1. Can we use an active control when the active control is not approved for the indication, but used as standard care (off-label)?
This was answered in section V of the draft guidance. "The active control does not have to be labeled for the indication being studied in the NI study, as long as there are adequate data to support the chosen NI margin. FDA does, in some cases, rely on published literature and has done so in carrying out the meta-analyses of the active control used to define NI margins. "
2. When literatures are used to support the choice of NI margin, what if the endpoints are different from various historical studies?
in Section V of the draft guidance, it says "...among these considerations are the quality of the publications (the level of detail provided), the difficulty of assessing the endpoints used, changes in practice between the present and the time of the studies, whether FDA has reviewed some or all of the studies, and whether FDA and sponsor have access to the original data. As noted above, the endpoint for the NI study could be different (e.g., death, heart attack, and stroke) from the primary endpoint (cardiovascular death) in the studies if the alternative endpoint is well assessed".
3. What if there is no historical clinical trial that directly compare the active control vs. Placebo?
We would typically think that if this is a situation, NI study design is not an option any more because there is no way to estimate the NI margin (precisely M1 margin). However, Dr. Ed Cox presented an example during the webinar to estimate the non-inferiority margin in an indirect way. While there is no clinical trial directly comparing the active control with Placebo, we can still estimate the treatment effect of active control by search for evidence separately for active control group and for Placebo group. For example, in anti-infective area, a lot of antibiotics have been used for many years (perhaps even before FDA is formed). There might never been a formal clinical trial to show that certain antibiotics are better than placebo. Now in pursuing a new antibiotics for indication, a placebo controlled study is not ethical (since other antibiotics products are the standard care). In order to conduct a NI study, it is challenging in choosing the NI margin. The suggestion from Dr Ed Cox's presentation is to derive estimate of effect of active control over placebo by:
- Estimate the placebo response rate or the response rate if untreated
- Estimate the response rate in the setting of "inadequate" or "inappropriate" therapey
- Estimate the response rate of the active control therapy from literatures with active control therapy information
Notice that for each estimation, a collection of literatures are analyzed and often the meta analysis is required. The meta analysis may require the random effect estimate. In Dr Cox's presentation, DerSimonian Larid random effects estimates is used. This approach is described in the original paper as well as many books on meta analysis (for example, "meta analysis of controlled clinical trials" by Anne Whitehead). My colleague wrote the SAS program for this approach. A SAS paper compared the results from DerSimonian approach with the results from SAS Proc Mixed and NLMixed.