FDA approach to evaluation of pathogen reduction technology

Pathogen reduction (PR) is a novel approach to decreasing pathogen transmission by blood transfusion. It has the potential to inactivate a broad range of pathogens that could be found in donated blood products and thus it would complement existing methods to prevent or decrease the presence of pathogens. The current methods include donor selection, skin disinfection, diversion of initial collection, and testing for specific agents. The concept of PR holds great promise. Ideally, PR methods should inactivate all pathogens found in blood products, not damage the transfusion product, and be safe to be administered to all patients. In reality, PR methodology is in its infancy and has yet to reach its true potential. In their current form, PR treatments are unlikely to sterilize the transfusion product. This results from large loads of certain pathogens that could overwhelm the capacity of the treatment, resistant forms of pathogens, inaccessible pathogens due to interference from storage bag geometry, poor light energy delivery due to interfering substances, and the potential for human error during processing. The PR methods are not strictly pathogen specific and produce collateral damage to the transfusion products that is often evident by the decreased retention of these products in circulation. In addition, the toxicity of PR chemicals and their metabolites and adducts may not be realized until a large-scale patient population is exposed to them. The FDA will evaluate PR treatments for their efficacy in decreasing pathogens in blood products, their effect on the transfusion product, and their safety to the recipient of treated products. Efficacy of the PR treatments will need to be established. One way may involve in vitro experiments where pathogens, relevant to transfusion-transmitted diseases, will be added or “spiked” into full-size blood products. The artificially contaminated products would then be treated with the PR method and the level of pathogen inactivation quantified at the end of the storage period. For viral pathogens, sufficient experience has been collected over the years from plasma product viral reduction steps so that model viruses could be used to demonstrate efficacy. Table 1 lists commonly used model viruses and their physical characteristics for a panel of transfusion-relevant viral pathogens.1 For bacteria (Table 2), a list of potentially relevant pathogens was developed through discussions with the FDA Blood Product Advisory Committee2, 3 and at the PR workshop.1 The list is based on published reports of the relevant bacterial species found in blood products that have been used to evaluate devices for detecting bacteria in transfusion products.4 In addition, protozoal organisms such as Trypanosoma cruzi, Babesia sp., Plasmodium sp., and Ehrlichia sp. may also be used in the evaluation.1 A demonstration of efficacy against as wide a list of pathogens as possible will be desirable, because this will serve as the basis of the PR treatment labeling at the time of approval and will support its use in the future against emerging pathogens in the blood supply. The in vitro testing may be used to define the maximal load of the pathogen that the PR treatment could reduce. Ideally the PR treatment would have the ability to reduce the pathogen load in a blood product by 6 to 10 logs.1 This level of efficacy was suggested at the PR workshop as the appropriate range, because some viral titers in the window period of infected donors can reach levels of 108 to 1010 geq per mL.1 In some cases, the amount of the pathogen that can be grown or sustained in a blood product will limit the range that can be used to demonstrate reduction by the PR treatment. In certain cases this may be surmounted by the use of virus-infected primate models to define the efficacy of the PR treatment in a transfusion-mediated transmission during the window period.5 The demonstration of efficacy in preventing disease transmission in a clinical setting may not be feasible. Such studies would follow the infectivity rate in a patient population transfused with PR-treated products and compare this to a control group that receives untreated blood products. The size of this type of clinical study would have to be extremely large due to the current low rate of disease transmission achieved by current practices including the introduction of NAT. Moreover, there are many sources of infection in patients that require transfusions and not all types of transfusion products would undergo PR treatment. Thus, demonstration of in vitro efficacy of the PR treatments will be sufficient. There may be alternate ways of evaluating the efficacy of these treatments by following transmission of viruses not associated with any disease, but so far such studies are only at the discussion stage.1 The PR chemicals may have many sites of interaction with the cellular and plasma components of the transfusion product. The chemical may crosslink with lipids in the plasma membrane or in membranes of cellular organelles and with proteins involved in cellular signal transduction pathways, respiratory pathways or structural components. The effect of the bound PR chemicals on the function of the transfusion products may range from negligible to alterations that may critically compromise them. For currently licensed PLT and RBC products there is a long history of evaluating optimal in vitro characteristics and responses that would predict in vivo performance.1, 6,7 It may be possible to apply these methods to evaluation of the PR treatment effect on the transfusion product to eliminate the PR methods that clearly damage the products. Unfortunately the results of in vitro tests do not correlate closely with