The truth about serum
A horse under anesthesia has lost a large volume of blood secondary to removal of a vascular tumor in its sinus. The anesthesia team is transfusing the patient with plasma believed to contain normal to high protein concentrations.
Another veterinarian is giving plasma to a foal born on a farm at which Rhodococcus equi pneumonia is endemic. He assumes the product is free of bacterial contaminants and contains the specific antibodies needed.
Knowing that the Department of Agriculture regulates vaccines and the Food and Drug Administration regulates drugs, these veterinarians are confident that plasma products are subjected to regulatory oversight as well.
The truth about serum and other equine blood products is that some products are actively regulated while others are not. To make informed therapeutic decisions, veterinarians must distinguish between them to understand their inherent risks and benefits.
This message is important for all veterinarians, especially those practicing equine medicine. The equine industry has been at the forefront of plasma production, notes Dr. T. Douglas Byars, who represents the American Association of Equine Practitioners on the AVMA Clinical Practitioners Advisory Committee. The AVMA Council on Biologic and Therapeutic Agents and CPAC have been advocating for the profession on this issue.
"There is getting to be a menu of products out there, and veterinarians generally don't understand how they're produced and what quality they should be looking for," Dr. Byars said.
"The range of production can be anything from what we call bathtub brew—which is you just go bleed the horse on the farm, let the blood settle out, and pull the plasma off, which is a very imprecise thing—to plasmapheresis, where the horse is hooked up to a machine the same way a human goes to a plasma blood collection unit in the community."
Veterinarians commonly use plasma to treat failure of passive transfer of maternal antibodies in newborn foals and to administer immunoglobulin G, but Dr. Byars said the growing product menu includes such products as anti-Rhodococcus infection plasma, antiendotoxin plasma, and customized plasma—to combat West Nile virus infection, for example.
What is and isn't regulated
Just as with antibody products, the USDA Center for Veterinary Biologics regulates blood-derived products that are marketed as treatments for various conditions and that act via immunologic mechanisms. It is authorized to do so under the Virus-Serum-Toxin Act, using Antibody Product Standards. Immunoglobins, serum, and plasma for passive transfer of immunity are considered veterinary biologics.
Antibody products that are not submitted for the licensure process as required by law may slip under the regulatory radar screen.
The FDA Center for Veterinary Medicine has regulatory authority over animal blood products that make no immunologic claim for treatment, but they generally receive little active oversight from the agency, which regards them as a low priority. These products include whole blood and transfusion and clotting products, except serum and plasma products indicated for passive transfer of immunity.
Whether a product is produced and sold for intrastate or interstate commerce has no bearing on licensure regulations overall.
A provision in the Code of Federal Regulations (9 CFR 107.2), however, exempts biologic products from the USDA licensure requirement if they are licensed by a state that has its own program to license products for intrastate distribution. Currently, California has the only program that meets the federal requirements.
Why choose a licensed product?
When you buy a unit of plasma, how confident are you in its quality? Have you checked how it was processed, what it purports to do, what studies support those claims, and whether the government has overseen the product?
Dr. Byars said the primary concerns over unlicensed products center around production standards, product labeling and licensure, and a veterinarian's potential liability for an unfavorable clinical outcome resulting from administration of an unlicensed product.
Licensure by the USDA provides certain quality assurances to veterinarians.
Michel Carr, PhD, senior staff microbiologist for the USDA-CVB Policy, Evaluation, and Licensing unit, said, "In addition to an individual product being licensed, we license the manufacturer and their products. The protocols they use to immunize those animals and the care the animals receive are known to us. The facilities that are used to hold the animals and to do the plasmapheresis are inspected. Things need to be clean, well-organized; the records need to be up-to-date.
"Once we're satisfied with the facility, then yes, the individual products are evaluated. ... We do evaluate them for safety in use, and if they are making a specific therapeutic claim, we will evaluate the product for potency."
The USDA testing standards also ensure purity—both in the general sense and with respect to being free from contamination with coliforms, salmonellae, and fungi. To ensure that the product has a proven shelf life, the manufacturer must strictly follow an outline of production, a detailed protocol of methods of manufacture for a veterinary biologic product.
A USDA license means that the production animals had no clinical signs of disease and were under veterinary supervision, were maintained on licensed premises, and were quarantined to prevent contact with infected or potentially infected animals. The USDA requires that horses used in production, for example, be tested for such diseases as equine infectious anemia, piroplasmosis, dourine (a chronic venereal disease caused by Trypanosoma equiperdum), glanders (Burkholderia mallei infection), and brucellosis.
Dr. Carr said that licensed establishments cannot make unlicensed products, unless the CVB issues a formal exemption.
The issue of noncompliance
Deciding to choose licensed products is only the first step. A veterinarian should ask when phoning in an order whether the products are licensed and scrutinize the labels once the products have arrived.
By law, any plasma product sold with an immunologic, therapeutic claim must be licensed by the USDA-CVB, and its label must bear an establishment license number. The problem is, manufacturers allegedly don't always comply. Veterinarians may encounter a product that is unlicensed but whose advertising and promotional materials make an immunologic claim.
"Currently it varies from a production company that may be very forward with its labeling to those who will say that the less you put on a label, the better off you are," Dr. Byars said. "So if you want to hyperimmunize against J5 E(scherichia) coli or Rhodococcus, but (the producer doesn't) measure the amount of antibody or the neutralizing effect of that plasma, then the veterinarian doesn't know what level of quality he or she is buying."
