drug approval

What if, rather than being too stringent about drug approval, the FDA is not being stringent enough?

oracknows — Mon, 13 Feb 2017 02:00:49 +0000

What if, rather than being too stringent about drug approval, the FDA is not being stringent enough?

There is a belief that is very prevalent among policymakers right now, particularly Republican policymakers, that the key impediment to drug development is the Food and Drug Administration. According to this narrative, the FDA is an overly strict, overly bureaucratic, and rigid organization that is the main barrier keeping fantastic cures to all sorts of deadly and debilitating diseases from flowing to the people at a reasonable price. The basic idea, as I've discussed many times, is that, if only the FDA would get out of the way, universities and pharma would be free to open the floodgates holding back the cures, and the free market would sort out the rest. It's a myth, of course. Actually the FDA is faster than its European counterparts at approving drugs and could work faster still if it weren't chronically underfunded. Even so, basically, every candidate being considered by President Donald Trump for FDA commissioner subscribes to some version of this myth, some even more far out than what I've heard before. In any case, as of this writing, Trump still hasn't picked an FDA Commissioner, and I've seen an article that makes a good argument that, if anything, the FDA is not stringent enough, at least at the preclinical level.

A couple of weeks ago Jonathan Kimmelman & Carole Federico published a commentary in Nature entitled "Consider drug efficacy before first-in-human trials." I thought it an important topic considering the speculation over who will be pointed FDA Commissioner by President Trump. As a a New York Times article published last week discusses, Donald Trump’s three most likely picks for FDA Commissioner (that I knew of at the time) all favor loosening drug approval standards and could very well undo decades of safeguards. Two are cronies of technolibertarian Peter Thiel, who will have a major input into Trump's ultimate decision. Of these two, one (Jim O'Neill) believes that the FDA shouldn’t have to require evidence of efficacy, only safety, before approving drugs and devices for the market. (Apparently the free market will sort it all out.) The other (Balaji Srinivasan) believes that a “Yelp for drugs” would do a better job than the FDA in assuring drug safety. (Apparently he's never actually spent much time reading online ratings systems.) The third candidate (Scott Gottlieb) is the closest thing I've ever seen to a bona fide, honest-to-goodness pharma shill, who called the early termination of a multiple sclerosis drug study “an overreaction,” even though three participants had died, defended the off-label marketing of Evista, and, when he was Deputy Commissioner of the FDA, harassed underlings when FDA scientists rejected Pfizer’s osteoporosis drug candidate Oporia, forecast to earn $1 billion a year.

Srinivani appears to be no longer in the running, thanks to his rookie mistake of not taking down his Twitter account before meeting with President Trump, allowing some of the dumber things he said about using the Uber model or the Yelp model for online reviews of drugs to be brought to light. However, there's now a new candidate, Joseph Gulfo, executive director of the Lewis Center for Healthcare Innovation and Technology at Fairleigh Dickinson University, the author of Innovation Breakdown: How the FDA and Wall Street Cripple Medical Advances and the former President and CEO of the medical device firm MELA Sciences. More on him later, but you can see from the title of his book that his philosophy is from the same mold as O'Neill's and Srivinasan's, but, unlike them, appears a bit more grounded in reality, although he appears to share O'Neill's and Srivinasan's unshakeable belief that the FDA is far too strict.

Basically, no matter who is finally chosen by the Trump administration to run the FDA, it is clear that the mandate will be to decrease regulation. Indeed, less than two weeks ago President Trump told a gathering of pharmaceutical executives, "We’re going to get the approval process much faster." The only question, thus, will be by how much. If it's O'Neill or Srivinasan, I'd expect a push towards a radical overhaul of the FDA. If it's Gulfo or Gottlieb, I'd expect a less radical, but still highly deregulatory, approach. Add to that President Trump's recent executive order mandating that federal agencies eliminate two regulations for every new regulation they issue, as well as a legislative agenda designed to "decrease regulatory burden," and under this administration we will almost certainly see a loosening of drug approval standards, all in the name of "fostering innovation." It's a process that actually began before Donald Trump with the passage in the waning days of the Obama administration of the misbegotten 21st Century Cures Act, which promised to get the cures flowing from industry by authorizing the FDA Commissioner to develop a framework decreasing the level of evidence needed for drug and device approval. That's why this Nature commentary is so important now. It argues for a higher standard before even allowing a drug to be tested for the first time in humans, thus going very much against the prevailing sentiment in Washington right now.

A disaster in a "first in human" drug trial

Kimmelman and Federico begin by describing an incident to illustrate the problem. It's not an example from the US, but it is a good starting point to discuss the dangers of "fast-tracking" new drugs:

On 17 January 2016, a healthy man was declared brain-dead after receiving an experimental drug in a first-in-human trial in France. Four of five other subjects receiving the same dose have serious, ongoing neurological complications. Investigations into the trial described many troubling safety practices, such as steep increases in dose levels delivered to sequential subjects without sufficient delays to check for safety.

The year since has brought intense scrutiny about how the debacle could have been anticipated and prevented. However, another issue is still largely overlooked: the duty to evaluate whether an experimental treatment is promising enough to warrant testing on people.

When thinking about drug approval, most people focus on phase III clinical trials, which are large randomized, double-blinded (when possible) trials designed to test the efficacy of an experimental drug versus placebo and/or existing drugs. However, phase III trials are only the culmination of the process of pre-approval drug development. Long before that there is preclinical research in chemistry, cell culture, and laboratory animals. Only when there is deemed to be sufficient evidence of promise does an experimental drug advance to phase I trials, also known as "first in human" trials. Incidents like the one above are one reason why I view "right-to-try" laws with such alarm, as such laws require nothing more than that a drug has passed phase I tests to be eligible for a patient to use them outside of a clinical trial.

Be that as it may, the French medicines safety agency (ANSM) ordered an investigation and re-examination of the data provided to the French ethics panel by the drug company Bial, based in Trofa, Portugal—in essence, the French version of what we in the US call the Institutional Review Board (IRB). This re-examination resulted in a report, with the following findings:

The report notes that the 63-page Investigator Brochure describing the trial included fewer than two pages of evidence that the drug had the desired pharmacological activity. It identified only two studies presented as evidence for efficacy, both problematic. In one, Bial had data for a different marketed drug showing it was more effective than Bial’s drug at relieving pain in animals, but did not include that information in a summary figure. Both preclinical studies showed only “moderate” positive effects. Moreover, Bial’s drug had been tested at a range of doses in mice that made it impossible to estimate the most likely effective dose in humans.

Press coverage following the tragedy quoted independent experts concluding that there was little evidence to support a trial, and that at least five other drugs designed to act in a similar way had been tested in people without success.(Bial maintains that toxicities were not predictable and that it has followed all human-testing norms. We approached the company for more information about the event for the purposes of this Comment but received no response.)

This incident is a good way to start a discussion about just how much preclinical evidence for a compound is enough to justify a first-in-human (FIH) clinical trial.

Efficacy versus safety in clinical trials

Kimmelman and Federico are bioethicists who have studied the ethics of first-in-human (FIH) and early-phase drug research for more than a decade. They wrote this editorial because they are concerned that there is a lack of emphasis on the efficacy of drug candidates observed in pre-clinical research during decisions about whether to advance a drug candidate to FIH clinical trials. They call for "infrastructure, resources and better methods to rigorously evaluate the clinical promise of new interventions before testing them on humans for the first time," noting that more than half of all drugs that reach later stage trials (Stage II and III) fail because they do not demonstrate efficacy, going on to write:

Today, the evaluation of preclinical evidence is especially important. Favoured picks for the next commissioner of the US Food and Drug Administration (FDA) are likely to lower the current requirements that a drug must demonstrate efficacy in humans before entering the market. If so, low standards for launching clinical trials in the United States could result in ineffective drugs being approved, while also decreasing incentives.

Regulators in Europe and North America evaluate safety before human trials can proceed, but they do not currently demand evidence for potential efficacy. At a workshop of the US National Academy of Sciences in September, Robert Temple, a veteran at the FDA’s Center for Drug Evaluation and Research, said that the agency largely left it to drug sponsors to evaluate their rationale that an experimental drug was likely to work. “I can’t think of any cases where [FDA has] said you can’t do this [phase I] study because we’re just too sceptical.” The European Medicines Agency (EMA) — Europe’s drug regulator — is similarly silent about the evaluation of clinical promise, even in proposed revisions to guidelines prompted by the Bial affair.

I'd say that Kimmelman and Federico are, if anything, understating the case. Lowering drug approval standards with respect to efficacy would not only be likely to result in more ineffective drugs being approved, but, if coupled with a generalized anti-regulatory push and an attitude to approve more drugs, likely to lead also to a decrease in safety standards as well, as the two are coupled. Think of it this way. We accept high levels of toxicity in chemotherapy drugs because they treat a deadly disease, but would never tolerate toxic side effects as serious to treat, for instance, a headache. Perfect safety is never possible in any drug, but must always be weighed against efficacy and the seriousness of the condition for which the drug is to be marketed. If efficacy is overestimated or de-emphasized, then considerations of the benefit-risk ratio will be skewed.

Kimmelman and Federico go on to argue that commercial interests "cannot be trusted to ensure that human trials are launched only when the case for clinical potential is robust." While I accept that this is true, I also can't help but note that commercial interests also do not want to spend boatloads of money carrying out clinical trials on experimental drugs unlikely to be shown to be efficacious and safe. When a new drug fails phase III clinical trials, it's a huge loss to a company, both in terms of development costs and in terms of the loss of projected revenue from sales of the drug, which explains why Scott Gottlieb was so upset when the FDA rejected Oporia. No, I'm not being sucked in to Jim O'Neill's fantasy that the free market will guarantee drugs that are safe and effective. I'm just noting that the situation is...complicated. There are competing incentives, both regulatory and financial. Nor do I disagree that commercial interests should be trusted to ensure that the preclinical evidence is robust and bulletproof before launching a clinical trial. Rather, I'm emphasizing again that lowering the standards would shift the incentives to make it more worthwhile to pharmaceutical companies to see what they can get away with.

What is to be done?

It's certainly true that very few FIH trials have resulted in disastrous outcomes like the one in France. Indeed, it's noted that in Europe only 2 out of 3,100 FIH trials overseen by the European Medicines Agency since 2005 have had disasters like the one in France and that serious harm and that the record in the US is similarly good. However, Kimmelman and Federico are correct to point out:

But, even if individual participants are not harmed, trials of ineffective therapies place burdens on society. Drug development is costly, in terms of money and people. Patients, healthy volunteers and experts involved in testing a dud treatment are not available for more promising ones. Expenses wasted on ineffective therapies and uninformative trials result in higher drug prices. Investigators, host institutions and sponsors have a responsibility to consider all this before embarking on new research programmes.

Moreover, researchers have ethical obligations to “assure that the risks to subjects are reasonable in relation to the anticipated benefits”, according to FDA guidance. Such regulators explicitly delegate these appraisals to ethics review committees.

Basically, the problem is that drug developers can, in essence, cherry pick favorable preclinical evidence in order to make their case that a clinical trial should be allowed. The other problem is that regulatory agencies will accept weak evidence of efficacy in animal models. Basically, the three questions that have to be answered in assessing whether preclinical evidence justifies a FIH trial:

What is the likelihood that the drug will prove clinically useful? (In other words, have other similar drugs worked? What drugs already exist for the disease and how well do they work?)
Assume the drug works in humans. What is the likelihood of observing the preclinical results? (How robust and reproducible are the preclinical data? How large are the effects observed? Do the animal models used reflect human disease well enough?)
Assume the drug does not work in humans. What is the likelihood of observing the preclinical results? (How do we know that the preclinical observations aren't due to random variation and bias?)

