by Jen Acker
Before a new pharmaceutical makes it to market, it undergoes years of clinical trials to test and prove its efficacy and safety. Data safety monitoring boards (DSMBs) are small committees of individuals tasked with ensuring that throughout the three phases of the clinical trials process, the researchers running the study remain uncertain as to whether the trial drug or the control drug is more effective, and whether participant patients are being harmed by the trial drug. A recent editorial, however, suggests that DSMBs might not be acting objectively because of undue influence by interested parties: namely, the pharmaceutical company that manufactured the trial drug.
Drug trials are often conducted double-blind, where neither the doctors and researchers nor patient participants know whether the control drug or the trial drug is being administered. Trials must not put human subjects at unnecessary risk, a determination made by DSMBs at regular intervals during the course of the trial. If, at any point, one drug poses a risk of harm, the DSMB decides whether the study should proceed. If the control drug is shown to be more effective mid-trial, the DSMB might stop the study, and the trial drug will not be approved. Likewise, if the trial drug is shown to be much more effective than the control, it might be approved for widespread patient use before the study is completed (this is rare).
The members of DSMBs are intended and expected to be unbiased. For the members to remain impartial evaluators, they must periodically receive objective information about the progress and interim results of the study. Their priority is to protect the volunteer participants in the study. DSMBs are governed by regulations developed by the National Institutes of Health (NIH). These regulations require that DSMBs are independent decision-making entities throughout the process of reviewing and determining whether trial drugs are safe and potentially effective. DSMBs must strive to adhere to the NIH guidelines, which include the following provision:
Ideally, participants in monitoring outcomes of a trial are in no way associated with the trial. For trials that are conducted as part of a cooperative group, a majority of the individuals monitoring outcome data should be external to the group. ICs [Institutes and Centers where trials are conducted] should require policies that evaluate whether the participants have conflicts of interests with or financial stakes in the research outcome; and when these conflicts exist, policies must exist to manage these in a reasonable manner.
The recent editorial published in the New England Journal of Medicine suggests that actions by pharmaceutical companies have flown in the face of the NIH’s policy. The Journal cited instances from 2007 and 2008 of the drug companies GlaxoSmithKline and Merck/Schering-Plough manipulating mid-study data reports that were reported to DSMBs. In both instances, the New England Journal of Medicine published reports influenced by the drug-makers, without knowledge of the interference.
First, a 2007 report in the New England Journal of Medicine indicated an increased risk of adverse cardiovascular events by patients who were administered a drug for diabetes by GlaxoSmithKline which was the subject of an ongoing trial. In response, GlaxoSmithKline conducted a mid-study analysis of the data, reporting positive outcomes. This report was then published in the New England Journal of Medicine. The DSMB was undoubtedly influenced by the reported positive outcomes, and despite the New England Journal of Medicine’s original report, did not conduct an independent investigation into the safety of the drug.
And, again, in 2008, after interference from Merck/Schering-Plough, data from a different drug trial was unblinded, revealing information identifying the control and trial drugs. As a result, the DSMB was not able to able to impartially evaluate a higher incidence of cancer among patients receiving the trial drug.
As the Journal’s editorial recommends, changes need to be made to ensure greater objectivity in the clinical trials process. DSMBs must be able to function as intended. A boundary between interested pharmaceutical companies and independent DSMBs must be respected. For a truly independent evaluation of the study’s status, mid-trial data must be revealed directly to the DSMB, rather than as interpreted by the pharmaceutical company whose drug is on trial. The process of drug approval is long and expensive, and one can imagine a company’s frustration over the failure of a drug in the clinical trials process. However, we cannot allow one company’s profit-driven motives and expectations to undermine the safety of the pharmaceuticals that ultimately make it to market and into our bodies.