Posts Tagged Clinical Trials

The 21st Century Cures Act: The (Somewhat) Good, The (Mostly) Bad, and The (Very) Ugly

The 21st Century Cures Act: Unnecessary and misguided.

The 21st Century Cures Act: Unnecessary and misguided.

The approval of new drugs and medical devices is a process fraught with scientific, political, and ethical landmines. Inherent in any such process is an unavoidable conflict between rigorous science and safety on the one side, which tend to slow the process down by requiring large randomized clinical trials that can take years, versus forces that demand faster approval. For example, patients suffering from deadly diseases demand faster approval of drugs that might give them the hope of surviving their disease, or at least of surviving considerably longer. This is a powerful force for reform, as evidenced by HIV/AIDS activism in the 1980s and 1990s that led to the development of fast-track approval mechanisms for drugs for life-threatening conditions, a change whose effects have been mixed. It’s also a powerful force potentially for ill, as I’ve documented in my posts about the understandable but misguided “right-to-try” movement. After all, what politician can say no to a constituency representing desperately ill people who only want a shot at survival? It’s not all desperate patients, however. Also wanting more rapid drug approval are powerful business interests in the form of the pharmaceutical and medical device industries, for whom the time and expense of prolonged clinical trials eat into profits and make some drugs not worth developing from a business standpoint.

In 1962, after Frances O. Kelsey, MD, PhD (who died on Friday at the age of 101) successfully prevented the approval of the drug thalidomide in the US, a drug found to cause serious birth defects, 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 before their drugs could be FDA-approved, as had been the case prior to the amendments, 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 in the United States 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

Medicine is a lot more complex now than it was in the 1960s however, and there has been a growing sentiment that the system is, if not broken, at least functioning in a way that is behind the times, a manner that was acceptable and appropriate 40 years ago but is no longer so in this era of genomics, precision medicine (formerly known as “personalized medicine”), and targeted therapies. The new drug approval process, which can take up to a decade and cost a billion dollars, it is argued, is too rigid, cumbersome, and slow for the 21st century. (Why it wasn’t too rigid, cumbersome, and slow in the 20th century, no one seems to say. I guess that “21st century” sounds way cooler.)

Into this ongoing controversy have marched Rep. Fred Upton (R-Mich.) and Rep. Diana DeGette (D-Colo.), who have sponsored a bill passed by the House of Representatives in a rare display of bipartisanship in July. The bill, H.R.6, is entitled the “21st Century Cures Act“. Given how it passed the House by a vote of 344-77, one would think that it should glide through the Senate easily. Certainly, its sponsors and supporters have mounted a mighty PR effort. That might not be the case, given that in the Senate a single senator can hold up or even kill a bill through a filibuster, and to shut down a filibuster or prevent a threatened filibuster requires 60 votes. Be that as it may, I’m not so much interested in the politics of this bill, which, if it survives the Senate, will almost certainly be significantly amended, but rather what the bill does.

Posted in: Basic Science, Clinical Trials, Politics and Regulation

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As in 2014, “right-to-try” laws continue to metastasize in 2015, part 2

As in 2014, “right-to-try” laws continue to metastasize in 2015, part 2

When I wrote a week ago about the sham that is “right-to-try”, one criticism (among many) that I made of these misguided, profoundly patient-unfriendly laws was that I have as yet been unable to find a single example of a patient who has managed to obtain access to an experimental therapeutic through such a law, much less been helped by it. So-called “right-to-try” laws, of course, claim to provide a mechanism by which patients with terminal illnesses can obtain access to experimental therapeutics not yet approved by the FDA but still in clinical trials. They are, as I’ve pointed out, a cruel sham, placebo legislation that makes lawmakers feel as though they’ve done something good but do nothing of substance for patients while providing them with false hope. The federal government through the FDA controls drug approval, which means that states can’t compel a drug company to provide a drug to a patient, and most drug companies would not want to risk jeopardizing approval of their drug, which is what could happen if they grant access to an investigational drug under right-to-try and the patient suffers an adverse event. After all, the success rate for drugs that have passed phase 1 (which is all that right-to-try requires) in phase 3 trials is only on the order of 9-12%, meaning that that’s the most optimistic probability that such drugs would benefit a patient. In reality, it’s almost certainly much, much lower.

