Drug Approval Process Bogged Down

The Animal Drug Availability Act of 1996 was designed to give a much-needed boost to the approval process for new animal drug applications (NADAs). Instead, the drug review process has bogged down, creating a serious backlog which threatens animal health, according to AHI, an industry trade group representing animal health manufacturers. The backlog creates a chilling effect on the animal health industry's

The Animal Drug Availability Act of 1996 was designed to give a much-needed boost to the approval process for new animal drug applications (NADAs). Instead, the drug review process has bogged down, creating a serious backlog which threatens animal health, according to AHI, an industry trade group representing animal health manufacturers.

The backlog creates a chilling effect on the animal health industry's investment in research and development, threatening the pipeline of products that producers need to manage future livestock production, says AHI.

The logjam also casts a cloud over the U.S. food supply and food safety, according to a prepared statement from AHI.

Serious Backlog

A recent AHI survey of member animal health suppliers found:

  • The backlog on review times for NADAs is huge. By law, a complete review for NADAs is to be completed within 180 days. Yet individual applications may take from over a year to several years to process. On average, the review process is delayed about two years.

  • Eighty-eight percent of original NADAs were overdue, the longest delay time at 717 days.

  • Companies submit design protocols to FDA's Center for Veterinary Medicine (CVM) for review and approval. Those submitted with no data, which should take 50 days, are 70% overdue, with the longest delay of 780 days. Those submitted with data, which should take 100 days to review, are 68% overdue, the longest at 280 days.

  • Administrative NADAs — the paperwork to be signed after the technical reviews are done — are taking an average of 199 days.

    AHI has developed a long list of other lengthy delays. Two are especially noteworthy:

  • Four years ago, a company submitted the target animal safety and efficacy data for an existing product NADA supplement. The human health safety area has been approved for two years. But there is still no word regarding target animal safety and efficacy.

  • A company submitted a NADA for review in 1988. The target animal safety portion of the review took seven years to resolve. The efficacy review began in 1988. CVM asked for more data in 1992. It took CVM 10 months to review the protocol. The company generated the data in 25 months. Now, some 14 years after the initial submission, the company is still waiting for an answer to its original application.

Abysmal Record of Approvals

Tom Burkgren, DVM, executive director of the American Association of Swine Veterinarians (AASV), says there has been “continued progress” on the biological side, with the U.S. Department of Agriculture (USDA) approving new swine vaccines for the marketplace.

But the record for approvals on the pharmaceuticals side from the FDA has been abysmal. “A quick review of the number of new chemical entities approved for swine since 1990 shows only ceftiofur and tilmicosin have been granted licensure,” says Burkgren.

Otherwise, the only antibiotics being licensed are new indications and combinations of some old products. For instance, Lincomix Feed Additive, on the market since the late '70s, was just licensed as the only FDA-approved product to fight both Mycoplasmal pneumonia and ileitis.

In essence, the approval process has become basically “non-functional” for all the new antibiotic products reported to be in the pipeline, charges Burkgren.

And he lays blame with CVM's December 1998 “Framework” document (“Microbial Effects of Antimicrobial New Animal Drugs Intended for Use in Food-Producing Animals”). According to a statement released last fall by CVM (“Antibiotic Resistance and Animals,” found on their Web site at www.fda.gov/cvm), the agency continues to change the way it regulates antibiotics for livestock. It is enhancing monitoring for antimicrobial resistance, improving monitoring of the use of these drugs in animals and using tools to better assess the risk of using these drugs. The agency says the stepped-up surveillance is based on increased risk to people from “ample scientific data linking antimicrobial, food-borne resistant infections in humans to the use of these antimicrobials in livestock and poultry.”

Battle Over Resistance

AASV's Burkgren strongly disagrees with CVM's stance. “Only by default is antibiotic resistance becoming part of the antibiotic approval process. There is data out there that shows that if you use antibiotics, you will have selective pressure, and you may get an increase in antibiotic-resistant bacterial organisms. That is a given fact.

