NIMH Clinical Trials Funding Opportunity Announcements - Applicant FAQs
- 1. What is different about the new NIMH-issued Funding Opportunity Announcements (FOAs) seeking Clinical Trials? What is an "experimental therapeutic approach" to designing a clinical study?
NIMH is asking investigators to use an experimental therapeutic (or experimental medicine) approach in the design of their clinical trial studies. An experimental therapeutic approach rigorously tests the intervention in a clinical trial design. The approach assesses the ability of the intervention to alter a well-defined target, such as a regional brain or neural network function, or other well-defined targets such as psychological-level processes (e.g., attentional bias) that could lead to an improvement in symptoms or other desired outcomes (e.g., improved cognitive functioning). Rather than testing the intervention in a traditional efficacy outcome trial, the experimental therapeutic trial requires objective measures of target engagement as initial evaluation points. Particularly in trials where the intervention is a medication or brain stimulation device, a dose finding study would be employed to identify a dose that adequately engages the target without producing significant side effects. For other types of interventions, parameters of the protocol can be manipulated to insure adequate intensity and other factors needed for a definitive test of target engagement. Results from the study inform a first "go/no-go" decision point: only if the intervention adequately engages the target can an investigator definitively evaluate whether the effects on the target can affect clinical symptoms.
In a subsequent study, using the experimentally defined dose(s) or optimized protocol, a positive impact on clinical symptoms at doses that achieve target engagement constitutes proof of concept of a role for the target in the clinical or behavioral problem under study. The same principles are applicable to all intervention types (including devices, psychosocial/behavioral interventions, and organizational behaviors); for instance, a new behavioral intervention might target a psychological mechanism in which "dose" might correspond to length/number of sessions, and target engagement would be assessed via quantitative measures of the mechanism. Note that in experimental therapeutic trials for drugs, devices, or psychosocial interventions, a negative result is also informative, suggesting attention and investment should be focused on other, more promising targets.
It is a common misconception that adding a biomarker or cognitive measure to a study designed primarily to examine clinical outcomes will make that study an "experimental therapeutic" trial. Rather, the target engagement measure should be used to determine how the dose or protocol parameters impact the target. Otherwise, a negative clinical outcome could be due either to inadequate dosing or intensity of treatment, or to failure of the change in target to affect a change in clinical outcomes. The more systematic experimental therapeutic strategy aims to accelerate treatment development by avoiding such inconclusive results.
For additional discussion of the experimental therapeutics approach to drug development, see:
- Soares HD. The use of mechanistic biomarkers for evaluating investigational CNS compounds in early drug development. Curr Opin Investig Drugs. 2010 Jul; 11(7):795-801.
- Morgan P et al. Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving Phase II survival. Drug Discov Today. 2012 May; 17(9-10):419-424.
We encourage you to contact the Scientific/Research Contact listed at the end of the relevant FOA to discuss how the experimental therapeutics approach might be best applied to your particular study. See Q5 for advice about finding the most relevant FOA.
- 2. What is a target?
The term “target” refers to a factor that an intervention intends to modify, based on a hypothesis that modification of that factor will result in improvement of symptoms, behavior, or functional outcomes. Targets can range from molecular entities, synaptic- and circuit-level regions or networks proposed for pharmacologic agents, to neural systems and cognitive or emotional processes for psychotherapeutic interventions, to provider behavior, decision-making or organizational policies or behaviors for services interventions. An appropriate target is an intervening variable that has either been demonstrated to be associated with a clinical symptom or functional deficit, or is hypothesized (based on empirical evidence) to impact the biological pathway through which a clinical or functional benefit would be expected to occur, and thus is hypothesized to contribute to the intervention’s impact. In the case of services interventions, the intervention may target the patient (e.g., adherence), the provider (e.g., adherence to prescribing guidelines, fidelity in the delivery of research-supported psychosocial interventions), or the system/organization (e.g., organization climate, readiness to adopt evidence-based practices) in the service of improving access, engagement, or quality of mental health services.
- 3. How do I incorporate targets into my trial design?
Successful applications to NIMH Clinical Trials FOAs will explicate a conceptual framework that clearly identifies the targeted mechanism and provides solid evidence of the relevance of that mechanism to the clinical symptom, behavior, or functional deficit that the intervention hopes to improve. The conceptual framework should also provide a scientifically-grounded hypothesis about the ability of the intervention to engage (or modify) the target, and the means by which target engagement will be assessed or measured.
