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Do clinical trials work? It depends on what you mean by “work”

Introduction

(Skip to the next section if you want to miss the self-referential blather about TAM.)

As I write this, I’m winging my way home from TAM, crammed uncomfortably—very uncomfortably—in a window seat in steerage—I mean, coach). I had been thinking of just rerunning a post and having done with it, sleeping the flight away, to arrive tanned, rested, and ready to continue the battle against pseudoscience and quackery at home, but this seat is just too damned uncomfortable. So I might as well use the three and a half hours or so left on this flight to write something. If this post ends abruptly, it will be because I’ve run out of time and a flight attendant is telling me to shut down my computer in those cloyingly polite but simultaneously imperious voices that they all seem to have.

I had thought of simply recounting the adventures of the SBM crew who did make it out to TAM to give talks at workshops and the main stage and to be on panels, but that seems too easy. Even easier, I could simply post my slides online. But, no, how on earth can I reasonably expect Mark Crislip to post while he’s at TAM if I’m too frikkin’ lazy to follow suit? I’m supposed to lead by example, right, even if what comes out is nearly as riddled with spelling and grammar errors (not to mention the occasional incoherent sentence) as a Mark Crislip post? Example or not, lazy or not, I would be remiss if, before delving into the topic of today’s post, I didn’t praise my fellow SBM bloggers who were with me, namely Steve Novella, Harriet Hall, and Mark Crislip, for their excellent talks and insightful analysis. Ditto Bob Blaskiewicz, with whom I tag-teamed a talk on everybody’s favorite cancer “researcher” and doctor, Stanislaw Burzynski. It’ll be fun to see the reaction of Eric Merola and all the other Burzynski sycophants, toadies, and lackeys when Bob’s and my talks finally hit YouTube. Sadly, we’ll have to wait several weeks for that. (Hmmm. Maybe I will post those slides later this week.)

Finally, before I delve into the meat of the post, I do have to suggest to you all one last thing. Please go back and reread this post. Those of you who were at Penn Jillette’s Private Rock & Roll Bacon & Donut Party this year will understand the reason for the request. Those who weren’t (i.e., the vast majority of you) will, I hope, find it worth reading again. Let’s just say that Penn apparently actually read it, his profanity-laden protestations otherwise at the party notwithstanding, and was unhappy enough with me both to kick me out of his party, and have a song prepared about the incident to sing at the party. Let’s also just say that his choice of reaction wasn’t one of Penn’s finer moments, even by Penn’s usual standards of decorum. (Stay classy, Penn. Stay classy.)

Now that I’ve completed the obligatory 400-500 self-indulgent, introductory blather that no one cares about but is nonetheless a mandatory part of nearly every Gorski post because I can’t help myself and need an editor, let’s get to it. Just be thankful that it’s only 500 words this time.

The real post: Do clinical trials work?

One of the issues I discussed at our SBM workshop was something I’ve written before, namely the “methodolatry” that sometimes infests evidence-based medicine (EBM), “Methodolatry” has been defined as the profane worship of the randomized clinical trial (RCT) as the only valid method of clinical investigation, and it’s a symptom of the way that EBM 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. However, never let it be said that RCTs aren’t actually important in SBM. Our problem with how EBM worships them derives from how it even bothers to do trials in the first place of modalities that can best be described by Harriet Hall’s brilliant appellation, Tooth Fairy Science. However, these days RCTs are widely perceived to have a serious problem. They have become so expensive to do and there have been so many failures of drugs that looked promising to show efficacy in clinical trials that some have even questioned whether there is something fundamentally wrong with how we do clinical trials now. Some even ask, as the title of an article by Clifton Leaf that appeared in the New York Times over the weekend, Do Clinical Trials Work?

It begins with the story of Avastin in brain tumors. I’m sure that Eric Merola will likely jump all over this, given how he tried to use the example of Avastin being approved for glioma on fast track approval that used phase II trials as the basis for doing so as an argument for why antineoplastons should be approved by the FDA. Or maybe he won’t. Here’s why. The story explains that there were two single-arm trials of adding Avastin to glioma therapy in which the tumors “shrank and the disease seemed to stall for several months when patients were given the drug.” Then Clifton points out the results of the randomized clinical trial presented at the American Society of Clinical Oncology (ASCO) meeting a month and a half ago:

But to the surprise of many, Dr. Gilbert’s study found no difference in survival between those who were given Avastin and those who were given a placebo.

Disappointing though its outcome was, the study represented a victory for science over guesswork, of hard data over hunches. As far as clinical trials went, Dr. Gilbert’s study was the gold standard. The earlier studies had each been “single-arm,” in the lingo of clinical trials, meaning there had been no comparison group. In Dr. Gilbert’s study, more than 600 brain cancer patients were randomly assigned to two evenly balanced groups: an intervention arm (those who got Avastin along with a standard treatment) and a control arm (those who got the latter and a placebo). What’s more, the study was “double-blind” — neither the patients nor the doctors knew who was in which group until after the results had been assessed.

The centerpiece of the country’s drug-testing system — the randomized, controlled trial — had worked.

This study could certainly be taken as evidence supporting a position that we shouldn’t approve drugs based on single-arm phase II clinical trials, even under fast track. It is indeed a very good example of how promising phase II clinical trial results are not always validated when the bigger and more rigorous phase III RCTs are performed. In one way, it is a good thing. Negative results, be they experimental or clinical trial, are just as important in science as positive results, if not more so. In another way, however, it’s a bad thing because, as the NYT article points out, “doctors had no more clarity after the trial about how to treat brain cancer patients than they had before.” A seemingly promising addition to the armamentarium against a deadly cancer that has too few effective treatments was shown not to work in an RCT that was designed to be, more or less, definitive. However, the key thing to remember about such an RCT is that it is looking at populations of patients. Overall, there was no difference in overall survival between the control and Avastin group, but that doesn’t necessarily mean that Avastin is useless against glioma.

