Monday, August 13, 2012

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 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 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, 2007-2010. JAMA : the journal of the American Medical Association, 307 (17), 1838-47 PMID: 22550198

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