Conducting Research with Participants at Elevated Risk for Suicide: Considerations for Researchers
This document serves to update National Institute of Mental Health (NIMH) guidance on suicide intervention research.1 It is intended to support the development of NIMH research grant applications in suicide research, including those related to clinical course, risk and detection, and interventions and implementation, as well as to support research conduct that is safe, ethical and feasible. An additional purpose is to point readers to current federal policy and guidance documents on human subject research, privacy protections, participant safety monitoring and reporting, common data elements, data sharing, and Institutional Review Boards (IRBs). It is not intended to provide enforceable guidelines for researchers, or to establish policy for any agency on human subject research protections.
In 2015, suicide was the 10th leading cause of death in the United States, with more than 44,000 deaths (CDC).2 In addition to the burden of mortality, 9.8 million adults aged 18 or older thought seriously about trying to kill themselves in 2015, including 2.7 million who made suicide plans and 1.4 million who made a nonfatal suicide attempt.3 Over the past several decades, suicide prevention efforts have yet to significantly reduce the rates of suicide and suicide attempt in the United States.4
To address this public health crisis, NIMH helped develop the Prioritized Research Agenda for Suicide Prevention, requested by the National Action Alliance for Suicide Prevention (NAASP), a public-private partnership among federal agencies, state governments, private sector companies, and national suicide prevention advisory and advocacy groups. The Agenda identifies research gaps, such as limitations in understanding of the etiology and course of suicidal ideation and behavior, the need for new interventions specifically targeting suicide, better matching of existing treatments to individual needs, and implementation of effective suicide prevention practices. The Action Alliance’s (NAASP) Zero Suicide effort has shaped suicide research in this country by identifying the implementation steps needed to shift the culture of health care to include more practices that actively support suicide prevention.5 NIMH has recently solicited applications to increase the evidence base for Zero Suicide approaches in health care systems (RFA-MH-16-800). This effort is also consistent with the NIMH Strategic Plan for Research, Objective 4, improving public health through more practice-ready suicide prevention interventions.
Ethical and Participant Safety Questions
Developing additional novel suicide prevention and treatment approaches, as well as testing best practices in pragmatic trials, presents a range of safety and ethical questions. Some of these questions are familiar to the field, for instance:
- What is adequate clinical management for potentially suicidal participants in the context of a research study?, and
- What is a methodologically appropriate and ethical comparator arm for a study looking at treatment of suicide?
Below are cross-cutting ethical and participant safety questions that researchers should consider when including suicidal or potentially suicidal participants in their research. In addition, new ethics and safety questions are arising from scientific, methodological, and technological developments in the field, such as the use of emerging technologies in clinical research and the increased adoption of pragmatic effectiveness study designs. These will be discussed as emerging questions.
Notably, in October 2016, NIMH was part of a group of NIH Institutes issuing a Notice of Interest in High Priority Research in Bioethical, Legal, and Societal Implications of Biomedical Research (NOT-LM-17-001). The high priority research areas include numerous topics addressed below: new and emerging technologies, data sharing, learning health care systems/pragmatic trials, informed consent, and regulatory and oversight issues.
Cross-cutting and emerging ethical and participant safety considerations
- Research Design: Are the study design and methods appropriate for the aims of a suicide relevant research project with regard to safety, ethical approaches, and the knowledge to be gained? For suicide prevention trials, does the design allow for a comparator that is both informative and ethical?
- Common Data Elements and Data Sharing: What measures are used to detect, assess, and/or manage suicide risk, side effects and/or adverse events, and study outcomes? What are specific considerations for data sharing?
- Informed Consent: What elements should be considered for inclusion as part of the informed consent process?
- Monitoring and Reporting: What level of data and safety monitoring is appropriate for the study? What are the adverse events and side effect reporting expectations for the study? What are the reporting expectations for suicidality as a treatment side effect for FDA Phase 1 and 2 IND studies? What unique issues arise in monitoring and reporting in multi-site trials? For non-clinical trials, what risk management and data and safety monitoring elements are appropriate to include in non-intervention studies?
- Responding to Suicidal Crises and Clinical Worsening: What study procedures need to be in place to respond to suicidal crises and clinical worsening that occur during the study?
- End of Study Participation: What are the issues to anticipate and plan for when participants come to the end of their study participation due to early termination, study completion, or a participant death? In the case of a study participant death, what protocol is in place for contact with the family, and support of research staff?
- Pragmatic Trials: What are the unique issues presented by pragmatic trials involving individuals at higher risk for suicide?
- New Technologies: What are the unique issues presented by research involving individuals at higher risk for suicide which use newer technologies as a central part of study conduct?