To address these questions and existing problems, the authors propose the following:

Require drugs sponsors to include negative results from animal studies in documents submitted to investigators and ethics committees. This is similar to the approach of All Trials in that greater transparency is recommended. Just as drug companies should have to report the results of negative preclinical trials, it only makes sense to apply the same standard to preclinical evidence submitted to support a FIH clinical trial. It's even suggested that an additional way to discourage data cherry-picking would be to require that drug sponsors sign a statement testifying that the clinical and preclinical evidence presented on clinical promise is complete and unbiased.
Encourage reviewers to consider a broad base of evidence in assessing the probability that a drug will prove clinically useful: for example, how have other drugs in the same class performed in trials? One important part of any application, be it for a grant or for approval of a clinical trial is the "Background and Significance" section. That is the part of the application where the applicant summarizes the existing evidence base supporting the application, discusses shortcomings in current knowledge and potential controversies, and makes the case for the significance of what is proposed before presenting the applicant's own preliminary data supporting the proposal. It's very easy to cherry pick studies that are positive and leave out studies that are negative. If the reviewer examining the application is not very familiar with the field, he could easily be unaware of the information left out. Similarly, it makes sense not to consider a drug in isolation. If another member of the class of drugs as an experimental drug being considered for a clinical trial failed its clinical trials, it's important to make a case for why this experimental drug is different, why this drug is expected to succeed where the others in its class failed.
Allow trials to proceed only after careful vetting of the preclinical evidence by independent experts. See above. Basically, in order to detect cherry picking and evaluate the evidence with a hard, cold eye, you need reviewers who are truly experts in the field and who have no vested interest in whether the FIH clinical trial proceeds or not.

Of course, all of this would require more investment. For example a new centralized FIH system is proposed:

Instead, we suggest the creation of a centralized FIH advisory system that combines ethical and scientific review. Several precedents exist. The Recombinant DNA Advisory Committee (which reviews new gene-transfer protocols) has assessed evidence of both risk and efficacy since it began reviewing human gene-transfer studies in 1989. Further examples of centralized, expert review of clinical trials in the United States include the SMART IRB Reliance Platform at the National Center for Advancing Translational Sciences; the National Cancer Institute’s Central IRB; and the Office for Human Research Protections’ ‘407 review process’ for certain paediatric trials.

The FIH advisory mechanism we envision would consist of subcommittees that specialize in clinical areas (for example, neurodegenerative disease, cancer and cardiovascular disease). Advisory-committee assessments would, like most of the above examples, be included in materials presented to physician–investigators and local ethics committees.

The authors anticipate some criticisms. For example, setting up a system like this would cost money. Their response is that such a review system might actually decrease cost and burden to the pharmaceutical companies, through the prevention of clinical trials unlikely to show a positive result by insuring a more sound basis for late-stage clinical trials, thus offsetting the cost at least partially.

Another anticipated criticism is exactly the sort of argument several of Trump's candidates for FDA Commissioner make, namely that such a system could prevent truly promising candidates from being tested. Of course, I can't help but point out that I'd be hard pressed to consider a candidate to be "truly promising" if the preclinical evidence supporting it is weak and or the effect size of the compound is small in animal models. The authors note:

However, we are not arguing that the preclinical evidence must be strong, rather that it be examined critically to inform ethical judgement. For diseases in which robust preclinical evidence is impossible — for instance, where animal models are clearly inadequate as in many neurodegenerative disorders — a limited suggestion of clinical promise might be enough to justify trials for a relatively benign drug candidate aimed at a great unmet medical need.

In other words, as I mentioned above, we need to look critically at all the evidence for new drugs and put it in the context of the seriousness of the disease, whether effective therapies already exist, and existing science and evidence.

Joseph Gulfo: Use biomarkers, not overall survival, to show drug efficacy

Much of philosophy behind the Trump administration's approach to the FDA seems to be based on a technolibertarian fantasy that, if only the "heavy hand" of government regulation were removed from entrepreneurs and industry, the cures would flow and the free market would sort out which drugs do and don't work. That is not surprising, given that Peter Thiel, who's never met a regulation he didn't hate, appears to be having an outsized influence on whom Trump will nominate for FDA Commissioner, so much so that, ironically, I'm actually hoping for the pharma shill to be chosen rather than the Thiel cronies who want, in essence, to dismantle the FDA. The FDA could survive Scott Gottlieb (indeed, it already has). I don't know if it could survive Jim O'Neill or Balaji Srinivasan. But what about Joseph Gulfo, whom I haven't discussed before?

Joseph Gulfo doesn't (quite) fit the mold of the Thiel cronies and was dismissive of Scott Gottlieb, even saying, "If you want safe snake oil, Jim O'Neill's your man." He also believes that the FDA should require evidence of efficacy before approving a drug. Oddly enough, he wasn't a big fan of the 21st Century Cures Act. The problem is, though, that he defines "efficacy" differently from how the FDA does. Basically, he redefines efficacy by using a lower standard of evidence. In a WSJ editorial written in November, "A Trumpian Cure for the FDA’s Chronic Lethargy", he explains:

The first change involves returning the FDA to its original role under the law. That is to prevent snake oil from getting on the market by ensuring that the only drugs approved for sale have demonstrated biological activity in fighting a disease and can be labeled for safe use. The FDA would no longer require approvals based on long-term health outcomes—a practice that dissuades development and increases the complexity, cost and duration of clinical trials.

This argument sounds at least semi-reasonable on the surface, but has huge holes in it, as you will see. You will also see that there is at least one area where Gulfo does fit in with the Thiel crony contingent:

This revision would pave the way for products proven safe and effective to be made available to determine which are most beneficial for individual patients. Patients and their physicians, not the FDA, need to make private health decisions; the Internet of Things would ensure that they have the best information to make these choices.

What is it with this touching faith in technology to fix all the problems in drug development that so many share?

But let's get back to what, specifically, Gulfo means by returning the FDA to its original role:

The way to return the FDA to its proper role is to pass legislation that defines effectiveness categories for the agency, such as:

How the drug affects biomarkers, such as the lowering or raising of blood-test parameters associated with disease, e.g., glucose levels, blood coagulation parameters, and cancer proteins. How it affects clinical signs and symptoms, e.g., blood pressure, tumor-shrinkage, pain, fever and infection. How it affects disease modification, e.g., prevents joint damage, relapses of multiple sclerosis or migraines. And how it affects long-term outcomes, e.g., survival, stroke and heart attack.

These categories would form the basis of approval, and the labels would be color-coded so that physicians and patients know precisely the nature of the clinical evidence used to prove that the drugs are effective and what to expect when using them.

Yes, he wants to color code FDA-approved drugs based on the level of evidence—because there's no way that can go wrong, right? In a more recent interview, Gulfo makes similar arguments.

None of this is a new debate, actually. In oncology, for instance, we've been debating over whether drugs should have to show a benefit in overall survival (OS) in order to be approved for at least two decades. Cancer therapies are generally evaluated using a number of endpoints. The most commonly used include OS and progression-free survival (PFS). OS is what it sounds like: How long do patients survive their cancer after diagnosis? Period. It’s hard for an endpoint to be more objective than that: Either the patient is alive or he is dead. This number is usually expressed in terms of median survival, which is the period of time after which half of the patients under study are still alive and half have died. This includes all causes, not just cancer. If a patient with cancer under study dies of a heart attack that is not related to his cancer or his cancer treatment, that counts. Traditionally, OS has been the “gold standard” endpoint in measuring the efficacy of a cancer therapy, because the primary goal has been to prolong survival, the ideal case being prolonging survival to the point where it is indistinguishable from life expectancy if the patient never had cancer in the first place. PFS is survival without progression; i.e., how long the patient with cancer survives before his or her tumor starts measurably growing again or metastasizes. While PFS is often measured as well as OS, it’s generally considered less useful because it is entirely possible for a treatment to prolong PFS without prolonging OS. This sort of result can happen when the treatment is effective at shrinking a tumor or slowing its growth but its toxicities can result in death. Thus, PFS can improve with no improvement in OS.

I mention this distinction because several years ago, the FDA approval for Avastin to treat metastatic breast cancer was revoked because it had been based on studies showing improvements in PFS but later studies failed to show an improvement in OS in a later study. I discussed the case in detail in 2010, if anyone's interested. The point is that short term surrogate markers often don't correlate with long term health outcomes. Sometimes they do. For instance, pathologic complete response (pCR) of breast cancer to chemotherapy (in which a tumor melts away completely, so that not even a single cell is detected when the area where the tumor was is resected) does correlate with long term survival, so much so that the FDA proposed allowing the use of pCR as a surrogate endpoint in clinical trials for the accelerated approval of drugs targeting breast cancer, although more recent work has suggested caution and pointed out that only in certain subtypes of breast cancer does the surrogate endpoint of pCR appear to predict OS.

Yes, again, it's complicated. John LaMattina over at Forbes.com points out the major holes in Gulfo's plan:

Let’s take Alzheimer’s Disease (AD). Just last week, Lilly reported very disappointing results for its AD drug, solanezumab, which failed in a long-term clinical trial. The drug was essentially safe, but it just didn’t work. Under Dr. Gulfo’s plan, solanezumab would have been approved years ago based on its effects on biomarkers and millions of desperate people would have taken it in the hopes that it would have halted or delayed the consequences of this ravaging disease. Furthermore, the healthcare system would have paid at least hundreds of millions, if not billions, of dollars for what essentially is a placebo. Under the Gulfo Plan, patients would have felt betrayed and cheated had they been taking an ineffective drug for five years or more, regardless of whatever color was on the label.

Didn't Gulfo criticize Gottlieb as someone who'd approve a bunch of "safe snake oil"? Well, that's basically what Gulfo's plan would do—and likely to an even greater extent! That's not all:

Furthermore, the importance of demonstrating real-world effectiveness is not just limited to AD drugs. There are drugs that were believed to be the ultimate answer for treating heart disease–the CETP inhibitors, developed by Pfizer, Roche and Lilly–that simultaneously raised “good cholesterol” (HDL) and lowered “bad cholesterol” (LDL). By totally remodeling one’s lipid profile, these drugs were hoped to be the answer in preventing heart attacks and strokes. Again, the Gulfo proposal would have had these drugs on the market for years before long-term cardiovascular outcome studies showed that not only were these drugs ineffective in reducing cardiovascular disease, but that they could actually be harmful despite the fact that these drugs more than doubled HDL levels and, in combination with statins, lowered LDL levels by 50-60%. Such activity was unprecedented and had heart patients and cardiologists very excited. Had these drugs been approved based solely on lipid modulation, their sales also would have been in the billion-dollar range. Yet, they ultimately offered no benefit to patients.

Yes, as LaMattina notes, not all drugs that shrink tumors prolong survival (Avastin for breast cancer) and not all drugs that lower blood glucose prevent the end complications of diabetes. Just because a drug changes your biomarkers doesn't necessarily mean it's improving your health. Yes, shortcuts are tempting. What researcher wouldn't want to be able to do a two year trial based on surrogate endpoints and biomarkers instead of a ten year trial looking at long term health outcomes if the surrogate endpoints and biomarkers predict the long term health benefits? The problem is that, far more often than people like Gulfo seem to think, they don't.