Indeed, as someone who’s been studying angiogenesis and how to target it therapeutically in cancer since the heady days of the late 1990s, when findings by Judah Folkman and other pioneers in this field led to headlines in the lay press like “The Cure for Cancer” and it really did look as though the discovery that inhibiting angiogenesis produced dramatic results and outright cures in preclinical rodent models of cancer. Over the years, the study of angiogenesis has been gradually de-emphasized in my research, correlating inversely with the rise of other interests, but I do have a small project in targeting tumor-induced angiogenesis still ongoing and hope to publish on it before the end of the year. In any case, reality shut down those heady days, as it became clear that Avastin and other antiangiogenics were not as nontoxic in humans as they were in mice, nor were they nearly as effective. Still, it is clear that Avastin has contributed to significant increases in median survival in a number of tumor types, such as colorectal cancer. However, overall it’s hard not to conclude that antiangiogenic therapy has been, by and large, a disappointment, if only because the hype and hope were so sky-high 15 years ago. Rare indeed would have been the treatment that could have lived up to such expectations when tested in RCTs.

One thing that has been apparent for quite some time is that there appears to be a subset of patients who have remarkable responses to Avastin. Many oncologists get this feeling anecdotally, even if they don’t have evidence, and evidence has popped up in clinical trials. Assuming this is true, while it might not now make sense to treat all or most glioma patients with Avastin, it might very well make sense to treat that subset who have such dramatic responses if we could identify them beforehand. There’s the rub, though. We can’t, and Leaf points this out:

Some patients did do better on the drug, and indeed, doctors and patients insist that some who take Avastin significantly beat the average. But the trial was unable to discover these “responders” along the way, much less examine what might have accounted for the difference. (Dr. Gilbert is working to figure that out now.)

Indeed, even after some 400 completed clinical trials in various cancers, it’s not clear why Avastin works (or doesn’t work) in any single patient. “Despite looking at hundreds of potential predictive biomarkers, we do not currently have a way to predict who is most likely to respond to Avastin and who is not,” says a spokesperson for Genentech, a division of the Swiss pharmaceutical giant Roche, which makes the drug.

That we could be this uncertain about any medicine with $6 billion in annual global sales — and after 16 years of human trials involving tens of thousands of patients — is remarkable in itself. And yet this is the norm, not the exception. We are just as confused about a host of other long-tested therapies: neuroprotective drugs for stroke, erythropoiesis-stimulating agents for anemia, the antiviral drug Tamiflu — and, as recent headlines have shown, rosiglitazone (Avandia) for diabetes, a controversy that has now embroiled a related class of molecules. Which brings us to perhaps a more fundamental question, one that few people really want to ask: do clinical trials even work? Or are the diseases of individuals so particular that testing experimental medicines in broad groups is doomed to create more frustration than knowledge?

While it’s an excellent point that we don’t have predictive biomarkers (say, something in the blood we could measure) that tell us which patients are most likely to respond to Avastin (or most other drugs), Leaf seems to be indulging in a false dichotomy. Just because we don’t have predictive biomarkers for various drugs does not imply that clinical trials don’t work. Very clearly, they do. The problem is that they have limitations, and one of those limitations is that, without predictive biomarkers, we have no choice but to test the drug in a controlled population and see if there is a difference between control and the treated population that can be observed on a population level. The smaller the difference, the harder it is to detect and the more patients are needed to detect it. That’s why we need and want predictive biomarkers in the first place.

Worse, even the biomarkers we have are nowhere near 100% predictive. Let’s take a look at the prototypical targeted therapy, arguably the oldest targeted drug of all, Tamoxifen, which blocks estrogen activity. It is only used in tumors that make the estrogen receptor and are therefore presumed to be estrogen-responsive (i.e., estrogen stimulates them to grow). I remember a talk by the director of the Cancer Institute of New Jersey at the time I worked there, William Hait, who pointed out that Tamoxifen is effective in ER(+) cancers about 50% of the time. Around 70% of breast cancer is ER(+), and that means that if you treat all patients with breast cancer with Tamoxifen, you will see responses only 35% of the time, whereas if you treat only ER(+) cancers you will see responses 50% of the time. Another example is Herceptin, which targets amplified HER2 in breast cancer. Even though it is a targeted drug, it is effective against approximately 30% of HER2(+) cancers. Now, approximately 30% of breast cancers are HER2(+), which means that if you treat all comers with Herceptin, it will only be effective 0.3 x 0.3 = 0.09 (9%) of the time, but if you treat only HER2(+) cancers it should be effective 30% of the time. There are other examples he gave us. Taxol, for instance, is effective in 75% of breast cancer with p53 mutations. Since approximately 50% of breast cancers carry p53 mutations, if you treat all comers with Taxol you will get responses around 37.5% of the time, whereas if you treat only cancers with p53 mutations you should expect a 75% response rate. Of course, a 37.5% response rate is good enough that pretty much everyone with breast cancer who needs chemotherapy will get a Taxane, but you get the idea.

Now here’s where the devil is. These biomarkers that I’ve described are crude, and not even that predictive. But what, if anything, is better? That’s the problem, and that’s where most articles like this break down. They do an excellent job of identifying the problems with clinical trials, and there’s no doubt that Clifton Leaf does just that. None of these problems discussed in his NYT article are unfamiliar to most clinicians and clinical investigators, particularly in cancer. However, one notes that he has a book out entitled The Truth In Small Doses: Why We’re Losing the War on Cancer — and How to Win it. Personally, I hate that meme of “we’re losing the war on cancer,” because it’s not a war, and whether or not we’re “losing” depends on what your vision of “victory” is and how fast we can win the war. As I’ve pointed out many times, particularly around the 40th anniversary of Richard Nixon’s declaration of “war on cancer,” what do you expect in 40 years, given that the amount of resources we pour into this “war” are minuscule compared to what we spend on other things, such as—oh, you know—actual war? How much progress can we realistically expect in 40 years given that investment, the incredible complexity of cancer, and cancer’s ability to out-evolve almost anything we have as yet been able to throw at it. Clifton Leaf is a cancer survivor; so I can totally understand his frustration. However, that doesn’t stop his use of that tired old meme from irritating me. I’ll stop whining about that particular pet peeve of mine right now, but as everyone knows I do so love a good whine. Sorry.

