National Advisory Board on Medical Rehabilitation Research (NABMRR)
National Center for Medical Rehabilitation Research (NCMRR)
Eunice Kennedy Shriver National Institute of Child Health
and Human Development (NICHD)
May 7-8, 2018
The 56th meeting of the NABMRR was called to order at 9:00 a.m. Board members introduced themselves, followed by brief introductions from NIH staff and other visitors. Minutes from the previous meeting of December 4-5, 2017, were unanimously approved. Future Board meetings will be December 3-4, 2018, May 6-7, 2019, and December 2-3, 2019.
Robyn Watson Ellerby
Ex-Officio Members Present:
Daofen Chen, NINDS
Lyndon Joseph, NIA
Kristi Hill, NIDILR
Joan McGowan, NIAMS
Ralph Nitkin, NICHD
Lloyd Rose, DoD
Lana Shekim, NIDCD
Cathy Spong, NICHD
Ex-Officio Members Absent:
NICHD Staff and Visitors:
Joe Bonner, NICHD
Andy Bupp, AOTA
Tim Brindle, VA
Scott Campbell, AOTA
Dawn Corbett, NIH OER
Theresa Cruz, NICHD
Meredith Daly, NICHD
Diane Damiano, NIH CC
Anthony Duttine, WHO
Jacklyn Ebiasah, NIBIB
Tinera Fobbs, NICHD
Jennifer Jackson, NICHD
Lyn Jakeman, NINDS
Lisa Kaeser, NICHD
Naomi Kleitman, CH Neilsen Fdn
Sue Marden, NICHD
Catherine Meyers, NCCIH
Stuart Moss, NICHD
Grace Peng, NIBIB
Charlotte Peterson, NIAMS
Rebecca Poku, NIH OER
Louis Quatrano, NICHD
Merav Sabri, NCCIH
Mathew Scherer, DoD
Reva Singh, PARMDR
Matthew Souman, DOD
Erin Spaniol, NIH OBSSR
Meredith Temple-O'Connor, NICHD
JoAnne Thierry, CDC
Biao Tian, CSR
Lois Tully, NINR
David Weinberg, NICHD
Paul Williams, NICHD
Setting the Stage
Alison Cernich, Ph.D., Director, NCMRR
Dr. Cernich announced that the meeting was being videocast. The recording will be archived and available on demand. Dr. Cernich reported on the activities of the NCMRR. The Trans-NIH Medical Rehabilitation Coordinating Committee welcomed the addition of the Fogarty International Center and the National Institute on Minority Health and Health Disparities (NIMHD). Beyond the NIH, the NCMRR forged new partnerships with the World Health Organization (WHO) and the Agency for Healthcare Research and Quality (AHRQ) and continued to build on existing collaborations with the National Institute on Disability, Independent Living, and Rehabilitative Research (NIDILRR). Across the government, federal funding for rehabilitation research was significantly increased.
Dr. Cernich also discussed some changes in leadership. Dr. Theresa Cruz, NCMRR has taken on the lead of the NIH BRAIN (Brain Research through Advancing Innovative Neurotechnologies®) Initiative Team B, and Dr. Robert Jaeger has taken over as NIDILRR Director. Dr. Catherine Spong, Deputy Director of NICHD, who has been a great supporter of NCMRR, will be leaving NIH.
Having published the NIH Research Plan on Rehabilitation in 2015, NCMRR will spend the next 3 years exploring new collaborations and initiatives, validating data (2019), proposing an outline for the revision of the research plan and planning for a scientific conference (2020), and ultimately publishing a revised research plan (2021).
NICHD Director's Report
Catherine Y. Spong, M.D., Deputy Director, NICHD
The government is funded through September 30, 2018. NIH was appropriated $37.084 billion for fiscal year (FY) 2018, a $3 billion increase over FY 2017. This includes the 21st Century Cures Act funding. NICHD's appropriated budget increased by $75 million. NICHD Director Diana Bianchi, M.D., attended the Congressional budget hearings and was asked questions about the trans-NIH Down syndrome initiative, the Task Force on Research Specific to Pregnant Women and Lactating Women (PRGLAC), and maternal mortality.
The Down syndrome initiative involves NICHD, the National Institute on Aging (NIA), and the National Cancer Institute (NCI), and will focus on trisomy 21, with the aim of making scientific discoveries to improve the health and neurodevelopment of individuals with Down syndrome and neurotypical individuals at risk for Alzheimer's disease, cancer, cardiovascular disease, immune system dysregulation, and autism, among other conditions. Funding for this trans-NIH initiative will supplement, not supplant, existing NIH funding levels for Down syndrome research.
NICHD Inclusion Activities
Dr. Spong described current NICHD efforts to foster more inclusive engagement. The Voice of the Participant program provides an inspiring platform for sharing stories. Presenters have included a mother talking about her daughter's life with Cushing's disease; a young woman who battled cancer twice but underwent egg preservation prior to her first chemotherapy treatment; a man with Down syndrome; and a woman recounting her pregnancy loss.
Pregnant women are routinely excluded from clinical trials. A concerted effort is underway to encourage the inclusion of healthy pregnant women in research protocols. An NICHD research project called PregSource® aims to elicit information about the pregnancy experience directly from pregnant women. This information will help researchers build a more complete picture of normal pregnancy and develop strategies for improving maternal care. PRGLAC, which is mandated by the Cures Act and includes NICHD representation, is tasked with identifying gaps in knowledge and research on safe and effective therapies for pregnant and lactating women. A working group at the NIH Clinical Center has been formed to examine the benefits and risks of having healthy pregnant women participate in research studies.
NICHD has worked closely with the All of Us Research Program (https://allofus.nih.gov), which aims to build a national research cohort of 1 million or more U.S. participants, and supports the inclusion of children, pregnant women, and people with disabilities in this ambitious undertaking. NICHD brought together a working group and developed 17 unique use cases, which were submitted to the All of Us Research Program survey platform. NICHD also conducted strategic outreach to advocacy groups. As a result of feedback from NICHD populations, the NICHD All of Us team finished first in the leaderboard and three NICHD use cases finished in the top 10 of the 793 total use cases submitted. Examples of top-scoring use cases included "What are the long-term effects and risks of opioid use disorder during pregnancy on maternal and child health?" and "What genetic markers predict consequences of pregnancy-associated hypertension and gestational diabetes for mothers and offspring?" The All of Us national enrollment began on May 6, 2018, but 25,000 participants were enrolled prior to the launch as part of a yearlong beta test. The American Association on Health and Disability is raising awareness among people with disabilities and will work with partners in Alabama, Montana, and New York to conduct local outreach with the disability community to enroll them in All of Us. Enrollment is currently limited to people age 18 and older, regardless of health status. The intention is to begin enrolling children in 2019, after ethical, regulatory, and responsible return of information issues are addressed. The kinds of questions this resource might help answer include how to prevent chronic pain, slow or even stop dementia, develop better pain medicines that aren't addictive, and develop more cancer cures that work the first time. The program will not only address new and exciting scientific opportunities, but also empower study participants with data and information to improve their own health.
Training the Next Generation of Researchers
NICHD has a history of focusing on the next generation of researchers. In FY 2017, NICHD funded 29 early stage investigators (ESIs), defined as program directors/principal investigators (PDs/PIs) who have completed their terminal research degree or post-graduate clinical training, whichever date is later, within the past 10 years and who have not previously competed successfully as a PD/PI for a substantial NIH independent research award. With the FY 2018 budget, NICHD will identify ESIs to be preferentially funded.
NICHD has analyzed its training programs to ensure they are the right fit for the community. An analysis of NICHD-funded physician scholars who received either an institutional K award (K12) or an individual K award (K08 or K23) appeared in JAMA Pediatrics in January 2018, showing that physician scholars (those with an M.D. only) who received individual K awards were more likely to apply for and receive an independent NIH grant later. Moreover, a comparison among NIH Institutes showed that NICHD had significantly more K12 awards than any other Institute. This finding resulted in a policy change to shift the NICHD paylines from institutional to individual K awards.
The annual NICHD Young Investigators Conference—a meeting to facilitate the training of physician scientists that has been offered for 30 years—will also undergo changes to reflect current needs. In the past, the conference was held in various locations around the country and was open only to fellows and junior faculty in neonatology, maternal-fetal medicine, and reproductive endocrinology who planned to become principal investigators. Attendees were nominated by their program directors. Beginning in 2018, this conference will focus on skills needed by young clinician-investigators working in any area funded by NICHD. It will be held locally so more NICHD "faculty" can participate. Activities will include study design, a mock study section, setting up a wet lab, work–life balance, and networking with program staff. Lesser-known grant and career opportunities will also be presented, and chairs of pediatric, obstetrics and gynecology, and rehabilitation medicine departments will be asked to nominate attendees. This year's conference will be held August 26-29, 2018.
2018 Strategic Planning Process
The last NICHD strategic plan was done in 2000, although a Scientific Vision for the Next Decade was published in 2012. Since the last strategic plan nearly 20 years ago, there have been major changes in the research topics and technologies supported by NICHD. These emerging challenges and opportunities must be addressed by a new strategic plan.
The strategic planning process will enable internal and external stakeholders to look at NICHD's portfolio with a fresh perspective, review and refocus the science to encourage new partnerships and collaborations, and improve the health of the populations served by NICHD. The process, which began in January 2018, is expected to take a year to collect and analyze data, develop objectives, and refine the vision and mission. A set of focus questions has been developed and an NICHD planning subcommittee has met. The plan will be evidence-based. A Strategic Plan Work Group comprised of about 50 people, half from NIH and half from external communities, will be assembled. The goal is to determine scientific priorities for NICHD moving forward in a systematic way and to align resources with priorities. Updates will be posted on the NICHD website.
A Board member asked whether there would be ongoing collection of data about successful K award opportunities with a breakdown of various types of K awards. Dr. Spong said there would, citing the need to evaluate the ongoing success of the approach. NICHD was the outlier in awarding so many institutional K awards largely because, 20 years ago, it did not have the mentors in the field to help people get individual K awards, so institutional awards were favored. Now NICHD has the mentors and the ability to encourage individual awards to leverage more success for the field. But it is important to monitor this to ensure that it leads to better training so that these researchers are likely to get funding from NIH.
Dr. Cernich noted that the NICHD program welcomes the inclusion of clinician-physician scientists who specialize in physical rehabilitation medicine. That information was distributed on the listserv for the rehabilitation department chairs, and nominations are coming in. She also mentioned funding for Training in Grantsmanship for Rehabilitation Research (TIGRR), which is held every year in January and is open to non-physician scientists who are looking for training on grantsmanship and developing into independent researchers. There are multiple opportunities, and people are encouraged to think differently about how NICHD is approaching training because NABMRR does want to provide robust support for independent K awards. The Board should spread the word to their communities. It is also important to realize that the All of Us program is funding outreach by community partners and that NABMRR is one of those partners, so this is very valuable. Board members should follow these efforts and help amplify this message to the disability community because there is a real emphasis on ensuring that inclusiveness is a priority.
