Smart, small scale first-in-human phase 0 or 1 clinical trials offer a solution to significantly reduce drug development costs. These trials can be referred to as Proof-of-Concept (PoC) studies. Although PoC clinical trials have the ability to evaluate the potency of a new drug, clearly defined end-points and biomarkers of disease presence and progression are needed. Molecular imaging would be the technology of choice to measure these end-points and biomarkers of disease in early proof-of-concept clinical trials. However, how does one achieve broad implementation of molecular imaging in drug development?
Drug development is an expensive undertaking. In general, most costs are made in the last phases of clinical evaluation through phase 2 and 3 clinical studies in humans. High costs combined with pressure to generate ROI on new drugs show a need for a cost-effective drug development process. A solution that significantly reduces costs is implementing smart, small scale first-in-human phase 0 or 1 clinical trials. In these trials, promising new drug candidates can be selected at an early stage.
Usually phase 0/1 clinical trials are mainly focused on safety and pharmacokinetics and pharmacodynamics of the drug. They are based on blood measurements in most of the times healthy volunteers without the disease (target) present. However, these trials have no predictive value on feasibility and efficacy of the drug in the target patient population of interest. Although Proof-of-Concept (PoC) clinical trials have the ability to evaluate the potency of a new drug, clearly defined end-points and biomarkers of disease presence and progression are needed. Molecular imaging would be the technology of choice to measure these end-points and biomarkers of disease (together with classical blood measurements) in early proof-of-concept clinical trials.
Molecular Imaging in drug development.
The use of molecular imaging in drug development is perfectly summarized by Murphy et al . The authors clearly state that molecular imaging has the potential to measure biomarkers and endpoints in early proof-of-concept clinical trials.
They mention the use of the “three pillars” postulated by Morgan et al.  that need to be characterized in order to decrease drug development program failure: drug access to tissue, target engagement and demonstration of downstream pharmacology. Molecular imaging could be used to measure these “pillars”. The technology is already used in early phase clinical trials, albeit at a small scale. There are several reasons for the small-scale use of Molecular Imaging and progress has to be made for large scale implementation.
Large Scale implementation of Molecular Imaging.
The main reason for small-scale use of molecular imaging is the necessity of specialized labeling procedures and innovative imaging equipment. Moreover, specialized equipment and expertise is not easily available at every hospital or institution. In turn, this limits the technology to early phase clinical trials in a single site or maximum of few sites. Dissemination of molecular imaging within the pharmaceutical industry, combined with a consorted investment in multicenter installment of innovative imaging equipment will close the gap between small and large-scale application world-wide in the drug development process. Late phase clinical trials could clearly benefit from measurement of the “three pillars” and presence of the target by molecular imaging. Overall, it provides better data and scientific evidence of the efficacy of a novel drug in an early stage.
Another aspect is the limited validation and standardization of the molecular probe, image acquisition and analysis methodologies. Usually, limited clinical data of the molecular probe is available and the clinical significance remains unknown. Furthermore, image acquisition and especially image analysis is poorly standardized. Recently Koller et al.  described standardized analysis of in vivo and ex vivo imaging of a fluorescent probe. This approach could be used as an example to standardize the analysis of molecular imaging results with both fluorescent and radiolabeled tracers within the molecular imaging and drug development community.
How to achieve a broad implementation of molecular imaging.
In conclusion, molecular imaging has the potential to play a major role in drug development. Nevertheless, advances in availability and validation and standardization are needed to make broad application in drug development clinical trials possible. A more intensified collaboration between the pharmaceutical industry, specialized imaging CROs and academic centers is warranted to speed up the development in molecular imaging. Moreover, the molecular imaging community should promote their field of expertise to create awareness of the great potential of molecular imaging in drug development.
- Murphy PS, Patel N, McCarthy TJ. Has molecular imaging delivered to drug development? Philos Trans A Math Phys Eng Sci. 2017 Nov 28;375(2107):20170112
- Morgan P, Van Der Graaf PH, Arrowsmith J, Feltner DE, Drummond KS, Wegner CD, Street SDA. 2012 Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving Phase II survival. Drug Discov. Today 17, 419–424.
- Koller M, Qiu SQ, Linssen MD, Jansen L, Kelder W, de Vries J, Kruithof I, Zhang GJ, Robinson DJ, Nagengast WB, Jorritsma-Smit A, van der Vegt B, van Dam GM. Implementation and benchmarking of a novel analytical framework to clinically evaluate tumor-specific fluorescent tracers. Nat Commun. 2018 Sep 18;9(1):3739