The FDA is almost certainly going to go in the wrong direction

Kimmelman and Federico lay out a persuasive case that there is insufficient attention paid to the robustness of preclinical evidence by the FDA and European regulatory agencies and that something should be done to correct this problem. Unfortunately, here in the US under President Trump, we are poised to go in exactly the wrong direction, thanks to a faith-based belief in the almighty power of the free market and an unrelenting hostility to even justified government regulation. No matter whom Trump appoints as FDA Commissioner, we can expect the level of clinical evidence necessary to approve drugs to become less rigorous, at least as much as current law allows, and we might even see legislation passed to make the approval of drugs even easier, in essence building on what the 21st Century Cures Act did. A new FDA Commissioner could undo regulation in several ways without Congressional approval though; e.g., by interpreting existing regulations as loosely as possible, so that requirements for certain clinical trials—especially large-scale ones that can take years and involve thousands of patients—can be weakened or eliminated. Ironically, the most effective way to speed up drug approval would be to add staff, not cut it; yet there's no sign that the Trump administration has plans to do that.

I concede that a reasonable argument can be made for a drug that impacts surrogate endpoints but not long term health outcomes if it significantly improves patient quality of life. In oncology, for instance, it is sometimes argued that if a drug improves PFS, but not OS, it should be approved if it improves patient quality of life. (Unfortunately, in the case of Avastin, the evidence for improved quality of life was very weak.) However, that is not the primary argument being made by Gulfo, and it's not the argument being made by any of Trump's other candidates known to be under consideration for FDA Commissioner. All of them, particularly the Silicon Valley contingent under the thrall of Peter Thiel seem to think that an overly strict FDA is the key impediment to innovation, when in fact it is primarily the limits of our knowledge. Computer developers control the hardware and software. Medical researchers do not have that advantage, but technolibertarians keep making simplistic analogies to computer development when discussing drug development.

If the preclinical evidence requirements for efficacy are already too low, then lowering the clinical requirements for efficacy (e.g., by approving drugs based only on biomarker changes) will be an even bigger disaster than I thought before, because more ineffective drugs would be approved. Given that no drug is completely safe, the approval of such drugs could then result in harm and expense with no benefit. No one, least of all I, is saying that the FDA is perfect or that there aren't ways of streamlining the FDA approval process, even though it is already fast compared to European agencies. Moreover, the FDA has already started to adapt to new science by incorporating biomarkers and new trial designs for precision medicine into its approval process. Dramatically decreasing the bar that new drugs have to clear to be approved is not the answer to developing treatments and cures for deadly diseases. It's as though the Trump administration assumes that more and faster drug approvals will translate into better health when they would be unlikely to benefit patients and more likely to result in more expense and harm.

oracknows Sun, 02/12/2017 - 21:00

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Next up on the Trump crazy train: A man who thinks that a "Yelp for drugs" will do a better job than the FDA

oracknows — Mon, 16 Jan 2017 02:00:46 +0000

Next up on the Trump crazy train: A man who thinks that a "Yelp for drugs" will do a better job than the FDA

One of the most important, if not the most important, officials in the federal government responsible for applying science-based medicine to the regulation of medicine is the FDA Commissioner. As you might imagine, particularly after his having met with antivaccinationists like Andrew Wakefield and Robert F. Kennedy, Jr., I am concerned, and I think I have good reason to be, about Donald Trump's plans for the FDA. After all, consider the people who have been under consideration for the post thus far (that we know of). First, there was Jim O'Neill, a flunky of Silicon Valley venture capitalist Peter Thiel who does not believe that the FDA should have to require evidence of efficacy before approving a drug for market, only of safety. Then, there was Scott Gottlieb, a bona fide, honest-to-goodness actual pharma shill with deep ties to the pharmaceutical industry who once complained about the cessation of a clinical trial after the deaths of subjects.

So it was with interest that I saw stories over the weekend about a third person under consideration for the position of FDA Commissioner: Balaji Srinivasan. I had never heard of him before, but I quickly learned that Srinivasan is also a Silicon Valley entrepreneur. Like O'Neill, he is not a scientist, but rather CEO of bitcoin start-up 21.com. He is also a partner at venture firm Andreessen Horowitz and teaches at Stanford University. His primary expertise is in the area of digital payments and computational biology, and his expertise in health regulation stems from a start-up company he co-founded, Counsyl Inc., which offers DNA screening, especially for people considering having children. He also shares the same sort of views as O'Neill:

Thiel, who’s advising Trump on science and technology in the new administration, is a libertarian who has advocated for disrupting society with technology in order to improve it. Srinivasan’s views about the U.S. government—and the FDA in particular—may create challenges in getting confirmed, if nominated. He’s called for letting Silicon Valley entrepreneurs secede from the U.S. and “build an opt-in society, ultimately outside the U.S., run by technology.”

It's interesting to note that late last week after his meeting with Donald Trump, Srinivasan deleted his Twitter account, leaving only a single Tweet:

Don't argue on Twitter.
Build the future.

— Balaji S. Srinivasan (@balajis) January 14, 2017

So very "responsible," right? So very oozing with self-righteousness! I call bullshit. Indeed, Srivivasan's pious act is pretty disingenuous, given that, prior to meeting with Trump, he was well known for loving to mix it up on Twitter even more than Trump does. (For one thing, he actually responded to Tweets directed at him.) Not surprisingly, the deletion of his Twitter archive did not go unnoticed:

Possible FDA pick @balajis deleted all his tweets after mtg with Trump today. I archived some from the google cache: https://t.co/WgOHNijpNM

— Christa ? Peterson (@christapeterso) January 15, 2017

And:

Trump's pick to lead the FDA, @balajis, just deleted his tweets, including this one: who needs the FDA when we have online reviews? pic.twitter.com/koexKqS4uk

— Christa ? Peterson (@christapeterso) January 14, 2017

Also, Peter Kafka at RECODE noted:

Why would Srinivasan delete his Twitter archive? It would be nice to hear from the man himself, but here’s a reasonable guess: He spent a lot of time criticizing the FDA, and he’d rather pretend those criticisms didn’t exist.

Then again, Srinivasan understands how technology works, so he certainly knows that deleting your tweets doesn’t make them disappear. You can get a sense of what Srinivasan used to tweet about by looking at this Google cache.

And you can get much more specific, courtesy of people who took screenshots of some of his tweets: In short, Srinivasan seems to think the FDA prevents drug companies and startups from innovating by imposing unnecessary regulations.

Kafka includes several examples of Srivinasan's anti-FDA Twitter rants, many of which indicate that he shares O'Neill's delusion that the free market is the best method for determining which drugs work the best. In fact, he goes even beyond O'Neill! For instance, in one Tweet from 2014, he said that we "can do vastly better than FDA w/ a Yelp for drugs, including MD star ratings (like all other products)." Last year, he made similar arguments, except that he used eBay, Uber, and Airbnb as the model, as noted here by Christa Peterson:

.@balajis is pretty into this whole replace-the-FDA-with-online-reviews thing pic.twitter.com/7YeGE4vzH1

— Christa ? Peterson (@christapeterso) January 14, 2017

Notice in one of these, Srivinasan is asked, "But how do you prevent quacks?" His answer: "Scaled Internet reputation systems. Works at massive scale in other areas."

Yeah, right. Does this guy have any clue how ignorant of how drugs are developed he sounds? I mean, seriously. This is weapons grade stupid with respect to drug development.

Elsewhere:

idk if this needs to be said, but this is a really stupid idea.

— Christa ? Peterson (@christapeterso) January 15, 2017

Of course, there are many huge problems with a "Yelp for drugs" or using the Uber model. First of all, for restaurants or rides, it's very much apparent to the end user whether the service "worked" or not. Either the food was good or it wasn't. Either it was worth the price to the user or it wasn't. Either the service was good or it wasn't. Either the ride showed up on time and got you where you wanted to go at a reasonable price or it didn't. People can judge these things without any specific expertise. For drugs and devices, that's just not so easily done. Whether a drug is working or not is not necessarily obvious to the user (although it can be sometimes). Also, thanks to something we discuss very frequently here at SBM, whether a drug "works" or not also can be affected by patient expectations and placebo effects, hence the need for randomized, double-blind clinical trials. Peterson nails it again:

Even if we could get accurate descriptions of users' experiences (we wouldn't), we wouldn't be getting the data we need to evaluate a drug.

— Christa ? Peterson (@christapeterso) January 15, 2017

She's produced a pretty comprehensive archive of deleted Srivinasan Tweets regarding the FDA that's worth perusing. His whole philosophy seems to boil down to this:

Don't argue about regulation.
Build Uber.
Don't argue about monetary policy.
Build Bitcoin.
Don't argue about it.
Build the alternative.

That's nice. However, to build an alternative, you need to know how the existing system actually works and why. Srivinasan shows no sign of that with respect to the FDA, as this Tweet showed:

FDA bears responsibility for many deaths. Blocked many good drugs. http://www.theatlantic.com/health/archive/2011/12/before-occupy-how-aids-activists-seized-control-of-the-fda-in-1988

This is, of course, complete and utter nonsense, as I explained when I deconstructed Nick Gillespie and Ronald Bailey's articles claiming the same thing.

So two of Trump's FDA picks are libertarians, one who thinks that the FDA should only require evidence of safety and that the free market should figure out efficacy, the other who thinks that online reputation systems and ratings can replace FDA regulation. This should not be surprising, as both are acolytes of Peter Thiel.

If you haven't heard of him, Peter Thiel is a Silicon Valley venture capitalist who is the co-founder of PayPal. He is also a fervent libertarian known for his belief in a technological singularity, which is, in brief, the hypothesis that the invention of artificial superintelligence will abruptly trigger runaway technological growth, resulting in unfathomable changes to human civilization. According to this hypothesis, an artificial intelligence that is self-upgradable would enter a "runaway reaction" of self-improvement cycles, with each new (and more intelligent) iteration appearing faster and faster, ultimately resulting in a superintelligence that would far surpass all human intelligence, resulting in a radical change in human civilization. Lots of science fiction is based on concepts very much like the singularity. For instance, basically The Terminator movies can be viewed in part as exploring what would happen if the singularity resulted in machine intelligence that decided humans are superfluous. Some believers in the singularity predict that the singularity will be the path to human immortality through evolving into something else, such as an immortal, ever-improving machine intelligence.

Thiel also strongly supports life extension research that often delves deep into woo. Indeed, more than anything, Peter Thiel appears to want, more than anything else, to find a way to escape death and, to that end, has invested millions of dollars into startups working on anti-aging medicine. For instance, Thiel is into parabiosis, which Steve Novella refers to as the "next snakeoil." Basically, it's another "fountain of youth," that postulates that the blood of the young (or, in this case, plasma) will reinvigorate and reverse aging in the old. There's a bit of science there, but let's just say the claims go far beyond what the science supports. Thiel is also very much into supporting seasteading, a movement whose mission is to "to establish permanent, autonomous ocean communities to enable experimentation and innovation with diverse social, political, and legal systems." Basically, the idea is to escape existing governments to try to develop libertarian paradise.

Relevant to his influence on Donald Trump's science policy is Thiel's view that the government in general—the "progressive left" in particular (whatever that means)—always impedes scientific innovation:

Most of our political leaders are not engineers or scientists and do not listen to engineers or scientists. Today a letter from Einstein would get lost in the White House mail room, and the Manhattan Project would not even get started; it certainly could never be completed in three years. I am not aware of a single political leader in the U.S., either Democrat or Republican, who would cut health-care spending in order to free up money for biotechnology research — or, more generally, who would make serious cuts to the welfare state in order to free up serious money for major engineering projects. Robert Moses, the great builder of New York City in the 1950s and 1960s, or Oscar Niemeyer, the great architect of Brasilia, belong to a past when people still had concrete ideas about the future. Voters today prefer Victorian houses. Science fiction has collapsed as a literary genre. Men reached the moon in July 1969, and Woodstock began three weeks later. With the benefit of hindsight, we can see that this was when the hippies took over the country, and when the true cultural war over Progress was lost.

