Opinion
VIEWPOINT
Thomas R. Insel, MD Office of the Director, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland. Nitin Gogtay, MD Office of the Director, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland.
Corresponding Author: Thomas R. Insel, MD, Office of the Director, NIMH, National Institutes of Health, Department of Health and Human Services, 6001 Executive Blvd, Room 8129, Bethesda, MD 20892 ([email protected]).
National Institute of Mental Health Clinical Trials New Opportunities, New Expectations 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 compounds 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. Recently, many pharmaceutical companies have exited the field of psychiatry, citing the high failure rates in clinical trials, a glut of successful generic compounds, 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 disease mechanisms. Much of psychiatric research has focused 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. The role of the National Institute of Mental Health (NIMH) in treatment development has historically been different from that of industry. In an earlier era, the NIMH supported some of the definitive studies on lithium, psychostimulants, antipsychotics, tricyclic antidepressants, and selective serotonin reuptake inhibitors. However, in the past 2 decades, the NIMH’s investment of public dollars has favored the development of psychosocial treatments and devices. The NIMH-sponsored pharmaceutical studies have largely focused on pilot studies of efficacy, with the exception of comparative effectiveness trials (including Clinical Antipsychotic Trials of Intervention Effectiveness [CATIE], the Sequenced Treatment Alternatives to Relieve Depression [STAR*D] study, and the Systematic Treatment Enhancement Program for Bipolar Disorder [STEP-BD] study) completed several years ago. As in other areas of medicine, the public investment in treatment development research has been relatively limited, compared with industry investments in preclinical development and large-scale clinical trials. 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.
jamapsychiatry.com
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 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. 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 “nogo” outcome). These principles hold true for medication, devices, and psychosocial treatments, as well as services interventions. 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 treatment 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 JAMA Psychiatry July 2014 Volume 71, Number 7
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpsyc.jamanetwork.com/ by a Yale University User on 07/10/2015
745
Opinion Viewpoint
psychosocial behaviors, to organizational behaviors that are thought to underlie service-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. These concepts, perhaps familiar to scientists developing drugs for industry, may appear alien to anyone involved in psychosocial treatment development. 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 psychosocial 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. In addition, improvement in function, an outcome promulgated by the US Food and Drug Administration for drug development (http://www.fda.gov/Drugs/DevelopmentApprovalProcess /DrugDevelopmentToolsQualificationProgram/ucm284077.htm), should be an outcome assessed for both pharmacological and nonpharmacological trials. The new funding announcements also require a change in “how” trials are conducted. An internal review revealed that NIMH trials ARTICLE INFORMATION
Burden of Disease Study 2010. Lancet. 2013;382 (9904):1575-1586.
Published Online: May 7, 2014. doi:10.1001/jamapsychiatry.2014.426. Conflict of Interest Disclosures: None reported.
2. Insel TR. Next-generation treatments for mental disorders. Science Transl Med. 2012;4(155):155ps119.
REFERENCES
3. Hyman SE. Revolution stalled. Science Transl Med. 2012;4(155):155cm111.
1. Whiteford HA, Degenhardt L, Rehm J, et al. Global burden of disease attributable to mental and substance use disorders: findings from the Global
746
needed to improve their efficiency, transparency, and reporting (http: //www.nimh.nih.gov/funding/opportunities-announcements /clinical-trials-foas/changing-nimh-clinical-trials-efficiency -transparency-and-reporting.shtml). 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. These changes are the result of the changing ecosystem of treatment development, the advent of new tools to look at mechanisms of change, and the advice of experts both within and outside of our field. They are also a response to many patient advocates who remind us that “time matters.”6 The current timetable 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.
4. Paul SM, Mytelka DS, Dunwiddie CT, et al. How to improve R&D productivity: the pharmaceutical industry’s grand challenge. Nat Rev Drug Discov. 2010;9(3):203-214.
5. Mello MM, Francer JK, Wilenzick M, Teden P, Bierer BE, Barnes M. Preparing for responsible sharing of clinical trial data. N Engl J Med. 2013;369 (17):1651-1658. 6. Baxter K, Horn E, Gal-Edd N, et al. An end to the myth: there is no drug development pipeline. Science Transl Med. 2013;5(171):171cm171.
