Thursday, October 4, 2012
Monday, August 20, 2012
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
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 clinicaltrials.gov. As with many such surveys of clinicaltrials.gov, 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)
Monday, March 21, 2011
Every early phase trial begins with a series of predictions: that a new drug will show clinical utility down to road, that risks to study volunteers will be manageable, and perhaps, that patients in trials will benefit. Make a bad prediction here, and people potentially get hurt and resources wasted. So how good a job do we do with these predictions?
Tuesday, February 8, 2011
Monday, December 20, 2010
Monday, November 29, 2010
Two weeks ago brought good news and bad news for gene transfer. First the good news. New England Journal of Medicine beatified a new gene transfer strategy for Wiskott-Aldrich Syndrome (WAS). WAS is a primary immunodeficiency that primarily affects boys. It is thus in the same family of disorders that have been, in varying degrees, successfully addressed using retroviral gene transfer. Like other immunodeficiencies, this represents relatively low hanging fruit for an approach like gene transfer, because scientists can access and target stem cells, and because corrected cells should be at a selective advantage for survival compared with uncorrected cells.
The NEJM article reported clinical, functional, and molecular outcomes for two boys in a trial based in Germany. Briefly the two boys were given a type of chemotherapy (in order to make space for genetically corrected cells), and then transplanted with “corrected” blood stem cells. The corrected blood stem cells contained a viral vector similar to those used in previous gene transfer trials of primary immune deficiency. The team saw: 1) stable levels of genetically corrected stem cells that expressed the WAS protein (indicating the genetically modified cells “took,” and produced WAS; 2) recovery of the function of a variety of immune cells; 3) reduction of disease symptoms, including improvement of eczema, and reduced severity of infections.
The article exhaustively ruled out events that have occurred in other, similar gene transfer trials in which children developed leukemias from the vector. Now the bad news. The same day NEJM published the results, American Society of Gene and Cell Therapy (the largest professional society devoted to gene transfer) released a statement saying that the German team just announced “a serious adverse event in a gene therapy trial for Wiskott-Aldrich syndrome (WAS)”- one of the ten children in the German trial developed a leukemia.
And so continues the saga of gene transfer: three steps forward, one back. (photo credit: vk-red 2009)