FAQs for RFA-MH-15-800 Consortium on Biomarker Outcome Measures of Social Impairment for Use in Clinical Trials in Autism Spectrum Disorder

FAQs for RFA-MH-15-800  Consortium on Biomarker Outcome Measures of Social Impairment for Use in Clinical Trials in Autism Spectrum Disorder

1. What is the purpose of this FOA?

The goal of the Consortium project is to generate objective tools for use in clinical trials of behavioral or pharmacologic interventions to address social impairments in ASD.

• Stratification biomarkers
• Objective measures of social impairment in ASD
• Collection of blood (DNA) samples from all subjects, including the parents of ASD subjects, for future genomic analyses

2. What are the questions that must be addressed in applications submitted to this FOA?

• Are lab-based measures of domains of social impairment in ASD more sensitive indicators of clinical status than clinician and caregiver assessments as outcome measures?
• Do eye-tracking, EEG paradigms, or a combination, have potential utility as stratification biomarkers and/or as sensitive and reliable measures of change?
• Is there a relationship (correlation) of lab-based measures of domains of social impairment to eye tracking or EEG (resting state and task-based) paradigms?
• Is there a relationship (correlation) of lab-based measures of social impairment to clinician and caregiver assessments?

3. What are the minimum requirements for the design of the clinical study:

Multi-site study in ASD:

• School age individuals (ages 6-11)
• Possibility of adding adolescent or toddler groups based on availability of funds

Assessments:

• A well-justified set of standardized lab-based measures of domains of social impairment
• Neurophysiological measures
• Resting state and task-based EEG and eye tracking measures
• Commonly used clinician and caretaker assessments of social function

Time points:

• Baseline, 6 and 24 week time points

4. What are the expected outcomes of the research to be supported by this FOA?

• Identification of eye tracking and EEG biomarkers that can be used for stratification of school age ASD subjects in trials
• Utility of investigator-administered assessments of domains of social impairment as objective predictors of clinical outcomes
• An integrated data set of EEG, eye tracking, and clinical measures from school age ASD subjects, as well as blood (DNA) samples from ASD subjects and their parents, made available for data analyses through NIMH databases

5. The RFA solicits research on the potential of EEG and eye tracking as biomarkers for ASD. Our research team has expertise in one of these biomarker modalities. Can we propose a study addressing one of these modalities only?

Applications that propose to study only one of these biomarker modalities will not be responsive to this RFA. It is expected that applicants will convene a team of experts that have the capabilities and experience to assess both EEG and eye tracking modalities at each clinical site. Investigators may need to form new collaborations to accomplish this; the expertise of the team as a whole will be considered in NIH peer review of the applications. It is in the best interest of applicants to convene the most experienced and technically-proficient research team possible.

6. Is it expected that all clinical sites will have technical expertise in both EEG and eye tracking modalities?

Yes. Again, new collaborations may be formed if necessary, but it is expected that each site will be proficient with both EEG and eye tracking measures.

7. Does the overall PI need to have expertise with both EEG and eye tracking?

No. The team as a whole should have expertise in both modalities. The overall PI should have a strong track record in leading large projects, and demonstrated proficiency in coordinating ASD research involving multiple coordinated sites. The overall PI may also be a PI of a Collaborating Site but this is not a requirement.

8. Does the overall PI need to have a minimum % effort?

The PI should propose a level of effort that is appropriate for oversight of a multi-site U19 project, which would likely be greater than the % effort expected for an R01 (e.g., 15-20%).

9. I heard that applications may be returned without review if they are not considered to be responsive to the FOA. 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 many RFAs issued by NIH.) Thus, applications submitted in response to this RFA will be reviewed for responsiveness prior to 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 (see questions 2 and 3 above).

10. A key goal of the FOA is to provide a community resource for broad sharing of all data generated including processed/analyzed data, with rapid and timely deposition of data into the National Database for Autism Research (NDAR ). Will it be acceptable to share data through another database other than the NDAR?

No. All data will be deposited and shared through NDAR.

11. What is the timeline for sharing data generated in the Consortium project?

All data (including raw data) will be deposited and shared through NDAR as soon as data QA/QC is complete. NDAR staff will be involved to facilitate sharing. Centralized coordination and local data management for data cleaning and entry, as well as bio-statistical consulting will be the responsibility of the awardee Data Coordinating Core (DCC). Data are expected to be submitted to NDAR every 3 months, and made available for access to other researchers within four months or less after submission, allowing the DCC and their team sufficient time to complete appropriate quality assurance/quality control (QA/QC) procedures.

