Great! You decided to conduct a first-in-human microdosing study with your therapeutic compound. To safely test your compound in humans it must undergo a clinical translation process. The steps below will tell you exactly how you can move your compound, fast and safely, from preclinical work to your first in-human study.
The clinical translation of your compound follows 6 key steps:
Step 1: Preclinical in vitro evaluation of your compound
Step 2: Preclinical in vivo rodent models of your compound
Step 3: Toxicity study on your compound
Step 4: GMP production of your compound
Step 5: Prepare your study documentation
Step 6: Start your first-in-human clinical trial
Step 1 – Preclinical in vitro evaluation of your compound.
For a first-in-human microdosing study you need to label your compound with a radionuclide or fluorescent dye. In the end, this is what allows you to obtain in-human data on the biodistribution of your compound.
The first step is to see and confirm that labeling your compound does not influence the binding properties of the therapeutic compound at the target of interest. Usually this is done through in vitro binding affinity, internalization, and cell stimulation assays. For these in vitro assays you should use (tumor) cell lines that express the compound’s target of interest.
Step 2 – Preclinical in vivo rodent models of your compound.
Once you show that labeling does not affect the binding properties of your compound you can start step 2. Test your labeled compound in vivo in rodent models.
During this step you investigate whether the compound binds to the target of interest. The most used animal model to test binding properties of labeled compounds are tumor xenografts in immunodeficient mice. Tumor xenografts are usually induced by injection of a (human) tumor cell line that expresses the target of interest.
At the same time, you should look at the specificity of the binding. Namely, does my labeled compound only bind to the target of interest? Or does it also bind to other targets in the cell?
You can examine this by conducting blocking studies with an excess of unlabeled compounds. Another option is to use a tumor xenograft that doesn’t express the target of interest (i.e., “negative tumors”).
You research the binding properties and specificity in so-called biodistribution studies. In these studies, the labeled compound is administered to tumor-bearing mice. They are euthanized at various time points after administration. Next, the organs and tumor are dissected, weighed and the radioactivity concentration is measured in a gamma counter. You can then calculate the radioactivity concentration as percentage of the injected dose per gram of tissue. With this data, you can determine the biodistribution and pharmacokinetics of your compound. The same process is used to perform dose finding studies at this stage.
To better understand the mechanism of action of your labeled compound, you can perform additional preclinical animal models that closely mimic the human disease. However, this is not a prerequisite before you initiate your first-in-human trial. It can also be execute in parallel or after the first-in-human trial.
Step 3 – Toxicity study on your compound.
When your compound shows specific binding to the target of interest and a good biodistribution profile, you can start preparing it for first in-human use.
Before use in clinical trials the FDA and EMA often require you to conduct a preclinical toxicity study. Following microdosing regulatory guidelines a single dose extended single-species animal toxicity study is sufficient for labeled therapeutic compounds.
However, in some cases, you do not need to do additional animal toxicity studies. Are you unsure what applies to your compound? Try our toxicity study tool to see if your in-human trial requires an animal tox study or not.
Step 4 – GMP production of your compound.
The next step in the clinical translation of your compound is to prepare the labeled compound for human use. You need to manufacture the precursor (antibody, peptide, or small molecule) of your therapeutic compound under GMP conditions. Also, the label you will use needs to be GMP-compliant.
Sometimes you can use a non-GMP compliant precursor or label if the labeling procedure is performed under GMP conditions. This GMP procedure does require additional testing of the non-GMP material. You need to validate and qualify the quality control of the labeled compound. Once the labeled compound complies to all specifications set forth in the ICH guidelines, you can release it for use in clinical trials.
Step 5 – Prepare your study documentation.
All information about the studies you conducted in the previous steps need to be documented in a submission package. Local and national authorities review this package and decide whether they allow your clinical trial to start. Among others you include the following documents in your submission package:
- Investigational Medicinal Product Dossier (IMPD)
- Research Study Protocol
- Patient Information File
- Informed Consent Form
- Investigators Brochure
Step 6 – Start your first-in-human clinical trial.
You have now successfully completed all steps needed for the clinical translation of your compound. The only thing left to do is start your first-in-human clinical trial.
At TRACER, we work on the clinical translation of compounds on a daily basis. We provide you with a tailor-made plan for the development of your innovative compound based on its development stage, type of compound, and anticipated patient population. So, you can move easily from your preclinical studies to the conduction of your first-in-human trial.