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Regulatory Affairs

A New FDA Commissioner, Suddenly

The big news late yesterday afternoon was the resignation of Scott Gottlieb as FDA commissioner. I have no idea why he’s leaving, naturally. He’s spoken about wanting to spend more time with his family and being dissatisfied with going back and forth between Connecticut and DC, and I have no doubt that both of those are true. But one has to wonder if they’re the full story.

Gottlieb has done a good job, and there are too few appointments at his level in the current administration that you can say that about. He’s been active and public-facing (as a look at his Twitter account will demonstrate), and he’s been addressing some big issues in both public health and in drug industry regulation. I’m unhappy to see him leaving, and there’s a tiny bit of evidence at right that others feel the same way. The XBI biotech index staggered the minute the news came out, and it’s down even more today. That’s many billions of dollars of market cap disappearing before your eyes, and it’s due both to the loss of Gottlieb and the fear of what might come after.

I suspected that that fear was one of the things that smoothed Gottlieb’s own confirmation, but the issue is back. Names were floated earlier of people with rather. . .vigorous. . .views on the role of the FDA in drug research, views mostly leaning towards images of a bunch of old tractor tires dumped across a busy road. You’d think naively that the biopharma industry would be all for someone who would reduce the regulatory burden, but that’s really not the case. The thing is, a relatively high bar for approval has a lot of good futures. It forces companies to innovate, to come up with things that are worthy of close scrutiny, and it simultaneously discourages shortcuts and sloppiness. The worry is that if someone tries to do the world a favor by getting the big ol’ slow FDA out of the way, that the result will not be a flood of grateful innovation, but rather a flood of lower-quality drug submissions. At the extreme, you’ll get junk, but even short of that you run a real risk of letting therapies through that are both less effective and more harmful.

The moral hazard – well, one of the moral hazards – is that such moves would be justified by pointing to an apparent surge in drug applications and approvals. See, just get the government out of the way and everything starts to flourish! But as I’ve said many times, the FDA is not the real roadblock in this business. It’s biology. More specifically, it’s our lack of understanding of biology. Lowering standards will do nothing to help that at all.

39 comments on “A New FDA Commissioner, Suddenly”

  1. Chad Irby says:

    It’s more than probable that the FDA’s recent stance on vaping has at least something to do with it…

  2. Hap says:

    Gotttlieb was one of the few of Trump’s picks for a major position (Mattis, and though I don’t like him, Gorsuch, for example) that I thought were competent and reasonable, and it’s not good to see him leave.

    I can see an Ajit Pal-type pick for FDA, and that probably wouldn’t be good for most people – letting companies with no real products (products with no evidence of efficacy) make money means that lots of people will get ripped off or dead, and the industry will take the blame. That seems like a recipe for government takeover, which will also be a bad idea.

    1. Vader says:

      I have never feared that Trump would become any kind of dictator. He might aspire to it, but he doesn’t have the intelligence or determination.

      What I’ve feared is that Trump will break a lot of things that will make it easier for his Democratic successor to become a dictator.

      Trump deregulating the pharmaceutical industry more than is wise, triggering a backlash that allows his Democratic successor to nationalize the entire industry, would be a fine example.

      1. Hap says:

        The “Dark Phoenix” saga of US government?

      2. Project Osprey says:

        America having little experience with nationalisation, you can be forgiven for believing that a plausible outcome. Even if the ruling party wanted it, getting such changes pass both houses and then legal challenges by both companies and states while simultaneously preventing the industry from relocating overseas… It’s not impossible but its as close as.

      3. Derek Lowe says:

        Enough. We’re not going to have this stuff in here. If you’d like to talk about the FDA, go right ahead. If you’d like to talk about the FDA and the Trump administration, go ahead. But I’m not going to give a forum to conspiracy theories and talk of executions and political revolution. Start your own blog if you want to do that.

        I’ve deleted your comments – the other two were even less germane and were nothing but ad hominem insults. I’m also clearing out the replies to you, since otherwise we’re just going to have a political flame war in here, and God knows there are plenty of other places to do that. This is a rare event around here, but left unchecked this sort of flame war will make this whole site fall to pieces. I have done explicitly political posts on rare intervals, but at least those are fair warning (and I think that many readers avoid their comments sections entirely).

        I hope everyone whose comment has been cleared out will understand the reasons for this – and will understand that they’re more than welcome to keep on contributing in a less directly political fashion.

    2. Dr. Manhattan says:

      Its OK, you can come out and say “Prevagen”…

  3. navarro says:

    Is it hard to imagine a commissioner who could have made it easier for Theranos to keep going for a while? Or maybe someone who thinks we’re still over-regulating the herbal supplement industry.

