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On the FDA, Drug Approvals, and Not Knowing Enough

It doesn’t seem to have generated many headlines, but the FDA recently released a report (PDF) on the pace of drug development. Titled “Targeted Drug Development: Why Are Many Diseases Lagging Behind”, it seems to be motivated, at least in part, by a desire to answer “Not Because of Us!” The agency goes into some detail about the state of knowledge in Alzheimer’s, diabetes, hepatitis C, and rare genetic diseases, as examples of target-driven drug discovery. They note, correctly, that in cases like Alzheimer’s that we have such an incomplete understanding of the causes of the disease that it’s hard to see how to speed up drug discovery (other than by continuing to figure out what’s going on).

Now, you could imagine one way that wouldn’t seem to depend on knowing what really causes Alzheimer’s: a solid phenotypic assay. Those are target-agnostic, and in fact can be one of the best ways to actually track down the targets themselves, once you screen and find some agent that gives you the right effects. But there are no appropriate small animal species that get Alzheimer’s (and there’s room to argue about the situation even with the larger primates, some of which clearly don’t have AD pathology). And despite a great deal of work over the last 25 years and more, no such animal model has really emerged. No spontaneous mutant rodents, for example, have ever shown up with AD, and the many efforts to engineer some all suffer from a circular reasoning problem: you have to know what defects to engineer in the first place. Putting human-style amyloid genes (and amyloid-processing genes) into a mouse is not a good way to track down a new Alzheimer’s target, because you have to assume that the amyloid pathways you’re putting in are the important ones. If they turn out to be, and if they express correctly, then you do have a platform for screening, but so far (to my knowledge) none of these attempts are generally accepted as appropriate models.

Part of that problem is, to be sure, that the timeline of AD research is so long that the real test of an animal model (whether a drug that works in it works in humans) is always going to be a long time coming. But remember, the point isn’t to validate the animal model. The point is to treat human disease, and no one has been able, with much confidence, to advance any small-animal system that can do that.

How about something like diabetes? That’s understood far better than Alzheimer’s; I don’t think anyone would argue that point. There are even animal models for the disease – they’re not perfect, but compared to the situation in Alzheimer’s, they’re terrific. But even there, when you get right down to the causes, things get fuzzy. Type I diabetes, for example, occurs when a patient’s immune system targets their islet cells in the pancreas. That seems well established – but what sets off that immune response? What distinguishes a baby who will go on to develop classic childhood Type I from one who won’t – can you go through a list of newborns and pick them out? Not yet, although some of that is probably because the autoimmune problems may be set off by environmental factors like an infection. But I don’t think we can even say which babies are at higher risk, in most cases. Then there’s Type II, a major feature of which is the development of insulin resistance in the peripheral tissues. But if that is the root of the problem, what molecular pathway, exactly, causes insulin resistance? There are some good candidates out there, but that crucial question still hasn’t been nailed down.

(As an aside, you may wonder where those diabetes animal models came from. There are compounds that have been found to selectively damage islet cells, so you can induce a fairly realistic insulin secretion deficiency on that end. And if you alter a rodent’s metabolism so that they put on fat (and there’s more than one way to do that), something about that condition seems to also bring on insulin resistance – quite likely via the same sorts of pathways, whatever they are, that make obesity a risk factor for Type II in humans.)

The FDA is quite right to point these things out, because it’s for sure that a lot of people don’t realize them. But as you read the report, it does start to come across as an apologia pro vita sua, a brief for the defense. Here’s what the agency is doing to speed things up, here’s where we’ve helped, here’s where it’s just not our fault that we don’t have a flippin’ Alzheimer’s drug yet. They do get a lot of flak from the people who think that the main problem is regulatory overkill, and that if the government would just get out of the way that we’d have more cures. And although I have libertarian sympathies, I know too much about drug discovery to buy into this position. (Someone unsympathetic to libertarianism in general would no doubt add that this happens every time it touches on something that you actually know something about!)

