New Drug Evaluation Workshops Focus on Improving Psychiatric Research

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.

One response by the NIMH, described by Javier Escobar, MD, of the University of Medicine and Dentistry of New Jersey, is the development of a program with 15 to 20 senior researchers to serve as mentors for young investigators. Another NIMH initiative is formation of a National Psychiatry Training Council to assess the shortage and recommend corrective measures. The council, consisting of about 75 representatives of varied stakeholders, issued a report in 2006 that indicates that the shortage of physician investigators is acute in clinical and translational research, particularly in the subspecialties of child and adolescent, addiction, and geriatric psychiatry.

Minority involvement in research

A program to increase the number of minority postdoctoral investigators was described by Warachal Faison, MD, and Jacobo Mintzer, MD, of the Medical University of South Carolina (MUSC). Their group used a grant from the National Institute on Aging to develop the Institute for Research Minority Training on Mental Health and Aging. The program was characterized as a "unique approach that combines the benefits of a national cadre of mentors with a locally produced and nationally delivered research didactic training."

In discussions on recruiting research subjects, there were similar concerns with the low representation of minority populations. "Historically, people of African descent in the United States have been largely excluded from clinical trials, possibly contributing to health and health care disparities," Basil Halliday, MSc, of Meharry Medical College, observed.

Halliday identified several factors contributing to this underrepresentation, including the cost of delaying clinical trials to undertake more difficult recruiting programs, acceptance of status quo, and the practice of obtaining data from diverse populations outside the United States. Halliday advocated, however, for systematic planning to improve recruitment of African Americans. These plans, he indicated, "should acknowledge the history of mistrust borne by this group, and attempt to establish clear guidelines that address this history."

Mintzer described an approach at MUSC to increase recruitment of African American subjects for a clinical trial in Alzheimer disease (AD). This recruitment effort emphasized education about the early symptoms of AD and potential therapies and involved local primary care physicians and family members.

Danielle Laborde, PhD, MPH, of HERMES LLC, a health research and educational services company in Durham, NC, pointed to a lack of formal training programs to prepare mental health researchers to engage diverse populations in research programs. In response, her company has developed a training module to facilitate collaborative efforts of investigators with African American community leaders. "The training materials, which include experiential exercises and case studies, have been well received by research psychiatrists and other mental health researchers in cooperative learning and workshop formats," Laborde indicated.

Research on children

The challenges in recruiting suitable populations of children for clinical trials were addressed; it was noted that there are particular difficulties in recruiting children for studies of schizophrenia. "Juvenile-onset schizophrenia has unique treatment challenges and requirements, particularly in confirming the diagnosis for adolescents exhibiting symptoms and the interacting combination of biopsychosocial factors that occur in this population," observed Margaretta Nyilas, MD, of Otsuka Pharmaceutical.

Linmarie Sikich, MD, of the University of North Carolina, Chapel Hill, related her experience with recruiting child subjects for 2 studies, one of early-onset schizophrenia and the other of pharmacological interventions for autism. Sikich noted that the enrollment eligibility criteria for the first study had been changed twice-once because of safety concerns, and the other in response to challenges associated with recruiting subjects receiving only an antipsychotic medication. Sikich indicated that there had been a particularly high standard set by the Investigational Review Board before approving the study, including the requirement for both informed consent and assent.

The lack of data on drug dose response in children, and the relatively few approved indications for psychiatric drugs provide impetus for conducting studies with this age group, however, and several examples of successful large-scale studies with children were described at the meeting. John T. Walkup, MD, of Johns Hopkins University, noted 3 clinical drug trials that also provide a comparison of medication to psychotherapy: the Multimodal Treatment Study of ADHD, the Treatment for Adolescents with Depression Study, the Pediatric Treatment Study, and the Child/Adolescent Anxiety Multimodal Study.

Walkup noted that the lack of sham psychotherapeutic arms and combination treatment with placebo in these studies may limit inferences about the interaction of treatment conditions, but found this arguable flaw in design to be "offset by enhancement in feasibility and generalizability of study results to clinical practice."

Involvement with research design and methodology at this year's NCDEU appeared to go beyond academic interest to embrace the responsibilities in moving compounds from bench to bedside. In introducing a workshop on assessment design, detection of onset and suicide risk, Mark Rapaport, MD, Cedars-Sinai Medical Center, Los Angeles, cautioned, "In this time of continued public scrutiny, stringent regulatory and congressional oversight, it is imperative to carefully assess and rigorously re-evaluate how we conceptualize treatment outcomes that are employed to determine the success of our experimental interventions."