Inclusion at NIH
Catherine Y. Spong, M.D., Deputy Director, NICHD
Dawn Corbett, M.P.H., Office of Extramural Research
Dr. Spong said that inclusion is a recurring theme at NIH, citing the Adolescent Brain Cognitive Development Study, which will recruit 10,000 healthy children; the All of Us Research Program, which puts an emphasis on recruiting underrepresented populations; the 21st Century Cures Act, which established the NIH Inclusion Across the Lifespan Workshop and PRGLAC, which was mentioned earlier. And especially within the broad NICHD mission, which includes children, pregnant women, and people with disabilities. Even so, more inclusion is needed, because the goal of precision medicine—which tailors therapy to individual patients based on their predicted response or risk of disease—cannot be accomplished if all types of people are not studied.
Citing a recent online article in the Journal of the American Medical Association titled "Improving Public Health Requires Inclusion of Underrepresented Populations in Research" that she and Dr. Bianchi wrote, Dr. Spong said that up to 59 percent of the U.S. population comprises underrepresented groups that typically are not included in research studies (i.e., pregnant women, children, older people, and those with intellectual and physical disabilities). However, 90 percent of pregnant women take medications, and one-half of people with autism take at least one psychotropic medication over long durations, and despite the need for specific information for these groups, they are not included in research studies. Moreover, very little research has been done on labor pain, and it is shocking how little research information is available on pregnancy. Although insufficient milk supply is one of the most commonly cited reasons for early cessation of breastfeeding, only 48 articles relating to medicinal therapies for low breastmilk supply were published between January 2006 and July 2017.
How Do We Know These Groups Are Not Included?
A study looking at the exclusion and inclusion criteria for underrepresented groups in open NIH-funded phase III and IV studies found significant explicit exclusion of pregnant women in 68 percent of trials, lactating women (47 percent of trials), children (76 percent of trials), and older people (28 percent of trials). People with intellectual or developmental disabilities were specifically excluded in 12 percent of trials and those with physical disabilities in 2 percent of trials. Similar exclusion rates for pregnant and lactating women were observed at the NIH Clinical Center. Only 3 percent of 300 randomly chosen clinical trials published between 2007 and 2011 in the six highest-impact medical journals included people with intellectual disabilities, yet 70 percent of those studies could have done so with only minor modifications. This population takes psychotropic drugs with potentially significant side effects with minimal evidence to support their usage but does not get the benefit of being included in testing for most available therapies. Individuals with physical disabilities face similar issues, including exclusions for motor impairment, disability diagnosis, and the need for caregiver assistance with tasks.
Why Are They Not Included?
Pregnant individuals are excluded because of concerns about liability, the complex physiologic changes during pregnancy, the changes of the fetus and placenta over time, and co-existing chronic or acute conditions. Lactating individuals are excluded because of limited assays for assessment of medications in breastmilk. People with intellectual and developmental disabilities are excluded for a variety of reasons, including research tasks requiring cognitive demands; investigators concerned about the time and effort needed to obtain truly informed consent; additional regulatory requirements for enrolling vulnerable subjects; the lack of robust, reproducible clinical outcome assessments; and complications of co-morbidities. People with physical disabilities are excluded because they cannot meet the physical performance requirements of the study; physical access to the facilities and equipment is limited; and varying etiologies of impairment or comorbidities that may pose a challenge to stratification or complicate clinical analyses. However, it may not be appropriate to simply extrapolate from studies on non-impaired adults to these specialized populations. Given the lack of inclusion, personalized medicine becomes "exclusive medicine." Without these data, more than one-half of the U.S. population will be left behind and unable to reap the benefits of biomedical research and personalized care.
What Are We Doing to Address This?
NIH policies require inclusion of children and women in the clinical trials NIH funds. The Pediatric Research Equity Act (2003) authorizes the U.S. Food and Drug Administration (FDA) to require pharmaceutical companies to include children in their new drug applications. However, an assumption that research studies should include a range of populations would represent a seminal shift.
- Intellectual and developmental disabilities: emphasized including this population in funded studies and the All of Us program and established the Down Syndrome Registry (DS-Connect)
- Physical disabilities: emphasized including this population in the All of Us program and established the Limb Loss Registry
- Children: promulgated a new NIH inclusion policy and emphasized including children in the All of Us program
- Older adults: promulgated a new NIH inclusion policy
- Pregnant and lactating women: established the PregSource® registry, which uses crowdsourcing to define typical, normal pregnancy and provides links to professional information sites; emphasized including this population in the All of Us program; and taken part in PRGLAC, which has held meetings open to the public and will submit a report to Congress in September 2018
- Inclusion Across the Lifespan: established the policy that NIH applicants and grantees include individuals of all ages in clinical research, unless there is a strong justification for their exclusion, starting on or after January 25, 2019
This is progress, but much remains to be done.
Key Inclusion Policies at NIH
Ms. Corbett updated the Board on current NIH inclusion policies. The Cures Act mandated revision of NIH policies and procedures requiring the inclusion of women, minorities, and children. NIH already had inclusion policies in place pursuant to the NIH Revitalization Act of 1993, which required inclusion of women and minorities in all clinical research studies unless there was a compelling rationale for exclusion (note that cost is not a valid reason for exclusion). The Revitalization Act also required that NIH-defined phase III clinical trials (studies that evaluate an intervention in large groups of people by comparing the intervention to other standard or experimental interventions) be designed to permit analysis by sex/gender, race, and ethnicity. To obtain a valid analysis, investigators generally stratify the primary outcome by sex/gender and/or race/ethnicity. In most cases, high statistical power is not necessary, because the intent is to inform future studies.
In response to the Cures Act requirements, NIH now requires that the results of analyses by sex/gender and race/ethnicity (analyses that had been required since 1994) must be reported on ClinicalTrials.gov if the study is an applicable clinical trial. The revised NIH policy on children requires that children must be included in research studies unless there are scientific or ethical reasons not to do so. NIH now defines “children” as individuals younger than 18 years of age.
The Cures Act also required that NIH convene a workshop on age grouping and age exclusion in clinical research, post the workshop findings on the NIH website, publish guidelines addressing this topic, and publish the number of children included in NIH research. In response, NIH hosted the Inclusion Across the Lifespan Workshop on June 1-2, 2017, to discuss the challenges and barriers to including children and older adults in clinical trials and to identify strategies that would produce more age-inclusive trials. As a result of the feedback from this workshop, NIH expanded its policy to include individuals of all ages in clinical trials. The age range must be justified in the context of the scientific question proposed. Clinical research studies are also expected to submit individual-level data on sex/gender, race/ethnicity, and age at enrollment with progress reports. In general, exclusion or inclusion based on age requires a scientific justification. This should encourage investigators to think more critically about their criteria and ensure there are good reasons for their age limits. In addition, collecting individual data on age, as opposed to aggregate data as was done in the past, will help NIH evaluate this issue in a more comprehensive way.
Dr. Nitkin observed that expanding inclusion to other groups will require education, because some clinicians have no background in recruiting and sustaining these populations. He asked whether NIH would be doing anything to promote best practices and what NIH might do to build more trust with populations that have felt disenfranchised and do not want to participate in clinical trials. Ms. Corbett said it will take the entire scientific community to work on trust. Investigators will be asked to include outreach plans with their applications and to think more critically about how to include these groups.
A Board member asked whether there might be a disconnect between NIH policy and Institutional Review Boards (IRBs) because IRBs are used to allowing many exclusions for age, children, and other criteria. The Board member asked how would IRBs be educated about these inclusions that NIH requires? Dr. Spong said part of the plan is to elucidate the types of things to study and then educate the IRBs proactively; she added that this component is important at the highest level of NIH. The Office of Extramural Research website should help with this education, and the Board must help make the best case. It also depends on who is on the IRB and how open they are to feedback. Ms. Corbett added that this is a culture shift and will take time. NIH is not asking that every group be included in every study, only that inclusion be considered in a more critical way to ensure that there is an ethical or scientific justification for the decisions that are made.
A Board member reported on a researcher who is developing a series of assessments to assess outcomes in individuals with disabilities and noted that what is captivating about this work is that it looks at stakeholder engagement to understand, for example, how people understand questionnaires and how to better optimize that experience. The member suggested that tapping into this type of effort would be helpful. Dr. Spong agreed, saying this highlights the issue of how many more people could be included in studies just by making minor tweaks or having helpful resources available.
A Board member asked what entities have been identified to address some of the transportation issues and physical barriers faced by those with physical disabilities and whether there are cross-sector collaborations that have been identified. Dr. Spong observed that transportation should not be a blanket reason for exclusion. Dr. Cernich added there are three different things going on. First, the U.S. Access Board is publishing its final policy change with respect to access for medical devices. There have been conversations about using the criteria of standing weight and height, but many people with disabilities cannot meet these criteria, so alternative measures need to be identified. The access to medical devices may help here because it will create a federal guideline for what has to be in any health clinic, doctor’s office, or hospital. Second, transportation is an issue across diverse groups. It is not just a disability issue; it is also a socioeconomic and ethnic issue. There have been a number of workshops about the environmental barriers to research for those populations and how to better address transportation, access, and child care needs. Third, research needs to recognize the need to reach out to the community to find out what works. She added that we need to work with the community to understand the needs, as All of Us is doing, by asking people what they need in order to build trust and get them involved in the research. There are a number of elements that are helping, and people across the board are becoming more invested. Dr. Nitkin said he is seeing more research applications putting in transportation costs, so investigators are starting to realize that this is a key issue in getting people to participate in trials. Ms. Corbett agreed that investigators should consider the costs of such things as transportation or home visits when writing their applications because it is much harder to do that after the fact.
A Board member described having excluded people based on age from clinical trials and suggested that while there is value in including populations across a broader range of ages, it also raises the issue of variability. Dr. Spong said that this is a generalizability issue. While there is certainly complexity and all humans are different, the question to ask is what is so physiologically different or harmful about a particular group or subgroup that justifies excluding them. An exclusion may be justified, but there must be more critical thought about it. The Board member noted that greater inclusion would require a much larger sample size to account for the variability. Dr. Spong agreed that a larger sample size might be required.
