Masterstudiengang "Drug Regulatory Affairs"


European and German Regulatory Requirements to the Design and Validation of Nucleic Acid Tests for Blood Screening ***

Sabine Wolf (Abschlußjahr: 2010)

Language: English
Serological screening assays testing blood donations for antibodies to blood-borne viruses have greatly reduced, but not completely eliminated, the risk of transmitting viral infections by blood or blood products. Transmission of virus still occurred due to donations made during the pre-seroconversion period, i.e., the time between the infection of the donor and the rise of antibodies to the virus in its bloodstream, or by carriers who do not seroconvert or who lack antibodies to epitopes detected by the immunological assays.
A significant number of such window case donations could be detected and removed from the blood supply since the implementation of nucleic acid testing, first by means of Polymerase Chain Reaction (PCR), in 1999. Between 1999 and 2007, in Germany alone, 103 transmissions were prevented.
However, ten years ago the nucleic acid technology was still in its infancy and implementation in routine was facing major hurdles. None of the commercial PCR tests were approved as an in-vitro diagnostic test, let alone validated for screening purpose. The PCR tests were largely manually requiring highly trained personal, separate rooms for sample preparation, amplification and detection, throughput was low, costs immense and the rate of false positives results high.
Enormous and sustained efforts were made by authorities, blood banks and test manufactures in order to ensure the safety of the blood supply, and to restore the confidence of patients in blood products.
The quality and performance of an assay is primarily determined by its design. IVD manufacturers of NAT developed a variety of innovative solutions to minimize the technology inherent risks and limitations and set up completely new control concepts to handle residual risks. Today, fully automated systems are in place, which allow for high throughput of samples within a closed system, minimizing human failures, improving control for contamination and resolving the space restrictions of earlier times.
Even with all such innovations in place, a residual risk for breakthrough transmissions cannot be completely ruled out. The main challenge for IVD manufacturers are new virus variants that continually emerge making global surveillance for new mutations and continuous evolvement of primer and probes indispensable.
Authorities on a national and European level, from the diagnostic and pharmaceutical domain, they all developed validation guidelines for nucleic acid tests, trying to address the possibilities, challenges and risks of this technology. Especially criteria for performance evaluation were defined and analytical sensitivity limits were specified. With fully automated tests systems in place today, the numbers of samples to be tested for the determination of the analytical sensitivity and the diagnostic specificity could now be adapted in order to substantiate the analytical claim by acceptable confidence intervals. Further on, the analytical sensitivity of nucleic acids tests has been improved in the past ten years by a factor of five to ten and would allow an adaption of the sensitivity limits as viral dynamics during early infections suggest. However, respective changes of the CTS and national legislations are currently not envisioned.
The safety of the blood supply is a highly sensitive area. Especially since the HIV and HCV transmissions in the eighties and nineties, it is also of high interest by politicians and public. This is all the more surprising as in-house nucleic acid tests used for blood screening do not necessarily need to comply with the requirements laid down in the IVD Directive and as blood donations for transfusion do not necessarily need to be tested with nucleic acid methods.
Due to the free movement not only of goods but also of citizens throughout the Community territory, a common level of safety for all kind of blood products by including nucleic acid testing to the testing requirements of Annex IV of the Directive 2002/98/EC would be highly appreciated.