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The truth about ‘breakthrough’ drugs (washingtonpost.com)
69 points by wellokthen on Aug 20, 2018 | hide | past | favorite | 16 comments



Looking at the original paper, the author does the analysis looking at breakthrough drug trial design, but doesn't really talk about what it means.

Of the 46 drugs approved under breakthrough designation, 25 were for oncology. The FDA often allows for a lot of flexibility with trial sign in oncology due to the high unmet need.

The author mentions a lack of trials being double-blinded, having a placebo or active comparator and clinical outcome vs. surrogate marker.

All of this is quite common outside of the breakthrough drug designation. Nothing new here. Double-blinding a trial isn't as big a deal when what you are measuring is not impact by observer bias (tumor size). In addition, if you're measuring a surrogate marker (that is an accepted proxy for clinical outcomes), you don't need a comparator arm.

I don't think any of these findings should be all that surprising or concerning.


> if you're measuring a surrogate marker (that is an accepted proxy for clinical outcomes), you don't need a comparator arm

Why is this the case? Wouldn’t there be concerns that a study population might be different from the general population and thus require an internal control?


Here is a good example of FDA guidance on the issue.[1]

FDA acknowledges that FVIII levels can serve as a proxy for clinical outcome (reduced bleeding episodes) in hemophilia A.

Our understanding of what is "normal" in FVIII blood levels is such that a single arm, surrogate biomarker study is sufficient for approval.

[1]https://www.fda.gov/downloads/BiologicsBloodVaccines/Guidanc...


Could you help by pointing out where they talk about not obtaining baseline/control data? After a quick glance, they only seem to mention using a within-subject design.


Sorry, misread your reply. Yes, they do an internal baseline/control, but don't have a control arm (either placebo or active comparator) in the trial.

That was the focus of the JAMA article.


>"Double-blinding a trial isn't as big a deal when what you are measuring is not impact by observer bias (tumor size)."

Have you ever tried to measure something like this and analyze the data? There are so many ways to skew the results...

EDIT:

That's not even to mention basic stuff like handling the treated rats more carefully so they are less stressed, etc.


Sketchy stuff. The two drugs that come to mind are Xigris [0] and Celebrex [1]. There is so much money to be made and so few incentives to be rigorous in the trial process. It's no surprise we get cases where big pharma companies cook the books on efficacy and go to great lengths to ensure there is a market for their latest "blockbuster."

[0] https://en.wikipedia.org/wiki/Drotrecogin_alfa#Marketing_con...

[1] https://en.wikipedia.org/wiki/Celecoxib#Fabricated_efficacy_...


The unintended consequence of the onerous FDA approval process is that only a few extremely large players have the resources to develop and bring new drugs to the market. Therefore they need to make a lot of money back to cover their costs.

On the other hand, in earlier times we had a lot of drugs that were in the "snake oil" category, making a lot of claims but doing nothing at all (or that were actually harmful).


But in a bid to mitigate risk (from their shareholders) big pharma effectively outsources lots of compound discovery to biotechs. This has helped create a large pool of biotech startups that never intend to run a phase 1 study but instead prepare for acquisition upon promising preclinical.


IMO the only criteria should be safety. Medicine doesn't have to work for everyone to be useful for a lot of people.


A great many drugs are grossly unsafe if you even minorly exceed the clinical dosage threshold, but are still regularly used by people because we haven't found better replacements.

A much larger set of drugs fall into a gradient of "as far as we can tell you'll just excrete it if you take too much" to "it's probably not _good_ if you unnecessarily take it, but it won't really be detectable in 4 weeks" to "oh god why would you ever prescribe that".

So if we were purely grading on safety, we'd be out quite a lot of pharmacology.


Sam Peltzman writes about this in "Regulation of Pharmaceutical Innovation"

https://www.amazon.com/Regulation-Pharmaceutical-Innovation-...

And does a statistical evaluation of the effects of the FDA regulations.


the entire FDA approval process was heavily gamed before, and is probably even more heavily gamed now. i'm talking about companies specifically starting drug discovery -- without anything in hand -- targeted at diseases where there is the reputation for the FDA playing loose with the approval process for whatever reason. fewer regulatory issues translates cleanly into more profit.

as the author points out, the incentives are always in favor of doing a bad job with regard to efficacy and trial design. a company that can produce a really great and well-proven drug is not going to make more money than a company that produces a shitty drug that is also approved for the same condition.

in fact, with the right marketing efforts, the execs would even see similar sales figures for both of these hypothetical drugs. hence why more is spent on marketing than R&D.


The "whatever reason" is that the level of long-term side effects that can be tolerated depends on the disease being cured. A drug that cures a previously fatal cancer should be approved, even if there are some long-term side-effects, because it's better than death. A drug that treats hair loss or heartburn needs studies to make sure that serious long-term side effects are extremely rare.

Testing for rare long-term effects requires a huge sample size, and billion dollar clinical trial budgets.

Teams do decide, early on, to try to discover drugs for serious diseases or common diseases, depending on how much money they think they can raise. Usually only proven teams can raise the huge amounts, so most pharma startups target serious niche diseases hoping for approval under the orphan drug program.


>"a company that can produce a really great and well-proven drug is not going to make more money than a company that produces a shitty drug that is also approved for the same condition."

Yep, there is only a weak mapping between FDA approval and actual drug usefulness.


The FDA recently granted MDMA their 'breakthrough therapy designation'.

https://maps.org/news/bulletin/articles/429-maps-bulletin-sp...




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