After contamination of factor concentrates with blood-borne viruses, U.S. FDA requirements for new product licensure was based on the safety and efficacy of new biologicals as determined in previously untreated patients (PUPs). While PUPs provided an excellent model for assessing contamination of new products HIV, hepatitis, and other blood-borne viruses, they were not a good model for risk of inhibitor development, since inhibitor development in one form or another was unpredictable and occurred in up to 30-35% of PUPs. More recently, the Factor VIII & IX Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis has recommended that inhibitor induction potential of new factor replacement products is best studied in previously treated patients (PTPs). At the conclusion of the five-year study of 73 PUPs on Recombinate (Baxter) [Bray GL, Gomperts ED, Courter SG et al. A multicenter study of recombinant factor VIII (recombinate): safety, efficacy, and inhibitor risk in previously untreated patients.

Blood
1994
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83
:
2428
–35.
], the Data Safety and Monitoring Board (DSMB) independently initiated a five-year follow-up to determine how many new inhibitors occurred, and how many transient inhibitors recurred during this time. Data collection was a simple form to determine presence or absence of inhibitor yearly; if an inhibitor was reported to develop, did the subject remain on Recombinate or use other recombinant factor concentrate, and the inhibitor titer. Sixty-five of the original PUPs had data reported. For all 5 years, there were 21, for 4 years, 20, for 3 years, 5, for 2 years, 9, for 1 year, 10. For the 65 who have provided adequate data: Two subjects had a recurrence of their transient inhibitor with titers ranging from 0.78 to 1.3. They both stayed on Recombinate. They lost these inhibitors over the ensuing two years. Three subjects developed a new inhibitor. Their titers ranged from 0.9 to 4 Bethesda units. All stayed on Recombinate. None of these inhibitors were of high titer (>5.0 BU). These patients are PTPs, and on continued recombinant factor replacement, few new inhibitors occur, and those that did were low-titered, and some that disappear recur. Thus, five-year follow-up does not tell the whole story and continues to raise the issue of how many inhibitors are acceptable to regulatory agencies for licensure of a new product.

Topics:
follow-up, concentrate dosage form, post-thoracotomy pain syndrome, protein tyrosine phosphatase, biological products, factor viii, hemostasis procedures, hepatitis, recombinant antihemophilic factor viii, thrombosis
2005, The American Society of Hematology
2004
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