NUCOAT Updates
2022
The finalized Validation Study protocol was submitted to NU IRB the first week of December 2022. As the team transitions into the month of December, NUCOAT is working on scheduling January meetings with the CEP, ETAC and SEG members. These meetings will focus on commencement of the Cognitive Interviews and Validation Study phases, eliciting feedback as NUCOAT moves forward in the new year.
During November 2022, the NUCOAT team used qualitative and quantitative data to reduce the bank of candidate PF PRO items from 112 items to less than 30. The team is currently working with the FDA to generate a final measure to undergo cognitive debriefing. Aligned with these efforts, the Cognitive Interview protocol was approved by the NU IRB. The team is currently discussing recruitment efforts for this phase, with the goal to start conducting cognitive interview training and recruitment by December or January. The mid-November FDA meeting involved a discussion on patient-centered measure development and the use of a recall period for items assessing aspects of physical function.
By October 2022, NUCOAT team members drafted protocol documents for conducting the selected PerfOs and PROs for the Validation Study. The team began timed trials of these activities, developing standard operating procedures and working out assessment logistics. The mid-October FDA meeting examined NUCOAT’s concept elicitation data and refined the proposed approach of anchoring using patient-reports of severity (PGIS) and change (PGIC). Throughout the month of October, the NUCOAT qualitative team continued concept mapping to develop and refine an item pool for the final PF PRO. This early item pool was comprised of 112 unique items with the expectation that the final PRO measure will be comprised of 10-20.
In September 2022, NUCOAT continued designing the Validation Study and the team continued with data analysis of the concept elicitation interviews, preparing quotes from the interviews as well as other documentation of findings in anticipation of our September 8th meeting with the FDA. We also attended an ad hoc meeting with the FDA to discuss concept prioritization to support item selection for the Physical Function PRO measure.
By mid-August 2022, NUCOAT wrapped up the rare disorder concept elicitation interviews. Conceptual saturation for sarcopenia for Sarcopenia interviews was also achieved around this time, kicking off data analysis of the full qualitative study population. Throughout the month, the team continued to plan for the Validation Study, which included consultations with experts in PerfO administration and DXA scanning for participants with sarcopenia.
In July 2022, the NUCOAT Qualitative Team continued conducting interviews for the Concept Elicitation phase of UH3. The team focused efforts on recruiting additional IPF participants through registry outreach and working with NORD to advertise the study to a wider network. The qualitative team also continued conducting interviews with individuals with sarcopenia, recruiting from both NMHC clinics and Chicago-area assisted living facilities. The team continued to discuss concept elicitation findings and drafted an FDA-facing report detailing preliminary identified concepts. Finally, the NUCOAT study team held a meeting with the NUCOAT CEP to share study updates, discuss best practices on PerfO assessments, and elicit feedback on the proposed recruitment approach for the Validation Study.
In June 2022, the NUCOAT progress report was submitted to FDA and an initial draft of the validation study protocol was produced and circulated both internally and to FDA in preparation for a late June NUCOAT-FDA meeting.
The qualitative team continued to recruit participants and conduct concept elicitation interviews throughout the spring, successfully reaching our quota of 10 participants with myositis and 10 with systemic sclerosis by the beginning of May 2022. Interviews for idiopathic pulmonary fibrosis are almost complete and the qualitative team is starting to analyze the rare disorder participant interview data. Interviews with participants with sarcopenia continue, in addition to the expansion of our recruitment outreach to additional sites, including retirement communities in the Chicago area. On May 9th, the NUCOAT team participated and discussion grant progress in an FDA-hosted Program Steering Committee meeting with other Core Outcome Set grant awardees. On May 27th, the NUCOAT team met with FDA to discuss recruitment, national representativeness and content validity in performance outcomes.
In April 2022, the team convened an in-person meeting to discuss planning of the pilot study and validation study for UH3. The team discussed the ongoing development of the pilot and validation study protocols, as well as staffing needs and other logistical concerns related to the validation study. The team also discussed current and future recruitment efforts and plans for exploring additional sites for recruitment outreach outside Northwestern.
