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Regulatory Affairs

The Politics of the 21st Century Cures Act

The “21st Century Cures Act” has now been signed into law. I only wish it promised the cure for some of what the 21st century has had to offer so far, but we’ll take what we can get. So what are we getting? Steve Usdin of Biocentury put it well when he said “Start with a large number of policy options, subtract any that don’t appeal to Republicans, remove any that Democrats adamantly oppose, delete any that industry hates, and kill or revamp those that FDA says it cannot live with“. I’m surprised that there’s a lot left after that process, but there is.

In addition to my thoughts the other day, I wanted to bring up some others that Biocentury identifies. Usdin’s concerned about the NIH funding provisions in the bill, because it’s so heavily tilted towards high-profile translational projects and perhaps away from basic science. There are also some significant changes in the way that even the institute’s common funds can be used that I hadn’t realized – the “other transaction authority” mechanism is significantly expanded, which seems to give the various NIH heads much more discretion about where the money will go, and how quickly. Overall, funding power seems to have been (very much) centralized, and we’ll have to see what that produces in practice.

I didn’t go into the antibiotic and antifungal approval changes in my earlier post, but the idea is that approval paths for drugs in these categories for “limited patient populations” have been enhanced. These approvals will bear special labeling and other mechanisms to keep them from being prescribed outside the group that’s been shown to benefit. Of course, if later studies show that a compound in this class can be more broadly useful, it can be taken out of this category, but overall, this seems to be a sort of “orphan antiinfective” pathway. What I’m not sure about yet is how this would work financially – would such compounds come in at the high prices that would seem to be indicated by their small approved patient population?

One area that’s gotten plenty of attention is the mandate for “real-world evidence” in drug approvals. Usdin’s less worked up about this one:

Critics of the 21st Century Cures Act have warned that it would erode approval standards by allowing FDA to approve drugs based on anecdotal evidence. This is a huge exaggeration. What Cures would do is start FDA down the long road toward relying on real-world evidence to support selected regulatory decisions. The agency would have two years to establish a draft framework for two specific uses of real-world evidence: label expansions, and supporting or satisfying postapproval requirements.

The definition of “real-world evidence” appears to be evidence obtained by other means than randomized clinical trials, which is what has people worried. But as in the above, the bill isn’t saying that the FDA can approve drugs via such mechanisms; it’s saying that after trials and approval that other means (such as “ongoing safety surveillance, observational studies, registries, claims, and patient centered outcomes research activities“) can be brought in for label expansions, etc.

In another area, explicit “right to try” provisions did not make it into the bill. What’s there is more guidance on compassionate use provisions. Companies working on drugs for life-threatening conditions will be required to make their policies on compassionate use publicly available, with contact numbers, etc., but there are no requirements for any of these compounds to be made available – the publicly stated policy, in other words, could be “We do not make this compound available for compassionate use”, and that’s within the law.

The Biocentury article is particularly good on the regenerative medicine parts of the bill. There was an awful lot of back-room scuffling in this area:

FDA and the Alliance for Regenerative Medicine (ARM), an organization dedicated to advocating legislative and regulatory policies, beat back attempts to allow marketing of certain cell-based therapies based solely on small Phase II trials.

FDA Commissioner Robert Califf co-authored an article published Nov. 30 in the New England Journal of Medicine that addressed some of the arguments that had been presented to Congress to support reduced safety and efficacy requirements for regenerative medicines. According to the article, “the assertion that existing standards for regulatory approval are too rigorous for stem-cell therapies results largely from a lack of familiarity with the available pathways for developing cellular therapy products and from the lack of a systematic, facilitated approach to assembling the clinical data necessary to support the licensure of stem-cell therapies produced by individual practitioners at different sites.”

The final version of the bill, which ARM supports and which has not raised objections from FDA, would create a system for designating therapies as regenerative advanced therapies, and would treat designated products like breakthrough drugs. For example, sponsors of designated products could get meetings with FDA early in product development to discuss potential surrogate endpoints.

The actual standards for approval (and even accelerated approval) in this area have not changed, though. There are new provisions for post-approval studies and further demonstrations of efficacy, but you’re still going to have to show efficacy (and safety, of course) to get through the first time.

