First-In-Man study

First-In-Man study (single ascending/multiple ascending dose study SAD/MAD) and how new investigational drugs are investigated for safety, tolerability and pharmacokinetic and pharmacodynamics PK/PD.

Following the pre-clinical (in vitro studies or animal models) testing, every new investigational drug product (IP) enters into clinical investigational stage, which aims to collect very early data on tolerability, safety, and examine the pharmacokinetics (PK) and pharmacodynamics (PD) profile of the IP obtained in healthy subjects.

First-in-man clinical studies are performed by the inclusion of healthy men and sometimes women (non-childbearing potential) aged 18-60 years. Usually, small group of study participants are involved: 24 – 48 subjects separated within cohorts. First-In-Man (FIM) studies or so-called pharmacological studies consist of two parts in a row – Single Ascending Dose (SAD)/ Multiple Ascending Dose (MAD).

This First-In-Man study Phase I (SAD/MAD) study on healthy volunteers typically aims to collect the following clinical data:

  1. General safety dose range of an IP and tolerance assessment on human subjects;
  2. QT/QTc prolongation evaluation from cardiac safety perspective.
  3. IP pharmacokinetic/pharmacodynamic PK/PD profile following a single dose administration and a multiple-dose regimen – provide valuable information on bioavailability and body compartment distribution of a drug;
  4. Entire metabolic pathways of an IP;
  5. Additional explanatory data for future clinical studies (Phase II- III multi-center studies performed on much larger population of patient participants, whereas, it aims to demonstrate or confirm efficacy and identify common adverse drug reactions);
  6. Optimization of final IP formulations and dose regimens.

The primary endpoint, however, for FIM studies or Dose-tolerance studies is determination of safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) profile of an investigational product. Single Ascending Dose and Multiple Ascending Dose first-in-human studies differs by the number of doses given to each clinical participant. In a SAD study, healthy volunteers are dosed only a single time, compare to a MAD study whereas each healthy subject receives multiple doses of the IP for a certain time period determined within the clinical study protocol within a specific dose range.

As already noted in dose escalation study we aim to estimate what dose can be given before any unacceptable toxicity is experienced by the study participants/healthy volunteer. For this reason, we initiate the dosing process by providing lowest possible dose, determined from the pre-clinical testing, to the first clinical subject scheduled in the first study cohort.  In regards to Single ascending dose studies, starting dose is discovered based on the pre-clinical and animal studies.

The one used in multiple ascending dose studies is identified based on results from the SAD study

In general, if the dose is accepted well, we continue dosing the remaining number of participants within the same cohort. The decision of stepping forward to the next dose escalation level is based on very specific evaluation performed by the investigational team and trial sponsor.

However, in many cases, within the same evaluation an independent committee such as data and safety monitoring committee (DSMB) can also be involved and responsible for providing their evaluation and decision to move forward with the next dose range.

Once this single dose of an IP is identified as safe our research team proceed further to next cohort, whereas, the dose is escalated, respectively. This dose escalation process by following the study protocol, continue until we determine signs of toxicity, identified by appearance of adverse events in any matter. Such dose is determined whether approximately 20-30% of the number of subjects report unacceptable toxicity/ adverse events and/or based on the discretion of the principal investigator. It is usually referred to as the maximally tolerated dose.

Then, the dose escalation process is terminated. Single ascending dose studies (SAD) and multiple ascending dose studies are usually conducted within the same study protocol. Both studies are performed in a small group of healthy volunteers compare to FIM study on oncology investigational product, whereas, the study participants are always patients having oncology disease due to toxicity nature of the IP itself.

The pharmacokinetic (PK) profile of an IP is determined by the evaluation level appeared into the human blood after single dose-intake. These blood levels are evaluated by multiple blood samples collected from study subject in specific timepoints. Usually, the first time point is always pre-dosed followed by multiple timepoints afterwards most of which take place within the first few hours upon the investigational medical product has been administered.

Pharmacokinetic profile is observed strictly within the first 24 hours

Usually, a pharmacokinetic profile is observed strictly within the first 24 hours in short periods, however, other IPs might require longer time for assessment and PK samples can continue to be collected until 48h. 72h. or even longer. The frequency of sample collection within the first 4 hours is always the most frequent.

Other studies in phase 1, aim to identified interaction with other drugs or food. So-called drug-drug interaction or drug-food interaction studies. These First-In-Man study conducted by clinical pharmacology investigators examine the profile of an IP and estimate its pharmacodynamic (PD) within interaction of specific drug or food. Again, a range of doses and dosing intervals is researched in a sequential approach.

In Convex phase 1 research unit (CRU), our investigational early First-In-Man study phase team is dedicated to understand drug pharmacokinetic (PK) profile, mechanisms of action. Identifying preferred routes of administration, interaction with specific drug/food/ estimate pharmacodynamics (PD).