"Guinea Pigs" on CBS is Going to be Super Great, I Can Just Tell

An open letter to Mad Men producer/writer Dahvi Waller

Dear Dahvi,

I just wanted to drop you a quick note of congratulations when I heard through the grapevine that CBS has signed you on to do a pilot episode of your new medical drama, Guinea Pigs (well actually, I heard it from the Hollywood Reporter; the grapevine doesn’t tell me squat). According to the news item,

The drama centers on group of trailblazing doctors who run clinical trials at a hospital in Philadelphia. The twist: The trials are risky, and the guinea pigs are human.

Probably just like this, but
with a bigger body count.

(Sidenote: that’s quite the twist there! For a minute, I thought this was going to be the first ever rodent-based prime time series!)

I don’t want to take up too much of your time. I’m sure you’re extremely busy with lots of critical casting decisions, like: will the Evil Big Pharma character be a blonde, beautiful-but-treacherous Ice Queen type in her early 30’s, or an expensively-suited, handsome-but-treacherous Gordon Gekko type in his early 60’s? (My advice: Don’t settle!  Use both! Viewers of all ages can love to hate the pharmaceutical industry!)

About that name, by the way: great choice! I’m really glad you didn’t overthink that one. A good writer should go with her gut and pick the first easy stereotype that pops into her head. (Because the head is never closer to the gut then when it’s jammed firmly up … but I don’t have to explain anatomy to you! You write a medical drama for television!)

I’m sure the couple-three million Americans who enroll in clinical trials each year will totally relate to your calling them guinea pigs. In our industry, we call them heroes, but that’s just corny, right? Real heroes on TV are people with magic powers, not people who contribute to the advancement of medicine.

Anyway, I’m just really excited because our industry is just so, well … boring! We’re so fixated on data collection regulations and safety monitoring and ethics committee reviews and yada yada yada – ugh! Did you know we waste 5 to 10 years on this stuff, painstakingly bringing drugs through multiple graduated phases of testing in order to produce a mountain of data (sometimes running over 100,000 pages long) for the FDA to review?

Dahvi Waller: bringing CSI
to clinical research

I’m sure you’ll be giving us the full CSI-meets-Constant-Gardener treatment, though, and it will all seem so incredibly easy that your viewers will wonder what the hell is taking us so long to make these great new medicines. (Good mid-season plot point: we have the cure for most diseases already, but they’ve been suppressed by a massive conspiracy of sleazy corporations, corrupt politicians, and inept bureaucrats!)

Anyway, best of luck to you! I can't wait to see how accurately and respectfully you treat the work of the research biologists and chemists, physician investigators, nurses, study coordinators, monitors, reviewers, auditors, and patient volunteers guinea pigs who are working hard to ensure the next generation of medicines are safe and effective.  What can go wrong? It's television!

The Case against Randomized Trials is, Fittingly, Anecdotal

I have a lot of respect for Eric Topol, and am a huge fan of his ongoing work to bring new mobile technology to benefit patients.

The Trial of the Future

However, I am simply baffled by this short video he recently posted on his Medscape blog. In it, he argues against the continued use of randomized controlled trials (RCTs) to provide evidence for or against new drugs.

His argument for this is two anecdotes: one negative, one positive. The negative anecdote is about the recently approved drug for melanoma, Zelboraf:

Well, that's great if one can do [RCTs], but often we're talking about needing thousands, if not tens of thousands, of patients for these types of clinical trials. And things are changing so fast with respect to medicine and, for example, genomically guided interventions that it's going to become increasingly difficult to justify these very large clinical trials. 

For example, there was a drug trial for melanoma and the mutation of BRAF, which is the gene that is found in about 60% of people with malignant melanoma. When that trial was done, there was a placebo control, and there was a big ethical charge asking whether it is justifiable to have a body count. This was a matched drug for the biology underpinning metastatic melanoma, which is essentially a fatal condition within 1 year, and researchers were giving some individuals a placebo.

First and foremost, this is simply factually incorrect on a couple extremely important points.

