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Drug Industry History

The Sad (and Saddening) History of Makena

Longtime readers (and longtime drug industry folks!) may remember the Makena story from 2011. That is a progesterone ester drug that has been given to women at risk of preterm labor, and it came into the news when a small company called KV Pharmaceuticals used an FDA program that encouraged modern trials of older medicines to get market exclusivity. Whereupon they ran the price up by nearly one hundred-fold.

There are quite a few stories like this, and I’ve written many times about how these grants of marketing exclusivity have probably been handed out too freely, given how valuable they can be. After KV got into this business, though, there was some question about the size of the actual market for Makena. At the same time, the FDA (in a rather odd move) announced that it would not bring actions against compounding pharmacies that provided the drug themselves, at whatever price they chose, which effectively negated some (perhaps all) of the market exclusivity the agency had just awarded. KV filed for bankruptcy the next year (this wasn’t their only problem, as that article shows), and emerged under a new name (Lumara). The pharmaceutical end of that business was bought in 2014 by another company, AMAG.

One thing that AMAG inherited was the FDA mandate to conduct a post-marketing trial to make sure that Makena actually worked. The trial that led to the KV approval had been done in 2003, and did not have robust outcomes data – it showed a reduction in preterm births, but nothing on overall mortality and morbidity results. There were other problems with the trial, actually, including treatment and control groups that may not have been comparable, and even the KV approval was controversial at the time. In March of last year, the new study reported its data: no benefit. No reduction even in preterm labor, much less other bad outcomes. The 2003 clinical trial appears to have been flawed all the way through. An FDA advisory committee said that the drug’s approval should be revoked.

So what we have is a drug that had been used for decades on the basis of not-very-good evidence that it could prevent preterm births. The FDA’s attempt to bring it into a modern regulatory environment relied on a single clinical trial that was not well run and (we now know) could not be reproduced, and led to bizarre market effects besides. It took eight more years to confirm that yes, this drug does not actually work. And now it’s been a year and half since that confirmation of non-efficacy, and Makena is still on the market and (presumably) still being prescribed. That last link above is a plea from almost a year ago for the FDA to pull the drug, and it’s well worth a read.

So, October of 2020, and the FDA is now formally proposing to withdraw marketing approval (thanks to Ed Silverman at Stat for that link). It’s worth noting that Makena was actually an accelerated approval, and the language of that process is particularly infuriating now:

FDA’s accelerated approval regulations, included in 21 CFR part 314, subpart H, describe the procedures for accelerated approval and the expedited withdrawal procedures for drugs approved under the accelerated approval pathway. These regulations state that FDA may grant marketing approval “on the basis of adequate and well- controlled clinical trials establishing that the drug product has an effect on a surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity” (§ 314.510). 

Expedited withdrawal? Approval on the basis of adequate and well-controlled trials? I’m not seeing much sign of either of those. Makena (and the brand-name-less progesterone ester formulation it superseded in the market) has traced a long, slow trail through the US drug regulatory regime, and we now know that it doesn’t do anything to help anyone. Never has. It shouldn’t have been a drug in the first place. It shouldn’t have gotten a new life as a branded, FDA-approved one. It shouldn’t still be on the market over a year after it’s become clear that it’s worthless. This story does no credit to the FDA nor to the practice of medicine in general, and the sooner we can finally close it out, the better.

25 comments on “The Sad (and Saddening) History of Makena”

  1. UserFriendly says:

    Lovely. It’s always good to know that our 100% corrupt government really has it’s eye out and takes extra care when it comes to pregnant women. I am always so perplexed when people try to assure me that one of our political parties is pro-life; seems obvious to me they are both extremely pro-death. Well, pro-poor people dying as young as possible, anyways.

    1. Oudeis says:

      Never ascribe to malice what can be explained by incompetence (and in this case, presumably, industry capture of a regulator).

      1. Marko says:

        A captured regulator is hardly a good example to toss up while offering the excuse of incompetence. “Capture” here implies a willingness to overlook the job of protecting the public good in exchange for some other incentive , invariably financial at its root. That’s malicious greed.

        “Incompetence” of the intelligence community was the excuse used for the failure to find WMDs in Iraq. If you believed that story , I know a Nigerian prince who’d love to pitch an investment opportunity to you.

        Incompetence is a cover story , willingly proffered after the scam has been exposed. A more reliable rule of thumb in today’s world : Never ascribe to incompetence what can be explained by malice.

        1. Oudeis says:

          Industry capture doesn’t necessarily mean corruption. Regulators have to get their information from somewhere, and they’re required by law to give people a chance to comment on their rules, etc., and take those comments into account. Plus, the people who staff regulators tend to get their degrees alongside the people who work in the regulated industry, maintain friendships with them, and even move back and forth between the regulator and the industry.

