One of the critical phases of translational research is preclinical to clinical translation. Preclinical translational studies include in vitro and in vivo animal studies to justify human trials and ensure participant safety. Translational clinical research, meaning first in-human trials, is designed to reproduce previous findings in humans and to inform and support further development. The objective of translational medicine is to provide sufficient evidence of efficacy and safety, and to provide information on dosing for each subsequent step.
Webinar on preclinical to clinical translation
Before clinical trials can be initiated, a strong preclinical package is required. Missing data in the preclinical package can delay the drug development program. But, how do you know what data you need in the first place? TRACER, specialized in early phase clinical trials, and BIOEMTECH, provider of preclinical imaging systems and services, addressed this together in a webinar. This article summarizes the process to move a promising preclinical candidate into clinical trials. You can access the webinar recording via the form below. After submission, you’ll receive the link to the video.
Watch the recording
Key takeaways for drug delivery and translational research
- Translational research bridges preclinical and clinical development.
- Animal studies are an evaluation of the biodistribution, efficacy and safety.
- Nuclear imaging enables quantitative biodistribution analysis.
- Phase 0 studies may reduce preclinical requirements.
- Adaptive Bayesian designs can accelerate early clinical development.
The need for translational research
Translational studies form the bridge between preclinical and clinical trials.
- In vitro and in vivo animal studies provide evidence on the therapeutic effect and form the rationale for clinical research.
- In addition, in vivo animal toxicology studies safeguard participant safety and inform the selection of the initial dose for the first in-human study.
- The contents of the preclinical package depend on the choice for the first in-human study: a traditional Phase 1 trial or a faster Phase 0 exploratory trial.
The various types of translational research form together the evidence to support further development.
Every translational study is not just a checkbox to cross, but an opportunity to learn more about a compound and its target.
In vitro research
In vitro research aims to move biologically relevant compounds to in vivo studies through various assays. This includes testing for target engagement, but often also takes into account mechanistic insights on the kinetics of the drug in the cell and biological activity. In the preclinical stage, the goal is not simply to generate data in an isolative way but to already build evidence for clinical translation. Appropriate animal model selection, generation of quantitative data, and determining risk signals are all parts of translational research.
In vivo preclinical studies
A proof-of-concept and imaging study in rodents must first demonstrate that the substance binds to the target. After that, other studies in animal models can be initiated, such as radioligand therapy studies in xenograft models. After this study, and following a 14-day extended-dose toxicity study, a Phase 0 in-patient trial using a microdose is also an option. Additional in vivo preclinical studies are conducted in animal species and models that are most relevant to humans. For example, in oncology research, absorbed dose–response relationships may be evaluated using xenograft models.
There are two main goals of animal studies. Efficacy studies relate pharmacokinetic exposure to therapeutic outcomes. Furthermore, toxicology studies assess the safety profile and support the determination of a safe starting dose for first-in-human studies. The first in-human dose is dependent on sensitivity, reversibility, and the absorbed dose in critical organs.
Nuclear imaging in translational development
In animal studies, nuclear imaging can support the creation of a dose-risk framework based on toxicological and dosimetric data. The starting dose for the first in human trial is determined at the organ and tissue level. For radiopharmaceuticals, the bone marrow and kidneys are often considered dose-limiting organs/tissue. In in vivo preclinical studies, imaging allows for a spatial, longitudinal, and quantitative assessment of biodistribution. This includes on- and off-target accumulation over time. Ex vivo analysis (gamma counting) can provide highly accurate data on biodistribution at levels that are difficult to quantify using imaging alone, such as at the tissue level.
Preparing for first in-human trials
After all preclinical work is done, the next step is the translation to human studies. Regarding this, you need to:
- produce an investigational medicinal product (IMP) according to good manufacturing practices (GMP), which is a requirement for human use;
- create a study design, and write all required protocols and other study documentation;
- select the site(s) where the clinical trial will be conducted, and perform audits, and train the staff;
- submit the preclinical package, study documentation, and IMP dossier (IMPD) to the institutional review board and follow the process for trial approval;
Phase 0 versus Phase 1 studies
When you move from preclinical to clinical, you can choose between a Phase 1 or Phase 0 trial. Both studies are in humans, but there are important differences.
Safety and dose finding or biodistribution and target engagement.
Phase 1 mainly assesses safety and dose finding, while Phase 0 can be used to obtain biodistribution and target engagement. For the latter, the drug is radiolabeled for positron emission tomography (PET) or single-photon emission computed tomography (SPECT). Depending on the research question, other methods are also available in Phase 0. Examples are fluorescent imaging, or, with an unlabeled compound, RAMAN or liquid chromatography-tandem mass spectrometry (LC-MS/MS).
Healthy volunteer study or patient trial.
In general, Phase 1 studies are conducted in healthy volunteers. However, certain drug types, like biologics and radiopharmaceuticals, and certain indications, like oncology, may be evaluated directly in patients. Phase 0, on the other hand, is often conducted in the patient population or even with patients with various indications, such as different cancer types (i.e. basket trial).
Phase 0 microdosing studies require lower preclinical requirements.
When in Phase 0 a microdose is used, which is sufficient for sensitive visual and quantitative measurements such as PET or SPECT, preclinical requirements for study approval are less stringent. Not all preclinical toxicology studies are necessary, and a good laboratory practice (GLP)-grade drug substance radiolabeled under GMP conditions may be sufficient.
GMP manufacturing and CMC preparation
When imaging is used, part of the CMC’s work involves developing the labeling strategy. If a labeling strategy is already present from the preclinical work, transferring and validating it for GMP implementation is sufficient. After positive tests for purity, stability, and in vitro binding, the patient batches of the labeled product can be produced.
Operational preparation for the clinical trial
In parallel with the CMC work, other tasks necessary to conduct the clinical trial can be performed. This includes site selection, audits, setting up the eCRF (electronic Case Report Form), TMF (trial master file), and writing the study design, protocols, training material, and patient information folder (PIF) and informed consent form (ICF).
Study design for clinical translation
The translational research question is defined in a study design, and all relevant study documentation is written. TRACER often chooses an adaptive trial design, especially in translational trials, which have an exploratory nature. A certain level of flexibility is written in the initially approved study design to prevent amendments that would result in delays. An adaptive clinical trial design allows for changes based on emerging data. This increases the efficiency of the research, enables the exploration of emerging insights, while reducing the burden on participants and ensuring safety. Examples are expansion of cohorts, adding additional indications, changes in dosing or dose regimen, and changing or reducing the scanning schedule.
Bayesian optimal interval (BOIN) design for radiopharmaceuticals
A Bayesian optimal interval (BOIN) design may combine a dosimetry and imaging study with a therapeutic dose escalation study. In the first part, the imaging study with PET or SPECT results in the starting dose for the therapeutic part. After the first part, in the second part, that dose is administered to the first cohort as a therapeutic. After the interim analysis, the dose may be escalated or de-escalated for the following cohort. Combining the dosimetry study with the therapeutic clinical trial can improve efficiency and reduce timelines.
Learn more from the webinar
If you’d like to learn more about translational science, drug development, preclinical and clinical trials, and the wide range of possibilities offered by imaging, you can watch the webinar recording. Request the video or contact us if you have specific questions about your project.