For pharmacological agents and devices, the measures used should be able to detect differences in the level of target engagement as the intervention is optimized (through changes in dose, intensity, frequency, etc.) and how it associates with side effects. These data are critical for demonstrating optimal target engagement of the treatment level or intensity to be evaluated in a future clinical trial. It is recognized that some cognitive, behavioral, and psychotherapeutic interventions without a direct biological impact may not be conducive to the same type of dose finding strategy. However, all interventions should be able to demonstrate adequate target engagement, and make use of measures at multiple timepoints to inform questions of sequencing of intervention effects on proximal and distal measures (see Table in FAQ 4), timing of improvement in the course of intervention, and other questions related to the optimal intensity of the intervention.
Clinical trials can then rigorously test whether this target engagement changes symptom or functional outcomes in predicted directions. Verification of target engagement and associated symptom or functional improvement provides evidence in support of “validating” a target for further study. On the other hand, demonstration of adequate target engagement without symptom or functional change would support “rejecting” the target in the sense that change in the target was found to be insufficient for resulting in meaningful clinical change. Either outcome would be highly informative for next steps in treatment development.
- 4. How is "target engagement" best measured?
Measures of target engagement must be objective, sensitive, and reliable. Ideally these measures show variation in the clinical population that mirrors specific functional deficits. Brain based measures could include, for example, neurochemical assessment of receptor occupancy or enzyme activity via positron emission tomography (PET) or single-photon emission computed tomography (SPECT), measures of circuit activation via functional magnetic resonance imaging (fMRI) or regional brain metabolism using fludeoxyglucose positron emission tomography (FDG PET), or measures of neuroplasticity via electroencephalography (EEG), as well as performance on behavioral tasks that reflect circuit activation. Other measures may be used for identifying engagement of clinician- or system-level targets. Note that target engagement measures need not correspond to the intervention target as in the table, but should reflect the mechanism of action of the intervention as directly as possible. For example, in the absence of a PET ligand, an fMRI measure may provide a sufficiently proximal surrogate of the intervention's action at a target that it can be used to determine an optimal dose.
Table: Examples of Targets, Descriptions, and Target Engagement Measures
Targets Examples of Target Engagement Measures Molecular PET receptor occupancy Neural Circuit/Systems/Physiology FDG PET, fMRI, MRS, EEG, MEG Psychological or Behavioral Processes performance in attention bias paradigms, empathic accuracy, fear-potentiated startle Clinical Process referral or prescribing behavior, fidelity to effective intervention protocols, retention of patients in care Organizational/Systems level e.g., organizational culture, climate, and/or structure, financing models, leadership, coordination/collaboration within and across systems
- 5. How do I decide which FOA to apply for?
NIMH strongly encourages potential applicants to talk with a Program Officer (Scientific/Research Contact) before preparing and applying for one of the clinical trial FOAs. Program Officers can assist with determining the appropriate FOA, as well as give advice to optimize the project's fit with NIMH priorities. Program Officers are listed as Scientific/Research Contacts at the end of each FOA; using the guidance below, determine which FOA seems like the best fit for your project, and email or call the Scientific/Research Contact for advice.
Your choice of FOA will depend on the stage of intervention development or testing you propose. The table at the top of the Clinical Trials Funding Opportunity Announcements web page, “Clinical Trials Pipeline – Phase of Intervention Development ” illustrates how each FOA supports different phases of the intervention development pipeline.
There are three FOAs that support very early stages of intervention development (e.g., the translation of basic research into novel intervention targets and strategies), including tests of target engagement and evaluating the impact of change in a target on clinical outcomes in proof-of-concept and pilot studies. The FOA entitled “First in Human and Early Stage Clinical Trials of Novel Investigational Drugs or Devices for Psychiatric Disorders (U01) ” supports the rapid collection of data to “de-risk” novel investigational drugs or devices in order to attract private funding for further clinical development as FDA-approved treatments. Additionally, this FOA is intended to support the testing of novel drugs or devices for use in pediatric populations (e.g., first in pediatric populations) to provide initial proof of concept for further development toward pediatric approval.