Dr. Cernich said that in the literature excluding for disability, intellectual disability is mentioned more often mostly for consent issues. Moreover, restriction is often based on population. There is not much information on pediatric rehabilitation, sometimes because the research often involves issues occurring later in life, so there may not be a plan to integrate children. This may be the real-world situation, but it is important to think about how to plan for pediatric inclusion if it is feasible, because it is clear from the literature that there are significant gaps. For a brain injury or spinal cord injury (SCI) study, there must be a significant scientific justification for exclusion of children, because otherwise a big part of the target population would be excluded. Dr. Spong added that unless these populations are studied, science does not have data and is just guessing. Ms. Corbett suggested the investigators should ask whether they would do a complementary study on this excluded group.
A Board member noted that even pediatric-targeted clinical trials have problems with the exclusion of subsets. For example, in muscular dystrophy clinical trials, some of the subjects could have cognitive or behavioral impairments. If the primary outcome measure is a physical measure, children with cognitive or behavioral impairments may not be able to do the primary assessments and be excluded. It is heartbreaking for families when their child does not get the benefit of participating. The FDA allows for a clinical trial to be powered on the basis of a subgroup of the primary outcome measure and then allows a broader population in studies. But for industry sponsors, the trial must be cost effective. Ms. Corbett noted that the FDA has been working to adopt similar policies to promote inclusion.
A Board member suggested that because it can be so difficult to recruit some populations, it is simply easier to exclude them. Dr. Spong agreed that when something takes more time, effort, and money, it is easier to exclude it. But it is essential to include those who should be there and not exclude them just because it is easy.
A Board member suggested that NIH provide training on how to recruit certain populations and spread that training across the country so that people could tap into it in a cost-effective strategies and best practices. Ms. Corbett said that NIH has funded studies on recruitment, which has also involved the NIMHD. Dr. Cernich added that Clinical and Translational Science Awards (CTSA) programs have recruitment strategies with additional materials available through NIH. It is necessary to think about how to educate the community and what resources need to be developed to recruit and include across the lifespan. This could be something to consider as a Board. Ms. Corbett said her office has a compilation of materials from NCI that she will provide to the Board. Dr. Cernich said this information would also be made available on the listserv.
A Board member praised the All of Us program’s intention to target disability populations but wondered how successful it would be in recruiting Asians and Hispanics by only focusing on Alabama, Montana, and New York. Dr. Cernich explained that those states represent just the initial kickoff with the All of Us community partners program. The program also has community partners for targeting other underrepresented populations, including Hispanic, Lesbian-Gay-Bisexual-Transgender (LGBT), American Indian/Alaska Natives, African American, and Asian populations, so this outreach will continue to evolve.
NIH Clinical Trials Policy Update
Meredith Temple-O’Connor, Ph.D., NICHD
NIH initiatives to enhance clinical trial stewardship focus on the areas of good clinical practice, the single IRB, registration and reporting, clinical trial review criteria, new application forms, and clinical trial funding opportunity announcements (FOAs). Dr. Temple-O’Connor referred Board members to https://grants.nih.gov/policy/clinical-trials.htm for more information.
The first round of applications started in late January and will be reviewed this summer. There had been some concern about how many investigators might be mismatched in terms of whether they accurately identified whether their study(s) was an NIH-defined clinical trial or not, but this has not been a problem: Less than 5 percent of applications are misclassified and/or submitted to the wrong FOA.
Monitoring, reporting, and meeting milestones are necessary to ensure that the trials stay on course and proceed smoothly. NICHD is in the process of discussing how to think about monitoring and oversight of clinical trials, which involve implementing milestones associated with a given trial. There are two core pieces of this discussion: evaluating risk from the Institute perspective and understanding how different elements of risk defines the milestones needed to ensure the study stays on track. From the NICHD perspective, risk is more than human subjects risk, although that is an important variable to consider; it also includes other risks, such as those related to the intervention, trial operations, and financial investment. Examples include: the experience of the PI(s), the complexity of the intervention, whether the study is first-in-human, etc. Considering whether the proposed budget is realistic can help ensure that the study is not hamstrung before it even gets started. Dr. Temple-O’Connor emphasized that participant risk is always paramount, but other risk factors must also be considered. Assessing the risk is important for establishing a milestone plan and reporting frequency.
Dr. Temple-O’Connor said that because NICHD has such a broad scientific portfolio, identifying milestones relevant to various branches early in the process would be helpful. The Research Performance Progress Report will have a section asking for certain milestone elements such as whether the first patient has been recruited and what percentage of enrollment has been achieved. In the new NIH Human Subjects/Clinical Trials form, the Study Timeline field is the beginning of the milestone plan. If an application is being considered for award, a milestone plan will be further developed collaboratively with the investigator and the Institute to develop milestones and outline a process for reporting to NICHD, depending on the risk. Having a workable framework is critical to ensuring that clinical trials stay on track. This will be the focus of continued internal discussions at NICHD that will inform future policy announcements.
Dr. Cernich asked for the Board’s input on risk determination and this policy initiative to incorporate their views on risk and how to monitor it. She noted that the practices and milestones being discussed for NICHD are also being discussed by other Institutes and Centers (ICs). She said that there would likely be changes and updates to this policy by the next meeting.
A Board member noted that some investigators get funded toward the end of the fiscal year, so they have less than 12 months to meet milestones; there should be an adjustment for that. Dr. Temple-O’Connor said this process is not meant to be a “gotcha,” but rather a collaborative partnership to ensure everyone is on the same page and has reasonable expectations for when a given milestone will be met. Everyone knows that unexpected things happen, but the intent is to help keep the clinical trial within the guardrails. The point about the budget crunch is well taken. For example, one question being debated was whether to hold awards until the investigators have their Investigational New Drug application. NICHD does not expect all the milestones to be met at the first report; but if there were too much delay, a conversation would be necessary to understand the issues and why milestones are not being met.
Molecular Transducers of Physical Activity Consortium (MoTrPAC)
D. Lee Alekel, Ph.D., National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Charlotte Peterson, Ph.D., NIAMS
Joan McGowan, Ph.D., NIAMS (ret.)
Dr. Alekel, the MoTrPAC Program Director, presented an overview of this large NIH Common Fund program, which includes 31 researchers across the country. The study aims to (1) assemble a comprehensive map of the molecular changes that occur in response to exercise as measured in human subjects and rats and, when possible, relate these changes to the benefits of physical activity; and (2) develop a user-friendly database that any researcher can access to develop hypotheses about how physical activity supports or improves health.
The program includes seven Clinical Centers (CCs)—six adult centers and one pediatric center—to study physical activity in healthy human subjects. Adults will provide human muscle, fat, and blood samples; children will provide only blood samples. These samples will be collected over 4 years and analyzed to produce a molecular map. There are three pre-clinical animal study sites, seven chemical analysis sites, a Bioinformatics Center, and a Consortium Coordination Center (CCC). The investment in the study is $172 million.
In the organizational chart, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the NIA, the National Institute of Biomedical Imaging and Bioengineering (NIBIB), and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) comprise the NIH MoTrPAC Working Group, which receives input from outside consultants, oversees the 19 sites, and interacts with the 19-member MoTrPAC Steering Committee. The CCC will organize, monitor, and support the Steering Committee. The study is monitored by a Data and Safety Monitoring Board (DSMB) and reports to a single IRB at Johns Hopkins. NIH does not have direct contact with the IRB but learns of their expectations from the CCC. The CCC is currently working on the forms that must be submitted to the IRB and DSMB.
The CCs are the key to the success of the program. MoTrPAC investigators will recruit approximately 3,000 healthy adults of both sexes with a wide range of ages, races, and ethnicities to engage in physical activity programs. Both active (n = 300) and sedentary (n = 2,100) volunteers will perform resistance or aerobic exercises. There will also be a sedentary control group (n = 300) that does no exercise. Rodents will undergo complementary protocols. The human and animal samples will be sent to the chemical analysis sites to be analyzed using various genomic, epigenomic, transcriptomic, proteomic, and metabolomics technologies, with the goal of measuring an appropriately wide range of molecular changes most likely to characterize the response to physical activity.
Dr. Alekel presented the pre-launch timeline for Years 1 and 2. During this period, the CCs have been developing protocols, procedures, and case report forms; the animal sites have refined their protocols and piloted phase I tissue collection; the chemical analysis sites have piloted the analysis procedures; the bioinformatics center has established data standards, cloud storage infrastructure, and is considering what “open data sharing” means; and the CCC continues to work on developing documents. It will likely take 3 months, until August or September 2018, for the IRB to approve all materials.
Dr. Alekel presented the next steps for all the MoTrPAC entities:
- CC and CCC: Between April and September, train staff, complete all materials for the DSMB and obtain DSMB approval, complete case report forms, submit all materials to the IRB, form a working group on internal data sharing, and conduct a clinical trial “dress rehearsal.”
- Pre-clinical animal sites: Finalize tissue collection and processing and procedures, conduct VO2 testing, and conduct acute and training studies.
- Chemical analysis sites: Finish the Human Tissue Analysis Plan, integrate biospecimen collection and processing plans, and finalize procedures.
- Bioinformatics center: Build the team, complete database/data sharing infrastructure, and complete data quality control, validation/reproducibility, and analysis models and plans.
Dr. Alekel concluded by showing the initial recruitment video featuring astronaut Peggy Whitson. Dr. Alekel noted that the study will probably have to recruit 10 to 20 times the number of people needed for the study because of the challenge of finding individuals who are used to being sedentary but willing to do the exercise training.
Dr. Cernich said that she and Dr. Alekel have had discussions to better understand the meaning of “physical activity” and what it means to be healthy. Once MoTrPAC is up and running, there will be discussion about how to include healthy people with physical disabilities, but doing so would be premature at this point. Dr. Cernich observed that there would be opportunities to add ancillary studies to MoTrPAC, and Dr. Alekel added that a number of ICs are interested in testing this out in their own populations, so the idea of other parallel studies mimicking this protocol is possible. Dr. Cernich said that NCMRR is funding a couple of announcements looking at physical activity.
A Board member asked how supplements and other medications would affect the study. Dr. Alekel said that there are extensive exclusion/inclusion criteria for this study and a number of medications are disallowed. Other medications will be allowed depending on how often they are taken. The idea is to get the healthiest population possible that can feasibly be recruited, so some criteria may change if recruitment is a problem. Dr. Peterson said that most supplements are allowed and will be tracked. The hope is to have a population that takes as few supplements as possible. Dr. Alekel added that the more unusual supplements will be excluded. She noted that diet is not going to be controlled in this study. Participants will continue with their usual dietary intake, but they will record their intake the day before and the day of their activity. It is expected that the investigators will examine about a year’s worth of food intake per participant.
A Board member suggested that the diet piece is critical, noting that in the military there is a high usage of energy drinks, so not excluding those drinks is powerful. Dr. Alekel said that except for the 300 participants who are highly fit, most participants are sedentary and are not likely to be taking supplements as performance enhancers. This study is not intended to be generalizable in the sense that it is looking for healthy individuals who are non-exercisers. That may sound like a contradiction, but the study is taking a lot of factors into account and must exclude other factors, so it is a delicate balance.