Relevant Federal Policies and Guidance
Although not specific to research on suicide, the Office of Human Research Protections (OHRP) announced revisions to the Federal Policy for the Protection of Human Subjects (the Common Rule) in January 2017 with the goal of better protecting “human subjects involved in research, while facilitating valuable research and reducing burden, delay, and ambiguity for investigators. These revisions are an effort to modernize, simplify, and enhance the current system of oversight.” Revisions to the Common Rule will affect some research on suicide; for example, changes in the categories of research exempt from the Common Rule will be relevant to some investigators.
The NIH and NIMH have numerous published policies and guidance relevant to the ethical and safe practice of clinical research on suicide prevention or with potentially suicidal research participants. In addition, there are new websites available that are useful resources to investigators conducting human subjects research. The Office of Extramural Programs of the NIH recently launched a new human subjects research website that provides information to investigators and institutions conducting human subjects research. Additionally, in September 2016, a NIH policy was published establishing the expectation that all NIH awardees funded to conduct clinical trials will receive good clinical practice (GCP) training (NOT-OD-16-148). For NIH and NIMH policies and guidance related to the monitoring of clinical trials and reportable events, refer to the NIMH Clinical Research webpage.
For those clinical trials evaluating drugs developed for psychiatric indications, investigators are referred to the Food and Drug Administration’s (FDA) draft Guidance for Industry: Suicidal Ideation and Behavior Prospective Assessment of Occurrence in Clinical Trials. Additional FDA guidance that may be of interest relates to whether a given mobile application will be deemed a device to be regulated by the FDA. For multi-site clinical trials, the newly published NIH policy on the use of single IRBs is also relevant (NOT-OD-16-094).
Another arena of relatively new NIMH policy and guidance relates to data sharing expectations and guidance regarding common data elements (CDEs). Current guidance on data sharing (NOT-MH-14-015) emphasizes the importance of making research data available to the scientific community. NIMH clinical Requests for Applications (RFAs) now include specific language on CDEs and data sharing expectations that provide additional guidance to NIMH investigators developing grant applications. For low-base rate events like suicide death and suicide attempts, data sharing and the use of CDEs show great potential to advance the field. To support data harmonization, the NIMH published a guide notice (NOT-MH-15-009) relevant to clinical trials funding opportunity announcements (FOAs).
Cross-cutting considerations are discussed below, with the goal of identifying issues that researchers may find useful to address when developing a research project involving participants at heightened risk for suicide.
Are the study design and methods appropriate for the aims of the suicide relevant research project with regard to safety, ethical approaches, and the knowledge to be gained?
The safe and ethical design of research studies enrolling participants at heightened risk of suicide raises unique considerations for researchers. Methodological questions need to be addressed, as well as practical considerations about the physical environment and clinical setting where study procedures will be taking place. Risk monitoring and safety planning have to be considered on a concrete level in the process of thinking about where study procedures will take place. The physical environment where study activities are completed represents an important consideration for studies including individuals at risk for suicide.6 Study visits can involve participants spending time in spaces that include items which could be used as means for self-harm (e.g., wires, needles, heights, glass). Thinking through these physical space considerations during the planning phases of a project allows researchers to develop procedures to protect participants.
Relatedly, researchers conducting studies in settings where participants are receiving clinical care (e.g., inpatient units, emergency rooms, outpatient clinics) will benefit from thinking through how the research staff and clinical providers will communicate with each other about patient needs and clinical status. For example, studies that include assessments of suicide risk with patients in an emergency room or outpatient context will want to determine in advance, and in collaboration with the clinical providers in the setting, how a positive risk screen will be handled in order to assure that patients receive appropriate and timely care.
Researchers can take advantage of existing tools to assist them in pro-actively thinking through potential safety, ethical, and care delivery issues that could arise over the course of study operations.7 The Institute for Healthcare Improvement has developed a program that can be adopted for this purpose, the Failure Modes and Effects Analysis Tool.
Finally, ethically-informed decisions regarding the design and methods for a study involve deliberate consideration of the study population, and the specific ethical questions that arise when conducting mental health research with a given community. As one example of such efforts in the field of suicide research, the American Indian/Alaska Native (AI/AN) Task Force of the NAASP convened at expert meeting in 2013 to address how to advance suicide prevention research with rural AI/AN populations. The 2015 report from that meeting provides useful ideas for researchers interested in conducting ethical suicide prevention research with native communities.8
For suicide prevention trials, does the design allow for a comparator that is both informative and ethical?
