FAQ: FDA draft guidance #256, compounding animal drugs from bulk drug substances

Quick links

Compounding and the AVMA’s work
FDA approved, conditionally approved, and indexed drugs
Bulk drug substances, compounding, GFI #256, and FDA authority
GFI 256
Nominations for BDS list
Quality control: USP as compared with cGMP

Compounding and the AVMA’s work

Q: What is compounding according to the USP?
A: United States Pharmacopeia (USP) General Chapter <795> Pharmaceutical Compounding—Nonsterile Preparations (last revised 2008) defines nonsterile compounding as the preparation, mixing, assembling, altering, packaging, and labeling of a drug, drug delivery device, or device in accordance with a licensed practitioner’s prescription, medication order, or initiative based on the practitioner/patient/pharmacist/compounder relationship in the course of professional practice. USP General Chapter <797> Pharmaceutical Compounding—Sterile Preparations (last revised 2014) defines sterile compounding as combining, admixing, diluting, pooling, reconstituting, repackaging, or otherwise altering a drug or bulk drug substance (BDS) to create a sterile medication.

Q:  What is AVMA doing in the compounding space?
A:  AVMA is working to preserve appropriate access to drugs compounded from bulk drug substances so that veterinarians may continue to care for a diverse range of species with significant size and metabolism differences. Many compounded animal drugs must be available for immediate use to avoid patient suffering or death, and there are often no alternatives available that will achieve the necessary therapeutic effect. Our current efforts include working with USP to develop a veterinary-specific compounding chapter; responding to federal agency proposals, such as the FDA Center for Veterinary Medicine’s (CVM) Draft Guidance for Industry (GFI) #256—Compounding Animal Drugs from Bulk Drug Substances; and engaging with compounding pharmacies, drug sponsors, and other stakeholders to ensure they are aware of veterinary needs and concerns. Members guide the AVMA’s work. Member input, careful consideration, and support of AVMA’s responses help ensure the AVMA appropriately and effectively conveys the veterinary profession’s unique compounding needs.

Q:  What is AVMA doing about USP <795> and <797>?
A:  AVMA filed an appeal with USP and met with its staff requesting a veterinary-specific general chapter on compounding, and asked for flexibility when developing and applying standards of beyond use dates (BUD) that were published in drafts of USP <795> (nonsterile compounding) and <797> (sterile compounding). During its May 2020 convention, the USP voted to further develop and revise their compounding standards based on input from healthcare professionals, including veterinarians. Resolution 9—Compounding was developed and adopted based on requests from the AVMA and other stakeholders. The USP white paper accompanying the resolution identified veterinary medicine specifically as an area for which additional support was needed: “Through stakeholder engagement, USP has learned of the request for standards specific to veterinary practitioners, who treat a range of species and practice in varied settings and environments.”

Q: What is AVMA doing in response to draft GFI #256?
A: AVMA filed comments in response to FDA CVM’s draft GFI #256 after seeking feedback from members, volunteer leadership, state and allied veterinary associations, and other impacted stakeholders. All input was considered by subject matter expert volunteers serving on the AVMA’s Council on Biologic and Therapeutic Agents and its Clinical Practitioners Advisory Committee, who are responsible for recommending association policy in this area. They worked with AVMA Policy and Advocacy staff to compile and review the feedback received and to draft AVMA’s comments. AVMA anticipates continued dialog with FDA CVM as the agency works to finalize this GFI.

FDA approved, conditionally approved, and indexed drugs

Q:  What is a ‘new animal drug’, and what makes it “new”?
A:  The Food, Drug, and Cosmetic Act (FD&C Act) states that, a ’new animal drug’ means any drug intended for use for animals other than man, including any drug intended for use in animal feed except that “… a drug shall not be deemed to be a ’new animal drug’ if at any time prior to June 25, 1938, it was subject to the Food and Drug Act of June 30, 1906, as amended, and if at such time its labeling contained the same representations concerning the conditions of its use; …” [21 USC Sec. 321(v)]

Q:  What is an ‘approved’ animal drug?
A: An ‘approved’ drug is a drug approved by the FDA CVM for sale in the United States. FDA CVM approval means the animal drug is safe and effective when it is used according to the label. ‘Safe’ includes safety to the animal and of food products made from the treated animals, if the drug is for use in food-producing animals. ‘Effective’ means the drug consistently does what it is expected to do. FDA CVM approval also ensures that the drug’s strength, quality, and purity are maintained from batch to batch and that the drug’s labeling is truthful, complete, and not misleading. The FDA CVM also considers the drug’s impact on the environment and the safety of the people who will give the drug to the animal or who may otherwise come in contact with the drug. 