The FDA Law Blog comes away with the same opinion, and they have a theory about why this is going on:

. . .we note that, when taken in the context of the current legislation before Congress (e.g., 21st Century Cures Act), the blog post and white paper seem to indicate a degree of defensiveness on the part of FDA.  The blog post, in particular, begins by stating that FDA’s drug approval process “is the fastest in the world.”  It then relates that “[w]hen research does not offer answers to important scientific questions, cures cannot be developed.  And when viable cures are not in the pipeline, focusing on regulation will not improve the situation . . . .”

There we are: the 21st Century Cures Act. That’s been passed by the House (and here’s the sponsors’ summary of it and case for it). And here’s policy wonk Norm Ornstein’s article on it in The Atlantic. He’s a fan:

But getting to “yes” was not so easy. First, it required a bundle of money—at a time when federal dollars are particularly difficult to come by. Many Republicans do not want to expand government of any variety, and the zeitgeist is to slash more, not spend more. The Brat Amendment reflected that view, and would have cut the innovations in the Act off at the knees. Second, the Act tries to reduce the daunting costs of bringing promising treatments through the lengthy and difficult process of laboratory work, animal trials, and several phases of human clinical trials—something that is opposed by many people who fear that any shortcuts could be dangerous, and who do not want to do anything that might reward pharmaceutical companies. Thus, such luminaries as David Kessler, the former head of the FDA, opposed the bill.

Kessler’s not alone. Here’s a worried editorial at the New England Journal of Medicine that cheers some aspects of the bill, but is not so happy about others. The authors note that the general emphasis on speeding everything up and approving more drugs runs the danger of relying on trials that are too small, too underpowered, too reliant on early-stage biomarkers, etc. And they have some strong points: if an Alzheimer’s therapy looks sort of promising in Phase II, but wipes out completely in Phase III (as has happened many times in the last few years), then the problem is not that the Phase III trial got in the way. Drugs that are going to benefit people actually work in big, well-designed Phase III trials, and a lot of things that look like they’re going to work before hitting them die off when they finally do. That’s a feature, not a bug.

So, defensive language aside, I think that the FDA has a point in its white paper. The reason we don’t have cures for a lot of diseases is not so much that pesky regulations keep great drugs from getting to the market. It’s that we don’t know enough – yep, even in 2015 – to make so many great drugs.

30 comments on “On the FDA, Drug Approvals, and Not Knowing Enough”

  1. Rule (of 5) Breaker says:

    I agree we don’t know nearly enough Derek. I am always amazed at how little we know about human biology. We are probably lucky to have drugs at all. Alzheimer’s is certainly a prime example of not understanding causes vs. correlations. Consider even a few examples like how our gut microbiome or circadian rhythms affect our gene expression, drug responses, and general health. We really don’t have much of a clue about them.

  2. Gerry says:

    Aging underlies Alzheimer, diabetes and many other diseases we can not currently treat effrectively. As long as we do not seriously target and fund research to understand the aging process we won’t progress to a cure of those diseases.

  3. roger says:

    Here’s a doctor who thinks we’ve got the type II diabetes cause and effect backwards…
    drmalcolmkendrick.org/2015/08/04/turning-diabetes-upside-down/

  4. Glen Weaver says:

    What, if anything, can be done on the regulatory level to make clinical trails and the approval process lest costly? The cost involved seem to limit the process to those entities which are effective fund raisers, and not necessarily those that are most effective in science.
    One could argue that the majors buy promising candidates, and that the majors have the scientific background to choose wisely. The results do not seem to support this argument.
    If altering the process could significantly reduce cost to reaching completion of phase II trials*, this would provide more opportunity for smaller entities to bring new products into the system.
    I would include the patent/ IP law and tax law as part of the “regulatory system” to be reviewed for systemic improvement. This could include having a division of the patent office attached to the FDA. Patent status might be modified for certain classes of discovery. A once daily TB drug? Patent could be renewed until resistance developed.
    These are changes in things under government control. They should probably be reviewed every generation to match the needs of the modern world.

