In toxicologic pathology, “blind slide reading” involves procedures in which the pathologist is unaware of the treatment group status of individual animals during the histologic slide evaluation phase of a toxicologic bioassay. Blind slide reading continues to be a controversial topic, despite published recommendations on this subject authored by professional societies and governmental regulatory agencies (e.g., The Society of Toxicologic Pathology and the US FDA). The reason for this is understandable.
From the earliest days of their careers, scientists and statisticians are cautioned repeatedly about the perils of sampling and observational bias, and correctly so, because it is undeniable that such factors have the potential to adversely impact study findings. Consequently, randomized sampling and blinding procedures have become axiomatic in contemporary scientific research, and experimental designs routinely incorporate such measures to varying degrees. Given this practice, the following question is often posed: “In terms of blinding, why should histopathology be handled differently from other endpoints?” This is a valid point of concern, but one that is easily addressed. Unlike most other types of assays, which typically generate a set of quantitative results that are not subject to optical recognition or experience-based interpretation, toxicologic histopathology involves the visual observation of morphologic differences in histologic sections from substance-treated specimens as compared to those of untreated controls. This observational step requires the pathologist to first discern such differences, some of which may be very subtle, among myriad complex microanatomic features that exist within each of the examined tissue types. Therefore, the initial goal of the histopathological assessment is to ensure, to the greatest extent feasible, that toxicologically-relevant findings are not missed, i.e., to guard against false negative (= Type II) errors. In order to best accomplish this objective, it is imperative that the pathologist be allowed to knowingly compare tissues from test subjects that are most likely to exhibit changes (i.e., those of the high dose group) to the tissues of concurrent negative controls. The importance of this step cannot be overemphasized, as there may be little future opportunity to detect findings that were missed originally (unless the slides are ultimately peer-reviewed). Once the initial examination has revealed all relevant findings, it becomes a simple matter for the pathologist to then mask and randomize slides that contain the target tissues, and re-assess the now blinded slides in order to confirm (or disprove, as the case may be) the existence of one or more previously recognized effects. This second phase of the histopathologic evaluation is equally critical to the first, as it prevents the pathologist from reporting findings that represent false positive (= Type I) errors. It is through this two-phase process, in which blinding only occurs after all important findings have been identified, that experienced toxicologic pathologists can successfully mitigate issues of observational bias, and thereby produce histopathology data that are both accurate and reliable.
“Blind slide reading” is prevalent in the medical device evaluation industry. Much of this is undoubtedly driven by the quantitative basis of engineering and manufacturing devices to exact specifications. Medical device design teams often pull heavily from engineering and materials scientists who are used to precise measurements and quantitative data sets. For all the reasons enumerated above, the histopathologic analysis of device and biological systems interactions relies on observational differences between the interaction of the test device with the biological test system in comparison to a predicate device or sometimes a sham, which a blinded slide review negates to a large extent. Also, “blind slide reading” for some medical device studies may extend to having different sacrifice intervals masked from the toxicologic pathologist. Without knowledge of time events, the visual observations that together with the pathologist’s experience yields a comparison of early to later tissue reactions is hampered. Pertinent changes may be lost in the background of findings that are reported, often the default when the toxicological pathologist reports all changes whether important to the test device and its timeline or not. In other words, the noise of many diagnoses may obscure subtle differences. Furthermore, many devices are unique in material, material composition percentage and structure. It is very helpful to the toxicologic pathologist to have a test sample of the device, either whole before processing to slide or on the slide, in order to have a full three dimensional idea of its potential interactions with the biological system under test. This is often not done when ‘blind slide evaluation’ has been requested.