Q:  Where do I find the list of FDA-approved animal drugs?
A:  Applications for drugs approved by FDA for use in animals are published at Animal Drugs @ FDA and
those for humans at Drugs @ FDA.

Q:  What is a ‘conditionally approved’ animal drug?
A:  Only drugs for minor species or minor uses in a major species are eligible for conditional approval. Minor species are all animals that are not one of the seven major species: horses, dogs, cats, cattle, pigs, turkeys, and chickens. A drug to treat a disease in sheep or goats, for example, is eligible for conditional approval because both are minor species. A minor use in a major species is the use of a drug in a major species for a condition that occurs infrequently and in only a small number of animals each year or in a limited geographic area and in only a small number of animals each year.

For both conditional approval and full approval, the drug company must prove, among other
things, that the animal drug is safe when used according to the label. The difference between conditional approval and full approval lies in the effectiveness requirement. For full approval, the drug company must provide “substantial evidence of effectiveness”. For conditional approval, the drug company must demonstrate a “reasonable expectation of effectiveness” for the drug, but the “substantial evidence” standard required for full approval of the drug has not yet been met.

Conditionally approved drugs must state on the label, “Conditionally approved by FDA pending a full demonstration of effectiveness under application number XXX-XXX.” Conditional approvals are valid for one year. The drug company can ask the FDA to renew the conditional approval annually for up to four more years, for a total of five years of conditional approval. To receive a renewal, the company must show active progress toward proving “substantial evidence of effectiveness” for full approval. During the conditional approval period, the company can legally market the animal drug for the labeled indications while collecting the remaining effectiveness data. Extralabel use is not permitted for conditionally approved animal drugs. The labeling for every conditionally approved drug states, “It is a violation of Federal Law to use this product other than as directed in the labeling.” 

Q:  Where do I find the list of FDA conditionally approved animal drugs?
A:  FDA CVM has published information about two conditionally approved new animal drugs: paclitaxel and rabacfosadine. Paclitaxel is conditionally approved for treatment of nonresectable stage III, IV, or V mammary carcinomas in dogs that have not received previous chemotherapy or radiotherapy, and for the treatment of resectable and nonresectable squamous cell carcinoma in dogs that have not received previous chemotherapy or radiotherapy. Rabacfosadine is conditionally approved for treatment of lymphoma in dogs.

Q:  What is an ‘indexed’ animal drug?
A:  The Index of Legally Marketed Unapproved New Animal Drugs for Minor Species (the Index) is a list of new animal drugs intended for use in minor species that have had their safety and effectiveness affirmed through an alternative FDA review process. In many cases, minor species drug products are intended for uses that cannot reasonably go through the standard drug approval process. They are often intended for use in species too rare or too varied to be used in traditional safety and effectiveness studies. Indexing is especially helpful for veterinarians treating animals or classes of animals representing markets too small to support the cost of the drug approval process, even with the incentives of the Minor Use and Minor Species (MUMS) Animal Health Act of 2004. As an alternative to the drug approval process for non-food producing minor species and non-food early life stages of food-producing minor species, indexing provides a faster and less expensive process to obtain legal marketing status for eligible products.

Q:  Where do I find the list of indexed drugs?
A:  The Index of Legally Marketed Unapproved New Animal Drugs for Minor Species is available here.

Bulk drug substances, compounding, and FDA authority

Q:  What is a ‘bulk drug substance’?
A:  A ‘bulk drug substance’ (BDS) is any substance incorporated into a finished drug product that furnishes its pharmacological activity.