In late March 2022, the NUCOAT team met with FDA to discuss pilot study procedures, including feasibility of performance outcome (PerfO) assessments using water weights, patient-relevance, and in-person/remote score comparability of these assessments. To further develop PerfO protocols for both the pilot and validation studies, the NUCOAT team held a Stakeholder Engagement Group (SEG) meeting in mid-April. The NUCOAT team presented descriptions and demonstrations of the proposed remote and in-person PerfOs to the SEG members and elicited feedback from members on the relevancy and ease of completion of each. The SEG members were extremely forthcoming and helpful with their feedback and the team continues to work with the SEG to gather input on PerfO relevance and feasibility of remote administration to inform final selection of the PerfOs.
As of late-March 2022 the team continues to work on document development for the validation and performance outcome piloting studies. The Qualitative team is making progress in recruitment of rare disorder and sarcopenia participants, connecting with geriatrician Dr. Sara Bradley for recruitment at additional clinic locations. The sIRB and associated documentation was approved in mid-March, allowing for NORD’s participation in UH3 Qualitative data collection procedures.
Throughout February 2022, the Qualitative team continued the development of rare disorder recruitment documents, REDCap survey development, and completed weekly interview trainings. Rare disorder recruitment began, starting with patients of Northwestern Medicine physicians. The team also submitted ‘single IRB’ (sIRB) documentation for multi-site research, so that NORD can participant in ongoing qualitative interviews with rare disorder patients. After receiving feedback from myositis experts, the NUCOAT team decided to exclude inclusion-body myositis from the myositis subtypes.
Shortly after returning from winter recess in January 2022, the NUCOAT team met with Dr. Anna Liggett to discuss sarcopenia recruitment plans at Chicago-area clinics and retirement homes, and the team started visiting Dr. Liggett’s clinic on Fridays to recruit patients. On January 13th the team met with FDA for their monthly NUCOAT-FDA meeting and discussed myositis subtypes, their inclusion/exclusion in UH3 qualitative and quantitative research, and the application of water weights in remote performance assessments. In an internal meeting afterwards, the team developed a plan to consult myositis experts about the inclusion of myositis subtypes. On January 26th, the NUCOAT team began sarcopenia recruitment.
2021
The NUCOAT team submitted qualitative protocol to NU IRB mid-November 2021 and received feedback and requests for revisions. After revising, the Qualitative Team plans to start recruitment of participants in December 2021. The Pilot Study protocol continues to be developed, with plans to start internal testing in December. Collaboration with NUCATS Enterprise Data Warehouse (EDW) for using machine learning methods to detect/classify sarcopenia participants continues, with updates expected from NUCATS in December-January 2022.
Also in November, NUCOAT continued discussions with the rare disorder experts regarding collection of treatment history and common therapies/medications/interventions for rare disorder participants. By mid-November, after several discussions between NUCOAT and FDA, it was decided that FDA would allow the reuse of a small amount of participants (<20%) between the concept elicitation and the cognitive interview phase studies. NUCOAT hopes not to need to reuse participants but will revisit later if necessary. During the November NUCOAT-FDA meeting, the team discussed the purpose of piloting and remote/in-person comparison testing, including the ordering of remote/in-person test administration.
On November 30, the NUCOAT External Technical Advisory Committee convened to discuss project updates and the plan for remote assessment piloting and machine learning. The ETAC confirmed that the order of remote/in-person administration in pilot comparison testing should be randomized or alternated. The ETAC provided additional feedback and direction to how machine learning might be conducted in UH3. The NUCOAT team will keep ETAC and other interested parties updated on the possibility of using machine learning to classify/detect sarcopenia participants.
In October 2021, the NUCOAT team worked on finalizing eligibility criteria and developing relationships with rare disorder and sarcopenia physicians for expert guidance and recruitment. The team continued their discussion with NM physicians regarding DXA logistics. The qualitative team revised the qualitative materials, concept elicitation and cognitive interview protocols and interview guides, with the goal of finalizing and submission to IRB early November 2021. Additionally, NUCOAT team members continued to discuss the logistics of remote performance assessment logistics and development of pilot study materials.
Representatives from the NUCOAT team presented UG3 findings via a poster and video at the annual NORD Rare Diseases and Orphan Products Breakthrough Summit (October 18-19, virtual), with the NUCOAT abstract having been selected as one of the top NORD Summit submissions.
