COMPANY EXPERTISE STUDIES
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First time in Human FTIH

CRO is a specialist in the design and conduct of FTIH studies. In addition to the traditional SAD approach in healthy volunteers, we can demonstrate a track record in the successful implementation and completion of multi-part SAD + MAD studies. These are conducted in patients and healthy volunteer / patient combinations. We have become a preferred partner to many sponsors in this area. This is not only for our ability to handle the clinical aspects of FTIH work, but also for our ability to contribute to both the design process and the regulatory approval process.

CRO’s successful approach to patient recruitment is frequently able to ensure that both healthy volunteer and patient FTIH studies can be completed as single-center studies. This considerably increases the exploratory efficacy opportunities open at the FTIH stage, eases logistics and minimizes design compromises.

We can bring a wealth of expertise to the design of FTIH studies. On the one hand this covers typical considerations on basic study design, in-house observation periods and appropriate safety monitoring. On the other, in collaboration with our partners at Charité - Universitätsmedizin Berlin, we are able to contribute to discussions regarding selection and inclusion of biomarkers and diagnostics. Inclusion of such markers may be of great value, both to enhance safety monitoring and to facilitate the early exploration of efficacy.

For instance, we are able to work with medical immunologists to incorporate receptor occupancy monitoring to assess the validity of pre-clinical models. This allows for dynamic adjustment of dose levels during the course of the study based on observed results. Another example would be the inclusion of MRI and/or ultrasound imaging to chart the course of sub-clinical effects on bone and tissue following administration of a biologic. Such information may be utilized to assist in the selection of dosing intervals for subsequent studies and to ensure appropriate future use and timing of imaging.

With respect to regulatory support, we have established a tried and tested approach to gaining approval for multi-part studies from ethical committees and competent authorities. This approach not only allows us to gain approval for multi-part studies in Germany, it has also allowed us to gain approval for multi-part studies in which SAD and MAD are run in a semi-parallel. Our ability to handle ethical committee submissions and competent authority CTAs is increasingly recognized by sponsors, many of which are delegating the CTA responsibility to us for FTIH submissions.

When it comes to the clinical conduct of FTIH studies our team places subject safety at the forefront of everything we do. Our Phase I unit is located in Germany’s largest university hospital, Charité - Universitätsmedizin Berlin. This provides direct access to state of the art emergency and intensive care facilities. Our own medical team includes board certified critical care medicine specialists. Our unit is also equipped with bedside cytokine monitoring. This allows us to obtain readout on cytokine levels within 20 minutes of sample collection, ensuring that early action can be taken in the event a potential problem is seen.

Summary

Study Design

Charité Research Organisation possesses a wealth of expertise and experience in the design of FTIH studies. In particular, this is true for the design of complex multi-part, multi-population, adaptive design studies. Such studies often combine both healthy volunteer and patient dosing, along with SAD and MAD dosing parts. These studies can present specific regulatory challenges, making a fully considered design and implementation imperative - for instance, with respect to stopping criteria and transition criteria. CRO is also working closely with therapeutic area, imaging and biomarker specialists to facilitate the inclusion of exploratory efficacy into FTIH studies in a way that is both meaningful and practical.

Safety First

Subject safety is the first priority of any clinical study and CRO. Charité Research Organisation takes every measure possible to ensure subject safety and minimize risk. With its research unit located inside Germany’s leading university hospital, access to first class emergency and intensive care facilities is assured. The CRO medical team itself also includes critical care medicine specialists. From a technology standpoint, safety is also prioritized. For example, the research unit’s laboratory provides access to “bedside” cytokine testing. This allows analysis of key cytokine levels within 20mins and is typically utilized in FTIH studies with biologics to provide the earliest possible indications of any potential issues prior to clinical symptoms developing.

Patients and Healthy Volunteers

FTIH studies are conducted in healthy volunteers, patients and in some cases a combination of both. For instance, FTIH studies with new biologics targeting MS maybe undertaken entirely in MS patients. Patient resources are available to facilitate such studies with a single center approach. Complex FTIH studies in SLE may compromise healthy volunteer dosing at the SAD stage followed by MAD in patients, minimizing patient requirements in this indication.

Combined SAD and MAD

Charité Research Organisation has built a reputation for designing and implementing complex FTIH studies combing SAD and MAD components – sometimes with a semi-parallel design. CRO’s experience in handling submissions for such studies with both ethics committee and competent authorities ensures timelines to initiation are minimized and that regulatory work during the study is handled efficiently.

Exploratory Efficacy

By working closely with therapeutic area, imaging and biomarker experts, Charité Research Organisation is able to design and implement FTIH studies that introduce exploratory efficacy investigations in addition to safety, tolerability and PK. Such studies may combine a range of imaging approaches together with novel biomarkers to explore sub-clinical effects – potentially even at the single dose stage. For instance, the use of MRI and ultrasound to investigate changes in sinutvitis following a single dose administered to RA patients.