Another Layer of Safety for the Blood Supply

Cerus has received European regulatory approval for a pathogen inactivation system that its president describes as the first "prospective" approach to blood safety. Cerus and marketing partner Baxter plan to launch the device in Europe by year-end. The device inactivates all pathogens in platelets, in contrast to existing blood screening tests, which look for specific infectious agents and don't address the risk of emerging pathogens. The partners have a long series of hurdles to overcome, not least of which is the difficulty of convincing potential buyers to pay more for a technology that addresses theoretical risk.

Guardians of the world's blood supply live in perpetual fear of the next AIDS or hepatitis C virus (HCV)—blood borne-diseases with the power to kill that lurked hidden and latent in donor blood. Thousands of blood transfusion recipients were infected with these deadly diseases before the pathogens were identified.

Today, the blood supply is largely safe from these infectious agents, thanks to measures both mandated by the FDA and European regulatory agencies and adopted independently by blood banking centers. These include identifying—based on behavior and lifestyle—risky donors who may be infected and eliminating them from participation in donation programs. Blood banks also run donated blood through a series of sophisticated and sensitive diagnostic screens for infectious agents. Moreover, most Western countries recently began to require blood banks to perform nucleic acid-based tests (NAT) capable of detecting extremely low levels of HIV and HCV in donated specimens.

Now, Cerus Corp. and its development and marketing partner Baxter Healthcare Corp. (a division of Baxter International Inc. ) have received European regulatory approval for a pathogen inactivation system that Cerus president Stephen Isaacs describes as the first "prospective" approach to blood safety [See Deal]. The partners plan to launch in Europe by year end a product that they claim broadly inactivates all pathogens in platelets—both known and unknown—with a technology that keeps cells containing DNA and RNA from replicating. Isaacs contrasts this approach to blood screening, which is designed to look for specific infectious agents and doesn't address transfusionists' fears about emerging pathogens.

Pathogen inactivation could potentially kill unknown pathogens, as well as rarer pathogens not currently tested for under today's probabilistic blood screening paradigms—malaria, tick-borne disease babesiosis or parvovirus, for example. So far, Cerus has documented the successful inactivation of 17 different pathogenic bacteria, including gram-negative and gram-positive, envelope and non-envelope viruses, and a wide variety of parasites, says Isaacs.

The Intercept system received the European CE mark in early June for the decontamination of platelets, one of three separate blood components (including red blood cells and plasma) used in transfusion medicine. Platelets play an important role in the clotting process and are administered to patients experiencing massive blood loss, or bleeding, usually due to chemotherapy or cardiac surgery. Intercept uses a small-molecule derivative of natural compound psoralen, in conjunction with a compound-activating ultraviolet light source, to inactivate DNA and RNA-containing cells in blood, which makes the process selective for pathogens, and also leukocytes. The latter can cause unwanted immune reactions, so inactivating them provides an additional benefit. On the other hand, Intercept won't harm red cells, plasma or platelets themselves, since these don't contain nucleic acids.

Baxter's Dean Gregory, head of global commercialization for Intercept, says that ease of use is an important factor in influencing adoption of the product. In the past, blood banks have held back from using cumbersome blood safety processes, for example, a solvent detergent method for decontaminating plasma, which received FDA approval in 1998. The Intercept process involves only a few steps. First, platelets are diluted with an additive solution and dosed with psoralen derivative amotosalen, a procedure not unlike transferring blood from one bag to another—something blood banking personnel routinely do. The mixture is subsequently illuminated with ultraviolet light for six minutes. Light degrades the drug to photo byproducts, and a filter in the bag absorbs them, to make sure that no compound or byproduct remain in the platelets when they are transfused into patients.

Clinical trials of the pathogen inactivation agents, both in Europe and in the US (where Cerus has completed Phase III and initiated its modular Pre-Market Approval (PMA) filing), are designed to demonstrate the safety of Intercept, rather than its efficacy at inactivating particular infectious agents. The European regulators wanted Cerus and Baxter to prove that treated platelets are as viable and as effective at controlling bleeding in patients as untreated platelets. The companies did this successfully, achieving a major triumph for the field of pathogen inactivation—in which future potential competition includes VI Technologies Inc. (Vitex), Gambro BCT , and Amersham Biosciences (formerly Amersham Pharmacia Biotech), among others. Vitex provides the closest competition for Cerus and Baxter in the red blood cell market—it recently initiated pivotal phase III trials in the US for its Inactine pathogen reduction system for red blood cells; Cerus and Baxter are also in Phase III with an Intercept red blood cell product.

However, the Cerus/Baxter milestone is only the first in a long series of hurdles for the company. They must now obtain separate regulatory approvals of their Intercept processes for other blood components in Europe and the US, as well as gain acceptance in the complex and unpredictable blood banking market.

Founded in 1991 with technology licensed from the University of California, Berkeley , Cerus, and its partner since 1993, Baxter, have invested pharmaceutical-like development resources in the Intercept system. Isaacs reports that the two companies have spent more than $100 million to develop three Intercept products, including conducting clinical trials on more than 700 patients for the platelet product (103 for the CE mark, and 645 for the US PMA). In return, the partners hope to operate in a $3 billion pharmaceutical-sized market, based on annual transfusions of 4 million units of platelets, 7 million units of fresh frozen plasma, and 7 million units of red blood cells, in the US, Western Europe and Japan.