  5. steve says:

    In response to the Kendrick link, GLP-1 agonists already act at least in part through lowering glucagon but do not cure diabetes. I think part of the reason Alzheimer’s and diabetes are difficult is that they are multi-factorial diseases. Simply hitting one target may not be enough (it’s the amyloid! not it’s the tau! no it’s the peroxynitrites!) without understanding the underlying etiology. For example, in the case of both T1D and T2D there are compelling data suggesting that ER stress is an important component. It wouldn’t surprise me if this plays a role in Alzheimer’s as well. It’s rather disconcerting to note that the most effective drug in diabetes is metformin, which was developed over 50 years ago without any molecular targeting and we still don’t understand how it works. Maybe the whole approach of creating drugs for particular preconceived targets is not the answer.

  6. Eric says:

    I tend to agree with the FDA’s position. Excessive regulations certainly slow things down (and I’ve seen that firsthand on numerous occasions) but that’s not the fundamental issue. We are simply more ignorant of disease processes than we would like to admit. Save for acute infections and certain genetic mutations identified in rare diseases, we generally don’t know the root cause of most chronic diseases. Cardiovascular disease is a good example of our ignorance: HDL-c is known to correlate with CV risk on a population level which resulted in a hypothesis that raising HDL levels would have beneficial effects. So far clinical trials haven’t supported this which probably demonstrates high HDL levels isn’t the answer; it depends on how you get there. So a field that has been extensively studied for decades still doesn’t have a complete understanding of basic lipid biology. These are not easy questions to answer and loosening government regulations might speed things up, but it isn’t going to solve that fundamental problem.

  7. johnnyboy says:

    “What, if anything, can be done on the regulatory level to make clinical trails and the approval process lest costly? ”

    Considering that the bulk of clinical trial costs consists of the payments to physicians acting as PIs, then on a regulatory level you could regulate the maximum payment they get per procedure. Doing clinical trials is currently a boondoggle for physicians (11$ billion a year in the US, counting only private (ie. non-academic) physicians); if you want to limit costs that would be the first place to look.

  8. Mark Thorson says:

    . . . an incomplete understanding of the causes of the disease . . .

    No, that’s not the problem with Alzheimer’s. It’s that the Amyloid Cascade Hypothesis has dominated the field for the last 20 years.

    It isn’t what we don’t know that gives us trouble, it’s what we know that ain’t so.

  9. Anon says:

    Take every single penny given to people whose entire career cannot handle the end of the beta amyloid hypothesis and give it to the clinician that is willing to run a decently powered human trial on even the most outlandish theory, and maybe we will find the broad street pump that will allow us to solve this.

    1. Ian Musgrave says:

      Everything we have tried for Alzhemier’s (inhibition of inflammation, lipid altering drugs, NMDA anatgonists, antioxidants and more) has failed. Thrashing around with off the wall hypotheses will not help in the slightest. Lots of things are neuroprotective in tissue culture that do not translate clinically.

  10. Anony says:

    Just a reminder to the extreme. She died today. Regulating clinical trials is a painful, burdensome necessity (not that it can’t be done in less painful more intelligent ways), see Vioxx.

    http://www.washingtonpost.com/national/health-science/frances-oldham-kelsey-heroine-of-thalidomide-tragedy-dies-at-101/2015/08/07/ae57335e-c5da-11df-94e1-c5afa35a9e59_story.html

  11. hypnos says:

    Well, one could argue that some well-established drugs (e.g. Aspirin, Tylenol, Warfarin) that help patients every day would not be approved today. Clearly, the standards have changed over time and the risk aversion became larger.

  12. Mark Thorson says:

    Add colchicine to that list. It’s therapeutic index is among the lowest of drugs, and the mechanism of action is frightening when safer alternatives are available. I wouldn’t be surprised if it was useful in cancer chemotherapy (due to the resemblance of its mechanism of action to vinorelbine), but it seems insane to use it for gout.

  13. Kelvin says:

    “Clearly, the standards have changed over time and the risk aversion became larger.”

    Of course the standards have changed, because each new drug sets the bar (standard of care) higher for the next…

  14. While your focus is on new drug development where the FDA adds a lot of value, I think there is a case to be made that drugs that are known to work in other places will never be available here because of over regulation. The best case I have heard on this is sunscreen were products from other countries have not gotten approved here.
    See link above.

