In short, RxSignal identifies serious adverse events (AEs) being reported at an elevated rate, which are not listed in the drug's current prescribing information. RxSignal alerts our clients to 72% of all FDA Safety Labeling Changes, on average 5 years prior to FDA announcement.
Within our RxSignal system, a drug/AE pair can be designated as Active, Watchlist, or Expired.
Active RxSignals meet the following criteria:
The AE must be on our RxSignal term list
The AE must not be listed on the drug's current label or prescribing information
There must be at least 2 primary suspect cases for the drug/AE pair*
The ROR(Reporting Odds Ratio) value must be 2.0 or greater**
The AE cannot be related to the disease the medication is FDA-approved to treat
*There are three very serious AE terms that do not require these minimums, as they are so closely monitored by FDA: Stevens-Johnson Syndrome, Toxic epidermal necrolysis, and Progressive multifocal leukoencephalopathy.
**See point 4 below to read detailed criteria for ROR cut-offs.
Watchlist RxSignals follow the same criteria as Actives, except that their ROR value must be between 1.0 and 2.0
Five years after an Active or Watchlist RxSignal has been triggered, it becomes an Expired signal if FDA has not acted on it.
Detailed Methodology
Users can read our research article published in Drug Safety journal, or take a look at our RxSignal methodology described in the following paragraphs:
To create a term list which included AEs FDA was most likely to act upon, were viewed over 1,000 FDA Drug Safety Communications and Safety LabelingChanges issued from 2008 to 2015. Our analysis did not include any SafetyLabeling Changes that detailed AEs that were already on a given drug’s label. We also included FDA Designated Medical Event (DME) List terms.
To identify which AEs were listed on a drug’s prescribing information we mined each drug label to record listed AEs and we also determined which section(s) of the drug insert they were listed under.
When the ROR (Reporting Odds Ratio) reaches 2 or above for an RxSignal-eligible AE that is not listed on a drug's label, an Active RxSignal is triggered. A Watchlist RxSignal is triggered if an unlisted RxSignal eligible AE has a ROR between 1 and 2.
Previously we had a minimum of 5 cases for a signal to be Active. Now, however, if a drug/AE combination has between 2-5 cases it will be deemed Active if the ROR has a lower 95% confidence interval greater than 2.0. If a drug/AE combination has between 2 and 5 cases, it will be deemed Watchlist if the ROR has a lower 95% confidence interval between 1.0 and 2.0. We made this modification because the 5-case minimum lacked enough sensitivity to predict certain label changes and ROR calculations tend to become unstable when the number of cases is small, particularly for rarely reported AEs.
If the signal could potentially be related to the underlying disease, we created a new category for those signals called Active DR and Watchlist DR.
There are now 3AEs which are so closely watched by FDA that they only need 1 case, and noROR minimum, to generate an Active RxSignal: PML (Progressive MultifocalLeukoencephalopathy), SJS (Stevens-Johnson Syndrome), and TEN (ToxicEpidermal Necrolysis).