Precision of psychiatric drug safety assessments, availability of adequately trained psychiatric researchers, and participation of a diverse research population were prominent among the topics of several panels and workshops on research methodology at the NIMH-sponsored 47th annual New Clinical Drug Evaluation Unit (NCDEU) meeting that took place earlier this year in Boca Raton, Fla.
Efforts to standardize the monitoring of suicide-related adverse drug effects and suicide risk factors have followed the FDA finding that younger patients may be at increased risk for antidepressant treatment-linked suicidality. Kelly Posner, PhD, with the New York State Psychiatric Institute, Columbia University group, which aided the FDA in analyzing these events in antidepressant studies with children, described recently developed methods and training programs to improve monitoring and assessment.
The Columbia Suicide Severity Rating Scale was offered as a means to facilitate prospective, systematic monitoring for emergence of suicidality within clinical trials, in contrast to the spontaneous reporting that was the basis for the FDA determination of treatment-emergent suicidality. "The potential for bias in reporting is clear," explained Posner, "and only prospective systematic monitoring in future trials will provide a clearer picture of true risks and benefits posed by medication."
Posner characterized the new rating scale as a low-burden, clinician-administered tool that covers the wide spectrum of suicidality from ideation to behavior. With suicide attempts too infrequent to serve as an outcome parameter, this suicide assessment scale provides a validated measure of such related variables as impulsivity, poor frustration tolerance, sadness, and hopelessness. In addition to facilitating monitoring throughout a trial, the measure can be used to differentiate suicide attempters from non-attempters at study baseline, and to predict those who are most likely to go on to commit suicide.
Posner credits the controversy regarding antidepressant-linked suicidality for highlighting the need for improved tools and techniques to assess other side effects of psychotropic medications. One recent development is a computerized, self-administered screening for adverse events. The screen was developed with NIMH funding to identify such side effects as activation and agitation, and uses audio technology to ask questions of respondents who have limited reading ability.
"The screen is brief enough to be feasible in psychopharmacological research trials, including those conducted in community practice networks," Posner indicated. "The screen yields a report that will indicate areas of concern that should be further assessed by a medical professional."
Improving safety assessment
Improved detection of adverse events in short-term trials does not necessarily reduce their occurrence and improve safety of medications in the general population, however, particularly with rarely occurring adverse events. Controlled clinical trials do not reflect the longer periods of medication use, nor the varied medication combinations used in the general population.
This disparity was addressed by Donald Robinson, MD, a consultant with World Wide Drug Development, who recommended several measures that the pharmaceutical industry could implement to improve safety assessment of new drugs. Some drug trial data should be shared, he recommended, in order to develop better predictors of drug safety. In addition, the industry could have a greater commitment to conducting phase 4 postmarketing studies of safety and effectiveness. Such postmarketing surveillance is particularly important, Robinson emphasized, "during the critical transition period from investigational agent to drug product in wider use."
Robinson recommended increased use of large clinical databases, such as those maintained by health maintenance organizations and by Veterans Affairs, Medicaid, and other governmental organizations. These are, Robinson indicated, "rich sources of safety data that can help guide the FDA as well as pharmaceutical sponsors in early detection and assessment of newly recognized adverse events."
Recent efforts by the FDA to strengthen their drug safety programs were recounted by Gwen Zornberg, MD, ScD. These include sponsoring a study by the Institute of Medicine on the agency's drug safety system, with emphasis on its postmarketing assessment and surveillance; conducting workshops and publishing reports on new means and methods to ascertain safety and manage risk; and creating a new drug safety oversight board within the agency. "Postmarketing drug safety surveillance by the Division of Psychiatric Products of the FDA has been vigorous," Zornberg declared, "and is being further bolstered through a host of new initiatives."
Recruiting researchers, selecting subjects
Strategies for recruiting trial participants are commonly discussed at these NCDEU forums, but the need to also recruit and train researchers was emphasized this year. Mayada Akil, MD, a senior advisor to the director of NIMH, characterized the current shortage of physician researchers in psychiatry as a "national crisis."
"This shortage undermines the ability to translate basic research findings into clinical medicine relevant to people's lives," Akil indicated.
According to the 2003 Institute of Medicine report "Research Training in Psychiatry Residency: Strategies for Reform," the shortage of psychiatric investigators has been worsening. Akil pointed to a steep decline in the numbers of applications for NIMH-monitored research grants, the number of research fellowships to train physician scientists, and the number of clinical fellows training in NIMH intramural programs.