The Clinical and Expert Panel convened on October 27 and discussed rare disorder and sarcopenia inclusion/exclusion criteria. It was recommended to broaden systemic sclerosis inclusion/exclusion criteria to all subtypes, not specifying limited or diffuse cutaneous subtypes. The meeting also covered confounds in grip/gait screening assessments, e.g., osteoarthritis pain preventing participants from completing grip strength tasks. Lastly, meeting participants discussed the methods for requesting participant medical records, in order to confirm rare disease diagnosis. The CEP recommended using a physician letter/confirmation form when feasible.
The September 2021 FDA-NUCOAT meeting addressed the UH3 qualitative cognitive interview guide and the potential reuse of participants between the UH3 qualitative concept elicitation and the cognitive interview studies. The team also discussed the length and level of detail for participant clinical and treatment history forms in the UH3 studies, qualitative assessment of the physical function recall period.
Also in September, the team expanded the NUCOAT Clinical and Expert Panel to include Dr. Daniel Rooks, Dr. Christine Hsieh and Dr. Sonya Danoff as sarcopenia and rare disorder representatives. The team also met with Dr. Margaret Danilovich regarding recruit sarcopenia participants via her pool of older adult participants at various assisted living facilities. Throughout September, the team continued to discuss remote performance assessment, eligibility criteria, recruitment and confirmation of rare disease diagnosis in the qualitative and validation study. The NUCOAT team also talked with NUCATS EDW team about machine learning methods for detection/classification of sarcopenia in Northwestern’s medical record systems and access and usage of DXA scanning of sarcopenia participants at Northwestern.
In late August 2021, FDA notified the NUCOAT team that they will be funding NUCOAT’s project through the research phase (also known as UH3 phase). During the research phase, NUCOAT researchers will develop and validate a physical function clinical outcome assessment including a performance outcome and patient reported outcome assessments. We will continue to research in myositis, IPF, systemic sclerosis, and sarcopenia in older adults in further detail through conducting in depth interviews, consulting key experts and stakeholders, and developing and validating physical function assessments. Once the assessments are finalized, the NUCOAT team will work with FDA to distribute the assessments to interested groups of patients, care partners, industry professionals, and policy makers.
In early June 2021, the team met with the FDA to discuss project updates and discuss the use of remote functional assessments. The FDA did not come to a conclusive answer on remote assessments. The FDA continues to discuss chronic conditions comorbid with sarcopenia internally. Also in June, NORD’s Chief Medical and Scientific Officer joined the NUCOAT team as a co-investigator.
Throughout May 2021, the NUCOAT team continued work on the transition package and planning the qualitative and quantitative validation studies. The NUCOAT team began outreach to rare disorder physicians for expert input on inclusion criteria and special considerations. In mid-May, the NUCOAT team decided on using remote functional assessments for patients with rare disorders and brought the discussion to the ETAC meeting.
April 2021 The NUCOAT Qualitative Team began to identify DEXA machines available at NM for sarcopenia diagnostics. The team connected with the Northwestern Medicine Director of the Women’s Bone Health program to discuss DEXA scan logistics, special considerations, and overall science of DEXA scans. Additionally, NORD hosted a webinar on “Contemporary Trends in Rare Disease Research and Development” for the NORD Corporate Council in April. As one of the invited speakers, NUCOAT’s primary investigator provided an overview of the NUCOAT project.
The NUCOAT team also began preparing for the transition from the planning phase to the research phase. In mid-April 2021, the NUCOAT team received feedback on the PF definitions and began integration of feedback into the qualitative study protocol while waiting for FDA recommendation of PF sub-domains in the research phase. The team continued discussions around DEXA and how it will be used for inclusion criteria in the research phase. These discussions led to drafting sarcopenia inclusion criteria and presenting them to the FDA in late April.
During the next FDA meeting in late April 2021, the FDA confirmed that they would not require DEXA scans for a low lean mass criterion for sarcopenia and recommended a subsample in the validation study for the research phase. The FDA also confirmed that sarcopenia in older adults will be one of the sarcopenia conditions, but they were still in discussion regarding the other three proposed chronic conditions comorbid with sarcopenia. The FDA also noted that PF domain selection for the research phase would be provided within a few weeks of the meeting.
