[Summary] National Institute of Mental Health Clinical Trials: New Opportunities, New Expectations (Insel, Gogtay 2014)
TLDR; NIMH is setting guidelines to make mental health studies more scientifically rigorous in order to make more effective treatments in a timely manner.
https://zero.sci-hub.do/4311/5a35d604428cd18f7203db0550eafb35/insel2014.pdf?download=true
TLDR; NIMH is setting guidelines to make mental health studies more scientifically rigorous in order to make more effective treatments in a timely manner. The focus is finding more specific disease mechanisms (eg what are the brain circuits and genes behind depression?) by requiring measuring "target engagement” (eg did the experimental treatment activate the specific brain circuit?). This will build toward more informative studies and more effective treatments.
We need much more effective treatments for mental health: the problem is growing, but there have been few breakthroughs.
“There can be little question that we need better treatments for mental disorders. The recent Global Burden of Disease Study1 demonstrates how neuropsychiatric disorders are a leading source of medical disability in the United States, increasing since 1990 despite a concomitant increase in pharmacologic treatments.2 Although there have been many commercially successful medications for anxiety, depression, and psychosis, few com- pounds have shown truly new mechanisms of action, and even fewer represent true breakthroughs in efficacy.3 For many of our most serious clinical challenges, such as anorexia nervosa, posttraumatic stress disorder, the core symptoms of autism, and the cognitive deficits of schizophrenia, to name a few, we lack effective medications altogether.”
More specific treatment targets and disease mechanisms will enable more successful treatment development pathways and trials; as of now, pharmaceutical companies are investing billions of dollars elsewhere.
“Recently, many pharmaceutical companies have exited the field of psychiatry, citing the high failure rates in clinical trials, a glut of successful generic com- pounds, a lack of biomarkers, and the absence of valid animal models. But perhaps the most critical driver for this exodus has been our lack of understanding the dis-ease mechanisms. Much of psychiatric research has fo- cused on the drugs and not on the disease mechanisms, resulting in a continued lack of disease-relevant targets for novel drug development. Little surprise then that pharmaceutical companies are increasingly investing in other disease areas (even in rare diseases) where the targets are known and the development pathways are clearer.”
“Whereas industry invests nearly $2 billion for each drug brought to market,4 the NIMH’s full annual budget is less than $1.5 billion, with less than 10% of this invested in clinical trials.”
In 2010 the NIMH has decided to focus on experiments that test for specific disease mechanisms in order to address the need for new treatments.
“With this background, in 2010, the NIMH asked its advisory council for guidance on the best way to address the urgent need for new treatments. The National Advisory Mental Health Council’s report, “From Discovery to Cure,” recommended several changes to the NIMH clinical trials portfolio (http://www.nimh.nih.gov/about/advisory-boards-and-groups/namhc/reports/fromdiscoverytocure.pdf). Among those recommendations was a call to accelerate the development process, moving quickly into humans for proof-of-concept studies, and a request for trials that identify and validate new targets. From these recommendations, the NIMH has developed a focus on experimental therapeutics, in which interventions are used as probes of disease mechanisms, as well as tests of efficacy.”
In Feb 2014 NIMH released 4 funding announcements with a goal of learning more about disorders and specific mechanisms in order to inform future research and treatments.
“In February of this year, the NIMH released 4 new funding announcements to transform its investments in clinical trials. These new announcements can be summarized as calling for changes in “what” and “how” trials are conducted. What are we looking for in these new announcements? Each of the 4 covers a different phase or area of clinical investigation, but they all share a focus on learning more about the disorders, as well as the mechanisms of intervention. Each requires a demonstration of target engagement, in addition to assessing changes in symptoms. And each seeks to identify a critical dose and duration of intervention that would engage or modulate the target in addition to assessing symptom change, with a goal of informing further research or treatment strategies.”
An example of a trial that adequately explores “target engagement” is one that measures how different doses of a new compound affects receptor activation measured by PET scan (measure of target engagement).
“A prototype of such trials might first explore adequate target engagement (eg, positron emission tomographic receptor occupancy) by examining a range of doses and durations of intervention (eg, a novel compound). Once target engagement is defined, a clinical trial can yield important information whether the efficacy signal is positive or negative. Thus, if the target engagement is associated with clinical efficacy, there is the potential for further development (a “go” outcome), whereas if the target engagement is without clinical efficacy, this would allow for rejection of the target (a “no- go” outcome). These principles hold true for medication, devices, and psychosocial treatments, as well as services interventions”
Given the state of mental health science “target engagement” can be much broader than brain receptors and can include other biomarkers or cognitive processes.
“Of course, if receptor occupancy were the requirement for clinical trials, then the NIMH would fund very few new studies and would have little impact on treat- ment development. Thus, the NIMH concept of “target” is broader and refers to a hypothesized mechanism of action and its ability to modify disease, behavior, or functional outcomes. Targets can range from molecular- and circuit-level mechanisms proposed for pharmacologic agents, neural systems or cognitive processes for psychosocial behaviors, to organizational behaviors that are thought to underlieservice level benefits of the intervention.Biomarkers(including cognitive markers) that serve as predictors of clinical response can also be helpful for studies focused on targets, as well as symptomatic change.”
Traditional psychotherapy treatments studies must become more rigorous, include dose/duration, and a hypothesis for target engagement or mediator, especially as payers are asking for more evidence.
“The NIMH believes the rigor that has been applied to drug development in industry will also be critical for testing nonpharmacological therapies, especially in the new health care environment where payers are asking for the same evidence for psycho-social treatments, such as required dose and duration, as they expect for medications. This is not to say that every psychotherapy trial needs to test for target engagement with functional magnetic resonance imaging, but testing for symptom change is not enough. Every trial will need to include a mediator that tests the mechanism of action, informs the dose and duration required, and allows a negative trial to be informative.”
There are also new trial requirements around recruitment, reporting, data, finishing under 5-years, etc as well.
“As a result, all new trials will have to meet milestones for initiation, recruitment, completion, and reporting. Multisite trials will be expected to have a single institutional review board of record to reduce the time for initiation and increase efficiency of monitoring. All trials, both pharmacological and psychosocial, will need to be registered in ClinicalTrials.gov before they can be funded. Data sharing, including sharing of patient-level data, will be expected of all trials regardless of their size,5 and trials will need to be completed in less than the traditional 5-year cycle.”
Ultimately people need help now; and we need more effective treatments we can deliver to them in a timely manner.
“They are also a response to many patient advocates who remind us that time matters.”6The current time table for a clinical trial, which spans nearly a decade from proposal to publication, is not acceptable to families with a child with autism or an adolescent with psychosis. However, in addition to fixing the delay, these families need to know that we are doing everything possible to deliver treatments that are better than what is available today. New treatments will require a deeper understanding of the disorders and a new approach based on experimental therapeutics for pharmacological, psychosocial, and neuromodulatory interventions.”