prior to the submission of a new animal drug application. The purpose of the presubmission conference is to reach an agreement acceptable to FDA for establishing a submission requirement, including a requirement for a field study when necessary. This enables the sponsor to play a larger role in deciding what types of studies are needed to demonstrate their products are safe and effective. A presubmission conference agreement, administered by CVM, is binding upon CVM and the sponsor unless CVM and the sponsor agree to modify a requirement, or the sponsor fails to meet the conditions of the presubmission conference agreement. CVM may, by written order, determine that a substantiated scientific requirement essential to the determination of safety or effectiveness of the animal drug involved has appeared after the conference and modify the requirement.
CVM is developing regulations and guidance, as needed, to establish formal procedures for requesting, holding, and documenting presubmission conferences, as provided under the ADAA.
This change in the Act allows FDA/CVM to establish tolerances for animal drugs that are not approved in the United States. This will help FDA assure that animal-derived food products imported into the United States are free of unsafe residues of animal drugs. There are instances in which food-producing animals raised in other countries are treated with animal drugs that are not approved in the United States, especially for a disease or condition that does not occur in the United States. Previously, there have been concerns about residues of such drugs in food products derived from these animals which were imported into the United States.
The changes brought about by the ADAA have increased the number of new animal drugs, and created a new class of drugs (VFD’s). Also, the paperwork associated with the manufacturing of medicated feeds has been greatly reduced. Further, by working with drug sponsors in identifying the least burdensome and appropriate means for demonstrating that a new animal drug is safe and effective, CVM continues to implement the spirit and intent of the ADAA.