Okay, this paper is not going to make a lot of people happy. The authors are reviewing oncology approvals by the European Medicines Agency (EMA) from 2009 to 2013 – overall, there were 48 drugs approved for 68 indications, which sounds like good news. 24 of the 68 were approved with survival benefit shown in the clinical trials – the rest were approved on progression-free survival or the like. So how has that been working out, post-approval? Data are more scarce than you’d expect, and what’s available isn’t that encouraging:
This systematic evaluation of oncology drug approvals by the EMA in 2009-13 shows that most of the drugs (39/68, 57%) entered the market without evidence of improved survival or quality of life. At a minimum 3.3 years after market entry, there was still no conclusive evidence that 33 of these 39 cancer drugs either extended or improved life. Our findings suggest it is extremely rare for new studies or follow-up analyses of pivotal trials in the postmarketing period to report results confirming that new cancer drugs have a positive impact on the two most important outcomes for patients—survival and quality of life. When survival gains over existing treatment options or placebo were shown, they were often marginal and judged to be clinically meaningful in less than half (11/23, 48%) of all cases.
So roughly half the cancer drugs approved during this period are without this information – it’s not necessarily that these approvals have not led to any survival benefit – it’s that we don’t know if they have or not, because nothing has been reported. It has to be noted (as the authors mention) that only 18 of the indications were supported by trials that had survival as a primary endpoint, and that crossover trial designs often obscure survival in general.
A major factor in all this, of course, is what the regulatory agencies want to see and will accept. Despite a lot of talk about overall survival, the EMA seems to accept a lot of surrogate endpoints as enough for drug approval. And they’ve also been quite generous with approvals based on (basically) any statistically significant difference in survival between treatments, regardless of whether this will be something that looks to hold up in the real world.
Though surrogate endpoints are argued to have the advantage of allowing quicker drug development and patient access, it is questionable whether studies based on surrogate measures of efficacy provide optimal, or even meaningful, information for patients and clinicians. Moreover, our analysis raises the possibility that regulatory and current research practices have created a situation in which critical information about the outcomes that matter most to patients might never be generated once oncology drugs are approved for widespread use.
That’s not a good situation. I’m sure that there will be room to argue about some of the figures in this paper – and there’s plenty of room to argue about whether the situation here in the US, with the FDA, is any better. (There are plenty of arguments waiting when such data become available, too, believe me). But in general, I have to say that I agree with the conclusions that regulatory agencies should be asking for more survival data – if not at approval, then in required postmarketing surveillance. For those cheering this on, though, be aware that nothing comes for free: if you want more solid data on real-world survival, then you’re going to be paying for that, in both money and time. Tightening up the survival requirements will inevitably slow things down, and if you’re in the “Regulations are strangling drug innovation” camp, you’re not going to care for the idea much to start with.
But you pays your money and you takes your choice: faster, cheaper, and less proven – or slower, more expensive, and more proven. The only way I can see to split the difference is as mentioned above: if you’re going to approve on surrogate endpoints, then make it mandatory to collect data on what happens afterwards, and set an appropriate date to review it, with approval to be rescinded if things don’t work out. Sounds good – but remember what happened when the FDA did that with Avastin’s breast cancer indication? Nothing is simple, not with so many lives and so much money on the line.
Update: the EMA has a response to this here – I’ll add more details later, but I wanted to get the link up, because it’s very useful reading.