In the world of bleeding disorders, choice is never simple

Debate over products—plasma derived (PD) versus recombinant—has been raging for a long time. A panel assembled on Tuesday afternoon to discuss this issue for the session, “Making a Choice: How to Determine the Optimal Choice to Treat PUPs.”

Cedric Hermans, Belgium, began by providing an overview. “Globally, severe hemophilia A patients only develop antibodies if exposed to FVIII. In less developed countries, patients are exposed later and less frequently and there are less options available as well as less research.”

The evolution of FVIII/FIX concentrates has mainly been driven by the need to improve infectious safety. Improvements have been successful and there have been no infection transmissions since 1985. But he cautioned that safety should remain a concern. “Improvement in immunological safety has been much less successful.”

Risk factors for inhibitors are driven by genetics and type of treatment. “Family history is critical since the type of mutation is clearly important,” said Hermans. “The intensity of treatment and type of concentrate also play a role.”

Strategies to reduce inhibitor development include starting prophylaxis at a young age to prevent bleeds and to provide exposure to factor.

Alok Srivastava, India, spoke to the use of PD in previously untreated patients (PUPs). “No concerns have ever been expressed about the efficacy of PD product as long as you use the recommended dosage. In the last 20 to 25 years there hasn’t been any transmission of documented infection. The manufacturing industry has greatly reduced the chance of transmitting any know infectious agents.”

“The first priority is the adequate quantity of safe clotting factor concentrate (CFC). Once adequate quantity is achieved, consider options for type of CFC,” he said. “The cost of recombinant is nearly double of PD.”

Srivastava said that there is little experience in the world regarding the use of recombinant products with PUPs. “Using any safe product is better than using none.”

“The rationale for developing recombinant products was that they would be safer than PD counterparts,” opened Steven Pipe, USA. “Consistent manufacturing and processing liberated us from the uncertainty of securing source plasma. There is also a potentially unlimited supply.”

Pipe stated that over the last 20 years of clinical use of recombinant factor, there has been no infectious pathogen transmission and no evidence of increased rate of inhibitors in previously treated patients (PTPs). “Inhibitors in PUPs are common and are considered a natural immune response to a foreign protein,” he said. “It is commonly accepted that product-related immunogenicity is best assessed by using PTPs.”

He said that there are conflicting reports from pivotal studies and other forms of data collection. Some suggest no difference between PD and recombinant forms. You need to look further into the research to really see what was being assessed. “Some studies are non-homogenous, the length of the study is different, some include only severe populations, gene mutation types are not aligned, what is the ethnicity and therapy regimen and are they prophylactic or on demand use.”

“The SIPPET study looked at PDFVIII/VWF versus rFVIII,” Pipe said. “There was a significant increase in inhibitor development in the rFVIII treated patients. But a large proportion of patients had gene mutations associated with increased inhibitor risk and half the patients were treated on demand.”

He also pointed out that only 16 percent used third generation rFVIII. “The data doesn’t address any of the newer recombinant products being used in the US. It is not a head to head product comparison.”

Julie Malan, South Africa, spoke from a mother’s point of view about the choice her family made to select a recombinant product.

With no known family history of hemophilia, her 6 day-old son received a diagnosis of severe hemophilia. “We needed to get him FVIII and only plasma derived product was available in South Africa. We weren’t given any choice,” Malan said.

The majority of patients are state patients in South Africa and do not have a choice. “All plasma products have an intermediate purity,” she said. “Even on medical insurance, not all patients are guaranteed the option of using a recombinant product. And the one recombinant product available is double the price of plasma.”

After a scare that her son was Hepitis C positive—later finding out he wasn’t—she asked her hemophilia treatment center about recombinant product. “My choice was made by the fear I experienced,” she said. “I still fear the unknown viruses. Changing to recombinant gave me peace of mind and since we have insurance the choice was there. It is not a choice most South Africans have.”

Speakers on both sides of the issue supported their stance with data. The debate of this complex issue is not yet settled.