In the beginning of March 2021, while waiting for FDA feedback, the Qualitative and Quantitative Teams began planning their respective study designs for the research phase and drafting the Gap Analysis Report. Late March, the NUCOAT team met with the FDA to provide program updates and discuss the research phase planning. The team discussed health conditions (rare disease and sarcopenia-related) to move forward with in the research phase and the PF definitions. The FDA confirmed the three rare disorders in the research phase: myositis, SSc, and IPF. Further, the FDA confirmed that they would review the PF definitions and provide feedback, and chronic conditions comorbid with sarcopenia and primary sarcopenia were under consideration for the research phase.
Early February 2021, the NUCOAT team finalized and sent the condition reports to the FDA to review ahead of the FDA-Grantee meeting scheduled in mid-February. The team recommended six conditions to move forward with in the research phase: SSc, myositis, IPF, heart failure, COPD and Parkinson’s disease. Shortly after the condition reports were sent, the FDA alerted the team that they would not be able to provide feedback on the condition reports or recommended condition during the upcoming meeting, due to insufficient time for review. During the FDA-Grantee meeting mid-February, the NUCOAT team reviewed the executive summary of the condition reports and research phase transition plan with the FDA. The NUCOAT team asked the FDA whether they could receive feedback on the physical function sub-domains and definitions by the end of March 2021. The week following the February FDA-Grantee meeting, the Qualitative Team prepared and sent an updated domain codebook with the definitions, frequencies, and example items to the FDA for review.
January 2021 It was agreed that the condition reports will be resubmitted to the FDA in January. The FDA rescheduled the late January meeting series to late March or early April 2021. The NUCOAT team reviewed the FDA feedback with ETAC during a mid–December 2020 meeting and obtained additional guidance. The NUCOAT team met with the FDA in mid-January to review and discuss the ETAC recommendation to focus on primary sarcopenia in the research phase, rather than focusing on three conditions associated with sarcopenia. The FDA emphasized their desire for a cross-cutting physical function assessment. Shortly after the FDA meeting, the team reconvened the various stakeholder groups to review the condition reports further. Throughout January, the Qualitative team continued to work on final edits to the condition reports, including integrating the stakeholder groups’ feedback.
2020
In the first half of December 2020, the NUCOAT team built a plan for finalizing the condition reports with input from the FDA and various stakeholder groups. The Qualitative Team closed chronic conditions comorbid with sarcopenia recruitment and interviewed the final hip fracture patient to complete scoping interviews in that group. In early December, the NUCOAT Team and the FDA met and discussed revising the condition reports to provide additional justification for the patient-reported and performed measures of physical function to be used in the research phase, as well as providing tables summarizing condition specific and cross-cutting physical function concepts.
November 2020 The Qualitative Team closed rare disorder recruitment and interviewed the final HCC patient for scoping interviews. The team continued to recruit and interview chronic conditions comorbid with sarcopenia patients. Reading and data extraction of the rare disorder literature review articles were completed. The draft condition reports were sent to ETAC for review and discussion during a mid-November meeting. During this meeting, the ETAC provided recommendations and feedback on the preliminary results of the condition reports, which were relayed to the FDA for later discussion in December 2020. In late November, the FDA called a meeting to discuss plans and preparations for a late January meeting series about the Core Outcome Set grants, including an FDA Public meeting, Program Steering Committee meeting and Scientific Policy Board meeting.
Throughout October 2020, the NUCOAT team continued data collection and analysis work. The Qualitative Team made progress on recruitment and interviewing for rare disorders but ran into a few roadblocks with recruiting a final HCC patient. The team continued to recruit and interview patients with chronic conditions comorbid with sarcopenia. The remaining rare disorder articles were read for the scoping literature review, and data was extracted for analysis.
August 2020 the FDA held their annual COA grantee meeting remotely due to COVID-19 precautions. NUCOAT presented project updates to the FDA and other grantees in addition to presenting updates in the FDA public forum.
