The adventures of medieval knights have fired our imagination since their first description in books such as Search for the Holy Grail, Sir Gawain and the Green Knight, and Parzifal to name a few. I was recently struck by an interesting link between such knights errant and clinical trials when I asked the question: what were the eligibility clinical trial criteria for knighthood?
The medieval knights we recognize inhabited the highest positions of the feudal systems of the European Middle Age. They owed allegiance to their lord who in turn would serve the King or reigning monarch. At times of war they were required to dispatch a cohort of their men to serve in their respective armies. The power of knights came into prominence with the Crusades (11th – 14th centuries) and reached their zenith in the 14th century with none better than the Teutonic Order which yielded considerable political, military and economic power. Inclusion in such a group was certainly an honor and came with many benefits.
Inclusion and Exclusion Clinical Trial Criteria – Is There a Link Between Clinical Trials and Knights in Shining Armor?
The eligibility criteria for becoming a knight were quite simple. For inclusion, it was essential to be a free man. In medieval Europe, this would exclude serfs, prisoners, and non-Christians. Also any exhibition of non-chivalric behavior would mean automatic exclusion.
This idea of inclusion and exclusion is the basis of clinical trial eligibility which is central to the concept and spirit of clinical trial design. While clinical trial "eligibility" is frequently used in the context of defining a study population, it is more relevant to think of eligibility as encompassing the terms inclusion/exclusion.
The appropriate inclusion or exclusion of subjects satisfies regulatory, safety and scientific clinical trial criteria. Although there has been a sharp increase in criteria based on molecular and/or genetic readouts, the principle remains unchanged from the publication of the first cancer clinical trial in 1960. Inclusion criteria define the Intent to Treat (ITT) population whilst the exclusion criteria define the safety population. In design terms the aim is to minimize adverse events and to decrease bias by defining a homogenous disease population.
When I joined the CRO business, I was surprised at the number of clinical trial eligibility reads on the books. With the current emphasis on standardized response criteria, the thought that there may be a need for eligibility standardization had not crossed my mind. Perhaps I shouldn't have been so surprised. It seems reasonable to apply the same rigor to trial entry as it is to its execution and analysis.
Imaging Role in Clinical Trial Design
Imaging of course plays a pivotal role in solid tumor and lymphoma protocols by confirming the presence or absence of measurable disease thereby determining patient eligibility. Several questions already familiar to designers of imaging reads come up when you consider eligibility standards. Some are practical; others are more related to design.
Let's look at the practical issues first. A prospective clinical trial subject must be assessed for eligibility with minimal delay. This is a multi-step process, and requires rapid and efficient transmittal of image data to the CRO, QA of those images, delivery to the reviewer, and return of the results to both the CRO and site while creating a validated audit trail. Until recently, close to 90 % of imaging data were delivered to BioClinica via hard copy media, making for a rather slow process. BioClinica has made great strides in promoting a priori electronic transmission of data via our WebSend™ web portal solution, a variation of which is used to transfer data to our reviewers.
From a design perspective we have approached the anticipation of reader variability by including 2 +1 paradigms though time considerations practically means that a single reader is used more often than not. Where I have heard recent debate is how to most effectively interact with a site at times of disagreement. Understandably, site readers would wish feedback if a read is turned centrally. I personally think this is appropriate in an ideal world but practicality rarely affords the time for such feedback. In addition it is rarely considered when defining the scope of work of a study.
Finally, it is worth emphasizing that clinical trial eligibility reads are not clinical reviews meant for patient management but rather part of a scientific protocol meant to control a defined experiment as tightly as possible.
As I continue to ponder my initial question it is clear that just as clinical trials require subjects who meet the right eligibility, only those of the highest caliber of bravery and nobility were bestowed the honor of knighthood. Perhaps St. George may not have been so proud of his victory if the Dragon was included in the fight despite having poor standardized fire breathing capabilities.
If you have any questions or feedback, please feel free to comment below.
Dr. Andy Dzik-Jurasz will attend the American Society of Clinical Oncology (ASCO) Meeting June 1 – 5, 2012 in Chicago Illinois. Mirada Medical and BioClinica will jointly demonstrate the expanded molecular imaging capabilities that BioClinica can provide through their recently announced partnership in Booth#16105.