  15. DrSnowboard says:

    “I think there is a case to be made that drugs that are known to work in other places will never be available here because of over regulation. ”
    I’m with Anony , see http://www.bbc.com/news/world-us-canada-33831451

  16. TX raven says:

    @Citizen Chemist
    “there is a case to be made that drugs that are known to work in other places will never be available here because of over regulation.”

    I’m not sure that’s true. In fact, that was the business model of companies like Ovation or Chelsea. So, for them it worked.

    Candidly, I’m surprised by the lack of self-criticism of us, scientists working in drug discovery.
    Chemists, following a decade seeking to industrialize drug discovery and rule-making.
    Biologists, not recognizing the weaknesses in the biological hypotheses that serve as starting point for expensive multi-year projects.
    As for research management, well….. I’m short of time for that one 🙂

    So, we seem to be near the end of the current paradigm. But will we be able to create a new one? That may require more changes than we can digest…

  17. CMCguy says:

    While it may be true that the FDA is not to blame for the lack of sufficient knowledge to effectively treat many diseases that seems to be a straw man if they do not acknowledge much of what they now do often inhibits rather than encourages or aids drug development. Theirs is certainly a tough job but the lack of consistency and bureaucratic approach make it tougher to take the often limited validated knowledge or concept and turn it into a useful drug. Breakthrough and other initiatives could improve interactions yet unfortunately there are too many counter forces that do not really allow cooperation between Academia, Industry and Government that might enhance the process. The Industry has many flaws although some are a result of having to deal with an Agency that likes to talk science but with unreasonable or illogical CYA controls.

  18. Erebus says:

    On the whole, the FDA does far more to inhibit rather than encourage drug development — and they seem to get worse every year, as costs keep rising. (What was the latest figure? $2B to get a drug approved these days?) Pournelle’s Iron Law of Bureaucracy comes to mind…

    I believe that it’s disingenuous to try and shift blame. Instead, they should ask themselves what they could do to change things for the better. A few ideas: (A) Reduce the staggeringly high, indeed onerous, costs associated with regulatory drug approval, as this would open the door to more innovation and a more favorable business environment. (B) Standardize the drug approval process inasmuch as possible, as the current practice has rightfully been described as mercurial and unpredictable. (C) Actively lead in developing technologies to further the mission of the organization — e.g. organs on chips, and so forth.

    …But the FDA is content to sit on its hands and do nothing. “But.. but… We’re not to blame, it’s the scientists that haven’t figured out Alzheimer’s yet!” Contemptible.

  19. Lane Simonian says:

    Dogs are one of the few animals that can naturally develop a condition like Alzheimer’s disease. Here is the effect of air pollutants–a number of which can produce peroxynitrites–had on some dogs exposed to high levels of air pollution in Mexico City:

    Dr. Lilian Calderón-Garcidueñas, lead investigator of the studies, noted that some dogs exposed to Mexico City air began to exhibit “decrements of attention and activity.” Caretakers of other dogs “were aware of alterations of sleep patterns and barking,” she wrote. Some “reported transient episodes during which the dogs failed to recognize [them].” Inside their brains, Calderón-Garcidueñas found dramatic tissue damage—the cells in the dogs’ olfactory-processing center were dying, with the scars of disease traceable out to the nose itself—that was strangely reminiscent of the damage that sometimes appears in an entirely different study population: Alzheimer’s and Parkinson’s patients.

    http://www.motherjones.com/environment/2015/05/air-pollution-dementia-alzheimers-brain

    This is the same researcher, who found diffuse amyloid plaques and hyperphosphorylated tau and subtle cognitive deficits in children exposed to high levels of air pollution in Mexico City (which were all worse in children with the Apoe4 gene).

    Here are two keys, it does not matter how much amyloid (either oligomers and plaques) one has in one’s brain as long as some balance remains between oxidants and antioxidants in the brain. When peroxynitrites are scavengers for instance, they produce nitrite and water. Peroxynitrites or nitrite oxidized by transition metals attracted to amyloid oligomers can lead to nitration but water is a putative de-nitrating agent. So as long as peroxynitrites are being scavenged, hyperphosphorylated tau does little damage. But once peroxynitrites stop being scavenged permanently nitrated hyperphosphorylated tau interferes with neurotransmissions and the transport of nutrients. Amyloid oligomers increase hydrogen peroxide levels but once oligomers are nitrated into plaques this problem ends.

