Red blood cell substitutes: evolution of approaches to demonstrating efficacy

There has been a striking advancement in our understanding of red cell substitutes over the past decade. Throughout this period, regulatory oversight influenced many aspects of product development. The approach to demonstrating efficacy was an important example. I will review some events of the decade so that we may consider the question, "If we had it to do over again, could we do any better?" At the start of the decade, there were sufficient data on the mechanism of hemoglobin-induced renal toxicity to reach consensus among investigators that the content of alpha beta-dimers in any hemoglobin product must be strictly limited. An array of additional, unexpected reactions were seen in early clinical studies, reactions that led to several conclusions: hemoglobin is a pharmacologically active material; more basic studies are needed; and it would all be so much easier if communications between investigators were open and unhindered. Meaningful studies of efficacy could not be approached until the safety issues had been solved or until the community was convinced that they were not serious. The initial approach was based on the meager experience gained with previous products, e.g., Fluosol. That experience led to policies which required that, for example, if the product was to be used as a red cell substitute, it must be compared with red cells, and if it was to be used as an oxygen carrier, it must be shown to support organ function. Endpoints of clinical trials were based on delivery of a clear clinical benefit to the patient--surrogate endpoints could be used only if their relationship to clinical benefit had been demonstrated.