Central Pathology Review for Phase III Clinical Trials: The Enabling Effect of Virtual Microscopy

Abstract

Context.—Central pathology review (CPR) was initially designed as a quality control measure. The potential of CPR in clinical trials was recognized as early as in the 1960s and quickly became embedded as an integral part of many clinical trials since. Objective.—To review the current experience with CPR in clinical trials, to summarize current developments in virtual microscopy, and to discuss the potential advantages and disadvantages of this technology in the context of CPR. Data Sources.—A PubMed (US National Library of Medicine) search for published studies was conducted, and the relevant articles were reviewed, accompanied by the authors' experience at their practicing institution. Conclusions.—The review of the available literature strongly suggests the growing importance of CPR both in the clinical trial setting as well as in second opinion cases. However, the currently applied approach significantly impedes efficient transfer of slides and patient data. Recent advances in imaging, digital microscopy, and Internet technologies suggest that the CPR process may be dramatically streamlined in the foreseeable future to allow for better diagnosis and quality assurance than ever before. In particular, whole slide imaging may play an important role in this process and result in a substantial reduction of the overall turnaround time required for slide review at the central location. Above all, this new approach may benefit the large clinical trials organized by oncology cooperative groups, since most of those trials involve complicated logistics owing to enrollment of large number of patients at several remotely located participating institutions.

The importance of central pathology review in international trials: a comparison of local versus central bone marrow reticulin grading

“…12 Ab-producing cultures were established of both unmutated (6 of 10) and mutated CLL samples (4 of 10), including two, CLL102 and CLL616, that belonged to previously described stereotypic subsets. 2 Addition of 1.5 μg/ml of the TLR9 ligand CpG-DNA ODN2006 (Invivogen) to CD40L-stimulated cultures resulted in a similar frequency (5/9) of Ab-producing cultures as obtained with R848. Ab concentrations of up to 13 μg/ml were reached, with an average of 4.7 μg/ml (Figure 1c), which are lower than those obtained with R848 stimulation.…”

“…1 Although widely recognized as an essential measurement of quality assurance and in use for over half a century, only rare reports exist comparing the histopathological evaluation of hematopoietic neoplasms between the central review and the contributing local pathologists in clinical trials. 2,3 The BCR-ABL1-negative myeloproliferative neoplasms (MPNs) primary myelofibrosis (PMF), polycythemia vera (PV) and essential thrombocytopenia (ET) are characterized by variable degrees of bone marrow fibrosis (BMF) at presentation or upon disease progression. [4][5][6] It is well known that development of BMF is an adverse event and has been associated with inferior prognosis in MPN.…”

Future perspectives of digital pathology

“…By means of WSI platforms and the transfer of digital images together with teleconsultation, it is possible to shorten, simplify and standardise the process of qualification. When considering clinical trials involving large groups of patients, there is also the possibility of standardising quantitative measurement of immunohistochemically-labeled proteins intended as therapeutic targets through applying automated analysis of digital images [55]. This thereby creates huge digital repositories of standardised diagnoses and specimens that can be used for future research on new therapeutic targets.…”

Morphology in the Digital Age: Integrating High-Resolution Description of Structural Alterations With Phenotypes and Genotypes

“…Their use is permitted for consultation (second opinion and frozen section review) and research applications including clinical trials. 1819,20 The use of digital pathology in the clinical setting outside of the USA is governed by local regulation and varies from country to country. The clinical implementation of digital pathology is not cost-neutral, unlike the conversion to digital radiology, and no doubt has slowed its adoption.…”