My pet peeve aside, what can we do better? Most of us in oncology believe that the answer will likely come down to personalized medicine based on the genomic profile of each cancer, but how to get from the enormous amount of data from genomic studies of various cancer to actual validated treatments is not at all clear at this stage (other knowing that Stanislaw Burzynski’s doing it wrong). Right now, personalized medicine has a lot of promise but has even more hype with little or nothing as yet in the way of concrete results that clearly benefit patients. Many have been the ideas to overcome these problems and validate genomic-based personalized medicine. Leaf actually mentions an interesting one: The I-SPY2 TRIAL (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis 2). (Whew, what a name!) It’s a very interesting prototype of how clinical trials might be done in the future, and if it works I can see a lot more trials like this:

The I-SPY 2 TRIAL (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis 2) is a clinical trial for women with newly diagnosed locally advanced breast cancer to test whether adding investigational drugs to standard chemotherapy is better than standard chemotherapy alone before having surgery. The treatment phase of this trial will be testing multiple investigational drugs that are thought to target the biology of each participant’s tumor. The trial will use the information from each participant who completes the study treatment to help decide treatment for future women who join the trial. This will help the study researchers learn more quickly which investigational drugs will be most beneficial for women with certain tumor characteristics. The I-SPY 2 TRIAL will test the idea of tailoring treatment by using molecular tests to help identify which patients should be treated with investigational drugs. Results of this trial may help make investigational drugs available to more women in the future.

The beauty of this trial is that it uses Bayesian analysis of responses to have the trial, in effect, evolve in response to what is found at earlier stages. My main quibble with the study is that it requires that all subjects undergo pretreatment breast MRI before surgery, which has a tendency to upstage women through the Will Rogers effect and thus result in more mastectomies. I understand that the trial investigators probably wanted advanced imaging to follow tumor response and that MRI can also show blood flow and therefore measure tumor angiogenesis, but I always worry when I see a design like this one, that it might promote unnecessary mastectomies. On the other hand, the inclusion criteria require a tumor that is 2.5 cm in diameter or greater so perhaps this will be less of a problem. That quibble aside, as Leaf describes, it is an intriguing design and it does evolve based on previous results:

In fact, a breast cancer trial called I-SPY 2, already under way, may be a good model to follow. The aim of the trial, sponsored by the Biomarkers Consortium, a partnership that includes the Foundation for the National Institutes of Health, the F.D.A., and others, is to figure out whether neoadjuvant therapy for breast cancer — administering drugs before a tumor is surgically removed — reduces recurrence of the disease, and if so, which drugs work best.

As with the Herceptin model, patients are being matched with experimental medicines that are designed to target a particular molecular subtype of breast cancer. But unlike in other trials, I-SPY 2 investigators, including Dr. Berry, are testing up to a dozen drugs from multiple companies, phasing out those that don’t appear to be working and subbing in others, without stopping the study.

Here’s the design (more details can be found here and here, and some of the investigational drugs tried can be found here):

ISPYdesign

The difficult part of the study, of course, is designing the algorithms by which drugs are swapped out as they appear not to be working. If these decisions are made willy-nilly, then this trial would be no better than what Burzynski does (i.e., making simplistic guesses). However, there is a sophisticated analysis and algorithm by which treatment decisions are made. It does have to be remembered, though, that, although I-SPY2 does represent personalized medicine, it is not yet full genomic medicine. Most of the biomarker tests used are biomarkers that already exist, and the additional biomarkers measured will not affect patient treatment. This part of the trial is for discovery of biomarkers, not validation.

The bottom line

I’ll be watching the progress of I-SPY2 closely, because it’s a new kind of clinical trial. Whether it will succeed in improving the success of the followup clinical trials of agents identified through I-SPY remains to be seen, as it also remains to be seen whether it will speed up the pace of discovery. I’m probably less hopeful than Clifton Leaf, but that doesn’t mean I’m not hopeful.

So do clinical trials work? It depends on what you mean by “clinical trials” and “work.” I would argue that they do, in fact, still work in that they are still the best method we have to determine whether science-based therapies with preclinical promise actually translate into useful therapies. They’re simply evolving with science, as they must under the “selective pressure” of advances in technology and understanding of biology.

Posted in: Cancer, Clinical Trials

Leave a Comment (52) ↓

52 thoughts on “Do clinical trials work? It depends on what you mean by “work”

  1. phayes says:

    “I’ll be watching the progress of I-SPY2 closely, because it’s a new kind of clinical trial.”

    Doing inference right works better than doing it wrong even in the older, simpler contexts: http://www.indiana.edu/~kruschke/BEST/ ;-)

  2. Stephen H says:

    Randomised control trials are better than the generally offered alternative, which is anecdote. I know which I would prefer to be supporting my treatment.

    But there may be other (scientifically valid) ways of assessing treatments, and if so great. The RCT has only been around for seventy-odd years, and we would be crazy to think it cannot be improved upon.

  3. Dr. Gorski wrote:

    [...] there appears to be a subset of patients who have remarkable responses to Avastin

    I can imagine two explanations for this: (1) Tamoxifen/Herceptin scenario (there are actual biological reasons for why that particular subset of patients improve better but not others) and (2) for statistical reasons, grouping together the outliers makes it appear as if a subset of patients improve better than others.

