What does surrogate end point mean?

[Music] What does surrogate endpoint mean? So an end point is the goalpost for efficacy in a given trial. Now, it's different for early stage trials versus late stage trials. For example, a phase one trial, really the endpoint is safety. You want to ensure that a drug can be given safely to patients in a given population. But what we're really talking about in terms of endpoints is efficacy endpoints. In other words, is a drug effective in treating a given disease. So historically the gold standard was overall survival. In other words, does a treatment result in improvement in overall survival over either best supportive care for advanced disease or for a comparable standard of care in a given phase of disease, either upfront or relapsed disease or whatever. And in the early days of myeloma research, 2000 to 2005, you know, that was a relatively low bar because we had very poor outcomes with current with the treatments that were available at that time. So overall survival was a very reasonable endpoint for a trial for a new drug or a new agent to get FDA approval. But as we've introduced better and better drugs into the treatment for myeloma, myeloma patients are living longer and longer. So the second commonly used endpoint is something called progression free survival, which means how long do people stay in remission? So although that historically wasn't considered a gold standard, progression free survival has become accepted as an indicator of efficacy for new drugs. But now we're in a situation where, you know, even if a patient is on a given treatment, even if they're on a clinical trial, they may relapse. That doesn't mean that they're doomed because there's other trials, there's other drugs that can be used. So both progression free and overall survival become very difficult goals to reach in a clinical trial. So we want to bring effective new drugs into a field. But in order to achieve FDA approval, there's a very high bar that needs to be cleared. If you use traditional endpoints such as overall survival, progression free survival. So now we started thinking about what is an appropriate or accurate predictor of overall survival or progression free survival. So that's when we start talking about surrogate endpoints. And the big one under discussion in myeloma is what's called minimal residual disease assessment. And there's a couple of different technologies to do minimal residual disease assessment. Essentially, it's an ultra sensitive way of measuring for the presence or absence of myeloma cells. And in several trials, there's been demonstration that minimal residual disease negative. In other words, no detectable disease by ultra sensitive tests predicts for better outcome either progression free survival, mostly progression free survival, I think, would be fair to say. So now there is a push to use something like MRD negative status as a surrogate for progression free survival. Right. that's what we talk about when we're talking about surrogate endpoints and as you can imagine, you know, being able to measure MRD status, positive or negative after six months of therapy is a lot more feasible rather than waiting. You know, we have some drugs that have progression free survival of two or three years. It would take a long time to reach a reasonable endpoint that would then be acceptable to the FDA for approval. So surrogate endpoints are an important topic and there is I think the likelihood is in the near future the FDA will accept something like MRD as a surrogate endpoint for clinical trials, for a provisional approval for new medications that are coming into the field, that this has been supported by a lot of translational and clinical research by investigators all over the world. It's a very important topic and it's been very well researched. And I think there's going to be a lot of support for surrogate endpoints to be acceptable in clinical trials. It's not going to be a complete replacement. We're still going to follow patients to get the real progression free and overall survival, obviously, that takes much longer. So provisional approval based on something like MRD negative will become acceptable in the near future. I think that there's general agreement in the field that it is important in a prospective manner. In other words, we can look back at a lot of trials and say, Oh well, was there a relationship between MRD and progression free and overall survival? And there's been a lot of interest in that. A lot of work has been published on that. But the true acid test of that hypothesis is to do it in a prospective manner. In other words, the plan from the outset is to use both MRD and either progression free or overall survival as endpoints in the study. It may be acceptable for provisional approval of a medication to use the MRD results, but we will still follow patients out for the progression free and overall survival. And this will tell us in a rigorous, statistically rigorous manner whether we can actually whether it's MRD does in fact act as a surrogate endpoint for these traditional endpoints, What are the challenges of clinical trials? One of the challenges that we have right now with new therapy development in myeloma and it's quite frankly quite a positive, but it does represent a therapy development challenge, is that the gold standard that we use for if a treatment works is does this allow a patient to live longer? Fortunately, our patients are living much longer and after a certain treatment, they have access to two, three, four or five more therapies. So we have to use things different than how long the patient lives, what we technically call overall survival. And we look at surrogates called progression free survival. How long does this therapy prevent the myeloma from getting worse? And again, we're using that as a marker, a predictive marker, to say how long someone's going to live. Now, fortunately, our therapies are so effective that progression free survival is very long. And so we're trying to look in order to help our therapy development, to look at earlier markers. And one of the earlier markers that we could possibly use is something like MRD. We think that if the more the patients on a certain treatment, go to MRD negative. That is, we can't detect myeloma by our most even most sensitive measures that will predict improvement in how long the myeloma stays in remission and substantively predict how long patients will live. [Music]