Today’s aged hippies no longer understand that there is a difference between the election of a black president and the creation of cheap solar energy; in their minds, the movement towards greater civil rights parallels general progress everywhere. Because of these ideological conflations and commitments, the 1960s Progressive Left cannot ask whether things actually might be getting worse. I wonder whether the endless fake cultural wars around identity politics are the main reason we have been able to ignore the tech slowdown for so long.

One can't help but note that Robert Moses couldn't have achieved anything like what he achieved without the full power of government behind him to condemn property, bulldoze opposition (literally and figuratively), and pour resources into projects that were often controversial. Ditto Oscar Niemeyer. In any case, to Thiel, it's those nasty "aged hippies" and "Progressive Leftists" (why the capitalization, I wonder) who are to blame for the FDA's problems through their damned "overcautious" insistence on scientific evidence that a drug is effective and that its risks do not outweigh its benefits (i.e., it is safe) before approving drugs.

In other words, there is much magical thinking here.

Obviously, I don’t like any of the candidates under consideration by the Trump transition team to become FDA Commissioner. Any of them would be very likely to significantly seriously weaken regulations that protect consumers from dangerous and/or ineffective drugs and contaminated food, some more than others. Basically, you have to pick your poison: Do you pick a libertarian who doesn’t think that the FDA should have to require the demonstration of efficacy before approving drugs, a libertarian who thinks that drug approval and regulation can be replaced by online reputation systems, or a bona-fide, honest-to-goodness pharma shill, someone who’s a pharma shill to a level that most pharma shills only dream of?

Unfortunately, we probably don't have long to find out. Given the news stories late last week about Trump meeting with Jim O'Neill and Balaji Srinivasan, coupled with his tight relationship with Peter Thiel, my guess is that Gottlieb's star is on the wane and that it's probably already a done deal that either O'Neill or Srinivasan will be the new FDA Commissioner, possibly with the other to be appointed Deputy Commissioner. Peter Thiel is basically calling the shots here, and these are his boys. Compared to them, Scott Gottlieb—who, being a physician with deep ties to big pharma, would be the more conventional conservative pick—probably doesn't have a chance. Ironically, to me Gottlieb would be the "least bad" selection because at least we'd know how he would be likely to change the system, even though we know it would be bad.

And that's very, very scary.

oracknows Sun, 01/15/2017 - 21:00

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Ironically it's the 'progressive left' who are responsible for Trump becoming the President.

Many of them decided that either the Democrats needed to be 'punished' for choosing the wrong person to put up against Trump or that Hillary Clinton 'offended' them and needed to be 'made to go away'.

Of course none of them actually bothered to think what that would resort in or if they did all they thought of was the fun they would have protesting Trump becoming president.

They have made the same mistake the Tupamaros made in Uruguay in the 1960's/early 1970's unfortunately it's everyone else who has to live with the consequences.

If libertarians had their way, they would ban the installation and approve the removal of all those annoyingly socialist stops signs that for decades have hindered the 'freedom' of drivers.

Whether the choice for Commissioner is the uber pharma shill or the libertarian who hasn't a clue about the approval of medicines, I would simply refuse to prescribe any drug allowed on the U.S. market during their watch. I can think of a number of countries whose regulators would take a similar if not more rigorous stance. A drug approved for prescription in the U.S. would face greater obstacles in receiving approval in the EU, for instance, if not also Japan, Canada, and Britain, just to name a few countries.

Oh holy hell.....and we think drugs and research is China are bad.

Imagine how the rest of the world will start looking at products and research coming from the US, if this type of "anti-regulation" is enacted.....

Anyone who believes that on-line reviews written by the general public are generally accurate and useful is profoundly ignorant, a complete idiot, or both.

Probably at about the same time Orac was writing this piece, I was having a conversation about reviews of potassium iodide tablets sold by an Amazon vendor. I noted that many reviewers gave four or five stars. I would bet very substantial sums that next to none of those reviewers even knew for certain that what they received was KI.

VAERS comes to mind. Testimonials for homeopathic nostrums and other quack remedies abound. "Writers" (those are contempt quotes) post copious disinformation on eHow and nothing gets fixed when errors are pointed out. Businesses that offend some public sensibility get copious bad reviews on Yelp from people who have never even been in the same state as the business, much less the business itself.

My general impression is that perhaps something around 5% of on-line reviews by the general public rise to the level of vaguely helpful. Reviews that are well written and show evidence of thought and objectivity are scarce. Technology forums, as a sort of related class, are almost invariably abominations, where you're really lucky if your question about how to do X using product or operating system Y isn't responded to with replies that you should be using operating system Z and why would you want to do X in the first place - reflecting the mindset of tech types. Useless, opinionated, ignorant, arrogant idiots abound. Some are elected to office.

Where can I post a review of Srinivasan?

One can’t help but note that Robert Moses couldn’t have achieved anything like what he achieved without the full power of government behind him to condemn property, bulldoze opposition (literally and figuratively), and pour resources into projects that were often controversial.

Robert Moses was also more or less singlehandedly responsible for turning the Bronx into the hellhole it is today, and his counterparts in other US cities were largely responsible for making inner city neighborhoods in their cities the hellholes they are today. Leaded gasoline was sill in wide use at the time, and its impacts fell disproportionately on the neighborhoods through which these highways (intended for people passing through the neighborhood, not people actually living there) were built. It is no coincidence that many of the cities that had freeway revolts (e.g., Boston, San Francisco, Washington, and eventually even New York) are among the most livable cities in the US.

The law of unintended consequences is strictly enforced, so there would almost certainly be downsides to any proposed "progress". We always have to ask ourselves whether the claimed "progress" is worth the price. In the case of the FDA, we have specific experience that what Thiel, O'Neill, and Srinivasan have in mind will not be worth the price.

doug said, "Where can I post a review of Srinivasan?"

doug, I think you just did :)

You're absolutely on target with your comments on reviews and their relative worthlessness, but you left out a key issue that REALLY makes online reviews a terrible idea as a way to determine the worth of a service or product.

Review shills. There are companies who pay for good reviews of their products. Happens all the time. Some are even well written and thoughtful. Some are just, "Great product, don't know how I lived without it."

How I use online reviews is to look at the complaints; how did a vendor resolve a dispute? What problems with the service or product came up, and do they show user error on the part of the consumer, or hint at something I might want to avoid?

Even then, it's a crap shoot. Heck, I've bought products based on reviews from Consumer Reports that turned out to be a waste of money, and they at least try to have some kind of process in their reviews (how good you think they are is a conversation for another time, I know some people don't think much of CR).

Honestly, when I hear the word "libertarian" anymore, I don't think good things. I basically think "anarchist." They claim they want a "light" regulatory hand but they really mean no regulation at all and a return to caveat emptor.

I really don't want to see our society turn into the Ferengi. But that's where it's headed, including the part where women are objects who aren't allowed to wear clothing.

I believe Graham has leveled enough enough simple-minded BS to obtain a post in the Trump administration. I'd explain why the Tupamaros comparison is especially insane, but no doubt, I'd be wasting my time. The outcomes of close elections in the U.S. have so many factors, singling out one is a game for fools.

You might not be wasting your time for others in the comment thread, even if you are for Graham. I, for one, am not familiar with the Tupamaros.

sadmar:

I’d explain why the Tupamaros comparison is especially insane, but no doubt, I’d be wasting my time.

Not for me. I'm always interested when I learn something I didn't know before.

No, Robert Moses didn't destroy the Bronx single-handedly, any more than Bernie made Trump president. Again, so many factors involved, and Moses 'just worked there', in the sense he was just the guy who did the detail work on what all sorts of powerful people wanted done.

What's scary about the Trump picks is how narrow the interests they serve, how many people stand to get badly harmed, how predictable the consequences are, and how thin the veneer that would pretend they're unintended.

To know that Srinivasan is a dangerous kook, you didn't need to read past "Bitcon Startup CEO". Or "Peter Thiel". As awful as Nick Gillespie is, he's capable of putting on a show of being sensible. Pretty much everyone in Silicon Valley is some sort of techno-libertarian, and there are some who are more, shall we say 'careful' or 'limited' in their philosophy. They wouldn't want to run the FDA. Thiel and his crew are the most extreme wackos by orders of magnitude. I think they are clinically nuts, though I'll leave a specific distance diagnosis to Denice.

That's the problem with Gillespie and other Libertarians with even less crazy proposals. They all break in the end for laissez faire, and that means Thiel and O'Neill and Srinivasan get the 'liberty' to whatever they want with their money, no matter who and how many their bat-crap insane 'innovations' screw over. Pick Nick, you get Peter.

Of course he's trying to sell the idea thinks Sci-Fi has collapsed. He doesn't want anyone reading Ubik or watching Mr. Robot.

"hence the need for randomized, double-blind clinical trials. "

Which the FDA never does for vaccines ...

The FDA approved Flublok with 300% of the HA protein as the regular flu vaccine. Can Orac explain why?

Predictable result:
https://www.ncbi.nlm.nih.gov/pubmed/25428412

Thanks Orac and Julian:
I haven't slept and I'm super busy. but, brief vewrsion: socialist movement in Uruguay, began in the early 60's, began as labor actions, protests, a bit of Robin Hood steal from the rich and give food to the poor. In 1968, the right-wind El Presidente declared a state of emergency, repealed constitutional protections, shut down all street protests with violence, imprisoned and tortured the political opposition. The military officers who did all this stuff had been trained at the CIA-run School of the Americas, and the CIA was backing the regime. In 1970, the Tupamaros began a series of political kidnappings, They would interrogate their captives, and if they got them to reveal their misdeeds, make tapes of the interviews public. The most famous of these was an American advisor named Dan Mitrone, who was later found dead in a car shot twice in the head.,The Tupamaros leadership had wanted him held alive, but when they were all arrested, the men in charge of guarding him panicked and decided to get rid of him.

The Mitrone story was the inspiration for the fiction film State of Seige by Costa-Gavros, starring Yves Montand. Excellent movie, btw.

Go to Wikipedia [http://tinyurl.com/h93j3gk} to read what Mitrone had actually done, and what the US government said about him after his death, if you want to get sick...

I'll leave you all to observe the differences between Uruguay under fascism in 1970, and the U,S. under Obama in 2016.

“Writers” (those are contempt quotes) post copious disinformation on eHow and nothing gets fixed when errors are pointed out.

That, being a content farm, is a somewhat different beast. I forget what they pay freelancers to churn out that crap.

Also, the line about Science fiction has collapsed as a literary genre. really makes me wonder if Thiel has connected himself to the whole Sad Puppies/Rabid Puppies attempt at taking over the Hugo awards. Given that the former group has complained about 'affirmative action Hugo awards' and the latter group is run by Theodore Beale, aka Vox Day, it wouldn't entirely surprise me.

@ Lighthorse

I would simply refuse to prescribe any drug allowed on the U.S. market during their watch.

That was my thought as well. It means that we would be unable to trust any new drugs coming out of the USA. The only responsible thing would to be to demand legitimate trials in other countries.

Come to think of it, what does this do to Big Pharma? Would something like this suggest that they would have to migrate all their drug development and trials to anywhere other than the USA?

You do know what Stage 1 & Stage 2 clinical trials consist of, don't you, Vinu?

"You do know what Stage 1 & Stage 2 clinical trials consist of, don’t you, Vinu?"

Yes, fraud. Like using AAHS as control.
http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedPr…

I, for one, am not familiar with the Tupamaros.

Although the neutrality of the relevant Wikipedia page is in dispute, there is enough there to demonstrate that Gilbert's invoking them is not even wrong. For starters, the Tupamaros were never part of the Uruguayan government (although one of their member later became President). It gets worse from there.