A Board member asked whether the study is set up in such a way that the methods used and the reporting could facilitate other investigators piggybacking on the study. Dr. Alekel said it was. The study will share the data as widely as possible and also have design papers and protocols published in the public domain for the widest possible sharing. The protocol will be fine-tuned as needed as the study progresses.
A Board member asked for more information on the relationship between the pre-clinical and clinical studies. Dr. Peterson said that the animal sites will conduct both acute and training bouts and try to mirror the human study as much as possible. Tissue taken from rodents is particularly valuable because the investigators will be able to salvage about 16 tissues from every rat.
A Board member suggested that as the study moves into ancillary studies, it would be important to involve ancillary study groups with the MoTrPAC Steering Committee to provide additional expertise that the MoTrPAC might not have. Furthermore, the may allow for transferring the research protocols to mobility-impaired populations. Dr. Alekel said that there is a standing ancillary study committee, which investigators go through before getting to the Steering Committee. She said she liked the idea about that type of discussion at the Steering Committee level. Dr. McGowan added that the ancillary studies include the use of the MoTrPAC facilities. Some studies might be independent and done at other sites, while others will use the MoTrPAC coordinating centers. She agreed that the availability of other expertise is important but noted that getting too many measures is a concern right now. Dr. Cernich agreed with Dr. McGowan about laying down a baseline, noting that NCMRR has funding opportunities that investigators can take advantage of, independent of but in parallel with MoTrPAC. Even the idea of being an athlete could be investigated within the disability community; there are not many studies on that topic. There are omics possibilities to explore that NCMRR does not normally look at in rehab protocols. This is a key study for NCMRR to understand; as the study progresses, NCMRR will think about how to look at the infrastructure from the NCMRR perspective.
A Board member asked how ancillary studies would access data in repositories. Dr. Alekel said that at this point the genetic and genomic data would reside in the Database of Genotypes and Phenotypes (dbGaP), so it should be available to investigators. Other data housed at the Biomedical Center will be stored on the cloud. The plan is for as much open data sharing as possible.
A Board member asked about the experience of using one IRB for seven CCs. Dr. Alekel said each of the CCs must get permission from their institutions to relinquish their authority to the single IRB. This involves more than just those seven CCs, because there are also sub-sites. It seems to be working well. NIH is not interacting directly with the IRB but instead working through the CCC. Dr. McGowan said that the National Center for Advancing Translational Sciences (NCATS) was very helpful to MoTrPAC in setting up this IRB, as were the CTSA programs. Many of the necessary agreements were already in place, and many MoTrPAC sites are CTSA sites, so it went smoothly. The video was also facilitated by the recruitment intervention center. She emphasized how important these collaborations were the process.
A Board member suggested that MoTrPAC may be able to borrow from the NeuroNEXT (Network for Excellence in Neuroscience Clinical Trials) study, which has 25 sites. This study allows for ancillary proposals, and applicants can become honorary NeuroNEXT sites and use the existing infrastructure. Dr. Alekel said that the NeuroNEXT model had been discussed, but at this point, the study is not ready for long-term plans.
Dr. Cernich said that NCMRR will be tracking this study. She offered to have a presentation from NCATS about resources if the Board were interested.
Pathways to Prevention (P2P) Workshop
Joe Bonner, Ph.D., NCMRR
The purpose of the proposed P2P workshop, which Dr. Bonner introduced in May 2017, is to produce an evidence-based report on the current state of preventative medicine for people who require a wheelchair for mobility; identify clinical practices that successfully encourage disease prevention among wheelchair users; identify research gaps; and recommend best practices for research on preventative medicine for wheelchair users. The knowledge gained will be used to better address the preventative medicine needs of the wheelchair user populations and may result in a future FOA.
The Office of Disease Prevention (ODP) would sponsor the P2P program and provide funding and logistics. The chair and workshop panel would be composed of people outside NIH. Proposals would come from ICs (NICHD/NCMRR and the National Institute of Neurological Disorders and Stroke [NINDS]) to identify the population, intervention, and outcome measures and produce the preliminary literature review. AHRQ would perform the evidence-based literature review and provide guidance on what is possible and practical.
Dr. Bonner described how the PICOT (population, intervention, comparison, outcomes, timing, setting) system would be used to select the analytical framework:
- Population: the initial choice was between all wheelchair users and wheelchair users with SCI only. The SCI populations would allow for a more focused review, and there is deep clinical trial literature related to prevention. After a search of the MEDLINE database for clinical trials on SCI, multiple sclerosis (MS), stroke, Parkinson’s disease, muscular dystrophy, frail elderly, and cerebral palsy (CP) and finding that “wheelchair user” is not reliably reported or defined in the clinical literature, it was decided to define the population by the condition that led to wheelchair use and study individuals with SCI, MS, and CP. These populations offered the widest range of outcomes while still meeting ODP and AHRQ’s needs.
- Intervention: many potential interventions were considered, with weight given to which interventions that had have robust clinical trial literature and the greatest potential impact. It was decided to use directed physical activity in a supervised or group setting as the intervention. The activities would include aerobic exercise, strength training, balance, flexibility, and combination interventions.
- Comparison: compare interventions to no physical activity or other types of physical activity.
- Outcomes: include oxygen consumption, cardiovascular health, balance, disability and activities of daily living, metabolic role, quality of life, depression, generalized anxiety disorder, and stress, using validated measures. These are the outcomes most commonly seen in the literature.
- Timing: at least 10 days with at least one session of physical activity.
- Setting: in the interest of being very inclusive, any setting could be used, including the clinic, home, or community (e.g., gym or athletic class).
Dr. Bonner reviewed the four key questions to be answered:
- What are the benefits, adverse events, and harms of physical activity for people with a disability who will potentially use or currently use a wheeled mobility device?
- What are the outcome measures, physical activity interventions, inclusion/exclusion criteria, and research methodologies related to prevention of obesity, diabetes, cardiovascular conditions, or adverse events in studies of physical activity for people with disability at risk for or currently using a wheeled mobility device?
- What factors may affect the effectiveness of physical activity interventions?
- What methodological weaknesses or gaps exist in the evidence to determine benefits, adverse events, and harms of physical activity interventions for people at risk for or currently using a wheeled mobility device?
Currently, NCMRR and NINDS are gathering nominations for the various panels to bring the workshop to fruition.
Dr. Cernich noted that there is a serious lack of systematic evidence reviews, which are the criteria for physical activity guidelines for this population. There are people in physical activity protocols who are participating even though there is no evidence about how much activity to use with various devices. The lack of this evidence makes it difficult to assess adverse events or evaluate benefits. She commended Dr. Bonner on his analyses.
A Board member asked whether the SCIs are limited only to traumatic injuries or whether people with congenital injuries, such as spina bifida, are included. Dr. Bonner said it will be predominantly traumatic injury.
A Board member commended this study and asked how compromised the populations in this study would be; for example, someone who sometimes used a walker? She wondered how those issues would be teased out as the study moves to the content discussion phase. Dr. Bonner said that for many SCI trials, there is not a wide range of being compromised. Similarly, with MS, toward the high end of the scale with greater impairment, there is less inclusion. Regarding the content area, there is a federal partners meeting being held to discuss nominations, but it is not clear whether nominations can be taken from the Board. Dr. Cernich added that part of this is to identify the gap in the literature to see where the evidentiary basis for some of these interventions is strong. Much of this focuses on disease, not prevention, so many things relating to the person’s condition will be identified. Part of the prevention aspect is determining not only how it affects the person’s condition but also to understand what is being done for people’s health outside of their condition or disability. There is a whole population of people who could benefit from physical activity intervention, but there are not always ways of telling them what the safety, adverse events, benefits, and limitations might be.
A Board member suggested looking at the outcomes of physical activity in terms of function and whether it decreases the burden of care or increases functional independence in a meaningful way. Dr. Bonner said it comes down to what people report and how they report it. One thing that might come out of the workshop is whether there are some basic things that could be reported about the technology that people are using that would be very helpful.
Update on Medical Rehabilitation Research Resource Network
Ralph Nitkin, Ph.D., NCMRR
For the past two decades, NCMRR has provided special support for networks that provide technical expertise and research support in domains that are particularly relevant to rehabilitation. The question for the Board to consider is how the rehabilitation research infrastructure should look going forward.
Dr. Nitkin provided a historical overview of the rehabilitation research infrastructure program. Since 2000, there have been four rounds of funding networks. The support model has evolved with recompetition every five years. This has resulted in a healthy turnover in research domains across the International Classification of Functioning, Disability and Health (ICF) range.
Dr. Nitkin described the solicitation process for the most recent 2015–2020 round of funding. The solicitation requested expertise in specific targeted domains but also allowed for any other appropriate applications in other key research areas. NCMRR received 20 applications, but they represented only a partial response the specific domains requested: Clinical Trials (5 applications); Engineering and the Environment (4 applications); Individualized Rehab and Dynamic Reassessment (2 applications); and Applied Behavioral Supports and Healthy Outcomes (0 applications).
As a result of peer review and NCMRR funding priorities, three existing networks (modeling and simulation of movement; analysis of large data sets; and technology assessment, product development, commercialization, and regulations) were renewed and three new networks (clinical trial design; regenerative medicine; and neuromodulation: clinical applications) were funded. These six centers were funded at the annual level of about $1 million total costs each but about 20 percent of the funding passes through to pilot funding. NINDS and NIBIB continue to provide cofunding to this program. Subsequent to funding this round, a supplemental “coordination center” was developed. The network centers give presentations, webinars, and workshops and generate databases, software, and other technical content. They also provide outreach to less-resourced institutions through free workshops, travel awards, targeted solicitations to minority institutions. Dr. Nitkin noted that given the current funding constraints, NCMRR support of research infrastructure slightly limits direct support of research grants and other NCMRR activities.
Dr. Nitkin reviewed some metrics from the research infrastructure program that included website contacts, substantive collaborations, presentations, webinars, pilot grants, and research application and publications that resulted from interactions with these networks. The number of research publications varied quite a bit across the six networks depending on the research domain and expertise provided, ranging from virtually none for the commercialization center to 560 for clinical trials support. Annual publications citing the medical rehabilitation infrastructure networks rose steadily to a high of 99 in 2015, just before the current program was recompeted. However, the actual number of research applications to the NIH and other federal agencies that resulted from interactions with these networks was somewhat disappointing.