One thing that I don’t think many people talking about this bill have realized, and that Usdin emphasizes, is that many of its provisions are going to come right back before Congress pretty shortly, when user fees for the FDA will come up to be reauthorized. A lot of things are going to be thrown into that legislation, and you can expect that people who particularly dislike some aspect of this new law (or particularly think it missed something that might have been taken out along the way) will come back around for another try.

There’s another wild card, too. Depending on who the next FDA Commissioner is, the emphasis placed on all these things could well change a bit. I know that there have been a lot of stories recently about candidates with what appear to be pretty radical ideas, but I’ve already gotten tired of the new administration’s reality-show approach to floating names for these things, and I’m going to reserve my comments for when someone actually gets nominated. The President-Elect is already (in my view) well on his way to wearing everyone out by throwing shiny objects all over the landscape, and we’ve just barely made it out of the first week of December.

In all the horrified talk – and some of the horror would be justified – it’s worth remembering that the FDA’s mandate to consider efficacy and safety is not up to the desires of any one commissioner or administration. It’s part of the legislation establishing the entire agency. If you want to change that, you have a lot more shovel work to do. In general, I think that the incoming administration will be finding out (as many of them do) that causing Giant Transformational Change is not so easy in Washington. That’s partly by design; our entire system is set up to make it difficult to get things done, for fear of what might happen when it’s too easy.

This causes periodic cries from both the Right and the Left about how it keeps Good Things from being showered on the country by the Good People when they finally defeat the forces of darkness and get into office, but that’s how it is. I’m fine with that, and in fact, the main thing I’m looking out for are attempts to shortcut around these checks and balances. For example, I really dislike the expansion of executive power that’s taken place over the years, not least in the past eight, and would like to see some of that stuffed back into the box. Give me more gridlock.

19 comments on “The Politics of the 21st Century Cures Act”

  1. David says:

    My main concern is that (I haven’t actually read the bill) I don’t see anyone writing about what the evidence for label expansion will have to consist of. In a world where the placebo effect is apparently getting stronger, it seems to me that taking patient testimonials, no matter how controlled, is only going to magnify that effect, over a randomised controlled trial.

    On the other plus or minus side…cutting funding for preventative measures combined with more money/concessions for industry/research seems like a win for the industry. I personally read about this and think we’re protecting the supply of patients needing treatment as well as the supply of drugs, which is great economically, but I’d rather the treatment wasn’t needed in the first place.

  2. steve says:

    Every time there’s a discussion about this it seems to center on worry that a drug will get approved that hasn’t proven efficacy and will “endanger patients”. What’s missing in all this analysis is that many patients are already in danger, dying due to lack of effective treatments. There has to be a balance. If I’m dying of a disease I don’t want to wait 10 years for large multi-center Ph3 trials until I can access a drug that might very well treat my illness. On the other hand, I obviously don’t want something toxic. Thus the push to allow access if safety has been shown. With regard to regenerative medicine, this is the approach Japan adopted several years ago. To date there haven’t been any of the horror stories people worry so much about and there are cell therapies now on the market in Japan that showed safety and Ph2 efficacy. The bottom line is that you can’t just argue about crossing every t and doting every i with regard to patient safety without recognizing the huge cost to patients in delaying the time it takes for new therapies to get to market.

    1. halbax says:

      I think the problem is that society has to balance the desire of patients to take safe but ineffective drugs with the fact that someone actually has to pay money for the drugs. Why should the government or insurance companies have to pay money — potentially large sums of money — so that patients can try drugs that are not effective? There is only so much money available to spend on health care, and while it is certainly worthwhile to spend hundreds of thousands of dollars to treat an individual patient, that money shouldn’t be wasted. The balance you described neglects the fact that healthcare budgets can be a zero sum game and wasting money on ineffective drugs has the potential to keep other patients from receiving treatments that are actually effective.

      1. steve says:

        The question is whether we as a society can afford to spend a billion dollars for every single drug approval. I suspect not. This will hit the fan as the population ages and there is increasing demand for more rapid approvals. Sticking our heads in the sand and saying “my way or the highway” won’t fly for much longer.