    In what ways can one select between these two hypotheses (besides first identifying a relevant biomarker)?

  4. WilliamLawrenceUtridge says:

    Ugh, clinical trials attempting to link subsets of patients to positive outcomes seems very much like the fishing expeditions we so despise in so many quack trials. I can’t wait until we can start hypothesis-testing with a priori designs…

    1. Young CC Prof says:

      There’s nothing inherently wrong with a fishing expedition for hypothesis GENERATION, as long as everyone remembers that’s all it is, and no one runs screaming to the popular media with the results.

      1. David Gorski says:

        Exactly. Fishing expeditions are often necessary for hypothesis generation. It’s the confusion between hypothesis generation and actual conclusions where the CAM “researchers” go so wrong.

        1. Stephen H says:

          Doing a trial, and finding that there is a correlation between a subset of patients with “parameter x” and positive outcomes in the trial is good – as long as you then move on to perform a new trial, testing that discovered correlation.

          This is an area that is begging for work. For instance, I have a condition called Restless Legs Syndrome (it is far worse than it sounds). The drugs that are used in treating this are same as in treating Parkinson’s, and are notoriously hit and miss. So far, I have found nothing that works (including combinations – although one drug worked for about six weeks of bliss before going off the boil (a known problem)). Maybe a better idea of how these drugs work in specific categories of patient would lead to better matching of patients to particular drug cocktails.

  5. Janet Camp says:

    I responded to the article with a paraphrase of your words:

    “…the answer will likely come down to personalized medicine based on the genomic profile of each cancer, but how to get from the enormous amount of data from genomic studies of various cancer to actual validated treatments is not at all clear at this stage…”

    Did I do good? I’m glad to see that you took your flight time to respond. As I read the piece in the NYT, I kept wondering what you’d have to say, and for once I find out very soon. :-)

    Aside: Dr. Crislip’s posts have recently been remarkably free of error, both type and syntax.

    1. David Gorski says:

      That’s because we have a dedicated proofreader now. Paul is doing so many other things for us that he didn’t always have the time it took to proofread and correct a Crislip post every week. It is, as you might realize, a rather monumental task (proofreading Crislip, not doing all those other things). :-)

  6. Jay Gordon says:

    I read Leaf’s article as I was falling asleep last night. It’s soporific nature was helpful.
    Your post is far better. Thanks.

  7. Carl says:

    Among the few who benefited from Avastin, exactly how much better did they do compared to normal variation?

    1. Barbara says:

      Our Oncology unit participated in the Avastin in glioblastoma study (AvaGlio). We enrolled 12 patient of which two did very well (still alive after 2+ years). Roche unblinded all patients in February 2013 and both patients were on placebo. Interestingly, one of the patients on this trial progressed after about 7 months of treatment. He ended up flying from New Zealand to Texas and received “treatment” from this Burzynski guy. Sadly, our patient spent the family’s life savings, came back to NZ and died a couple months later.

  8. Rork says:

    I don’t like folks calling highly stratified treatment designs “personalized”.
    Leave personalized to quacks please.

  9. TwistBarbie says:

    I would like to hear more about what happened to Dr. Gorski at Penn Jillette’s party if anyone has any info. I am going to Vegas in September, my boyfriend wants to see Penn & Teller but as I greatly admire Dr. Gorski, I’d rather not throw my $ in their direction if Mr. Jillette was particularly uncivil. The Oz appearance was bad enough :(

    1. mcrislip says:

      I am happy to gossip, it is what separates us from the chimps.

      Every year Penn Gillette has a concert to raise money for the JREF with his bacon and donut show. It is **not** sponsored by JREF or TAM. He pays for it all and gives the money to JREF. I have been before and it was fun. And I enjoy their stage show, having seen in three times in the last 25 years.

      Penn is explicit that not only is this not assoicated with the JREF, but a [private event]:

      “It’s my private party. In terms of manners, you’ve been invited to my home. If you don’t like me, don’t come to my party. This party is for my friends. Please respect that. We just want to have fun. I have no desire to offend anyone, at least not tonight. If you are here, I love and respect you. I don’t want to cause you any discomfort. So, if you aren’t just thrilled about being here, please leave — it’s Las Vegas and a nice hotel, there’s plenty of fun stuff for you to do. The second something offends you, just leave, it’s not going to get better. Just go away. We’ll talk another time. I take no offense with your avoiding my offensive party.
      Deal?
      But, if you walk through these doors, you have given your consent to enjoy all of the above. You’re at my party and I welcome you and love you with all the madness.”

      I am good with that. His ball, his rules. Works for me.

      There is a wee bit of irony in what follows since I am relying on my memory when I was tired, full of good food and wine and enjoying the music. I was not taking notes or the paying close attention I would if it were something I wanted commit to memory. I was having fun. So my memory of the events may be faulty; I am sure I will be corrected by others, or, even better, by the video. But as I remember it:

      Half way into the set Penn mentioned that Penn & Teller had been on the Dr. Oz show and the appearance had generated an open letter. He said several times that he did *not* read the open letter and would *not* read it. I was distinctly surprised by that admission. Evidently someone had told him about the open letter and that the author of the open letter had attended and enjoyed prior TAM bacon and donut shows.

      He then said something to the effect that if that ass hole is here today, he needs to leave now, he is not welcome, how dare that ass hole come to his living room, and once that the ass hole had left the room he said something about ‘suppressing my freedom of speech’ I did not quite catch and launched into a Dylanesqe song about the Oz show. I did not catch the words as I was explaining the back-story to my wife.

