Thursday, October 4, 2012

Missing Reports: Research Biopsy in Cancer Trials

A growing number of drug trials are collecting tissue to determine whether the drug hits its molecular target.  These studies are called “pharmacodynamics.”  And in cancer, many pharmacodynamics studies involve collection of tumor tissue through biopsies.  These procedures are painful, and are performed solely to answer scientific questions.  That is, they generally have no diagnostic or clinical value.  As such, some commentators worry about their ethics.

In a recent issue of Clinical Cancer Research, my Master’s student Gina Freeman and I report on publication practices for pharmacodynamics studies involving tumor biopsy.  The basic idea is this: the ethical justification for such invasive research procedures rests on a claim that they are scientifically valuable.  However, if they are never published, it is harder to argue that they have a sound scientific justification.  So we set out to determine how frequently results are published, and reasons why some results are never reported. Briefly, we found that a third of promised analyses are not published- which is more or less in line with the frequency of nonpublication for trials in general.  We also find that researchers who perform pharmacodynamics studies regard reporting quality as fair to poor, and many perceive the most common reason for nonpublication to be “strategic considerations” (as in: result does not fit the narrative of the overall trial).

Does our article support a definitive statement about the ethics of research biopsy in cancer trials?  No.  But it does point to a number of ways that the ethical justification can be strengthened- and questions clinical investigators and ethics boards should be asking when designing and/or reviewing protocols involving research biopsy. (graphic: cole007 2011)

Monday, August 20, 2012

Targeted Cancer Drugs: The "Price of Progress"?

So here is the party line on the newest generation of cancer drugs.  Unlike older generation drugs, which are generalized poisons, newer cancer drugs hone in on very specific molecular targets.  Because of this specificity, they have fewer "off-target" effects, and hence fewer side effects.

In the current issue of Journal of Clinical Oncology, Niraula et al offer a more nuanced picture of newer cancer drugs and safety.  In it, they used meta-analytic techniques to compare rates of life-threatening side effects for patients receiving new cancer drugs against patients receiving standard of care. Briefly, they report that newer cancer drugs were associated with significantly greater probability of experiencing a life threatening toxicity. In short, new cancer drugs may have resulted in better clinical outcomes like survival, but at the cost of greater toxicity.  How can this be?  According to the report's authors, one possible explanation is the fact that many newer cancer drugs require prolonged exposure to new drug, resulting in greater risk of cumulative toxicity.

A few other tidbits.  Safety reporting in cancer drugs is very problematic.  The authors found 8% randomized trials in their sample made no mention of drug-related mortality(!).  Only 34% of trials reported the proportion of patients experiencing at least one life-threatening toxicity.  Journal editors and referees have a lot of demands on their attention, but when it comes to safety reporting at least, they are asleep at the switch.

What makes this study particularly interesting is the way the authors combined results of trials testing a variety of different style interventions. Through studies like this, we get an aerial view of where things are headed in cancer drug development, and provide a basis for assessing whether the field is achieving its goals. (photo credit: Martin Deutsch 2009)

Wednesday, May 2, 2012

Registration of Trials: A Census

Apologies to the millions of avid followers of Lost in Translation for the long haitus.  In response to an international petition campaign, with several Nobelist signatories, I am cautiously restarting this blog with the aim of (monthly??) blogposts on troubles and turmoil in clinical translation.

We lead off with an article in this week's JAMA, led by Robert Califf, which provides a census of the clinical research enterprise through an analysis of registered trials at  As with many such surveys of, the picture w/ respect to registry compliance ain't pretty.  Some particularly troubling highlights: the proportion of trials that were registered AFTER beginning enrollment was 52% between Oct 2007 and Sept 2010, and 6.8% of trials do not report their primary purpose (as required).

More generally, Califf et al finds 62% of registered trials are drug trials (the remainder involve procedures, diet, etc.); 63% involve North American research sites; 32% are industry sponsored; 15% are phase 3.

There are some interesting tidbits buried here.  For instance, many commentators are critical of phase 4 studies- viewing many such studies as trials aimed primarily at marketing (phase 4 trials test drugs that have already received regulatory approval for marketing).  Califf et al find that phase 4 studies are significantly less likely to report using blinding compared with phase 3.

The commentary by Dickersin and Rennie makes for a riveting read for those interested in the broader clinical research enterprise.  (photo credit: D. Clow 2008)