In the arena of methodological issues, efficacy and/or effectiveness studies of suicide prevention interventions have the challenge of determining an appropriate comparator arm when conducting trials, as there may be no established effective standard of care for reducing suicidal ideation and behavior in the population specified for study, or appropriate for the research intervention and study design. In these situations, ethical questions arise, such as risk to suicidal individuals of being assigned to the “placebo arm” versus the active intervention, or risks raised by engaging in an untested intervention. These dilemmas can often be addressed by providing risk monitoring and safety planning throughout the study. Risk monitoring and safety planning may significantly enhance the standard of care typically available. In these cases, investigators will be concerned with how the enhancement of usual care will impact their ability to determine if the new treatment is a significant improvement over true, unenhanced standard care. The enhanced treatment as usual (TAU) approach brings up another ethical dilemma: as more safety measures are put in place for the comparator TAU arm, studies then need to enroll more individuals to be appropriately powered to find a statistically and clinically significant effect, leading to more participants being enrolled and exposed to risks that may come with study involvement.
Different questions arise for studies that look at suicide as an outcome, but are not addressing suicide reduction as a primary study aim, i.e., a treatment study of individuals with mood disorders. In these cases, established psychosocial and/or pharmacological treatments can be used as the active comparison group. Monitoring and risk management plans for suicidal ideation and suicide attempt will need to be developed that are appropriate for the study design and for the population, depending on the study inclusion criteria. Studies attempting to maximize external validity may elect to have broader inclusion criteria which can result in including individuals in the study who are at increased suicide risk. These design decisions have implications for safety monitoring and clinical risk management plans as noted above, as well as adverse event reporting expectations (e.g., considerations of what will be expected adverse events, and the rates of those events). As an example, studies that include individuals with substance abuse disorders might consider a psychiatric hospitalization for detox an expected serious adverse event, while this type of hospitalization might be considered unexpected with a study population that excluded current substance abuse.
Common Data Elements and Data Sharing
What measures are used to detect, assess, and/or manage suicide risk, side effects and/or adverse events, and study outcomes? What are specific considerations for data sharing?
The NIMH is strongly encouraging data sharing and the use of common data elements (NOT-MH-14-015; NOT-MH-15-009). These efforts are vital in the field of suicide research because suicide attempt and suicide death are low base rate events, thus the value of individual studies is significantly enhanced when researchers collect and share data that can be harmonized with other suicide-related research studies. One aspect of data harmonization involves using assessment instruments being used by others in the field, following the guidance provided in NIMH clinical trial FOAs (e.g., PhenX Toolkit). Another aspect of data collection to consider with regard to harmonization relates to data extracted from setting-specific sources, such as electronic health records (EHR), in contrast to data collected using standardized assessment instruments. Researchers may want to think through and collaborate around which elements in the medical record will best synchronize with data from other studies. Efforts at cross-walking data elements during the development of a study protocol will promote data harmonization, and in turn improve the likelihood of data sharing. As more studies use EHR data sources, policy and practical questions related to harmonizing data across EHR systems will become more salient.
Discussion of data collection and data sharing raises an issue that has long been a concern for the field of suicide research: how to encourage mental health researchers working in other areas to include questions about suicide risk in their assessments in order to gather needed data on larger study populations, as well as to identify risk in individuals who could benefit from information or services. Non-suicide researchers may need guidance on how to provide appropriate follow up, given their study design and staffing, to individuals who endorses some level of risk (e.g., what level of follow up is needed? what staffing and training is required to provide that follow up?). Regulatory bodies, such as IRBs, may also benefit from guidance on the topic of how to think about managing suicide risk in the context of a study that may neither be focused on suicide, nor include individuals at heightened risk of suicide (e.g., survey research that is not suicide focused, but opts to include questions relevant to suicide risk). The experience and expertise of suicide researchers can be leveraged here, to help evaluate when the provision of crisis line information is sufficient, when facilitating contact with a crisis line is warranted (a “warm transfer”), or when study staff trained to do a suicide risk evaluation is needed.9
What elements should be considered for inclusion as part of the informed consent process?
Informed consent in suicide prevention studies raises a number of issues, some of which are unique to suicide research and some which have heightened importance because of the risk issues presented in these studies. A primary issue arises in studies consenting individuals who may be in the midst of, or coming out of, a mental health crisis. In addition to considering if there are factors that may alter a person’s capacity to consent for themselves or their child, and for a child (e.g., a person under the age of 18) to assent to participation, the study team needs to communicate that involvement in research does not provide participants with “protection” against future suicidal behavior.10 A different set of issues arises for suicide prevention studies that seek waivers or alterations of consent; see references in discussion of pragmatic trials below.
The language on confidentiality has particular relevance in studies with a higher likelihood that confidentiality would need to be limited due to concerns about harm to self. Similarly, informing individuals, and families when relevant, of the risk management plans in place in case of imminent suicide risk is an important aspect of safe and ethical research. A related discussion with study participants (and, in some case, family members) is needed at the outset of a study: addressing potential role confusion between a participant’s clinical care providers and study staff.11 In situations when both care providers and study staff may be assessing for suicide risk or providing related care, participants will need guidance on who to reach out to and in what circumstance.