‘Bulk drug substance’ and ‘active pharmaceutical ingredient’ have the same definition in GFI # 256. More specifically , GFI # 256 states, “FDA regulations define ‘bulk drug substance’ and ‘active pharmaceutical ingredient’ as any substance that is intended for incorporation into a finished drug product and is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body.” The terms do not include intermediates used in the synthesis of the substance. 21 CFR 207.1

Q:  Does FDA regulate human and animal drug compounding?
A:  Yes, the FD&C Act does not generally distinguish between compounding drugs from bulk drug substances and other methods of drug manufacturing. FDA conducts inspections, recalls, and other enforcement actions with respect to both animal and human drug compounders. Information on these FDA webpages includes notes made by the inspector or investigator, warning letters, recalls of compounded drugs, statements from FDA and the compounders, and other enforcement actions.

A few federal court cases provide examples of legal challenges to FDA authority to regulate compounding of drugs for animals. A brief summary of the case, key issue considered, and a summary of the court’s decision follow.

Case 2011:       United States vs. Franck’s Lab, Inc. (816 F. Supp. 2d 1209 (M.D. Fla. 2012) vacated by 12 WL 10234948 (11th Cir. Oct. 18, 2012)).

          Key Issue:

                           Whether the FDA has authority to prevent a pharmacy from compounding drugs for animals from bulk active pharmaceutical ingredients under the Federal FD&C Act.

          Decision Summary:

                           The U.S. District Court, Middle District of Florida, held that “in enacting the [Federal Food, Drug, and Cosmetic Act] in 1938, Congress did not intend to give the FDA per se authority to enjoin the long-standing, widespread, state-regulated practice of pharmacists filling a veterinarian’s prescription for a nonfood-producing animal by compounding from bulk substances.” 816 F, Supp. 2d 1256. FDA appealed, but the case was subsequently vacated by the appeals court on appeal by joint motion of the parties, because the defendants stopped compounding animal drugs from bulk active pharmaceutical ingredients. 2012 WL 10234948.

Case 2008:       Medical Center Pharmacy v. Mukasey (536 F.3d 383 (5th Cir. 2008).

          Key Issue:

                           Whether drugs compounded for human and animal use are new drugs and subject to FDA’s approval, and whether federal law permits compounding drugs from bulk active pharmaceutical ingredients for nonfood animals.

          Decision Summary:

                           The U.S. Court of Appeals for the Fifth Circuit ruled that compounded drugs are ‘new animal drugs’ under the Federal FD&C Act, and are subject to FDA’s approval unless the drugs meet the relevant qualifications of the Animal Medicinal Drug Use Clarification Act (AMDUCA) of 1994. 536 F.3d 408.

Case 2005:       Wedgewood Village Pharmacy, Inc. vs. United States (421 F.3d 263 (3rd Cir. 2005)).

          Key Issue:

                            Whether a pharmacy is exempt from FDA’s general inspection authority under the Federal FD&C Act, and whether a pharmacy suspected of large-scale compounding is covered by the pharmacy exemption for inspection of records under the Federal FD&C Act.

          Decision Summary:

                           The U.S. Court of Appeals for the Third Circuit held that pharmacies are not exempt from FDA’s general inspection authority, and despite the statutory exemption for pharmacies from records inspection provisions for pharmacies, FDA does not violate due process by conducting records inspections when there is probable cause to believe that the exemption does not apply. 421 F.3d 268-275.

Case 1989:       United States vs. Algon Chemical, Inc. (879 F.2d 1154 (3rd Cir. 1989)).

          Key Issue:

                           Whether FDA can enforce regulations that essentially limit the sale of new bulk pharmaceuticals to holders of ‘new animal drug applications’. Specifically, whether FDA could prevent a firm from distributing bulk active pharmaceutical ingredients to veterinarians for use in compounding animal drugs if the firm failed to abide by labeling requirements.

          Decision Summary:

                           The U.S. Court of Appeals for the Third Circuit held that FDA acted within its statutory authority in promulgating and enforcing regulations. 879 F.2d 1155.

GFI #256

Q:  What is the purpose of GFI # 256?
A:  GFI #256 describes those conditions or situations under which the FDA does not intend to take enforcement action against entities compounding animal drugs from BDS.

Veterinarians treat a wide variety of species for many different diseases. Animal drugs are approved, conditionally approved, or indexed by FDA for use in specific species for particular conditions. Veterinarians may also prescribe approved human and animal drugs for extralabel use. Sometimes, however, no such drug can be used as labeled, or in an extralabel manner, for a particular patient. In those situations, veterinarians may need compounded drugs.

