By James Perhach, Director of Clinical Development & Research on Oct 11, 2017 9:00:00 AM
Conducting a First In Man (FIM) clinical trial with a novel drug product is a complicated process that requires an abundance of caution.
Also known as Phase 0 trials, FIM trials crucial tests of a drug product’s ability to enter the trial pipeline and make it toward the market. In real terms, FIM trials are basic PK/PD tests that justify future trials by not harming the trial subjects.
But what factors are the most important to pay attention to before moving into Phase 0, and what does preclinical research contribute?
At the most basic level, the drug product’s preclinical information must prove beyond any doubt that in vitro the drug product can access its intended target and effect the target the intended way.
For most drug products, this means performing binding studies in vitro and collating the data to demonstrate perfect reproducibility of effect. Without this most basic proof of drug efficacy, it’s unlikely that a prospective FIM trial will get conditional approval.
Moreover, the drug product’s effect on its intended target must be quantifiable via a change or a biomarker that is measurable. FIM studies are likely backed by an abundance of preclinical efficacy assays intended for in vitro or in vivo use, and it’s critical to carry this information forward so that the trial can generate as much data as possible.
There’s a little bit more to this part of the story, however. Simply proving that the drug product can produce its desired effect in vitro does little to bridge the gap between laboratory and clinic. In vivo studies are the bridge that all FIM studies have crossed to gain critical PK and PD data.
Predicted Pharmacokinetics and Pharmacodynamics
Every drug product that makes it to the FIM stage has likely already undergone many rounds of preclinical tests in vivo to demonstrate biological processing and clearance of the drug product.
While these studies will generate a lot of data that isn’t objectively transferable to human physiology, there are many mathematical models which allow for approximation between PK and PD attributes in model animals and humans.
Scrutinizing the information generated from this math is typical before FIM studies proceed. In particular, every FIM study is preceded by poring over the in vivo data regarding the drug product’s therapeutic window and dose-response curve. Fleshing out the pharmacokinetics of the drug product will help to develop clinical trial dosing protocols which keep the steady state drug product concentration exactly where the trial requires.
If preclinical studies suggest a narrow therapeutic window or a high toxicity, it isn’t the end of a prospective FIM trial—it just means that the dosing must be calibrated even more carefully and narrowly to avoid hurting the human subjects.
FIM studies have small cohorts of recruits who are typically healthy. This means that their PK and PD attributes may be totally unrealistic in comparison to sick patients in subsequent trials, which could potentially cause a false positive or a false negative for safety concerns and side effects.
After harvesting data from the FIM trial, hard PK and PD data from human subjects can help to greenlight the drug product into Phase I or Phase II directly with the relevant dosing adjustments.
Like all clinical trials, first in man studies seek to improve human health by exposing volunteers to calculated risks—and above all, those who conduct FIM trials must understand how to calculate that risk in order to realize the benefit down the line.
-  https://www.fda.gov/ForPatients/Approvals/Drugs/ucm405622.htm
-  http://www.abpi.org.uk/our-work/library/guidelines/Documents/First%20in%20Human%20Studies.pdf
-  https://www.ncbi.nlm.nih.gov/pubmed/10100300
-  http://www.bmj.com/content/350/bmj.h1831.short
-  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)61309-X/fulltext