December 26, 2007
Jaroslav G. Vostal, MD, PhD
Laboratory of Cellular Hematology
Division of Hematology
Office of Blood Research and Review
1401 Rockville Pike, Suite 200N
Rockville, MD 20852-1448
Dear Dr. Vostal,
I am writing on behalf of the AABB Bacterial Contamination Standard Task Force. We urge FDA to modify its current regulatory approach and thereby facilitate the availability of point-of-release assays (e.g. Verax PCD and other such assays) for pre-transfusion quality control testing of platelets derived from whole blood near the time of issue for transfusion.
It is the opinion of the Task Force that the agency’s intention to require a manufacturer to pursue approval as an adjunct to culture-based quality control testing is inappropriate. As we understand the current situation, the FDA is willing to consider clearance of a device for stand alone use only after demonstration of substantial equivalence to culture-based testing. We think this is more extensive than should be needed for a de novo quality control claim. This approach is burdensome and will delay the availability of what we believe is an important improvement in blood safety.
The apparent reason for this path to approval is FDA’s determination that a culture-based test, as is used on apheresis platelets, is the predicate device for an application for a point-of-release bacterial detection assay for pooled platelets. We disagree vigorously with this position. In a practical sense, the predicate device for the PGD test is the approach that is actually being used in hospital transfusion services. This is primarily measurement of pH or glucose with urine dipsticks, pH meters or other devices that were never cleared for this indication and have been shown to be insufficiently sensitive to allow detection of bacteria in many cases. In addition, these test methods are nonspecific and result in the discard of many safe units of a product often in short supply. With use of the current “predicate device”, there are two different levels of safety for transfused patients based on whether they receive apheresis platelets (safer) or pooled platelets from whole blood (less safe). This situation should not be acceptable as it endangers patient welfare. It will be corrected when tests like PGD, that are sufficiently sensitive and used near the time of issue at the point-of-release, are cleared by FDA.
We understand that there is an approved system allowing pooling and storage of whole blood derived platelet concentrates that allows use of culture-based testing early during storage. This system is not in wide use due largely to the requisite training, validation, implementation and quality control aspects of its adoption, especially in centers currently using bags from other manufacturers. Individual platelet concentrates are not cultured early in storage because the sample volume required would compromise the therapeutic benefit of the product and because the number of cultures required would overwhelm facilities and resources available in any reasonable scenario. Therefore, a culture-based system can not be considered a predicate device for the vast majority of whole blood derived platelets transfused in the real world.
The Task Force believes that the simple demonstration of acceptable sensitivity at an agreed upon threshold with the Verax device (or another point-of-release assay), when used as intended near the time of platelet issue in the hospital transfusion service, should be sufficient for approval as a quality control assay. Spiking data should be adequate for these studies. Post-marketing surveillance can be used to assess the specificity of positive results on a point-of-release assay, and to provide data about septic reactions associated with their use.
An alternative approach for the blood community is prohibition of the use of glucose and pH measurement, leaving the blood community only with the off-label use of the Verax (or subsequent point-of-release assays) to meet AABB Standard 22.214.171.124. This does not harmonize with FDA’s publicly stated commitment to evidence-based regulation nor will it stimulate the blood community to do the appropriate studies that AABB agrees are ideal for validating these tests prior to their widespread use. However, we believe that off-label use can be rationalized and will be adopted if the regulatory burden delays approval of a point-of-release test with analytical sensitivity three to four orders of magnitude better than currently used surrogate testing methods.
Therefore, we urge the FDA to adopt a different regulatory approach that will lead to an improvement in the safety of platelet transfusions in the United States.
Louis M. Katz, MD
Chair, AABB Bacterial Contamination Standard Task Force
CC: Jonathan C. Goldsmith, MD
Jay S. Epstein, MD
Jesse L. Goodman, MD