@doug #4:

Where can I post a review of Srinivasan?

Print it out, roll it up tight and thrust it forcefully down the nearest toilet. I get the impression he won't be far away.

What is it with these people? How stupid and immoral do they have to be not to realise that their bright ideas will kill people? If they want to ignore regulation in their dealings because 'all regulation is bad', move to China and bribe the local party bigwig. There's a reason they want to build seasteads and not just emigrate to Somalia (Bond villain fantasies not aside).

Related gossip on the NIH from Nature News: Ioannidis? Yah.

Jenora @ 15, naw, it's because Thiel hasn't saw Azimov. Clarke and Bradbury write any new works.
So, it's obviously because of the hippies.

Seriously weapons grade stupidity, assembled in a supercritical configuration.

As for online testimonials, I did use a couple of online sites that had physician reviews, in specific, looking for "that miserable doctor wouldn't give me antibiotics for my flu" types of ratings. I also ruled out all physicians who weren't permitted to prescribe controlled substances (I was quite surprised how many there were in the Shreveport metropolitan area).

Thiel’s view that the government in general—the “progressive left” in particular (whatever that means)—always impedes scientific innovation

You are making the mistake of assuming intellectual honesty / consistency from Thiel, and confusing his loudly-expressed ideological stand with his actual policy proposals:

I am not aware of a single political leader in the U.S., either Democrat or Republican, who would cut health-care spending in order to free up money for biotechnology research — or, more generally, who would make serious cuts to the welfare state in order to free up serious money for major engineering projects. Robert Moses, the great builder of New York City in the 1950s and 1960s, or Oscar Niemeyer, the great architect of Brasilia, belong to a past when people still had concrete ideas about the future.

He is calling for new Manhattan Projects, new Brasilias, more top-down authoritarian planning; massive government investments / subsidies, so long as they are in projects in infrastructure and medical research that stand to benefit him and so long as there is no democratic oversight.
Thiel may elsewhere complain that the post-Reagan small-government consensus did not go far enough (stand back, get out of the way of corporations, let the market decide where research money goes!), but here he is complaining that it went too far, and he is blaming it on hippies and the Progressive Left.

there is much magical thinking here.
I'd call it "massive intellectual dishonesty from a bullsh1tting douchebag"... but tomahto, tomayto.

I submit that after Thiel won the Golden-IPO Lottery and convinced himself that it was all due to his technological nous, he became best-known for using censorious legal asshattery to bankrupt people who speak of him disrespectfully. While Trump has promised stronger defamation laws to stop people criticising him. So I can predict in all confidence that any replacement of the FDA by a Yelp-style consumer-feedback network would be accompanied by corporate-defamation laws, allowing pharmaceutical companies to seek damages from anyone who hurts their business by posting negative reviews.
Not to mention good old-fashioned Tort Reform to stop those frivolous lawsuits from customers claiming "side-effects" or "death".

naw, it’s because Thiel hasn’t saw Azimov. Clarke and Bradbury write any new works.

I'd replace Asimov by Heinlein in your list. Asimov was never afraid to admit that he was a liberal. Heinlein started out as a liberal, but sometime in the late 1940s (following his marriage to Virginia Gerstenfeld) his politics shifted to the ultra-libertarianism for which he was known.

There has always been a right-wing element among sci-fi authors. Larry Niven and Jerry Pournelle are notorious examples. Bradbury, late in life, criticized Michael Moore's explicit reference to his novel Fahrenheit 451 in the latter's movie Fahrenheit 9/11 (though Moore saw what was happening as more of a validation of Bradbury's novel).

Thiel may be lamenting the ascendance of authors who are more in the tradition of Asimov than of Heinlein. It's still a bunch of weapons-grade stupid.

Rich Woods: How stupid and immoral do they have to be not to realise that their bright ideas will kill people?

Killing people is the point, really. They get a tingle, just like God does, when people die. Especially if people die because of lack of health care, or because of complications of pregnancy, or because a chemical spill wiped out a whole town. God is fine with this, and so are they.

I’d replace Asimov by Heinlein in your list. Asimov was never afraid to admit that he was a liberal. Heinlein started out as a liberal, but sometime in the late 1940s (following his marriage to Virginia Gerstenfeld) his politics shifted to the ultra-libertarianism for which he was known.

Indeed. For example, in his novel Starship Troopers, Heinlein basically played the militarism straight, while in the movie Paul Verhoeven played the story as a satire of fascism and militarism.

Do any of these people even remember how things were like before the FDA was created? We’d go back to the era of medicine shows and likely another incident similar to the elixir sulfanilamide debacle of 1937. These clowns essentially want to repeal the 1938 Food, Drug, and Cosmetic Act passed in the wake of that debacle, thereby removing the fangs from the FDA which had for the past 78 years done a reasonably good job of preventing a similar incident from happening again. So they want to remove the FDA’s mandate to force drug manufacturers to prove their products effective? Well, I suffer from hypertension, and if the drugs I’m taking aren’t truly effective I could suffer a heart attack or a stroke. Perhaps my widow can write the review on that “Yelp for Drugs” that Mr. Srinivasan is proposing that the drugs I were taking didn’t work. Fat lot of good it does me when the urn with my ashes sits in its crypt.

@sadmar

To make things clear, first up I never stated that I supported Trump, and in fact I don't, the man should never have been elected.

I bought up the Tupermaros as an example of the law of unexpected consequences. My understanding of their activities was that they wanted to force the govt of Uruguay to become 'facist' so that the ordinary citizens of Uruguay would throw their support behind the revolution. It didn't work out that way.

The thing is, in several of the states that Clinton lost to Trump, the difference between them was less than the number of votes given to Jill Stein, and then there is the large number of Democratic registered voters who chose not to on the day.

It is discussed on the 394th episode of the Strange Frequencies Radio podcast.

https://strangefrequenciesradio.wordpress.com/2016/11/21/sfr-394-how-it…

The thing is, in several of the states that Clinton lost to Trump, the difference between them was less than the number of votes given to Jill Stein, and then there is the large number of Democratic registered voters who chose not to on the day.

It is discussed on the 394th episode of the Strange Frequencies Radio podcast.

Yes, there's nothing like waving in the general direction of a two-hour podcast to make a case. There's a relevant 538 chat here; I haven't read it, as I'm not particularly interested in whining about the existence of other candidates for one not getting one's druthers.

Do any of these people even remember how things were like before the FDA was created?

When you are profoundly arrogant and believe that you will make your mark by "disrupting" all that went before, remembering or learning about the past isn't likely to be much of a consideration. If your disrupting product doesn't catch on, oh well. Fiddle with the design, release the new version and see if it does better.

I happened to watch the final episode of season 5 of Call the Midwife today. It was partly about the thalidomide disaster in the UK. I was reminded of Dr. Frances Oldham Kelsey, who, in her role at the FDA kept thalidomide from being approved in the US. In Germany, the UK, Canada and other countries the reviews of thalidomide did come in, and were quite negative. But those reviews came after great harm was done. Oh well. Do-over. Better luck next time.

Once again I will mention that Tamara Lovett went to the web looking for reviews of dandelion tea and oil of oregano, found positive reviews and used those "remedies" instead of real medicine to treat her 7 year old son Ryan. Ryan is dead. There is no do-over for him.

Graham: sadmar has a point. If you are going to overgeneralize the results of the election to disengaged voters or spoilers, you are grossly underestimating the complex reasons behind Trump's victory. That's not a path to getting a better result in four years.

Panacea: That’s not a path to getting a better result in four years.

In four years we're either not going to be voting at all or it'll be scumbags as far as the eye can see. The Democratic party needs to accept that we're done for this generation. The US doesn't want progress now or ever.

@Doug #4:

Anyone who believes that on-line reviews written by the general public are generally accurate and useful is profoundly ignorant, a complete idiot, or both.

Because I like XKCD...
https://xkcd.com/958/

It seems that Randall Munroe has made some further cartoons about the dangers of trusting online reviews and ratings. For instance, XKCDs 325 (A-minus-minus), 937 (Tornado Guard), and 1098 (Star Ratings). Not linking to them directly since it makes my post look like spam to the filters… Orz

"I am not aware of a single political leader in the U.S., either Democrat or Republican, ... who would make serious cuts to the welfare state in order to free up serious money for major engineering projects."

Huh. In my world, Democrats have been screaming for infrastructure projects for years, blocked by Republicans. Not, mostly, big new projects, but maintaining the older ones at least, with a few big-transit enthusiasts. If the Republicans ever stopped screaming about the deficit (like they will right now), Democrats could afford to start dreaming big again.

"Science fiction has collapsed as a literary genre."

That's not true from a mass-market standpoint, or from the value of what's being written. Definitely a victim of the Sad Puppies propaganda.

"Today’s aged hippies no longer understand that there is a difference between the election of a black president and the creation of cheap solar energy"

Uh, we have both? And I'm too young to be a hippy but I am quite aware that a) they are independent forms of progress and b) one party is for them both and one is against them both.

Assuming he's not just lying like a MFer, it's kind of sad that he's blind to all the cool new tech that is happening. And yet I can generate only so much sympathy.

@jkrideau #16:

"Come to think of it, what does this do to Big Pharma? Would something like this suggest that they would have to migrate all their drug development and trials to anywhere other than the USA?"

Not all drugs receive approval by regulators in foreign countries on the basis of trials solely conducted in the U.S. In some instances, at least one further trial in patient populations of the foreign country is required before a decision is made. Assuming that rigorous trials in the U.S. were abandoned or the results of what trials were conducted had otherwise become questionable or compromised, far more independent foreign trials would be demanded by the EU, Japan, and Canada before the approval of a drug or therapeutic product from an American source would even be considered.

PGP: I respectfully disagree . . . and you sound like you've given up. That sounds as bad as the uber liberals who are currently frothing at the mouth in a state of panic.

I know a lot of people who think that after one party has had the White House for 8 years, the other should get it. Their politics don't get any more complex than that. And we've certainly seen enough of it in the past 50 years or so, including a couple of double Republican terms. Yet progress steadily marches on. It may zig, it may zag but it gets there eventually.

A lot of people thought the world would come to an end with the election of Andrew Jackson. It didn't. He did a lot of damage in 8 years, some of which we're still living with today (the destruction of a central bank is his enduring legacy), but we survived it.

We'll survive this.

@ Panacea:

I agree.

Already there are conflicts within the 'winning' party and actions being planned by the opposition.
When Reagan was elected, he had a higher approval rating and the 'consent' of the electorate in order to push his programme. It won't be easy but DJT will not rule with an iron hand and/ or confidence. Just follow his twitter.
He's not happy.

In related news..

The Donald is rather unhappy about the press and is pushing them off into other quarters under some excuse or other.

As the saying goes ( paraphrase)
Never make enemies of those who have unlimited supplies of ink.

Panacea: I respectfully disagree . . . and you sound like you’ve given up.

Well, the country did turn into pretty much wall-to-wall scumbags overnight, and all the news is bad, and will be bad for the foreseeable future. Barring an unlikely accident with catfish or freshwater sharks, we're stuck with scumbags all the way down the chain of command.

P:I know a lot of people who think that after one party has had the White House for 8 years, the other should get it.

I hope these people are all men, since women are affected more by one party's rhetoric and policies and should really pay more attention to politics. It's literally a matter of life and death.
After all, after these four years are up, we're not even going to be able to vote anymore. If there is another election, which is doubtful.

Whereas PGP has given up & should probably just put herself out of her self-imposed misery, I have determined that the best course of action, for the near term, is to act locally.

Just because idiots elected Drumpf, doesn't mean that I can't work to ensure that my community maintains its place as a diverse, educated, and welcoming area.

