A Benefit-Risk Analysis Approach to Capture Regulatory Decision-Making: Multiple Myeloma

Abstract

Drug regulators around the world make decisions about drug approvability based on qualitative benefit-risk analysis. In this work, a quantitative benefit-risk analysis approach captures regulatory decision-making about new drugs to treat multiple myeloma (MM). MM assessments have been based on endpoints such as time to progression (TTP), progression-free survival (PFS), and objective response rate (ORR) which are different than benefit-risk analysis based on overall survival (OS). Twenty-three FDA decisions on MM drugs submitted to FDA between 2003 and 2016 were identified and analyzed. The benefits and risks were quantified relative to comparators (typically the control arm of the clinical trial) to estimate whether the median benefit-risk was positive or negative. A sensitivity analysis was demonstrated using ixazomib to explore the magnitude of uncertainty. FDA approval decision outcomes were consistent and logical using this benefit-risk framework.

Figure 1

Analysis of benefits and risks (a). First-line (b). Nonfirst-line. The naming convention for the points in the chart above is as follows: NNN-LL QQQQ-YY; where: NNN represents the first three letters in the name of the drug (e.g., “Len” for lenalidomide; LL represents the line of treatment (e.g., 1L indicating lenalidomide used as the first-line of treatment); QQQQ (if needed) is a description of a relevant subpopulation and/or specific pivotal trial; YY represents the year associated with the study/decision pertaining to the data point. The PFS improvement shown for the point Pan+Bor+Dex-2L-14* in Figure 1b is based on an assessment by an Independent Review Committee (IRC).

Figure 2

Benefit-risk of ixazomib plus lenalidomide plus dexamethasone.

Figure 3

Sensitivity analysis of benefit-risk over control: ixazomib plus lenalidomide plus dexamethasone.

Figure 4

Evolution of estimated clinical outcome of OS benefit-risk over time for MM patients. The starting point for the blue line at year 2001 is taken as the estimated median OS of newly diagnosed MM patients prior to 1996 with the ratio of risk to benefit the same as that of thalidomide plus dexamethasone.