Benefit-Risk Evaluation of SGLT2 Inhibitor Safety Issues

The rating-based conjoint analysis experiment was introduced by providing some basic information about a medicine for the treatment of T2DM. The medicine was presented as a hypothetical drug, without mentioning a specific medicine or class of medicines. However, the provided information regarding the medicine was based on real information regarding SGLT2 inhibitors and included a short summary of selected favourable and unfavourable effects. To obtain an indication of the responders’ benefit-risk evaluation of the drug, they were asked the question “How would you rate the benefit-risk balance of this drug?” (using a visual analogue scale (VAS) from 0 to 100).
Next, we presented various scenarios of safety issues described in terms of four characteristics, termed attributes. Each attribute had two or three alternatives, termed levels. The first attribute was the ADR, which could have three levels, namely DKA, amputation, or bone fracture. These ADRs have been associated with SGLT2 inhibitors and were described according to the definitions available in the EMA assessment reports of this drug class [24 –26 ]. We selected these ADRs because of the previously reported discrepancies in safety advisories among regulatory agencies worldwide [5 (link)]. The other three attributes were hypothetical for each scenario and had two levels each (Table 1): (1) source of information (i.e., spontaneous reports/epidemiological studies or clinical trials), (2) level of causality (possible or probable), and (3) frequency of the ADR (two times higher or three times higher than the risk with the standard of care, which was specified for each ADR). These attributes were selected because of their possible relevance at the time of assessing a safety issue, based on input from pharmacovigilance experts and information from regulatory guidelines [24 –29 ].Table 1

Attributes and attribute levels used in the rating-based conjoint experiment

Attributes	Levels
ADRs	Diabetic ketoacidosis—Serious complication caused by low insulin levels that leads to the accumulation of acidic ketone bodies in the blood. Patients may require hospitalization or treatment in an emergency department*
	Amputations—Lower limb amputation (mostly affecting the toes)
	Bone fracture—Bone fracture and decrease in bone mineral density. Bone fracture may occur when minor trauma. For example, when falling from standing height
Source of information	Spontaneous reports and/or epidemiological studies*
	Clinical trials
Level of causality	Possible—the ADR happened within a reasonable time sequence to drug administration, but it could also be explained by concurrent disease or other drugs or chemicals*
	Probable—the ADR happened within a reasonable time sequence to drug administration, and it is unlikely to be attributed to concurrent disease or other drugs or chemicals
Frequency of the ADR	Two times higher than with the standard of care (this was specified for each ADR)*
	Three times higher than with the standard of care (this was specified for each ADR)

ADR adverse drug reaction

*Reference level

To obtain the minimum number of scenarios necessary to estimate all main effects and all possible interaction effects between the ADRs and the other attributes, we generated an orthogonal fractional factorial design for each ADR. This process resulted in a total of 12 scenarios, four per ADR, with differences in the level of at least one of the attributes. We created three blocks of scenarios based on the ADRs, and the order of the scenarios within each block was randomised. The order in which the blocks were presented in the survey was also randomised, and all participants were asked to assess the 12 scenarios.
For each scenario, the participants were asked three questions. The first question assessed their concern for the safety issue: “With this additional hypothetical information available, how concerned are you about this safety issue?” (VAS from 0 to 100). The next questions addressed their opinion on the need to communicate about the safety issue: “In your opinion, should the summary of product characteristics (SmPC) of the drug be updated?” (yes or no) and “In your opinion, should a direct healthcare professional communication (DHPC) be sent out?” (yes or no).