“The debate comes in about transfer of those bacteria that are resistant to antimicrobials through the food supply. We don't deny that there may be some risk, but there is no smoking gun there. What there is, is tremendous controversy over the true measurable impact on human health of the use of antimicrobials in animals,” notes Burkgren.

“While we note that some resistance occurs from use of antibiotics in livestock, it is still apparent from the scientific literature that most of the resistance we see in human pathogens is due to the widespread use of antibiotics in human medicine,” says University of Tennessee animal scientist Alan Mathew. “While some researchers suggest that resistant bacteria from animals could ultimately find their way into human populations, little if any direct evidence of such has been observed,” he says.

The Coalition for Animal Health (CAH) reports the most recent data from the National Antimicrobial Resistance Monitoring System (NARMS) suggests levels of resistance for 17 common antimicrobials have not shown large changes in historical patterns. NARMS is administered by FDA, the Centers for Disease Control and USDA.

“The stability of resistance in animals, coupled with changing levels of resistance in humans, is just one of the conflicts that raises questions about the alleged link between animal antibiotic use and human resistance,” says a statement from CAH.

AHI's Richard Carnevale points out that less than 50% of the antibiotics used in animals have no relation to those used in humans. He questions whether FDA should continue to monitor all drugs used in animals vs. those used in both humans and animals. Only 13% of the drugs fed to animals are for growth promotion.

FDA/CVM held a workshop recently to identify concerns about antibiotics to treat Mycoplasmal pneumonia. Disease expert Eileen Thacker, DVM, Iowa State University, says there are three main concerns that need to be addressed in targeting mycoplasma or any other animal health problem: What's the best way to ensure the veterinarian is able to treat sick animals, how can we provide humane treatment of animals and what's best for the public?

In the case of mycoplasma, some see eradication as a worthy goal. Vaccination use will become increasingly important in reducing our reliance on antibiotics, says Thacker. But she believes antibiotics will always be needed to ensure animal welfare and food safety.

Burkgren says the livestock industry is getting squeezed two ways on the antibiotics issue, with the lack of new drug approvals and products taken off the market. The poultry industry is facing that fate for the powerful, broad-spectrum class of antibiotics known as the fluoroquinolones.

Removing antibiotics from the livestock market and concerns about human health have spurred growth of antibiotic-free meat production. Roy Schultz, DVM, Avoca, IA, speaking at the FDA workshop, surveyed a few large hog integrators he consults for. He says their production costs are 19-20% higher raising antibiotic-free pigs.

Europe Proposes Phase Out of Growth Promotants

The last four antibiotics used for growth promotion in the European Union would be phased out by January 2006 under a proposal by the European Commission.

The remaining four are monensin sodium, salinomycin sodium, avilamycin and flavophospholipol. All are substances that are not currently used in human medicine. Antibiotic feed additives containing microbials that are used in both human and veterinary medicine have already been phased out by previous commission actions.

The latest action to phase out growth promotants is part of a continuing effort to combat the perceived threat to human health posed by antibiotic resistance in bacteria that can cross between humans and animals.

All new feed additive approvals would be limited to a 10-year period. Companies marketing feed additives under current rules would have to apply within the next seven years for reevaluation and reauthorization of their products. New rules would require that companies demonstrate product efficacy, the absence of risk to human and animal health and to the environment.
Joe Vansickle

Congressmen Propose Drug Ban

For the second year in a row, Rep. Sherrod Brown (D-OH) has introduced legislation to ban routine use of antibiotics for growth promotion in livestock.

Brown introduced the Preservation of Antibiotics for Human Treatment Act of 2002 in late February. HR 3804 proposes to eliminate the subtherapeutic use of several classes of antibiotics used in, or related to, antibiotics used in humans to treat infectious diseases and also routinely administered in feed or water to farm animals.

