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Regulatory Affairs

Gottlieb At the FDA

So today is when FDA Commissioner nominee Scott Gottlieb goes before the Senate committee, and it’s time for some thoughts on him, and some more thoughts on the FDA under the new administration. I purposely did not write about all the names that were mentioned for the post, because I just didn’t feel like spending the energy trying to catch all the trial balloons, but it seems clear that there was quite a bit of relief when Gottlieb’s name finally came up. He’s definitely not the FDA head that you’d have seen under a Hillary Clinton administration, but compared to some of the touted candidates, he came across as noticeably sane and reasonable. And that’s all we can expect these days.

Steve Usdin at Biocentury has a good piece on Gottlieb leading off their April 3 issue. He emphasizes that the man is going to be in a tough position, because there are a number of vocal, powerful constituencies that want contradictory things from him. I’m going to stipulate right off that Gottlieb will be approved. I think that enough Democratic senators were relieved that he was chosen, versus some of the more. . .colorful. . .possibilities, and enough of them fear what could come their way if they were to block Gottlieb’s nomination, that he’ll have more than enough votes to be approved. That’s actually one of the Trump administration’s more potent weapons (“Just think whom we could have chosen!”), and although it’s not a particularly honorable one, it has a long tradition in politics and I’m not surprised at all to see it being used.

So there are going to be ritual expressions of horror and pledges of I Cannot In Good Conscience Vote For This Person, but in the end, I fully expect that Gottlieb will be running the FDA. What happens then? Here’s Usdin:

Once he’s confirmed, Gottlieb will probably spend more time dodging friendly fire from the White House than deflecting attacks from congressional Democrats. The White House budget proposals indicate that FDA will not be exempt from the Trump administration’s project to dismantle the administrative state.

Most people who care about FDA, including members of Congress, biopharma CEOs and patient advocates, think the agency is on the right track. . .Trump, however, has spoken often and loudly about FDA, always to criticize the agency. He has said the agency is slow and burdensome and too often dashes the hopes of desperate patients. He has proposed rewriting medical product user fee deals. And he has promised to appoint a commissioner who will unleash a flood of new drugs by wiping a huge number of regulations o the books.

This puts Gottlieb in a tight spot because FDA regulations aren’t holding back huge numbers of great new therapies.

Exactly. I’ve said so at length myself, and most people who have experience in drug development say it, too. From the outside, it looks like FDA approval must be the rate-limiting step for drug approval, but it isn’t. The mental picture of a giant dammed-up lake of wonderful therapies, held back by a huge concrete bureaucracy that allows only a mocking trickle to get through at any one time – is wrong. There is indeed a huge lake of potentially great stuff out there, but the dam that’s holding it back is our lack of understanding of human biology. That seems kind of unbelievable to people without biomedical experience – I mean, we know so much – but believe me, we know so much on the relative scale of what we used to know, but we know so little compared to what we need.

Investigational drugs fail because they don’t work, and they fail because they cause too much harm. Those two reasons account for the great majority of all clinical failures, and 90% of all investigational drugs still fail in the clinic. Neither of them represent situations that you’d want to hand on to the public. I know that there are many people who believe that a less restrictive FDA would bring drug prices down, but I don’t see it: if you let through a lot of stuff that just doesn’t do anyone any good (or outright causes them harm) then you have caused patients (and their insurance companies) to pay for things that have not advanced human health at all. How that saves money is beyond me.

Yes, the thought is that if trials are less onerous, that they’ll cost less and those savings will be passed on to the customers, but that’s not how it works. Drugs aren’t priced the way that they are just because of the cost of trials – they’re priced the way that they are mainly because people (and their insurance companies) will pay those prices. Just like any other good on the market, although it’s true that drugs aren’t quite like many of those other goods. Anyway, the contribution of drug trials to the cost of drugs isn’t that the trials are so long and expensive, as much as the fact that so many of those trials tell us that our drugs don’t work, and we have to eat those costs. Ah, but what if those trials are cheaper? Won’t the failures sting less, then, financially? But if those trials are cheaper, which means faster and smaller, then they won’t even be powerful enough to even tell us if the drugs worked or not, or if they’re safe or not. What then has been gained?

