How to manage Safety Data in a blinded Trial?

The British MHRA Inspectorate recently clarified the agency´s expectations regarding the unblinding and reporting of serious adverse reactions (SARs) and suspected unexpected serious adverse reactions (SUSARs) associated with comparator drugs.

According to the MHRA both comparators and placebos must be considered as investigational medicinal products (IMPs). Therefore, SUSARs associated with a comparator product should also follow the same reporting requirements as for the test drug. If the reaction is unexpected for either, then the blind should be broken. In addition, the way the data is collected might help to make this process easier - for example, 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. The following examples show how to proceed in these cases:

If the SAR is

  • unexpected for the test drug and the comparator -> Unblind and report as SUSAR if the subject is on test or comparator,
  • expected for the test drug, but unexpected for the comparator -> Unblind and report as SUSAR if the subject is on comparator,
  • unexpected for the test drug, but expected for the comparator -> Unblind and report as SUSAR if the subject is on test drug,
  • expected for the test drug and the comparator -> No unblinding or reporting.

However, the agency says that "this could create problems for some trials and generate a lot of potentially unnecessary unblinding, especially where the comparator drug is marketed and with a well-known safety profile, and where unblinding would not be necessary for the safety assessment of the test drug". In addition, this could potentially have an impact on data integrity (DI) if there is a large amount of unblinding in the trial, and it is not well controlled. Therefore the MHRA would expect that there is a procedure in place to protect the blind for the study team for those SARs unblinded by the sponsor for regulatory reporting purposes. With regard to DI it is therefore for some SARs allowed not to be unblinded. But this is a specific part of the protocol and has to be agreed on as part of the Clinical Trial Authorization. For example, when trial endpoints are also potential SUSARs (e.g. death or myocardial infarction in a cardiovascular trial). In these cases, an independent Data Safety Monitoring Committee should be used. "The committee would be unblinded and could monitor the safety of the trial subjects and adverse events can then be reported if the committee sees any concerns, such as the drug increasing death rates" says the agency.

More Information can be found in the MHRA Inspectorate Blog entitled "How to manage safety reporting in a blinded trial".

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