The sponsor of a recent Phase 2 global study, conducted at more than 50 sites, invested in a centralized digital pathology core lab to ensure a homogenous and representative study population.  For this study, the lab, powered by Biomedical Systems, worked to confirm the pathological diagnoses of patients’ disease states.   

The investment proved advantageous, and Biomedical Systems’ findings were startling:
30 percent of patients submitted for central review did not meet the inclusion criteria.  Failure to properly classify its patient population can leave sponsors with a significantly underpowered study—rendering the drug manufacturer with inaccurate efficacy results, a failed study and heavy price tag.

To understand how the study sites, which relied on patient medical histories combined with site-prepared histology biopsy slides, approved patients who did not meet the inclusion criteria requires an understanding of the digital pathology evolution.

Unbreakable

Before the advent of slide digitization, pathologists reviewed specimens on glass slides under their microscopes.  To secure multiple pathologists’ interpretations, labs would prepare several sets of slides from the patient’s tissue block—each slide containing a different level of tissue shipped to the reviewer.  Variance in tissue levels triggered variability among inter-reader interpretations of the specimens.  Subsequently, sponsors began leveraging digital pathology to provide reviewers with identical digital images of patients’ tissues, effectively reducing variability.

In the referenced Phase 2 study, variability could explain the 30 percent discrepancy between internal site review and the central review process.  With the study, pathology slides were reviewed at more than 50 sites; each of the sites employs its own pathologists, who innately apply their schooling, training and personal experiences to the review process.  In addition, each site offers its own equipment and methods for slide collection and patient history documentation.

With centralized digital pathology, the study and its readers must follow rigorous, standardized processes focused solely on inclusion criteria.  Pathologists may only assess the morphology depicted in the digital slide image sets, which reduce variability and bias. 

For the Phase 2 global study, Biomedical Systems relied on Aperio equipment and its applications, in combination with its own validated proprietary systems, to manage digital slides and facilitate simultaneous independent reviews from anywhere in the world.  Biomedical Systems trained readers on the standardized equipment, scoring methodology and the Electronic Case Report Form application.  Each reader in the study viewed the exact same digital slide image sets from their various locations.  Readers followed proven project management practices and systems to ensure their assessment results were directly linked to the evaluation.  The Electronic Case Report Form guided each of the readers through the same protocol-specific evaluation and grading scale. 

After a reader completed each required field in the Electronic Case Report Form, he or she would enter a given password to apply a digital signature and date/time stamp to the completed record. The Electronic Case Report Form application sequestered the completed record, preventing the reader from returning to the record or the digital slide image set.  These processes effectively reduced variability, promoted homogenous analysis methodology across all readers and ensured complete records were provided in a format conducive to statistical analysis.

Centralization and Variability
By centralizing a study, sponsors and its study partners can typically decrease the number of pathologists needed to evaluate patients for inclusion. This reduction in pathologists lessens the variability associated with the inclusion assessments.  In the Phase 2 study, the centralized lab effectively worked to significantly decrease the number of pathologists evaluating patients.  Biomedical Systems coupled the reviewer reduction with standardization—providing uniform training, equipment and review processes to improve patient inclusion percentages and reduce variability.

Independent Review and Bias
According to the U.S. Food and Drug Administration[1], independent reviews can reduce bias in clinical trials.  In this study, the independent review, which is inherently part of the centralized review process, proved effective in ensuring only patients who met the protocol inclusion criteria were enrolled in the study. 

In cases of site-selected inclusion, site pathologists review patients’ history, test results and histology primarily for patient care.  Study inclusion criteria often serve as the site’s secondary goal.  The pathologists’ expanded patient knowledge, which is important for patient care, can potentially hinder the clinical trial process by injecting unintended bias into the patient inclusion evaluation.  For example, during the slide interpretation process, pathologists could be influenced by their knowledge of the patient’s history and his or her symptoms that seemingly match the inclusion criteria.  

The Phase 2 study readers, required to follow Biomedical Systems’ centralized digital pathology process, were only focused on the morphology represented within the digital slide images.  For the study, Biomedical Systems blinded its readers to all extraneous patient information.  Readers’ evaluations and diagnoses were made solely on the pathology employing a standardized process, void of patient information or variability often inherent at a study site.

Summary
The impact of an underpowered study can cost drug manufacturers millions of dollars and their reputations.  Centralized digital pathology helps reduce bias and variability while increasing the probability of accurately assessing efficacy and statistically relevant data in clinical trials.

[1] Food and Drug Administration. (2011). Guidance for Industry Standards for Clinical Trial Imaging Endpoints (DRAFT). Washington, DC:  Government Printing Office