Steve Usdin’s sources tell him that Gottlieb was picked over strong objections from some of Trump’s advisors, who wanted a more burn-it-down approach, and there will still be pressure to do as much of that as possible. (This piece at Stat seems to confirm that). I’ve never envied the job that the FDA and its commissioner have to do, and I envy Gottlieb even less than usual. He’s going to have to deal with fights about user fees, regulatory reform, budget cuts, the opioid epidemic, and more, and quite likely do do some of those under fire from his own administration. Good luck to him, and good luck to us.

28 comments on “Gottlieb At the FDA”

  1. luysii says:

    Gottlieb is a reasonable person. Back in 2009 he had a great article in the Wall Street Journal about why the vaccine against the H1N1 flu was so late — basically because the FDA knuckled under to people who thought the mercury in vaccines caused autism. Hopefully, running the show, he’ll have more backbone. For details please see —

    1. NJBiologist says:

      Somewhere (I can’t find a link), Matt Herper has an annotated bibliography of Gottlieb opinion pieces. They paint a picture of a thoughtful guy with a broad attention span. Add to that the fact that he has leadership experience in the agency he’s been chosen to run, and he looks like a good choice.

    2. Johannes Høher-Larsen says:

      Not to get dragged into this thiomersal-autism debate, but the science of mercury is far from settled. In general the inorganic residues left behind from organomercurials has an extremely slow elimination from the human brain, but not known exactly. It’d do well to use a preservative with less ability to accumulate in the human body

      1. Scott says:

        Pretty sure you get more mercury from eating a couple cans of tuna fish (seriously, check out the mercury concentrations!).

        And you DEFINITELY get more mercury from eating a can of tuna once a week for a couple years, like I did growing up.

  2. anon says:

    FDA regulation is not only about approval of new medications. From your perspective in drug discovery, Derek, I realize that’s what you focus on. But there really is an enormous amount of regulatory red tape affecting many of the functions of the pharmaceutical industry. I have experience with the regulatory environment around existing pharmaceutical products and it is indeed burdensome. The armies of personnel and the months of paperwork it takes to do anything – even trivial things like aesthetic changes to packaging or changing an expiration date – would surprise most people. I’m certainly not a fan of Trump, but if he can deliver on cutting some of the red tape associated with getting normal business functions done in the pharmaceutical industry, I think it would have a real financial savings – freeing up more money to be spent on the important work that you and your R&D colleagues do.

  3. Aurelis says:

    The assumption in your analysis of the FDA is that the current patent-based model is preferable to one without monopolies on compounds and certifications.

    1. Hap says:

      Even if patents and priority went away, someone would have to test drugs to see if they work and if they’re safe (and since drugs aren’t risk-free, you need to know both the safety risks and their likely benefit to determine their safety). Since that process is a big chunk of the money put into a drug (it may not set the ceiling for a drug’s price, but it sure as heck sets the floor), making patents go away isn’t necessarily going to make drugs cheaper.

    2. tangent says:

      Can you outline that post-patent model a little? Who’s going to have the financial incentive to run the trials for everybody’s benefit? And do not tell me “Big Data post-marketing surveillance” please my dear sir.

      I still harbor some teen libertarian antipathy to the basic idea of ‘intellectual property’, but you need somebody to fund the studies somehow. And no, they’re not pro forma egghead red tape, or people wouldn’t be funding giant Phase 3 studies that fail.

  4. SteveH says:

    Industry always blames the FDA.

    There are reasons for the regulatory environment overarching the pharmaceutical industry. What things you call “trivial” actually have real scientific reasoning behind the decision-making. Data supporting the setting of expiration dating gets reviewed before the expiry gets assigned. Otherwise, drugs that can’t be assured that they meet quality standards might remain on the shelf or in the distribution system.