Dr. Joseph Bertone, a member of COBTA, said manufacturers who undergo the antibody product licensing process and submit to inspection are trying to do the right thing. "Others are selling the product for maybe only $5 or $10 less, and veterinarians in their ignorance are willing to buy it," he said. "The good guys are getting penalized."
Costs and risks
A veterinarian might very well pay less for an unlicensed product with a therapeutic claim, but is the savings worth the risk to patient—and practitioner?
Dr. Carr said his agency always recommends that when given a choice, veterinarians use a licensed product. "Just about anybody could hop on the Web right now and find all kinds of things being advertised with a lot of claims that, frankly, we haven't evaluated," he said.
A strong argument for using licensed products is that a practitioner's potential liability is greatly reduced, Dr. Carr said, adding, "The caveat to all of this also is just because they're not licensed and just because they're not regulated does not automatically mean it's going to hurt your animal, it's a horrible thing, or that you can be locked up for using it."
The CVB does not have records that would shed light on the prevalence of problems resulting from use of unlicensed products. According to the AVMA-PLIT, the incidence of claims arising out of the use of unlicensed blood products is low, but Dr. Linda Ellis of PLIT said the trust recommends that veterinarians use a licensed product whenever one is available, because it's been tested and proved safe and effective for the labeled use(s). Dr. Bertone points out that plasma products are often used in foals that are already ill, and practitioners have a tendency to blame a patient's death or deterioration on the illness rather than the product.
Dr. Carr urges veterinarians to report unlicensed products that appear to promote specific therapeutic effects as well as difficulties they encounter with licensed products, such as adverse events, failure to work as advertised, or inadequate indications or directions for use. "We do follow up," he said.
The legalities
Dr. Donna M. Gatewood, CVB section leader for Virology, said, "We have taken action against firms that are marketing unlicensed products with therapeutic claims."
While acknowledging that the USDA doesn't regulate a blood product that starts out with no therapeutic claim, she said, "When people attach a claim to it with a nod and a wink, we may not hear about that unless they're splashing it all over their Web site."
Within a valid veterinarian-client-patient relationship, veterinarians can use unlicensed products in the course of their practice, Dr. Gatewood said. They themselves may keep a donor horse on premise.
But to package, market, and distribute material for which they are making a therapeutic claim, without pursuing licensure, would be in violation of the Virus-Serum-Toxin Act, she added.
Blood products with no immunologic claim
Besides choosing a licensed product for blood with a therapeutic claim via an immunologic route, there is a secondary issue—being aware that other products are seldom regulated.
"If you donate to the Red Cross, the FDA monitors the quality of those drug products that have no claim—in other words, just blood," Dr. Bertone said.
"'Veterinary FDA' is supposed to do the same thing, but they most often don't monitor anything that doesn't have a claim." Dr. Bertone ascribes this to limited resources but adds, "If it's a law, they ought to do it, and if it's not a law, they ought to take it off the books so that people know they're not protected."
Dr. Bertone, who represents private clinical practice/predominantly equine on COBTA, noted that the council has made that plea to the FDA-CVM—unsuccessfully, prompting the council to shift to an educational approach.
In 2004, the AVMA contacted the USDA-CVB and FDA, asking the agencies to regulate all equine plasma products intended for use in horses, with or without claims, according to the USDA standards for animal blood product quality. The Executive Board had adopted this position on recommendation of COBTA. A response from APHIS and FDA informed AVMA that the FDA and USDA were reviewing the options available for regulating such products.
According to Dr. Vitolis E. Vengris, special assistant to the director of the FDA-CVM Division of Surveillance, the agency evaluates blood products on a case-by-case basis, depending on the product claims. He acknowledged that many indications are allowed under regulatory discretion for reasons that include the agency's limited resources. The CVM has "approved" products for (nonimmunologic) therapeutic indications, such as plasma extenders, though none is currently being marketed.
The term "approved" is the CVM's counterpart of the USDA's term "licensed," but Dr. Vengris said that a veterinarian would not necessarily be able to identify an approved product from its label. A list of all approved products is available online on the CVM Web site by clicking on the Green Book link. By selecting the Adverse Drug Reactions link on the main site or calling the agency, veterinarians can report problems.
Animal blood banks fall under FDA's regulatory jurisdiction, but Dr. Vengris said that oversight is "practically nonexistent" because of limited resources and inspection capabilities. Blood banks voluntarily register their establishment with the CVM's sister center, the Center for Drug Evaluation and Research, but drug listing is not currently required. Voluntary standards are being developed withn the animal blood bank community.
The CVB is considering avenues for simplifying and expediting licensure of equine plasma and serum products, as well as products derived from the other host animal species it oversees—sheep, pigs, dogs, and ducks. This should encourage manufacturers to comply with licensure regulations.
Louise Henderson, PhD, section leader for Biotechnology, Immunology, and Diagnostics within the CVB Policy, Evaluation, and Licensing unit, said, "Current regulations require significant resources to perform the validation studies required to achieve licensure, and the kinds of firms that are interested in producing these products are usually very small and have limited resources."
This has been in discussion for a long time, but Dr. Henderson said that recently, the agency has begun devoting human and laboratory resources toward developing standardized assays and reagents. "Basically, we would like to provide the kind of reagents and assays that would assure a uniform standard is applied to the product, regardless of the manufacturer." These reagents would facilitate licensure, since each license applicant would not have to develop and validate the assays and reagents independently.
In the meantime, Dr. Byars called for regulatory standardization for education of veterinarians as to what they're actually buying. "Veterinarians need to be aware for the future, because commercial activity is going to continue to approach veterinarians, and it's going to become more and more intense."
USDA-CVB: (800) 752-6255
FDA-CVM: (888) FDA-VETS