Supplements And Drugs
There is much confusion among horse owners about products. This stems from the avalanche of new products being marketed over-the-counter as nutraceuticals or nutritional supplements. The claims made about these products often are what classifies them either as a drug or a nutritional supplement, and determines whether the Food and Drug Administration (FDA) has control over their sale.
Sharon Benz, PhD, leader of the Nutrition and Labeling Team at FDA's Center for Veterinary Medicine, clarified some government definitions at an American Horse Council meeting. "A drug is any substance, food, or non-food that is used to treat, cure, mitigate, or prevent a disease," she said. "A drug is also any non-food substance that is intended to affect the structure or function of the animal. Drugs must be shown to be safe and effective for their use. Any product administered by injection is also considered a drug," such as Adequan, Legend, or Hylartin V.
Benz continued, "Part of what distinguishes a food from a food additive is intended use. For example, when vitamin E is used as a source of an essential dietary nutrient, it is considered a food. If it is used to treat or prevent azoturia or tying-up, it is a drug.
"Unapproved drugs on the market are deemed adulterated drugs and may be subject to regulatory action," explained Benz. "In contrast, the law does not require a food to be subject to a pre-market approval process unless it is considered to be a food additive.
"If the label for a vitamin E supplement bears claims that consumption of the product will treat, prevent, or otherwise affect azoturia or tying-up, such claims establish the intent to offer the vitamin E supplement as a drug. Furthermore, since vitamin E is not approved for this use, it is considered an unsafe new animal drug under the Act (Federal Food, Drug and Cosmetic Act)."
But things become even more complicated than vitamin and mineral supplements. Owners today can get their hands on products that are claimed to be similar to "ethical" products that only a licensed veterinarian can distribute. For example, at a horse show, a glucosamine injectable solution was being marketed as an "Adequan-type" product for $50 a bottle. A woman who bought the bottle took it to Joe Bertone, DVM, MS, Dipl. ACVIM, who was an FDA investigator at the time. She told Bertone that the marketer claimed the FDA had given permission to sell it, as it was a nutritional supplement.
"I went over and pulled out a bottle of saline solution," said Bertone. "I asked her, 'Can you see the difference between these two?' She said no. 'Well, for all intents and purposes, your bottle could be saline and you wouldn't know.' "
The FDA regulatory standards for drugs aren't simply a matter of "getting permission," as entepreneurs illegally touting products might like. Testing standards for a product coined as a "nutritional supplement" are just beginning. Creating a uniform system for drugs and food additives would help protect the consumer from peddlers who capitalize on the unclear standards of products going into the horse's system, but that system isn't in place at this time.
The distinction between a food and a drug governs the FDA's regulatory authority. "The FDA drug approval process controls scientific method, time, and money, bringing a guarantee of the quality of the product under conditions of use," Bertone said.
For nutritional supplements that don't undergo FDA scrutiny, Bertone said, "A lot of what gets sold is no better than talcum powder." The FDA doesn't have the resources to go after all the fraudulent manufacturers. "These people can sell a product a long time before the FDA can shut them down," she added.
The fraudulent glucosamine cheated the consumer of certain FDA guarantees, the first of which is that it had gone through the process known as a Good Manufacturing Practice (GMP) source, which effectively guarantees the process under which a compound is being produced. (In other words, that it was manufactured under strict conditions that test what is in the product meets the label claims, among other things.)
The next product assurance is for conditions of use, which is where the product is tested for safety. In that process, a group of study animals is given an exaggerated dosage to determine toxicity levels and reactions. Researchers try to identify what is called the "therapeutic window," or clinical effects of giving more than the standard dose. In that procedure, a standard study is to give the product at one, three, and five times the recommended dose for twice the duration of treatment recommended. If, for example, the drug is to be administered for 10 days, the researcher will give one, three, and five times the standard dose for 20 days.
