In late December 1998, the community of vascular practitioners became aware of a shortage of the tissue-culture urokinase compound known as Abbokinase (Abbott Laboratories, North Chicago, Ill). Abbokinase, originally approved in 1978, is the predominant form of urokinase in widespread use throughout the United States and Canada. The reason for the shortfall is now well known to clinicians and many lay persons alike. The US Food and Drug Administration (FDA) put a hold on the release of Abbokinase on the basis of presumed deviations in the Current Good Manufacturing Practice regulations, guidelines that were developed to protect the consumer (patient) from the administration of unsafe products.
The FDA inspected Abbott’s manufacturing facility in North Chicago, Ill, in late 1998. Shortly thereafter, the FDA issued a letter to the company that raised concerns over the manufacturing of Abbokinase. The FDA directed Abbott to cease further release of Abbokinase pending resolution of several manufacturing issues. Foremost in this regard was concern about the neonatal kidney cells that Abbott used as a source for Abbokinase. The cells originated in Cali, Columbia, and were obtained through a separate company, BioWhittaker (Walkersville, Md). The cells were from a population thought to be at high risk for a variety of diseases, including tropical diseases. The mothers of the potential donors were not screened on a consistent basis. Although the cells themselves were tested for human immunodeficiency virus, hepatitis B virus, and hepatitis C virus (HCV), the test for HCV was not validated to the FDA’s satisfaction. Further, before use in the manufacturing process, infectious contamination of the kidney cells may have occurred as a result of the manner in which they were harvested, handled, and stored. Lastly, although a viral inactivation procedure is used in production that substantially inactivates human immunodeficiency virus, hepatitis B virus, and HCV in most biologic products, the procedure has variable effects on other infectious agents and is not fully validated for viral inactivation of Abbokinase. The FDA conceded that they were unaware of any cases of infectious transmission by Abbokinase but suggested that any connection between the drug and such cases might have gone unrecognized and unreported. On January 25, 1999, the FDA issued an “Important Drug Warning” communication to the medical community that outlined the risks associated with Abbokinase and encouraged prescribers to consider alternatives to its use.
As a result of efforts by Abbott, the members of the Society of Cardiovascular and Interventional Radiology, and the medical community at large, the FDA released several lots of Abbokinase in early 1999. Abbott implemented additional testing of Abbokinase lots, and neither Abbott’s nor the FDA’s tests of finished lots detected the presence of infectious contamination. Reovirus was, however, found in three lots of in-process product. Reovirus is an etiologic agent responsible for minor upper respiratory and gastrointestinal illnesses. These lots were not manufactured into finished Abbokinase, and, in addition, the heat inactivation step performed during further manufacturing would be predicted to inactivate the virus. Additional lots have not been released, and the Abbokinase shortage remains critical, but upper level discussions between Abbott and the FDA are ongoing.
The urokinase story has been quite disconcerting to vascular practitioners. The FDA issued a proclamation that severely impacted the availability of a drug important to the practice of a large body of physicians without consulting representatives of that specialty group. In fairness, there were informal communications that suggest that the FDA was interested in replacing drugs of human tissue origin with recombinant agents. In fact, at least two manufacturers did institute development plans for alternate thrombolytic agents for use in peripheral arterial occlusion. Specifically, a recombinant form of urokinase, recombinant tissue plasminogen activator, and recombinant prourokinase were studied. Unfortunately, the attempts to secure a lower extremity arterial indication for these agents either were unsuccessful or remain incomplete.
At this date, the development and execution of a trial designed to gain a lower extremity indication for a thrombolytic agent remain highly problematic. The Center for Biologics Evaluation and Research (CBER), the branch of the FDA with the responsibility for thrombolytic agents, presently requires the successful completion of at least one, and sometimes two, randomized clinical trials that compare the use of the thrombolytic agent with a control group of patients who undergo “standard medical treatment,” in this case open surgical revascularization. The new therapy must be superior to the standard therapy, with a 95% degree of certainty. Alternatively, approval of the new therapy is possible with the demonstration of equivalence to the older treatment, but we must be 95% certain that the new therapy is not more than 5% worse than the old one. Moreover, the primary endpoint must be “clinically relevant” in any acceptable trial. In other words, the primary endpoint must be something that is directly appreciated by the patient. Thus, clot lysis, patency rate, or ankle-brachial indices are not accepted as clinically relevant endpoints. Rather, amputation-free survival rate has been the primary endpoint most agreeable to CBER.
The assumption that surgical revascularization is the only standard of care in 1999 is an opinion unlikely to be shared by many in the medical community. In fact, most vascular practitioners believe that Abbokinase is as much a standard of care as primary operative revascularization, and choices regarding the most appropriate initial therapy depend on the specific clinical presentation. If the FDA will accept the premise that Abbokinase is an acceptable standard of care for patients with lower extremity peripheral arterial occlusion, the door would open for a variety of well-designed trials that compare newer agents to Abbokinase. The vascular community would readily embrace such a position and could be relied on to design, organize, and execute a variety of multicenter clinical trials to gain approval for alternate thrombolytic agents. It seems that such a change in the stance of the FDA would predictably achieve the stated goal of replacing Abbokinase with other agents.
On an optimistic note, CBER has recently been quite open and helpful in forging new clinical trials aimed at garnering approval for peripheral thrombolysis. In the historical novel The Leopard, Guiseppe Tomasi di Lampedusa wrote, “If we want things to stay as they are, things will have to change.” The continued availability of peripheral thrombolysis is dependent on the ability to alter our scientific complacency. We must collect sound data to prove beliefs that heretofore have been based on little more than anecdotal experience.
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