    Packaging (trade dress) is evaluated for clarity, absence of obscuration of important and required information, etc. FDA cannot let marketing get in the way of important labeling elements that directly relate to the SAFE use of drugs. If your “trivial” color change or flashy logo overshadows the strength, dosage form or administration directions, it SHOULD get close scrutiny, and if it’s too much, be denied. There are too many accounts of medication errors to justify slacking off on elements that contribute to safety.

    Industry should look at itself. If it takes an “army of personnel” to oversee the information needed, perhaps the industry should become more efficient – investing in electronic NDA submissions, for example – something that everyone expects the government to be.
    Individual FDA reviewers are responsible for review of dozens of drug products at a time, from multiple firms, all of which have different ways of doing things and documenting them. Efficiency can come from standardization, but the diversity of the industry limits the level of standardization possible.

    And don’t get me started on the economic pressures to cut corners, from raw materials to manufacturing to regulatory compliance.

    1. Ken says:

      Not to mention for packaging, the amount of impurities that can leach or extract into the API can surprise you.

    2. Emjeff says:

      Why is it that industry must continually examine itself, but everything the government does is perfect?

      1. SteveH says:

        We are constantly under pressure to improve – faster, better, with less. Hopefully, HHS will not have to operate with a 17% budget cut, as under Trump’s proposed budget. But even if that goes through, we’ll still get the job done.

        1. Concerned Citizen says:

          An audit of HUD found $500 billion dollars wasted due to mismanagement, fraud and accounting errors. And their annual budget is something like $36 million. How does that even happen?

          1. Concerned Citizen says:

            that 36 million should read “billion”

    3. CMCguy says:

      SteveH I don’t always blame the FDA but most the time do feel they are more part of the problems and not functioning effectively to approve and prioritorize new drug development. Unfortunately many “real scientific reasoning behind the decision-making” appears to have gotten lost in bureaucratic check box mind set which does influence industry to create there version of bureaucracies to deal with old low value and new hot button demands of the moment. They never really give straight-forward answers and guidance defaulting to “review issue during marketing application”. Appears disingenuous to point to industry when FDA reviewers are not standardized or very efficient even though granting are understaffed for ever explaining mission that more often deals with enforcing outdated issues rather that meaningful long-term improvements. Reg CMC Gal is correct there are other agencies out they and interactions with some of them are more helpful than with FDA.

      1. SteveH says:

        FDA is much more efficient today than it was 20 years ago, and the goal of “continuous improvement” is SOP. That said, efficiency is always highest when the tasks a simple and repetitive, which simply cannot be applied to the regulation and review of pharmaceutical products – there’s too much variation. Products from the same manufacturer, even in the same product line, can be significantly different. And FDA has to treat everyone fairly and to protect the trade secret information to which it has access. So FDA reviewers might know how you might approach or solve some issue, because another firm has done it, but they can’t tell you – you have to figure it out yourself.

        I think the industry should be wary of advocating risk-based assessment – it would probably feel enormously unfair to watch a “low-risk” drug sail through with less scrutiny while your risky blockbuster gets taken apart with a fine-toothed comb.

  5. Chris Phoenix says:

    I remember a few years ago I wanted to do some psychological research, but I wasn’t connected with an academic or commercial institution with an IRB (Institutional Review Board, whose purpose is basically to make sure human rights aren’t violated in the proposed research).

    I wanted the research to be publishable, so I tried to set up an IRB. I put about 200 hours into it – much of that simply doing the paperwork. Eventually, we failed to bring a functioning IRB together.

    I’m not arguing that IRBs should be abolished. I’m not even arguing that the paperwork requirements are too onerous – I’m not sure which detail I would change.

    I will say that one relatively small and straightforward task was far more difficult than I would have expected it to be, out of proportion to the benefit we and our proposed experimentees would have gotten. The intersection of bureaucracy and getting-things-done was pretty expensive.

    I also got FCC certification for a product I designed. It was really easy. I just had to find a company that would do it, take the product in, get it tested… then pay them to do lots and lots of paperwork. The cost of paperwork was probably half or 2/3 the total cost I paid. But the process itself took a pretty small amount of my time.

