Some happenings at USDA and FDA that may impact your business are noteworthy.

On November 16, 2018 FDA released for public comment “proposed research to validate an alternative approach for bioequivalence studies for certain animal drugs.”

Bioequivalence studies are required before drugs are approved by FDA (for humans or animals) as safe and efficacious.

The proposed study will measure the bioequivalence of the approved antiparasitic drugs ivermectin and praziquantel by in vitro dissolution compared to blood levels that indicate how the drug is dissolving in the body (also known as blood-level pharmacokinetics), with the goal of validating these laboratory-based alternative (i.e., surrogate) endpoints. Ivermectin is used in dogs to treat heartworm, a potentially fatal infection. Praziquantel treats tapeworms, an internal parasite that lives primarily in the gastrointestinal tract but can form cysts in liver and other organs.

Comments to the proposed white paper, Alternative Methods for Evaluating Locally Acting, Nonsystemically Absorbed Drugs in Canine Disintegrating or Chewable, Single Layer Combination Drug Products, are available here.

To date, 46 comments are posted.

Recently the Secretary of the Department of Veterans Affairs expressed continued support for the use of dogs in certain research, without which significant gains in medical care for people and pets would not be possible.

On October 30, 2018 FDA announced “the Plant and Animal Biotechnology Innovation Action Plan to outline the key priorities the agency will pursue to support innovation in plant and animal biotechnology while advancing the agency’s public health mission.”

The overall goal of the action plan is to ensure the safety of plant and animal products of biotechnology while avoiding unnecessary barriers to future innovation.

Titled, the “Veterinary Innovation Program (VIP)” the program is designed to “guide sponsors [of certain veterinary products] through the regulatory process . . .”

Some of these innovations involve genome editing in animals, and exciting new frontier that will benefit humans and animals alike.

As reported by USDA Research, Education & Economics Information System a project titled “Improvement of Dairy animal Well-Being By Genetic Dehorning,” sponsored by the National Institute of Food and Agriculture “will evaluate gene-editing as a means for genetically dehorning cattle without crossbreeding in three steps.”

First we will introduce the polled genetics into dairy cattle by gene-editing and determine if it has the same effect as crossbreeding. Second, we will determine if there are any unintended effects on the animals; and third, we will evaluate the feasibility of deploying this technology in a variety of breeds to enable broad acceptance and rearing of genetically dehorned cattle.

The project end date is April 14, 2019.

Finally, as United States Cattlemen’s Association recently announced, USDA and FDA “will jointly oversee the regulation of cell-cultured food products from cell lines of livestock and poultry.”

FDA will oversee cell collection, cell banks, and cell growth and differentiation. A transition from FDA to USDA oversight will occur during the cell harvest stage. USDA will then oversee the production and labeling of food products derived from the cells of livestock and poultry.

USCA noted that their pending petition for rule making to define “beef” and “meat” remains outstanding and should be addressed to ensure truth in labeling for consumers.

More to come about all these programs.

The Food Animal Residue Avoidance Databank (FARAD) recently provided guidance to small ruminant producers and their veterinarians in an article titled “Extralabel drug use (ELDU) in small ruminants” in JAVMA, Vol 253, No. 8, Oct. 15, 2018, pp 1001-1009.

FARAD is a university-based national program that serves as the primary source for scientifically-based recommendations regarding safe withdrawal intervals of drugs and chemicals in food-producing animals. As such, FARAD is a key resource for protection of our nation’s food supply, including meat, milk and eggs, against accidental contamination of animal-derived foods with violative residues of drugs, pesticides or other agents that could compromise food safety.”

FARAD regularly provides guidance to the food animal producing industry and veterinarians regarding “the use of therapeutic drugs, pesticides and other agents that improve overall animal health and promote safe, efficient and humane production practices.”