JAMA Psychiatry July 2014 Volume 71, Number 7
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpsyc.jamanetwork.com/ by a Yale University User on 07/10/2015
jamapsychiatry.com
VIEWPOINT
Thomas R. Insel, MD Office of the Director, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland. Nitin Gogtay, MD Office of the Director, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland.
Corresponding Author: Thomas R. Insel, MD, Office of the Director, NIMH, National Institutes of Health, Department of Health and Human Services, 6001 Executive Blvd, Room 8129, Bethesda, MD 20892 ([email protected]).
National Institute of Mental Health Clinical Trials New Opportunities, New Expectations 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 compounds 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. Recently, many pharmaceutical companies have exited the field of psychiatry, citing the high failure rates in clinical trials, a glut of successful generic compounds, 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 disease mechanisms. Much of psychiatric research has focused 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. The role of the National Institute of Mental Health (NIMH) in treatment development has historically been different from that of industry. In an earlier era, the NIMH supported some of the definitive studies on lithium, psychostimulants, antipsychotics, tricyclic antidepressants, and selective serotonin reuptake inhibitors. However, in the past 2 decades, the NIMH’s investment of public dollars has favored the development of psychosocial treatments and devices. The NIMH-sponsored pharmaceutical studies have largely focused on pilot studies of efficacy, with the exception of comparative effectiveness trials (including Clinical Antipsychotic Trials of Intervention Effectiveness [CATIE], the Sequenced Treatment Alternatives to Relieve Depression [STAR*D] study, and the Systematic Treatment Enhancement Program for Bipolar Disorder [STEP-BD] study) completed several years ago. As in other areas of medicine, the public investment in treatment development research has been relatively limited, compared with industry investments in preclinical development and large-scale clinical trials. 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.
jamapsychiatry.com
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 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. 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 “nogo” outcome). These principles hold true for medication, devices, and psychosocial treatments, as well as services interventions. 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 treatment 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 JAMA Psychiatry July 2014 Volume 71, Number 7
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpsyc.jamanetwork.com/ by a Yale University User on 07/10/2015
745
Opinion Viewpoint
psychosocial behaviors, to organizational behaviors that are thought to underlie service-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. These concepts, perhaps familiar to scientists developing drugs for industry, may appear alien to anyone involved in psychosocial treatment development. 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 psychosocial 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. In addition, improvement in function, an outcome promulgated by the US Food and Drug Administration for drug development (http://www.fda.gov/Drugs/DevelopmentApprovalProcess /DrugDevelopmentToolsQualificationProgram/ucm284077.htm), should be an outcome assessed for both pharmacological and nonpharmacological trials. The new funding announcements also require a change in “how” trials are conducted. An internal review revealed that NIMH trials ARTICLE INFORMATION
Burden of Disease Study 2010. Lancet. 2013;382 (9904):1575-1586.
Published Online: May 7, 2014. doi:10.1001/jamapsychiatry.2014.426. Conflict of Interest Disclosures: None reported.
2. Insel TR. Next-generation treatments for mental disorders. Science Transl Med. 2012;4(155):155ps119.
REFERENCES
3. Hyman SE. Revolution stalled. Science Transl Med. 2012;4(155):155cm111.
1. Whiteford HA, Degenhardt L, Rehm J, et al. Global burden of disease attributable to mental and substance use disorders: findings from the Global
746
needed to improve their efficiency, transparency, and reporting (http: //www.nimh.nih.gov/funding/opportunities-announcements /clinical-trials-foas/changing-nimh-clinical-trials-efficiency -transparency-and-reporting.shtml). 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. These changes are the result of the changing ecosystem of treatment development, the advent of new tools to look at mechanisms of change, and the advice of experts both within and outside of our field. They are also a response to many patient advocates who remind us that “time matters.”6 The current timetable 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.
4. Paul SM, Mytelka DS, Dunwiddie CT, et al. How to improve R&D productivity: the pharmaceutical industry’s grand challenge. Nat Rev Drug Discov. 2010;9(3):203-214.
5. Mello MM, Francer JK, Wilenzick M, Teden P, Bierer BE, Barnes M. Preparing for responsible sharing of clinical trial data. N Engl J Med. 2013;369 (17):1651-1658. 6. Baxter K, Horn E, Gal-Edd N, et al. An end to the myth: there is no drug development pipeline. Science Transl Med. 2013;5(171):171cm171.
JAMA Psychiatry July 2014 Volume 71, Number 7
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpsyc.jamanetwork.com/ by a Yale University User on 07/10/2015
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