Two versions of the FOA, “Exploratory Clinical Trials of Novel Interventions for Mental Disorders (R61/R33 and R33 ) ” support early stage investigations of target engagement and whether change in the target is associated with change in clinical measures. support early stage investigations of target engagement and whether change in the target is associated with change in clinical measures. A range of intervention types are of interest, including behavioral, pharmacological, biologics-based, cognitive, device-based, interpersonal, physiological, or combined approaches.
The FOA, “Confirmatory Efficacy Trials of Non-Pharmacological Interventions for Mental Disorders (R01) ” is available to support confirmatory efficacy trials of non-pharmacological therapeutic and preventive interventions, for adults or children with mental disorders, for which there is evidence of target engagement and a signal suggesting intervention efficacy. Interventions can include, but are not limited to, behavioral, cognitive, and interpersonal approaches, or combinations thereof. This FOA does not support confirmatory efficacy trials of pharmacological interventions, as it is expected that industry would support these types of trials.
There are also three FOAs that support studies to establish the effectiveness of interventions for use in community practice settings and to test hypotheses regarding moderators, mediators, and mechanisms of action of these interventions.
“Pilot Effectiveness Trials for Treatment, Preventive and Services Interventions (R34) ” encourages pilot research on the effectiveness of preventive and therapeutic interventions with previously demonstrated efficacy, as well as research on the development and preliminary testing of innovative services interventions that target patient-, provider-, organizational- or systems-level factors to improve access, engagement, quality, efficiency, and delivery of services.
Two versions of “Clinical Trials to Test Effectiveness of Treatment, Preventive, and Services Interventions (R01 and Collaborative R01 )” support larger clinical trials with adequate power to definitively address questions of effectiveness and services interventions. This set of FOAs is explicitly focused on research that addresses practice-relevant questions.
Each FOA describes (in Part 2, Section 1, “Funding Opportunity Description”) the purpose or objectives of the FOA, as well as NIMH priorities related to that announcement. Use the “Clinical Trials Pipeline – Phase of Intervention Development” Table to narrow down the FOA that is most likely to support the research you would like to propose, and then read the descriptions of each FOA. Scientific/Research Contacts are listed at the end of each FOA; they can advise you about the most appropriate FOA, and may direct you to other Program staff in the relevant research area for additional advice. You may call or email these contacts, but it is particularly helpful and efficient if you send a brief description of your project, including specific aims, in an email.
- 6. My trial does not fit any of these FOAs. Can I just submit an application to the parent NIH FOAs [ PA-13-302 (R01) , PA-13-303 (R21) , and PA-13-304 (R03) ]?
No. NIMH is only allowing clinical trial applications to be submitted in response to these FOAs (see NOT-MH-14-007 ). The only exceptions to this submission policy are applications that are not developing or testing the efficacy of interventions, but utilize an intervention as a probe to identify biomarkers or otherwise interrogate the pathophysiology of a disorder or treatment response. These exemptions are detailed in Q7 . All other treatment development clinical trial applications submitted to NIMH must be in response to specific NIMH Clinical Trials FOAs and may not be submitted to any NIH parent FOA announcements.
- 7. Which types of clinical studies involving a clinical trial component may be submitted to the parent R01, R21, or R03 announcements, as outlined in NOT-MH-14-007 ? Can collaborative R01 clinical studies be submitted?
There are a few specific scenarios in which a study with an intervention component is exempt from the requirement to submit through the specific NIMH Clinical Trials FOAs, and could be submitted through the parent R01, R21, and R03 announcements. These exemptions primarily apply to projects that involve the use of efficacious interventions, including biomedical, behavioral, cognitive, and other psychotherapeutic approaches, where the aims do not involve establishing the efficacy/effectiveness of the intervention. Additionally, Collaborative R01 clinical studies meeting these exemption requirements can be submitted under PAR-14-165 , Clinical Studies of Mental Illness Not Involving Treatment Development, Efficacy, or Effectiveness Trials (Collaborative R01). Please contact your program officer well before the receipt dates, to ensure adequate time to determine whether an application is eligible to be submitted under the parent FOAs [PA-13-302 (R01) , PA-13-303 (R21) , and PA-13-304 (R03) ] or PAR14-165 . Applications submitted under the parent FOAs that involve clinical trials to develop or test efficacy of interventions will be returned and not reviewed.