        1. Hap says:

          Spending half that much to not know whether a given drug actually works is even more of a waste of money, though. That doesn’t even counting the money that will be spent by someone to buy an expensive placebo.

          Making drug trials quicker and cheaper by getting less reliable data on whether they work isn’t going to help patients. It may make patients feel better (and help a little by that, I guess) but it won’t make them less sick. Even if lower trial barriers lowers costs for drugs, not knowing if they’ll work means that more of what money is spent on drugs will be spent on things that don’t work (and some of that will be used to hinder the development of drugs through patent and supply chain hindrances, preventing drugs that might work from displacing those that don’t provably work).

          In addition, people who are sick have a limited number of shots to get cured. Having no drugs means they won’t get cured at all, Having lots of choices with unknowable results for any of them might get them cured, but unpredictably, and the money you spend there (for what you don’t know) can’t be spent elsewhere.

          You need more reliable data, not less.

    2. David says:

      Well that’s fine, except most drugs are *not* “safe,” even OTC meds. Ibuprofen can kill if taken too much. Numerous GRAS drugs aren’t good for the stomach/liver/kidneys, especially when these systems are weak/overtaxed in the first case.
      “Safety” seems in many cases to be a cost-benefit determination eg chemo/radiation – both very much toxic/poisonous, yet they are approved only because of their efficacy, where their effectiveness is deemed to outweigh their destructive impacts.
      Many antivenoms share a similar cost-benefit determination, some make you very, very sick…but you don’t die, or die much less often than without the antivenom.

      It’s only with the efficacy studies that these determinations can take place, otherwise, a large portion of those very lifesaving treatments you describe would not be on the market.

      1. steve says:

        @David, Ibuprofen is a great example but not in the way you mean – the fact is that there’s no way it would have made it through today’s regulatory environment even though it’s been in use for decades. As I said, it comes down to balance. When the largest killer of Americans is cardiovascular disease but you have large pharma leaving the CV space in droves because of the cost and complexity of the clinical trials then you know there’s something wrong. The costs have become too high and the reimbursments too low to justify. Without taking into account the counterfact that patients die when drug approvals are delayed as well you end up with an unbalanced system.

    3. Shalon Wood says:

      I’m pretty sure that anyone who actually manages to speed up the time to approval of new drugs while reducing cost _and_ not compromising either safety or effectiveness should be a) filthy rich, and b) in great demand by every single industry out there.

      Because to me, this looks like a pretty classic buyer’s triangle:
      1) Cheap
      2) Good
      3) Fast

      Pick any two.

    4. Derek Lowe says:

      Steve, my other big worry – which I think is well-founded – is that stuff that harmless but useless will find an easier path to approval under many of these proposals. I know that you’re wanting access to a drug “that might very well treat your illness”, but what if it comes with even better odds of a drug that might well do nothing at all? Well, except drain your savings.

  3. Tim Gallagher says:

    I still think there’s a need for follow-on legislation to liberalize the FDA, as it seems the FDA insiders still have a strong bias for control over industry growth. This isn’t so evident in therapeutics, but easily seen in 3 areas that the 21CC Act doesn’t seem to address:

    -LDT/CLIA/IVDMIA molecular diagnostics. We’re still subject to the FDA’s discomfort with anything but a 100% predictive (and 0% FDA culpability) assay and we’re still waiting on FDA clarity (as since 2009) on multi-variate predictive tests. Result: innovation in molecular diagnostics is still-born. There are swarms of MDx assays out there that aren’t bulletproof (R<100%), still worthwhile, though not with any chance of FDA approval, leaving the only route to the patient the very odd LDT exception/expensive CLIA delivery channel.

    -Consumer genomics. You still (basically) can't access your genome without a doctor, per the FDA.

    -Autologus regenerative medicine. The points above represent the FDA affirming that ANY regenerative medicine needs to be approved, willfully ignoring therapies generated using the patient's own stem cells. At this point, there is substantial data from ex-US experience indicating safety and efficacy, but left on it's own, the FDA hews to maximum control and demands approval of each procedure as a new drug.

