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U.S. Department of Health and Human Services

Animal & Veterinary

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A Decade in the Director’s Office: An Interview With CVM Director Dr. Stephen F. Sundlof

FDA Veterinarian Newsletter March/April 2005 Volume XX, No II

Part one of a two-part series

Stephen F. Sundlof, D.V.M., Ph.D., has been Director of the Food and Drug Administration’s (FDA) Center for Veterinary Medicine (CVM) since 1994. FDA Veterinarian interviewed Dr. Sundlof about 10 years ago, roughly a year after became CVM Director. We recently sat down with him again to get his views about the Center’s progress now that he has a decade’s worth of experience at the Center. This first article discusses the Center’s policy development work since Dr. Sundlof became CVM’s director. In the next issue, he will talk about administrative changes he brought to CVM.

When asked why you were interested in the position of CVM Director, you cited your involvement with several aspects of animal drug regulation and safety—the National Research Support Program #7 [NRSP-7] and the Veterinary Medicine Advisory Committee (VMAC, as chairman). You also said that, as a result of reviewing 75 volumes of data related to a controversial CVM decision, you had gained new respect for the work of the Center. When Dr. Guest retired, you accepted the urging of some respected people and applied for the job. Now that you have seen the Center inside and out, how have your views changed?

After 11 years as Center Director, my views have changed in a number of respects. But, the fundamental reasons I wanted to come to CVM are the same now as when I applied for the job. One is that I believe in the mission of CVM and share that commitment to our mission with a cadre of very talented people. Most people who like animals recognize the importance of CVM’s role in protecting animal health and assuring the availability of safe and effective products for animals. Being a veterinarian, I have an interest in the health care needs of animals. At CVM I have the opportunity to improve the health of individual animals as well as the health of herds and flocks of animals. That’s very rewarding to me.

Another reason I enjoy being CVM Director is the opportunity to contribute to the protection of the public health—that is FDA’s mission and also part of CVM’s mission. I am also impressed by the high level of scientific expertise that exists in FDA. FDA is strongly grounded in science. That level of scientific expertise made it attractive for me to leave an academic environment and come to a regulatory environment. Now that I’ve been here for 11 years I have increased respect for the people who make the Center what it is.

Ten years ago, you said the most important issue facing the Center was drug availability. You said the approval process, with the expected increase in the supply of safe and effective drugs, was the key to food safety. You also wanted to create a regulatory environment that encouraged drug research and development and that allowed economic advantages for small market/small profit drugs so that they would be submitted for review. What progress have you made is this area, and how has that affected drug availability? How has the regulatory environment changed?

When I came to CVM, I believed that the way to significantly impact public and animal health was to have a regulatory process that facilitates the approval of important drugs for animal use. In the absence of safe and effective new drugs, veterinarians, animal owners, and producers will use unapproved products that may not work or be safe for the animals or the public. A clear regulatory pathway that would facilitate the approval of safe, effective, and needed animal drugs was needed. In trying to create that regulatory environment, I’ve had my share of success, and I’ve encountered some speed bumps along the way. It hasn’t been a smooth and straight path, but, overall, we’ve made considerable progress in the right direction. I think the destination is a drug review process that is transparent and efficient—and one that facilitates the approval of safe and effective drugs. By facilitating the process, we haven’t lowered our standards or regulatory requirements in any way. What we have done whenever possible is to articulate clear guidance to the regulated industry, so they are better able to meet the regulatory requirements for animal drug approvals.

MUMS—the Minor Use and Minor Species Animal Health Act of 2004—provides incentives to animal drug companies for increased investment in research and development to facilitate approval of drugs for minor uses and minor species. This legislation is the result of many years of hard work by Congress, the Center, and a coalition of stakeholder groups. Creating a situation in which drug sponsors were interested in developing drugs for a small market was something we could not do within the regulations that existed prior to 2004. There was a need for fundamental change to the Federal, Food, Drug, and Cosmetic Act in order to create an economically viable pathway to approval for these minor use, minor species drugs. MUMS made those changes. The availability of approved drugs for minor uses and minor species is as relevant today as it was 11 years ago when I was working on what is now the National Research Support Program-7. (NRSP-7 is a U.S. Department of Agriculture program created to foster development of minor use drugs for animal species of agricultural importance. It coordinates with animal producers, drug manufacturers, CVM, the USDA, other government agencies, universities, State Agricultural Experiment Stations, and veterinary schools in the development of minor species drugs.)

