Making the most of preclinical evidence

15 December 2016

Interview with

Manoj Lalu, The Ottawa Hospital

Clinical trials are usually based on findings from animal studies. But, it turns out some of those studies are based on dubious methodology, so a comprehensive review of the background literature is absolutely critical, as clinical investigator Manoj Lalu explains to Chris Smith...

Manoj - Many investigators in the past have looked at individual studies that have been performed in the lab and said, “Hey, this looks great. Let’s try this out in patients now.” However, that’s been met with largely, unfortunately, negative results. Meaning, most things don’t work that way.

Chris - Is that not what we call evidence-based medicine?

Manoj - It is in some ways, but the problem with what we called preclinical work or basic science work, the evidence base is usually pretty small, and you're talking about experiments with 10 to 20 animals. However, clinical medicine usually, we’re talking about evidence that covers thousands of patients.

Chris - So you're saying there's a fundamental problem here. people do research on a small group of animals and then call those men not mice.

Manoj - Unfortunately yes, that’s usually what occurs and what we’re trying to do is provide an alternative pathway that perhaps people can explore to get things from the bench to the bedside. Basically, we’re looking at using stem cells to treat septic shocks. So that’s when you have a life-threatening infection – when a person has this, their blood pressure gets very low. They get admitted to an intensive care unit. Right now, what we do for these patients is we give them antibiotics. We give them lots of fluids and then we give them other supportive treatment. We treat the underlying infection if we can find one as well.

Chris - What would be the rationale then for attempting to use stem cells in that sort of setting? How might stem cells assist a doctor making someone with septic shock get better?

Manoj - We think they might work in several ways. So, often people think stem cells go in and they become part of your body. However, in the setting of septic shock, we think these cells go in and they have anti-inflammatory effects. So, when you have septic shock, you get really a huge amount of inflammation that occurs in your body. We think these cells decrease the inflammation and allows the body to recover a little bit better that way.

Chris - What did you find when you began to survey the landscape of this subject a bit?

Manoj - What we did which was different from what other people have done in the past when they're trying to move from bench to bedside, we looked at the complete literature. So, we performed what's called a systematic search to try to find every single study where they had given animals these stem cells. What we found was that overall, that these stem cells, when you looked at the broad literature, reduced death in these animal models of septic shock.

Chris - Were you happy that those studies that you were looking at had been conducted in a rigorous way, in a way that could be translated to the bedside in an appropriate way rather than in a speculative one?

Manoj - First of all, I guess on the surface, yes, we’re happy that many different labs and many different groups have almost replicated the same sort of results, meaning that they had these animal models of septic shock and overall, it appears that these cells are protective. On the flip side which is a little bit concerning, the rigour that you were speaking about there, that’s where I think we can improve ourselves as basic scientists in terms of looking at ways that we can reduce what we call bias in our studies.

Chris - Is that not something though that basic science should be across anyway, somehow who is training to become a professional scientist should understand from the get-go, how you do an unbiased balanced, and rigorous study? Otherwise, it’s not valid science.

Manoj - That's a very good point and I think it speaks to something that we’re only recognising in the last few years, and that’s that we don’t get this sort of training. Really, when you're looking at these sort of methods to reduce bias to improve rigor, they're not really taught in a systematic way to trainees.

Chris - Would not a cynic put it to you though Manoj, that actually, what you’ve done is what you should be doing anyway before going anyway near a patient with any piece of research. We ought to make sure that we have thoroughly appraised the literature so that we make completely evidenced based and informed decisions about anything we do.

Manoj - I would agree with the cynic and say, yes, this is what we should be doing. However, unfortunately, that’s not what's been done in the past. There's a couple of very good examples of this where clinical trials have been designed and the push to move from animal work to patients was around a couple of positive papers. So, one was on endothelium receptor antagonist for heart failure and second was on an antioxidant agent for stroke. There was what we thought were promising preclinical results. However, the clinical trials ultimately failed and then retrospectively, scientists went back and looked at the complete literature. Surprisingly, what they found was the evidence really wasn’t that great when they conserved the complete body of literature.

Add a comment