The purpose of its latest digest, as stated, “was to provide US veterinarians guidance regarding ELDU in small ruminants. The lack of FDA-approved drugs for sheep and goats frequently necessitates ELDU in those species. When the FDA approves a drug for use in a particular species, it establishes a tolerance or that drug in the various tissues or products (eg, milk or eggs) of that species that might be consumed by people. When a drug not labeled for use in a small ruminant is administered in an extralabel manner, there is a zero tolerance for residues of the parent drug or its metabolites in the edible tissues or products of treated animals, and detection of the parent drug or metabolites in any product marketed for human consumption is considered a violation and subject to regulatory action. Given the lack of tolerance and pharmacokinetic and tissue depletion data for many drugs administered in an extralabel manner to small ruminants, extended meat and milk WDIs are generally required to ensure that drug residues are undetectable. Veterinarians need to be cognizant of the requirements for legal ELDU in food-animal species to safeguard the human food supply while continuing to promote the health and welfare of small ruminants.”

As a former owner of a veterinary large animal practice in which 50% of my patients were small ruminants (goats, sheep, alpaca and llama), it was imperative to be able to prescribe or administer drugs in an extralabel manner to provide humane care and prevent animal suffering.

Extralabel use means actual use or intended use of a drug in an animal in a manner that is not in accordance with the approved labeling. This includes, but is not limited to, use in species not listed in the labeling, use for indications (disease or other conditions) not listed in the labeling, use at dosage levels, frequencies, or routes of administration other than those stated in the labeling, and deviation from the labeled withdrawal time based on these different uses.  21 CFR 530.3.

Some of these uses have included medications added to commercial feeds, that are now governed under the Veterinary Feed Directive that FDA enforces for use in major, but not minor species.

According to guidance from FDA, “many commercial medical feeds that require a VFD are not approved for use in minor species,” defined by FDA as all species other than cattle, horses, swine, chickens, turkeys, dogs, and cats.  Compliance Policy Guide Sec. 615.115 Extralabel Use of Medicated Feeds for Minor Species.  A veterinarian may consider ELDU of medicated feed in minor species if:

There are no approved treatment options available;

The health of the animals is threatened; and

Failure to treat the animals would result in suffering or death.

The veterinarian must provide a written recommendation that includes the medical rationale for ELDU of medicated feed.

Before a veterinarian can provide such professional guidance, a valid veterinarian-client-patient relationship (VCPR) must exist.  While state laws govern the practice of veterinary medicine, including such relationships, FDA has inserted itself in the equation by identifying which states do not require the elements of a VCPR that FDA considers sufficient for the purposes of enforcing its Veterinary Feed Directive and other federal laws.

These multilayered state and federal laws can be difficult for veterinarians and small ruminant producers to decipher—hence the necessity of FARAD and other agencies to provide more specific guidance.

As part of its Five-Year Plan for Supporting Antimicrobial Stewardship in Veterinary Settings—just released—FDA announced that it plans to shift from “educating” food animal veterinarians and producers about the 2016 Veterinary Feed Directive (VFD) to “ensuring compliance with the . . . regulation to further ensure the safety of animal and human health.”  In other words, producers, veterinarians, and VFD medicated feed distributors (e.g., feed mills, retailers) should expect enhanced enforcement by FDA inspectors.

Those regulated should keep in mind that FDA inspectors will “examine VFD orders, requirements for the parties involved, and recordkeeping” during inspections.

FDA’s overall plans include three broad-based goals:

  1. Align antimicrobial drug product use with the principles of antimicrobial stewardship;

  2. Foster stewardship of antimicrobials in veterinary settings; and

  3. Enhance monitoring of antimicrobial resistance and antimicrobial drug use in animals.

While described as a One Health initiative, FDA’s plans favor the preservation of medically important antibiotics for humans over animals, particularly food animals.  Also, while acknowledging that it does not regulate either veterinary medicine or farming activities, FDA has set forth plans that appear to attempt to extend their regulatory reach, through proposed expansion of inspection and testing of animals, including food animals, companion animals, animal feed, farm-raised seafood and retail meat.