Those in question include penicillins, tetracylines, macrolides (including but not limited to erythromycin and tylosin), lincomycin, bacitracin, virginiamycin, aminoglycosides and sulfonamides.

The bill suggests “mounting evidence shows that this non-therapeutic use of antibiotics in agricultural animals can lead to development of antibiotic-resistant bacteria that can be transferred to people, making it harder to treat certain infections.”

Similar legislation was introduced in the Senate by Sen. Edward Kennedy (D-MA).

The Coalition for Animal Health (CAH) responded that enactment of Brown's legislation “would be a devastating blow to animal health while providing little public health benefit.” The bill overrides congressional authority to protect human health by removing products from the market when they present a risk to public health. It puts politics ahead of science, says CAH.

Although there is currently no mechanism nor process for reporting, a survey of animal health companies by the Animal Health Institute (AHI) indicates that 87% of antibiotics used in food-producing animals are used to treat, control or prevent disease, with the rest used for nutritional efficiency. Also, nearly half (47%) of the antibiotics used in animals are not used in human medicine or are not medically important.

Reports from Denmark indicate that when the country banned some routine uses of antibiotics, more livestock and poultry became sick, requiring greater therapeutic use of antibiotics.

Controlling Antimicrobial Resistance

Antibiotic resistance in pigs given feed additives can be controlled with proper management strategies and sensible application of antibiotics.

That's the conclusion of P. Cullen, A.G. Mathew, R. Clift and S. Chattin, University of Tennessee-Knoxville.

Resistance Challenge

The team challenged 58 weaned pigs with Salmonella typhimurium and also monitored the group for antibiotic resistance in naturally occurring Escherichia coli.

The pigs were separated into eight test groups, consisting of: a control group with no treatments; a control group treated with apramycin (approved for control of E. coli infections); and separate apramycin-treated groups that suffered from either cold stress, heat stress, overcrowding, commingling or poor sanitation. One group also provided intervention with oxytetracycline (broad-spectrum antibiotic).

The goal of the project, says animal scientist Alan Mathew, was to determine the impact of various environmental and management conditions on the development of antibiotic resistance among salmonella and E. coli bacteria.

Each of the treatment groups, except the one control group not given any feed antibiotics, was administered apramycin sulfate at 150 g./ton for 14 days starting two days after intranasal challenge with salmonella. Management and environmental treatments were applied seven days post-challenge to allow time for the bacteria to colonize.

Fecal swabs were taken prior to challenge and again during the trial period to check for the presence of salmonella and E. coli organisms.

The team reported that control pigs (no apramycin) showed the lowest levels of resistance throughout the study. Peak antibiotic resistance was seen at Day 14 of the apramycin treatment. When the antibiotic was withdrawn, resistance waned in the control group housed under optimal conditions. However, groups maintained in stressful conditions continued to exhibit higher levels of antibiotic resistance.

Pigs in the cold stress, overcrowding and oxytetracycline treatment groups continued to show higher levels of antibiotic resistance out to Day 64.

Salmonella typhimurium was recovered from pigs on day 0 to Day 64. Salmonella isolates remained susceptible to apramycin and ceftiofur, while resistance effects were found for oxytetracycline and sulfamethazine.

Mathew explains it's becoming more common that resistant bacteria carry genes for resistance to multiple antibiotics at one time. And these genes are all connected so they are transferred as a group from one bacterium to another. Thus, if you select for apramycin resistance by using apramycin in pigs, you find some of those bacteria that became resistant also suddenly become resistant to antibiotics that weren't even used, like sulfamethazine.

As shown, antibiotic resistance increased when pigs were exposed to various environmental stressors.

While salmonella resistance to apramycin did not occur, the potential threat of resistance transfer from naturally occurring bacteria in animals to food-borne pathogens remains a concern, according to the researchers. They also state that the increase in resistance to oxytetracycline indicates that prolonged use of low-level antibiotics may promote development of resistance in some types of bacteria.
Joe Vansickle