Informed consent documents often include language regarding Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule protections. Federal guidance on the limits to HIPAA in situations involving concerns about self-harm should be reviewed (see HIPAA Privacy Rule and Sharing Information Related to Mental Health). State laws may have specific provisions related to limits of HIPAA when there is concern about harm; consulting with the legal counsel of state professional associations can provide helpful state-specific information regarding how to navigate privacy protections and their limits when concerns about self-harm arise.
Other confidentiality considerations include whether a study obtains an NIH Certificate of Confidentiality as an extra protection for research participants, or whether there are options for stronger confidentiality protections to consider for the specific study population. For example, those doing research with prisoners (and others with arrest histories) can apply for a Privacy Certificate from the National Institute of Justice that provides a higher level of confidentiality protections to study participants.
In a discussion about informed consent with youth at elevated risk for suicide, King, et al. (2008), describe a number of issues to consider, including the need for study teams to be knowledgeable about state laws on emancipated minors, mature minors, and other special circumstances. State law should also be consulted regarding the question of whether it is allowable to consent individuals who are involuntarily committed in a psychiatric facility.12
Another set of issues needing attention during the informed consent process relates to the time period after active study participation. As noted above, suicide attempt and suicide death are low-base rate events; extending the data collection period is one way to increase the chances of capturing a higher event prevalence. Asking potential participants if they are willing to be contacted after the initial study is completed to participate in either follow-up or additional related research is crucial for progress in this field. It is also especially important to include appropriate language on data sharing to facilitate learning across studies. The data sharing language should be explicit about the degree of data sharing that could take place. A link to sample data sharing language for informed consent forms is available on the National Database for Clinical Trials (NDCT) website.
Furthermore, research with suicide death as an outcome can include ascertaining participant-level information from state or national death records, e.g., the National Death Index. Informed consent language permitting the study to access personally identifiable information (PII) from specified databases can facilitate vital statistics searches.
Monitoring and Reporting
What level of data and safety monitoring is appropriate for the study?
Monitoring of clinical research refers to a study’s ongoing and systematic review of data integrity, protocol adherence, and participant safety. As such, monitoring includes: 1) the clinical/safety monitoring of individual participants; 2) the monitoring of safety data across treatment arms and/or across sites; 3) monitoring of study documents and study data to ensure that research is being conducted according to the standards of good clinical practice (GCP) and in accordance with the approved study protocol; and 4) review of study data to assure data accuracy and consistency from collection through storage, retrieval, analysis, and reporting. With the risk and ethical issues that arise when doing research on suicide, all four of these monitoring components are relevant.
This discussion of monitoring will refer to three distinct types of oversight: medical monitoring, GCP monitoring, and Data and Safety Monitoring Board (DSMB) oversight. The study design, size (sample size/number of sites), and risks presented by the population and intervention or procedures, will determine the specifics of what should be put in place for a given study.
There has been a NIH-wide shift toward greater clinical research stewardship by the funding institution, as well as more emphasis on study monitoring conducted by the research team itself.13 The expectation of funder and study team monitoring and oversight is applicable to all clinical research. Nevertheless, research involving suicidal or potentially suicidal participants is reviewed carefully by the NIMH to assess the adequacy of data and safety monitoring, particularly plans to protect at-risk individuals.
Concretely, this means that study teams will want to consider whether to include a medical monitor (sometimes referred to as a safety officer) as part of the study staffing, and whether the medical monitor will be independent. The medical monitor role needs to be delineated in the study protocol (i.e., will this person look only at participant-level safety, or will they also review study data to look for study-wide safety trends), and the timeframes defined for medical monitor review of specific events and/or study-wide trends. Additionally, the study team will need to address who will provide the GCP oversight and quality assurance (QA) for the project. This can involve site study staff (or staff from a Data Coordinating Center [DCC] for multi-site trials) tasked with document and data review, or an independent study monitor, typically a Certified Research Associate (CRA). These staffing decisions about both medical monitoring and data monitoring have budgetary implications that are useful to have in mind during project planning.
In addition to internal data and safety monitoring, clinical trials involving suicide are often expected to have an independent DSMB whose function is to provide independent oversight to assure that safety trends are being evaluated. While IRBs review matters of ethics, safety, and protocol integrity from individual research sites, DSMBs tend to focus on multi-site studies and look for trends that might only become evident when aggregating or comparing data across sites. The DSMB looks at whether study participation is leading to increased risk of harm to subjects by comparing rates and types of harm events across treatment arms and across sites in multi-site studies. Typically, adverse events and serious adverse events are reported to DSMBs, as well as data on study progress and protocol integrity to assure that the study is moving forward as planned and that the data are robust. For assistance determining the appropriate level of monitoring for a specific study and guidance on developing a data and safety monitoring plan for an NIMH-funded study, investigators can refer to the NIMH Clinical Research webpage.
