By: Mikhail Ovanesov, Ph.D.
The Food and Drug Administration’s Office of Blood Research and Review (OBRR) has a broad mission to ensure the safety and efficacy of products it regulates. It also does mission-related research, some of which can be described as problem-solving.
One of the problems on which OBRR focused recently was a serious adverse effect linked to some treatments with immune globulin intravenous (IGIV), a product that contains pooled immunoglobulin (antibody) extracted from the plasma of thousands of donors. Licensed IGIV uses include the treatment of immune deficiencies and autoimmune disorders.
These immunoglobulin treatments are generally safe, although they can cause mild to moderate adverse effects during and after infusion, such as headache, malaise and nausea. Less common but potentially fatal complications are the formation of blood clots. These thrombotic events (TEs), as they are known, can block large arteries or veins, causing heart attack, stroke, deep venous thrombosis and pulmonary embolism.
That’s why, since October 2003, FDA has recommended precautionary labeling for IGIV products that includes the risk of thrombotic events. But while the new labeling helped raise awareness of this risk, the causes of TE remained unclear. In fact, since many patients receiving IGIV are already considered at risk for thrombosis, the causes were often attributed to the patient’s medical condition. The fact that TEs only rarely occurred in clusters linked to a single lot of IGIV from a particular manufacturer also made it difficult to pin down a specific cause for these adverse effects.
That all changed in May 2010 when TEs – stroke and myocardial infarction in several patients – linked to two lots from one manufacturer prompted the company to put a hold on the release of these lots. My laboratory responded by launching a series of tests to find out what caused the TEs. We studied the ability of four different lots of IGIV to generate the blood protein thrombin, which triggers clotting. Specifically, we compared two lots which caused stroke or myocardial infarction in several patients with those that did not. Our work showed that the lots linked to TEs induced faster and higher generation of thrombin. We then confirmed these results by recording blood clot formation under a specially designed video microscope. The lots associated with TEs again demonstrated higher rates of clotting. Additional tests confirmed that the thrombin generation test reliably identifies lots that are potentially thrombogenic.
In early August 2010, OBRR shared its data with the company, which confirmed the results and established product evaluation methods using similar coagulation assays. After the company voluntarily withdrew 31 IGIV lots from the United States market, there were many more international reports of TEs. By the end of September, all product lots were voluntarily removed from the U.S. market.
But we still didn’t know what was triggering the rapid rise in thrombin. So we continued our studies and identified a blood protein called coagulation factor XIa as an impurity in IGIV products causing thrombosis. This enabled us to develop a Factor XIa assay that could determine if an IGIV lot contained this thrombogenic impurity. We then tested other lots of licensed and investigational IGIV products, which prompted testing and manufacturing changes by industry to improve the safety of several other products.
OBRR has since then been working with the World Health Organization and other laboratories to ensure that tests for factor XIa done anywhere in the world will work the same way and give reliable results.
This work has also contributed to the ongoing development in CBER of a new lot release assay for immunoglobulin products.
These important contributions by OBRR illustrate the leading role the FDA plays in ensuring the safety and efficacy of the products it regulates. As FDA Commissioner Margaret Hamburg, M.D., put it when discussing the role of the agency: “The bottom line is that if FDA does not do its job, there is no backstop. Ours is a unique role, and it is critical that we do it well.”
Mikhail Ovanesov, Ph.D., is a visiting scientist in the Laboratory of Hematology in the Office of Blood Research and Review at CBER