    With regard to the FDA, I’m not arguing for burn-it-down. But I’d like to see an alternative, designed from the ground up. The aggregate cost of the bureaucracy is immense, and incremental changes won’t fix it. If it were possible to create alternative infrastructures to oversee the evaluation, manufacture, and sales of drugs, then perhaps a substantially more efficient and acceptably effective alternative could be developed.

    As I was writing the previous paragraph, I looked down and noticed that an extension cord I’d been using for months, next to my bed, was abraded down to the metal in several places. It was a cheap indoor extension cord that I’d used for outdoor Christmas lights. Yikes! Of course it went in the trash immediately, with a strong mental note to only use outdoor cords outdoors in the future.

    That cord could have killed someone or burned my house down – or both – simply from an off-label use. What’s the solution to this? Government inspections of Christmas light installations? Forbidding the manufacture and sale of cheap extension cords? If it were in the medical field, something similarly Draconian and bureaucratic would have been completely acceptable and even considered desirable. After all, cheap extension cords are not a necessity of life, and surely they aren’t worth the harm they can cause…

    Somehow, we have managed to regulate our use of electricity in a way that balances harm, benefit, tragedy, and convenience, in a way that usually works and allows a vast array of products to be invented and brought to market quickly.

    But medicine has a monopoly – in fact several intertwined monopolies. I have seen a bag of sterile water marked with a warning that it is illegal to sell without a doctor’s prescription. Surely this is excessive. Yes, if sterile water were widely available, people might find it easier to practice medicine without a license. But I can do electrical work without a license – and despite having just discovered something really scary in my own home from my own actions (that seemed reasonable at the time), I would argue against more regulation there.

    Bottom line, medicine is treated very differently from other things that can kill us, and I wonder whether it really should be. If not, then let’s look for some alternative to the existing bureaucracy.

  6. Reg CMC Gal says:

    It’s also important to remember the FDA isn’t the only regulatory authority in the world. There are many other health authorities that have their own requirements, and if drug makers want to market their product outside the US, they will still have to meet those requirements, regardless of how regulation is slashed in the US.

  7. Alan Goldhammer says:

    I worked with Scott on a couple of occasions when he was McClellan’s deputy at FDA and I was at PhRMA. Scott has conservative/libertarian leanings to be sure but he is extremely thoughtful and conscious of FDA’s main mission. There are always things that take way too long to get accomplished (moving to paperless drug labels took just over 15 years from the time it was conceived). The bigger issues right now are not regulatory but scientific. Will we ever see the development of biomarkers for a variety of neurological and mental disorders? Can new classes of antibiotics that don’t rely on microbial screening (long since past its heyday) be developed? And so on.

    Derek’s points are spot on. I think the one big issue Scott is going to face will be increasing the availability of experimental drugs to patients. We went through this 25 years ago with HIV investigational drugs when the Public Health Service developed a ‘parallel track’ outside the clinical trial so ill patients could get access. It took some intense discussions with FDA, NIH, the pharma industry and patient groups to come up with something that worked. We did it back then and the groups advocating for increased availability would do well to learn from that lesson.

  8. Emjeff says:

    With all due respect, Derek, I think your FDA interactions have been extremely limited.

    1. Derek Lowe says:

      Probably true – got some counterexamples to share?

  9. SteveH says:

    In response to Chris Phoenix, I read somewhere once that there are independent IRB’s (I think it was at a research hospital) that reviewed research proposals. Google it. I know, it’s too late now, but there are usually alternatives.

    About the electrical cord, see what might happen when someone doesn’t follow the directions? I bet that cord manufacturer sent Underwriter’s Laboratory samples of their product (and a good-sized check) to get certification that their cord, if used properly, probably wouldn’t burn your house down. But if that manufacturer switched to cheap plastic coating or fewer wire strands per cable to save a few bucks, the “new and improved, but uncertified” cord could still burn your house down.

    And do-it-yourself electricianing? There are good reasons for all those complicated electrical codes. Look up aluminum wiring sometime. DIYers don’t always know why things are done the way they are, but it’s not usually completely arbitrary.