Another aspect of safety monitoring for investigators to consider involves developing appropriate study procedures for assessing and addressing clinical worsening and suicidal crises. Depending on the research design, these issues are more or less likely to be detected, and investigators will want to think about the risk ascertainment opportunities presented in their study design, as well as potential ascertainment biases (e.g., interventions with more patient contact may have more opportunities to detect risk status than control arms). In addition to established in-person or remote assessments of suicide risk, the emergence of real-time data capture and transfer provides researchers with the opportunity to attempt to monitor clinical states in real-time using ecological momentary analysis (EMA) and other forms of active and passive data capture, to examine daily fluctuations in suicidal ideation and/or intent that also incorporate assessment of clinical worsening. Decisions for when and how to address clinical worsening in real-time should be considered during the development of the study protocol and informed consent.
Methodologically, study teams assessing clinical worsening and suicide risk will need to determine the timeframes to consider in these assessments. For example, should the study participants’ clinical state over the course of the study be compared to their previous assessment, or to their baseline status at the outset of the study? Also, is status at a given assessment point going to be based on what they report at a given moment in time (as is captured with EMA), or on what they report has occurred during a specific time period? The answers to these questions will depend on many methodological and study design factors, as well as the purpose of the data being collected (i.e., risk management versus outcome data). Thus, when developing safety monitoring protocols, numerous questions arise for investigators to address:
- What frequency of safety monitoring is appropriate for the study design and the risk level of the population?
- What assessment tools will be used to detect suicide risk and in the protocol developed to respond to identified risk?
- What procedures are established to respond to suicidal crises and clinical worsening?
- What level of professional training is required for study staff involved in assessing and responding to suicide risk?
- Are these procedures being adequately conveyed as part of the informed consent process?
What events are appropriate to consider as expected and unexpected adverse events and serious adverse events for the study?
Suicide-related clinical research studies are unique in that adverse and serious adverse events involving suicidal ideation and behavior are expected to occur. Moreover, these are often the primary study endpoints. In some cases, the safety monitoring protocols encouraged in studies with suicidal participants make it more likely that these events, and clinical worsening, will be identified and reported to designated funding agencies and regulatory bodies. Reporting of AEs to the various governmental agencies and non-governmental entities that provide regulatory oversight or funding to a study can present challenges to study teams due to the variability in definitions of AEs and reporting expectations utilized by different federal funding agencies, governmental regulatory agencies, and non-governmental regulatory entities.14 NIH follows OHRP guidance on the definition of AEs and associated reporting expectations. In addition, NIMH has a reportable events policy that delineates timeframes for reporting events to the NIMH. Suicide prevention studies also present a unique circumstance for the reporting of SAEs because suicidal behavior (ideation, attempts, and suicide deaths) are both expected occurrences and primary study outcomes.
As noted above, there is variability in the field and among regulatory bodies on definition of AEs and SAEs, specifically about whether expectedness and relatedness should bear on whether an event is considered an SAE. Oquendo, et al. looked at the issue of variability in the definition and reporting of adverse event in suicide prevention trials and recommended that the definition on an AE and SAE stand independent of assessments of relatedness and expectedness. As there continues to be inconsistency in the field, however, it is critical that study protocols provide clear definitions of what will be considered AEs and SAEs. In addition, specifying what events (i.e., non-suicidal self-injury, suicidal ideation, suicide attempt, hospitalization, suicide deaths) will be expected AEs and SAEs in the study determines parameters for IRB and DSMB reporting.
In psychiatric medication studies, suicide attempts are typically considered unexpected and immediately reportable SAEs regardless of relatedness, and thus follow immediately reportable guidelines specified by regulatory bodies overseeing the study. For suicide research studies, given that these SAEs are expected, the reporting guidelines may be different for expected and unrelated suicide ideation and attempts, i.e., these events might not be deemed immediately reportable. Delineating in the study protocol what SAEs are immediately reportable based on regulations and determinations of expectedness and relatedness is necessary. The protocol then provides needed guidance to study staff, as well as to funding and regulatory bodies providing study oversight. A final aspect to include in a research protocol is the AE and SAE documentation and reporting procedures, specifying both the staff workflow and timeline for reporting to relevant funding and regulatory bodies.
What are the reporting expectations for suicidality as a treatment side effect for FDA Phase 1 and 2 IND studies?
In 2012, the FDA issued a draft guidance on the assessment of suicidal ideation and behavior in psychiatric and non-psychiatric drug trials using compounds under development. This guidance provides an informative framework for investigational new drug (IND) studies conducting these prospective assessments, and also encourages common safety data be collected across studies to allow for meta-analysis of these data. Language in the guidance can help investigators determine whether these expectations apply to their research, as well as recommendations on the timing and content of the assessments.
What unique issues arise in monitoring and reporting in multi-site trials?
