I. BACKGROUND

A. Legal Marketing Pathways for Animal Drugs

To be legally marketed, animal drugs, with few exceptions, must be approved, conditionally approved, or indexed by FDA.

Animal drugs that are not FDA-approved, conditionally approved, or indexed are considered "unsafe" and, therefore, "adulterated" under sections 512(a)(1) and 501(a)(5) of the FD&C Act (21 U.S.C. §§ 360b(a)(1) and 351(a)(5)).

The FDA approval process provides important protections for humans and animals. A drug company (sponsor) seeking FDA approval of an animal drug application must submit data and information that demonstrate, among other things, that the animal drug is safe and effective (or in the case of a generic drug, that the drug is bioequivalent to an already FDA-approved drug), properly manufactured, and accurately labeled. If the drug is for use in food-producing animals, the sponsor must submit data regarding the drug's potential for creating harmful residues in the meat, milk, eggs, and other edible products from treated animals.

FDA's application review encompasses, among other things, the specific active and inactive ingredients to be used; manufacturing methods; and labeling, including the drug's indications, intended species, warnings, safety information, and other conditions of use. FDA approval means that FDA has determined that the data demonstrate that the approved animal drug is safe, effective, properly manufactured to ensure drug quality, and adequately labeled. For drugs approved for food-producing animals, labeling must provide:

• data-based residue tolerances;
• withdrawal,
• withholding, and/or discard times; and
• other conditions of use needed to prevent products from treated animals that contain harmful residues from entering the food supply.

In addition to pre-market review, FDA-approved animal drugs are subject to requirements once they are on the market. For instance, sponsors must submit reports of adverse events, product defects, and manufacturing quality, and provide copies of any post-approval laboratory or clinical studies conducted or obtained by the sponsor throughout the lifetime of the product. This information allows FDA to continue to monitor the safety and effectiveness of the drug after approval.

The conditional approval and indexing processes provide alternative pathways to legal marketing that address the specific challenges associated with full FDA approval for drugs intended for minor uses, minor species, or for certain other new animal drugs. Like the full approval process, these provisions protect human and animal health by requiring FDA review of information regarding safety, effectiveness, manufacturing, and labeling before a drug that qualifies for these pathways can be legally marketed. They also provide for FDA to monitor safety and effectiveness after the product is on the market.

The conditional approval allows the sponsor to make a drug for a minor use or minor species and certain other new animal drugs available before collecting all effectiveness data necessary for approval of a new animal drug application (NADA) under section 512 of the FD&C Act, but after proving the drug is safe in accordance with the full FDA approval standard and showing that there is a reasonable expectation of effectiveness. FDA may permit the drug sponsor to keep the conditionally approved new animal drug on the market for up to 5 years, through annual renewals, while collecting the remaining required effectiveness data. Indexing allows drug companies to market certain unapproved drugs for minor species. The Index is limited to drugs intended for use in nonfood-producing, minor species and some early non-food life stages of food-producing minor species.

The term "minor use" means the intended use of a drug in a major species for an indication that occurs infrequently only in a small number of animals, annually, or in limited geographical areas. Section 201(pp) of the FD&C Act (21 U.S.C. § 321(pp)).

The term "minor species" means animals other than humans that are not major species. Section 201(oo) of the FD&C Act (21 U.S.C. § 321(oo)). Major species are dogs, cats, horses, pigs, cattle, turkeys, and chickens. Section 201(nn) of the FD&C Act ((21 U.S.C. § 321(nn)). or for certain other new animal drugs.

B. Animal Drugs Compounded from Bulk Drug Substances

The law permits compounding of an animal drug when the source(s) of the active ingredient(s) for compounding is a finished FDA-approved drug(s) and not a bulk drug substance. Specifically, the extralabel use provisions of the FD&C Act permit the compounding of animal drugs made from FDA-approved animal or human drugs, provided the conditions for legal extralabel use described in the FD&C Act and FDA's extralabel use regulations are met, per Sections 512(a)(4) and (5) of the FD&C Act (21 U.S.C. § 360(a)(4) and (5)) and 21 CFR part 530. These regulations state that, "[n]othing in this part shall be construed as permitting compounding from bulk drugs."

The FD&C Act does not generally distinguish between compounding animal drugs from bulk drug substances and other methods of animal drug manufacturing. The FD&C Act's requirements regarding drug approval, drug manufacturing, product quality, and labeling apply to animal drugs compounded from bulk substances, just as they apply to drugs manufactured by pharmaceutical companies. As explained above, drugs compounded from bulk drug substances violate the FD&C Act because they are not approved or indexed, are not made according to CGMP, and cannot satisfy the FD&C Act's adequate directions for use provision (which requires, among other things, that a prescription drug have FDA-approved labeling).

When a drug is compounded from bulk drug substances using the same active ingredient that is in an approved or indexed drug, it is not the equivalent of the FDA-approved or indexed brand-named drug, not the equivalent of an FDA-approved generic drug, and cannot be presumed to have the same effect as the approved or indexed drug. When FDA approves or indexes a drug, FDA review and approval or index listing covers not only the active ingredient but the finished product, with specific active and inactive ingredients, sources of ingredients, manufacturing processes, drug specifications, and labeling. All of these factors are critical in determining the safety and effectiveness of a drug product prior to approval. Further, the approved animal drug becomes part of FDA's post-approval monitoring and pharmacovigilance programs, where FDA monitors adverse events, product defects, prescription drug advertising, and changes in the manufacturing and labeling of the approved animal drug. Because compounded animal drugs are not FDA-approved, they do not have these same assurances of safety, efficacy, and quality as FDA-approved and indexed products.

The overview of this Guidance will continue next week.

Loyd V. Allen, Jr., PhD, RPh
Editor-in-Chief
International Journal of Pharmaceutical Compounding
Remington: The Science and Practice of Pharmacy Twenty-second edition