
The truth about ‘breakthrough’ drugs - wellokthen
https://www.washingtonpost.com/news/to-your-health/wp/2018/07/17/the-truth-about-breakthrough-drugs/
======
refurb
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.

~~~
ejstronge
> 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?

~~~
refurb
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...](https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM610801.pdf)

~~~
ejstronge
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.

~~~
refurb
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.

------
jihadjihad
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...](https://en.wikipedia.org/wiki/Drotrecogin_alfa#Marketing_controversy)

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

~~~
ams6110
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).

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

~~~
rincebrain
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.

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

[https://www.amazon.com/Regulation-Pharmaceutical-
Innovation-...](https://www.amazon.com/Regulation-Pharmaceutical-Innovation-
Amendments-Evaluative/dp/0844731285/)

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

------
cryoshon
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.

~~~
tlb
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.

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

[https://maps.org/news/bulletin/articles/429-maps-bulletin-
sp...](https://maps.org/news/bulletin/articles/429-maps-bulletin-
spring-2018-vol-28-no-1/7256-breakthrough-therapy-designation-streamlining-
the-path-to-approval-spring-2018)

