The drug approval process for food-producing animals has evolved gradually, with sporadic bursts of new regulations. Now it appears the pork industry is on the verge of a major change in the way food animal antimicrobials are approved.

An understanding of the drug approval process today involves the laws and regulations that apply, the general data and information requirements for approval, and expected changes in these requirements.

Early in this century, it became apparent that the manufacture and sale of drugs for use in humans and hogs required regulatory oversight. The term "snake oil" still lingers from the days of exaggerated or false efficacy claims for sometimes toxic products.

As we approach the 21st century, we have become confident in the safety and efficacy of the drugs we use and in the safety of the food supply. How did we get from "snake oil" to the drugs we have today?

Regulations For Drug Approval The Federal Food, Drug and Cosmetic Act was passed in 1938. This law is still in force today, although with many amendments. The original act provided only for safety of drugs in a specific species.

In 1951, the Durham-Humphrey Amendment separated drugs into two categories, prescription and "over-the-counter" (OTC). Prescription drugs are evident in veterinary medicine by the inscription: "Caution: Federal law restricts this drug to use by or on the order of a licensed veterinarian."

The Durham-Humphrey Amendment is actually worded so that if adequate directions for safe and effective use by a lay person can be put on the product label, then the product must be classified as OTC.

In 1958, the Delaney Clause addressed the regulation of chemical substances added to food for human consumption. It stated that no additive shall be deemed to be safe if it can induce cancer in man or animals when ingested. For consumption of food animal products, this meant a zero tolerance for residues.

The Kefauver-Harris Amendment of 1962 provided for the authority of the Food and Drug Administration Center for Veterinary Medicine (FDA-CVM) we have today. It established the current method of drug approval and the following drug manufacturing and sales practices under FDA-CVM control:

Drug manufacturing, including inspection of plants and manufacturing practices;

Labeling of drugs (The FDA-CVM actually approves the label, not the drug.); Generic names;

Product promotion;

Reporting of adverse effects; and

The authority to withdraw a previously approved drug from the market.

It is important to note that the "label" encompasses much more than what is attached directly to the bottle. The package insert (which sometimes is also affixed to the bottle) contains key information about product use. A label must include indications, directions for use, precautions/warnings/adverse reactions (the withdrawal time is included here), storage requirements and expiration date.

Recent laws affecting the drug approval process include the Generic Animal Drug and Patent Term Restoration Act (1988), which provides for approval of generic copies of approved animal drugs once the patent or period of marketing rights has expired.

The Animal Drug Availability Act (1996) added more flexibility to the way FDA regulates animal drugs and medicated feeds.

Marketing A New Animal Drug A "new animal drug" is a drug approved since the Food, Drug and Cosmetic Act of 1938. First comes discovery. In the past, many new drugs were discovered by collecting soil or other environmental samples from around the world and testing them.

For example, the fungus that produces a widely used anthelmintic was isolated from a golf course in Japan. Now the discovery process uses efforts based on synthesis of specific molecules for testing.

Once a promising compound is discovered, it is run through a set of screening tests.

If a product makes it to the development stage, the first step is to develop preliminary pig efficacy and safety data, environmental and food safety data. This data is required to apply to the FDA-CVM for listing as an Investigational New Animal Drug (INAD).

Then, the drug may be subjected to large-scale testing for efficacy and safety in hogs. Drug metabolism and slaughter withdrawal time are also evaluated.

"Radiolabeled" (to label with a radioactive atom or substance) compounds are often used to accurately determine the time it takes the drug to leave the body. These studies often start in lab animals with a final study in hogs to set the final withdrawal time. An assay to detect residues in edible pork products is also developed by the company.

Safety tests include a study in the hog and determination of the potential carcinogenicity of the drug and reproductive safety.

These tests are carried out in both hogs and lab animals as required. The required carcinogenicity studies in rats and mice may cost up to $1 million each and take up to three years to complete. They can't be started early in product development because they require other data to set doses used.

Setting the correct therapeutic dose takes a lot of time and money. For an antibiotic, the pharmacokinetics (how it moves in and out of the body) of the drug and the concentration required to retard growth of the disease organism are used to derive a range of reasonable dose regimens. Dose titration studies will give the most effective dose.

