The Medicines and Healthcare Products Regulatory Agency (MHRA) have written a blog to clarify their expectations regarding the unblinding and reporting of serious adverse reactions (SARs) associated with comparator medicines.
It is stated in the Good Clinical Practice (GCP) guide that if there is a SAR in a blinded trial, then expectedness is assessed with the assumption that the subject is taking the test drug. If the event is assessed as unexpected against the reference safety information (RSI) for the test medicine, then treatment is unblinded. If the patient is taking the test product, then this is reported as a Suspected Unexpected Serious Adverse Reaction (SUSAR). If the patient is on the comparator, then expectedness is reassessed against the comparator RSI; if the SAR is unexpected then it will be reported as SUSAR.
Although questions raised include what happens if the SAR is expected for the test drug but not expected for the comparator? If the process outlined above is followed then this would be reported as a SUSAR, as the event would not be unblinded. However, there is no legislative difference, thus everything that is listed in section D of the EudraCT application form must be considered as Investigational Medicinal Products (IMPs). This means that SUSARs associated with a comparator product should also follow the same reporting requirements as for the test drug.
Efficient data collection may make this process more straightforward. The MHRA have stated that if the Serious Adverse Event (SAE) form was detailed enough to be able to capture whether the investigator considered the reaction to be associated with the test drug only, the comparator drug only, or both. Hence prompting the expectedness assessment against the suspected drug only, or both.
The MHRA expects companies to have a procedure in place to protect the blind for the study team for those SARs which are unblinded by the sponsor for regulatory reporting purposes. The MHRA may allow for some SARs not to be unblinded for trial integrity, but this is a specific part of the protocol and the MHRA have to agree to it as part of the Clinical Trial Authorisation.
To read the MHRA Inspectorate blog on how to manage safety reporting in a blinded trial, please click here.