Discussions with the trans-NIH Medical Rehabilitation Coordinating Committee strongly suggested that infrastructure funding should be targeted to opportunities highlighted in the NIH Research Plan on Rehabilitation, which include research across the lifespan, community and family, technology and development, translational science, and research design and methodology. The Committee was also open to considering targeted initiatives and “centers without walls” that would be relevant to their respective research missions.
Dr. Nitkin asked for input from the Board on where rehabilitation research infrastructure should go from here. He presented four questions for the Board’s consideration:
- Should we consider another round of funding networks?
- Should we restrict networks to domains linked to the NIH Research Plan on Rehabilitation?
- Should we consider targeted initiatives? Some examples:
- Adaptive fitness for people with disabilities, which could also connect to the NIH P2P workshop
- Promoting self-management and healthy behaviors
- Pediatric rehabilitation, which could involve issues in recruiting and supporting children in research; unique responses to therapeutics; vulnerabilities but also increased plasticity; and rapidly changing physical, behavioral, and emotional repertoire
Dr. Nitkin noted that in the past, solicitations in these domains have not gotten adequate response, so perhaps some additional groundwork would be required.
- Should we consider “centers without walls”? This concept could support collaborations between basic scientists and clinicians and focus on specific impairments and rehabilitation issues, such as:
- Contractures and spasticity
- Prevention of secondary complications
- Proving the value of chronic rehabilitation support, maintenance therapy, and community support.
Dr. Nitkin added that perhaps results could go to a Knowledge Translation Center for dissemination to professional groups and translation of available evidence into clinical practice.
A Board member asked for more clarification about the tradeoffs that would be involved in making changes. Dr. Nitkin said each center currently gets $1 million per year and this displaces a certain number of individual grants. The Board member asked whether these centers have fulfilled their purpose and made enough progress that it is time to move on to something new. Dr. Nitkin said that is exactly the point of the discussion.
Dr. Cernich explained that NCMRR has a statutory mandate to support infrastructure. It is currently using P2C grant mechanism, but she wondered if that was the only way to do it. Likewise, NCMRR has $5 million for K12 career development programs. Recently the NCMRR budget was increased to $70 million but some money may be redirected to targeted initiatives, such as those in the NIH Research Plan on Rehabilitation. NCMRR has supported research infrastructure for 20 years; she reiterated the question: what do we do going forward?
A Board member suggested that unless there is something important missing from the NIH Research Plan on Rehabilitation, the plan should be used for guidance going forward. Dr. Cernich noted that the current round of infrastructure networks were recompleted before the NIH Research Plan was formulated, so now it is time to consider what to do going forward.
A Board member agreed with looking to the Rehabilitation Research Plan for guidance. But she noted the differences in the publications that are citing the P2C resources, with one center having as many as 500 citations and another having none. Dr. Nitkin cautioned that the metric is an underestimate because sometimes infrastructure collaborators may do not publish until a year or later after funding is received and may forget to make full acknowledgments.
A Board member asked about targeted funding for infrastructure, noting that if there is concern about having a more inclusive mindset, perhaps funding centers without walls should be considered to determine how to do cross-sector collaboration more effectively. Or, alternatively, look at the Triple Aim framework of the Institute for Healthcare Improvement to help people support decreasing costs and increasing value for the population with physical disabilities. Dr. Cernich said that they must keep in mind the NIH focus on behavioral and biomedical research and not veer off into issues of economics and cost effectiveness that are beyond this central mission. The Board member suggested that NCMRR consider what answers are not yet available and what questions are not the Center’s to ask. If the point is to get others to address these gaps, can NCMRR use some of its knowledge and design for collaborative solutions, if it just asks the right questions?
A Board member advised adherence to the Rehabilitation Research Plan, noting it is designed to guide the Board’s activities. The idea of the center without walls is intriguing. As long as there are no lost efficiencies and there is an accountability structure, that model could be effective.
A Board member asked whether the centers understood the metrics for success when they were funded. Dr. Nitkin said they were told they were responsible for maintaining metrics, such as number of citations, but also understood that depending on what they were trying to deliver, the metrics could be very different. In quarterly phone calls, they have been reminded of this goal. Another Board member with experience being funded as an infrastructure center said that the centers deal with different topics, so the metrics will differ. Much has changed since his center, devoted to data, was funded in 2010, before the Big Data to Knowledge initiative. There was a need for building research capacity, and that was not being done in rehabilitation. When these centers started 20 years ago, there was much less rehabilitation research capacity than there is now. The centers, in general, were set up to look at areas that were not well developed, and that were important to the field but not yes something for which universities offered degrees in. That has changed. Today, everyone is involved with data and research capacity and people get advanced degrees in data science. If this center were to recompete, which it is not, the focus would clearly have to change with the times. Now the emphasis should be on trying to build infrastructure around priorities, but with enough flexibility to pivot if there are not competitive applicants for some priorities.
A Board member, noting that six centers are currently funded, asked whether there would be that many centers without walls. She suggested that if one goal is collaborating with clinicians, the center without walls might be a good opportunity. Dr. Nitkin said it is an open question and will depend on the topic. For a given topic, we would have to determine what model would work best. Dr. Cernich added that depending on what model is chosen, making it successful may require increasing the budget, so there would not likely be six centers without walls. She assured the Board that their point is well taken that the undertaking must be targeted to the rehabilitation research plan. The funding model may be different, depending on the type of research model chosen. However, a coordinating center was effective in promoting the overall program and coordinating activities and best practices among the programs. That may change depending on the new infrastructure model. NCMRR wants to hear from the Board about what to target, what model to use, and whether other types of approaches, different from our current infrastructure, to consider.
A Board member suggested that the current infrastructure networks have been methodologically focused, whereas the centers without walls with a dream team would be more content focused on scientific questions. Perhaps one issue to consider is whether there is room for a methodological advancement and, if so, what form of infrastructure provides the best network. Dr. Cernich agreed that the centers-without-walls concept is more content focused and may require a different template.
A Board member, noting the centers without walls are more content- or problem-specific, asked whether it would be more difficult to score applications that are more infrastructure based and methodologically oriented as compared to the centers without walls, which is focused on a specific problem. Peer-review panels would score those applications differently in terms of evaluating approach and innovations. Dr. Cernich clarified that if it came to that, there would be separate solicitations for infrastructure networks and centers without walls; these approaches would not be put head to head.
A Board member observed that 9 of the 20 applicants responded to the NCMRR-targeted initiatives and the others were investigator-initiated concepts. For the targeted area of adaptive fitness for people with disabilities because new initiatives will be funded in 2020, NCMRR might take advantage of the consortium being developed that is focused on physical activity and perhaps also add a pediatric focus. Some targeted initiatives that benefit from that infrastructure could be adopted. Dr. Nitkin noted that there was a Request for Applications on this topic a few years ago, but there was not much response to it. It is a great topic, but more groundwork might be needed before that center could be created.
Dr. Cernich said NCMRR could stay with methodological infrastructure if that is serving the need, and it would be targeted to the rehabilitation plan. Dr. Nitkin added that the health turnover in networks may reflect research growth and evolving opportunities.
A Board member, referring to the data showing that investments in individual investigators are more productive than K12 institutional awards, suggested that the NCMRR research program parallels that discussion. He asked whether the times had changed so much that the current infrastructure approach was no longer relevant.
A Board member said the advantage of the network is the speed at which it facilitates pilot studies and new initiatives. There are still gaps that can be filled, whether it is education or infrastructure. It is important be careful about the metrics used to measure success: If publications and grant applications are the only metrics, it raises the question of whether that is having the most impact on clinical communities.
Dr. Nitkin said this discussion will be ongoing and welcomed any further comments. He thanked the people at the infrastructure centers who have done great work. Dr. Cernich thanked Dr. Nitkin for his work as program director and for shepherding this program so well.
NIH Rehabilitation Landscape and Research Plan Analysis
Alison Cernich, Ph.D., Director, NCMRR
Jennifer Jackson, Ph.D., NCMRR
Drs. Cernich and Jackson presented data tracking the progress and impact of the NIH Research Plan on Rehabilitation. Dr. Jackson cautioned that all data presented are considered draft data until validated by all ICs. The trans-NIH Medical Rehabilitation Coordinating Committee has reviewed these data, and the NABMRR data subcommittee provided input. Feedback from the Board is needed to determine whether these are the types of data that best track the progress of the research plan.
The baseline data are from the FY 2015 portfolio. The analysis uses the Research, Condition, and Disease Categorization (RCDC) system. It contains the physical rehabilitation category but not intramural projects. Each project was categorized into two tiers. Tier 1 is based on a keyword approach for six categories within the NIH Research Plan on Rehabilitation as follows:
- Rehabilitation Across the Lifespan
- Community and Family
- Technology Use and Development (includes telemedicine)
- Research Design and Methodology (includes all clinical trials)
- Translational Science (includes all animal research and biomarkers)
- Research Capacity and Infrastructure (includes training grants)
Tier 2 defines the phase of research for the project, including basic, disease-related basic, or applied translational or clinical.
Two coders from NCMRR coded each relevant grant in the portfolio of the participating ICs. “Physical activity” is a new code for 2016. Each IC validated the coding for its portfolio showing 98 percent agreement with the initial NCMRR coders. All ICs were integrated for the final analysis. Specific aims are assumed to stay the same from year to year. Each subsequent year will be coded for new grants only. The analysis returned 1,394 total projects, of which 491 were new. Funding totaled $466.3 million.
Dr. Jackson summarized the findings of the portfolio analysis. Sixty-five percent of the projects are research projects, 14 percent were other research-related projects, 8 percent were research centers, 7 percent were small business, 5 percent were individual training projects, and 1 percent fell under the category of “other.” The National Institute on Deafness and Other Communication Disorders (NIDCD) had the greatest number of projects, followed by NINDS and NICHD. Of the 27 ICs, 22 had at least one rehabilitation project.
Dr. Jackson showed the funding data broken out by IC and by RCDC category. Most of the funding fell under “clinical research,” followed by “neurosciences,” “behavioral and social science,” “bioengineering,” and “brain disorders.”
Dr. Jackson also provided an analysis of topics for co-occurrence networks to show potential relationships among the various RCDC categories. For example, co-occurrence networks were evident among the “clinical research,” “rehabilitation,” “neurosciences,” “bioengineering,” and “brain disorder” categories. Grant topic clusters were examined using latent Dirichlet allocation, which represents documents as mixtures of topics. A topic was considered connected if there were four or more grants on that topic. As an example, in the grant topic cluster category of “cognitive and social therapies,” connection was strongly shown among the “cancer rehabilitation,” “pain management,” “caregiving and community,” “clinical trials,” and “cognitive function and therapy” categories.
Dr. Jackson presented a graph showing number of grants and funding per topic to demonstrate that funding does not always correlate with the number of grants as some topics have a similar number of grants but very disparate funding. A graph showing the number of grants per IC per topic continued to show that ICs are funding rehabilitation projects in categories that would be expected for their respective missions.
