September 15, 2007

 

 Out of Rockville and Laurel - September 15, 2007

 

FDA-CVM initiatives span individualized medicine to aquaculture research

posted September 1, 2007

 

Certain Collies and other breeds of herding dogs as well as hounds are sensitive to the avermectin class of drugs. In fact, ivermectin-sensitive Collies are bred for this trait because before the Food and Drug Administration's Center for Veterinary Medicine approves new avermectin products, it requests that they be tested in these dogs.

If the product is found toxic when administered to ivermectin-sensitive Collies, the safety margin is considered inadequate for the drug to be used even in the general dog population.

A genetic mutation is responsible for ivermectin sensitivity. It affects dogs that are homozygous-recessive for a deletion in multidrug-resistance gene 1, which encodes for P-glycoprotein.

The CVM's approach toward this MDR-1 defect is an example of how the agency is refining the use of drugs on the level of individual patients.

Individualized medicine, or pharmacogenomics, is an area where CVM Director Stephen F. Sundlof predicts much progress. This field of research focuses on variations in the molecules that interact with medicines moving through the body. Dr. Sundlof and CVM Deputy Director Bernadette M. Dunham spoke with AVMA News recently about the agency's future directions and recent challenges.

"Whereas the human drugs and biological centers within the FDA really have the lead on (pharmacogenomics), a lot of the things they're learning about specific genes and their impact on disease and how drugs result in differences based on the genetic makeup of the person or the animal—all of that is going to come to the Center for Veterinary Medicine," Dr. Sundlof said.

In humans, for example, pharmacogenomics is minimizing the adverse effects of a chemotherapy drug called Camptosar (irinotecan). Variations in a human gene that produces a specific enzyme can influence a patient's ability to metabolize Camptosar. If given standard doses, about half of the 10 percent of North Americans who have this genetic variation will develop severe, potentially fatal neutropenia. A molecular assay has been developed, however, to identify patients with the variant.

"The dog and cat genomes have already been mapped out," Dr. Sundlof noted. "As we understand more about how drugs work at a genetic, molecular level, we will be able to approve products based on the genetic makeup of an animal."

Continuing with the technology update, Dr. Dunham said, "A budding area that we are moving into more and more is biotechnology, and that's going to encompass a lot of the scenarios that will come from cloning and, potentially, transgenic animals.

"Nanotechnology is another portion of new technology which, down the road, will probably be impacting how some drugs are formulated and delivered."

Educational outreach, also a CVM priority, has encompassed issues such as nonsteroidal anti-inflammatory drugs and involved collaboration with the AVMA and American Animal Hospital Association. The address of the CVM Web page on NSAID is www.fda.gov/cvm/nsaids.htm.

The CVM's newest office, Minor Use and Minor Species Animal Drug Development, is directed by Dr. Dunham. In the July 26 Federal Register, the FDA issued final regulations (www.fda.gov/cvm/CVM_Updates/finalruledrugs.htm) on Designation of New Animal Drugs for Minor Uses or Minor Species, in response to the Minor Use and Minor Species Animal Health Act of 2004. The MUMS act established new regulatory procedures that provide incentives to make more drugs legally available to veterinarians and animal owners for the treatment of minor animal species and for uncommon diseases in major animal species. The final rule on designation, which will take effect Oct. 9, 2007, can be viewed online at www.gpoaccess.gov/fr/.

In all, approximately 75 veterinarians are on staff with the CVM, most of them working from the Rockville, Md., area northwest of Washington, D.C. These FDA veterinarians direct field staff—generalists who inspect facilities ranging from pet food companies to pharmaceutical production plants.

Several veterinarians are on staff at the CVM research office in Laurel, Md., midway between Washington, D.C., and Baltimore. The Laurel facilities are geared toward food animals, with housing for cattle, swine, chickens, turkeys, sheep, goats, and various aquatic species. Highly functional, the site includes a surgical suite, necropsy facility, operating feed mill, and milking barn.

Research on a variety of fish is conducted at the aquaculture facility. One current project is related to the massive pet food recall earlier this year.

"One of the (fish studies) that we are conducting in response to the pet food outbreak is creating what we call incurred residues," Dr. Sundlof said, "that is, feeding melamine, cyanuric acid, and other components to food-producing animals, including fish, to see how and where that product accumulates and how rapidly it is eliminated."

This research is important because during the pet food contamination, some of the recalled product was fed to food-producing animals. Dr. Sundlof said questions were asked by the Department of Agriculture and others about the safety of animals entering the food supply.

Dr. Sundlof said FDA received an unprecedented number of phone calls from the public in the midst of the pet food crisis. During the first three weeks, the FDA received 12,000 calls about pet food—more than the agency normally receives in two years for all the products it regulates.

An import alert is in place for all vegetable protein products (eg, wheat gluten and corn gluten) entering the United States from China. Dr. Sundlof said that these products are subject to "detention without physical examination," meaning they can enter the United States only with documentation that the product has been analyzed and is free of any contaminated ingredients.

"A lot of our efforts in the future are going to be directed at making sure the pet food industry as well as the human food industry is sourcing its materials from reputable vendors or suppliers that can vouch for, and stand behind, the safety of their products," he said.

Dr. Dunham added that the tragedy highlights trade issues and will lead to better communication, transparency, and, therefore reassurance that strict quality standards are met and that "everybody's aboveboard." She said, "It has been a big eye-opener as to how things are happening around the world. It's truly a global village that we live in."

During the recall, the agency found that simply putting the information on its Web site was not sufficient. Dr. Sundlof explained that a substantial number of Americans, especially seniors, do not access the Internet. In the future, the FDA will endeavor to reach all of the public.

He added, "If this had been a human food outbreak, the Centers for Disease Control and Prevention would have been out there talking to people who believed they were infected, talking to their physician, and doing a thorough epidemiologic investigation. Anything that could fill that void would have been helpful to us in this case, and I believe would be helpful in the future."

The CVM is in preliminary discussions with interested parties such as the American Association of Veterinary Laboratory Diagnosticians about such a program.

Asked whether the CVM has adequate staff and budget to fulfill its mission, Dr. Sundlof said the agency has not been handicapped to the extent some other parts of the FDA have. "It's no secret that the total number of inspectors has been going down at the same time that we're seeing a great increase in imported products that need inspection. But as far as CVM is concerned, we're doing fairly well," he said.

Specific expertise is needed to cover everything from pre-market drug reviews to post-market surveillance. Dr. Dunham said, "In one sense, our mission is quite diverse, and we try to take the most highly qualified people who apply so we have the best of the best in those positions."

Many FDA veterinarians have acquired additional skill sets that enhance their value to the agency, such as master's or PhD degrees or board certification. According to Dr. Sundlof, "We don't have a problem attracting highly qualified people. People really like working here at CVM."