Lynn O. Post, DVM, Ph.D. and William C. Keller, DVM, MS
The University of Georgia, College of Veterinary Medicine, Veterinary Diagnostic and Investigational laboratory, P.O, Box 1389, Tifton, Georgia, 31793 and Division of Epidemiology and Compliance, Office of Surveillance and Compliance, Center for Veterinary Medicine, Food and Drug Administration, Rockville, MD 20855
The availability of antidotes in veterinary medicine has been an issue for over a decade. There is little economic incentive for pharmaceutical companies to pursue approval of antidotes and other drug products that have a small market. In addition, human food safety concerns must be addressed when approving antidotes for use in food-animals. This article provides a brief history of antidote availability, present alternatives, possible new legislation and antidote availability in food-animals.
In 1991, the American Board of Veterinary Toxicology (ABVT) requested that the Center for Veterinary Medicine (CVM) investigate avenues to improve antidote use and availability in food-animals. At the FDA Veterinary Medicine Advisory Committee (VMAC) Meeting on April 29 and 30, 1992, a Center for Veterinary Medicine (CVM) representative stated that CVM was determined to address problems of antidote use and availability. The CVM presentation was in response to concerns expressed by the American Board of Veterinary Toxicology (ABVT). An ABVT member stated that many commonly recommended poison antidotes for food-producing animals were not commercially available or were not approved for use in food-animals. The ABVT expressed concern that food animal veterinarians have no approved products for treatment of many acute poisonings due to regulatory restrictions.
CVM presented four options for the VMAC's to consider to assure antidote availability in food-producing animals. 1) Investigational New Animal Drug applications (INAD) could be established for drugs with insufficient human food safety information. The sponsor of the INAD would develop study protocols and collect effectiveness data. It was proposed that human food safety data collection might be addressed by National Research Support Project-7 (NRSP-7) funding in connection with the "minor use and minor species" initiative. 2) Regulatory discretion was another option where antidotes that presented low human food safety and environmental concern would not be required to have New Animal Drug approval as a condition of marketing. 3) Extra-label use of human-labeled antidotes was suggested as a means to save the life of an animal. 4) Two drugs, atropine sulfate and epinephrine injection were exempted by regulation from certain drug-labeling requirements "when intended for those veterinary uses for which they were generally employed by the veterinary medical profession."
The compassionate use INAD option replaced the emergency use INAD. It provided a process leading to approval although it did not address chemistry and manufacturing requirements. This is in contrast tot he emergency use INAD application which was a mechanism for allowing unapproved products to be made available without regard for ultimate FDA approval. It was proposed that one INAD sponsor for each antidote be established with various participating antidote depots serving as clinical investigators. The depots would receive the bulk chemical, compound the bulk ingredient into a dosage form according to an established protocol and distribute the product to veterinarians. This option would have required the allocation of CVM resources for the review of safety and efficacy data. Human food safety data including residue depletion studies would be funded through the USDA in conjunction with the NRSP-7 program. Under this option, "Emergency use" INADs were discontinued because studies were not actually being conducted to support the INAD.
Regulatory Discretion Option
If commercially available, CVM allowed low regulatory priority products to be marketed. These antidotes (EDTA, sodium sulfate, sodium nitrite, sodium thiosulfate, bromosulphalein and menadione) were classified as low regulatory priority because of minimum human food safety and environmental concerns. However, this process provided no incentive for obtaining approved antidotes.
Extra-Label Use Option
Extra-label use before 1994 was illegal but enforcement discretion was exercised by CVM.