Another major milestone in improving the review process was the passage of the Animal Drug User Fee Act (ADUFA) in 2003. What we heard from the animal health industry was that uncertain review times were forcing manufacturers to make business decisions that did not favor the submission of animal drugs to CVM for review for approval. Anything that could be done to provide more predictability to the process would result in additional research and development and lead to more approvals. We discussed this with representatives of the animal drug industry, and they made a compelling business case for providing greater predictability to the industry. They also made it clear that they would be willing to share the financial burden of an enhanced review program, because it would result in a greater return on investment. Their willingness to share in funding an enhanced review process by FDA has been key. In April 2004, the Agency received its first user fee check as part of this initiative.

We are now in an era in which we are increasing staff to review animal drugs, setting clear targets and time frames for the review process, and working with industry to reduce the number of review cycles to approval. FDA and industry would like all applications to receive a “yes” or “no” answer in one cycle, rather than going through multiple submissions and reviews. We are working with the pharmaceutical industry to make sure applications are as clear as possible and to find solutions to problems that have, in the past, led to multiple review cycles. ADUFA is giving us the time and resources to make that happen.

Antimicrobial Resistance

The concern that the use of antimicrobial drugs in food-producing animals can lead to resistance to antimicrobials of importance to human medicine has been a challenge for the Center. How have you handled this challenge?

Shortly before I was selected for this position, a number of articles were published indicating that the “age of antibiotics” was over. The articles stated that fluoroquinolones represented the last new class of antimicrobial drugs for human use, and no new antibiotic drugs were in the development pipeline. Therefore, because fluoroquinolones were the last of the antimicrobial wonder drugs, their effectiveness needed to be protected and preserved at all costs. Within a few months of my becoming CVM Director, the Center was faced with the decision of whether or not to approve the first fluoroqinolone for use in a food animal.

We held a joint meeting of the Veterinary Medicine Advisory Committee (VMAC), and the Center for Drug Evaluation and Research’s Anti-Infective Drugs Advisory Committee to make recommendations about conditions for the potential approval of fluoroquinolones to treat respiratory disease in poultry. The drug companies testified that flouroquinolones would be used to treat only about 1 percent of poultry. But about 9 billion chickens and approximately 290 million turkeys are produced yearly in the United States, so 1 percent translates to a large number of birds. Fueled by the fear that human medicine would run out of antibiotics and that animal drugs were to blame, there was intense media interest in the meeting. The FDA press office arranged for an interview with a network evening news program. Antimicrobial resistance had been a growing public health concern for more than 20 years, and by the time of the advisory committee meeting, the issue was highly visible, both in the United States and abroad.

The advisory committee generally agreed that there was a need for fluoroquinolone in food-producing animals if certain conditions were met. The conditions proposed were, first, that the fluoroqinolone be sold by prescription only to veterinarians and not be permitted for over-the-counter sales; second, that it be approved only for therapeutic uses—no sub-therapeutic, growth promotion uses; third, that no extralabel use be allowed; and fourth, that CVM institute a monitoring system to detect emerging antimicrobial resistance and mitigate it in timely fashion.

(The Center has more recently proposed to withdraw approval for the use of fluoroquinolone in poultry. The reason for the decision is that CVM officials detected an increase in resistance in the human pathogen Campylobacter. The Notice of Opportunity for Hearing, published in October 2000, said that FDA/CVM “proposed to withdraw approval of the new animal drug application for use the fluoroquinolone enrofloxacin in poultry based on CVM’s determination that the use of fluoroquinolones in poultry causes the development of fluoroquinolone-resistant Campylobacter, a human pathogen, in poultry; this resistant Campylobacter is transferred to humans and is a significant cause of the development of resistant Campylobacter infections in humans; and resistant Campylobacter infections are a human health hazard. Therefore, CVM is proposing to withdraw the approval of the new animal drug application for use of enrofloxacin in poultry on the grounds that new evidence shows that the product has not been shown to be safe as provided for in the Federal Food, Drug, and Cosmetic Act.”)

What has Guidance for Industry #152, “Evaluating the Safety of Antimicrobial New Animal Drugs with Regard to Their Microbiological Effects on Bacteria of Human Health Concern,” done for industry?