FD&C Act requirements regarding drug approval, drug manufacturing, product quality, and labeling may apply to animal drugs compounded from BDS, just as they apply to drugs manufactured by pharmaceutical companies. Unapproved drugs, including medications compounded from BDS, cannot be marketed legally. However, FDA recognizes that veterinarians need such products and GFI #256 is meant to clarify the circumstances under which FDA does not intend to pursue enforcement action.

Specifically, the Policy stated in GFI # 256 is:

  • FDA has developed this draft guidance to explain when the Agency does not intend to take enforcement action for violations of the FD&C Act’s requirements for approval, adequate directions for use, and cGMP requirements.
  • When pharmacies and veterinarians compound animal drugs from bulk substances as described, FDA intends to generally defer to their state licensing boards for day-to-day implementation oversight.
  • The Agency may take action when animal drugs compounded from bulk drug substances: (1) present particular human or animal safety concerns or (2) do not meet other manufacturing, product quality, labeling, or packaging requirements of the FD&C Act (e.g., if the product is made under insanitary conditions or the labeling is false or misleading). Regardless of whether FDA intends to take action, FDA may refer a case to the appropriate state entity.

Q:  Does GFI # 256 change the legal status of products compounded from bulk drug substances?
A:  No. GFI # 256 identifies for veterinarians, pharmacists, and others those activities already deemed unsafe and prohibited under the FD&C Act for which FDA does not intend to take enforcement action.

On page 4, GFI # 256 states, “… FDA does not intend to take enforcement action for violations of the FD&C Act’s requirements for approval, adequate directions for use, and cGMP requirements, for these products that meet the circumstances described below. The policies described in this document aim to protect human and animal health by limiting the use of animal drugs compounded from bulk drug substances primarily to situations in which a veterinarian is acting within a valid veterinarian client-patient relationship (VCPR) and there is no medically appropriate drug that is FDA approved, conditionally approved, or on the Index of Legally Marketed Unapproved New Animal Drugs for Minor Species (indexed) to treat the animal. …”

Q. What are the FDA’s concerns with compounding from bulk drug substances for animals?1
A: FDA’s concerns, as indicated in GFI # 256, are regarding drugs compounded from BDS that may present potential human or animal health risks or create disincentives to the approval process for new animal drugs. For example, when compounded drugs are:

  • Intended for use in food-producing animals, because of the risk of drug residues in the meat, milk, or eggs consumed by people. When FDA approves a drug for a food-producing animal, the Agency evaluates human food safety data to prevent violative drug residues in the edible products from those animals.  Drugs compounded for food-producing animals have not been evaluated by FDA for human food safety.
  • Compounded as office stock without a patient-specific prescription. Office stock exposes larger numbers of animals to drugs of unproven quality and undermines incentives to seek approval by distributing large quantities of unapproved animal drugs.
  • Copies of approved, conditionally approved, or indexed products. These undermine incentives for firms to invest in getting drugs approved, conditionally approved, or indexed by FDA CVM, which can reduce the availability of animal drugs for which safety and effectiveness has been established through the FDA review process.

Q:  If GFI # 256 were finalized in its current draft form what effect would it have on my ability to access medications compounded from bulk drug substances for my patients?
A:  Although there are multiple considerations for how GFI #256 may affect your practice, your access to compounded animal drugs will primarily depend on how often your prescriptions for medications compounded from bulk drug substances are patient specific (i.e., writing a prescription or calling a prescription into a pharmacy for an individual patient) as compared with the medication being kept on your shelf as  ‘office stock’. 

When issuing patient-specific prescriptions, the impact of GFI #256 on access to compounded medications is minimal. Patient-specific prescriptions can be compounded from a BDS as long as the  practitioner provides a short medical rationale for why the compounded medication will make a clinical difference in the patient that could not be achieved by use of, or compounding from, an FDA approved, conditionally approved, or indexed product. The guidance expects that the medical rationale will be documented in the patient’s medical record, but does not require it to be submitted to the FDA or other regulatory agencies.

