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Clinical Trials

The Coming Landscape?

Adam Feuerstein has an important list of companies (the “Gnarly Nine”) that will be going to the FDA soon. That process is always important for the companies involved, but these will serve as indicators of how the agency is dealing with the pressures for lowering the standards for drug approval. We don’t have a new FDA commissioner yet, of course, and who knows when someone is actually going to be nominated, what they think, or what even phylum they’re from, honestly, but pretty much all the names that have been floated have leaned in that direction.

One really out-there example is PTC Therapeutics, whose Ataluren has failed pretty much every test it’s been put to in the clinic (most recently for some forms of cystic fibrosis). The company has filed anyway, which is an unusual move, and I’ll let the legal language in a recent press release speak on that subject. I was going to excerpt this, but it’s pretty much all one sentence, so here goes (emphasis added):

PTC’s actual results, performance or achievements could differ materially from those expressed or implied by forward-looking statements it makes as a result of a variety of risks and uncertainties, including those related to PTC’s scientific approach and general development progress; the outcome of ongoing or future clinical studies in Translarna and PTC’s other product candidates; expectations for regulatory approvals; PTC’s ability to meet existing or future regulatory standards with respect to Translarna; the sufficiency of PTC’s cash resources and its ability to obtain adequate financing in the future for its foreseeable and unforeseeable operating expenses and capital expenditures; PTC’s ability to maintain its marketing authorization of Translarna for the treatment of nonsense mutation Duchenne muscular dystrophy (nmDMD) in the European Economic Area (EEA), including whether the European Medicines Agency (EMA) determines in future annual renewal cycles that the benefit-risk balance of Translarna authorization supports renewal of such authorization; PTC’s ability to enroll, fund, complete and timely submit to the EMA the results of Study 041, a randomized, 18-month, placebo-controlled clinical trial of Translarna for the treatment of nmDMD followed by an 18-month open label extension;  PTC’s ability to resolve the matters set forth in the Refuse to File letter it received from the United States Food and Drug Administration (FDA) in connection with its New Drug Application (NDA) for Translarna for the treatment of nmDMD, including whether filing the NDA over protest with the FDA will result in a timely or successful review of the NDA, and whether PTC will be required to perform additional clinical and non-clinical trials or analyses at significant cost; the eligible patient base and commercial potential of Translarna and PTC’s other product candidates; PTC’s ability to commercialize and commercially manufacture Translarna in general and specifically as a treatment for nmDMD; the outcome of pricing and reimbursement negotiations in those territories in which PTC is authorized to sell Translarna for the treatment of nmDMD; and the factors discussed in the “Risk Factors” section of PTC’s most recent Quarterly Report on Form 10-Q as well as any updates to these risk factors filed from time to time in PTC’s other filings with the SEC. You are urged to carefully consider all such factors.

Yeah, that last sentence is pretty sound advice. Some of risk factors themselves are pretty gnarly themselves. It’s a little rich of them to suggest that the FDA might not give them a review on schedule if they file their NDA at them, if that’s indeed what they’re suggesting, but the risk of it not being successful is very substantial indeed. In fact, I don’t really see any way the compound can be approved under current standards of efficacy, so PTC seems to be hoping that those standards will have changed by then.

But hey, all kinds of things might change. The former governor of my home state of Arkansas, Mike Huckabee, was on Twitter last night telling us all how to do it: “Take on 4 big diseases that cost the BULK of $$: Cancer, heart disease, Alzheimers, diabetes; find CURES like we did with polio in 50’s.” I just can’t tell you what that advice is worth, because mere scientific notation is not sufficient to denote its cash value. Times ten to the minus what, I wonder? Gov. Huckabee has probably been too busy going off the rails over the years (a full-time job) to notice that the biopharma business has actually been pouring countless billions of dollars into just those very diseases. And he might not realize that coming up with a vaccine for a virus whose only host is humans, while not easy, is still a lot easier than going after cancer (which is not just one disease, but thousands). He might also consider that while we knew that the polio virus caused polio, we still have no certainty about the cause of Alzheimer’s, despite decades of intense research. Perhaps it is a hard problem, as opposed to bloviating on Twitter?

34 comments on “The Coming Landscape?”

  1. Biden my time says:

    What we really need is a moonshot 😉

    1. DCRogers says:

      How about a czar?

      1. Pennpenn says:

        Czarshot? That either sounds like a lot of money poured in to one person in the hope they’ll fix the problem or an obscure Decepticon…

        1. a. nonymaus says:

          We tried that in 1918…

          1. Comrade Lipinski says:

            what we need to do is seize the means of pharmaceutical production and realize the final evolution of medical dielectical materialism. No drug will cost more than $40 million to make and all diseases will be cured.

          2. Derek Lowe says:

            And the FDA will wither away. . .

    2. David Antonini says:

      We’re getting a moonshot. What we need is a cure for cancer…

  2. Morten G says:

    As I said to my friend “At least that means he’s pro-vaccination”.

    That can be hard to find among Republicans these days.

    1. DJT says:

      I’ll call BS on that. For evidence see Figure 11 in this paper.

