White paper on imaging biomarkers

One area where imaging biomarkers have a critical role is new drug development. Drug development has considerably changed these last 20 years because impressive progresses in molecular biology have been made, leading to an increasingly detailed understanding of the genetic abnormalities in diseases [3]. The discovery of gene mutations and the identification of the cellular pathways that their encoded proteins control provide a wide range of new targets for drug development. Contemporary drug development is an ordered process starting with identification and validation of a target with high throughput methodologies and going through lead identification and optimization to preclinical and clinical trials of drug candidates [4]. In preclinical trials, the efficacy and toxicity of the drug is assessed in animals. Afterwards, the drug is tested in patients during three clinical phases. In phase 1, the toxicity, pharmacokinetics, pharmacodynamics, and optimal dose levels are assessed; in phase 2, the biological efficacy is determined; and in phase 3, controlled trials are performed to assess the effects on clinical endpoints [5]. The term “pharmacokinetics” denotes what the body does to the drug in terms of its absorption, distribution, metabolism, and excretion, including the concentration-time relationship and its dependence on dose, the term “pharmacodynamics” denotes what the drug does to the body [6].

Despite the successes with targeted drugs, there is a general concern about the slow arrival and increasing cost for development of new therapies. This is explained by the fact that the most reliable way to assess the clinical impact of a therapeutic intervention is through its effect on a clinical endpoint such as survival or disease-free survival. These standards may be impractical because long periods are required for these clinical endpoints to be achieved and trials with large number of patients are needed for their evaluation. The developments in quantitative medical imaging offer the opportunity of using imaging biomarkers to speed up the drug development process. For example, the lack of validated non-invasive biomarkers has been recognized as a major hinder to the development and use of antifibrotic drugs in patients with liver fibrosis [7].

In addition to technology stability (robustness), non-invasiveness, and broad availability, there are two main prerequisites for the effective use of imaging biomarkers, which are standardization and validation.

Anatomical, functional and molecular characteristics can be used as imaging biomarkers. In cancer treatment, CT (or MRI) measurements of changes of tumor volume are based on the “Response evaluation Criteria in Solid Tumours” (RECIST) criteria [17]. These anatomical biomarkers are the only imaging surrogate endpoints that are accepted in cancer treatment. However, these anatomical biomarkers are suboptimal to assess the effect of some targeted treatments that do not cause regression of tumor volume, but rather increase in the extent of tumor necrosis [18].

A lot of functional biomarkers obtained with several imaging methods, including PET, contrast-enhanced CT, perfusion CT and MRI, diffusion-weighted MRI, MR elastography and spectroscopy, have the potential to complement or even replace the RECIST criteria. However, important efforts of qualification and standardization remain to be done before the acceptance of some of these functional biomarkers as surrogate endpoints. ¹⁸F-FDG-PET may serve as an illustrative example. In clinical routine, ¹⁸F-FDG-PET is increasingly used to assess the response to treatment in tumor patients. However, ¹⁸F-FDG-PET as an imaging biomarker has not yet been sufficiently validated to be accepted as a surrogate endpoint for clinical studies by regulatory agencies. Currently, a multi-centre qualification study of ¹⁸F-FDG-PET/CT as a predictive marker of tumor response and patient outcome in patients with non-small cell lung cancer has been initiated by the American College of Radiology Imaging Network (ACRIN).

Functional imaging biomarkers are increasingly used as pharmacodynamic biomarkers. Relative to molecular imaging biomarkers, which are target-specific, functional imaging biomarkers have the advantage of being downstream markers that probe general capabilities of disease, including cell death, proliferation, glycolysis, hypoxia, tumor invasiveness, angiogenesis, inflammation and fibrosis. Although a lot of functional imaging biomarkers have been proposed as pharmacodynamic biomarkers in early drug development, most of these biomarkers need further validation and standardization for their qualification in phase 1 and 2 human studies.

The European Network on Imaging Biomarkers will work in cooperation with industry (pharmaceutical and medical device companies), European regulatory agencies (EMEA) [19], and international medical societies, including ECCO, EORTC, RSNA, EANM, ISMRM, ESMRMB and the subspeciality societies of the ESR for biomarker standardization, validation and qualification. The main purpose of ENIB will be to boost at the European level the development and use of qualified imaging biomarkers that will help in diagnosis, treatment assessment and drug development.