She can give up, if she wants, but I, for one, am bound and determined to actually do something about it.

The Donald is rather unhappy about the press ...

Hey, if online ratings are good enough to determine the quality and suitability for purpose of pharmaceuticals, surely press ratings should be adequate to determine the quality and suitability for purpose of loud mouthed ignorant arrogant liars.

AC & JF, thanks for the XKCD. I rate them several stars each.

Lawrence: I'm trying to do something about it "locally" myself. I spend a fair amount of time on FB debunking BS memes and fake news, whether it be "conservative" or "liberal."

These people can spread their BS on FB but I don't have to let them get away with it, and occassionally I do manage to get someone to actually think, so it's been worthwhile.

I'm also holding my elected reps feet to the fire. Letters and phone calls. I'm holding them accountable for what they do. I may live in a deep red Congressional district and a purple state, but I'm not giving them carte blanche to do what they want.

If people keep letting Congress know they don't have a mandate, they will get the message eventually. I think we'll have a Democratic Congress in 2108.

Which the FDA never does for vaccines

Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young ... - PubMed - NCBI
Sustained efficacy and immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine: analysis of a randomised placebo-controlled ... - PubMed - NCBI
Efficacy of 23-valent pneumococcal vaccine in preventing pneumonia and improving survival in nursing home residents: double blind, randomised and p... - PubMed - NCBI
Efficacy of nine-valent pneumococcal conjugate vaccine against pneumonia and invasive pneumococcal disease in The Gambia: randomised, double-blind,... - PubMed - NCBI
Efficacy of human papillomavirus type 16/18 AS04-adjuvanted vaccine in Japanese women aged 20 to 25 years: final analysis of a phase 2 double-blind... - PubMed - NCBI
Immunogenicity, reactogenicity, and safety of human papillomavirus 16/18 AS04-adjuvanted vaccine in Japanese women: interim analysis of a phase II,... - PubMed - NCBI ,Safety, efficacy and effectiveness of cold-adapted, live, attenuated, trivalent, intranasal influenza vaccine in adults and children.
A double-blind, placebo-controlled study of the safety and immunogenicity of live, oral type 4 and type 7 adenovirus vaccines in adults
Safety and immunogenicity following administration of a live, attenuated monovalent 2009 H1N1 influenza vaccine to children and adults in two rando... - PubMed - NCBI

My comment was based on Dr.Offit's response below.

http://www.pbs.org/wgbh/frontline/article/paul-offit-a-choice-not-to-ge…
"And if you have a large enough cohort of children who are vaccinated or unvaccinated, you can bet that there will be children in the unvaccinated group who will suffer that consequence. And no Institutional Review Board, and frankly no ethical researcher, could ever do that study, because you know that you have frankly condemned those in the unvaccinated group — some in the unvaccinated group — to develop diseases which can permanently harm them and/or kill them. You can’t do that study.And if you have a large enough cohort of children who are vaccinated or unvaccinated, you can bet that there will be children in the unvaccinated group who will suffer that consequence. And no Institutional Review Board, and frankly no ethical researcher, could ever do that study, because you know that you have frankly condemned those in the unvaccinated group — some in the unvaccinated group — to develop diseases which can permanently harm them and/or kill them. You can’t do that study."

Do you believe Dr.Offit, or do you believe the "unethical" researchers and their results from the trial in The Gambia?

@PanaceaB

Bienvenu au Canada.

Strangely enough, we tend to like immigrants, heck even Americans (my mother was one).

Check out the job listings and be prepared to argue with Immigration.

There has always been a right-wing element among sci-fi authors. Larry Niven and Jerry Pournelle are notorious examples.

"Oath of Fealty" comes to mind, as a depiction of a neo-feudalist utopia. The title is a fair description of the world-view... obedience to authority presented as Libertarian freedom.
I'm 99% confident that Thiel has read "Oath of Fealty", and thought "This high-tech authoritarian arcology sounds great, but it would be even better as a floating sea-stead rather than a land-based structure, so we could simply throw dissidents overboard".

@vinu #46:

Do you believe Dr. Offit, or do you believe the “unethical” researchers and their results from the trial in The Gambia?

Way to miss the point. Offit was talking about calls from antivaxxers to have large scale double blind vaccinated/unvaccinated studies for vaccines that are currently on the schedule. Those studies were to test the efficacy and safety of vaccines prior to deciding whether or not to add them to the schedule. You really are clueless.

If the original studies were done right, there would be no reason to repeat them now. Vaccine ingredients have not been individually safety tested (food protein contaminants for example).Severe adverse events are not on the "solicited adverse event list" and are therefore dismissed as not being caused by the vaccine.

Well, it looks like Srivanasan is out of the running, thanks to his many Tweets attacking the FDA:

https://www.statnews.com/2017/01/17/tweets-fda-srinivasan/

Matt Herper thinks it'll be Gottlieb, who, as bad as he is, would probably be the least bad of the three candidates:

http://www.forbes.com/sites/matthewherper/2017/01/18/what-trumps-libert…

it would be even better as a floating sea-stead rather than a land-based structure

What a wonderful idea. Of course, it didn't turn out so well for Rapture but that city was submerged. Nor did it fare well for Columbia, which was a city floating above the clouds... Maybe the objectionalism and minarchism are a problem after all?

https://www.youtube.com/watch?v=sN8LgXsJJNA

Today I read an opinion piece in my newspaper, stating Donald Trump wouldn't do crazy things, because he wants to be elected for a second term, because otherwise he would be a loser, which he doesn't want to be.

Still not sure this will keep him from doing the wrong things with the FDA.

I'm still not convinced Trump is going to last his first term, much less being concerned about a second.....I think we will learn a lot over the next 100 days or so.

That whooshing sound was the point going over Vinu's head (#46) so far a HAWK missile wouldn't bring it down.

That screed by Thiel is hilarious. He does realize that the Internet was basically created by the government doesn't he? No Internet, no Pay Pal. Of course, he did it all "by himself".

@Renate #53, true. One can still do absolutely idiotic things that are not insane.
@Riv #56:

He does realize that the Internet was basically created by the government doesn’t he?

I think not. Thiel is a libertarian. To him, "government is bad" is a truism. As is "I did it by myself".

Maybe Srivanasan's name was floated to make the eventual nominee look more palatable by comparison. Living just North of Silicon Valley, I'd never heard anything about Jim O'Neill, but Srivanasan has a public profile as a general purpose technolibertarian kook, unrelated to anything specific to the FDA. A sort of self-parody of the Twitter-pontificating "I can't believe he said that" tech-bro, indistinguishable from an Onion parody thereof...

@ Graham
Fwiw, I didn't say you had any affinity for Trump, as #1 expressed obvious dismay at his election. I was tossing a bit of 'unintended consequences' back at you, by saying your argument is as bogus as those made by various Trump appointees. As for the Tupamoros, their tactics at any point are certainly open to criticism. I doubt they set out "to force the govt to become ‘facist’ so ordinary citizens would support revolution." But that sounds like the kind of claim radical groups issue as propaganda to try to turn lemons to lemonade.

In any event, dissidents don't 'force' fascists to turn to repressive police/military violence, suspension of rights, mass arrests and torture. They do that because they're fascists. Unless you want to blame Pinochet on Allende, or blame the crimes of the Aparheid regime on the ANC, or other similar ridiculous arguments routinely offered by the American right. If you check the history of US activities and policies in Latin America, it was pro-fascist and anti-democratic from the get go of the 20th Century. The School of the Americas was created in 1946, and yes it was our military that taught Latin American scumbags how to stage coups, institute dictatorial regimes, 'disappear' any opposition, use torture more effectively, assassinate nuns and all that good stuff.

to make the eventual nominee look more palatable by comparison

My money is on Deepak Chopra.

My money is on Deepak Chopra.

He does have a YUUUGE Twitter following, after all...

I can't speak for any pharma CEOs (who generally wouldn't know science if it bit them in the face), but the actual people who work in pharma are not at all excited about a clinical-trial free future.
1) We want to know if the drug works, because we're scientists, and that's kind of the point of science, answers.
2) No insurance company in the world is going to pay for a drug without evidence that it actually works. And the patient pool who has hundreds of thousands of dollars lying around to drop on something that *might* work is infinitesimal.

As to Theil's comment about science fiction, yeah, he sounds somewhere between Sad and Rabid. Probably scared off by all the women authors who've won Hugos recently. Or Scalzi. Theil is making Elon Musk sound more sensible every day. HyperLoops for everyone!

@ JustaTech;

I hear you about the science-minded folks who work for the pharmas. Honestly, it's a head-scratcher even for half-marxist me that the pharmas are major bank-roll for the free-marketeer anti-regulatory warriors, but that's where the empirical facts lie. I probably wouldn't put it all on the CEOs, since they're responsible to boards, and big investors, and if they don't maximize profit every quarter, they get purged.

I'd also guess that they're counting on 'evidence that the meds actually work" jiggered a little in their favor, and have strategies on place to get insurers to pay for the new stuff – not the more long-shot right-to-try things, but the ones just over the line at present. And mainly, I think it's less about things-that-wouldn't-get-approved now than just getting the things-that-would-probably-get-approved out into the market faster. I'd also guess they're no much afraid of increased liability, as they're counting on those conservative politicos they back to get across 'tort reform' to make judgments limited and harder to get.

The biggest problem with getting a product to market earlier is, well, do you remember Vioxx?

Merck withdrew the drug after disclosures that it withheld information about rofecoxib's risks from doctors and patients for over five years, resulting in between 88,000 and 140,000 cases of serious heart disease.

This, of course, happened post-approval. Rushing a product to market can also result in missing similar problems, which would have been caught under our current approval regime.

@vinu #50:

If the original studies were done right, there would be no reason to repeat them now.

Um, the vaccine tested in The Gambia was the nine-valent pneumococcal conjugate vaccine. In other words, a very new vaccine. That was very likely the original study for that vaccine.

I was referring to the Offit article.

.Severe adverse events are not on the “solicited adverse event list” and are therefore dismissed as not being caused by the vaccine.

Neither is delayed flights, but I swear to the Flying Spaghetti Monster that the last two times I've had vaccines, I've had delayed flights within a fortnight.

Maybe they were left out of the list because rigorous studies didn't show a causation?

"rigorous studies "
Please point us to those studies.

vinu, I am having considerable difficulty working out what you're getting at.
In your comment #46 in response to shay, you end by saying

Do you believe Dr.Offit, or do you believe the “unethical” researchers and their results from the trial in The Gambia?

I responded at #49 by pointing out that

Offit was talking about calls from antivaxxers to have large scale double blind vaccinated/unvaccinated studies for vaccines that are currently on the schedule.

and that the vaccine trial in The Gambia

was the nine-valent pneumococcal conjugate vaccine. In other words, a very new vaccine.

You then responded at #50 with

If the original studies were done right, there would be no reason to repeat them now.

At #64 I pointed out that

the vaccine tested in The Gambia was the nine-valent pneumococcal conjugate vaccine. In other words, a very new vaccine. That was very likely the original study for that vaccine.

You then replied at #65 by saying

I was referring to the Offit article.

If that was the case, then why did you even say

Do you believe Dr.Offit, or do you believe the “unethical” researchers and their results from the trial in The Gambia?

That's just a non-sequitur.

" Offit was talking about calls from antivaxxers to have large scale double blind vaccinated/unvaccinated studies for vaccines that are currently on the schedule."

There would be no calls to perform these studies, if the proper studies were performed BEFORE placing them on the schedule. In fact, it is better late than never. But I suspect Offit knows what the results will be so he does not want to perform the studies.