The development of antimicrobial resistance in drugs of human importance had a dampening effect on the availability of new antimicrobial drugs for food animals. Dealing with this issue has been a challenge for me, for the Center, and for the drug industry. Guidance for Industry #152 laid out a suggested regulatory path drug sponsors can follow to demonstrate the microbial safety of proposed uses of antimicrobials. It uses risk assessment and risk management principles in determining the safety of the antimicrobial drug. Guidance 152 brought stability to the approval requirements for antimicrobial drugs by giving clear guidance to industry on the approval requirements. Now that there is a clear regulatory pathway addressing food safety issues associated with antibiotics, we are seeing a number of new applications for antimicrobial drugs.

BSE

Another challenge you found was BSE. How did you and the Center handle that one?

When I became the director at CVM, BSE was an animal disease with no known effect on human health. While there had been some problems with BSE in the United Kingdom, there had been no occurrences in the United States; and if there had been, it would have been handled by the U.S. Department of Agriculture’s Animal and Plant Health Inspection Service (APHIS). A year later, I was participating in a teleconference with members of the animal feed industry, cattlemen, APHIS, and others when I learned that the U.K.’s Transmissible Spongiform Encephalopathy Advisory Committee had reported that there might be an association between BSE and Creutzfeldt-Jakob Disease in humans. And at that moment, the world—and my universe—changed.

All of a sudden, BSE became a huge food safety crisis in Europe. It was later described as a “crisis of -confidence” in the minds of the European public because they felt that their government representatives had not been forthright and truthful. Political upheavals resulted, including large turnovers in government officials in countries where BSE was present. Millions of cattle were destroyed as a result of the outbreak, and there was great fear in the United States that this disease would penetrate the U.S. cattle herd and lead to human deaths, severe disruption of domestic agriculture, and have devastating effects on our economy.

The BSE crisis was one of those moments when the regulated industries and FDA worked together to get things done and manage the crisis. Even so, it was a monumental struggle to actually put the regulations in place that now prohibit the feeding of potentially infective material to cattle and other ruminants. In the end, there was a great coming together of government and industry to make sure that we got it right, and that we were adequately enforcing the regulations. The BSE crisis turned out to be a great success story. Out of the tumult that surrounded the issue we have a great triumph. The fact that we have high compliance with the regulation—greater than 99 percent for renderers and feed manufacturers—is an indication that there was essentially complete buy-in from the agriculture sector. Looking back, what effect did the Center’s requirement to respond to BSE have on other programs within the Center?

When we issued the 1997 rule prohibiting the feeding of certain cattle materials to ruminants to prevent the establishment and amplification of BSE, we made a major commitment to educate the industry and the public about the new feed regulation before going out to inspect the regulated the industry. We were not provided any additional resources at the time for BSE work, so we took resources away from other areas. Most notably, our tissue residue program, which takes enforcement action against livestock producers that market animals containing drug residues, suffered. But at that point, our highest priority was to make sure that the new BSE feed rule was adequately enforced.

Another impact of the BSE crisis was to divert our focus from the more core functions of CVM—drug approval, feed safety, compliance, and adverse drug reaction/postmarket surveillance. Over the years, we have received increases in the appropriated budget to expand BSE inspection and enforcement and to fund research to develop test methodologies that help us to enforce the feed rule.

Science

What developments in science have occurred within the past 10 years that have helped CVM the most? What developments are still needed? What scientific developments create the greatest challenges looking ahead?

Genetic engineering is perhaps the most important challenge. Some types of genetically modified animals that were strictly experimental a few years ago are now at the point where they can be produced commercially and have new traits that don’t exist in animals that have not been genetically modified. We are seeing transgenic animals that have the potential to grow much faster than non-modified animals, and soon we’ll be seeing animals genetically modified to render them immune to certain diseases. We have seen animals that have been genetically modified to produce drugs and biologicals that are harvested from the animals and used to make human vaccines and human drugs. In other words, there is a revolution unfolding before us. A dilemma for us is that the science that has made biotechnology possible has not helped us as regulators in determining whether those animals can be used safely for food.

Cloning is another technology that is at a point where it is ready to be used on a commercial scale to produce livestock and, to some extent, in companion animals. CVM is developing a risk assessment that we hope to release soon on food produced from animal clones. Pharmacogenomics is another new technology that will hopefully allow us to make safety and efficacy determinations using surrogate endpoints. This science promises a future in which we may use fewer laboratory animals, or maybe not have to use laboratory animals at all, to make safety and efficacy determinations. This could also help to reduce the cost of drug development and reduce the loss of life of animals presently used in making assessments of drug safety and efficacy. In addition, the technology used to monitor drug quality as the drugs are being produced is changing. This “real-time” quality testing is starting to take hold in some sectors of the pharmaceutical industry. Testing takes place during production, in real time, and not only at the end-product stage. We think this technology will give us better information than before, and will improve the quality of pharmaceutical manufacturing.