However, for medications that are kept on the shelf as ‘office stock’, GFI #256 indicates that FDA CVM expects such medications to be limited to those on an FDA published list of medications that must always be accessible in anticipation of an immediate need to prevent or relieve patient suffering or death. Therefore, FDA is requesting that nominations be submitted for those non-patient-specific products that must be kept on the shelf in anticipation of an immediate need for which an approved product is either unavailable or it is not feasible to use an approved product as the starting material to make a compounded animal medication. FDA has posted a list of BDS that may be used to compound new animal drugs for use as office stock, and will periodically update that list after reviewing additional nominations (see questions and answers regarding nominations below). Please see comments on this issue in the AVMA’s response to GFI #256.

1 GFI #256, Page 4

Q:  Is there a list of bulk drug substances for compounding patient-specific prescriptions?  
A:  No. As indicated in GFI # 256, if a prescription is written or called into a pharmacy, many medications can be compounded from a BDS as long as the practitioner provides a short medical rationale for why the compounded product will make a clinical difference in that patient that could not be achieved by use of, or compounding from, an FDA approved, conditionally approved, or indexed product. GFI #256 indicates that such justification needs to be documented in the medical record, but does not require it to be submitted to the FDA or other regulatory agencies. Please see comments on this issue in the AVMA’s response to GFI #256.

Q:  If GFI # 256 was finalized in its current draft form how might it affect the cost of medications compounded from BDS?
A:  GFI # 256 is a draft of a proposed guidance that will likely be the subject of further discussion among multiple stakeholders before it may eventually be finalized. We aren’t anticipating a significant price difference for those new animal drugs currently allowed to be compounded from BDS, such as those on FDA’s list. Similarly, we aren’t anticipating a significant price difference for those new animal drugs already compounded from FDA approved, conditionally approved, or index listed drugs, consistent with AMDUCA and Part 530.

However, if GFI # 256 were finalized in its current draft form, compounding pharmacies that currently market products compounded from BDS on a broad scale that are not FDA approved--and are therefore marketed illegally--have indicated that for those medications that are currently compounded from BDS that would need to be compounded from FDA approved, conditionally approved, or indexed products, an added expense is anticipated in order to comply with GFI # 256. The added expense would be specific to each individual prescription.

Q: Have compounded drugs been associated with any adverse effects or animal deaths?
A: Yes. In 2009, 21 polo ponies died after receiving a compounded selenium product. In 2014, 4 horses died or were euthanized and 6 more experienced adverse effects after receiving a compounded product with about 20 times more pyrimethamine than the labeling indicated, and in 2019, 3 additional horses died after receiving compounded pyrimethamine that was approximately 18 to 21 times greater in strength than that indicated on its labeling (see discussion on slide #6 of the AVMA Axon webinar titled Compounding: Understanding FDA draft guidance).

Q:  If GFI #256 were finalized as currently drafted, what drugs may be compounded from BDS?
A:  FDA CVM’s list of BDS for compounding office stock drugs for use in non-food-producing animals or antidotes for food-producing animals currently includes apomorphine hydrochloride, cisapride, guaifenesin, metronidazole benzoate, miconazole nitrate, potassium bromide, and tacrolimus.

Q:  If GFI #256 were finalized as currently drafted, what drugs may not be compounded from bulk drug substances?
A:  FDA CVM’s list of nominated BDS that may not be used to compound office stock drugs or antidotes for use in animals currently includes amlodipine, budesonide, chloramphenicol, dexamethasone, dipyrone, doxycycline, enrofloxacin, gabapentin, idoxuridine, itraconazole with DMSO, and voriconazole.

Q:  Do veterinarians have a way to provide feedback to FDA?
A:  Of course. GFI # 256 is a draft that will be the subject of further discussion among multiple stakeholders before it is eventually finalized. The comment period closes on October 15, 2020. See AVMA’s comments here.

Nominations

Q:  Is there a deadline for nominating bulk drug substances that may be used to compound office stock drugs? 
A:  The docket for nominating BDS for office stock is expected to remain open indefinitely.

Q:  What are the nomination requirements?
A:  For a complete list of information required for a BDS nomination, see the appendixin Draft GFI #256 or Part II of the Federal Register notice requesting nominations, under the header “What information should I submit with the nomination?” Please see comments on this issue in the AVMA’s response to GFI #256.