Posted in: Clinical Trials, Politics and Regulation

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As in 2014, “right-to-try” laws continue to metastasize in 2015

As in 2014, “right-to-try” laws continue to metastasize in 2015

Last year, I did several posts on what I consider to be a profoundly misguided and potentially harmful type of law known as “right-to-try.” Beginning about a year and a half ago, promoted by the libertarian think tank known as the Goldwater Institute, right-to-try laws began popping up in state legislatures, which I likened to Dallas Buyers Club laws. Both Jann Bellamy and I wrote about how these laws are far more likely to do harm than good, and that is a position that I maintain today. The idea behind these laws is to give terminally ill patients access to experimental drugs—in some cases drugs that have only passed phase I testing—that might help them. It’s an understandable, albeit flawed argument. After all, it’s perfectly understandable why terminally ill patients would fight for drugs that give them hope, and it’s just as understandable why politicians and the public would see such a goal as a good thing. In practice, as I will explain again in the context of this update, such laws are far more likely to harm patients than help them. Indeed, as you will see, in the year since the first wave of right-to-try laws have passed, not a single patient that I can find has obtained access to experimental drugs under a right-to-try law, much less been helped by them.

Unfortunately, given how effectively “right to try” has been sold on grounds of providing terminally ill patients hope and as a matter of personal freedom, it’s clear that this wave is not going to abate. Since Colorado passed the very first right-to-try law almost exactly a year ago today, a total of 17 more states now have passed passed similar legislation, the most recent being Tennessee, and 22 others have introduced legislation. It’s a good bet that right-to-try will pass in all of those states, because, as I’ve explained many times before and in many interviews, if you don’t understand clinical trial ethics and science, opposing the concept of right-to-try comes across like opposing Mom, apple pie, and the American flag, and leaves opponents open to false—but seemingly convincing—charges of callousness towards the terminally ill on the order of enjoying drop kicking puppies through flaming goalposts.

Posted in: Clinical Trials, Pharmaceuticals, Politics and Regulation

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Mediocre Expectations

Pictured: Relevant.  Oh yeah, it's going to get weird. Image courtesy of the Wellcome Trust Image Library via the Wikimedia Commons.

Pictured: Relevant. Oh yeah, it’s going to get weird.

I had a dickens of a time writing this entry. The last week has been spent in New York for NECSS. It is safe to say that New York has plenty of distractions for us Dug the Dog types. Reality may be a honey badger, but New York is a squirrel. I say that when I travel I usually do not come across food better than I can find in Portland. Nope. Not true of New York. It joins Paris and New Orleans in the holy trinity of good eats, although I will stick with Pacific Northwest beer. And the rule is that for every day you are gone, three days’ worth of work piles up. I really need to stop taking time off.

I spoke at NECSS on a favorite topic of mine, how acupuncture works. It doesn’t. But I discussed a few studies that I found interesting. Like all studies, no single paper is definitive. The third law of the medical literature states that for every study, there is an equal and opposite study. A bit of an exaggeration perhaps but I do find the direction that the following studies point interesting both as to acupuncture’s mechanism of inaction and how the mind functions, making them worth collecting in an essay. (more…)

Posted in: Science and Medicine

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Clinical trials of homeopathy versus “respect for science”

Trojan Rabbit

A few months ago, Steve Novella and I published an article in Trends in Molecular Medicine entitled “Clinical trials of integrative medicine: testing whether magic works?” It was our first foray together into publishing commentary about science-based medicine versus evidence-based medicine, using a topic that we’ve both written extensively about over the years on this blog and our respective personal blogs. Specifically, we discussed whether it is worthwhile to do randomized clinical trials (RCTs) testing highly improbable treatments, such as reiki and homeopathy, both of which have no physical basis to believe that they do anything whatsoever. As I’ve said many times before, reiki is simply faith healing in which Eastern mysticism is substituted for Christian beliefs, and homeopathy, as we’ve discussed many times here on SBM, is vitalistic sympathetic magic with no evidence to support its two laws.

