For those interested, here is some information regarding...

For those interested, here is some information regarding clinical trial data monitoring committees and the process of our interim analysis.

As we all patiently (...) wait for the results of the rem-L interim analysis, I thought it would be useful to provide some information on the DSMB (Data Safety Monitoring Board) and to clarify their responsibility and relationship to Mesoblast.

The DSMB is a group of individuals with relevant expertise that review on a regular basis the data from an ongoing clinical trial. As most posters have noted, it is their role to analyse the unblinded efficacy and safety data from our trial, and will provide recommendations at pre-determined points whether to continue the trial or stop due to efficacy (it works) or futility (doesn't work). For fear of throwing around terms that some may not have heard before - blinding in a clinical trial refers to the process of masking the therapeutic so the patient does not know what they are receiving. In our case, the trial is double-blinded meaning the administrator, Mesoblast, also does not know which patient is receiving what. This is to minimise any potential bias in results. Everything NEEDS to remain objective.

The DSMB is appointed by Mesoblast. Meaning that the appointees will likely have previous working relationships with the company, or individuals within the company. This does not mean there is a lapse in objectivity due to their relationship as the FDA recommends strict procedures to assess potential conflicts of interests. What it does mean however, is that the DSMB is extremely clued into the the progress, enrollment, safety and context of the trial, due their closeness to Mesoblast. The trial investigators, the study steering group and Meso would have developed the analytical plan collaboratively. These individuals are prohibited from being on the DSMB, however they will work with the principal statistician who will be preparing and presenting the interim analysis prior to the analysis of the unblinded data to develop a template. Ergo, the DSMB definitely KNOWS what it is looking for.

Before someone says, 'duh, they just have to compare the deaths!!!'. That's not entirely true. Plenty of great work has gone into this thread to mock up scenarios to estimate survival ratios that will results in 'overwhelming efficacy' but as some have posted, this trial utilises 'Bayesian predictive probabilities'. So we only have half of the solution. As simply as I can put it, Bayesian predictions use the prior observations of the 30% who were enrolled and had 30 days of monitoring, to estimate the probability of seeing a significantly positive result IF the trial were to continue to the 300 patient sample size. As a result, the interim analysis is not something that happens in 5 minutes with the push of a button as some have posted. This type of modelling often requires intensive computer simulations with repeated sampling of future observations to form the predictive distributions. So we are not just looking at deaths, we are also calculating the probability of death for 210 patients who may not have even enrolled yet across multiple different parameter settings!

This type of analysis is best used for trials with lagging outcomes, such as our 30 day all-cause mortality primary endpoint and our 60 day number of days off mechanical ventilatory support. This ALSO provides predictive modelling for the multiple other secondary endpoints.

It's worth noting that the DSMB may recommend a stop to the trial without the results crossing the desired 'efficacy boundary', depending on how close the data is to the boundary and other circumstances. It's also worth noting that this recommendation is non-binding and it is purely up Mesoblast to decide whether to continue to stop the trial early.

I'm sure you can tell but I'm excited as hell for the results and the maturation of Mesoblast, being a shareholder for 5+ years. I'm rationally optimistic that this company will become a sweetheart and staple of the Australian bio-pharmaceutical industry for years to come.