    Of course, you’re right. Gottlieb was one of the few appointees who deserved consideration for his post and it’s hard to be optimistic about what will come next.

    1. SP says:

      Did somebody say, “Commissioner Hatch”?

      1. Doctor Memory says:

        “FDA Commissioner Robert F Kennedy, Jr.”

  4. SirWired says:

    Here’s to hoping that whomever is appearing on Fox News the morning it gets into Trump’s head to pick a replacement isn’t one of the loonier talking-heads appearing there.

    Certainly, even if one thinks Gottlieb was Pharma-Shill Incarnate (I happen to agree he did just about the best one could expect a GOP appointee to do), one should never, ever, ask “How could the replacement be worse?” in regards to Trump Administration appointments.

    A commissioner similar to Mulvaney in charge of the CFPB or Pruitt in charge of the EPA (both people who thought the agencies they were picked to lead shouldn’t even exist) or Huckabee (who didn’t even know what the Dept. of Energy even did) would definitely fit the bill.

    1. Hap says:

      Other than my religion (which I don’t consider superstition but others do), one of the superstitions I don’t let go is never to say that things can’t get worse. Daring divine beings, supernatural forces, or something else much bigger than you to make your life worse doesn’t seem to work out well.

      1. Scott says:

        Never, EVER taunt Murphy. He responds every time!

        1. NoniMausa says:

          But when the toast lands butter side up, he doesn’t mind a heartfelt “Hail Murphy!”

    2. Lane Simonian says:

      The person you are thinking of is Rick Perry who wanted to abolish the Department of Energy but could not remember its name, but your point is well-taken.

      Former Governor Mike Huckabee does not serve in the Trump administration, but his daughter does (Press Secretary Sarah Huckabee Sanders). Her main function in the White House is to put lipstick on a pig.

  5. Emjeff says:

    I think the pessimism here is a bit mis-placed. First, the Clown-haired one did manage to pick this guy, and all agree he was a good choice – there’s no reason to believe that he can’t pick another good person. Secondly, while Gottlieb was a good commissioner, his skill set is not really that rare. There are plenty of good people out there who could do this job and do it well.

    Derek, I was disappointed to see you write this;

    “The thing is, a relatively high bar for approval has a lot of good futures (sic). It forces companies to innovate, to come up with things that are worthy of close scrutiny, and it simultaneously discourages shortcuts and sloppiness. ”

    This high bar also acts to keep small companies out of competition with the large companies who can absorb the cost of these regulations. I believe that we need a strong regulatory agency, but we also need a “number needed to harm” analysis on a lot of regulations. In other words, how many people will be harmed if we don’t do X ? And, what is the harm?

    A very good example of this is the current obsession FDA has with metabolites. The regulation is arbitrary (measure and follow every metabolite that is10% or greater of the total AUC. Why?). There has been not one word said about why this was put into place, and no data on how this has improved the public health. As a result, bioanalytical CROs are being overwhelmed with work (good for them, but it affects timelines) , and costs increase dramatically with every metabolite one must measure. I’d like to see what benefit the public has received as a result of these regulations.

    The problem with regulation is that it always goes in one direction.

    1. Hap says:

      His batting average on picking people isn’t that good though – it’s a lot easier for a .300 hitter to get two hits in a row than a .200 hitter, and President Trump’s candidate batting average appears to be well below the Mendoza Line.

      Isn’t the point of regulation to be negative? Generally the government doesn’t make things, but is there to prevent people (who do things) from doing bad ones or from hurting others in the process. It’s always a cost, but one that is hopefully counterweighed by the good it allows others to do.

      Is there someone who could legitimately make those kind of distinctions (or would be committed to looking at them) who would run FDA?

      1. Chris Phoenix says:

        Regulation is often phrased negatively, but there are lots of examples of “you should” regulation in addition to “you shouldn’t,” especially in well-established fields like manufacturing.

        When interests aren’t aligned, regulation imposes unwanted behavior. But it’s also very valuable when interests are aligned but skills are imperfect.

        1. loupgarous says:

          Give me “negative” regulations, every time. It’s usually much easier to comply with “Thou shalt not” than “Thou shalt”, all things being equal.

          Emjeff makes a good point:

          “A very good example of this is the current obsession FDA has with metabolites. The regulation is arbitrary (measure and follow every metabolite that is10% or greater of the total AUC. Why?). There has been not one word said about why this was put into place, and no data on how this has improved the public health. As a result, bioanalytical CROs are being overwhelmed with work (good for them, but it affects timelines) , and costs increase dramatically with every metabolite one must measure. I’d like to see what benefit the public has received as a result of these regulations.