July 2020 The NUCOAT literature review team finalized rare disorder search terms and began rare disorder abstract reviews. The chronic conditions comorbid with sarcopenia abstract reviews were also completed in early July 2020 with full text data extraction complete in mid-August 2020.
Due to the State of Illinois and Chicago’s COVID-19 guidelines, in-person research activity is discouraged. Patients and physicians voiced their concern over in-person physical function assessments due to COVID-19, which led the Northwestern team to suggest to the FDA using the SARC-F as a sarcopenia screener for scoping interviews with the potential of physical function assessments conducted on a later date. By mid-July 2020, the team received approval from the FDA to move ahead with using the SARC-F as a sarcopenia screener.
By late July 2020, the NUCOAT Qualitative Team began chronic conditions comorbid with sarcopenia patient recruitment. Recruitment for chronic conditions comorbid with sarcopenia is ongoing with 7 interviews complete to date. Throughout the quarter, the qualitative team has been diligently working on completing rare disorder interviews. As of now, interviews for SSc, IPF and FSHD are complete with myositis and HCC interviews due to be complete by mid-October 2020.
June 2020 Chronic conditions comorbid with sarcopenia abstracts are being screened for the literature review. Full text data extraction is scheduled to begin in early June. Rare disorder search terms are in process of finalization. NUCOAT held the third SEG meeting where the team introduced a new rare disorder patient SEG member, reviewed the interview guide and provided updates on the rare disorder scoping interviews. Members were asked in what ways that they would like to be included in NUCOAT. The SEG overwhelmingly agreed that they would appreciate one or more of the SEG members attending other NUCOAT groups to report back to the SEG with a summary and any updates. A co-chair for SEG will be attending the upcoming September 2020 Committee meeting as an observer.
Following the early June 2020 SEG meeting, two more rare disorder care partners were identified to become members of the SEG. In mid-July 2020, NUCOAT organized a meeting with SEG patients and care partners eliciting more insight and feedback on the scoping interviews and asking for perspective regarding conducting research during a pandemic.
May 2020 NUCOAT held their second CEP meeting where the finalization of rare disorders, sarcopenia comorbid conditions, scoping interviews, and physical function assessments were discussed.
April 2020 Remote interviewing of rare disorder patients began. As of now, 11 rare disorder patient interviews have been conducted. In late May 2020, the Qualitative Team submitted an IRB modification to include remote recruitment procedures specific to recruiting hepatocellular carcinoma (HCC) patients through Northwestern’s Comprehensive Transplant Center.
Due to the State of Illinois’s stay-at-home order, in-person sarcopenia recruitment and interviewing has been on hold. NUCOAT’s Qualitative Team submitted an IRB modification for revised recruitment procedures to include remote screening and recruitment of sarcopenia patients. In late April 2020, the team received notification of IRB modification approval and team members contacted recruiting clinicians regarding revised recruitment procedures.
Also in April 2020, the Northwestern team coordinated scheduled the NUCOAT stakeholder groups’ second meetings. NUCOAT Qualitative Team members identified a rare disorder patient for the SEG. The Qualitative Team is continuing work to identify an appropriate rare disorder care partner to participate in the SEG. The NUCOAT website was created and approved by the Northwestern University Office of Communication. The team has been creating content pages for chronic conditions comorbid with sarcopenia, rare disorders, both project phases, and updates. Content will be finalized by mid-June 2020.
Late February 2020 and into March 2020, the various stakeholder groups held their kick-off meetings. During these meetings, members were introduced to the NUCOAT project and the expectations of them as group members going forward. The Northwestern team also met with two other physicians for recruitment of heart failure and advanced cancer patients and discussed recruitment procedures.
The Northwestern qualitative team held interview and performance assessment training for research staff tasked with these responsibilities. Because this activity occurred concurrently with the escalation of the COVID-19 pandemic and associated campus closure to all but essential activity, this work is now on hold until the health restrictions are lifted.
Work continues, however, with literature reviews, including the review of abstracts for the chronic conditions comorbid with sarcopenia abstracts and the revision of search terms for the newly finalized list of rare disorders. Sarcopenia scoping in-person interviews are delayed due to the COVID-19 social distancing and “stay-at-home” guidelines from the State of Illinois, but remote recruitment with clinicians is proceeding. IRB revisions for rare disorder interviews have been resubmitted mid-March 2020 and are under review. Training for rare disorder scoping interviews is continued and will be finalized with final IRB approval. A sustainability plan for the Core Outcome Set of measures was under development.