JustaTech: "2) No insurance company in the world is going to pay for a drug without evidence that it actually works"

When I read that I was thinking of the recent article on SBM on how a jury ruled in a cross action suit against a company selling homeopathic remedies:
https://sciencebasedmedicine.org/junk-science-helps-homeopathic-remedy-…

Every homeopathic remedy gets a pass for every ailment, because they are just sugar pills. Too many people claim they work, so they must work. Take that to the next logical conclusion. ;-)

Chris @69: Well, homeopathic stuff is already kind-of sort-of covered by some FDA-ness. And I don't think that any of the over-the-counter homeopathic stuff is covered by insurance anyway (like most OTC stuff).

I was more thinking the super-expensive new cancer treatments.

But yeah, the trial in that article was pretty irritating.

One problem is, insurance companies don't want to pay for expensive treatments at all and use every dodge in the playbook that they can to keep a new and hence, expensive drug off of their formulary.
My wife was prescribed an immunotherapy for her advanced osteoporosis, the insurance company declined it, another proposed, declined, rinse and repeat for all such therapies.
I changed insurance companies, BCBS covers several of such therapies, doesn't a bunch more.

The same is true on procedures. 30 years ago, I knew a man who couldn't get coronary bypass surgery performed. The insurance company called it an experimental procedure that hence, was not covered. He died soon after.
After a hue and a cry over a handful of years and needless deaths, my father had a heart attack and insurance covered his coronary bypass surgery when he was age 61.
He died a few years ago at age 84. At least his great grandchildren can remember him.

There would be no calls to perform these studies, if the proper studies were performed BEFORE placing them on the schedule.

The proper studies WERE done before placing the vaccines on the schedule. The problem is, wooden-headed antivaxxers insist that the studies weren't good enough.

"The proper studies WERE done "
Please point us to the studies demonstrating that the amount of milk protein in a vaccine is safe. Same for yeast, soy etc.
The only antibody titers measured are to the viral/bacterial proteins. Why not for ALL the contaminating proteins?
Why would Amorphous Aluminum Hydroxyphosphate Sulfate [AAHS] be used a control in the study?
http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedPr…
The vaccine safety studies are a joke. That's why vaccine safety is an oxymoron.

Dr. Jay Gordon,
It would be interesting to hear your understanding of the following:

https://iom.nationalacademies.org/Reports/2011/Adverse-Effects-of-Vacci…

Document Pg. 65 (pdf pg. 94 ):

“Adverse events on our list thought to be due to IgE-mediated
hypersensitivity reactions
Antigens in the vaccines that the committee is charged with reviewing do
not typically elicit an immediate hypersensitivity reaction (e.g.,
hepatitis B surface antigen, toxoids, gelatin, ovalbumin, casamino acids).
However, as will be discussed in subsequent chapters, the
above-mentioned antigens do occasionally induce IgE-mediated
sensitization in some individuals and subsequent hypersensitivity
reactions, including anaphylaxis.”

Was the reference to Robert Moses supposed to be an argument for or against government?

Dr. Jay Gordon,
It would be interesting to hear your understanding of the following

Is there anything in particular that causes you to think he's, y'know, reading this comment thread, Vinu?

Thiel, who’s advising Trump on science and technology in the new administration, is a libertarian who has advocated for disrupting society with technology in order to improve it.

The idea of Thiel as a stalwart member of the Trump administration became even more delightful when we learned that such is his patriotism and his confidence in the benefits that will result from his advice, he recently bought citizenship in New Zealand.

How much does one pay to buy citizenship in New Zealand?
I've been considering moving there and raising sheep after I retire.

If you have not been there, the sand flies are horrible ...

For your "entertainment".
http://www.timeslive.co.za/thetimes/2017/02/07/Consumers-must-be-protec…
This is why a Yelp for drugs will fail.

Mr. Frost: "This is why a Yelp for drugs will fail."

Another fail is an executive from Cisco to avoid WiFi. Especially since that company made it ubiquitous everywhere.

Hello, Vinu the hypocrite.

The guy who invented E=mc^2 had no control of how it would be used. He can only warn of the danger ...

Laughably, I am EM sensitive. After having a cataract removed and an IOL inserted, I can now see into near-UV and long wae UV bands.
Apparently, the natural crystalline lens filters all forms of UV light. The plastic entirely refrains from doing so, so it's up to one's receptors.

Yes, I can see "black light" illuminated items far better than most. Using a UV flashlight (or sunlight), I can see the security markings on US currency as well as the primary markings.
Downside, it also illuminates what is likely proteins in my eye, so higher illumination in long wae UV tends to dazzle me badly.

Vinu maligns the NZ sandflies. They are no problem at all if you restrict your beachtime or river activities to the hours of darkness. When the mosquitos will get you instead.

A tribute to Dr. Frances Oldham Kelsey: A woman who made a difference

oracknows — Mon, 10 Aug 2015 01:00:32 +0000

A tribute to Dr. Frances Oldham Kelsey: A woman who made a difference

I learned over the weekend that a historic figure in science-based medicine has died. If you know anything about the history of the Food and Drug Administration (FDA), you will know this woman's name, Frances O. Kelsey, MD, PhD. It turns out that Dr. Kelsey died on Friday at the age of 101. Somehow I missed the news on Friday, but once the story showed up in my news feeds over the weekend, I knew I had to make her today's topic. Here's the short version:

The sedative was Kevadon, and the application to market it in America reached the new medical officer at the Food and Drug Administration in September 1960. The drug had already been sold to pregnant women in Europe for morning sickness, and the application seemed routine, ready for the rubber stamp.

But some data on the drug’s safety troubled Dr. Frances Oldham Kelsey, a former family doctor and teacher in South Dakota who had just taken the F.D.A. job in Washington, reviewing requests to license new drugs. She asked the manufacturer, the William S. Merrell Company of Cincinnati, for more information.

Thus began a fateful test of wills. Merrell responded. Dr. Kelsey wanted more. Merrell complained to Dr. Kelsey’s bosses, calling her a petty bureaucrat. She persisted. On it went. But by late 1961, the terrible evidence was pouring in. The drug — better known by its generic name, thalidomide — was causing thousands of babies in Europe, Britain, Canada and the Middle East to be born with flipperlike arms and legs and other defects.

It's important to understand the context. When Dr. Kelsey received the application for Kevadon, the laws governing drug approval and the power of the FDA were very different than today, and the FDA was a very different agency. Back then, all the FDA was charged with doing was to make sure that the drugs it approved were safe. It's worth reviewing the history of the FDA up to 1960, when that fateful application for approval from the Merrell Company first crossed the desk of a new medical officer, who also happened to be a woman in what was then most definitely a man's world in science.

Before 1906, there was no federal law protecting the public from dangerous drugs or food. The decades leading up to that year were a golden age of quackery, with all sorts of patent medicines being sold by wandering salespeople and Bayer sold Heroin as a non-addictive morphine substitute and cough suppressant. Pharmaceutical companies didn't have to demonstrate safety or efficacy of their drugs before marketing them. It is an age that quacks, understandably, pine for. In 1906, Congress passed and President Theodore Roosevelt signed the Pure Food and Drug Act of 1906. Then, as now, such regulation was not easy to pass. It took muckraking and exposes such as The Jungle by Upton Sinclair to rally support for such a law.

The original law was relatively modest, its main purpose being to ban the foreign and interstate traffic in adulterated and mislabeled food and drug products. It required that active ingredients be placed on the label of a drug’s packaging and that drugs could not fall below purity levels established by the United States Pharmacopeia or the National Formulary. Originally, the law was enforced by the Bureau of Chemistry in the Department of Agriculture, a bureau that didn't become the Food and Drug Administration until 1930. Originally, the law didn't require approval of drugs before they could be marketed, and the burden of proof was on the government to demonstrate that a food or drug was adulterated or unsafe.

Clearly, the law had relatively little in the way of teeth back then. For instance, in 1910 the government seized a large quantity of a product called Johnson's Mild Combination Treatment for Cancer, whose manufacturer falsely claimed it could cure cancer. In the legal action that followed the Supreme Court ruled that the false claims of effectiveness were not within the Pure Food and Drugs Act. To address this weakness, Congress enacted the Sherley Amendment in 1912, which prohibited labeling medicines with false therapeutic claims. Unfortunately, the burden of proof on the government under the Sherley Amendment was high:

"To establish fraud, the bureau had to show that the manufacturer knew the product was worthless, and this proved difficult in many cases," Swann says. For example, Lee Barlett, a former shirt salesman from Pittsburgh, promoted a medicine called Banbar as being effective for diabetes. Banbar was an extract of horsetail weed. The government took Barlett to court for selling a misbranded drug and even showed the death certificates of people with diabetes who had taken Banbar. But the jury ruled in Barlett's favor.

The next major change in the Pure Food and Drug Act came in the 1930s. By the early 1930s, it was widely recognized that the Pure Food and Drugs Act of 1906 was obsolete, but there was no agreement over how to modernize it. It took years to come up with a compromise, which did happen by 1937, but Congress was going nowhere in passing a new law. Then disaster struck, the 1937 Elixir Sulfanilamide Incident, which killed over 100 people in 15 states:

Sulfanilamide, a drug used to treat streptococcal infections, had been shown to have dramatic curative effects and had been used safely for some time in tablet and powder form. In June 1937, however, a salesman for the S.E. Massengill Co., in Bristol, Tenn., reported a demand in the southern states for the drug in liquid form. The company's chief chemist and pharmacist, Harold Cole Watkins, experimented and found that sulfanilamide would dissolve in diethylene glycol. The company control lab tested the mixture for flavor, appearance, and fragrance and found it satisfactory. Immediately, the company compounded a quantity of the elixir and sent shipments--633 of them--all over the country.

The new formulation had not been tested for toxicity. At the time the food and drugs law did not require that safety studies be done on new drugs. Selling toxic drugs was, undoubtedly, bad for business and could damage a firm's reputation, but it was not illegal.

Because no pharmacological studies had been done on the new sulfanilamide preparation, Watkins failed to note one characteristic of the solution. Diethylene glycol, a chemical normally used as an antifreeze, is a deadly poison.

From the perspective of 2015, it's hard to believe that any chemist could do something so completely boneheaded. Even back then, it was known that diethylene glycol was toxic, as even just a review of the medical literature would have revealed. After all, the first case of fatality from diethylene glycol poisoning had only been reported in 1930, and the studies showing that it could cause kidney failure had been published. Even in the absence of a literature review, animal testing would have revealed the extreme toxicity, but, for whatever reason, S. E. Massengill Company didn't do a literature search or animal testing. It just marketed the its new formulation of its drug.

This incident is worth remembering 80 years later, because the claim that the free market will guarantee drug safety because companies cannot bear the hit to their reputations that selling unsafe drugs would cause has not died, even though an incident like the Elixir Sulfanilamide incident should have put a stake in its heart. Indeed, I've documented such claims right here on this very blog as representing magical thinking.

It is also worth remembering how the victims died:

Victims of Elixir Sulfanilamide poisoning--many of them children being treated for sore throats--were ill about 7 to 21 days. All exhibited similar symptoms, characteristic of kidney failure: stoppage of urine, severe abdominal pain, nausea, vomiting, stupor, and convulsions. They suffered intense and unrelenting pain. At the time there was no known antidote or treatment for diethylene glycol poisoning.

Nor was there dialysis or kidney transplantation. The first dialysis machine was not developed until 1943.

Spurred on by the outrage caused by the Sulfanilamide incident, Congress passed the Food, Drug, and Cosmetic (FD&C) Act of 1938. For the first time, drug manufacturers had to demonstrate that their drugs were safe before they could market them. Manufacturers had to submit an application to the FDA before marketing a drug, but if the FDA didn't act on it within a certain time period the drug would be automatically approved. Further amendments allowed for factory inspections and the designation of certain drugs to be designated for sale by prescription only. That was the state of regulation at the time Dr. Kelsey received that fateful application for thalidomide.