To our surprise, that article generated a fair amount of press (for example this), with accounts of it showing up in the media in various places and Steven and I being asked to do a fair number of interviews. Part of the reason, I suspect, is that the editor made the article available for free for a month after its initial publication. (Unfortunately it’s back behind the pay wall again.) Part of the reason is that, intuitively, it makes sense to people not to waste money testing what is, at its core, magic. When I followed up that publication with an article criticizing “integrative oncology” in Nature Reviews Cancer entitled “Integrative oncology: Really the best of both worlds?“, the target was well and truly on my back. Indeed, let’s just say that the Society for Integrative Oncology and the Consortium of Academic Health Centers for Integrative Medicine (CAHCIM) are quite unhappy with me. When both their letters to the editor are published (right now, only one is), I might even blog about them.

In the meantime, I want to deal with criticism published in an unexpected place, albeit not by unexpected critics. The reason is that this criticism relies on a common straw man caricature of what we are saying when we advocate science-based medicine (SBM) that considers prior plausibility in determining what modalities to test in clinical trials and understands Bayesian thinking in which prior plausibility affects posterior plausibility that a “significant” result is not a false positive in contrast to the current evidence-based medicine (EBM) paradigm, which relegates basic science knowledge, even well-established principles of science that show that something like, say, homeopathy or reiki is impossible under the current understanding of physics, chemistry and biology, to the lowest rung on the EBM pyramid. It’s also a criticism that comes up frequently enough that, even though it’s been addressed before in various ways by various SBM bloggers, it’s worth revisiting from time to time. In this case, that’s particularly so because one of the two critics taking Steve and me to task is currently embroiled in a controversy about testing homeopathy for attention deficit hyperactivity disorder (ADHD) at the University of Toronto (more details on that later). Let’s just say, the criticism of Steve and me gives me an “in” to address a story that I thought had passed me by, and I intend to take it.

Posted in: Clinical Trials, Energy Medicine, Homeopathy

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Screening for disease in people without symptoms: The reality

One of the most contentious questions that come up in science-based medicine that we discuss on this blog is the issue of screening asymptomatic individuals for disease. The most common conditions screened for that we, at least, have discussed on this blog are cancers (e.g., mammography for breast cancer, prostate-specific antigen screening for prostate cancer, ultrasound screening for thyroid cancer), but screening goes beyond just cancer. In cancer, screening is a particularly-contentious issue. For example, by simply questioning whether mammography saves as many lives lost to breast cancer as advocates claim, one can find oneself coming under fire from some very powerful advocates of screening who view any questioning of mammography as an attempt to deny “life-saving” screening to women. That’s why I was very interested when I saw a blog post on The Gupta Guide that pointed me to a new systematic review by John Ioannidis and colleagues examining the value of screening as a general phenomenon, entitled “Does screening for disease save lives in asymptomatic adults? Systematic review of meta-analyses and randomized trials.”

Before I get into the study, let’s first review some of the key concepts behind screening asymptomatic individuals for disease. (If you’re familiar with these concepts, you can skip to the next section.) The act of screening for disease is based on a concept that makes intuitive sense to most people, including physicians, but might not be correct for many diseases. That concept is that early intervention is more likely to successfully prevent complications and death than later intervention. This concept is particularly strong in cancer, for obvious reasons. Compare, for example, a stage I breast cancer (less than 2 cm in diameter, no involvement of the lymph nodes under the arm, known as axillary lymph nodes) with a stage III cancer (e.g., a tumor measuring greater than 5 cm and/or having lots of axillary lymph nodes involved). Five year survival is much higher for treated stage I than for treated stage III, and, depending on the molecular characteristics, the stage I cancer might not even require chemotherapy and can be treated with breast conserving surgery (“lumpectomy” or partial mastectomy) far more frequently than the stage III cancer. So it seems intuitively true that it would be better to catch a breast cancer when it’s stage I rather than when it’s stage III.