    Without developments in any of the above areas – representing a change in FDA culture – one can only conclude that this is very much an incremental bill. (Though we ought to celebrate this, as the 21CC Act shows that compromise by our elected officials IS possible.)

    I look forward to the Gottlieb or O'Neill appointments to produce real movement on changing some of the regulatory stances listed above, and in changing the culture.

    1. Mark Thorson says:

      I’m reminded of the Chernobyl disaster. The nuclear reactor was not an inherently unsafe design. Run competently, it was perfectly safe. But the guy in charge was an electrical engineer, not a nuclear engineer. After doing some low power testing at night, the reactor needed to be throttled up to meet daytime load. It wasn’t heating up fast enough, so he pulled out all of the control rods. It still wasn’t heating up fast enough, so he overrode the safety system and pulled out the control rods that the safety system doesn’t let you pull out when you pull out all of the control rods. BOOM!

      That is what putting O’Neill in charge of the FDA will be like.

      1. Design Monkey says:

        Ummm. Mark, you described Chernobyl’s accident rather incorrectly. You really should look up not only IAEA INSAG-1 , but also the followup INSAG-7.

      2. loupgarous says:

        While Obama’s commissioner of the FDA for seven years arguably had a clear conflict of interest (married to manager of a hedge fund with not millions but hundreds of millions in drug company stock, but told Congress during her confirmation hearings she had no conflicts of interests) presiding over what at least one lawsuit in Federal court alleges was undue delay in black-boxing fluoroquinolones as being involved in tendon ruptures and aortic aneurysms and dissections. The major holding in her husband’s hedge fund was Johnson & Johnson, which through Ortho-McNeil makes Levaquin, one of the fluoroquinolone antibiotics associated with increased incidence of those adverse effects.

        So when we’re drawing nice crash-and-burn pictures of how this Trump appointee and that Trump appointee will cause horrible things to happen, let’s be even-handed and look at the messes the other guys have made in the time they had the White House.

  4. CBB says:

    “That’s partly by design; our entire system is set up to make it difficult to get things done, for fear of what might happen when it’s too easy.”

    Yes. I had this thought when arguing with a Libertarian the other day. They argued the best argument for Libertarianism was the past election. I’m of the belief that these big bureaucratic institutions that largely chug along regardless of the administration are one of the saving graces that insulate against executive incompetence. A government that is too limited has the potential to be too easily altered to meet someone’s agenda.

    1. ed says:

      I’ve not given up arguing with Libertarians, although it is kind of like arguing with any other kind of True Believer.

      I think most of them base their anti-regulation biases on the flawed logic of “evil bureaucrats trying to stifle innovation” rather than the historically valid logic of “we’ve got to put limits on idiots, because some of them think putting cocaine in soft drinks or radium in energy drinks or locking fire exits in factories full of inflammable materials is a good business model.”

  5. gippgig says:

    Article that should be of considerable interest in the Dec. 11 Washington Post newspaper:
    Enzyme research may ease studies’ placebo effects
    The same edition also listed for “The worst year in business” Elizabeth Holmes, founder of Theranos.

  6. loupgarous says:

    I can think of one case in which “real-world evidence” has already been of crucial help (though the speed with which it was acted on by FDA, and the conflicts of interest which may have affected that speed are debatable) – fluoroquinolone antibiotics.

    Standard pharmacovigilance doesn’t seem to have been as effective in picking up increased incidence of collagen breakdown leading to tendon and other skeletal integument damage, increased incidence of aortic aneursyms and aortic ruptures as two retrospective studies, one in Taiwan and one in Canada. These studies seem to be smack in the middle of “real-world evidence” as defined in Cures. And if Cures gets FDA to pay more attention to such studies and act on them more decisively earlier, lives can be saved.

    1. Ed says:

      You may be right, but I suspecct “real-world evidence” will be more of “llama menthol cigarettes: good for your throat and lungs!” and “laetrile cures cancer” than “Hey! That billion dollar drug causes people’s toes to fall off.”

      A significant number of people driving this reform are quite adamantly, even delusionally, denying a lot of real-world evidence, so expecting better logic in their regulatory behavior may be excessively optimistic.

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