Innovative treatment approaches for rheumatoid arthritis. Issues in clinical trials of biological agents

Biological agents have pointed out directions for future research, although none yet are therapies to be employed in the clinic. To date we have administered them at pharmacological; even industrial-strength doses, without demonstrating the desired cell- or diseased-specific effects. There are many issues specific to the clinical development of biological agents which distinguish them from pharmaceutical products. Most are immunologically active; early trials are performed in patients with disease, rather than normal volunteers. This poses multiple challenges: access to an appropriate patient population, as well as effecting immunomodulation without interfering with normal immune surveillance. Species-specificity of the agent may limit the use of preclinical animal models, and the duration of toxicology studies. Immunogenicity may preclude regular re-administration, necessitating prolonged benefit after single or limited treatment courses. Parenteral administration requires more careful monitoring, limits access to the agent, is associated with more expense, and may contribute to the high observed placebo response following treatment with biological agents. Requirements, and our expectations, for clinical benefit are therefore higher with these products than with traditional pharmaceuticals. Despite a scientific rationale and the use of biological markers, it is unlikely that development of a biological agent for the treatment of a chronic auto-immune disease can progress significantly faster than for a traditional pharmaceutical product. It is therefore important, particularly in the treatment of chronic RA, to develop a careful and rational step-by-step clinical development programme and to define the goals of the therapy: anti-inflammatory or symptom modification versus disease modification. Some biological agents may be expensive but safe NSAIDs. Others may treat disease flares. After 'induction therapy', utilizing a biological agent, followed by 'maintenance therapy' with a traditional DMARD agent, we may envisage 'combination chemotherapy', employing multiple biological products targeting different specific immunological aspects of the disease. We must therefore develop biological agents utilizing rigorous clinical trial principles, and follow suggested guidelines.