      1. Anon2 says:

        Looks like a fairly uniform distribution to me. It appears that we get anti-vaccination nuts of all political stripes these days (not something to cheer about).

      2. Morten G says:

        It seems you are right:

        I was confused by Donald Trump and Ben Carson backing the autism pish-posh in the 2016 debates.

  3. We need a Manhatten Project. On the moon. And I think we should start launching politicians into space to break ground starting ASAP.

    1. oldnuke says:

      What is the critical mass of politicians? I suppose we could start by compacting Congress into a soup can by the use of a small nuclear weapon (maybe 10-20 Kt for starters).

      Letting out my hidden Edward Teller here. 🙂

  4. Barry says:

    Trump’s nominee to run the FDA (Jim O’Neil) has no medical science background. He has advocated waiving all efficacy requirements for new drugs, shrinking the FDA’s mission to safety only, as it was in 1906 under Teddy Roosevelt.
    Why any insurer would cover a treatment that has no evidence of efficacy he leaves as a problem for the student. Underlying this change seems to be the mistaken belief that FDA approval is the slow step in drug innovation.

    1. Morten G says:

      Proving efficacy is the expensive step though.

    2. Fenichel says:

      Actually the 1906 Act required only accurate labeling, not safety. The safety requirement didn’t come in until the 1938 FD&C Act. (Of course, what was submitted under that Act was mostly handwaving, since safety couldn’t — and can’t — be defined except in relation to efficacy, and efficacy wasn’t required until 1962.)

    3. flem says:

      won’t insurers cover a drug they can make money on? As long as they can pass on premiums to payers (including their cut). As far as I know insurance companies don’t get paid by outcomes

      1. zero says:

        Insurance companies have to pay out if their clients do not recover and require ongoing (and expensive) treatment.
        It may be in their best interests (although not risk-free) to skim off the top from common medications like antibiotics or opioids, but that equation changes dramatically when we start talking about cancer treatments. Paying for a treatment that does nothing except hasten that patient into expensive surgeries is a losing prospect.

        1. SW says:

          If you’re cynical enough you could say that paying for a treatment that won’t prolong patient life might be in the insurer’s interest/

  5. Jake says:

    > mere scientific notation is not sufficient to denote its cash value

    “Zero” is perfectly fine scientific notation.

    1. Chrispy says:

      I think the value is actually negative: it harms progress.

      Or perhaps it is imaginary…

      1. RM says:

        I’m rather intrigued by the possibilities of infinitesimal numbers.

  6. mallam says:

    All the crazies have been allowed to tweet. Or is it that tweeting makes people appear crazy? Needs studying by scientific method.

  7. tnr says:

    If I read correctly, PTC has received marketing authorization for Translarna in Europe for nmDMD. I guess they are banking on some legislative changes regarding FDA and EU/Japan, perhaps for rare diseases. I have seen some proposals which mandate that FDA approve drugs which have been approved in either Europe or Japan. Otherwise, it makes no sense to file in the face of a previous ‘Refusal to File’.

    1. Isodore says:

      If their drug is not efficacious, how come they received marketing authorization in Europe? I though the EMA was as rigorous as the FDA and it may actually make sense for the FDA to wave through drugs that were approved by the EMA (I don’t know about Japan). But perhaps the EMA is more lax than I thought.

      1. tnr says:

        According to Google, they received conditional approval in Europe in 2014 based on a randomized double blind placebo controlled study in 174 boys where translarna was superior to placebo in the six minute walk test.

        Fair to ask why the FDA did not accept this study and even gave a Refusal to File.

        1. Derek Lowe says:

          The conditional approval happened before the drug went on to conclusively fail a Phase III trial. And that approval status is indeed in doubt:

          1. tnr says:

            I see that their Phase III trial was not statistically significant in 6 minute walk test (p=.213). Whether this constitutes conclusive failure is in the eye of the beholder. I find some of the secondary measures like lost ambulation, more convincing, 0 in drug versus 4 in placebo. This is where I think strict adherence to statistically significance at a 0.05 level makes no sense. For a fatal rare disease, the efficacy bar should be lower.

            Although I doubt that FDA will grant an approval, I also doubt that the EU will rescend their conditional approval either.

  8. Anon2 says:

    You might want to take a look at what a single study at P=0.05 means in terms of the ratio of maximum likelyhoods (nevermind P=0.213!). I realize that, if I were in the position of these children’s parents, I too would be grasping at straws. But as a society do we want to be paying large amounts of money for a small probability that the drug will help?

    1. Vader says:

      “But as a society do we want to be paying large amounts of money for a small probability that the drug will help?”

      I think the libertarian argument is that, if the parents want to pay the money themselves, we shouldn’t stop them. I don’t see any requirement here that insurers or Medicaid pay for it.

      I’m more concerned with how easily “It might possibly help, and we’re out of other options anyway” morphs into “My third cousin twice removes swears it helped him, so I want to use it now and not wait until all the conventional options have been tried.” But that may be more a matter of education.

  9. Kent G. Budge says:

    Quite a run-on … and on … and on … sentence there.

  10. Wallace Grommet says:

    Drugs that don’t work are, of course, supported by the administration that doesn’t work.

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