Posted in: Cancer, Clinical Trials, Epidemiology, Public Health

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Using the fear of Ebola to promote the placebo legislation that is “right to try”


Perhaps the most pervasive medical conspiracy theory of all involves stories that there exist out there all sorts of fantastic cures for cancer and other deadly diseases but you can’t have them because (1) “they” don’t want you to know about them (as I like to call it, the Kevin Trudeau approach) and/or (2) the evil jackbooted thugs of the FDA are so close-minded and blinded by science that they crush any attempt to market such drugs and, under the most charitable assessment under this myth, dramatically slow down the approval of such cures. The first version usually involves “natural” cures or various other alternative medicine cures that are being “suppressed” by the FDA, FTC, state medical boards, and various other entities, usually at the behest of their pharma overlords. The second version is less extreme but no less fantasy-based. It tends to be tightly associated with libertarian and small government fantasists and a loose movement in medicine with similar beliefs known as the “health freedom” movement, whose members posit that, if only the heavy hand of government were removed and the jack-booted thugs of the FDA reined in, free market innovation would flourish, and the cures so long suppressed by an overweening and oppressive regulatory apparatus would burst the floodgates. Under this views, these cures, long held back by the dam of the FDA, would flow immediately to the people, and there would be much rejoicing. (Funny how it didn’t work out that way before the Pure Food and Drug Act of 1906.) Of course, I can’t help but note that in general, in this latter idea, these fantastical benefits seem to be reserved only for those who have the cash, because, well, the free market fixes everything. At least, that seems to be the belief system at the heart of many of these conspiracy theories.

The idea that the FDA is keeping cures from desperate terminally ill people, either intentionally or unintentionally, through its insistence on a rigorous, science-based approval process in which drugs are taken through preclinical work, phase 1, phase 2, and phase 3 testing before approval is one of the major driving beliefs commonly used to justify so-called “right-to-try” laws. These bills have been infiltrating state houses like so much kudzu, and the Ebola outbreak has only added fuel to the fire based on the accelerated use of ZMapp, a humanized monoclonal antibody against the Ebola virus, in some patients even though it hadn’t been tested in humans yet (more on that later). Already four of these laws have been passed (in Colorado, Missouri, Louisiana, and now Michigan) with a referendum in Arizona almost certain to pass next week to bring the total to five states with such laws. Basically, these laws, as I’ve described, claim to allow access to experimental drugs to terminally ill patients with a couple of major conditions: First, that the drug has passed phase I clinical trials and second that the patient has exhausted all approved therapies. As I’ve explained before more than once, first when the law hit the news big time in Arizona and then when a right-to-try bill was introduced into the legislature here in Michigan, they do nothing of the sort and are being promoted based on a huge amount of misinformation detailed in the links earlier. First, having passed phase 1 does not mean a drug is safe, but right-to-try advocates, particularly the main group spearheading these laws, the Goldwater Institute, make that claim incessantly. Second, they vastly overstate the likelihood that a given experimental drug will help a given patient. The list goes on.

Posted in: Cancer, Clinical Trials, Pharmaceuticals, Politics and Regulation

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Clinical trials of integrative medicine: testing whether magic works?


I just thought that I’d take the editor’s (and, speaking for Steve, the founder’s) prerogative to promote our own efforts. Regular readers of SBM are familiar with our message with respect to randomized clinical trials of highly implausible “complementary and alternative medicine” treatments, such as homeopathy or reiki. Well, believe it or not, Steve and I managed to get a commentary published in a very good journal in which we present the SBM viewpoint with respect to these trials. Even better, at least for now, you can read it too, because it doesn’t appear to be behind a paywall. (I’m at home as I write this, and I can read the whole thing on my wifi, no VPN needed.)