      The introduction to the song was a excellent antithesis of much the intellectual content promoted that day at TAM. I hope a video goes up on the YouTubes as it will be a powerful example covering many of the concepts in my talk and those at TAM. It is a much better example than the one star review of my Quackcast referred to in my last post, although the language may not be appropriate for most of my venues. It was also uber cringe-worthy. Not offensive at all, at least to me. But oh so cringe-worthy, like when an elderly relative cuts loose with an unexpected bigoted comment at Thanksgiving dinner and all you can do is, well, cringe. But his party, his rules, he can invite who he wants, do what he wants. Fine with me. It is not as if we were not warned:

      “Lots of new songs you don’t know, and at least one song attacking some ass hole who might be at the party. Fuck him.”

      But it was the audience response that got to me:
      Loud cheers, applause and hoots of approval over the ejection of a fellow conference attendee over an internet post Penn did not read after a day where a recurrent theme was the importance of facts and understanding of those facts. Irony central.

      Nothing like alcohol and rock to cancel critical thought and ignore the raison d’etre of a skeptics meeting.

      Deep, depressed sigh. We are doomed. Really. Not a chance in hell of success.

      1. BillyJoe says:

        Asshole alright. But I’m not talking about Gavid Gorski. Really, what a moron. And it being his own private party is no excuse whatsoever in my opinion. Friends like these we don’t need in the sceptical movement. What surprises me is that anyone actually stayed. There should have been a mass exodus and a boycott of future events.
        Still, I wasn’t there so there may have been reasons why people stayed. Let’s hope it was more than just a free feed and alcohol.

      2. windriven says:

        I am absolutely dumbfounded. Gilette didn’t read the letter, had no second, third or fourth thoughts about toadying on the Oz show, and uninvites the ‘asshole’ who had the temerity to notice said toadying from a party celebrating skepticism. The only possible partial explanation would be irritation that Gorski chose an open letter rather than a private communication; publicly humiliating them rather than expressing the concern directly. But then I don’t know if their prior relationship would have allowed that. In any event – totally inexcusable.

        “I am the great and powerful Penn, a force of nature unto myself. I am above question or reproach.” Huh. Should’ve been a politician.

      3. David Gorski says:

        The whole experience was surreal. There I was, chilling and (mostly) enjoying the show (no one would accuse Penn of being a particularly talented vocalist or bass player and he has a tendency to forget lyrics, but somehow it doesn’t matter much most of the time) when suddenly I heard him begin a tirade about some “asshole” who had written an open letter about Penn & Teller’s appearance with Dr. Oz. Only gradually did it dawn on me that it was about my open letter from February. Now, those of you who were actually there should reread the post and see if it deserved such a tirade. Note that I had a hard time believing Penn when he claimed he hadn’t read the open letter. It strains credulity quite a bit. Now, if I had only sent it to his publicist (which I did), then maybe I’d believe that Penn hadn’t read it, but a lot of people Tweeted it at him, which probably annoyed him. I can’t help but point out that he specifically mentioned that the open letter had said I had attended Penn’s last two Bacon & Doughnut parties, which led the the introduction of his rant, which was, as Mark pointed out, truly cringe-worthy. That total cringe-worthiness of Penn’s tirade is why I don’t think the rant or the song will ever appear on YouTube. The rant says far more about Penn than it says about me. However, if I’m wrong and it does ever appear on YouTube, I will likely post it.

        When Penn started yelling over and over, “If you’re here, whoever you are, get the fuck out of here!” and “How dare you come into my house and eat my bacon and doughnuts?” (which he did, or words to that effect), I was briefly tempted to identify myself but decided that it would serve no purpose. As Penn had repeatedly reminded me, it was “his house,” so to speak. Penn paid for the party and controlled the stage and the microphone. Besides, he is also much better at being a belligerent blowhard than I could ever imagine being; I just thought I’d never be at the receiving end of one of his rants, even anonymously. I might have identified myself, but hearing the crowd cheer at Penn’s little tirade put a rather fast halt to any temptation that I might have had to do so. So I just left, which means I didn’t hear the song, other than that someone told me the next day that Penn finished by singing something to the effect of “fuck you in the neck.” (Again, stay classy, Penn. Stay classy.) Besides, as they say, when you wrestle with a pig in mud, all that happens is that you get dirty and the pig likes it.

        I can say that the next day lots of people came up to me and asked if that was about me. (Penn didn’t use my name, but regular SBM readers, of which there were a fair number in the crowd, knew whom Penn had been talking about.) They also expressed how appalled they were about what had happened. Whether they expressed it to DJ or anyone in charge I don’t know, although I doubt it would have done any good since Penn’s party is not an “official” TAM event. In any case, Penn’s little blow up was actually the talk of TAM on Saturday, which was just the sort of distraction I needed to help me to do my best for my talk that afternoon.

        If I can get a copy of the lyrics of the song, I might blog about it, but, on the other hand, at this point I’m not sure if doing that would serve any purpose. Maybe a second “open letter” to Penn. At the very least it would give me a shot at repeating my infamy at next year’s TAM if Penn’s memory is sufficiently long that he writes another song about it.

        Oh, well. My former opinion of Penn has been declining ever since I learned about his AGW denialism a few years ago. This just seals it. As I told several of the well-wishers who asked me about it the next day, when it happened on Friday night I was puzzled, confused, and angry. By Saturday, I had settled into being amused by the whole thing. As of today (Tuesday), I remain amused and bemused, but I also now consider it a bit of a badge of honor to have been singled out for such a rant. It means my open letter was noticed and hit home. It also makes me think that perhaps Penn will think twice before doing something similar again. (Or maybe he won’t.)

        I do wonder, though: Does Penn knows that I helped his producer with his research for the Bullshit! episode about the antivaccine movement? Yes, in my own small way I helped Penn’s crew put that show together and did it willingly and enthusiastically. :-)

        1. Triple Bee says:

          These lyrics?
          Song Title: Dave Dave

          I won’t call you cocksucker, my girlfriends all are that

          And I won’t call you, faggot, ‘cause my best friend frosts his bat

          And I won’t call you bastard, ‘cause my mentor’s folks weren’t wed

          But, we all stay awake at night and wish that you were dead

          And I won’t call you asshole, ‘cause I’ve licked and fucked my share

          There’s no way you could be a cunt, ‘cause our lives all came from there

          You sure ain’t no motherfucker, that would be my Dad

          And you ain’t no son of of mother fucking bitch, your Mom couldn’t be that bad

          So, I’ll just call you Dave, Dave

          Dave, through and though, Dave

          We all like to fuck, Dave

          But, not with you . . . Dave!

