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U.S. Department of Health and Human Services

Animal & Veterinary

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How CVM Uses Adverse Drug Experience Reports System

FDA Veterinarian Newsletter September/October 2004 Volume XIX, No V

The Center for Veterinary Medicine (CVM) collects and analyzes Adverse Drug Experience (ADE) reports to detect problems that may appear after a product has been in use. The ADE report system is complex and goes far beyond simply tallying numbers of complaints. Here’s a glimpse at the program’s workings, provided by the head of the program at CVM, Victoria Hampshire, VMD, Adverse Events Coordinator.

CVM cited ADE reports in the recent decision to recall a veterinary product. Does CVM determine actions based strictly on the number of ADEs it receives concerning a product, or are there other considerations?

No. CVM does not make decisions about products based solely on the number of ADE reports it receives. CVM makes a careful analysis of all relevant factors that might affect reporting patterns, such as what is happening in the group of animals taking similar drugs in the class and what animal handlers, owners and veterinarians are doing. Usually, we can come up with a label change that will reduce or eliminate an adverse experience. However, if label changes or packaging changes do not reduce or eliminate the adverse events, then CVM can take other regulatory actions, such as request a recall of the product.

CVM utilizes experienced clinical veterinarians as safety reviewers. The reviewers highlight adverse events that are unusually frequent or severe, as determined based on patterns of events and knowledge in the cohorts (which are same drug or similar drugs in same species, same route). CVM decides what actions by the drug sponsor would be appropriate to eliminate problems that become apparent through the ADE system.

What conditions or trends do you have to see before you take action against a product?

It depends upon the product. What is acceptable for a drug used to treat an old age condition, such as a non-steroidal anti-inflammatory drug for arthritis, would not be tolerable for a preventive used in a wellness program. Also, before we would take action, we would need to see increasing severity and frequency of an adverse event that was unexpected (not on the label), or one that we could not explain.

What actions other than a recall have been triggered by ADEs?

We have required label changes, changes in the dispensing apparatus, and box warning and prescriber information. We’ve required label changes for clomipramine for liver signs, carprofen and deracoxib for liver signs, enrofloxacin for rare events of blindness, etogesic for dry eye (KCS), moxidectin paste for slippage of the locking mechanism and accidental overdoses in horses, and increased box warnings, and prescriber information for tilimicosin to reduce and we hope eliminate human safety issues.

Are ADEs that prompt a label change fundamentally different than those that prompt a recall?

Yes. The actions prompting a label change mean that FDA feels that the label change will result in a significant reduction of the problem or condition, or will result in a change in prescribing advice that will lead to more judicious selection of candidates. The issues leading to a recall or withdrawal are related to conditions where the cause of the safety problem cannot be easily determined, thus the product cannot be labeled in such a way that adverse events can be reduced to a level of frequency or severity that is expected in the same population taking the same class of drugs for the same reasons.

What is the significance of the fact that the ADE program is partially voluntary? Does that mean the ADE reports are more significant? And what part of the program is voluntary, because aren’t the drug firms required to send ADEs to CVM?

Drug sponsors are required to report adverse event reports they receive regardless of whether the source is a veterinarian or the owner of the animal. The voluntary process relates to the fact that the veterinarian is not required to report an ADE to the firm.

The reports represent an index of suspicion that the drug caused the problem. The firm must report it at that point. FDA can then determine how likely it was that the drug was associated with the problem, based on what is known from the pre-approval studies and the label, and similar experience encountered in the post-approval -period.

Because reporting is voluntary on behalf of the veterinarian, it is classically associated with under-reporting. Veterinarians don’t always associate the reaction with the drug and, if they do, they may become busy and forget to call the firm.

What are the qualifications of the ADE reviewers?

ADE reviewers at CVM must have at least five years of clinical practice, preferably also bolstered by advanced training in academia, regulatory or research background, current licensure and continuing education. Our reviewers have, combined, more than 70 years of veterinary clinical experience, spanning large animal, emergency and critical care; biomedical research support; microbiology; public health; and large animal reproduction.

Is the ADE system for animal drugs similar to that for human drugs? What are the similarities? What are the differences?

The systems are very similar in the sense that we use many of the same methods for evaluating safety and efficacy. Common principles in evaluating drug causal relationships include previous experience with the drug or class of drugs, alternative etiologic causes, timing of the reactions, and what happens when the drug is withdrawn or re-introduced. They are different in that the veterinary medicine target animals vary much more in physiology at the level of family, genus and species, than does the human population.

We heard statements recently about “unfiltered reports” about drug experiences being sent to CVM. What’s an “unfiltered report?”

An unfiltered report is an ADE report that the drug sponsor receives from a veterinarian or animal owner because the veterinarian or owner suspects that a drug was related to a clinical sign in the animal patient. Drug sponsors are required to report adverse event reports they receive. It means every report gets sent to the Food and Drug Administration and CVM whether the drug was used according to the label instructions or not. The firm may express an opinion about the reaction and CVM may agree or disagree with the opinion after reviewing the report using the ADE evaluation process.

Does the ADE program conduct other sorts of surveillance activity to see if the FDA Form 1932 reports (the stand-ard report form used to file an ADE) are consistent with what is observed elsewhere?

Yes. First, nobody really knows the incidence of drug reactions, because the number of events is classically under-reported and the number of doses administered is not known. The number of doses administered is not the same as the number of doses the firm sells to practitioners.

The surveillance program personnel also monitor key veterinary Internet chat sites and CVM’s ADE phone hotline calls. The personnel also attend professional meetings to survey discussions about the products. We also routinely survey important medical literature and regularly read trade journals.

Most importantly, as practicing clinical veterinarians, most of the safety reviewers routinely use most of the products that CVM regulates so that they have a feel for what is normal as well as what is unexpected. This is a fundamental priority of the safety program and CVM. CVM personnel make no recommendation about any drug in an information vacuum. And CVM has a track record of making recommendations that result in a decrease of adverse reactions.

Other than ADEs, do you get other information from companies about various drug products?

Yes, we obtain information about product defects, so that we can try to determine if the ADEs may be product- or manufacturing-related. We also receive information about doses sold so that we have a feel for whether product use is static, decreasing or increasing, compared with the number of ADE reports. We can never determine with certainty how many doses are administered, but we can determine if overall use is up or down or the same by reviewing the number of doses sold.