12. How will my willingness to share data through NDAR be evaluated?

Past compliance with data and resource sharing policies, as well as the data sharing plan specified in the application, will be considered in in making funding decisions.

13. The RFA states that two measures from the EU-AIMS  study protocol must be included, and mentions 1) the upright and inverted faces task for EEG, and 2) the emotion-matching task for eye-tracking. Do you intend that these two measures are required, or only suggested? If these are meant as examples, how can I access the EU-AIMS protocol to choose measures?

NIMH recognizes that the EU-AIMS protocol is not publicly available at this time. The final decision about which measures will be coordinated with the EU-AIMs protocol will be determined after an award is made, during the process of finalizing the protocol. Applications should use these two measures in their proposed protocols in order to demonstrate their knowledge and technical expertise with EEG and eye-tracking measurement.

14. Should I include a letter of support or add an EU-AIMS investigator as a consultant on my application?

NIH is not requiring a formal collaboration with EU-AIMS investigators as either consultants or advisors on applications submitted to this FOA. NIH will not consider consultants or letters of support from EU-AIMS investigators, or prior collaborations, as a factor(s) in the review of the applications.

15. The RFA states that the Data Coordinating Center (DCC) must be “functionally separate” from the Collaborating Sites. Can the DCC be at the same Institution as the Lead Site or one of the Collaborating Sites?

The DCC can be at the same Institution as the Lead Site or one of the Collaborating Sites, as long as they are truly independent and there is a separate “chain of command”. The applicant should justify the choice and describe the functional separation. Applicants should propose a DCC with very strong expertise and track record of data management and coordination, whether they are at their Institution, another Institution, or a non-Academic research coordination site.

16. Must the core staff of the Data Acquisition and Analysis Core (DAAC) be located in one place, or could the Core be comprised of experts from more than one institution?

It is not a requirement that the DAAC staff be located in one place. It is more important to staff it with people with the most expertise.

17. Why does the RFA specify that the roles of the DAAC be described separate from the Data Coordinating Core (DCC)? Can a portion of the analytic responsibility be fulfilled by someone at the DCC?

We specified separate roles of the cores as a way to maintain objectivity in oversight and data analytic activities. However, it is acceptable for an applicant to propose another structure, as long as the plan adequately addresses objectivity and oversight, and the analyses are performed centrally.

18. What are the expectations about standardization and reliability across sites for behavioral measures?

The application should discuss a plan for assuring standardization, cross-site training and testing of reliability for all measures, including behavioral measures in the Research Strategy Overview section of the application.
19. Is the sex ratio of the sample expected to reflect the sex ratio of ASD, or is the expectation that the consortium balance by sex?

We are concerned about the feasibility of oversampling females with ASD to achieve an equal ratio, so we did not make that a requirement. The applicant can propose a ratio that is scientifically justified, and should address feasibility if planning to oversample females. Any planned analyses of sex differences should be adequately powered.

20. Within the specified IQ range (50-115), is there a preference for sampling uniformly across this range?

The sampling across the IQ range is not necessarily expected to be uniform. The application should propose a plan that is scientifically appropriate and feasible.

21. Are there expectations or preferences about the homogeneity or heterogeneity of the control group?

The control participants will provide an opportunity to evaluate the stability and reliability of measures in a healthy cohort. Therefore, exclusion criteria should be appropriate to eliminate significant comorbidity.

22. Please clarify this requirement listed under Research Strategy, Sample Size: “Subgroups of ASD based on IQ or other clinical measures should include a minimum of 50 subjects”.

If you propose to analyze subgroup differences within the cohort of 150-200 ASD participants, it is expected that the subgroups will contain at least 50 participants for adequate statistical power. Deviation from this expectation should be justified with a fully-explicated power analysis.

23. The RFA specifies the age range of 6-11, but indicates that toddlers and adolescents may be of interest. Can we submit a proposal that examines potential biomarkers in toddlers only?

No. To be responsive to this RFA, the proposed study must include participants who are 6 – 11 years of age. Applicants may propose to include toddlers and/or adolescents if if the task-based measures are appropriately adapted for these populations, and if resources permit an adequately-powered study with the expanded age range(s).

24. Should we propose to test the biomarker(s) of interest within a clinical trial, using an intervention, in order to be responsive to this RFA?