Q:  Are there limitations as to which products can be nominated to the list of drugs for use as office stock?
A:  Any product can be nominated, including products with an active ingredient in an FDA approved or indexed drug. Among other criteria, the nominator needs to provide support for why it is not feasible to use an approved product as the starting material for a compounded product. Justification may include pharmacological concerns, such as patient allergies, dietary concerns, or potential adverse effects known to be associated with certain medications, as well as owner compliance and patient acceptance concerns, such as chemical characteristics of the approved product that prevent manipulation of flavoring, texture, volume, or formulation necessary to produce the desired therapeutic effect.   

Q:  How do I know my nomination was received and a decision was made?
A:  Based on prior nominations, FDA CVM has posted a list of new animal drugs that may be compounded from bulk drug substances, those that may not be and why, and those for which sufficient information was not provided to enable FDA CVM to make a decision. FDA CVM has posted a webpage for nominations that are under review, so you know which nominations have been received.

Quality control: USP as compared with cGMP

Q:  What is the benefit to compounding medications from FDA-approved products as compared to BDS?
A:  Products approved by the FDA have been reviewed for evidence that they are safe, effective, properly manufactured, and accurately labeled. In contrast, the certificate of analysis that accompanies a BDS is created by the manufacturer and does not indicate that FDA has reviewed similar data and approved the BDS for safety, efficacy, proper manufacturing, or accurate labelling. 

Q:  What is Good Manufacturing Practice and how does it differ from United States Pharmacopeia chapters and monographs?
A:  Both current Good Manufacturing Practices (cGMP) and USP standards assure quality control (in this context) of drugs. All animal drugs are required to be made in accordance with cGMP requirements.2 Draft GFI # 256 states that FDA does not intend to take enforcement action for violations of the FD&C Act’s requirements for cGMP requirements,3 provided the patient-specific or office stock drug is compounded in accordance with current USP and National Formulary (USP-NF) Chapters <795>, Pharmaceutical Compounding – Nonsterile Preparations, or <797>, Pharmaceutical Compounding-Sterile Preparations, and that it complies with the standards included in all applicable USP-NF monographs.4

Q:  Would compliance with cGMP regulations have prevented the animal deaths associated with compounded products as described above?
A:  Quite possibly. cGMP for finished pharmaceuticals require quarantine of each lot or batch of drug product until acceptance criteria testing is performed for release for distribution (21 CFR Sec. 211.165). Testing, including the identity and strength of each active ingredient, is required prior to release and any products failing to meet established standards or specifications are rejected so the lot or batch is not distributed.

Q:  What quality control standards apply to veterinarians and pharmacists compounding from FDA-approved drugs and from BDS?
A: 
Who is compounding     Starting Material                          Non-Sterile drug             Sterile drug
No one – use of FDA approved dosage form drug           21 CFR Parts 210 and 211 – sterile & nonsterile
Veterinarian                    FDA-approved drug                        USP<795>(2014)             USP<797>(2008)
                                            BDS                                                      USP<795>(2014)             USP<797>(2008)
Pharmacist                     FDA-approved drug                         USP<795>(2014)             USP<797>(2008)
                                            BDS                                                      USP<795>(2014)             USP<797>(2008)

Q:  Does the Federal Food Drug and Cosmetic Act indicate that a drug compounded from a BDS and then marketed across state lines is legally unsafe?
A:  Yes, that is our understanding if the compounded drug is not approved, conditionally approved, or index listed by FDA. Section 360b of the US Code (FD&C Act) indicates that a new animal drug shall be deemed to be unsafe with respect to any particular use or intended use unless an approval or conditional approval of an application or an index listing is in effect and the drug and its labeling conform to the approved application or index listing. Unsafe drugs are considered adulterated (21 U.S.C. 351(a)(5)) and the introduction, or delivery for introduction, into interstate commerce of any adulterated drug is a prohibited act (21 U.S.C. 331). 

AMDUCA and its regulations at Part 530.13 provide specific conditions under which extralabel use from compounding of approved animal drugs or approved human drugs is permitted. The compounding must be in compliance with all relevant provisions of 21 CFR 530. The extralabel drug use regulation does not permit animal drug compounding from active pharmaceutical ingredients (i.e., BDS).

