On April 18, 2019, FDA issued draft guidance on Bispecific Antibody Development Programs. Bispecific antibodies are genetically engineered, recombinant antibodies that contain two binding domains capable of binding two different antigens or two different epitopes of the same antigen. Bispecific antibodies may be useful for targeting multiple molecules with one drug and for bringing two target cells or molecules into close contact with one another, such as an immune cell and a tumor-associated cell.

The draft guidance highlights the need for a bispecific antibody development program and discusses general regulatory, quality, nonclinical, clinical, and scientific considerations for bispecific antibodies. FDA regulation on fixed-combination drugs for humans does not apply to the development of bispecific antibodies because bispecific antibodies are single molecules. Further, the established regulatory pathway for monoclonal antibodies, which bind only one antigen, may not address issues specific to bispecific antibodies. For example, an immune response to one domain of a bispecific antibody may inhibit one function of the drug but leave others intact. Still, many aspects of the bispecific antibody development program may be similar to monoclonal development programs

One challenge is that bispecific antibodies may exist in diverse formats designed to match the proposed mechanism of action and the intended clinical application. In vitro and in vivo pharmacology studies may be required to provide information on relative binding activity, avidity, potency, process-related impurities, stability, and half-life of bispecific antibodies. The draft guidance suggests that nonclinical studies are needed to characterize the pharmacology and toxicity of bispecific antibodies and to determine a first-in-human dose. Multiple assays may be required to measure immune responses to different domains of each bispecific antibody. Clinical studies may include a comparison of the bispecific antibody to the standard of care or placebo. A clinical study comparing a bispecific antibody with one or more monospecific products maybe particularly useful for determining the risk and benefit associated with the bispecific antibody. Throughout the draft guidance, FDA notes the importance of working closely with FDA to customize nonclinical and clinical studies for each bispecific antibody.