Data and safety monitoring and reporting challenges arise for multi-site studies which need to coordinate these efforts across sites, and establish effective data quality and management procedures. Reporting expectations for NIH multi-site trials involve providing data to a DSMB, as NIH-funded multi-site clinical trials which involve interventions that present potential risk to participants are required to have an independent DSMB, or in some cases, one constituted by the NIH (NOT-98-084). These monitoring and reporting expectations are not unique to research on suicide, but their importance is underscored when the safety data being collected, reviewed, and reported are related to assessments of suicidal ideation and behavior.
A fundamental challenge that multi-site trials must address is establishing and implementing parallel monitoring and reporting processes across sites. Cross-site synchrony can be addressed by having centralized study staff providing site good clinical practice (GCP) monitoring, or medical monitoring. This centralized strategy for medical monitoring mitigates potential discrepancies in approach or implementation across sites for participant continuation determinations, clinical worsening assessments, and adverse and serious adverse event determinations. On the other hand, some studies opt for site-based medical monitors, as research teams want to have a medical monitor available to be part of the clinical assessment process for determinations of clinical worsening and study continuation. Medical monitors in multi-site trials often play dual roles, both making safety determinations for individual patients, and also looking at study-wide safety trends. Thus, if medical monitors are site-based, plans should be made for looking at study wide safety data, both to look for trends, as well as site variability issues. Similarly, for GCP monitoring, some studies opt to have site-based monitors implementing a study-wide monitoring plan, while others have study-wide monitors. Again, studies with site-based GCP monitoring should periodically review study-wide GCP compliance and site variability. Whether in a single-site or multi-site trial, decisions about how to structure the GCP and medical monitoring will be driven by issues of study design and patient population, as well as by available resources. As noted earlier, budgeting for adequate GCP and medical monitoring is appropriate for NIMH-funded studies.
What risk management and data and safety monitoring elements are appropriate to include in non-intervention studies?
The fields of psychiatry and neuroscience are engaged in research efforts to identify biomarkers that alter risk for suicide, as well as the mechanisms of action by which potential treatments have their effect. The level of monitoring indicated for these clinical research studies should be based on the risks presented by the participant population and the study procedures, as discussed in the NIMH Guidance on Risk Based Monitoring. Clinical research studies that include currently or recently suicidal participants will need plans for participant monitoring, risk management, and adverse events documentation and reporting that are in line with the study design. In some cases, an independent safety monitor or a DSMB would be appropriate for a non-intervention study; this would be influenced by the number of participants and sites, the length of study participation, the risks presented by the subject population, and the complexity and risks of the study procedures.
Responding to Suicidal Crises and Clinical Worsening
What study procedures need to be in place to respond to suicidal crises and clinical worsening that occur during the study?
Studies that include suicidal and potentially suicidal participants have developed a range of clinical management options appropriate for their study designs (i.e., in-person and remote risk assessments). This involves the safety monitoring referred to above, and then planning steps to attempt to connect participants with appropriate care. Study protocols should provide a detailed description of this process and its staffing (i.e., the provision of clinical backup for non-clinical staff conducting assessments). Some studies in which the intervention or rater sessions are completed remotely--and often by raters who are not clinicians--have developed clinical management protocols that include warm transfers to suicide hotlines (i.e., making a telephone connection to a crisis resource while maintaining contact with the participant in order to make a direct transfer). These protocols require establishing arrangements that set up the technical and contractual links necessary to do these transfers, training study staff, setting up the privacy and confidentiality protections that allow such information sharing to take place, and monitoring to ensure that all precautions are implemented as planned throughout the study. When high risk youth participants are involved in a study, there may be an additional step of informing parents and guardians about the crisis and the need for intervention. Whether for adults or youth, these risk management procedures need to be shared with participants as part of the informed consent (and assent) process.
Another aspect of clinical management arises when participant symptoms worsen and individuals need care outside the study protocol before further participation in the research. Determination of clinical worsening or suicidality can also trigger early termination from the study. In such cases, study teams will want to think through how to manage potential conflicts of interest that arise for researchers when an assessment of clinical deterioration could lead to loss of a study participant. Specifically, what internal and independent clinical review and oversight processes need to be in place to assure patient safety in cases when a change in a study participant’s clinical status determines ongoing research participation? Some studies, based on study design and risks presented, will benefit from an independent medical monitor in an oversight role to conduct clinical assessments as part of the evaluation of study continuation, and/or to review the documentation of the assessment and the study continuation decision made by a member of the study team. A DSMB can also play a role in this oversight, to assure that ethical decisions are being made with regard to ongoing study participation. Documentation of the decision making process regarding risk management and study continuation allows study monitors and DSMBs to assure that study teams are conducting studies safely, ethically, and as per protocol.