1. Zelboraf was not approved based on any placebo-controlled trials. The phase 1 and phase 2 trials were both single-arm, open label studies. The only phase 3 trial run before FDA approval used dacarbazine in the comparator arm. In fact, of the 34 trials currently listed for Zelboraf on ClinicalTrials.gov, only one has a placebo control: it’s an adjuvant trial for patients whose melanoma has been completely resected, where no treatment may very well be the best option.
2. The Zelboraf trials are not an example of “needing thousands, if not tens of thousands, of patients” for approval. The phase 3 trial enrolled 675 patients. Even adding the phase 1 and 2 trials doesn’t get us to 1000 patients.

Correcting these details take a lot away from the power of this single drug to be a good example of why we should stop using “the sanctimonious [sic] randomized, placebo-controlled clinical trial”.

The second anecdote is about a novel Alzheimer’s Disease candidate:

A remarkable example of a trial of the future was announced in May. For this trial, the National Institutes of Health is working with [Banner Alzheimer's Institute] in Arizona, the University of Antioquia in Colombia, and Genentech to have a specific mutation studied in a large extended family living in the country of Colombia in South America. There is a family of 8000 individuals who have the so-called Paisa mutation, a presenilin gene mutation, which results in every member of this family developing dementia in their 40s. 

Researchers will be testing a drug that binds amyloid, a monoclonal antibody, in just 300 family members. They're not following these patients out to the point of where they get dementia. Instead, they are using surrogate markers to see whether or not the process of developing Alzheimer's can be blocked using this drug. This is an exciting way in which we can study treatments that can potentially prevent Alzheimer's in a very well-demarcated, very restricted population with a genetic defect, and then branch out to a much broader population of people who are at risk for Alzheimer's. These are the types of trials of the future. 

There are some additional disturbing factual errors here – the extended family numbers about 5,000, not 8,000. And estimates of the prevalence of the mutation within that family appear to vary from about one-third to one-half, so it’s simply wrong to state that “every member of this family” will develop dementia.

However, those errors are relatively minor, and are completely overshadowed by the massive irony that this is a randomized, placebo-controlled trial. Only 100 of the 300 trial participants will receive the active study drug, crenezumab. The other 200 will be on placebo.

And so, the “trial of the future” held up as a way to get us out of using randomized, placebo-controlled trials is actually a randomized, placebo-controlled trial itself. I hope you can understand why I’m completely baffled that Topol thinks this is evidence of anything.

Finally, I have to ask: how is this the trial of the future, anyway? It is a short-term study on a highly-selected patient population with a specific genetic profile, measuring surrogate markers to provide proof of concept for later, larger studies. Is it just me, or does that sound exactly like the early lovastatin trials of the mid-1980’s, which tested cholesterol reduction in a small population of patients with severe heterozygous familial hypercholesterolemia? Back to the Future, indeed.


[Image: time-travelling supercar courtesy of Flickr user JoshBerglund19.]

Clinical Trial Alerts: Nuisance or Annoyance?

Will physicians change their answers when tired of alerts?

I am an enormous fan of electronic health records (EMRs).  Or rather, more precisely, I am an enormous fan of what EMRs will someday become – current versions tend to leave a lot to be desired. Reaction to these systems among physicians I’ve spoken with has generally ranged from "annoying" to "*$%#^ annoying", and my experience does not seem to be at all unique.

The (eventual) promise of EMRs in identifying eligible clinical trial participants is twofold:

First, we should be able to query existing patient data to identify a set of patients who closely match the inclusion and exclusion criteria for a given clinical trial. In reality, however, many EMRs are not easy to query, and the data inside them isn’t as well-structured as you might think. (The phenomenon of "shovelware" – masses of paper records scanned and dumped into the system as quickly and cheaply as possible – has been greatly exacerbated by governments providing financial incentives for the immediate adoption of EMRs.)

Second, we should be able to identify potential patients when they’re physically at the clinic for a visit, which is really the best possible moment. Hence the Clinical Trial Alert (CTA): a pop-up or other notification within the EMR that the patient may be eligible for a trial. The major issue with CTAs is the annoyance factor – physicians tend to feel that they disrupt their natural clinical routine, making each patient visit less efficient. Multiple alerts per patient can be especially frustrating, resulting in "alert overload".