in vivo performance and full evaluation of these products will need to rely on clinical studies to evaluate subtle levels of damage. Possible approaches may involve radiolabeling of PR-treated cells, infusion into autologous donors, and monitoring of the recovery and survival of the treated cells in circulation. These suggestions are based on the underlying assumption that damaged cells will be recognized by the body's own surveillance system and be cleared efficiently. Cells with minimal damage should be able to remain in circulation in a time frame comparable to healthy untreated cells. The ultimate goal of the evaluation would be to determine whether the PR treatment has compromised the clinical efficacy of the transfusion product. The performance of the PR-treated products in particular clinical situations could be evaluated in Phase 3 clinical trials that are adequately powered to detect differences in the appropriate clinical endpoints. For PLT products, the trials could evaluate the maintenance of hemostasis in thrombocytopenic patients, while for RBCs the trials could evaluate delivery of oxygen to tissues in chronically transfused patients or in surgical patients requiring a short-term transfusion support. The PR chemicals bound to proteins, lipids, and nucleic acids in the transfusion product create new biologic entities (novel biologic products). The safety of such new entities needs to be evaluated, initially in animal studies involving several species and eventually in humans. Because some patients will be chronically transfused with treated products, while others may receive a very high number of treated products at once, it would be appropriate to study both acute and chronic administrations. The PR chemical is, by design, capable of interacting and permanently modifying nucleic acids. It is often mutagenic in in vitro tests and thus has the potential of being genotoxic, carcinogenic, and toxic to the reproductive system. Animal models would be used to assess these characteristics.8, 9 The occurrence of unexpected toxicities and immunologic reactions to the novel biologics are special areas of concern. Because of the novel nature of the PR compounds and the PR chemical-biologic combination, the toxicity in humans may not be predicted by current standard tests. This suggests, if no toxicity is identified in Phase 1 and Phase 2 studies, that careful monitoring of toxicities or adverse events in Phase 3 trials would be needed. It is possible that the frequency of such toxicities would be very low in a given patient population, and Phase 3 trials may not be large enough to detect these. An after-market study (Phase 4) to collect data on a large and diverse patient population may be appropriate once PR-treated transfusion products are introduced into general use. Approval of PR treatments will depend on consideration of the benefits and the risks of using the treated transfusion products. The benefits will include a reduction in the risk of transfusion-transmitted diseases, but the toxicities associated with each particular PR treatment, either directly identified or theoretically based on the nature of the PR chemical, will need to be considered. However, the risk of transfusion-transmitted diseases is a moving target that has been shrinking dramatically with application of better donor selection, better blood collection practices, and improved testing of the collected product.10, 11 Although the current risk from bacterial pathogens is higher than for viral pathogens, this risk will most likely also decrease with advances in detection technologies.12 Thus, the added risk from a PR treatment needs to be sufficiently lower than the risk from infection to justify its use. The eventual outcome of a risk to benefit assessment is a determination that the product is safe for its intended use and may change based on different intended uses or patient populations. For example the risk to benefit ratio could change in favor of a PR treatment when a novel and/or unknown pathogen is identified as being transmitted by transfusion. It is unlikely that testing will be in place for a novel pathogen to detect its presence in transfusion products. In these cases, the availability of a PR process that could inactivate the pathogen would be desirable and its use could be justified against an emerging threat to the blood supply. A recent example of such a situation could have been the rapid spread of West Nile virus in the US between 2001 and 2003.13, 14 In the short term, it is highly unlikely that PR will generally replace testing of blood products by currently approved tests. The PR technologies will initially be unproven in a clinical setting and the processes will potentially be susceptible to user error. However, as clinical experience with the PR processes accumulates this issue may be revisited. So far no single PR treatment is being studied to treat all types of transfusion products. Some may be effective for RBCs while others might only be used on PLTs. When the treatments are all approved, a single patient could receive several different PR-treated products. The toxicity of these modified products and possibly the residue of the inactivating products may be additive when coadministered and thus future evaluations of toxicity will need to consider these possibilities. PR is a promising novel technology that will complement existing procedures aimed at limiting the presence of pathogens in blood products. Each PR method will be evaluated for efficacy in reducing pathogens and for safety to the recipient of the treated products. The FDA will approve methods with favorable risk to benefit ratios that may be appropriate in the general patient population, or in particular patient groups or clinical circumstances.