          I can actually see why FDA wants the industry to look at metabolites – some of them can be very toxic, and others can be as potent or more so than the study drug in the desired action, while still others have unanticipated therapeutic activity.

          NAPQI, as most reading this know, is a hepatotoxic metabolite of acetaminophen/paracetamol. A healthy adult liver metabolizes it as fast as it’s made, usually and no harm done. Overdose or ingestion by people with impaired glucuronidation in the liver can cause fulminant liver failure and death as NAPQI causes a cell death cascade in the liver – the story of a toxic drug metabolte that should have been studied more thoroughly, as acetaminophen’s therapeutic index is worse than aspirin’s and half that of hydrocodone.

          The specific antidote for acetaminophen/paracetamol poisoning is n-acetylcysteine, a prodrug of glutathione which acts rapidly to allow the liver to detoxify NAPQI, saving the patient if given in time – a case of a very useful prodrug/metabolite interaction, used to counter poisoning by a highly toxic metabolite of a medication sold over the counter to anyone and promoted by the CDC as a safe alternative to hydrocodone, which is less toxic and lethal.

          That’s one possible reason to study the fate of metabolites in drugs – because biology is complex and not always obvious, except in hindsight. “Raffiniert ist der Herr Gott, aber boshaft ist er nicht”

    2. CMCguy says:

      I am disappointed as well as unlike dealing with biology the FDA high bar appears to frequently sacrifice reasonable science justifications to artificial or arbitrary regulatory mandates in checking a box. This confuses, slows and add costs to innovation and while not the only factor drives higher drug prices. Regardless not sure a new FDA Director can really change that unless they sweep away the entrenched bureaucratic mindset.

    3. Professor Electron says:

      Why require monitoring of metabolites at the 10% level? Because there’s no guarantee that a metabolite isn’t toxic. There’s no guarantee that a metabolite is less bioactive than the parent. 10% is pretty generous for a drug that could be dosed at tens of mg a day. And costs don’t increase disproportionately for each extra metabolite you’re interested in – the cost increase is less than linear, because you’ll have to recruit all the patients (or animals) regardless and the same LC MS/MS run will work for multiple metabolites.

      1. Emjeff says:

        1) Why 10%? Why not 5%? Arbitrary.There are NO data which indicate this is needed.
        2) Where is the evidence that patients were dropping dead by the score from toxic metabolites? There is no evidence.
        Some of you will argue that “any” death is too many, and it’s hard to disagree with that from a humane stand-point – but we make those trade-offs all the time. We could eliminate car accidents due to brake failure by requiring daily brake inspections. Should we do that? The cost of owning a car would go up exponentially, many people would not be able to afford transportation, and there would be wide-spread and heated arguments about the cost of transportation. Sound familiar?

        1. loupgarous says:

          Roughly 10% of acetaminophen/paracetamol is metabolized into NAPQI. Josh Bloom quotes pain specialist Aric Hausknecht:

          “Each year a substantial number of Americans experience intentional and unintentional Tylenol (acetaminophen) associated overdoses that can result in serious morbidity and mortality. Analysis of national databases show that acetaminophen-associated overdoses account for about 50,000 emergency room visits and 25,000 hospitalizations yearly. Acetaminophen is the nation’s leading cause of acute liver failure, according to data from an ongoing study funded by the National Institutes for Health. Analysis of national mortality files shows about 450 deaths occur each year from acetaminophen-associated overdoses; 100 of these are unintentional.”

          So, that’s a case in which 10% of a common over the counter drug is made into a toxic metabolite that causes 450 deaths each year, and sends 50,000 people to the ER, half of whom are admitted for treatment. Not sure if this underlied the FDA’s reasoning, but it got my attention.

          1. Druid says:

            Reasonable, but the recommended dose of acetaminophen is 4g per day, so 10% is 400mg. Also it is low MW (151) so 400 mg is 2.6 millimoles. Although DILI is not usually dose dependent for any particular drug in any susceptible patient, it is generally thought that there are few cases where the dose is 50mg or less per day, and very few where the dose is 10mg or less. Lammert et al (Hepatology 2008) confirmed this, and although there were some problems at < 10 mg/ day, they were mostly down to cerivastatin where the parent compound is to blame. But, the idea that the molar rate of dosing might be the critical factor is too hard to grasp and too difficult to regulate so let's just make everyone work harder.