A very intriguing study recently in the Journal of the American Medical Informatics Association looked to measure a related issue: alert fatigue, or the tendency for CTAs to lose their effectiveness over time.  The response rate to the alerts definitely decreased steadily over time, but the authors were mildly optimistic in their assessment, noting that response rate was still respectable after 36 weeks – somewhere around 30%:

However, what really struck me here is that the referral rate – the rate at which the alert was triggered to bring in a research coordinator – dropped much more precipitously than the response rate:

This is remarkable considering that the alert consisted of only two yes/no questions. Answering either question was considered a "response", and answering "yes" to both questions was considered a "referral".

• Did the patient have a stroke/TIA in the last 6 months?
• Is the patient willing to undergo further screening with the research coordinator?

The only plausible explanation for referrals to drop faster than responses is that repeated exposure to the CTA lead the physicians to more frequently mark the patients as unwilling to participate. (This was not actual patient fatigue: the few patients who were the subject of multiple CTAs had their second alert removed from the analysis.)

So, it appears that some physicians remained nominally compliant with the system, but avoided the extra work involved in discussing a clinical trial option by simply marking the patient as uninterested. This has some interesting implications for how we track physician interaction with EMRs and CTAs, as basic compliance metrics may be undermined by users tending towards a path of least resistance.

Embi PJ, & Leonard AC (2012). Evaluating alert fatigue over time to EHR-based clinical trial alerts: findings from a randomized controlled study. Journal of the American Medical Informatics Association : JAMIA, 19 (e1) PMID: 22534081

Most* Clinical Trials Are Too** Small

* for some value of "most"
** for some value of "too"

[Note: this is a companion to a previous post, Clouding the Debate on Clinical Trials: Pediatric Edition.]

Are many current clinical trials underpowered? That is, will they not enroll enough patients to adequately answer the research question they were designed to answer? Are we wasting time and money – and even worse, the time and effort of researchers and patient-volunteers – by conducting research that is essentially doomed to produce clinically useless results?

That is the alarming upshot of the coverage on a recent study published in the Journal of the American Medical Association. This Duke Medicine News article was the most damning in its denunciation of the current state of clinical research:

Duke: Mega-Trial experts concerned
that not enough trials are mega-trials

Large-Scale Analysis Finds Majority of Clinical Trials Don't Provide Meaningful Evidence

The largest comprehensive analysis of ClinicalTrials.gov finds that clinical trials are falling short of producing high-quality evidence needed to guide medical decision-making.

The study was also was also covered in many industry publications, as well as the mainstream news. Those stories were less sweeping in their indictment of the "clinical trial enterprise", but carried the same main theme: that an "analysis" had determined that most current clinical trial were "too small".

I have only one quibble with this coverage: the study in question didn’t demonstrate any of these points. At all.

The study is a simple listing of gross characteristics of interventional trials registered over a 6 year period. It is entirely descriptive, and limits itself entirely to data entered by the trial sponsor as part of the registration on ClinicalTrials.gov. It contains no information on the quality of the trials themselves.

That last part can’t be emphasized enough: the study contains no quality benchmarks. No analysis of trial design. No benchmarking of the completeness or accuracy of the data collected. No assessment of the clinical utility of the evidence produced. Nothing like that at all.

So, the question that nags at me is: how did we get from A to B? How did this mildly-interesting-and-entirely-descriptive data listing transform into a wholesale (and entirely inaccurate) denunciation of clinical research?

For starters, the JAMA authors divide registered trials into 3 enrollment groups: 1-100, 101-1000, and >1000. I suppose this is fine, although it should be noted that it is entirely arbitrary – there is no particular reason to divide things up this way, except perhaps a fondness for neat round numbers.

Trials within the first group are then labeled "small". No effort is made to explain why 100 patients represents a clinically important break point, but the authors feel confident to conclude that clinical research is "dominated by small clinical trials", because 62% of registered trials fit into this newly-invented category. From there, all you need is a completely vague yet ominous quote from the lead author. As US News put it:

The new report says 62 percent of the trials from 2007-2010 were small, with 100 or fewer participants. Only 4 percent had more than 1,000 participants.

"There are 330 new clinical trials being registered every week, and a number of them are very small and probably not as high quality as they could be," [lead author Dr Robert] Califf said.

"Probably not as high quality as they could be", while just vague enough to be unfalsifiable, is also not at all a consequence of the data as reported. So, through a chain of arbitrary decisions and innuendo, "less than 100" becomes "small" becomes "too small" becomes "of low quality".