2Page 3, GFI # 256.
3Page 4, GFI # 256.
4Page 9, GFI # 256.

Q:  What do FD&C Act, USC, CFR, CPG, GFI all stand for, and which are law and which are not?
A:  Law:  Congress writes legislative bills that become statutory law after passage by the House and Senate, and signature by the President. These are often referred to as Public Law # xxx or an Act. Public laws are incorporated into the appropriate portion of the United States Code (USC), which is organized by Titles roughly associated with the overseeing federal agency or agencies. If authority is delegated to the agency by Congress, which frequently occurs, the agency may promulgate regulations consistent with the statutory authority delegated to that agency. These regulations promulgated by agencies often go through a public notice and comment rulemaking process and then, once finalized, are codified in the Code of Federal Regulations (CFR).   

As an illustration, the Animal Medical Drug Use Clarification Act of 1994 (AMDUCA) passed the 103rd Congress as Public Law # 103-396 on October 22, 1994. This Law changed language in Section 512(a) of the FD&C Act and part 21 of USC 360b(a), to state: "…(4)(A) Except as provided in subparagraph (B), if an approval of an application filed under subsection (b) is in effect with respect to a particular use or intended use of a new animal drug, the drug shall not be deemed unsafe for the purposes of paragraph (1) and shall be exempt from the requirements of section 502(f) with respect to a different use or intended use of the drug, other than a use in or on animal feed, if such use or intended use…”

Practitioners should be familiar with 21 CFR Part 530 – Extralabel Drug Use in Animals. Various updates have been made to Part 530 in federal register notices 62 FR 27947, May 22, 1997; 67 FR 5471, Feb. 6, 2002; 68 FR 9530, Feb. 28, 2003; 68 FR 14134, Mar. 24, 2003; 71 FR 14377, Mar. 22, 2006, and 77 FR 745, Jan. 6, 2012.

Authority for these changes appears to have been delegated by Congress to the Secretary of Health and Human Services under the AMDUCA, "(i) is by or on the lawful written or oral order of a licensed veterinarian within the context of a veterinarian-client-patient relationship, as defined by the Secretary;” and "(ii) is in compliance with regulations promulgated by the Secretary that establish the conditions for such different use or intended use.

The regulations promulgated by the Secretary under clause (ii) may prohibit particular uses of an animal drug and shall not permit such different use of an animal drug if the labeling of another animal drug that contains the same active ingredient and that is in the same dosage form and concentration provides for such different use.

Guidance:  Guidance is not law but generally referred to as an agency’s “current thinking” about how it is interpreting the law. Although a variety of documents from an agency are considered guidance, two are offered as examples, guidance for industry (GFI) and compliance policy guides (CPG). Two recent GFIs regarding compounding animal drugs from bulk substances are GFI #230 and GFI #256.

The FDA previously published draft guidance on compounding for public comment in May 2015 (Draft GFI #230, Compounding Animal Drugs from Bulk Drug Substances). Based on feedback from the veterinary community and compounding industry, as well as other stakeholders, FDA decided to withdraw GFI #230.   

The previously discussed GFI #256, Compounding Animal Drugs from Bulk Drug Substances, is also an example of a guidance. The new draft guidance, if finalized, would advise veterinarians on circumstances under which FDA does not intend to take action for certain violations of the FD&C Act when pharmacists and veterinarians compound or oversee the compounding of animal drugs from bulk drug substances.

CPG are often referred to as Guidance for FDA Staff. An example is CPG Sec. 635.100 Large Volume Parenterals (LVPs) for Animal Use, “The purpose of CPG 635.100 is to provide guidance for FDA staff on large volume parenterals (LVPs or large volume injections). The policy stated in CPG 635.100 is that LVPs may be considered new animal drugs and be considered unsafe under section 512(a)(1) of the … FD&C Act … and adulterated under section 501(a)(5) of the FD&C Act … if marketed in the absence of an approved new animal drug application. However, CVM generally does not intend to take action against LVPs and those marketing LVPs if all of the following criteria are met and the LVP is not otherwise adulterated or misbranded …”