Systematic Review: Faulty Clinical Trial Analyses Favor new toxic drugs

"Have last-observation-carried-forward analyses caused us to favour more toxic dementia therapies over less toxic alternatives? " is a systematic review of 57 randomized controlled drug trials for treatment of dimentia. The authors, Frank J Molnar, Malcolm Man-Son-Hing, Brian Hutton, Dean A Fergusson, from the University Ottawa (Canada)  found that in 34% of those trials the last-observation-carried-forward (LOCF) was used–a much higher proportion than the 19% across other medical speicalites.

The second, "Missing outcomes in randomized trials: addressing the dilemma" is an analysis and comment by Douglas Altman of Oxford (UK).

The LOCF method of analyzing randomized trials in psychiatry is favored by manufacturers of psychiatric drugs. This is likely an effort to counteract an important factor in psychotropic drug trials: missing data due to the inordinately high drop out rates in psychotropic drug trials.

Dr. Altman notes: "Even if missing outcomes are random across trial participants, LOCF analysis assumes that the missing final values would be the same as the last recorded values. That assumption is often implausible (even as an average), because dropping out is likely to be associated with response to treatment; obvious examples are failure to respond to treatment and adverse effects. In practice, missing data are very likely to be related to response to treatment and prognosis."

Drs. Molinar et al, suggest: “the onus is on the investigators who publish these trials to disprove the possibility that these analyses have introduced bias by performing intention to treat (ITT) sensitivity analyses … . This is particularly true for those studies demonstrating higher dropout rates in treatment groups.”

Drs. Molnar et al, suggest that the clinical impact of inappropriate use of LOCF data analysis skews the results:
The results of some randomized clinical trials of dementia drugs may be inaccurate or invalid because of bias through inappropriate use of LOCF analyses.” 

The authors note that this artificial enhancement of the actual safety and efficacy profile of new, often toxic drugs–"may be to limit funding of and patient access to less toxic alternatives to cholinesterase inhibitors."

Indeed, there is a pressing need for independent re-analysis of currently used psychotropic drugs: psychiatrists under the influence of industry have been following industry’s invalid methodological methods which have resulted in catapulting toxic, and mostly ineffective drugs into blockbuster sellers.

 Vera Hassner Sharav

 

Open Medicine
A peer-reviewed, independent, open-access journal
March 12, 2009

*    NEW IN RESEARCH: Have last-observation-carried-forward analyses caused us to favour more toxic dementia therapies over less toxic alternatives?
A systematic review. By Frank J. Molnar, Malcolm Man-Son-Hing, Brian Hutton, Dean A. Fergusson

*    NEW IN ANALYSIS AND COMMENT:  Missing outcomes in randomized trials:
addressing the dilemma. By Douglas G. Altman

*Clinical Epidemiology Program, Ottawa Health Research Institute
In this systematic review, Monar et al., consider the impact of a methodological technique-last-observation-carried-forward (LOCF), commonly used in the analysis of randomized clinical trials-on the treatment of dementia. Medical researchers have expressed concern since 1998 that LOCF may bias dementia drug trials in favour of cholinesterase inhibitors and against less toxic options. Considering the 24.3 million people worldwide suffer from dementia, it is essential that health practitioners optimize the use of dementia medications.

The authors compared 57 double-blinded, randomized controlled trials of cholinesterase inhibitors (donepezil, rivastigmine, galantatmine) and NMDA-receptor antagonists (memantine) used in the treatment of Alzheimer’s disease and dementia. The concluded that “the results of some randomized clinical trials of dementia drugs may be inaccurate or invalid because of bias through inappropriate use of LOCF analyses.”
Furthermore, they suggest that the clinical impact of this trend may be to limit funding of and patient access to less toxic alternatives to cholinesterase inhibitors.

In an accompanying commentary, Doug Altman, director of the Centre for Statistics in Medicine, University of Oxford, Oxford, UK, writes that the methodological issues raised in this review are relevant to trials in all medical specialties, and he summarizes the steps that medical researchers to take when conducting and reporting on randomized clinical trials.

For the full-text review article, please visit: openmedicine.ca _________ Open Medicine http://openmedicine.ca  Open Medicine is an independent, international general medical journal supporting academic freedom and open access.