- NOT-MH-14-007 states that "Applications…that utilize a clinical trial component…to examine potential novel biomarkers of treatment response for the intervention, rather than to test for efficacy," can be submitted under the parent R01 and R21 announcements. This notice exempts studies with aims that clearly indicate that the purpose of the study is to identify reliable and stable biomarkers that reflect a pathophysiological or disease process, that are correlated with individual treatment response, or identify subjects that would most benefit from the intervention, rather than having the primary goal of evaluating efficacy. This exception does not apply to early-stage novel treatment development studies in which biomarkers are collected during the intervention trial to establish CNS dosing for subsequent later stage trials. Trials that develop or test the efficacy/effectiveness of treatments as part of their aims are not exempt and must be submitted to one of the NIMH Clinical Trials FOAs. PIs are encouraged to contact program staff prior to submitting their application, to make sure it fits the appropriate FOA.*
- Studies in which an intervention with demonstrated efficacy for that population (e.g., an SSRI for depression) is used as a manipulation to understand mechanisms of response, non-response, or risk of adverse effects of an efficacious intervention. In the case of medications and devices, these would be FDA-approved indications only. In the case of non-pharmacological interventions, previous evidence of efficacy must be convincingly documented in the application.*
- Studies in which an intervention with known physiological effect (e.g., a neurotransmitter agonist, or activation of specific neurocircuitry via neurostimulation) is used as a manipulation to understand the pathophysiology of the disorder, but does not aim to establish efficacy or further treatment development. Evidence of adequate physiological effect at the intervention dose or intensity to be used must be clearly documented in the application.*
- Studies in which a manipulation (physiological or behavioral) is used to answer basic science questions about normal brain function, and not to establish efficacy or advance treatment development.*
- A clinical research study that administers a standard, indicated intervention in order to control for confounds related to treatment heterogeneity, and the aims do not include evaluation of efficacy of the intervention.*
- Longitudinal follow-up and assessment of participants from completed clinical trials where there will be no additional recruitment or further treatment of participants.**
- Continuations of NIMH-supported studies that have been added on to large clinical trials sponsored by other institutes or organizations, whether or not the NIMH-supported research involves examination of interventions outcomes, may be acceptable for submission to the parent FOAs.**
*Please contact your program officer to ensure the proposed study is within NIMH priorities before preparing applications.
**Please contact your program officer before preparing an application, to ensure that the proposed longitudinal follow-up and/or assessment of participants from completed trials is within NIMH priorities.
- 8. Where are applications submitted in response to these Clinical Trial FOAs reviewed?
Applications submitted in response to these FOAs will be reviewed by special emphasis panels at NIMH.
- 9. I heard that some applications have been returned without review because they are not responsive to the clinical trial FOAs. Is this true, and how can I be sure that my application is responsive?
It is standard procedure at NIH to return applications submitted to Requests for Applications (RFAs) that are not responsive to the RFA. (Language about this is found in the specific RFA issued by NIH.) Thus, applications submitted in response to the clinical trial RFAs are reviewed for responsiveness prior to scientific review, and returned to the submitting Institution if they are deemed not responsive to the scientific focus of the RFA. Applications are also returned if they are missing any of the key elements requested in the FOA.
To ensure that this does not happen to you, please carefully review two important sections of the FOA:
- Within Part 2, Section I, “Funding Opportunity Description” of each FOA, there are series of statements that describe the areas of research interest of the FOA, followed by several bullets under the header “Examples of studies that are not responsive to this FOA and will not be reviewed.” These examples should be carefully reviewed as research proposed in these areas will be returned as non-responsive.
- Within Part 2, Section IV, Number 2, “Content and Form of Application Submission” of the RFA, pay particular attention to the sections on “SF424(R&R) Other Project Information” and “PHS 398 Research Plan.” These sections outline the necessary components to be included in your application. If any these key components are missing, the application will be returned as non-responsive.