          I won’t wish you to be goddamned, ‘cause there ain’t no god to damn

          And I won’t say to go to hell, the whole thing’s a stupid scam

          I won’t call you a little-bitty shit, ‘cause shit sure has it’s place

          And I won’t call you pussy fart, ‘cause I like those on my face

          And I won’t call you retard, ‘cause I liked “Life Goes On”

          And schmuck and putz are too Hebrew and I can’t read the fucking Koran

          You ain’t sure no motherfucker, that would be my Dad

          And you ain’t no son of mother fucking bitch, your Mom couldn’t be that bad

          So, I’ll just call you Dave, Dave

          Dave, through and though, Dave

          We all like to fuck, Dave

          But, not with you . . . Dave!

          1. David Gorski says:

            Wrong song, I’m pretty sure. He did that song last year, although I suppose it’s possible he might have repurposed it. Several people told me that, and I vaguely remember the song. He also did “Dave, Dave” right after that song. The song he did was apparently, as Mark said, a Dylanesque number; that is, if you can call anything Penn sings or writes “Dylanesque.” :-)

            The No God Band actually did a number of the songs listed on the 2013 set list last year too, for instance “Thorazine Shuffle,” “Clothes of the Dead,” “Gas Station Men’s Room,” and “Fuck You, You’re an Atheist.” Ditto “Dave, Dave.” The song he did about Dr. Oz and me is not listed on his current set list.

        2. Triple Bee says:

          In case that last one doesn’t make it through moderation – are these the lyrics you’re looking for?

          http://nogodband.99k.org/NoGodBand.com/Dave_Dave.html

      4. Carl says:

        Yeah, I thought he wouldn’t like that “open letter” business. If you want to write a letter to someone, you should actually write them a letter. Don’t write a blog post and cc their publicist. And if you are not in a position to write a letter to them, just blog about it and don’t pretend with this weird fake buddy business.

        It was a waste of an attempt to straighten him out about Oz (a subject which wasn’t even addressed until Gorski rehashed his “don’t say you don’t know” policy). What are the odds that Penn has any idea what exactly he did wrong with Oz? Maybe the whiny song will tell.

        I don’t know why Gorski went. With the previous disagreement on whether or not an ignorant guy ought to run his mouth, I wouldn’t guess that Gorski and Jillette would like each other at all.

        It is pretty sad because my hope these past several months has been that Penn would eventually realize how dumb the Oz appearance was and possibly bury it. But definitely not hold on and dig deeper.

        1. David Gorski says:

          Open letters are a common technique to try to get a celebrity’s attention, and I certainly didn’t write as though I were Penn’s friend. I’ve spoken to the guy on maybe two or three occasions, if that, and then only briefly, as in, “great show” or “it’s an honor to meet you.” In fact, one reason for an “open letter” was because I’m not Penn’s friend or acquaintance. If I were his friend I wouldn’t have written an open letter. I would have called him or e-mailed him and asked him what the heck he was doing. In any case, it’s also not as though I was trashing Penn in the letter; the overall tone was more of disappointment that apparently P&T want to have it both ways. The want to be seen as skeptics, but they also want to be able to use the excuse that they’re “just entertainers” to excuse appearing on a show that has promoted huge quantities of quackery over the last couple of years, namely Dr. Oz. They can be one or the other, but not both, at least not credibly, and Penn’s justifications on Twitter are at best disingenuous, for example, this response to a recent question about why P&T went on The Dr. Oz Show:

          That’s a rather enormous flaming straw man. No one has ever said that Penn should only go on shows where he agrees with everything that’s ever been done on the show or that P&T’s performance wasn’t honest, only that Penn should not lend his considerable skeptical cachet to a show that so blatantly promotes such copious quantities of quackery and unreason, you know, the very things that Penn claims to stand so firmly against.

          As for why I went, even though I did read the intro described by Mark, for some reason the bit about the song about an “asshole” who might attend didn’t register. Certainly, it didn’t even occur to me at all that Penn was referring to me. Quite frankly, I didn’t think I was anywhere near the level where Penn might notice or even care much (if at all) about what I said. It really didn’t. It was just inconceivable to me (word choice intentional, you Princess Bride fans). After his dismissal on Twitter of the open letter, I assumed that Penn would just forget about it because he would view me as too insignificant for him even to bother with.

          I suppose in a perverse way, it is good to be mistaken in my self-perceived insignificance. If I go to TAM next year (which I probably will, assuming I do the SBM workshop and/or a panel or talk again), I might introduce myself to Penn if he’s there. Maybe a year’s time will settle him down.

    2. David Gorski says:

      @TwistBarbie:

      You could always go anyway and then ask Penn about it after the show. He and Penn always hang out in the lobby after the show to mingle and have pictures taken with audience members. One doubts that he would be as—shall we say?—vociferous about responding in front of his paying customers. :-)

      1. TwistBarbie says:

        Thank you everyone for your enlightening replies! I did think about attempting to ask Mr. Jillette about it personally at the post show mingle, but frankly, it’s my first trip to Vegas and my first real vacation with my boyfriend and I’d prefer not to make myself the target of any unnecessary unpleasantness. I wish I could separate the man from his opinions and just enjoy the show but I don’t think I could enjoy it knowing all of what you have told me. I did read the open letter (I’ve been lurking for at least a year) and it was frank and diplomatic in my opinion. Hard to believe a grown man would have such a tantrum over it. Once again, thank you so much for your replies, I think I’ll just see Blue Man Group instead :D

        1. WilliamLawrenceUtridge says:

          See the Blue Man Group. If you’ve got a choice between the two, if you can only do one anyway, TBMG is waaaayyyy better. They’ve got audience participation. I’ve never seen my wife fist-pump until that show. It is so much unbelievable fun, even if P&T was a skeptical miracle that invited Dr. Gorski, and all the SBM editors on stage and filled their pockets with gold bricks, I would still say see the Blue Man Group.