No. This FOA specifies support for qualification of a set of measures that could be used in future clinical trials, but does not provide funds for data to be collected in an intervention trial, as part of the consortium project.

25. How many Collaborating Sites should we propose in order to be responsive to the RFA?

A minimum of two and a maximum of six Collaborating sites is specified in the FOA. Standardization of biomarker measures, cross-site reliability, and timely recruitment of subjects should be considerations in proposing the number of Collaborative sites.

26. The RFA refers to Good Clinical Practice (GCP) standards and asks applicants to describe the plan for implementation. Where can we find someone with expertise in GCP?

Good clinical practice standards are international standards that apply to all aspects of a clinical trial including design, conduct, performance, monitoring, auditing, recording, analyses, reporting and the protections of human subjects. These standards are also important in clinical studies to evaluate biomarkers toward qualification. Contract Research Organizations (CROs) and private project management firms have GCP expertise. Some universities may have GCP experts as well on staff.

27. The RFA refers to Project Management experience to ensure QA/QC of the clinical study at each of the Collaborating Sites, as an important component of the Administrative Site. Where can we find someone with expertise in project management?

Project Management expertise often times resides at CROs and small firms that manage clinical trials.

28. Are foreign sites allowed for collecting biomarker data?

Foreign components are allowed in this FOA. Inclusion of a foreign data collection site or component should be based on special opportunities afforded for furthering the objectives of the FOA through the use of unusual talent, resources, populations, or environmental conditions in other countries that are not readily available in the United States or that augment existing U.S. resources. The scientific, financial, and logistical implications for including a foreign component should be considered and addressed in the application.

29. Where can I find more information about the FNIH Biomarkers Consortium?

The Biomarkers Consortium  is a public-private biomedical research partnership managed by the Foundation for the National Institutes of Health  that endeavors to discover, develop, and qualify biological markers (biomarkers) to support new drug development, preventive medicine, and medical diagnostics.

30. What level of effort/involvement is anticipated for the PD(s)/PI(s) involvement in the U19 Consortium Project Steering Committee and FNIH Biomarkers Consortium Project Team?

The Consortium Project Steering Committee (SC) will serve as the operational governing board for the Consortium project. The PD/PI should plan for: quarterly meetings (in person or by video or audio teleconference) to monitor progress on the project and to address issues or activities that impact the project ; teleconferences to address operational issues on a weekly or monthly basis, or as dictated by the needs of the study; and an annual in person meeting of the SC. In addition, workgroups may be established for specific tasks as the SC deems appropriate.

FNIH Biomarkers Consortium (BC) Project Team (BC PT) will provide a collaborative environment to promote standardization and harmonization of biomarkers across multiple research sites, coordination with the NIH, FDA, international efforts (e.g., the EU-AIMS), and engagement with non-profit foundations, industry, and regulatory agencies to qualify potential biomarkers of social impairment for their proposed context of use in ASD intervention studies and clinical trials. The PD/PI should plan for: an initial series of meetings to finalize the design of the Consortium project protocol and data analysis plan; and thereafter, quarterly meetings held in conjunction with the Consortium Project SC.

31. For a multi-PI application (which is allowed, per the RFA instructions), can one of the PD/PIs also be the Data Acquisition and Analysis Core Director?

The Director of the Administrative Core must be the overall PI of the U19. We would not expect core directors to be multiple PIs. However, if multiple PIs are proposed in the application, their leadership roles need to be well justified in the Leadership plan and will be evaluated in peer review.

32. A project manager is required for this RFA. Does the project manager need to be pre-existing personnel or can we propose a project manager to hire at the time of award?

The project manager should be specifically named, with biosketch included. However it is expected that the individual will be hired at the time of award, if the peer review of this investigator is favorable and NIH concurs with the strength of their qualifications. The Project Manager should have a Ph.D. or equivalent research training background and at least two years of private sector experience in implementing Good Clinical Practice (GCP) standards at academic sites. They should have significant experience in multi-site trial set up, data rigor, training and recruitment for industry run studies. NIH reserves the right to have input into the selection of the proposed Project Manager for the study prior to issuing an award.

33. What clinical status measures should we use in order to test the sensitivity of lab-based measures as indicators of social impairment?

Applicants should propose sensitive and specific measures that best reflect overall functioning. NIH reserves the right to modify the clinical status measure(s) before award of the grant, based on input from the FNIH Biomarkers Consortium Project Team.