Califf’s institution, Duke, appears to be particularly guilty of driving this evidence-free overinterpretation of the data, as seen in the sensationalistic headline and lede quoted above. However, it’s clear that Califf himself is blurring the distinction between what his study showed and what it didn’t:

"Analysis of the entire portfolio will enable the many entities in the clinical trials enterprise to examine their practices in comparison with others," says Califf. "For example, 96 percent of clinical trials have ≤1000 participants, and 62 percent have ≤ 100. While there are many excellent small clinical trials, these studies will not be able to inform patients, doctors, and consumers about the choices they must make to prevent and treat disease."

Maybe he’s right that these small studies will not be able to inform patients and doctors, but his study has provided absolutely no support for that statement.

When we build a protocol, there are actually only 3 major factors that go into determining how many patients we want to enroll:

1. How big a difference we estimate the intervention will have compared to a control (the effect size)
2. How much risk we’ll accept that we’ll get a false-positive (alpha) or false-negative (beta) result
3. Occasionally, whether we need to add participants to better characterize safety and tolerability (as is frequently, and quite reasonably, requested by FDA and other regulators)

Quantity is not quality: enrolling too many participants in an investigational trial is unethical and a waste of resources. If the numbers determine that we should randomize 80 patients, it would make absolutely no sense to randomize 21 more so that the trial is no longer "too small". Those 21 participants could be enrolled in another trial, to answer another worthwhile question.

So the answer to "how big should a trial be?" is "exactly as big as it needs to be." Taking descriptive statistics and applying normative categories to them is unhelpful, and does not make for better research policy.


Califf RM, Zarin DA, Kramer JM, Sherman RE, Aberle LH, & Tasneem A (2012). Characteristics of clinical trials registered in ClinicalTrials.gov, 2007-2010. JAMA : the journal of the American Medical Association, 307 (17), 1838-47 PMID: 22550198

Testing Transparency with the TEST Act

A quick update on my last post regarding the enormously controversial -- but completely unmentioned -- requirement to publicly report all versions of clinical trial protocols on ClinicalTrials.gov: The New England Journal of Medicine has weighed in with an editorial strongly in support of the TEST Act. 

NEJM Editor-in-Chief Jeffrey Drazen at least mentions the supporting documents requirement, but only in part of one sentence, where he confusingly refers to the act "extending results reporting to include the deposition of consent and protocol documents approved by institutional review boards." The word "deposition" does not suggest actual publication, which the act clearly requires. 

I don't think this qualifies as an improvement in transparency about the impact the TEST Act, as written, would have. I'm not surprised when a trade publication like Center Watch recycles a press release into a news item. However, it wouldn't seem like too much to ask that NEJM editorials aspire to a moderately higher standard of critical inquiry.

Public Protocols? Burying the lede on the TEST Act

Not to be confused with the Test Act.
(via Luminarium)

4 Democratic members of Congress recently co-sponsored the TEST (Trial and Experimental Studies Transparency) Act, which is intended to expand the scope of mandatory registration of clinical trials. Coverage so far has been light, and mainly consists of uncritical recycling of the press release put out by congressman Markey’s office.

Which is unfortunate, because nowhere in that release is there a single mention of the bill’s most controversial feature: publication of clinical trial "supporting documents", including the patient’s Informed Consent Form (ICF) and, incredibly, the entire protocol (including any and all subsequent amendments to the protocol).

How Rep. Markey and colleagues managed to put out a 1,000-word press release without mentioning this detail is nothing short of remarkable. Is the intent to try to sneak this through?

Full public posting of every clinical trial protocol would represent an enormous shift in how R&D is conducted in this country (and, therefore, in the entire world). It would radically alter the dynamics of how pharmaceutical companies operate by ripping out a giant chunk of every company’s proprietary investment – essentially, confiscating and nationalizing their intellectual property. 

Maybe, ultimately, that would be a good thing.  But that’s by no means clear ... and quite likely not true. Either way, however, this is not the kind of thing you bury in legislation and hope no one notices.

[Full text of the bill is here (PDF).]

[UPDATE May 17, 2013: Apparently, the irony of not being transparent with the contents of your transparency law was just too delicious to pass up, as Markey and his co-sponsors reintroduced the bill yesterday. Once again, the updated press release makes no mention of the protocol requirement.]