    Secondly, olfactory receptors are g protein-coupled receptors that are damaged by oxidants. They are often the first receptors damaged often even before the onset of Alzheimer’s disease. The other g protein-coupled receptors damaged in Alzheimer’s disease are muscarinic acetylcholine (short-term memory), sleep (melatonin), social recognition (oxytocin), mood (serotonin), and alertness (dopamine). And part of this damage can also be reversed via the nose with direct inhalation aromatherapy.

    But back to the dogs for a second. Certain antioxidants have partially reversed dog “dementia.”

    Neurobiol Aging. 2002 Sep-Oct;23(5):809-18.
    Brain aging in the canine: a diet enriched in antioxidants reduces cognitive dysfunction.
    Cotman CW1, Head E, Muggenburg BA, Zicker S, Milgram NW.

    Thus, studies in the canine model suggest that oxidative damage impairs cognitive function and that antioxidant treatment can result in significant improvements, supporting the need for further human studies.

    I am a Latin American environmental historian so in a sense I haven’t strayed that far from my area of expertise.

  20. Mark Thorson says:

    And part of this damage can also be reversed via the nose with direct inhalation aromatherapy.

    Lane, you are a crank.

  21. Lane Simonian says:

    Mark, you and I agree on one thing: amyloid does not cause Alzheimer’s disease.

    The key compound in some essential oils that may improve cognition in Alzheimer’s patients is eugenol.

    http://onlinelibrary.wiley.com/doi/10.1111/j.1479-8301.2009.00299.x/full

    Neurosci Lett. 1997 Apr 4;225(2):93-6.
    Eugenol protects neuronal cells from excitotoxic and oxidative injury in primary cortical cultures.
    Wie MB1, Won MH, Lee KH, Shin JH, Lee JC, Suh HW, Song DK, Kim YH.

    In Vitro Activity of the Essential Oil of Cinnamomum zeylanicum and Eugenol in Peroxynitrite-Induced Oxidative Processes

    Silvio Chericoni ,* José M. Prieto , Patrizia Iacopini , Pierluigi Cioni , and Ivano Morelli
    Dipartimento di Chimica Bioorganica e Biofarmacia, Università di Pisa, via Bonanno 33, 56126 Pisa, Italy

    Until someone provides a more convincing explanation for Alzheimer’s disease, I am all right with whatever labels people want to assign to me.

  22. Kelvin says:

    @Lane, “convincing evidence” is subjective because it needs to *convince* somebody. And when somebody is already convinced with their own per theory (whether amyloid or peroxynitrites) so that the ignore or cherrypick and interpret any evidence to fit their pet theory, then no amount of evidence will convince them otherwise. This is called faith, not science, and you act more like a religious fanatic than a scientist. And since you contribute no scientific experiments nor evidence to science itself, you will continue to be seen as a crackpot who is tied to their faith and blind to any contrary evidence. You are no better than those that are stuck to the amyloid hypothesis, but at least those others do experiments so that they can hope to find the truth even if it surprises them.

  23. Lane Simonian says:

    I cannot comment much on the clinical trial aspect of it, as this is now a very preliminary work in progress.

    As far as cherry picking, the oxidative stress hypothesis was not the first one I looked at, but the last one I looked at while trying to understand Alzheimer’s disease. The other way to look at this is that when most of the phenomena can be explained by a hypothesis, then it is likely a good hypothesis (a hypothesis not a theory; there is no guarantee that I or any of the scientists that support the oxidative stress hypothesis of Alzheimer’s disease are correct). For example, I cannot only connect the risk factors to the pathways that lead to peroxynitrite formation (which are also the pathways that usually lead to amyloid and hyperphosphorylated tau), I can specifically identify the various damage that peroxynitrites do to the brain. Again this is not proof that particularly effective peroxynitrite scavengers can treat Alzheimer’s disease (nor can the early “successful” clinical trials be considered proof in this regard), but it is a indication that peroxynitrite scavengers may be able to treat Alzheimer’s disease.