Clinical efficacy testing confirms that the drug is safe and effective for the intended use in the field, to be indicated on the label. The FDA recently published an amended definition of "adequate and well controlled studies" (21 CFR Part 514) in the Federal Register (Vol. 63, No. 43, March 5, 1998). This amendment was intended to allow more flexibility in the conduct of adequate and well-controlled studies in food-producing animals in the field.

The FDA-CVM encourages sponsors to submit investigational protocols for review and to attend a joint meeting prior to doing the studies so that the type of studies required, their design and their analysis may be established.

Development Process Good laboratory practices (GLPs) must be followed for laboratory studies, while good clinical practices (GCPs: Good Target Animal Study Practices: Clinical Investigators and Monitors, May 1997) must be followed during clinical trials (i.e., a respiratory disease trial in nursery pigs). Pharmaceutical companies maintain extensive quality assurance (QA) departments to audit studies to assure compliance with GLPs and GCPs. The development process is made even more complex by use of laboratory and clinical trial facilities that are under company control and private facilities used on a contract basis.

While the development process is ongoing, the company is also setting up a manufacturing process, which may involve construction of new facilities.

Manufacturing of pharmaceuticals is subject to good manufacturing processes. The manufacturing process must be approved before the drug is marketed. This means considerable money is invested in parallel development programs, both dependent on drug approval for a return on investment.

Big Changes Ahead In November 1998, the FDA released a draft guidance document which begins: "This draft guidance document announces that FDA now believes it is necessary to evaluate the human health impact of the microbial effects associated with all uses of all classes of antimicrobial new animal drugs intended for use in food-producing animals. To assess this impact, the following two, separate but related aspects, should be evaluated:

1. The quantity of drug-resistant, enteric bacteria formed in the animal's intestinal tract after exposure to the antimicrobial new animal drug; and

2. Changes in the number of enteric bacteria in the animal's intestinal tract that cause human illness (pathogen load).

In the past, the agency evaluated the human health impact of the microbial effects of only certain uses of antimicrobial new animal drugs in animal feeds. Based on scientific data, the agency now believes sponsors of all antimicrobial new animal drugs intended for use in food-producing animals should provide information on resistance and pathogen load. This information would allow the agency to determine that such products are safe under the Federal Food, Drug and Cosmetic Act."

The Proposed FDA Framework The new document to judge the "microbial safety" of antimicrobials used in food animals is entitled, "A Proposed Framework For Evaluating And Assuring the Human Safety of the Microbial Effects of Antimicrobial New Animal Drugs Intended for Use in Food-Producing Animals."

The document clearly states proposed procedures apply to both future approvals and existing antimicrobials as resources permit.

Drugs would be listed based on two criteria: importance in human medicine and "exposure" of the animal microbial flora to the antimicrobial.

Figure 1 (on page 44) summarizes the framework. It represents the author's interpretation and condensation of the actual document, which should be consulted for a clearer understanding of the framework. It is well recognized by all parties involved that the methods for many of these requirements have not been established. In fact, this has been one of the major criticisms of the proposed framework.

The public comment period on the proposed framework document ended April 6.

The future of antimicrobial drug approvals in food animals is best summarized by the comments of Steve Sundlof, director, FDA-CVM. He spoke in March at the annual meeting of the American Association of Swine Practitioners.

"FDA is concerned that the use of antimicrobial drugs in food animals will create antimicrobial drug resistance that could contribute to drug-resistant human pathogen bacteria. This is a unique issue since unlike drug residues, resistance can't be accurately predicted. Also, this problem crosses over into human medicine.

"FDA is in the process of developing a new regulatory approach for antimicrobial products intended for use in food animals. This new system will stress monitoring and surveillance. FDA believes that those individuals involved in developing this regulatory approach must include experts in human as well as veterinary medicine."

Drug approvals in the near future will wrestle with microbial safety. Subtherapeutic and over-the-counter use of antimicrobials in food animals will come to the forefront as major issues. Involving all parties in this process is vital to keeping antimicrobials effective for pork producers.