Occasionally, companies advance directly from phase 1 to phase 3 registration trials, skipping phase 2. This approach has been used for investigational drugs that address a high unmet need (based on FDA guidance) but it is high risk and rarely used.
This strategy requires many preclinical and early clinical development studies to be performed earlier than when a standard phase 2 study is conducted. Data must be available from all required non-clinical toxicology studies, alongside comprehensive in vitro and in vivo microbiology data.
In addition, a phase 1 programme must be larger than a standard single ascending dose/multiple ascending dose(SAD/MAD) trial. For example, participants must be included whose physiology could impact on exposure and/or safety of the investigational drug.
There must also be reasonable grounds for assuming that a drug’s pharmacokinetics and pharmacodynamics (PK/PD), at the dose to be used in a phase 3 trial, are compatible with likely efficacy across a target population. Data must therefore be accompanied by comprehensive non-clinical PK/PD analyses, a robust population PK model, and Monte Carlo simulations to determine the probability of target attainment with a given dosing regimen.
Skipping a phase 2 trial may potentially shorten the duration and reduce the cost of clinical development, but it is associated with significantly higher risk to developers. It requires significant investment before any data regarding the safety and efficacy in patients are obtained, as these data will only be available at the end of phase 3 studies.