End of Study Participation
What are the issues to anticipate and plan for when participants come to the end of their study participation due to early termination, study completion, or a participant death?
Studies which enroll participants endorsing recent/active suicidal ideation and behavior need plans in place for the end of study participation as it impacts patient safety and welfare, most importantly in cases when individuals are not engaged in ongoing care. Two issues that need attention include end of study procedures: 1) to assess that individuals are safe and have information that will help them stay safe (e.g., hotline numbers, clinic resources), and relatedly, 2) assuring that individual are not being “abandoned” without care by providing linkages to care when needed. Because many questions remain regarding the longer-term benefit of interventions, investigators may also wish to invite those terminating the initial study early to continue to participate in follow-up assessments, and/or allow the review of their records from health systems or other systems relevant to the study population (i.e., justice, schools) so that outcome data can continue to be collected.
In the case of a patient death, what protocol is in place for contact with the family, and support of research staff?
While suicide deaths in research studies are rare, participant suicide deaths are a critical topic that study teams need to plan for in their study procedures. As noted in the adverse and serious adverse events reporting discussion above, protocols should include language on whether suicide deaths are considered expected or unexpected adverse events, what oversight bodies need to receive serious adverse event reports, and on what timeline. Guidance can include planning who on the study team will speak with family members and, when appropriate, other study participants; how to talk about the suicide with these affected individuals; and what the process will be for providing support to study team members.
As new clinical designs, methodological approaches, and technological advances have been developed and applied to clinical research, additional considerations have emerged for investigators working with participants at heightened risk of suicide.
What are the unique issues presented by pragmatic trials involving individuals at higher risk for suicide?
Despite a growing number of efficacious treatments that reduce suicide risk,15, 16 few of these efficacious interventions have been studied in large-scale community or health delivery settings. The launching of pragmatic effectiveness trials to assess how effective specific prevention interventions are in existing health care systems raises new issues. These trials often have: 1) broad inclusion criteria and few exclusion criteria (e.g., any adult with a given diagnosis, or a given assessment score); 2) automated recruitment and/or enrollment; 3) a modified informed consent process and/or informed consent waivers; 4) care delivered as part of, and within the constraints of, existing health care systems; 5) outcome data extracted from medical records or other administrative health care data sources (i.e., insurance claim data); and 6) large numbers of sites and participants.
Suicide-focused pragmatic trials are likely to receive high levels of regulatory oversight, as they are often large multi-site trials, include a population at elevated risk for suicide, and are of significant public health interest given the hope to impact health policy and practice. At the same time, the research model for pragmatic trials (e.g., learning health care systems17) differs from those regulatory bodies, such as IRBs and DSMBs, are accustomed to seeing.18 Working out protocols for informed consent, risk management, and adverse events reporting may take more back-and-forth between researchers and regulatory bodies than a traditional efficacy trial, as the research study aims and designs are significantly different. For example:
- What is the appropriate informed consent process, or when is a waiver appropriate, in a trial enrolling individuals expressing suicidal ideation who will be receiving an intervention being newly implemented in a health care system, and whose outcome data will be collected through their EHR?19, 20
- Is a single post-randomization consent design appropriate for studies in which only those randomized to the active arm are approached for consent while the control arm participants are not aware their data is being collected as part of a randomized clinical trial?21, 22 and,
- What is the appropriate AE and SAE monitoring and reporting plan for studies in which suicide ideation and behavior are the study endpoints and thus are expected, and the outcome data on ideation and behavior are ascertained from administrative health records and state death records?20
Pragmatic trials, as they take place in existing health care systems, may face constraints to enhancing the risk assessment and clinical management available in that system. Enhancements to the treatment-as-usual study arm can be limited because study participants receive the care provided in that setting. Finally, how are privacy protections provided when large amounts of patient data are being transferred between administrative health system records and study databases?
Pragmatic effectiveness researchers, ethicists, and regulators are thinking through existing approaches to research ethics and safety to figure out how these apply within a learning health care context with regard to design,22 consent,19 and data and safety monitoring.20, 23 There are ongoing dialogues among the various stakeholders in this arena of research ethics and practice to address the debates presented by this emerging field.18 ,21, 24 The NIH Common Fund is supporting the Health Care Systems Research Collaboratory to explore these questions. The Collaboratory website has numerous relevant resources, including a link to a page of regulatory issues, as well as presentations on issues to think about in data and safety monitoring in clinical trials.
What are the issues presented by research involving individuals at higher risk for suicide which use newer technologies as a central part of study conduct?
A second emerging area in suicide research involves the use of technology in prevention and treatment, as well as in the conduct of the research. Mental health research in general is incorporating many aspects of technological innovation that are increasingly a standard part of health care delivery and research: cloud-based and mobile technologies and devices, social media, use of EHRs, web portals, secure messaging, and the development of big data platforms are all areas where research is rapidly growing.