Compounding is authorized by FDA Compliance Policy Guide, Compounding of Drugs for Use in Animals (CPG 7125.40). Licensed pharmacies are exempted from registration requirements by Section 510 (g) (1) of the Federal Food, Drug and Cosmetics Act (the Act). Drugs may be compounded by licensed pharmacies within the regular course of business of dispensing or selling drugs at retail. Licensed practitioners are also exempted from registration requirements by Section 510 (g) (2) of the Act, if drugs are manufactured, prepared, propagated, compounded or processed during the regular course of business or dispensed at retail. Drugs for resale by practitioners are not exempted from compounding registration. Practitioners and pharmacists are not exempted from approval requirements in the new animal drug provisions of Sections 501 (a) (5) and 512. Under these requirements, compounding is limited to the preparation of drug products which do not meet the definition of new animal drugs. The FDA Modernization Act of 1997 further clarified a pharmacist's or licensed practitioner's right to compound human products, but not animal products.
Under the Animal Medicinal Drug Use Clarification Act (AMDUCA) of 1994, veterinarians are permitted to legally use approved animal and human drugs in an extra-label manner. The veterinarian is responsible for insuring that no illegal residues occur in food producing animals following extra-label use. It also allows compounding from approved drugs but does not allow compounding from bulk drugs. However, if the need is great and the public health risk is small, FDA exercises regulatory discretion with respect to veterinarians compounding from unapproved drugs under CPG 7125.00, Extra-label Use of New Animal Drugs in Food-Producing Animals.
The Compliance Policy Guide acknowledges that circumstances do exist when it may be necessary for a veterinarian to compound or direct for a pharmacist to compound, an article that results in an unapproved new animal drug. This includes human and bulk drugs. The FDA will exercise regulatory discretion when unapproved new animal drugs are compounded to provide appropriate medical therapy. The following criteria must be met: 1) A legitimate medical need is identified where the health of animals was threatened and suffering or death would result from failure to treat the affected animal. 2) There is a need for an appropriate dosage regimen for the species, age, size or medical condition of the patient. 3) There is no marketed approved animal drug which could be used in a labeled or extra-label manner, or human-label drug, or there was some rare extenuating circumstance. Additionally, compounded drugs must be formulated under Good Compounding Practices (GCP). Compounded antidotes should not be stockpiled, advertised, promoted, displayed or marketed as unapproved new animal drugs.
Regulatory discretion continues to be an option because manufacturing of some unapproved antidotes for life-threatening situations would have no food safety concerns. However, manufacturing under Good Manufacturing Practices (GMP) may not be profitable to a manufacturer. Model labels (monographs) may be drafted as standard labels for various antidotes. This will allow any legitimate manufacturer to market antidotes made under GMP's. An unapproved antidote becomes a high regulatory priority when illegal residues occur in meat, milk, eggs, honey or aquaculture products. Illegal residues may occur when withdrawal times have not been established by the veterinarian or established without using adequate scientific information.
One way to increase antidote availability would be to pursue legislative changes. The Conditional Approval of Antidotes for Companion Animals, and An Alternate Process to Provide for Legal Marketing of New Animal Drug Antidotes with No Human food Safety Concerns have not been introduced into the legislative process, but are ideas for consideration.
Conditional Approval of Antidotes for Companion Animals
The Food, Drug & Cosmetic Act could be amended to allow the conditional approval of drugs for antidote use in companion animals. This would allow the antidote to appear on the market more quickly. Conditional approval would be contingent on the sponsor's commitment to pursuing full approvals. Conditional approval would be similar to compassionate INAD's because the product could be marketed without full approval pending the completion of the effectiveness data. A conditional approval for antidotes could parallel the conditional veterinary biologicals license, including the limited circumstances under which it would be considered. A conditional licensure from USDA currently is available for veterinary biological products such as vaccines to meet emergency conditions, limited markets, local situations, or other special circumstances (9 CFR Section 102.6). Although the purity and safety requirements of the Virus-Serum-Toxin Act of 1913, amended in 1985 (Pub. L. 99-198) did not change, the effectiveness data requirements were limited to those that establish a "reasonable expectation of effectiveness." For conditional approvals, some of the effectiveness data may be incomplete after the target animal safety and manufacturing chemistry data is accepted and marketing is conditionally approved. Upon satisfactory completion of the pending data requirements, the antidote would receive full approval.