Dr. Jackson summarized the research category analysis across the six primary categories of the NIH Research Plan on Rehabilitation (i.e., rehabilitation across the lifespan, community and family, technology use and development, research design and methodology, translational science, and research capacity and infrastructure). About one-third of all projects and one-third of all funding are in the “research design and methodology” category. “Translational science,” “technology use and development,” and “rehabilitation across the lifespan” were the next largest categories for projects and for funding, at about 20 percent each. Very few of the projects fall into the “community and family” category. The analysis of the Tier 2 categories showed that applied clinical trials accounted for about one-half of the number of projects and funding, with disease-related basic research next, at 25 percent.
Most clinical trials were supported through the R01 funding mechanism; they represented 46 percent of the 281 grants and 51 percent of the $139 million clinical trial budget. Within
Clinical Impact and Interdisciplinary Collaboration
Dr. Jackson reported on the clinical impact of the 2016 rehabilitation portfolio, based on a search of publications. Of the 25,363 publications identified, 7,276 (29 percent) have been cited by a clinical trial or guideline for a Relative Citation Ratio of 1.78 (average is 1.0). Based on the National Library of Medicine Medical Subject Headings (MeSH), a vocabulary thesaurus for indexing articles, about 5,000 of the articles had no human, animal, or molecular cellular terms. The remaining approximately 20,000 articles did have one of these terms, but the majority (52 percent) had only human MeSH terms. The Board should consider whether there should be an effort to make more impact on animal and molecular/cellular research.
To evaluate interdisciplinary collaboration, Dr. Jackson presented a biosketch analysis of the 2016 rehabilitation portfolio. Out of the 1,394 grant applications, biosketches were identified for 1,220 projects (88 percent). Most of the biosketches indicated physician specialties, with lesser representation from other specialties, such as occupational therapists, physical therapists, and speech language pathologists. Conducting this analysis by lead PI showed similar results, but the largest percentage was the “no rehabilitative specialties” category. Next steps include refining the analysis to reduce this category and review the biosketch extraction process.
Dr. Jackson identified the trends between 2015 and 2016 in the six primary categories. The number of projects and the funding for rehabilitation across the lifespan, technology use and development, and research design and methodology increased in 2016. The other categories stayed the same or decreased slightly. Tier 2 trends showed an influx of R13 and R35 grants, although the funding for the latter was down. Phase III clinical trials showed an increase in number and funding in 2016.
Challenges to this analysis include the possibility that RCDC categories can change, and the categories either do not include all projects that have a rehabilitation focus or conversely include some that are not rehabilitation-related. Changes in the overarching NIH budget could also affect all portfolios and should be considered. Dr. Jackson said she is working on an automatic coding algorithm and will report on that at the next Board meeting.
A Board member asked why physical and occupational therapists were not highly represented in the biosketches and wondered if it was based on how education was reported. Dr. Cernich said it would be possible to go back and look at how occupations are being classified, noting that biosketches had been examined as a whole, by the first 10 lines, the first 25 lines, and the first 50 lines. Biosketches are based on education but might only be capturing rehabilitation sciences. Maybe people are not indicating in their biosketch that they are clinically-trained therapists. Or they may be in the rehabilitation sciences category at the bottom and not showing up at the top. Results may be based on the number of lines being analyzed within the recipe card. These numbers may not be right, due to how the biosketches were analyzed. A refined algorithm or a rehabilitation sciences Ph.D. category might be needed to better capture the people who get those degrees.
A Board member noted that one analysis showed dollar figures by IC for 2016 and suggested that an additional analysis might be to give total funding for individual ICs and then indicate the proportion that is allocated to rehabilitation research. Dr. Cernich said that the investigator community, rather than the ICs, drives most of this research, and NCMRR does not have a target for what this proportion should be. She said she would talk to the committee about how other ICs feel about this metric.
Dr. Cernich said that doing the coding and conducting these analyses is a tremendous amount of work and requires a trans-NIH effort. She thanked Dr. Jackson for the excellent work on this project.
this group were 13 NIH-defined phase III clinical trials reported, funded at $12 million.
Communication and Dissemination Strategies
Paul Williams, Director, Office of Communications (OC), NICHD
Mr. Williams outlined the two-pronged function of the OC:
- News and science writing: includes content development, crisis communications and strategic messaging, making videos, and writing newsletters
- Public information and outreach: includes public health campaigns, fielding public and Freedom of Information Act inquiries, and providing publications and exhibits
Communication is important because NICHD, whose mission applies to a large portion of society, has important stories to tell. Strategic communications help influence perceptions about NICHD to the public, media, and Congress.
These are interesting times for communication efforts, because media consolidation means there are fewer trained reporters, there is the “Dr. Google” effect where people with health questions go first to Google, and ad-supported media has increased competition for readers. Content is in high demand because everyone has a mobile device and there is now a 24-hour news cycle. Mr. Williams said his goal is to help meet this demand for content with stories of research progress and discovery.
Mr. Williams said his office monitors scientific papers, determines what is newsworthy, drafts press releases, and works with grantees to ensure that they mention NICHD accurately. For more information on this, send an email to email@example.com.
The OC measures its success by the number of mentions and total impressions that appear in the media per month. If these impressions from NICHD press releases were calculated as advertisement values, they would be worth tens of thousands of dollars. An important media outreach strategy is doing podcasts, which Mr. Williams recommends for NCMRR. It is also necessary to harness social media (e.g., Facebook, Instagram, Twitter, Pinterest) to be able to quickly interact and share messages with the public. Interestingly, the majority (70 percent) of NICHD followers on Facebook and Twitter are women.
Other communications efforts include NICHDevelopments (http://go.usagov/xDp5m), which is a monthly roundup of news and funding opportunities with 4,500 subscribers, and the NICHD website, which was redesigned in December 2017. Most users of the website come from search engines like Google and are looking for information on health issues. The most visited topics are adrenal gland disorders, sexually transmitted diseases, and Down syndrome. These are health, not research, topics. There have been 6.1 million total visits to the website, with an average of 510,000 visits per month. There is also a Spanish website, with an average of 195,000 visits per month, that will be moving to a new design soon.
For NCMRR communications, the philosophical question is whether NCMRR should be marketed as an entity separate from NICHD. In either case, NCMRR needs to develop a communications plan that defines the audience it is trying to reach and whether this outreach can be accomplished with the resources NCMRR has available. This could include a SWOT (strengths, weaknesses, opportunities, and threats) analysis. The greatest need for the OC is to hear from researchers with advance notice of NCMRR-funded publications because these kinds of press releases give the greatest “bang for the buck.” Currently, the OC is not getting this kind of information in a timely way. The other need is for sharable content for social media, such as video, images, and text, on the types of projects that capture the public’s imagination.
A Board member asked about benchmarks, in particular how having 21,000 followers on Facebook compares to other agencies. Mr. Williams said that NIH is a government agency, which is not usually the most compelling entity on Facebook; 21,000 followers compares very well with other agencies.
Another Board member asked whether it would be more beneficial if NCMRR were promoted as a separate entity, more clearly distinguished as an individual center. He noted that even some people who work at NIH do not realize there is a rehabilitation center. Mr. Williams said the NIH-wide trend is to be less institute-oriented and more NIH-oriented. For example, the NIH website is moving toward greater consolidation. He added that his office is required to always refer to NIH in press releases. There is also the issue of logos; NIH discourages new ones that do not contain “NIH.” Mr. Williams asked whether the Board would want to create the 21,000 Facebook followers that NIH has from scratch, or whether it would want to use this established channel to disseminate NCMRR content.
Dr. Cernich said that there are two issues to consider. One is how to promote the identity of NCMRR; she and her staff make every effort to get out in front of the public in videos and presentations to do that. The other issue is content about NCMRR. Often, NCMRR does not learn about a publication that it supported until weeks after publication. Unless there is a steady stream of content to share, it is very difficult to develop a separate identity. She recalled polling 370 active projects and getting only 20 responses. This makes it challenging to build a brand and to know what to build the communication plan on.
A Board member observed that NCMRR has a great story to tell and asked how NCMRR can get this message out in an NIH-sensitive way. It should not be an “either NIH/or NCMRR” conversation, but rather a way to communicate to serve both interests. Mr. Williams agreed, but the question is how to accomplish this. Dr. Cernich said the goal is to amplify results. The problem is getting enough content to drive the communication. The professional associations deserve credit because they do take information and amplify it. But it is not being amplified enough and NCMRR is not tracking it. The research community is one audience, but that is not the only audience NCMRR wants to engage. The key communication questions to answer are: Who are we [NCMRR] targeting, what are we targeting them for, and where should we put our resources?
A Board member agreed that the challenge for NCMRR is with ongoing content. The NIH brand is more recognizable, but with $466 million invested in rehabilitation research, it would seem that NCMRR has a lot of content. Mr. Williams said that not all content is equal. The idea is to capture the imagination. NCMRR has that content but the OC needs to get hold of it. There must be at least a monthly stream to be effective; it cannot just be sporadic output because that will not sustain interest.
A Board member suggested that NCMRR is a catalyst that can help bring recognition to other Institutes. He asked whether the National Library of Medicine could help in providing timely information about publications. Dr. Cernich said NCMRR has both ongoing grants and developing grants. Knowing about a big publication two weeks in advance gives the press office a chance to coordinate press releases across NIH. It takes more coordination than simply knowing that something was published. The way to get maximum reach is through multiple press releases that have been properly coordinated, not just putting out one from NCMRR. Mr. Williams added that every press release is coordinated downtown and takes three business days, so if the OC gets two weeks’ notice, that actually gives them only about a week to write the release and clear it internally. For the intramural program, the OC knows about their papers at time of submission, which is ideal.
A Board member said his company spends heavily with one goal: to sell. He asked what the primary goal of NCMRR’s ad campaign is. He also wondered whether NCMRR is marketing to Congress. Mr. Williams said that his office does not do marketing and does not handle Congress. The primary goal of his communications is to show Congress that the investment in NICHD is working and making a difference and that more money would make an even greater impact.
Dr. Nitkin recalled that years ago, each IC director would go to Congress directly; now Congress is approached with a single voice for funding. He noted that NCMRR is not just competing for money but also for “eyeballs” to try to make more people aware of what NCMRR is doing, and he wondered whether those two issues should be approached differently. Mr. Williams said the problem is that NCMRR is not generating enough regular content to drive engagement.