In the arena of therapeutic devices, both mobile and non-mobile devices are of interest, as research on evolving electro-convulsive therapy (ECT) and transcranial magnetic stimulation (TMS) protocols, as well as more experimental treatments such as magnetic seizure therapy (MST), are assessing for potential impact on suicidal ideation and behavior. These treatment modalities may have a beneficial effect on suicidal ideation in some patients, including providing rapid anti-suicidality action. 25, 26, 27, 28 In contrast to their approach with psychiatric medications discussed above, the FDA has not issued a guidance with regard to assessment of suicidal ideation and behavior when conducting research using ECT, TMS, and other devices used in the delivery of psychiatric treatment.29
For suicide research, a key issue to consider is the conduct of risk assessment and management when some or all of the intervention and study contact is remote. Examples include: 1) studies attempting to identify suicide risk in individuals’ electronic communications or social media use; 2) cloud-based interventions that participants engage in through web portals, websites, or apps; and 3) symptom monitoring/care management interventions that tracks patient behavior and symptoms via EMA, smart phone sensors, or responses to automated surveys. In some cases, mental health interventions that use technologies that allow for remote contact and assessment may work to keep study participants more reachable and connected to the study team, or in the case of some pragmatic trials, to the study participants’ clinical providers. Alternatively, participants may be in studies conducted remotely without a study team member to contact in case of a psychiatric emergency, or a study design that involves minimal contact between research staff or clinical providers, and study participants. Traditional models of risk management that rely on in-person or telephone assessment may not be applicable for these studies, and alternative procedures need to be developed. Study teams and technology platforms are working on developing automated strategies for responding in cases where suicidal ideation and/or behavior are endorsed, with considerations about what type of response is needed (e.g., alerts, notifications, crisis line information) and to whom the response should be directed (e.g., providers, medical monitors, study participants, bystanders, those involved in treatment as usual and/or those in an active intervention).
Social media suicide prevention research raises ethical questions for investigators regarding not only the appropriate response to and management of the safety of potentially suicidal study participants, but introduces “by-standers”, those who become aware that someone is at-risk of suicide through an on-line setting (e.g., Facebook and Instagram tools). These are questions that are generating significant interest among researchers as technology represents a rapidly developing area impacting broadly on study conduct in areas such as informed consent, monitoring and reporting, risk management, and data quality and security.
Automated risk assessment and management is increasingly used in studies in which suicide-related outcomes are likely, and, in some cases, a primary study endpoint. Researchers need to anticipate what can go awry when using electronic methods of ascertaining suicide risk levels. For example, if study participant risk is identified via a computer program that processes electronic data based on participant responses to remote assessments, an error or bug in the program could interfere with planned safety procedures. Programming errors and bugs can impact the scoring of assessments and notification failures. This issue also applies to electronic methods of identifying participants eligible for study enrollment; programming errors or problems with an electronic algorithm can lead to participants who are eligible for the study not being enrolled or ineligible participants being enrolled. These types of potential problems should be anticipated, and stress tests and other types of accuracy checks built into procedures can allow study teams to identify problems and rectify them quickly.
Relatedly, study teams should consider what level of data security they need to build in to their study protocols when the study involves potential exposure of personally identifiable information (PII) and other sensitive information (e.g., suicide risk). Studies that include the use of relatively basic technologies (e.g., texting, email), as well as larger and more complex systems (e.g., sensor data, social media, EHRs, and studies with significant data being transferred between independent databases) will need to work with data security experts during the study planning process.
Finally, researchers developing mobile apps designed for mental health applications will want to consult the FDA’s guidance on mobile medical applications (MMAs); MMAs designed to help individuals with diagnosed psychiatric conditions are on the list of those the FDA has discretion on whether or not to regulate. The FDA provides information on what types of mobile apps the FDA regulates, and examples of mobile apps for which the FDA will exercise enforcement discretion.
As suicide prevention research has advanced to address clinical course, risk detection, treatment development, comparative effectiveness, and implementation, the contexts for research have also become more diverse. Researchers30 and institutions are beginning to share what they have learned regarding safety and ethical procedures. NIMH welcomes this reporting, and anticipates further challenges as research progresses. The purpose of this discussion was to provide an overview of issues and approaches for investigators undertaking research with participants at heightened risk of suicide. As is evident, unique ethical and safety considerations arise when doing research with individuals at heightened risk for suicide. Working through these issues when developing a research design and protocol, in consultation with federal policies and guidance, will promote ethically and scientifically robust studies to further the field of suicide research and strengthen suicide prevention efforts.
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Federal Regulations, Policies, and Resources for Support of Human Subjects Research
Department of Health and Human Services (HHS)
Federal Policy for the Protection of Human Subjects (the Common Rule)