    In reality, healthcare is regulated in proportion to the risk to our well-being, just like automobile and air travel is. And healthcare is as intimate, as personal as economic commerce can get. I certainly want to be sure that whoever is trying to get me to buy something to put INSIDE MY BODY is as legit as possible.

  10. Duane Schulthess says:

    “they’re priced the way that they are mainly because people (and their insurance companies) will pay those prices”

    No. They are priced the way they are because Medicare Plan D transfers the costs onto the American tax payer, funded via $1 bil in debt offset by deferred future tax liabilities as yet to be collected…(to quote Ross Perot, “politicians buying votes this year with what used to be our money”).

    I personally would LOVE to see a market driven system that is actually based upon both what people and insurance companies can pay, and the efficiencies created by effective drugs (i.e. Sovaldi) in current treatment pathways.

  11. Anonymous Researcher snaw says:

    Before I switched fields and got my doctorate in biology, I was an electrical engineer. So I have seen both UL Test Reports on electrical products and FDA Queries on Investigational Drugs. In both cases, there is usually a good reason for the rules.

    For instance, when I was an engineer, we had a thick book of California Seismic Code rules that we had to follow for any job going to that State. Such rules, and their enforcement, are the main reason why earthquakes in Chile, Japan, or California kill far fewer people than do comparable earthquakes in China or Haiti.

    And Derek is absolutely right that the cost of Pharmaceutical R&D is mainly due to the high failure rates. I consider myself extraordinarily fortunate that several molecules on which I worked are now on the market saving lives and others in late-stage trials. But the vast majority of the molecules on which I have worked were failures. The primary mission of the FDA is protecting public safety. But the FDA also pushes us to do better science. A pill is only as good as our knowledge about how well it works. And there’s only one way to get such knowledge: clinical trials. On which we spend buckets of money.

  12. Chris Phoenix says:

    SteveH, yes, I do see what can happen when directions aren’t followed; that’s exactly what I was writing about. For electricity, we’ve decided it’s an acceptable risk. And, in fact, houses rarely burn down.

    Reg CMC Gal, do you know how the bureaucracy and delay in other countries compares with the U.S.? Obviously, some countries have blatantly inadequate regulation, but there are a lot of reasonably well-run countries that do medical research; do they do it any faster?

    1. Petros says:


      Japan and the EU are the obvious examples of well run approval systems but, in most cases, neither delivers new drug approvals as quickly as the FDA does. The Japanese system has some distinct quirks while the EU system is more defined with clearly established timeframes set down for each part of the process.
      There are different, parallel, pathways for generic approvals in the EU with expeditious approvals effected by some national regulatory authorities while others are very tardy.

    2. NJBiologist says:

      @Chris Phoenix: “And, in fact, houses rarely burn down.”

      Funny that you should say that… the house three doors down from me is currently unoccupied due to damage from an electrical fire. Neighborhood rumor points to a 50-year-old heater as the cause.

      The National Fire Protection Association counted 45k structure fires, 420 deaths, 1370 injuries and $1.4bn in damage from 2010-2014 attributed to electrical failure or malfunction. You can call that rare, but 420 deaths is a lot more than the 8 attributed to the HERG inhibitor Seldane.

  13. John Thacker says:

    “Drugs aren’t priced the way that they are just because of the cost of trials – they’re priced the way that they are mainly because people (and their insurance companies) will pay those prices.”

    Yes, though it does mean that drugs for which the expected profit doesn’t exceed the costs aren’t researched and aren’t released. The equally true flip side of your argument is that when the costs of compliance increases, people aren’t just automatically willing to pay more, even if a drug works. Particularly egregious examples are vaccinations for infectious diseases endemic to other countries, where the US specific population at risk isn’t large enough to justify US trials, but it is a problem with diseases rare in this country for other reasons as well.

    Your point is true, but it equally implies that it’s just not true that if a drug works, prices will adjust upwards to cover the cost of regulations. We know that some drugs that work will not make it through because their potential market isn’t large enough. There’s a lot of programs designed to deal with this problem because it is a real problem.

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