A Board member said that one problem is that investigators simply are not aware of the need to report their publications for use as content and how they could help by being more communicative with NCMRR. Dr. Cernich said it might be helpful to remind investigators about this through their program officials. She asked whether content is the only metric. Mr. Williams clarified that it is his office that generates content from the information received from NCMRR. Dr. Cernich said part of the NCMRR focus is to inform people that rehabilitation research is done at NIH and how it improves people’s lives. She and Mr. Williams will be working on communication strategies over the summer. Dr. Cernich thanked Dr. Bianchi for always talking about the rehabilitation program, noting that she is one of NCMRR’s biggest advocates.
A Board member observed that academics are not aware of this issue and suggested that it be part of the script every time there is a phone conversation to remind them of the need for this kind of timely information.
Another Board member asked about the ideal timeline for the OC to receive information. Mr. Williams said that learning about publications upon submission is optimal, but if a paper has been accepted and a proofed copy is sent his way, his office will get it publicized.
A Board member asked about the efficacy of working directly with journal editors in the field. Mr. Williams said that some journals such as Nature and the New England Journal of Medicine, are better than others about giving an early heads up. Dr. Cernich agreed that working with the editors is a good idea; she and Mr. Williams will discuss how to target editors for better communication.
Update on NCMRR Concept Clearances
NIH requires concept review and clearance of all Requests for Applications (RFAs). The NABMRR is one entity authorized to conduct this review and clearance. The following two concepts were presented for the Board’s comments and vote.
Global Rehabilitation Initiative: Building Evidence Base in Low- and Middle-Income Countries
This concept is a funding initiative in concert with WHO’s Rehabilitation 2030 Initiative (WHO Rehabilitation 2030). The RFA will solicit applications for research to implement evidence-based rehabilitation practices in low- and middle-income countries and/or promote research capacity-building in this scientific area. In addition, NICHD may seek to join a National Institute of Allergy and Infectious Diseases (NIAID) FOA that enables the further development of work completed by WHO in global rehabilitation.
A Board member expressed support for this “fantastic” idea but was concerned that for some low- and middle-income countries that have fundamental health disparities, the proposal might be too advanced for the current level of rehabilitation expertise or programs in these countries. Dr. Cernich said the operational planning is 2 years in the future. The WHO has identified countries to pilot some of the rehabilitation packages for specific conditions in the health system of specific countries. While the research might not be feasible in some countries, there would be groundwork in the pilot countries to look at what the package could reasonably include, such as wheelchairs or bowel and bladder training, along with a determination of what type of infrastructure is required and what frequency and intensity would be needed. The effort is similar to the Global Mental Health Challenge. Another Board member noted that there are models for determining best practices in developing countries to clarify what can be done in the context of the country’s available resources. More information about this is available at the International Spinal Cord Society’s website, https://www.iscos.org.uk/ .
A Board member called this an awesome initiative, noting that for many developing countries, there is no experience with what rehabilitation really is.
A Board member who had spent time in the Peace Corps found this proposal exciting. There is a huge role to be played in encouraging partnerships whereby the local community can demonstrate that it is capable of carrying the program forward and making it sustainable. There are many countries that are not in a position to take this program, but others could benefit because they are farther along and can serve an aspirational goal.
A Board member agreed with the critical importance of going into a country and changing things. She recounted working in a country to help train patients and cautioned that the good work can be undone if there is not a partnership piece where the country owns it. Another Board member said he went to Iraq to teach rehabilitation and saw the benefit of empowering locals.
A Board member noted the grassroots activity in this area and found it important to hear the comments of people who have had these experiences. There is an incredible difference in standards of care, because when comparing whether someone has a wheelchair or not, significant results can be shown. Another benefit is that cell phone usage is high, so there is an opportunity for data collection.
A Board member suggested that the scope of this project fits into the specific conditions of the “rehabilitation across the lifespan” category and asked whether consideration might be given to broadening the population to include neurodevelopmental disabilities. Dr. Cernich said the list in the Scope section of the proposal is not exhaustive and should better be described as “including, but not limited to.”
A Board member noted that these countries experience a number of needs, injuries, and illnesses that are not experienced in the United States, particularly in pediatric populations, and asked whether the project should be broadened to include some of those disabilities. Dr. Cernich noted that stroke is becoming an international disability. Consideration will be given to how to drive the science to address the leading causes of disability, some of which are not issues in the United States.
The Board voted unanimously in favor of this concept to be supported by NCMRR.
Pediatric Rehabilitation Research Infrastructure
This RFA will solicit applications for a research infrastructure network to promote and support pediatric rehabilitation research. The RFA will solicit applications through a mechanism that allows for multi-component research resource projects and centers.
A Board member noted that this proposal has multiple priorities that are in the rehabilitation research plan.
A Board member asked whether this project would be a similar model to existing infrastructure grants. Dr. Nitkin said it would be a similar model but might be extended a bit. The member suggested that it could conceptually include some targeted content prioritization as well as investigator-initiated content. Dr. Nitkin added that part of the calculus is whether there is the necessary infrastructure and support in the community for this, including people who could be mentors.
A Board member asked why the Objectives section focuses only on children with physical disabilities. Dr. Nitkin said the NCMRR population is people with physical disabilities. Another part of NICHD deals with children with intellectual disabilities. The distinction is a little artificial, because children with physical disabilities may also have cognitive or behavioral disabilities, and the project would try to provide secondary support for that as well. Dr. Cernich reminded the Board that NCMRR is specifically directed for physical disabilities. A Board member added that for pediatric rehabilitation, there is probably a more developed infrastructure for cognitive and intellectual disabilities and likely a greater need for the development of next-generation researchers in the area of physical disabilities.
The Board voted unanimously in favor of this concept to be supported by NCMRR.
Pragmatic Trials at NIH
Catherine Meyers, M.D., Director, Office of Clinical and Regulatory Affairs, National Center for Complementary and Integrative Health (NCCIH)
In 2010, journal articles reported the need for new approaches to clinical trials, particularly for trials that inform practice and policies and disseminate information to help clinicians make decisions more quickly. A 2016 article in the New England Journal of Medicine specifically highlighted pragmatic trials, noting the need to focus on the research question as opposed to being optimized to determine efficacy. More recent articles have described pragmatic trials and reported on the PRECIS-2 tool, which helps investigators make design decisions and score their trial based on where their trial designs fall on a multi-axis spectrum of various explanatory and pragmatic attributes.
Dr. Meyers described the two general types of trials: explanatory clinical trials, which are more consistent with conventional trials, are designed to establish efficacy of a treatment, often under idealized conditions; and pragmatic clinical trials (PCTs), designed for the primary purpose of informing decision-makers about the comparative balance of benefits, burdens, and risks of a biomedical or behavioral health intervention at the individual or population level. PCTs include domains that differ from explanatory trials, such as broad eligibility, flexible interventions, no follow-up visits, objective clinical outcomes, usual compliance as opposed to close monitoring, and typical practitioners as opposed to expert practitioners.
Dr. Meyers described the NIH Health Care Systems Research Collaboratory, funded by the Common Fund, which began in 2012 with the goal of strengthening the national capacity to implement cost-effective, large-scale research studies that engage health care delivery organizations as research partners. The Collaboratory focuses on trials involving problems of significant interest to clinicians and patients that inform practice, integrate research in a real-world setting, and engage integrated health care systems with electronic infrastructure. There is a Collaboratory Coordinating Center (CCC), and currently there are three rounds of PCT demonstration projects. Another funding strategy is a two-phase demonstration project, with a 1-year planning phase and, if milestones are met, transition to 4-year implementation. Trial sites are located across the country.
Dr. Meyers reviewed the first set of NIH Collaboratory PCTs, which included such diverse topics as Time to Reduce Mortality in End-Stage Renal Disease (TiME), Suicide Prevention Outreach Trial, Strategies and Opportunities to Stop Colorectal Cancer (currently awaiting publications), Active Bathing to Eliminate (ABATE) Infections (an in-patient intervention), Lumbar Image Reporting and Epidemiology (in data analysis), Decreasing Bioburden to Reduce Healthcare-Associated Infections and Readmissions, and Collaborative Care for Chronic Pain in Primary Care. Despite the different clinical questions, the trials all have similarities in design and implementation. The TiME trial was the first trial involving a for-profit company, Fresenius, to work with NIH to support 266 dialysis units. The trials range from 5,000 to 350,000 participants and involve both clustered and individual randomization.
The second set of PCT demonstration projects, all of which began in 2016, focuses on multiple chronic conditions. The trials include Improving Chronic Disease Management with Pieces (which includes a Veterans Affairs [VA] hospital), Pragmatic Trial of Video Education in Nursing Homes, and Trauma Survivors Outcomes and Support. Dr. Meyers noted that PCTs have been challenging for some IRBs.
Interventions from the demonstration projects include organizational changes to patient care, such as time of dialysis or changes to bathing protocols; enhancing information available to providers in electronic health records to change care delivery; direct patient screening kits, video education, or online education; and enhanced coordination of care delivered to complex patients. This is a way to provide health care providers with useful information. Fifteen health care systems are partnering with the NIH Collaboratory on these projects. A third set of PCT demonstration projects will be launched this spring. These six new projects will have a new strategy for Collaboratory support, with funding from both the Common Fund and NIH ICs, to get the ICs thinking about their own interest in PCTs.
Dr. Meyers provided more detail about the CCC, which provides national leadership and technical expertise in all aspects of research with health care systems, supports the design and rapid execution of a set of high-impact PCTs, and makes available data, tools, and resources to facilitate a broadened base of research partnerships with health care systems. The CCC started with working groups looking at core areas of research to help investigators go through specific tasks. The working groups continue to be the workhorses in helping investigative teams, and this has been a key to the success of the projects. The CCC also describes lessons learned through weekly grand rounds every Friday at 1:00 p.m. EST.
The Collaboratory website (http://www.rethinkingclinicaltrials.org ) was completely revamped in the fall of 2017 and renamed “Rethinking Clinical Trials: A Living Textbook of Pragmatic Clinical Trials.” It is now more accessible and useful, providing information in three discrete “Living Textbook” areas: design of the study, conduct of the study, and dissemination. The information is reviewed and updated by the CCC team every 6 months and includes template documents for researchers. A training section has recently been added. The first training program in February 2018 was a successful 2-day meeting for mid-career investigators addressing the administrative underpinnings of clinical trials before moving on to pragmatic studies. The training modules are on the website.
Dr. Meyers said a workshop, “Embedded Pragmatic Clinical Trials of Therapeutic A vs. B Interventions” will be held in Bethesda on May 16, 2018.
Dr. Cernich asked Dr. Meyers to elaborate on the FDA Sentinel Initiative. Dr. Meyers said the Sentinel effort is a network of about 20 health care systems around the United States with the goal of using public health surveillance to leverage emerging technology to connect health care systems and help them provide data to the FDA. This effort aimed to organize safety data about products to be reported quickly, particularly in the post-market space. The team managing this effort has reached out to share this technology. It is a quantum leap to use this data stream for research purposes. There are a number of interactions across government where her office is working with the Sentinel team to strategize on how to tap into this data stream to ask important research questions.