FDA also plans on bringing the 5% of antimicrobials still available over the counter under veterinary oversight, including, for example intramammary treatment to prevent or treat mastitis.  Not only will this increase costs to producers (which will be passed along to consumers), but according to the AVMA, many farmers and ranchers in rural communities do not have access to adequate veterinary care because of veterinary shortages “in more than 180 rural communities across the country.”

Certainly, the issue of antimicrobial resistance is important.  However, the emphasis by some government officials and legislators too often focuses on limiting use of antibiotics important to maintain the health of animals.  And the collection and reporting of antibiotic use and test results are used by activists to eliminate the use of animals for food completely.

Testing of some food products, albeit for other purposes, resulted in the conviction of the owners and operators of the Decoster Egg Farms for “introducing eggs into interstate commerce that had been adulterated with Salmonella enteritidis,” even though the government admitted that it had not identified any personnel, including the defendants who knew that the eggs were contaminated.  United States v. Decoster, 828 F.3d 626 (8th Cir. 2016) (Beam, J., dissenting).

Keep in mind that preventing Salmonella enteriditis was the basis for the adoption of enlarged cage requirements for hens in California despite evidence that such measures do not decrease the prevalence of the bacteria.  Furthermore, California and Massachusetts have imposed their regulations on producers in other states—an impermissible extraterritorial regulation in violation of dormant commerce clause, which has been challenged.  State of Missouri, et al. v. State of California, No. 22O148 (2017); State of Indiana, et al. v. Commonwealth of Mass., No. 22O149 (201

FDA’s recent announcement that it is “withdrawing draft Guidance for Industry (GFI) #230, ‘Compounding Animal Drugs from Bulk Drug Substances’” reminded me that pet owners can become confused about what type of medications are available for treating their pets.  For example, while serving on the New Jersey State Board of Veterinary Medicine, I recall a fair number of consumer complaints that alleged that a veterinarian provided substandard medical care because the medication prescribed to a pet was labeled “for human use only.”  Consumers therefore concluded that the medication harmed their pet.

However, the fact that medication is not specifically approved for use in animals does not mean that it would necessarily be harmful to those animals.

In fact, the use of an approved drug in a manner that is different than stated on the label, has been a fundamental tool used in veterinary medicine since drugs were first labeled.  This “extralabel” drug use was memorialized by Congress in the Animal Medicinal Drug Clarification Act of 1994 (AMDUCA).  See AVMA’s description of AMDUCA.

As AVMA describes on it’s website, “Compounding: FAQ for Veterinarians,” “compounding for animal patients . . . [is] a subpart of  [the] Extralabel Drug Use (ELDU) Rules.”

The ability to use approved drugs in species, for treatments, or at dosages, frequencies, or routes of administration that are not included on the label, is a tool that veterinarians use on a daily basis.  Since obtaining drug approvals for all uses in all types of animal species is cost-prohibitive, the only way some animals can be treated is through the use of drugs in an extra-labeled fashion.

When used properly and pursuant to the standard of care in veterinary medicine, such use should be considered legal.

While FDA has stated that “[c]urrent law does not permit compounding of animal drugs from bulk drug substances,” whether, and to what extent FDA governs compounding in the veterinary space has been the subject of legal debate.

However, FDA’s withdrawal of its guidance document related to compounding animal drugs from bulk substances creates even more confusion and uncertainty for the regulated community.  The now withdrawn guidance document,  Guidance #230, had set forth the situations in which FDA had indicated that it would not take regulatory action against a pharmacy or veterinarian when “an animal drug compounded from bulk substances may be an appropriate treatment option.”

Now, instead of finalizing the draft guidance based on comments received, “FDA intends to publish the new draft in early 2018 for public comment.”

So, the regulated community will be without guidance for a short period of time.

Hopefully FDA’s new guidance will continue to permit compounding from bulk substances when needed to provide adequate medical care for animals in need thereof.