You mentioned earlier that one of the things that attracted you to FDA was the high level of scientific expertise that exists in FDA and how strongly FDA is grounded in science. Does science always dictate CVM’s regulatory policy?

One thing I didn’t understand prior to taking this job was what it really meant to regulate industries.

I naively thought that as a regulator in a science agency, you evaluate the science, you make your decision, and industry says “OK.” Science; decision; move on. I learned that in formulating regulatory policy, science alone is not necessarily enough. Science is not immutable; all science has some inherent uncertainty associated with it, and any decisions that are made based on that science can be challenged because of that inherent uncertainty.

There are a number of factors that influence regulatory policy, especially when risk decisions are being made, including economics and societal values. Because the science is not incontrovertible, and economics and values come into play, the Agency often finds itself in an adversarial role with the regulators, industry, and/or with consumers.

The tension that naturally exists between the regulators and the regulated industry is a lot of what the job is about. I think the industry representatives generally believe that they are right. I don’t believe they are being disingenuous for the most part, but they have a vested interest and that helps shapes their beliefs.

In the earlier interview, you said you wanted input from CVM’s many stakeholders—the pharmaceutical industry, the livestock industry, feed and pet food industries, companion animal organizations, zoological societies, wildlife conservation organizations, and the veterinary profession. How would you describe the response of these stakeholder groups to the progress of the Center over the past 10 years?

One of the things I probably didn’t fully appreciate when I came into this job is how interested CVM stakeholders are in what the Center does. Our stakeholders are generally pretty vocal. We regularly hear from them when they like what we are doing and when they don’t. Their comments help shape the policies CVM develops.

Are you saying that response has generally been strong?

Oh yes. I believe that public servants cannot make informed policy without a clear understanding of what the public wants. Of course, the public is not homogeneous. It’s made up of individuals who each have a unique perspective about what FDA should do. By listening to a number of diverse perspectives, I believe that our ultimate decision is a much more rep- presentative one.

In the earlier interview, you did not discuss CVM’s involvement in international work. But since that interview, CVM has become a major supporter and participant in international efforts to harmonize testing protocols and standards for drug approval under Veterinary International Conference on Harmonization (VICH), chairs the Codex Committee on Residues of Veterinary Drugs in Foods, and participated under Codex in developing an international code of animal feeding practices and significant international agreement in the area of antimicrobial resistance. How does this international work relate to your efforts to accomplish your original goals? Can you talk about the importance of these international activities to the Center and the regulated industry?

When I came to CVM, I focused first on CVM’s domestic programs, and on our core activities. It soon became apparent to me that we live in a global society and that the decisions we make in the United States have ramifications in other countries, and vice versa. This became abundantly clear early in my tenure, when we faced a World Trade Organization (WTO) dispute based on the FDA-approved use of growth hormones in cattle. Because the European Union did not agree with our position that meat from hormone-treated cattle was safe, U.S. cattle were denied access to European markets.

Hormones were just one issue. There were a number of other disputes that never reached the level of formal dispute resolution under the WTO. I learned that even minor areas of disagreement on the regulation of drugs and animal feeds can serve as a focal point for trade disputes. FDA is not a trade promotion agency, but we have a clear responsibility to explain the basis for our regulatory decisions when those decisions come into question as part of a trade dispute.

One way to minimize the likelihood of future trade disputes is to work with other countries to reach consensus on food and drug standards. The international work I have been involved with since coming to CVM has largely been focused on harmonization of veterinary drug residue requirements among the roughly 160 countries that are members of Codex—and to harmonize veterinary drug registration requirements among Japan, the European Union, Canada, Australia, New Zealand, and others that are members of the Veterinary International Conference on Harmonization (VICH).

Looking back over a decade or more, we have made substantial progress in Codex and in VICH, without lowering the high standards of product safety and efficacy that consumers and industry expect from FDA. We now have a Code of Practice for good animal feeding, which protects consumers from hazards like BSE, dioxins, and contamination with salmonella. Before coming to CVM, I didn’t have much of an appreciation for the importance of animal feed as a public health issue. Since then, I have come to understand that animal feeds and human food safety share a number of issues.

Next issue: Changes to CVM’s structure to bring about Dr. Sundlof’s goals.