The article is entitled “Clinical trials of integrative medicine: testing whether magic works?” There’s also been a fair amount of news coverage on the article, and I’ve been frantically doing interviews over the last couple of days, including:

There are likely to be at least a couple more, given the interviews I’ve done; that is, unless editors reject the ideas.

In any case, Steve and I are interested in your comments. Trends in Molecular Medicine is good in that it published our article and it’s a pretty high impact review journal, but it doesn’t have a section for comments. So consider this your section for comments on our article.

Posted in: Basic Science, Clinical Trials, Homeopathy

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The false hope of “right-to-try” metastasizes to Michigan

Nurse administers chemotherapy

Ed. note: Please read disclaimer in Dr. Gorski’s profile!

There are times when supporting science-based health policy and opposing health policies that sound compassionate but are not are easily portrayed as though I’m opposing mom, apple pie, and the American flag. One such type of misguided policy that I’ve opposed is a category of bills that have been finding their way into state legislatures lately known as “right to try” bills. Jann Bellamy and I have both written about them before, and with the passage of the first such bill into law in Colorado in May, I had been meaning to revisit the topic. Although “right-to-try” laws are a bad policy idea that’s not new, versions of such bills having been championed by, for example, the Abigail Alliance for at least a decade, the recent popularity of the movie Dallas Buyers Club appears to have given them a new boost, such that Colorado state Senator Irene Aguilar even frequently referred to her state’s right-to-try bill as the “Dallas Buyers Club” bill. It’s a topic I’ve been meaning to revisit since the news out of Colorado, but apparently I needed a nudge, given that it’s two months later now.

Unfortunately, that nudge came in the form of a right-to-try bill (Senate Bill 991) being introduced into the legislature in Michigan by Senator John Pappageorge and unanimously passing, almost without comment by the committee and certainly with minimal news coverage, through the first hurdle, the Michigan Senate Health Policy Committee. In parallel, the same legislation (House Bill 5651) has been introduced into the Michigan House of Representatives.

Posted in: Cancer, Pharmaceuticals, Politics and Regulation

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The Texas Medical Board vs. Stanislaw Burzynski, 2014 edition


As I begin this post, I’m on a miserably crowded, hot, stinky flight winging my way home from TAM. This puts me in the perfect mood to write about my bête noire to conquer all bêtes noires, namely Stanislaw Burzynski, the Polish expat doctor who claims to have much better results treating deadly brain cancers than conventional oncology, even though he is not an oncologist and has never even completed the prerequisite training for an oncology fellowship, namely an internal medicine residency. Actually, I don’t mean that in the way that you probably think I mean it. This time around, unlike the last time around, writing about Burzynski will put me in a better mood to endure being slapped into a sardine can in coach, barely able to move, barely able to type, but needing to get a blog post out on Monday.

If you remember, the last time I wrote about Burzynski, the Food and Drug Administration (FDA) had caved, and by “caved” I mean that it had lifted the partial clinical hold on Burzynski’s clinical trials. As is usual with the long and winding saga that is Burzynski, I feel compelled to give a brief review for any newbie who might encounter this post. Old hands at this story can skip ahead or just skim.

Two years ago, a child named Josia Cotto died of hypernatremia (elevated sodium level in the blood) due to receiving treatment for a brain tumor from the Burzynski Clinic using Burzynski’s “miracle drug” antineoplastons. Hypernatremia is a known complication of ANP treatment, and, as a result of this child’s death, the FDA put a partial clinical hold on Burzynski’s clinical trials for pediatric patients, which meant that he could continue to treat children already enrolled in his clinical trials but could not enroll any new patients. Six months later, this partial hold was extended to all of Burzynski’s clinical trials, and in early 2013 the FDA inspected the Burzynski Clinic and Burzynski Research Institute (BRI). (more…)

Posted in: Cancer, Clinical Trials, Politics and Regulation

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