Some applications propose study designs that are not in alignment with the experimental therapeutics goals of the FOAs. To avoid misalignment with the goals of the FOAs, we strongly recommend that applicants discuss their study plans with their Program Officer early in the development of their application. There are some additional common problems that have resulted in applications to the clinical trials FOAs being returned. For the phased “Exploratory Clinical Trials” R61/R33 FOA (RFA-MH-16-406 ), common problems include the lack of quantifiable milestones and timeline as well as a lack of clear “go/no-go” criteria for continuing into the R33 phase of the award. For the Effectiveness FOAs (RFA-MH-16-410 , RFA-MH-16-420 , RFA-MH-16-415 ), a common problem is the lack of a strong empirical justification of the need for an adaptation of a proposed intervention. For all of the clinical trials FOAs, common problems could include: a lack of study participant and recruitment descriptors; failure to provide evidence of an Investigational New Drug (IND) permission or Investigational Device Exemption (IDE) approval; or, documented FDA-submitted application for studies of pharmacologic compounds and devices.
- 10. I am an early career investigator who is eligible to apply for a mentored K from NIMH. I’m planning to propose a clinical trial in my mentored K application. Is NIMH still accepting mentored K applications that propose clinical trials?
Yes. However, as the notice (NOT-MH-14-007 ) indicates, mentored K award applicants should be aware that NIMH expects any clinical trial proposed to be consistent with the stated research goals and priorities relevant to clinical trials as outlined in the clinical trials FOAs and on the NIMH clinical trials website. Please be aware that applicants are strongly encouraged to review the NIMH clinical trials website and consult with NIMH staff early in the process of developing an application. This early contact will provide an opportunity to ascertain NIMH policies and guidelines, as well as to discuss whether the proposed project includes a requisite target(s) and objective measure(s) of target engagement. For additional information and Program Contacts, please see: Guidance for NIMH Mentored K Applicants Proposing Clinical Trials.
- 11. Are multi-site trials allowed?
Yes. However, NIMH strongly encourages a discussion with the Scientific/Research Contact for the relevant FOA before submitting applications for multi-site trials. If the purpose of the multi-site trial is to determine the effectiveness of interventions, and to test hypotheses regarding moderators, mediators, and mechanisms of action of these interventions, the applicant should use the Collaborative R01 for Effectiveness Research RFA .
- 12. Are multi-site trials expected to have a single Institutional Review Board (IRB)? Who will organize a single IRB?
Multi-site trials that propose a single IRB of record are preferred. It is the responsibility of the applicant to designate the IRB of record and secure appropriate agreements by IRBs from all institutions involved in the proposed multi-site trial. NIMH will expect all agreements to be in place prior to release of funding.
- 13. Is it necessary to register all clinical trials with clinicaltrials.gov?
Yes. All trials that are funded, regardless of the phase, will be expected to be registered with clinicaltrials.gov prior to funding.
- 14. Is data sharing encouraged? When are investigators expected to share the data?
Yes. NIMH expects investigators to share raw, de-identified, individual-level data via the National Database for Clinical Trials related to Mental Illness (NDCT ; see NOT-MH-14-015 and NOT-MH-15-012 ). Submission of descriptive/raw data is expected semi-annually (every January 15 and July 15); submission of all other data (processed, analyzed) is expected at the time of publication, or prior to the end of the grant, whichever occurs first. Established by the NIH, NDCT is a secure informatics platform for scientific collaboration and data-sharing that enables the effective communication of detailed research data, tools, and supporting documentation. NDCT links data across research projects through its Global Unique Identifier (GUID) and Data Dictionary technology. Investigators funded under this FOA are expected to use these technologies to submit data to NDCT. Planning and budgeting for data sharing should be described in your application. More details about the elements needed and budget guidelines can be found in Part 2, Section IV, Number 2, Resource Sharing Plan.
- 15. Is a recruitment plan required? Will NIMH monitor progress of the trial? What are the consequences for failing to meet the recruitment goals?
Yes. A detailed recruitment plan with target enrollment numbers is a required component of every application that enrolls participants. For each FOA, Part 2, Section IV, Number 2, Content and Form of Application Submission, provides instructions to include detailed information about plans for study recruitment and enrollment. NIMH requires reporting of recruitment milestones for participants in clinical trials as noted in NOT-MH-05-013 While trials in response to these FOAs may not seek 150 subjects or more (the level at which this reporting has been required), we expect reporting for all trials, even those with fewer than 150 subjects. Recruitment reports are expected every 4 months. Failure to meet recruitment goals may result in withholding of funds or suspension of the trial.
- 16. To assess long-term outcomes, I want to submit a grant application to conduct a systematic prospective follow-up of participants who took part in a now completed randomized trial. Should I use the Effectiveness Research FOA or the parent R01 FOA?