Researchers also give one dose at 10 times the standard; they do this only once. These applications are termed "tolerability studies." The tests mentioned here are just guidelines, and testing can vary depending on what the initial studies show. If they know a drug is toxic at two times the recommended dose, then the other doses aren't done.
For the manufacturing of the drug, there is a test known as the "sterile process." If the drug is an injectable, for instance, the FDA wants to know that the product will not contain bacteria or other contaminates. If it is a paste, the producers must demonstrate that within certain limits, the product doesn't "settle out;" it stays in consistent form.
Can the product stand being frozen? Can it stand the types of things that will occur that could change its composition or effectiveness? For instance, how long is that product's expiration date valid?
"You'll see products out on the market that have expiration dates on them that some of these companies have just made up," said Bertone.
The process of bringing a product from idea to FDA approval for a non-food animal (such as horses) can climb from $5 million to $10 million. For a food animal, it can go to $50 million. And it could take years or decades to get approval. Realizing how strict the testing processes are and how much it costs to go through these processes (sometimes unsuccessfully) often is an eye-opening experience to horse owners.
Some new products come on the market and are the only one available of that type for a time. This licensure helps the manufacturer recoup his expenses of bringing that drug to market. On the other hand, the process for bringing a generic product to the market (for example, phenylbutazone, or aspirin) takes about three years. The generic must prove to be bioequivalent to the original (same drug and same dosage form having a similar bioavailability).
From Idea To Product
Tom Kennedy, DVM, of Bayer products, discussed his company's testing process. He said testing is done on a wide variety of breeds and ages, as the effect of a product can vary even within breeds. "Safety is first and efficacy is second, because we don't want to harm animals," he explained. "It's not good for the horse, the owner, or us."
Developing a new drug begins by finding a novel compound and determining the utility of it. The discovery of a pharmaceutical "starts with the end in mind," Kennedy said. This means looking at the horse, determining the major health issues, and devising a drug that could treat that problem. Knowledge of specific ingredients are studies to determine their indications for that specific illness or problem (i.e., if this ingredient is used effectively to treat a similar problem in chickens, can it be used in horses?). Studies then are developed to determine whether the theories are correct. Controlled studies must show stable chemical action, which is what eventually determines the product's efficacy.
The next step involves testing for the drug's intended purpose. This part of the process can be done at a veterinary university, a contract research facility, or through a veterinary clinic. Most of Bayer's research is done at universities, according to Kennedy. "Modeling the diseases and deciding what variables we can really measure--those are the things the university professors are really good at," explained Kennedy. "They're on the front lines of the disease, they know what it is doing, they have all the clinical pathology information on what the disease might do to an animal. They actually define what the syndrome of the disease is, so when we say we think we have a drug that can modify the disease's condition, they'll say, 'Well, here are the variables you need to look at. These are the things I think are important.' So, we would work with them to try and design studies that would answer the questions."
Kennedy said a university works as a partner in the development of drugs and treatments. "We use their expertise because we don't have an expert on every disease on our staff," he explained. "At Bayer, we have people who are knowledgeable in veterinary medicine, veterinary science, and animal nutrition, so we can understand the principles of what we are trying to do. We can design studies with the help of the universities, then we assist the universities in running the studies to a certain standard by helping them analyze the data and write reports."
The scientists at a pharmaceutical company and at a university also look at what is happening with the disease. One product might be labeled for a very specific treatment for a very specific problem, but continued testing on the product might show that it is useful in treating other problems, or in a different manner for the same problem.
"We need to keep focused on whether there is a way we can develop an indication that we can get a label, and we can continue to work on the product and add additional label claims as time goes on." (Veterinarians often find applications for the drug beyond its original prescription.)
"I've been in the business a long time," said Kennedy, "and what we've tried to do is come up with a standard development model. You have to like the challenge of trying to figure out how to make the puzzle pieces fit into some sort of seamless frame, and have to want to have a process that goes smoothly from beginning to end. It's new every time you do it. I used to think there was a standard way to do this, but there's not. There are standards you have to fulfill, but how you fulfill them is different every time."
