There are numerous interested and experienced parties that could be assembled into a network of clinical centres to conduct small, short-duration, early-stage, proof-of-concept studies focused predominantly upon mechanistic outcomes, in order to permit a more rapid assessment of the clinical viability of find more a novel combination. Combinations that show

clear evidence of modulation of the immune system would be prioritized for more comprehensive clinical evaluation with C-peptide preservation as the preferred outcome. JDRF, through its Autoimmunity Centers Consortium [28], is currently assessing the feasibility of establishing such a network. Clearly, combinations that will be supported by industry and can navigate the regulatory process successfully will be those for which there is a compelling argument in terms of both efficacy and safety. In addressing the safety of the combinations, several key strategies can be applied to minimize the risk of harmful interactions between agents. Limit to two agents.  First, combinations should be limited to two agents. Both

agents may be immunotherapeutics, or one immunotherapeutic and one drug with an alternate mechanism – one that stimulates β cell regeneration, for instance. For reasons stated above, approved agents (or those nearing approval) would have initial priority for development in combination therapies. Independent/complementary mechanisms.  In the case of two immunotherapeutics, combinations should be selected such CP-690550 in vivo that individual agents work via mechanisms that are significantly different, so that safety 4-Aminobutyrate aminotransferase profiles could be considered as, essentially, independent. For instance, combining an antigen-specific therapy and a non-specific therapy would have a reduced theoretical likelihood of resulting in hitherto unrecognized side effects. Antigen-specific therapies in general are regarded as a safer treatment modality, with fewer systemic risks associated

with them, and so should be priority considerations for initial combination trials. Safety in protocol design.  Designing safety into clinical protocols is critical and there are a number of steps that can be taken to reduce the risks of harmful drug interactions. For instance, design of a protocol that uses sequential, rather than simultaneous, treatment would be preferred. Similarly, the dose of one or both of the drugs may be reduced in the combination protocol to increase the safety profile. In designing the protocol, implementation of these strategies can be guided by available pharmacodynamic data on each of the agents. With these considerations in mind, the Assessment Group listed and prioritized combination therapies (Table 1) with the understanding that developments in preclinical (combination safety and efficacy) testing and/or ongoing clinical trials could subsequently affect the relative ranking.

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