          No offence, Drs.

  10. MadisonMD says:

    I-SPY2 is the biostatistical-clinical trialist solution to the problem of matching drugs and biomarkers–but there are a lot of: (a) assumptions, (b) confounders, (c) complications:
    (a) -drugs will synergise or have additive effects with paclitaxel combination
    -12 weeks of therapy is sufficient to see effect
    -the a priori selected biomarkers are useful biomarkers to select drugs.
    -MRI response is adequate surrogate for effect on micrometastases.
    (b) -Taxol response is itself highly variable without established predictive marker (I’m not aware of evidence that p53 works)
    -ditto for AC response if endpt is pathologic response or disease free survival
    (c) -requisite phase I safety evaluation for each combination
    -multiple IRB amendments and consent form changes for each drug change in the study (OK maybe we need to change the system)
    -delay to start chemotherapy for weeks for initial biomarker (gene expr?) analysis
    Cool idea and kudos to Berry and Esserman for the novelty. But biomarkers are best discovered in the lab through mechanistic transitional research and then applied and tested in clinical trials. This could be efficient if we actually did the lab work well…

  11. WilliamLawrenceUtridge says:

    @TwistedBarbie

    I’ve seen P&T live. It’s an amusing show. They do good stage magic. You could see it as paying them for the parts of their talents that you value (entertainment) while refusing to endorse the parts you don’t (Penn specifically’s selective grasp and criticism of science and pseudoscience). Or, you could watch their stuff on YouTube.

    Sadly, no leader or spokesperson, self-selected or otherwise, are perfect. There will always be blind spots, pet theories, abrasive personalities and behaviours (I’m looking at you, WLU, you big potty-mouth) and it’s unrealistic to ask for or demand perfection from our leaders. I was disappointed by Dawkins’ response to Elevatorgate, while simultaneously enjoying his books on evolution and criticisms of creationism. I like Pete Moran’s cancer quackery site, I think I’ve read everything on it, while finding his double-standard for other types of quackery to be incredibly frustrating and counter-intuitive.

    We can’t ask perfection of people. On the other hand, you might be able to nag them into it. If enough people talk to Penn after the show about the issue, he might change his mind. He might pull a Randi (James Randi was a climate change skeptic but eventually and publicly announced, belatedly, that he had been convinced). Or he might marginalize himself even more, to the point that people begin to publicly and pointedly ignore or exclude him.

    It’s gotta be hard when you’re in the entertainment industry and constantly surrounded by people who are willing and paid to tell you how brilliant you are.

    In this, like so many things, Dara O’Briain has a point – anyone saying there are easy, bullshit answers, is wrong. Of course he was talking about the great questions in life, not delightful gossip.

    1. TwistBarbie says:

      Thank you WLU (am I being presumptuous by calling you that when I’m new?) I see your point, but I greatly admire Dr. Gorski, and I honestly would sit through the show seething and thinking angry thoughts after reading about the whole incident. It would be different if he was just some celebrity that had a different view on something than I have, but the immaturity and viciousness he apparently displayed really puts me off.

      1. BillyJoe says:

        Each to his own but, to me, he’s always been this big ugly guy with a big ugly mouth and so, I assumed, a big ugly mind. Let’s just say I’m much less surprised than most at this turn of events. He deserves a big backlash from the sceptical community, but I doubt he’ll get it. Which is part of the reason I’m not actually part of the sceptical community. Pun intended…they put up with too much bv||$#!+

        1. Pareidolius says:

          He won’t be rebuked by anyone in any skeptical organizations because he has really deep pockets and most people’s integrity crumbles before the Benjamins . . .

      2. windriven says:

        @TwistBarbie

        OK, Penn Jillette has feet of clay. That isn’t unusual.

        You said: “but the immaturity and viciousness he apparently displayed really puts me off.”

        But here’s the thing; if Dr. Gorski hadn’t hit a nerve we’d have never heard a thing about it. You’ll note that his rant did not, apparently, suggest that Gorski was wrong or that the Oz appearance was really a great idea. What he said, translated from testosterese, was: “Gorski, you asshole, you made me look like a schmuck in front of a bunch of people I really wanted to impress. No whiskey and clam dip for you. I’m not gonna play with you any more.”

        Puerile? Manifestly. But his magic still works and his humor is what it has always been. If you don’t go it is going to piss off your friend but it isn’t going to bother Jillette one bit.

      3. WilliamLawrenceUtridge says:

        I don’t stand on ceremony, “Mr. Utridge” will be fine.

        I find Penn’s immaturity and viciousness amusing, when pointed at quacks. It sounds like you wouldn’t enjoy his show because you would be too busy thinking about what a hypocrite he is – in which case why not take advantage of the multitude of other offerings in Vegas? When I was there, there were no less than five Cirque Du Soleil shows on, and the one I saw was excellent. The Blue Man Group is another great one, easily as funny as P&T. And, the are mute so they can’t offend you by saying something stupid. Plus, the P&T show I saw was all stage magic – unless you really like stage magic, why go? P&T didn’t do any skepticism-related stuff when we were there anyway.

        Or, just get blotto-drunk and wander the strip. Vegas is terrible when sober, but I bet it’s awesome when hammered. Make your own entertainment!