More On The Process
According to Bertone, who now conducts research testing in addition to his private practice, most testing occurs in the field. He said that method has the benefit of the most "true to life" conditions. The studies have to be conducted under certain protocol, and paperwork must be exacting, or the results can't be used as a true indicator. At www.fda.gov/cvm, the freedom of information section reports on each drug or vaccine that gets FDA approval, lists places where the product was tested, and tells what kind of testing the drug went through for evaluation.
The one legal avenue for "non-approved" drugs is a veterinary compounding pharmacy. These places take regulated items and mix or compound them for a specific purpose or veterinarian. However, the pharmacy must adhere to federal guidelines.
The process of drug testing and approval involves applications that are filled with pages of tests on whatever's necessary for a particular drug--it could be pharmacokinetics, limb flexion, or measuring parasite egg level. The parameters could be respiration, elements of blood and urine, or appetite.
In the realm of non-regulated food additives, the testing standards are in planning stages through various organizations. In 1999, a committee called the Nutraceutical Regulatory Advisory Panel was formed, initiating a definition for nutraceuticals as "various types of ingested substances that provide natural components of the body and/or offer nutrients that affect the physiological well-being of the animal." The group made recommendations to the Association of American Feed Control Officials (AAFCO), spawning a task force of the FDA, AAFCO, and trade associations. The National Association of Equine Supplement Manufacturers, begun last year, represents a certain portion of the equine camp in the task force. Leesa Nacht, a consultant for EQESTAR, a company providing consulting in the field of equine nutritional research, reported that AAFCO's Herb & Botanical Committee is addressing concerns of that industry section; a survey has been sent to animal practitioners and members of the herbal industry to find out what products are being used and what needs to be defined.
Canada has formed the Nutraceutical Alliance (NA), a similar, but more encompassing group that addresses the "alternative" supplement industry. The NA is allied with the Equine Research Center at Guelph. Partners in NA, the Ontario provincial government, and the Canadian federal government have made financial contributions supporting industry research.
Jamie Brooks of the National Association of Equine Sports Medicine (NAESM) and vice president of Vita-Flex, said NAESM is encouraging manufacturers to follow Good Manufacturing Practices. A list of ingredients is being created that have a general industry agreement as to their lack of toxicity or production of adverse reactions. NAESM will submit this list to AAFCO for temporary approval. In the meantime, there will be further research into the ingredients' efficacy and safety. Brooks said chondroitin and glucosamine were among the ingredients on the list. However, the timeframe for governmental drug approval and testing is similarly arduous for establishing standards: AAFCO can't approve this list until it meets again in January 2001.
Benz explained that non-approved products "are not removed because most of the FDA's limited resources must be focused on products or incidences that pose a known hazard to human or animal health. Thus, the FDA doesn't always have the time or resources to take enforcement action against products that are more fraudulent than dangerous."
Tips For The Horse Owner
Sharon Benz, PhD, leader of the Nutrition and Labeling Team at FDA’s Center for Veterinary Medicine, offered guidelines for the consumer to help make a decision about a non-regulated product.
Since there are no standards for the ingredients used in these types of products, ask the firm for information on the composition of the product and how they do quality testing. What are the standards each batch of product must meet? Do they test for contaminants? What safety studies have been completed with the product? (If the product is intended for horses, there should be adequate safety testing in that species.)
The firm should be asked to provide information on product usefulness.
Seek a knowledgeable equine practitioner’s advice about:
Are there effects that can result from interactions with a prescription drug and this product?
For topically applied products, are there toxic effects from a horse ingesting a product?
Be aware that many herbs have pharmacological activity; owners should consult their veterinarians before using.
About the Author
Andrea Reynes is a free-lance journalist specializing in horses and the human-animal relationship. She has an animal care business in Lincoln, Mass.
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