CV Outcomes Trials for Diabetes Drugs Soon to Run Out

But FDA might revise mandate to a more useful one, says Rury Holman

  • by Senior Associate Editor, MedPage Today
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    Medpage Today

Since the FDA started requiring large cardiovascular outcomes trials to affirm safety of diabetes drugs in 2008, a steady stream of results has flowed -- punctuated by ripples from superiority of a few.

However, the flow soon will slow to a trickle and could change course entirely, Rury Holman, MBChB, tells MedPage Today in this interview.

"What I think will change is I think the FDA will revise their guidance," he says, explaining: "What we really need is a trial in which the drugs are head-to-head and you can see which is best, and you can work out which patients it's best to give it to. I think you'll see more informative trials coming, and then if the FDA says that you have to do that, the companies will do it, of course."

I caught up with Holman, who recently presented results from the latest diabetes drug outcomes trial, the EXSCEL trial of extended-release exenatide (Bydureon), and heads the world's largest academic diabetes clinical trials unit at the University of Oxford in England. That conversation, lightly edited for brevity, follows.

Holman: The reason we are seeing the backlog clearing is that there have not been, apart from the SGLT2s, any more recent new classes of drug. The drugs that will go to the market in each class -- there's maybe three or four drugs -- they've all got trials running. They'll run now till 2020 ... Until we see a new class of drug, they're unlikely to start a new trial. So it depends on that process. There are new agents out there. We're working on them, but there's still a big translation stage.

MPT: Is there going to be a gap between now and 2020, or are they going to continue to come out until 2020?

Holman: There are trials planned for next year and 2019. Right through to 2020 are trials coming through.

MPT: Then maybe in 2020 it will start to drop off?

Holman: Each trial takes about 3 years now. We don't know what people are going to start in the next few months. What I think will change is ... the FDA will revise their guidance. So these big safety trials are not really clinically helpful. We've been very lucky that, in some instances, we got a great result. But remember, the trials were set up to show they didn't cause cardiovascular harm, which is a bit negative if you think about it.

I think the FDA -- and I know the FDA and the rest of us -- are talking about "If I could do a trial now, what would I want it to show?" Safety, of course. But actually, I would like to know which drug works best in which patients, and that means head-to-head trials. It means, perhaps, more complicated trials, but then the guidance for the clinician will be much better.

For the moment, each trial is separate. Oh, yes, we're trying to compare EXSCEL and LEADER and SUSTAIN, different populations, different entry criteria, so you have to make guesses. What we really need is a trial in which the drugs are head-to-head and you can see which is best, and you can work out which patients it's best to give it to. I think you'll see more informative trials coming, and then if the FDA says that you have to do that, the companies will do it, of course. So, the FDA is key to that and the EMA [European Medicines Agency], of course.

MPT: Back when the ELIXA trial results came out, the discussion arose whether the mandate for clinical safety trials could be money better spent doing something that's actually clinically useful.

Holman: What I have just said. Yes, so it transformed the landscape because the companies couldn't license their drug without the trial. So suddenly they invested a gazillion bucks into doing trials, which were very simple, not very informative, and some companies got lucky.

If you remember the SUSTAIN 6, which was the Novo semaglutide study, they didn't even specify superiority analysis in the analysis plan. It was just a non-inferiority study because they were doing it just for safety. Then they got lucky, and it shows cardiovascular benefit. So doing these big trials has yielded some good results, but that was, if you like, a chance finding. It wasn't because they were designed to do that. The trials that we need to do for the same money should be designed to give you clinical answers and [be] designed to find what's best, not what doesn't cause cardiovascular problems.

MPT: That's where pragmatic design comes in?

Holman: Yes. The important thing about pragmatic design is, in the early days, the big trials were done in special centers. Patients were taken out of normal care and treated extremely well, which doesn't reflect the normal practice. Our trials are done where the patient is, with the patient's own physician looking after them, and we just add on the trial medication and do the measurements.

That means that if we get a result and you put it into a clinical guideline, it will work because it was done in a clinical practice. If you do it in a special center, there's only three of them in the country and that's the only place you can do that sort of care; it's not transferable. The reason for that was in the early days trialists didn't want any confounding. They thought they needed to control everything, which is good for clinical experiment for a scientist, but it's no good at all when you want to know how a drug works for real.

We heard all about this real-world data, which is not a good place to go. That's all bias. What you need are real-world trials, which is what we're doing, where patients in their ordinary environment get to try a new drug, and we don't change anything else.

MPT: Do you think that these cardiovascular outcomes trials should be interpreted to say drugs that showed superiority should get top billing in treatment algorithms and expanded indications?

Holman: Our trial is more similar than different to the others. We think as a class, basically, once you've allowed for the difference in the population and different follow-up, they are almost identical in terms of what they deliver. But of course, companies and people with opinions will be trying to sway the formulary and things. That will always happen. The question is if a trial is put into meta-analysis and there's really no difference between them, it should be a class effect. I don't see the FDA cherry-picking individual drugs, unless you have a head-to-head study.

MPT: But they're not going to give somebody an indication when they don't have a trial for it.

Holman: It won't go on the label. No. ... But there's a difference between a label and the way physicians use the drug.

If it's in the label, it could be marketed for that purpose, and that's completely correct. If it's not in the label and people feel that the class is similar and maybe there's a price difference or a convenience difference, then the physicians may choose to do differently. That's a physician choice. It's more complicated than just being in the label. If it's not in the label, you can't make the claim. That's for sure. So anybody with a label should do better, but it doesn't mean that every physician will follow that.