    4. drsnowboard says:

      Because 1 patient death due to a measurable metabolite is too high a cost relative to a relatively minor analytical cost??

    5. NJBiologist says:

      Emjeff writes: “(measure and follow every metabolite that is 10% or greater of the total AUC. Why?)”

      Because any cutoff that is more sophisticated will require an order of magnitude more work? Let’s face it, if you want to say that a metabolite is irrelevant, it’s going to be hard to say that without running a tox package.

  6. JB says:

    FDA should promote from within, and preferably someone who has been there longer than 10 years. It shows commitment to the agency, its mission, and lack of ties to industry.

    There are a lot of complaints in this thread about the regulatory science and bars to meet the FDA imposes on industry, but if you’re a chemist you’ve likely only dealt with CDER more often than not. The requirements and bars are entirely center specific. Over in advanced biologics, CBER is very flexible and very reasonable for what they ask for as long as you provide adequate justifications and rationale. CBER doesn’t even always require GLP studies and doesn’t even require 2 species. If you have good enough data for your gene therapy in a mouse you can go straight to a human provided you give sound rationale. CBER also has two levels of interaction available to industry before you even file your IND. It’s like getting world leading scientific consulting for free…twice!

    1. CMCguy says:

      JB sounds like CBER behaves much like interaction with CDER did a couple decades ago in willingness be flexible in acceptance of rationale justifications supported with data. Not sure why and what changed as now where it seems more and more data needed to support narrow and particular answers without considering the value of the questions and if there may be appropriate alternative ways to get the answers. At times I do wonder if FDA is just setting certain standards based on the higher bars that Big Pharma companies like to establish to indeed make it more difficult for others.

  7. luysii says:

    You want to know how bad the FDA can be. Go back to the hysteria over silicone breast implants in the 1990’s. Although there was little evidence that they were harmful, the head of the FDA caved, and advised implantation to stop (but hilariously, that those already implanted should NOT be removed).

    It hurt many pediatric patients with hydrocephalus, who needed shunt, none being available due to the ban.

  8. Christophe Verlinde says:

    The commissioner’s name is Gottlieb, not Gottleib.

    1. Derek Lowe says:

      A guy like me who post-doc-ed in Germany should have gotten that right. I blame the high altitude – I’m at a Keystone meeting this week.

  9. DTX says:

    I work in pharma and our senior leadership (and underlings as well) would agree with Derek’s statement that a high bar is needed, that we don’t want FDA approving unproven remedies. Our SVP of research has previously said this.

    A good example were compounds that increased HDLs. EVERYONE had known for decades that high HDLs reduced cardiac disease – or at least we thought we knew. A simplistic view would have been that the drugs increased the HDL biomarker and therefore should have been approved. However, FDA required the industry to show that increasing HDLs actually resulted in a positive health outcome. Pfizer, Lilly, Merck & one other company all found that increasing HDLs didn’t reduce cardiac disease. FDA was right to request data that showed that the drugs did more than just changing a biomarker.

    Obviously, the supplement crowd thinks that this (and any type of testing) is unnecessary.

    1. Jim Hartley says:

      Wonderful example. Thanks.

  10. Murine says:

    Totally agree with Derek that road block is biology. Mice and cells don’t know who is FDA director or how much money it spends.

  11. Patrick says:

    I misread that as Sidney Gottlieb and almost had a heart attack.

  12. loupgarous says:

    The one thing we really should congratulate Trump for doing is not appointing an FDA commissioner who was married to a pharma hedge fund CEO with millions of dollars of Big Pharma stock in their family financial holdings. Like Obama’s FDA commissioner 2009-2015, Margaret Hamburg.

    Well-founded or not, some of the litigation over the fluoroquinolone Levaquin turns on the unwisdom of that appointment and major investment by Dr. Hamburg in the maker of Levaquin. It’s hard to imagine a less-appropriate FDA appointee than that.

  13. jmowreader says:

    According to their Wiki page, Tiger Global Management, Fidelity Investments and Tao Capital are all big Juul Labs investors, and Altria (they make Marlboros) owns 35 percent of the company. Gottlieb’s special emphasis was teen vaping. There’s no doubt why Trump forced him out: He was going after his friends’ money.

    1. chemist says:

      Nice baseless assertion there you retarded sack of shit.

      1. Ano says:

        It’s easy for people to read a comment and think “oh ok, wow, that makes sense” … so I’m always thankful for someone who chimes in with an opposing view. Not only did you make me laugh, but also — I’m sure — ensure that people don’t take comments for face value. Do your research, after all.

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