However, particularly in the US, the blood banking market is in many ways far more complex than pharmaceutical or medical device markets. To succeed, Cerus and Baxter will need to convince buyers to pay extra for blood safety benefits that are difficult to measure—that is, the elimination of theoretical infection risk. Blood centers will pass on the costs of these additional safety features in terms of higher per unit blood costs to the end users, the hospitals and transfusion centers. Cerus is expecting to capitalize on Baxter's clout in the blood banking market. Under a revenue sharing agreement, Cerus provides small molecule inactivation agents and Baxter contributes marketing, as well as devices and components for blood collection, processing and storage [See Deal]). Cerus and Baxter have already begun educating the multiple transfusion constituencies about the benefits of pathogen inactivation—approximately 200 non-profit blood banks in the US, hospitals, and also particular clinical specialties that use platelets heavily—hematology-oncology physicians, cardiothoracic surgeons that perform a large volume of coronary artery bypass grafts, and orthopedic surgeons. The companies hope to soon bring in revenues from Europe, where blood banking is largely controlled by government agencies, and where there are therefore fewer constituencies for the sales effort to target.

Ultimately, Baxter's Gregory argues, a product that broadly inactivates pathogens should become the first step in blood safety assurance, one that could eventually obviate the need for some of the expensive tests now used for blood screening. Initially, however, Baxter is positioning the system as an additional layer of safety to further reduce risk of infectious disease transmission from the blood supply. In addition to safety benefits, Cerus and others argue that the economics are favorable. Today, Isaacs explains, a single test, the P-24 antigen test, for example, can add several dollars to the cost of a unit of blood. In the future, a clinically proven pathogen inactivator may reduce the number of tests needed to ensure the safety of blood. The availability of an effective decontamination product could also shift product mix to less expensive products.

Finally, a decontamination product could potentially increase the number of donors eligible to give blood. The blood supply is safer than ever, says Richard Davey, MD, medical director of the New York Blood Center, but the trade-off has been less available blood. The recent FDA-mandated restrictions on potential donors who spent as little as three months in Europe aims to protect the public from the theoretical risk of Mad Cow Disease. But it has also severely reduced the number of eligible donors in the New York area, he says. The pathogen inactivation companies hope that widespread use of their systems will open the gate for donors who are currently deferred from giving blood because of their personal histories, increasing blood supplies and reducing the need for blood centers to spend money to recruit additional donors. It costs approximately $50 a head to recruit donors, says John Barr, president of Vitex.

Still, Davey's concerns are an example of what Cerus and Baxter may be up against. He agrees that the safety benefits are compelling, but notes that improved viral screening has raised the safety of the blood supply, raising the cost-effectiveness hurdle for new blood safety technologies that provide incremental improvements. Davey believes cost savings aren't likely to be realized from the elimination of current diagnostic tests, at least not for many years. "The FDA doesn't operate that way," he says.

Indeed, although the price hasn't yet been announced, Isaacs estimates that Intercept will initially add 10-15% to the cost of a unit of platelets, now about $500 for single-donor platelets, and $300 per unit for pooled platelets. Vitex's Barr says that the Inactine process could add more than $100 to the cost of a unit of red blood cells, which today averages $130.

Increases in blood costs have a tremendous impact on hospitals, particularly since more than 30 percent of all hospital admissions require blood transfusion support, according to a report by America's Blood Centers, an association of independent blood centers that handle 50% of the nation's blood supply. (American's Blood Centers' "Blood Counts," Vol. 3, No. 1, Spring 2002, "Inpatient Reimbursement May Improve for Blood and Blood Components for Transfusion.") Fortunately, Cerus and Baxter and their peers in the blood safety industry, and hospitals should benefit from recent changes in reimbursement for blood products. The Centers for Medicare and Medicaid Services recently proposed a new index and weighting factor for blood products that permits increases in blood utilization and/or prices to be reflected in increases to be applied across medical DRGs.

Cerus and its competitors are also heartened by the rapid adoption of NAT, introduced several years ago for HIV and HCV by Chiron Corp. , which has FDA approval for its Procleix HIV-1/HCV assay, and Roche , whose tests are approved in Europe and available in the US under an IND. These tests are more specific than traditional immunoassay-based assays because they identify the presence of the viruses themselves, rather than antibodies that develop in response to viral infection. Immunoassays, on the other hand, yield false negatives for recently infected donors who haven't yet developed antibodies.

But NAT also has limitations—the first generation tests can't be done within a practical time frame on high volumes of individual samples. Thus, they are run on pools of donated blood—combined samples from individual specimens. The process is laborious, and expensive, and less sensitive than individual unit testing. There have been reports of individuals infected by blood that has undergone nucleic acid testing. The recent news that two transfusion recipients in Florida have contracted HIV from donor blood that had been tested with NAT suggests, the pathogen inactivation companies point out, that there is a need for new blood safety technologies.

Despite NAT's drawbacks, political and public pressures have dictated its implementation. NAT is mandatory in blood centers in Europe and, while not mandated by the FDA, is nevertheless used by most blood banks in the US. Cerus and Baxter are hoping that the same pressures driving demand for imperfect NAT tests will fuel interest in their product.

These days, high cost of the new blood safety technologies is receiving close scrutiny at industry meetings. Michael Busch, MD, PhD, vice president for research and scientific services for the Blood Centers of the Pacific, speaking at Cambridge HealthTech Institute's "Blood Safety and Transmissible Spongiform Encephalopathies" conference in February 2002, estimated that NAT HIV and HCV testing in conjunction with the current FDA-mandated battery of tests adds $5-$10 to the cost of a unit of blood, or approximately $2.7 million per quality-adjusted life year saved. The New York Blood Center's Davey explains, "Our profession has been living under the shadow of the AIDS crisis in the eighties. The general feeling has been, ‘Blood safety at any cost.' But now those expenses are becoming burdensome, both in terms of a reduction in the blood supply and financially." Because of the additional costs of manufacturing processes, equipment, reagents, and the need, in some cases, for toxic waste disposal, the widespread adoption of pathogen inactivation technologies won't be a "slam dunk."