    On the other hand when a hypothesis (the amyloid hypothesis) produces disappointing results time and again and you try to manipulate or explain away those results each time, you (not specifically you) are not doing anyone any favors.

  24. Mark Thorson says:

    There’s a large population of people who dose themselves with large amounts of peroxynitrite all day, every day. These people are tobacco smokers:

    http://www.researchgate.net/profile/Thomas_Mueller41/publication/14156121_Evidence_for_peroxynitrite_as_an_oxidative_stress-inducing_compound_of_aqueous_cigarette_smoke_fractions/links/00b49536011180da52000000.pdf

  25. Mark Thorson says:

    If peroxynitrite _causes_ Alzheimer’s Disease, smoking would be a major risk factor for AD. But studies show it is not. If anything, tobacco smoking might be protective:

    http://www.researchgate.net/profile/Amy_Borenstein_Graves/publication/230584479_Alcohol_and_tobacco_consumption_as_risk_factors_for_Alzheimer's_disease_a_collaborative_re-analysis_of_case-control_studies/links/0deec53a5a4a677f32000000.pdf

    This is not to say that peroxynitrite plays no role in the pathogenic process of AD. I think it plays a major role sustaining and exacerbating the disease process after the process is initiated. But it is not the initiating cause. If it were, tobacco smoking would be a major risk factor for AD, and we would see AD developing frequently in youth and middle age in heavy smokers. We don’t see either of these things. Peroxynitrite does not cause Alzheimer’s Disease.

  26. Lane Simonian says:

    There is a second thing we agree upon (which I did not acknowledge before): peroxynitrites may play an important role in the pathogenesis of Alzheimer’s disease. And I will grant you this which I did not before: light smoking may actually decrease the risk for Alzheimer’s disease. I only have one thing new to add to the discussion: nicotinic acetylcholine recpetors may actually be a g protein-coupled receptor. Light stimulus of these receptors decrease the risk for Alzheimer’s disease via the neuroprotective phosphatidylinositol 3-kinase/Akt but heavy stimulus may increase the risk for Alzheimer’s disease through p38 MAPK/peroxynitrites. And even though the studies are small heavy smoking does appear to increase the risk for Alzheimer’s disease; a risk that would likely be higher if most heavy smokers did not die before Alzheimer’s had a chance to develop.

    http://archinte.jamanetwork.com/article.aspx?articleid=226695

  27. Lane Simonian says:

    I rarely post this one. Some of the feedback mechanism are missing and some things are not in the best places. For example, calpains are essential to the formation of amyloid oligomers as well as being a factor in hyperphosphorylation of tau. Amyloid oligomers do stimulate g protein–coupled receptors but less so than amyloid precursor proteins and g protein-coupled receptors stimulate the production of both via phospholipase C/intracellular calcium release/calpains/gamma secretase (in the case of amyloid oligomers) and phospholipase C/protein kinase C/ p38 MAPK/peroxynitrites/caspsases/beta secretases (in the case of amyloid precursor proteins). In regards to peroxynitrites (ONOO-) what is missing from this chart is tyrosine nitration. This chart was sent to me by a scientist who disagreed that peroxynitrites were the cause of Alzheimer’s disease but he consulted with friends working in the field and they asked him to send me the chart and he did.

    http://www.genome.jp/kegg-bin/show_pathway?hsa05010

  28. Ted says:

    Dalbavancin

  29. Anonymous BMS Researcher says:

    One can argue either way about the FDA: they famously prevented some nasty ones such as thalidomide going on the US market, but one can argue today they are overly cautious. However, if something really is very effective against something important, than its makers can get it approved elsewhere first and accumulate sufficient real-world outcomes data to get FDA to approve it.

    From my experience of drug discovery and development, I do agree with Derek and the FDA on the main point: for the toughest diseases regulatory approval isn’t the main rate-limiting factor. We just do not know enough about many diseases, and secondary endpoints are rarely as predictive as we would like them to be. Even when we think we know, big outcome trials have sometimes turned up major surprises about treatments that had been on the market for years based on what we had thought were highly predictive secondary endpoints.

    There just is not any good alternative to hard endpoints.

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