        1. David Gorski says:

          Only in the winter. Being blotto when it’s 105° out is not so cool. In that case, you have to pick a casino and stick with it, because going outside is brutal, even at night, when it’s often still over 90°.

        2. windriven says:

          ““Mr. Utridge” will be fine.”

          Oh, you are so begging for Billy!

          1. WilliamLawrenceUtridge says:

            In which cases, it will be one of the few situations where the universe is just and I get exactly what I deserve. Sadly, too often people let me get away with being a douche.

          2. windriven says:

            @WLU

            You and I really need to share a pint someday – sort of a dueling douches moment. Sadly, I rarely get to Ontario anymore (though I had a wife from there once upon a time). But if I find myself headed your way…

          3. WilliamLawrenceUtridge says:

            Ha, the last time I had a pint, it was nonalcoholic and only drunk to justify being present in a bar at all. I’m more of a dessert fellow/douche.

  12. Carl says:

    Well, first off I don’t want any of this to sound like a reasonable justification for how sh#tty he was to you. That was absolutely embarrassingly crude, even with the preemptive notice on the website. I am certain that I read that page this year, and I don’t recall thinking that it referred to you. But then I re-read it now, and woah boy!

    That said, I still disagree on the open letter. Yes, they are sometimes used as either somewhat respectful or just last-ditch attempts at contacting someone famous (though you seem not to have expected him to notice). But they are also sometimes used as a way of just bitching openly about someone while offering false “concern” as an excuse. I sure as hell wouldn’t write one, and there’s a lot of stuff I don’t seem to have a problem doing on the Internet. Heck, I’d call you an asshole to your face (assuming I haven’t already) before I wrote something and called it an open letter, but maybe I can’t really explain why. All I know is that when I saw that post, I thought “Is he TRYING to look like a nut?”

    I didn’t see it so much as a matter of the media of communication, but the phrasing. I don’t think you need to be a “friend” to try to call someone directly. As you said, you worked on one of his shows. Furthermore, Novella was actually in an episode (may have been two). I might be suffering from the delusion that all famous people sleep in the same giant bed while wearing striped pajamas and pom-pom hats, but I kind of imagined you might have been able to make use of whatever connections you had from that and say, “I’m a real doctor who worked on one of your shows, and that Oz thing looked like a scientific disaster. I’d like to explain why.” Instead, Penn the Unscientific wakes up and hears rumors about some guy on the Internet griping about him while also declaring that he intends to go to a party. If you had a practical interest in curbing nonsense, it wasn’t effective and I am not totally surprised by that even if I didn’t expect such dickishness on his part.

    1. David Gorski says:

      Well, first off I don’t want any of this to sound like a reasonable justification for how sh#tty he was to you.

      But it sure does sound at least a little like such a justification to me, particularly after the disclaimer saying that you don’t mean it as a justification. (Such disclaimers virtually always make me think more that you are doing exactly what you’re saying you’re not doing, even if you’re actually not doing it. If that makes sense.) Your whole complaint basically comes across as, “Well, what did you expect?” (My answer: Nothing specific, really. Maybe an answer, but I doubted I’d get that.) Or it came across as your saying I brought this on myself. I get it. You don’t like open letters. I think they’re appropriate sometimes and still do. Time for me to move on.

      Look, it’s not a big deal. It really isn’t. If there’s a similar warning next year, I simply won’t go to the party. If there isn’t, I might or might not go, depending on what my friends do, with the understanding that I might have to leave.

      1. Chris says:

        The ten minutes I spent at that party during TAM 9 was all I needed. It is not my kind of scene, and not just because I am old. I used to tell my dad to turn down his stereo.

        Also, I am not going to indulge in bacon and donuts. I like bacon on a sandwich once in a while, but I do have a genetic type of high cholesterol. Even though my HDL is in the 70s, I just try to limit bacon. At least so I can have more cheese. ;-)

        And, Carl, this system has one consistent problem: each and everyone of my comments go into moderation. It is something I have been told they are working on.

  13. Carl says:

    Also, this new website has once again failed to add my post in the proper hierarchy.

    1. David Gorski says:

      How so? I can report it to our WordPress guy.

      1. Carl says:

        I clicked the reply link under your post, but it adds my reply all the ay at the end/left of the comments as though I replied to nobody in particular instead of adding it stepped in directly under yours. Sometimes it works, sometimes it doesn’t.

  14. Carl says:

    I totally didn’t mean it like that, but I accept your interpretation. Good luck next year.

  15. Andrew says:

    Well I think clinical trials do work but the question is the effectiveness, some fail but I’m sure they didn’t do it on purpose right?

    1. WilliamLawrenceUtridge says:

      I’m not surprised you think clinical trials work, the website linked in your comment seems to be a for-profit site designed to recruit for clinical trials. Have you read Ben Goldacre’s Bad Pharma?

  16. Marten says:

    I think clinical trials “work” very good when it comes to large studies. However, when it comes to smaller studies for very rare diseases there’s usually not money enough to run these trials. Unfortunately, clinical trials and their outcome are highly dependent upon lots of money.

    Smaller promising start up biotech companies are having an even tougher time today…

    1. WilliamLawrenceUtridge says:

      Jebus, another clinical trial recruitment company.

      The failure of small clinical trials may also reflect that we simply lack an effective treatment for rare diseases. Small trials are perfectly serviceable in the face of powerful effects, but not all diseases are like scurvy, responding dramatically and quickly to a simple, single-factor treatment. When you’re talking incremental gains, it’s going to be a lot harder to demonstrate any sort of meaningful effect.

      1. Marten says:

        Well, my point was that no company would ever pay for clinical studies to test drugs for these rare diseases. Beacause if there aren’t patients enough to treat, the earning potential is not big enough.

        NNT for some very common diseases are in fact ridculously high, but since there’s such a great number of patients within e.g. the cardiovascular area, the earning potential is there anyway.

        It has nothing to do with “effective treatment” or not.

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