Early phase clinical trial protocols tend to become more and more complex, focusing on gaining as much scientific insight as possible. Multiple objectives are embedded into one single design. Today, in addition to safety assessments and pharmacokinetic (PK) sampling, pharmacodynamic (PD) read-outs are nowadays implemented as standard in phase 1 protocols. These PD assessments can come in different forms: blood or other body fluid samples followed by special assays, imaging or specific functional testing.
As a result, time critical PK and PD sampling and PD testing need to be integrated at specific post-dose timings. Also, some of the PD tests require the inclusion of specific populations related to the targeted disease. As a consequence, operational execution of early phase trials has become even more challenging.
Although a “perfect” protocol may have been created on paper, many study aspects need to be evaluated from a practical point of view. These include:
Despite timeline pressures, clear communication on content and operational feasibility is key to avoid issues. During a feasibility review and subsequent trial preparation, all worst-case scenarios need to be considered – as the laws of Murphy and Hofstadter also apply to clinical research. With some complex assessment schedules, it is often best to organize a mock test run.
Discover two interesting stories. The first one is about SGS conducting a feasibility review for a multiple dosing study, addressing challenges in age-related criteria. Compromises were made, highlighting the importance of meticulous assessments. In the second case, a US Biotech sought SGS for a phase 1 study on seasonal allergies. Thorough risk assessment and planning were crucial, emphasizing the pivotal role of meticulous risk assessment in successful early-phase clinical trials.
Case scenario
SGS reviewed a multiple dosing study designed to assess safety, pharmacokinetics and age effect.
The draft protocol of this multiple dosing study contained three different age groups: 18-50y, 65-75y, and >75y. After careful review, the team defined following criteria as not feasible:
Subjects among different age groups needed to be weight-matched
After an open discussion with the client, important compromises were implemented, without jeopardizing the scientific value of the data nor the recruitment and retention of the older population. In summary:
The weight matching was phrased more flexibly allowing a slightly bigger deviation
Case scenario
A US Biotech contacted SGS to perform a phase 1 study in healthy subjects with a seasonal allergy.
After a single ascending dose in healthy volunteers to assess safety and pharmacokinetics, the study included a second part to assess pharmacodynamic effects in healthy people with a seasonal allergy.
The pharmacodynamic tests consisted in a nasal challenge to provoke rhinitis, a skin prick inducing a flare and a food challenge inducing oral allergy symptoms. After a nasal challenge, different read-outs for rhinitis severity were combined using a symptom score card, peak nasal inspiratory flow and nasal aspirate for inflammation analyses.
As many allergic people have more than one allergy, the in- and exclusion criteria could not be too restrictive so as to exclude all co-allergies
In response to potential practical risks, a thorough review of the protocol was conducted, leading to the implementation of strategic measures.