Drugs for food-producing animals would not be eligible for a conditional approval. Human food safety data could not be incomplete for an approval because all of the toxicity and residue chemistry components of an INAD application contribute to calculation of tolerance and withdrawal time. The only way for a product to be available, if the human food safety data were not complete, is under investigational new animal drug exemption which requires a preliminary safety assessment and investigational withdrawal time. Manufacturing chemistry requirements for antidotes should be completed prior to obtaining a conditional approval. The conditional approval would be renewable for up to 5 years and would be subject to annual review. If the effectiveness requirements are not completed within the 5 year limit, the conditional approval would expire.
An Alternate Process to Provide for Legal Marketing of New Animal Drug Antidotes with No Human Food Safety Concerns
The statute could be amended to adopt an alternate process to provide for legal marketing of new animal drug antidotes. These products together would be referred to as the "Legally-Marketable Unapproved Animal Antidote Index" (the Antidote Index). The Antidote Index is also an extension of regulatory discretion. While the legal marketing of new animal drugs for antidotes appears to be another form of regulatory discretion, it really is an improvement over low regulatory priority. It makes unapproved antidotes that may be previously marketed under regulatory discretion and GMP a legal process.
The Antidote Index would benefit companion animal species. There will never be economic justification for development of standard drug approval packages to cover the use of a specific antidote in several species. If these products were to be made legally available at all, an alternate process must be considered. The indexing process would involve an assessment of target animal safety and effectiveness for the subject new animal drug by means of a non-FDA, expert review group. Thus, the risk : benefit analysis would be applied by panels of experts operating external to FDA, at little or no cost to the agency. The outside expert panels could operate under the auspices of a recognized professional organization or could be a non-affiliated ad hoc panel. The expert panels would typically comprise a minimum of three experts. The required minimum qualifications that include conflict of interest requirements would be defined, and an individual's inclusion on the panel would be subject to review by FDA.
The expert review panel looks for proof of the antidotes safety and effectiveness. Expert panels could also consider data gathered using a product other than the proposed final market formulation with minimal bridging information. The panels would provide an explanation of how the product formulation that they were reviewing (including excipients) could be bridged to the proposed market formulation. Such an explanation would not necessarily have to be drawn from the results of a formal study. Information regarding what was generally known regarding bioavailability and other comparable characteristics of the two formulations could also be included.
The Veterinary Medical Advisory Committee has specifically recommended 5% calcium EDTA for acute lead poisoning, 3% sodium nitrate/ 30% sodium thiosulfate for cyanide poisoning in ruminant and non-ruminant animals and 30 % sodium thiosulfate for cyanide poisoning in ruminant animals. In fact, the following seven antidotes/drugs may be manufactured under GMP using regulatory discretion: EDTA disodium calcium salt, EDTA tetrasodium salt, sodium sulfate, sodium nitrite, sodium thiosulfate, bromosulphalein, diagnostic for liver function with suspected poisonings, and menadione. Marketing under regulatory discretion would allow labeling to include indications, warnings, animal species, adverse reactions, contraindications, stability or parent compound, formulation practices, user safety, therapeutic regimen, dosage and administration procedures, discard or withdrawal times, and the disposal of dead animals or unused drug. These seven compounds have a zero withdrawal time and are of low toxicological concern in humans. Food-animals that receive these antidotes should not be intended for direct slaughter. Also, due to lack of residue information for milk after treating lactating dairy cattle and the potential for milk to be directly introduced into food, it is strongly recommended that the label state "Not for use in dairy cattle."