The Northwestern team is collaborating with the Northwestern University office of communication to develop a NUCOAT project website to go live on the Northwestern platform.
In late March 2020, the Northwestern team received notification of IRB approval of the modification allowing the recruitment and interviewing of rare disorders patients. NUCOAT Qualitative Team members then started recruiting NORD partner organizations for rare disorder patient referrals. The team was able to recruit organizations that began referring patients with various rare disorders.
In mid-February 2020, Northwestern and the FDA held their February FDA/Grantee teleconference meeting where there was further discussion about finalizing rare disorders. During the ETAC meeting in late February, an FDA participant confirmed approval of all five rare disorders. With the finalization of all five rare disorders, the Northwestern team submitted to IRB for recruitment of rare disorders and are awaiting approval. NORD and NUCOAT are working to identify potential rare disorder patients and care partners to join the SEG.
In late January 2020 and early February 2020 the Northwestern team coordinated scheduling of kick-off meetings for NUCOAT’s various stakeholder group meetings. Sarcopenia patient and care partner stakeholders were identified and recruited for the SEG. Clinician outreach for patient recruitment continued throughout February. NUCOAT Qualitative Team members met with and established recruitment procedures with clinicians working with osteoarthritis patients.
January 2020 The Northwestern team developed two literature review protocols: one outlining the protocol for the chronic conditions comorbid with sarcopenia and one outlining the protocol for the five rare disorders. The Northwestern team also developed qualitative scoping interview IRB materials and began outreach to Northwestern clinicians for referrals of their patients living with chronic conditions comorbid with sarcopenia. During the mid-January FDA/Grantee meeting the FDA provided feedback on scoping interview materials. Throughout January, NUCOAT personnel continued discussion with the FDA about the final list of five rare disorders to be included in the planning phase of NUCOAT. We also revised IRB and Scientific Review Committee (SRC) materials for the scoping interviews and revised and refined the literature review protocols.
2019
December 2019 An FDA clinical reviewer and geneticist asked that the NUCOAT list of rare disorders be revised to target conditions which start in childhood. The FDA is internally discussing the list of rare disorders and will follow-up with Northwestern on their decision for further revising the list of rare disorders.
In early November 2019, the Northwestern team met with the FDA for the initial FDA/Grantee teleconference meeting. During this meeting, the FDA reviewed the National Organization for Rare Disorder’s (NORD) list of rare disorders registries and proposed that the NUCOAT grant focus on five rare as well as provided direction for the development of the literature review protocol and revision of the planning phase milestones. By mid-November, the FDA reduced their list of five rare disorders to three rare disorders from NORD’s list of registries. The FDA also requested NUCOAT include two additional rare disorders that were absent from NORD’s registry list. The FDA further asked that the list of chronic sarcopenic-comorbid conditions be narrowed to specific subtypes. Through-out November, the NUCOAT team drafted a literature review protocol, revised and submitted the planning phase grant milestones and budget, and prepared presentation materials for the early December 2019 meetings at FDA headquarters.
September 2019 The FDA issued the Notice of Award for the NUCOAT grant. Through-out September and October 2019, NUCOAT co-investigators organized, established project internal logistics, posted and interviewed for project staff support positions, and drafted materials for the qualitative scoping interviews.
August 2019 The FDA leadership contacted Northwestern University and communicated the FDA’s interest in funding the NUCOAT grant proposal. The FDA also asked that Northwestern revise the planning phase of the grant specific aims to: remove irritable bowel syndrome as a model condition for developing Clinical Outcome Assessments (COAs) of physical functioning and instead focus on secondary sarcopenia with multiple comorbid chronic conditions and multiple rare disorders, for the purposes of better spanning the range of physical function impact. In late August, Northwestern tailored the aims of the NUCOAT planning phase to propose conducting qualitative scoping interviews and literature reviews in each of the six chronic conditions with comorbid sarcopenia and five rare disorders.