34. How should we plan for the possibility of adding a toddler group (ages 3-6) at baseline, 6 and 24 week time points?

Applicants should provide a brief description of a pilot feasibility study for this age range, if available at one or more sites, within the Research Plan section of the Overall component of the application, with the intention of staying within the funds available in the RFA. The description of this early age study (of not more than one page) should be included within the 12-page Research Strategy section and address experience and capabilities of staff to carry out the EEG, eye tracking, clinical and behavioral measures in the 3-6 year ASD cohort.

35. Given that central IRB is stipulated, is this an acceptable administrative cost?

The Administrative Core is responsible for establishing a central IRB. To clarify, applicants should consider using a single IRB at one of the Collaborative Implementation Sites. The costs associated with using a central IRB are “allowable costs”.

36. What are expectations for measuring sensitivity to change in the absence of an administered intervention?

Our primary goal is to determine how stable the individual biomarker measures are over the 24 week time period of the study. We would like to further clarify, that for sensitivity to change, our goal is to determine if lab-based measures of social impairment are correlated/related to changes in the clinical measures over time. That is, if subjects get worse or better over the 24-week period, based on clinical ratings, do the lab-based measures show the same direction of change. For subjects that do not show any change in clinical measures over time, the biomarker measures should remain stable.

37. Is it permissible to modify the EU-Aims tasks, i.e., to add an additional condition?

One task-based EEG and one eye tracking measure from the European Autism Interventions – A Multicenter Study for Developing New Medications (EU-AIMS) study must be included among the set of proposed biomarker paradigms (i.e., the upright and inverted faces task for EEG and the emotion-matching task for eye tracking). With that in mind, applicants may propose additional conditions that are scientifically justified; the specifics of the EU-AIMS task/design will be negotiated post-award in discussion with the FNIH Biomarkers Consortium Project Team.

38. The Data Coordinating Core (DCC) is charged with conducting site visits within the Clinical Investigation Unit (CIU) to monitor quality of record keeping, source documentation, and accuracy of data entry. The Admin Core is charged with implementing Good Clinical Practice (GCP) standards across sites. How are these intended to be distinct? Is there an expectation that there will be separate visits for each purpose? Or should the DCC Site Visits accomplish both, with the joint purview of the DCC and the Admin Core?

These functions could be assumed by the same person (the Project Manager) but it may require different expertise in data collection and data management. The GCP will entail site set up, standardization of measures, training of personnel, etc. All of these are within the domain of the Project Manager and should be described in the Overall Research Plan.

39. The RFA indicates that only Facilities and Resources are only for Sites. Resources of the DCC and DAAC must then be communicated with the page limits of the Core Research Plans?

Yes, this is correct.

40. The RFA indicates that the Research Strategy for the Collaborative Implementation Sites should describe the aspects of the project that are common to all of the Collaborating Implementation Sites. Should the preliminary data sections be site-specific and is that variability acceptable?

The preliminary data to support the overall application should be summarized and presented in the same way for all the sites. Unique information should be listed in a subsection under a heading, “Elements Unique to This Site”.

41. Standardized inclusion/exclusion criteria across sites defined by DSM-5 criteria, and supported with data from ADOS-2 and ADI-R (consider the possibility of enriching enrollment for individuals with a pre-specified range of social impairment)

Can we include subjects with known genetic conditions (Fragile X Syndrome, Rett Syndrome, Phelan-McDermid Syndrome, etc.)?

No, only subjects with idiopathic ASD should be included.

42. How much clinical staff time can be in the budget in year 4?

If you plan to include clinical staff time in year 4 of the budget, you need to provide a strong justification for the need. Final budgets will be determined through peer review and NIH review.

43. Applicants should propose a Technical Feasibility Study to be carried out by each Collaborating

Site prior to initiating the Implementation phase of the project. The Technical Feasibility Study should demonstrate each Collaborating Site's ability to carry out standardized collection and QC of biomarker data from an initial sample, to include subjects with ASD, across each of the sites within a timeframe of 3 months.

Should a blood draw be included in the Technical Feasibility Study? Also, can these subjects be included as part of the sample in the implementation phase?

Blood samples do not need to be collected in the Technical Feasibility Study. If subjects who participated in the Technical Feasibility Study are to be included in the implementation phase of the project, relevant issues related to consent and study design (screening, practice effects on any of the biomarker measures, etc.) should be addressed.