          Corruption happens, I’m sure, but I doubt it’s as significant a phenomenon as the other ways regulators start thinking like the people they regulate, and the other ways industry influences what the regulators are looking at and thinking about. To some extent those sorts of influence are necessary–do you really want (say) drug companies to have no opportunity to make their case to the people with life and death power over their companies? The problem is that, sometimes, they’re too good at it.

          As for the rest, assuming malice whenever something goes wrong is a great way to fall into conspiracy-theory wacko-hood. I’d recommend against it.

          1. Marko says:

            Do I detect a closing of the ranks here ? You continue to offer examples that are directly contrary your argument , with a curious lack of awareness or concern that you’re doing so:

            “…and even move back and forth between the regulator and the industry.”

            That’s one way the payoffs happen. Bags of cash are a bit too obvious. Closing the revolving doors is a basic goal of good government efforts , not that we ever get anywhere with it. Your argument is exactly what I’d expect to hear from someone closely involved with the captured and/or the capturers. Not what I want to hear from or about agencies that are supposed to stand between corporate greed and the public welfare.

            “It is difficult to get a man to understand something, when his salary depends on his not understanding it.” ― Upton Sinclair

          2. UserFriendly says:

            Do go on and tell me about this non corrupt country that isn’t anything like the United States. It sounds fascinating. I bet they don’t have to have facebook groups where poor people bargain to get insulin.

            This worthless country has two political parties that are totally owned by special interests. They have done nothing, and I literally mean nothing, that has helped anyone besides people who earn > 6 figures for about 40 years. This country is such a joke that life expectancy has been decreasing for a decade now. Do you have any idea how desperate people have to get before they start offing themselves in numbers big enough to decrease life expectancy for the entire country?

            And what you describe is literally the textbook definition of corruption; well textbook for everyone who isn’t on the SCOTUS. Doing a favor for your college buddy, who cares if that favor kills a few hundred thousand poor people by starting an opioid epidemic. Or let your college buddies on Wall Street off the hook for blowing up the entire world’s economy and destroying millions of lives. There is no crime too homicidal that elites can’t manage to get rewarded for. And it’s all us peons who pay the price, and heaven forbid we even commit the most minor infraction because that is either a death sentence or hard time.

          3. Oudeis says:

            Oy vey, you people. Did you miss the part where I agreed that corruption happens? Obviously a knowing favor for a college friend, or a wink-and-nod agreement to lighten regulation in exchange for a plum job later, is real corruption. And I suspect, though I do not know, that such things occur sometimes.

            But you’re hopelessly naive if you think that’s all that’s going on, or that if you get rid of that stuff it will fix everything. Even with everyone involved intending to act honestly and complying with strict conflict-of-interest rules, even with regulators who believe in and care about their jobs–which all the regulators I’ve known do, in various industries–there are a lot of hard-to-turn-off mechanisms through which the regulators start thinking like the industry.

            Shepherds end up smelling like sheep. And that, I submit, is a bigger problem than the real corruption you’re complaining about.

          4. Marko says:

            Oy vey , yourself. You said : “Industry capture doesn’t necessarily mean corruption.” Industry “capture” of the regulatory agency overseeing said industry is the very definition of a corrupted process. You’re attempting to rationalize and normalize behavior that is fundamentally odious , Oudeis.

            You can’t unring that bell.

    2. Peter S. Shenkin says:

      To me, the relevant questions appear to be:

      1. Is the drug unsafe? (I don’t think that’s been claimed.)
      2. Was the 2003 trial fraudulent? (I don’t think that’s been shown or claimed.)

      I’d also ask whether there were any warning signs in 2003 that should have raised doubt at the time? 2003 feels like yesterday to me. I’m surprised at the implication that the technology of ensuring and evaluating the correctness of clinical trials has advanced significantly in the past 17 years.

      And if the 2003 trial was done using the standard methodologies of the time, but it turned out later that we we were missing things that we are now smart enough to avoid, I would still ask “Well, what might we be missing now?” Is it ridiculous to imagine that a trial a decade or more from now, done with the benefit of insights gained from present-day trials, might actually show effectiveness again?

  2. navarro says:

    has the accelerated approval process gotten harder or easier in the intervening decades since makena’s approval? how can this be made better?

  3. Mike says:

    I think you’re looking at this from the benefit of hindsight Derek. The drug had been used for decades is my understanding. No solid efficacy data, but no major safety signal either. Hence the risk-benefit profile was pretty tolerable (I mean, if they didn’t approve it, it’s not like doctors would have stop prescribed the compounded product – the approval probably had minimal impact on total usage).

    Now I do agree that with a negative trial outcome, the approval should have been pulled pretty quickly, but again, I’d love to see data on prescribing volume. I’m sure there is still plenty of use even with the new data, I mean, it might not work, but it’s unlikely to hurt the mother or baby.