Molybdic acid salts and methylene blue have increased toxicological concerns which caused extended withdrawal periods of 30 and 180 days, respectively. These two unapproved antidotes are available under an INAD, because there is limited residue data available and they could be used in a herd or flock. Methylene blue is a mutagen and a suspect carcinogen and subsequently has a prolonged withdrawal time. Compounding of antidotes for emergency use is also allowed as described in this article under compounding. While compounding of molybdic acid salts would be acceptable to CVM, compounding of methylene blue would be a concern to CVM because of its potential as a carcinogen. Marketing of molybdic salts and methylene blue as antidotes under regulatory discretion is not acceptable to CVM because of lack of residue depletion studies. Methylene blue is rapidly excreted from the body but partitions readily into the milk, whereas the proportion of molybdate excreted in the milk is unknown. Therefore, it is strongly recommended that molybdic acid salts and methylene blue not be administered to lactating dairy cattle unless the extended withdrawal times are met. The withdrawal times for molybdic acid and methylene blue are subject to change with the collection of new residue data.
In 1989, the National Cancer Institute nominated methylene blue to the National Toxicology Program based on its mutagenicity and potential carcinogenicity in humans. Animal studies were inadequate and long term studies were lacking. Methylene blue was given a high priority based on its numerous medicinal and therapeutic uses in humans, industrial exposure and concerns about carcinogenicity. Additionally, methylene blue exposure in humans could occur after food-animals were treated for nitrate poisoning. To date, the 28 day subchronic, the 90 day chronic and the teratology studies have been completed. Continuous breeding reproductive studies were canceled. Long-term, 2 year, testing was scheduled for contracting in February of 1999. It may be another 3 years before the human food safety studies for methylene blue are complete which may allow it to be marketed as an approved antidote. If methylene blue is found to be a carcinogen after long term studies, it may never be approved for use in food-animals as an antidote.
The Center for Veterinary Medicine has acknowledged the lack of available antidotes and the reluctance of pharmaceutical sponsors to pursue approvals that have little economic incentive. FDA has tried to exercise flexibility to meet these needs since 1991, but even the most flexible application of standards and policies has proven to be inadequate. Legislative action could provide more antidotes as outlined under "Conditional Approval" and " The Legally-Marketed Unapproved Animal Antidote Index." The Food, Drug and Cosmetic Act will require amendment to allow conditional approval, an antidote index and create an expert panel or panels for antidotes. The use of unapproved antidotes in food-producing animals must be accompanied by human food safety concerns. Compounding may be the answer for antidote availability in food-producing animals on an emergency basis when the need is great and the risk is small. While this approach for food-animals presents an alternative, it may not be practical. In reality, an INAD is required by one or more of the chemical manufactures when bulk chemicals are intended for the therapeutic use in food animals. The chemical industry adopted this policy after FDA withdrew its blanket authorization for veterinarians and pharmacies to obtain bulk chemicals from industry for compounding, even though CVM does not require an INAD for emergency compounding..
Some antidotes are expensive, require large amounts to treat many animals or are unstable. Local antidote distribution sites could be established that are managed by colleges of veterinary medicine, state diagnostic laboratories or agricultural departments, state boards of veterinary medicine or veterinary associations. The advantage of antidote depots would be the availability of antidotes on a regional basis, prevent stockpiling at compounding pharmacies and ensure that antidotes would only be used for treating toxicosis.
Presently, there is no single solution for increased antidote availability. Antidote availability in the future may depend upon a combination of regulatory discretion, compounding, new legislation and the establishment of antidote depots. Interested parties are encouraged to ban together in order to draft new legislation. New legislation may originate from both within and outside the Center of Veterinary Medicine, but legislation that is drafted outside of CVM may have a greater chance for success.
The ideas for "Conditional Approval of Antidotes" and "An Alternate Process to Provide for Legal Marketing of New Animal Drug Antidotes with No Human Food Safety Concerns," were adapted from Proposals to Increase the Legal Availability of Animal Drugs for Minor Uses and Minor Species, Center for Veterinary Medicine ADAA Minor Use/Minor Species Working Group, August 19, 1998.
Sundlof, SF: Legal and responsible drug use in the cattle industry: Extra-label use. Vet Med (Food-Animal Practice) pp. 673-680, 1998.