Then this is what happened:

The company made glowing claims for Kevadon’s safety and effectiveness. It had been developed in West Germany, and since 1957 had been widely sold in Europe and elsewhere as an excellent sedative, Merrell said, giving prompt, deep, natural sleep without hangovers. Moreover, doctors had recently been prescribing it to women to suppress nausea in pregnancy.

Laws governing new drugs had been on the books for decades but were not always rigorously enforced, and F.D.A. approval was often routine. But Dr. Kelsey, working with a chemist and a pharmacologist, found the evidence for Merrell’s claims about Kevadon to be insufficient. She withheld approval and asked Merrell for more data on toxicity, strength and purity.

Merrell stood to make millions and was anxious to get moving. It had tons of Kevadon in warehouses, ready for marketing, and 1,000 American doctors had already been given samples for “investigational” research. The company supplied more data, but also mounted a campaign to pressure Dr. Kelsey. Letters, calls and visits from Merrell executives ensued. She was called a fussy, stubborn, unreasonable bureaucrat.

It wasn't just her, either. Dr. Kelsey and the other two FDA officials responsible for reviewing the application quickly developed questions about the drug. For example, the pharmacologist, Oyam Jiro, questioned whether the company's toxicity tests were adequate, while the chemist, Lee Geismar, was skeptical about the company's manufacturing controls. Dr. Kelsey thought that the safety data were inconclusive.

In pushing for more data, Dr. Kelsey was also prescient, with a very keen eye for spotting bullshit. As a result, she was subjected to intense pressure from Merrell executives. As described by Dr. Kelsey in the August 10, 1962 issue of LIFE, they "came to Washington in droves." They wrote letters, and they called her superiors as often as three times a week. They complained bitterly that Dr. Kelsey was being "unreasonable and irresponsible." Dr. Kelsey noted that, "Most of the things the called me, you couldn't print." To his credit, Dr. Kelsey's division chief, Julius Hauser, decided to back his young pharmacologist, joking, "When they would get too thick around Dr. Kelsey, I would just come in with my little hatchet and clear them out."

By February 1961, reports of thalidomide toxicity were filtering in from Europe, in particular a report in the British Medical Journal linking thalidomide to peripheral neuropathy. More cases were reported, and there were indications that the drug could cause numbness, shaking, and tingling of the hands and other disturbances. These reports lead Dr. Kelsey to wonder whether thalidomide could damage nerves in a developing fetus. By November 1961, the first report of phocomela linked to thalidomide was reported. Phocomelia is a severe birth defect in which the fetal limbs are horrendously malformed resulting from use of thalidomide in the first trimester, when the fetal limb buds are forming. Further clinical development of thalidomide ceased, at least until it was found to be effective against multiple myeloma decades later.

Dr. Frances Kelsey: Drug Detective

Alternative medicine quacks often like to attack the FDA by pointing out the thalidomide tragedy. Most of them seem not to know that thalidomide was never approved for use in the US, and that was almost entirely due to the vigilance and, yes, outright stubbornness of one brave woman, who could sniff out spin and misinformation in a drug company application and would not be swayed by unrelenting pressure. Thankfully, her superiors backed her up, something that wouldn't have happened if the FDA regime at the time didn't take drug safety seriously.

Dr. Kelsey's battle was unknown to the public until Washington Post reporter Morton Mintz broke the story in July 1962. The story led to public pressure for Congress to do something. As a result, Congress passed the Kefauver-Harris Drug Amendments to the Federal Food, Drug, and Cosmetic Act. These amendments required that drug companies not just show safety, as had been the case prior to the amendments, before their drugs could be FDA-approved, but also to provide substantial evidence of effectiveness for the product's intended use. That evidence had to be in the form of adequate and well-controlled clinical trials, which at the time was considered a revolutionary requirement. (Believe it or not, no requirement for high quality clinical trials existed before 1962.) This led to the current system of phase I, II, III, and IV clinical trials in force today. The amendments also included a requirement for informed consent of study subjects and codified good manufacturing processes, as well as the requirement that adverse events be reported. This has been, with some tweaking over the years, the law of the land regarding how the FDA approves drugs for specific indications. In 1962, President John F. Kennedy awarded Dr. Kelsey the Distinguished Civilian Service Medal, the nation’s highest federal civilian service award, saying she had “prevented a major tragedy of birth deformities, which she undoubtedly had.

That is the legacy of this remarkable woman, who will long be remembered for her achievement, as well as her decades of service to the FDA. Indeed, she didn't retire until 2005, and in 2010 the FDA she was the first recipient of an FDA award named after her and continues to be awarded annually.

oracknows Sun, 08/09/2015 - 21:00

Tags

Skepticism/Critical Thinking

drug approval

FDA

Frances Oldham Kelsey

New FDA rules mean better drug info for pregnant women

lborkowski — Mon, 08 Dec 2014 10:27:37 +0000

New FDA rules mean better drug info for pregnant women

Last week, the US Food and Drug Administration published a final rule that updates requirements for what prescription-drug information must disclose about potential effects for pregnant and breastfeeding women and their babies. Under the old labeling rules, drugs were placed in one of five categories -- A, B, C, D, or X -- depending on research findings (or lack thereof). An "A" designation meant that human studies did not find adverse effects in pregnant women or their babies, while and "X" designation meant that studies in humans or animals found a risk of problems to the baby and that there were no situations in which the potential benefits of the drug would outweigh the risks. The B, C, and D categories were for drugs with varying levels of evidence; see this Office on Women's Health fact sheet for more details.

“Prescribing decisions during pregnancy and lactation are individualized and involve complex maternal, fetal and infant risk-benefit considerations. The letter category system was overly simplistic and was misinterpreted as a grading system, which gave an over-simplified view of the product risk,” said Sandra Kweder, M.D, deputy director of the Office of New Drugs in the FDA’s Center for Drug Evaluation and Research, in a news release announcing the final rule's publication. “The new labeling rule provides for explanations, based on available information, about the potential benefits and risks for the mother, the fetus and the breastfeeding child.” The news release summarizes three subsections that must provide detailed information:

The Pregnancy subsection will provide information relevant to the use of the drug in pregnant women, such as dosing and potential risks to the developing fetus, and will require information about whether there is a registry that collects and maintains data on how pregnant women are affected when they use the drug or biological product. Information in drug labeling about the existence of any pregnancy registries has been previously recommended but not required until now.
The Lactation subsection will provide information about using the drug while breastfeeding, such as the amount of drug in breast milk and potential effects on the breastfed child.
The Females and Males of Reproductive Potential subsection will include information about pregnancy testing, contraception and about infertility as it relates to the drug. This information has been included in labeling, but there was no consistent placement for it until now.

An accompanying consumer update notes that women take an average of three to five medications during pregnancy, and that many women have chronic conditions (such as asthma, depression, and diabetes) that require ongoing medication use.

This isn't the only recent move from FDA to provide more information about how drugs affect various consumer populations. Last month, the agency released Drug Trials Snapshots, which is part of a pilot project to help consumers learn more about the clinical trials upon which new drugs' approvals are based. It has posted six examples, for drugs approved during a two-month period earlier this year, and is seeking public feedback on their content and utility. Starting next year, FDA aims to post a Snapshot for each newly approved drug classified as a "new molecular entity" (essentially, drugs that are truly novel rather than new versions or combinations of already-approved drugs).

Each of the six sample notes that "subgroup analyses were conducted for sex, race and age," and then spells out those findings. For five of the six drugs, the results of the sex subgroup analyses were either that reponse "was consistent between men and women" or that the drug "was shown to be similarly effective in men and women." For the same drugs, limited numbers of non-white participants in the clinical trials meant differences by racial subgroups could not be determined. For the drug Jublia, which treats toenail fungal infections, the snapshot has different answers, though: "A trend towards greater efficacy was observed in women than men taking JUBLIA," and "A trend towards greater efficacy was observed in Asians than in Whites or Black/African Americans taking JUBLIA." The Snapshots also give information about the number and demographics of the clinical trial participants, and report whether the trials compared the new drug to standard therapy or to a placebo. To view the Snapshots yourself, scroll down to the chart at the bottom of this page.

Trying to read the inserts that come with prescription drugs can be frustrating or intimidating. With these new actions, FDA is improving accessibility of information that can let us make informed decisions about the drugs we might take.

lborkowski Mon, 12/08/2014 - 05:27

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The dangers (?) of public funding of drug trials

ddobbs — Mon, 05 Jan 2009 22:20:47 +0000

The dangers (?) of public funding of drug trials

Ezra Klein relays Jim Manzi's worry that public funding of drug trials

exposes you to the inverse problems of the current system. Namely, "bureaucrats and politicians tend to have enormous career risk from an unsafe drug introduction, but almost none from a rejected drug that would have been effective had it been introduced...[it] would likely result in fewer new drugs being brought to market."

There's a bit to this. But it misses something important: The biggest problem with the present system may not be that deeply unsafe drugs are approved but that too many drugs that carry modest safety issues (and most drugs carry some safety issues) but little if any benefit are approved because their benefits are overstated. The risk-benefit ratio gets misrepresented, in other words, not so much because risks are understated (though that is done too) as because the benefits are oversold.

There are exceptions, of course, like Vioxx, in which an effective drug (it reduced pain) is more dangerous than revealed. But many of the most problemmatic drugs -- most notably psychiatric drugs, which get taken longer and by many, many people -- won approval and entered the market and became popular and then became safety problems, through sheer excess of unmonitored and ill-advised use, only because their benefits were exaggerated enough to win FDA approval and then get marketed as the Next Great Thing.

if the problem is overstated benefit rather than understated risk, then a move to public financing is not as apt to create an "inverse problem" in which risk-averse regulators Just Say No. TIghtening the risk filter, for instance, would probably have kept out only the most egregriously dangerous of the recent drugs-of-scandal, which we would hope is a good thing. A more balanced, skeptical approach to weighing risk against benefit, meanwhile, can only be a good thing. And I'm not sure how reasonable it is to fear that overcautious regulators would "likely result in fewer drugs being brought to market." Much of the drug problem the last few years is that too many drugs were brought to market -- drugs that improved little if at all on previous drugs (or even placebo) and that served mainly to increase health-care costs and, through the sheer hope of the New Good Thing, the number of people taking drugs with questionable efficacy.

Public funding of drug trials seems to me a promising idea, especially if, as Lisa Bero recommends, it emphasizes head-to-head drug competition (see bottom of post) rather than the rather empty requirement that a drug merely beat placebo rather than existing drugs.

ddobbs Mon, 01/05/2009 - 17:20

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As someone with experience trying to develop new drugs, I'm having a very hard time making sense of these arguments.

First, we already have a group of politicians and beaurocrats with high career risk from unsafe drug introduction but almost none from rejection of safe drugs: the FDA.

Second, what does public financing of clinical trials have to do with the approval process? Paying for the trials is completely independent of approving the drugs. (Witness our current system, where pharma pays but FDA approves.)

Third, I don't quite see how overstating benefits is primarily a problem during drug approval. After all, FDA has access to all the clinical data. They can and do determine for themselves what the benefits of a potential new drug really are. Sure, the drug sponsors try their best to convince FDA that the benefits are high and the risks low. But if anyone is in a position to see past overstated claims, it's FDA, precisely because they get to see all the data.

IMO, overstated benefits (and understated risks) are mainly a problem when pharma markets their drugs to MDs and consumers. We only get to see the data summaries in the package inserts and in whatever papers pharma chooses to publish. But that's essentially all post-approval.