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Vinay Prasad @VinayPrasadMD
, 27 tweets, 7 min read Read on Twitter
Looks like we need a TWEETORIAL about the FDA using surrogate endpoints to approve cancer drugs:
Are you ready?
Let's take a critical look at this paper:
The current commish seems to like it
But what background do we need to agree on
Do you agree: If you have cancer the only things that matter are quality or quality of life?
If you said anything other than: yes-- I cannot help you. If you think HbA1c numbers or LDL numbers of tumor dimensions matter in and of themselves, I cannot help you. These are surrogates. Please read Ending Medical Reversal or any of hundreds of explainations
Now, in cancer medicine there are 2 common surrogates PFS (progression free survival and response rate (RR).
Measuring these quantities is not an exact science. DIFFERENT PEOPLE make different measurements. We only measure 3 tumor sites (even though there may be many). There are issues with censoring.
Most importantly, how well do surrogates correlate with what we care about.
Most of the correlations between these measurements and OS are poor, especially in metastatic cancers where most drug approvals come
(@JAMAInternalMed we did)
What about RR and PFS with health related quality of life
What was known prior to the current study:
Lots of surrogate approvals. With 4.5 years f/u on market few generate OS data
(@JAMAInternalMed paper we did)
This wasn't just for ACCELERATED APPROVAL, it was for REGULAR APPROVAL too
That matters b/c regular approvals typically DO NOT HAVE post market efficacy commitments
For the record: I am OK with drugs approved via accelerated approval based on surrogates if OS or HR QoL is later demonstrated; What about you?
If you use a surrogate for regular approval, it has to be "established" but in Mayo Clinic Proceedings, we proved that the FDA used unvalidated surrogates in this space
Unvalidated, means we have not formally studied if the surrogate correlates with survival or quality of life--- (or poor correlation)
So, do you think using unvalidated surrogates is bad for regular approvals, with no post market commitment
Now, let us look at the current paper, where the FDA just looks at the Accelerated approvals (those with commitments)
Here is what they find
Is 45% withdrawn or not completed post-market commitment something to celebrate?
And, when these commitments are kept-- does that mean these drugs improve OS or QoL later?
Ruh roh; seems like a self fulfilling prophecy. But wait, lets look at those numbers like Kim and I did before:
So, does the current study by FDA provide reassurance FDA is doing a good job with accelerated approval?
[See also 2 government accountability office reports: 2009, 2015]
What about the FDA's arguments that we can't test these drugs for OS or quality of life-- that's not fair!
Some arguments discussed in @Annals_Oncology : academic.oup.com/annonc/advance…
In short: does it seem astonishing to say that drugs used in terminal settings that do not confer cure cannot be tested for survival or QoL?
If you only read 1 article on this topic, go with this: [open access] bmcmedicine.biomedcentral.com/articles/10.11…
More on the topic:
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