Digitally generated lock on circuit board in blue room.jpegClinical data transparency has been under fire for years. There are documented cases of negative clinical trial results not being reported, leading to organizations like Trial end-points are often a moving target, being changed mid-trial, leading to organizations like And it’s not only manufacturer sponsored research either. As STAT pointed out, most research institutions routinely fail to meet reporting requirements as well.

Furthermore, negative data and important safety issues are often “hidden” in publications, outside of the requirements of reporting laws and standard practices. The lack of full transparency leads to evidence based medicine without all of the evidence, and makes pharma CI's job of fully understanding competitors’ data especially difficult.

One form of hidden data points are adverse events that are not listed as “serious” in clinical trials because they do not lead to death, hospitalization, or life-threatening situations. 

When these events do not fall into the “serious” category, they are listed as “other” Adverse Events, and typically require a reporting threshold of 5% or more before they are reported in publications or  This reporting nuance can lead to missing data on adverse events issues that are serious enough to be included in the EudraVigilance list of Important Medical Events (IME)  but not important enough to be reported in the trial.   

An evidence aggregation platform that uses clinical trial results linked to real world data can identify these types of hidden events.

Take for example the hepatitis C drug Harvoni and the IME-classified adverse event hyperbilirubinemia. Hyperbilirubinemia is when there are an abnormally large amount of bilirubin in the circulating blood, resulting in clinically apparent icterus or jaundice when the concentration is sufficient. Throughout the reported clinical trials for Harvoni, there was only 1 case deemed “serious” and 11 cases regarded as “other”.  Both the serious and other cases occurred in both SOLAR-1 (7 others) and SOLAR-2 (4 others and 1 serious) where Harvoni was used in combination with ribavirin. Even though the 11 cases were not deemed “serious,” they are nonetheless clinically meaningful pieces of evidence that can be used to better understand the probability of a patient experiencing similar effects.

Interestingly, when looking at other trials that paired Harvoni with ribavirin, no cases of hyperbilirubinemia were reported, potentially because those cases did not reach the 5% reporting threshold in those trials

Often adverse events are found when performing in-depth literature reviews and secondary analyses of trial data. When these adverse events are found, manufacturers are required to report the adverse event to FDA, referencing the literature in which the AE was found. When clinical trial results and real world data, including FDA Adverse Event Reporting System (FAERS), are linked together in an evidence aggregation platform, it is easy to identify FAERS case reports that reference results from a trial.

Such is the case with the SIRIUS trial where an additional case of hyperbilirubinemia was found.  A case report filed by Roche, the manufacturer of ribavirin branded as Copegus, implicated Harvoni as the primary suspect and ribavirin as the secondary suspect in causing hyperbilirubinemia, abnormal hemoglobin, abnormal lipase, and abnormal lymphocyte counts in a patient. Roche provided Lancet’s publication of SIRIUS results as a literature reference of where that patient data was found. Interestingly, hyperbilirubinemia was the only AE not specifically listed in the literature. It was in non-reported patient records that were tied to this case and trial. There are several other instances of where hyperbilirubinemia FAERS cases were tied to clinical trials for Sovaldi, Harvoni and other compounds that did not appear in the original published literature.

Without an evidence aggregation platform there is little chance that data such as these could be easily uncovered.

With an evidence aggregation platform, clinical trial results are integrated with real world data to complete the overall safety picture of any drug. By tying individual IME serious cases to trials that previously were unreported, “hidden” data highlighting specific previously unknown safety issues of competitive compounds can come to light, creating potentially valuable added safety advantages that can change prescription practice and formulary coverage decisions.

Advera Health’s Evidex™ is an evidence aggregation platform that makes evidence collection and generation easy though a simple to use, yet powerful web-based application. To learn more about specific use cases of evidence aggregation platform's like Evidex for pharmaceutical companies, managed care organizations, hospitals, and product liability insurers, download our comprehensive guide to using drug safety data



Jim Davis, EVP Advera Health

Topics: Drug Safety, Clinical Evidence, Evidex, Pharmacovigiance 2.0

Jim Davis

Written by Jim Davis

As Executive Vice President, Jim is responsible for the commercialization strategy for Advera Health Analytics.