If you do not plan to enroll any new participants, and only previously randomized participants will be assessed, and you are not adding treatment as part of the proposed study, you should use the parent R01 FOA .
- 17. I want to apply for funding to further analyze an existing clinical trial database to address questions that are beyond those addressed in the planned primary analyses of the trial. Should I use the parent R01 FOA ?
Because you do not plan to enroll new participants, and will not be re-contacting study participants, you should use the parent R01 FOA .
- 18. I want to apply for funding to test if a training intervention for care providers enhances their competence in identifying patients at high risk for suicide. I plan to randomize providers to receive the intervention or not. Should I use the parent R01 FOA?
The proposed study is a clinical trial evaluating the effect of an intervention for care providers, so you should use one of the NIMH Clinical Trials FOAs. The relevant FOAs for this type of study are RFA-MH-16-420 (R01) or RFA-MH-16-415 (Collaborative R01), Clinical Trials to Test the Effectiveness of Treatment, Preventive, and Services Interventions; and RFA-MH-16-410 (R34) , Pilot Effectiveness Studies and Services Research Grants.
- 19. I want to apply for funding to conduct a prospective, naturalistic study of patients being treated in practice settings. Should I use the parent R01 FOA?
Because the participants are not assigned to treatment as part of the study, you should use the parent R01 FOA .
- 20. I want to apply for funding to test whether a treatment intervention results in a more efficient and/or better-accepted care delivery strategy than usual care. I plan to randomize practices to using the intervention or not. Should I use the new Effectiveness Research FOA or the parent R01 FOA?
The proposed study is a clinical trial, so you should use one of the Effectiveness Research FOAs (see Q5 , above, for more information).
- 21. What is a Data and Safety Monitoring Plan?
A data and safety monitoring plan (DSMP) is a plan that outlines oversight and monitoring necessary to ensure the safety of participants and the validity and integrity of the data in a clinical trial. This is required for all NIH-supported or conducted clinical trials . For more information, see:
- 22. How does an applicant decide whether a Data and Safety Monitoring Board (DSMB) is required?
- DSMBs are required for all multi-site clinical trials.
- DSMBs are generally required for Phase III clinical trials.
- A DSMB may be required for Phase I, Phase II, or Phase III clinical trials if:
- the clinical trial is blinded, or
- the clinical trial involves high risk intervention(s), or
- the clinical trial includes vulnerable population(s).
The Program Official, in consultation with the NIMH Office of Clinical Research, will provide oversight to determine the level of monitoring required for funded studies.
For more information, see:
- 23. Can applicants propose to use an Independent Safety Monitor (ISM) or a non-NIMH DSMB?
Yes. As part of a Data and Safety Monitoring Plan (DSMP), applicants can propose an ISM or an independent DSMB (subject to review and approval by the Program Official). The monitoring responsibilities of the ISM and DSMB enhance, but do not replace, the monitoring responsibilities of the Principal Investigator (PI) and the Institutional Review Board (IRB). The PI and study team retain responsibility for real-time clinical management of the study.
For more information, see:
- 24. How are adverse events reported?
The NIMH Reportable Events Policy outlines NIMH’s expectations regarding the submission of reportable events (i.e., Adverse Events (AEs); Serious Adverse Events (SAEs); Unanticipated Problems Involving Risks to Subjects or Others ; protocol violations; non-compliance (serious or continuing); suspensions or terminations by monitoring entities (e.g., Institutional Review Board (IRB), Independent Safety Monitor (ISM)); and suspensions or terminations by regulatory agencies) to NIMH. Also, see this Glossary of Terms for additional details.
This policy is specific to reporting to NIMH and does not replace regulations or policies requiring reporting of these events to other monitoring entities or regulatory agencies.
- 25. What materials can be included an appendix of an NIMH clinical trial application?
The following materials may be included in an appendix :
- Published manuscripts and/or abstracts only when a free, online, publicly available journal link is not available;
- Manuscripts and/or abstracts accepted for publication but not yet published;
- Patents materials directly relevant to the project;
- Surveys, questionnaires, data collection instruments;
- Intervention protocols and manuals;
- Informed consent documents
No more than three manuscripts may be included per application. It is strongly recommended that intervention protocols and manuals be included in the appendix.
Most importantly, the appendices should not be used to circumvent the page limitations of the Research Strategy.