Although advertisements for new human and veterinary drugs are common, FDA approval is granted (following rigorous testing to ensure safety and efficacy) to a relatively small number of products. Approval for veterinary drugs largely follows the same process as for human drugs, but there are noteworthy differences in categories and labeling. This article provides background on terminology, explains the steps of the FDA drug-approval process, and provides considerations for interpretation of package inserts.
FDA Approval Definitions
Drug
A drug is an article (other than food) intended to diagnose, cure, alleviate, treat, or prevent disease or affect the structure or function of the body in humans or animals.1 In human medicine, this definition includes biologic products (eg, vaccines, blood products); however, in veterinary medicine, biologics and pesticides are regulated by the United States Department of Agriculture Animal and Plant Health Inspection Service (USDA APHIS) and Environmental Protection Agency (EPA), respectively, rather than the FDA.
Drug Sponsor
A drug sponsor is the entity responsible for collecting information about a new drug and submitting it for review by the FDA Center for Veterinary Medicine (CVM).2 The sponsor is typically a pharmaceutical company—which may manufacture the drug or only market the drug—and is separate from the FDA.
Approved New Animal Drug
An approved new animal drug has gone through the New Animal Drug Application (NADA) process and received full approval from the CVM.2 Completion of this process grants the drug sponsor a period of market exclusivity, during which other sponsors cannot receive approval. The NADA process includes assessment of the safety and efficacy of the drug when used according to the label, as well as the environmental impact. Safety assessment includes the treated animal, food products that may come from the treated animal, and humans who may come in contact with the drug.
Abbreviated New Animal Drug (ie, Generic Drug)
Following the market exclusivity period for an approved new animal drug, drug sponsors may submit an Abbreviated New Animal Drug Application (ANADA) to the CVM for generic drug products. The ANADA process is considered abbreviated because it does not require new safety or efficacy studies; however, bioequivalence with the NADA product must be established.3
Conditional Approval
Conditional approval is an alternative drug approval pathway only available for some drugs intended for use in a minor species or under special circumstances for drugs intended for use in a major species.4,5 This pathway was created to encourage development of drugs for use in species with smaller populations (eg, ferrets) or for less common diseases in major species (eg, nonregenerative anemia associated with chronic kidney disease in cats). Safety must be assessed, and the drug sponsor must demonstrate the drug has a reasonable expectation of effectiveness but not enough efficacy evidence has been collected for full approval.6 Conditionally approved drugs can only be used according to label directions (ie, labeled species, indication, dosage); extra-label use is prohibited. Conditional approvals are valid for 1 year and can be renewed annually for up to 4 additional years. During this time, the drug can be legally marketed while remaining efficacy data is collected. If the sponsor has not applied for full approval by the end of the conditional approval period, the drug no longer retains legal marketing status and is removed from the market.
Indexed Drug
An indexed drug is a legally marketed, unapproved drug. Indexing is a faster and less expensive alternative to obtain legal marketing status but is only available for drugs intended for use in certain minor species.7 Indexed drugs are evaluated for safety and efficacy but are typically intended for use in species too rare or varied for traditional safety and efficacy studies, including ferrets, rodents (eg, rats, mice, chinchillas), and birds (eg, parrots, parakeets). These drugs can only be used according to label directions; extra-label use is prohibited. The drug sponsor has exclusive marketing rights for 7 years once indexed status is granted.
Dietary Supplement
A dietary supplement is a substance used to supplement the diet that can include vitamins, minerals, herbs, amino acids, and enzymes and often contains other ingredients (eg, fillers, binders, excipients, preservatives, sweeteners, flavorings).8 Human dietary supplements are considered a special category (neither drug nor food) and are regulated by the FDA under the Dietary Supplement Health and Education Act of 1994, which also provides enforcement framework if adulterated or misbranded products are found after marketing. The FDA does not apply this special category to veterinary dietary supplements. These supplements are regulated as either animal drugs or food for animals depending on intended use and ingredients.9
Drug Development Process From Concept to Market
The FDA drug development process incorporates 5 steps: discovery and development, preclinical research, clinical research, FDA review, and FDA postmarket safety monitoring.10 These steps are similar for both human and veterinary drugs, although veterinary drug clinical trials often contain a significantly smaller study population, and some phases are more condensed.10
Discovery & Development
Drug discovery occurs with directed research or accidental discoveries, followed by initial pilot experiments to understand the properties of the molecular compound of interest.
Preclinical Research
Preclinical research encompasses both in vitro and in vivo experiments to establish the potential toxicity of the molecular compound of interest. In vivo experiments typically use laboratory species, rather than the species of interest.
Clinical Research
Clinical research begins studies in the species of interest. Clinical trials are divided into 4 phases, with unique goals and an increasing number of participants in each phase. The majority of statistics provided in the following paragraph are for human drugs because relevant statistics and data for veterinary drugs are not widely available.
Phase 1 trials seek to establish safety and dosage in healthy participants of the species of interest. In human medicine, these trials can include up to 100 participants and last for several months, with ≈70% of drugs moving to the next phase. Phase 2, 3, and 4 trials seek to establish efficacy and adverse effects in increasing numbers of participants with the disease or condition of interest over increasing lengths of time. In humans, Phase 2 trials can include up to several hundred participants and last several months to 2 years, with ≈33% of drugs moving to the next phase. Phase 3 trials can include up to 3,000 participants and last 1 to 4 years, with ≈25% to 30% of drugs moving to FDA review. Phase 4 trials include several thousand participants and are considered part of FDA postmarket safety monitoring.
FDA Review
For FDA review, a drug sponsor submits the NADA (or New Drug Application for human drugs), which includes details of preclinical through Phase 3 clinical trials showing the drug's safety and efficacy within the population of interest, as well as proposed labeling. A review decision may take 6 to 10 months.10
FDA Postmarket Safety Monitoring
FDA postmarket safety monitoring is an ongoing process after the drug is on the market due to possible rare adverse effects. Reports are periodically reviewed and may lead to labeling or package insert changes.
Package Insert Considerations
Package inserts for human drugs are often more comprehensive than those for veterinary drugs. Inactive ingredients, a description of the drug (eg, color, imprint, flavor), pharmacokinetics in special patient populations, mechanism of resistance or cross-resistance for antimicrobials, drug interactions, and/or risks following overdose are often included in package inserts for human drugs but not for veterinary drugs. For example, a package insert for clindamycin hydrochloride capsules labeled for use in humans includes all inactive ingredients and a brief discussion of the mechanism of bacterial resistance and cross-resistance among other antimicrobials, whereas a package insert for a similar veterinary-labeled product only provides potentially harmful or important inactive ingredients in the oral liquid solution formulation.11,12 Although the additional sections of a human drug package insert may not be clinically relevant for every case, they can provide information useful for veterinary patients, including available dosage forms, potential allergens or dangerous inactive ingredients, and dose adjustment recommendations for special patient populations.
Study Population Considerations
Healthy Versus Clinically Affected Animals
Some veterinary clinical trials only enroll animals considered healthy during a physical examination, rather than animals clinically affected by the condition or disease of interest. Because the pharmacokinetics or pharmacodynamics of a drug may be altered in clinically affected populations, it is important to read the package insert to understand the impact for a specific patient.
Homogeneous Study Population
Animals included in Phase 1, 2, and 3 veterinary clinical trials are typically homogeneous (eg, similar breed, same sex). Depending on the condition or disease of interest, the pharmacokinetics or pharmacodynamics of the drug may be altered when used in a larger population. This may affect the ability to apply study results to the general population and should be considered when applying results to patients.