    1. Derek Lowe says:

      The hindsight point is valid, but there were also people sounding the statistical alarms about the 2003 trial at the time. And the apparently low safety problems are the only thing that make the story bearable at all!

      1. Mike says:

        Always appreciate your analyses Derek, so keep up the good work.

        If you start to dig into the FDA’s “Unapproved Drugs Program” it’s pretty fascinating. Drugs are still on the market that originated over 100 years ago and include random “tinctures” – drugs that went through some process, but not a thorough evaluation of safety and efficacy.

        It’s been a while since I’ve looked at the list, but the FDA has made quite a lot of progress in either forcing companies to pull them off the market or put them through the FDA approval process. But it’s tough because some of the drugs (colchicine prior to the FDA approval) are actually useful, medically necessary and have no other sources.

    2. x says:

      The benefit of hindsight is PRECISELY what rigorous testing mandated by the FDA is supposed to provide.

      1. Mike says:

        Sure, but this was a unique situation. The drug had already been used before decades before any formal FDA approval. This was an effort to bring a widely used, unapproved drug through the FDA process.

        I agree 100% that if this was a *new* drug, that it should go through the standard FDA approval process, which would have caught the lack of efficacy before any approval happened.

  4. Anon says:

    The “accelerated approval” …”Orphan Drug” and “breakthrough therapy” designations from FDA have always been exploited more for their commercial/stock market buzz rather than their clinical/product approvability potential. “Vouchers” for expedited approval have their own fungible cash value. This saga also draws attention to the whole “grandfathered drug” history where anecdotally effective or marginally effective drugs are part of our formularies worldwide.

  5. Wustlmed says:

    Biogen and Eisai’s aducanumab is coming, it will shade all the previous ones. The argument from Biogen probably is “no major safety signal”.

  6. Simon Auclair the Great and Terrible says:

    Here we go, marginal changes and its funny!

  7. Alyssa Vance says:

    There’s nothing wrong with OHPC/Makena being used for birth control or HRT, which it is in a number of other countries. It should just be a cheap generic along with everything else in that drug class.

  8. Simon Auclair the Great and Terrible says:

    Good article on new low mw antibiotics and isolation culture of previously unculturable soil microbes.

  9. In 2006, the Boston Globe published an article headlined, “How fish oil may have saved babies’ lives.”

    In 2009, “Parenteral fish oil improves outcomes in patients with parenteral nutrition-associated liver injury” was published (full article available on PubMed).

    In 2012, the Boston Children’s Hospital was the only place in the U.S. that could formulate a fish-oil rather than soy-oil formula (the FDA-approved one that the 2009 study compared), and it was illegal to sell the fish-oil formula across state lines.

    For a year or two in the mid-20teens, parenteral nutrition in the U.S. (sole-source IV nutrition for newborns with short bowel syndrome) contained no fat at all because the FDA-approved soy-oil source left the market and nothing else was approved. Even more babies died.

    Meanwhile, in Europe, a fish-oil formula had been available all along. In 2015, the FDA finally allowed it to be imported.

    In 2018, the formula – Omegaven – was finally approved by the FDA and is now available by prescription.

    Nine years of dead and brain-damaged and liver-failed babies.

    (The story through 2016 is told with more detail at the post linked on my name – text search for “liver damage”)

  10. albegadeep says:

    Did anybody else spot the irony of a pregnancy-related study not being, ah, reproducible?

    1. sgcox says:

      Yes, FDA approval was premature

  11. Uncle Al says:

    $ > patient. Bausch & Lomb EnVista IOLs, up through +9D, may display “harmless” purple fringing. Get those eyes behind Uvex polycarbonate glasses, then to the ophthalmologist.

    Your OEM eye lens is opaque to far blue and UV light lest your macula burn. Cataract surgery removes biology, adds a polymer lens (IOL) containing enough UV absorber. Enough is concentration times pathlength.

    Baby Boomers display spectacular myopia. Routine +20 diopter IOLs may now be +7D, a much thinner lens. If your implanted granny sees violet fringes in sunlight, that is UV frying her macula. UV absorber concentration is unchanged in the smaller pathlength . It needs higher concentration to be enough. Blacklight, 365 nm, is invisible. One batch of resin to FDA spec, and ignore the nuisance footnote.

  12. li zhi says:

    There are a lot of things wrong with the FDA. Regulatory capture is one, but here it seems possible that organizational passive aggressiveness was/is the problem. “I was just following orders” is such a natural and common excuse for what’s obviously bad behavior. Here, Derek seems to be posing the question “Why was this approved and why hasn’t it been corrected?” I suggest – but have no evidence to support the suggestion – that a “we’ll show them” attitude both then and now may be a large part of the problem. (i.e. You don’t like how we do things? You want to change our procedures? Go ahead, pass your legislation (we’ll show you!).)

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