Lessons learnt from TEGENERO: How the study design of first in man studies for biological molecules has evolved

Isabelle Pouliquen, Daren Austin. GSK, Stockley Park West, Uxbridge, Middlesex, UB11 1BT, UK.

Introduction : Back in 2006, events caused by the administration of an anti-CD28 antibody, TGN1412, prompted the pharmaceutical community to revisit the principles governing the administration of biological compounds for the first time in human (FTIH) subjects to ensure the safety of the volunteers enrolling in these trials. Particular attention was paid to immunomodulatory compounds.

Methodology : All study designs for FTIH studies conducted by GSK since 2006 involving biological compounds were reviewed. The type of design; single dose and/or repeat dose; the population selected; the type of target, the type of molecule, the starting dose, the range of doses investigated, and the dose escalation process were reviewed, summarised and contrasted with historic data for small molecule studies.

Results : Nine studies were conducted during the defined period. These studies included metabolic, immune-inflammation, respiratory and neurology indications. Six studies were conducted in healthy volunteers, two in patients, whilst one combined healthy volunteers and patients. Starting doses ranged from 0.0004 to 1mg/kg and the dose range within a study ranged from 30-fold to 10,000-fold. In all studies, dosing to subjects was staggered over several days, ensuring only limited numbers of subjects were exposed to the active drug at a day. When more than one subject was dosed on a single day, administration was also staggered to allow assessment of the first subject. Placebo blinding was also maintained.

Conclusion : Following the TEGENERO incident, extra precautions were incorporated into the design and execution of FTIH studies. Whilst some of these are generic, others are specific to biologicals. The widespread introduction of MABEL-based starting doses has driven the starting dose lower, whilst blinded staggering has increased the use of placebo. In general, when compared with NCE’s, studies of biologicals have used wider dose ranges, more patients and much longer follow-up. Evolution of FTIH trial designs is expected to continue.