A Board member said that there are great opportunities for PCTs in the area of rare diseases because these trials cannot enroll a large number of patients, but none of the initial demonstration projects focused on rare diseases. He suggested that many conditions in the area of physical disabilities are rare diseases. The member also asked whether there are any pediatric initiatives, as most seemed focused on adults. Dr. Meyers pointed out that the suicide prevention study focused on a relatively rare event, but the point about rare diseases is an important one. The National Human Genome Research Institute will launch a collaborative pragmatic trial focused on rare genetic disorders. There is a separate FOA to focus on diverse populations for a defined set of disorders. One possible strategy is for the research community to get together to develop trials in that area. The Collaboratory predated the Patient-Centered Outcomes Research Institute initiative, but that is an area where there has been more robust patient engagement. To the second point, pediatrics was not supported in the first two rounds, but it is expected that will change in this next round.
Dr. Nitkin noted that the rehabilitation field has practice-based trials that allow patients to self-select treatment options. He asked whether the general community accepts that PCTs improve translation by answering real-world questions. To the first comment about self-selecting, Dr. Meyers said that in a study with multiple interventions from which patients can choose, not all participants may be fully engaged. There should be a modicum of efficacy data showing that the intervention is feasible. It is often best to test these interventions in real-world settings to determine feasibility. Some complementary integrative health interventions really work in a subset of populations who are invested in the intervention and who stick with it. The real issue is whether those people will still be using these interventions a year later, but that answer will not be available immediately. Regarding the question of how pragmatic a trial really is and understanding what a pragmatic trial is, this entails educating a whole community. Some reviewers get it and others do not. Things are getting better, but it is a case of getting resources out and having a stable community of investigators doing this type of work and answering questions. The precursor to the ABATE trial was a critical care study with the same intervention, and the ABATE trial got a clear answer that the intervention reduced infection. It was published in the New England Journal of Medicine with an editorial that said, “Question Answered.” So now NCMRR is educating the community about how the question research set out to answer is being addressed.
A Board member asked how important it is to have some basis from a Randomized Clinical Trial (RCT) before undertaking a PCT. Dr. Meyers said that for the studies she presents, a modicum of efficacy and safety data is required. It would not be wise to launch a large-scale study if researchers and health care partners were not convinced that the intervention was reasonable. The perspective has been that there is some preliminary efficacy data and that is particularly true with interventions with medical devices.
A Board member noted that randomization for PCTs has been done by centers and asked whether PCTs randomize treatment A vs. treatment B, and what happens if care standards change right in the middle of the trial. Dr. Meyers said, depending on the intervention, it may be possible to implement randomization strategies by site, provider, and individuals, so randomization is not a limitation. The second issue is very much on investigators’ minds. A trial on blood pressure was stopped after it was suggested that standards for blood pressure management should be reviewed. A bigger concern would be studies that don’t involve published guidelines. For example, although the standard time for dialysis in the United States is 3 hours, there is a sense that outcomes are better outside of the United States, where the times are longer. A dialysis study was looking at increasing the dialysis time, but it was hard to do because the director of the unit was worried not about a published concern but about the general idea of increasing the time. So published factors are not the only elements that can interfere. Also, sometimes control sites drop out, companies buy and sell sites, or practices change. There are a lot of moving parts. The CCC has a lot of work to do even after the launch.
Rehabilitation 2030: A World Health Organization (WHO) Call to Action
Antony Duttine, Advisor, Disabilities and Rehabilitation, Pan American Health Organization
Mr. Duttine provided an overview of both the Pan American Health Organization (PAHO) and WHO. PAHO, which is composed of 52 countries and territories and functions independently of WHO, has both a Disability and Rehabilitation Advisor and a Regional Action Plan spanning 2014–2019.
WHO is a global entity with six regions: the Americas, African, Southeast Asia, Europe, the Eastern Mediterranean, and the Western Pacific. It has a Disability and Rehabilitation Team and a Disability Action Plan spanning 2014–2021. Of the six regions, only two have full-time disability rehabilitation programs. One of the WHO Disability Action Plan’s core objectives is to strengthen and extend rehabilitation, habilitation, assistive technology, assistance and support services, and community-based rehabilitation. The PAHO Regional Action Plan has a similar objective, which was the focus of today’s presentation.
Rehabilitation in global health has received scant attention, partly because rehabilitation is not being measured (and what gets measured is what gets done), and partly because global health goals have focused on disease and mortality, not rehabilitation. Rehabilitation is often seen as an expensive luxury needed only in disasters. There has been a sense that if investments are made in prevention, detection, and treatment, there would be no need for rehabilitation down the line. In truth, there is actually a greater need for rehabilitation, but there is no demand for it because of low awareness and a limited supply of it due to low capacity.
Where Are We Now?
There has been a global decline in infectious diseases and mortality, but the number of injuries has stayed the same and there has been an increase in the aging population and non-communicable diseases. With the steady increase in years lived with disability, as has been seen between 1990 and 2016, rehabilitation will be increasingly needed.
The United Nations Sustainable Development Agenda lists ensuring healthy lives and promoting wellbeing for everyone and all ages as one of its 17 goals. Rehabilitation has been recognized as an essential service under universal health care, but there is no global indicator to measure whether it is being obtained.
Over the past two decades, there have been some key moments for rehabilitation at WHO, including the 2011 World Report on Disability, which showed 15 percent of the global population with a disability, and the World Global Disability Action Plan of 2014. Then, in February 2017, at a WHO meeting of stakeholders, the focus turned to a call for action to strengthen the health system to provide integrated rehabilitation services through a program called Rehabilitation 2030.
What Is Rehabilitation 2030?
Rehabilitation 2030 aims to integrate rehabilitation along the entire continuum of care, from acute to post-acute and long-term care. It envisions rehabilitation for all, including older people and people with chronic and episodic conditions, not just people with disabilities. It is an overarching plan that addresses leadership and political support, emergency preparedness, building rehabilitation service delivery models, developing a multidisciplinary rehabilitation workforce, collecting health information, building research capacity and evidence, and establishing networks and partnerships, all on a global level.
How Does Rehabilitation 2030 Relate to NIH?
The following are key aspects of Rehabilitation 2030 that relate to NIH:
- Leadership and political support: There will be a need to gather global leadership.
- Delivery models: These will define what rehabilitation should look like.
- Health information: This information will be used as much-needed data for the rehabilitation sector that currently has collected only limited data. Such data are critical to show health ministries what needs to be done.
- Research capacity and evidence: Evidence-based clinical trials are needed.
- Networks and partnerships: Strong and dedicated global partnerships are needed.
The dual strategy to address global rehabilitation needs is to increase demand through advocacy (e.g., raising the profile of rehabilitation, generating evidence for comparisons among countries, and encouraging civil society engagement) and to increase supply through enhanced technical capacity (e.g., having a core competency framework for interventions and developing an Assistive Technology Essential Package to show what minimum standards look like in a country).
Another very exciting initiative, the Support Package on Rehabilitation manual provides a four-step process for developing and implementing a nation’s rehabilitative strategic plan and outlines the WHO tools available to support the plan development. It encourages countries to have a rehabilitation plan based on the specific situation in their country. This process is beginning in Botswana.
Rehabilitation 2030 in the Americas
Currently, little is known or documented about rehabilitation, and there is wide variation among countries in rehabilitation advancements. There are few national action plans on rehabilitation, rehabilitation data and research capacity are limited in many areas, and financing is variable, although most countries are aiming for universal health coverage.
To address these issues, the Rehabilitation 2030 program has begun and will continue to organize regional meetings on the key areas of the plan (leadership and governance, workforce, etc.) and engage in the Standard Assessment of Rehabilitation Systems (STARS) to allow comparisons country by country. STARS is ongoing in Guyana and will begin in Bolivia in June, with the Bahamas, Dominican Republic, and Brazil as future possibilities. The goal is to have 20 STARS assessments completed by 2020. Over the next 3 years, research will continue and reports will be made on health, economic, communication disorders, and assistive technology, and strategic plans will be developed.
This area also provides opportunities for NIH engagement, both in the areas of advocacy by raising awareness, supporting research and data collection, and participating in global and regional meetings and technical capacity, by building capacity with organizations, providing expertise, hosting and attending technical meetings, and building an evidence base.
Mr. Duttine concluded by outlining the key research questions:
- What is the current global status of rehabilitation and assistive technology?
- Is rehabilitation cost effective?
- What rehabilitation and assistive technology structure and financing works in different contexts?
- What is an appropriate rehabilitation workforce?
- What rehabilitation measures should be integrated into health care information systems, and how do we collect these?
- How are assistive devices best delivered?
- How do we improve awareness and leadership on rehabilitation?
A Board member asked how the question of whether rehabilitation is cost effective is being addressed in terms of a time scale for that evaluation. Mr. Duttine said it is not being strongly evaluated in most countries where he works. The benefit to society is what is evaluated. His interest is quantifying the cost effectiveness of preventing future health care issues by providing rehabilitation early on, but this is not far along. The United Kingdom has been doing interesting work, but the trouble with economic evaluations is that it is hard to prove cause and effect. Cost-effectiveness data needs to be collected country by country; researchers should not try to extrapolate results from other countries.
Dr. Cernich said the challenge in talking to partners in the global space is finding that there are no rehabilitation data about the early initiatives in developing countries that helped reduce things such as childhood mortality, HIV, and infectious diseases. There is a clear need and benefit in thinking about this from the perspective of asking what we have as evidence. The impact of all these professional organizations, federal agencies (including NIH), and international groups working together could be transformative, and to transform the culture is very compelling.
A Board member found this presentation inspiring and asked for more information about the minimal assistive technology that should be available. Mr. Duttine said that in 2016, global experts put forward 50 essential products and devices across various types of disabilities, as a sort of parallel to what WHO does for essential medications for a country. The Board member asked that this information on essential products and devices be provided to the Board.
Scientific Presentation: Multimodal Approaches in Rehabilitation Research
Edelle Field-Fote, Ph.D., Director of SCI Research, Shepherd Center, Atlanta, Georgia
Dr. Field-Fote described how multimodal interventions are associated with complex interactions, how they drive therapeutic benefit, how the phasing of trials is valuable for understanding interactions, and alternatives to randomized clinical trial designs for understanding these interactions. She noted that combination strategies in medicine are the rule rather than the exception, especially in the rehabilitation world where a given intervention is often combined with training, activity, and exercise.
Dr. Field-Fote described the common types of interactions:
- Mediators: variables necessary to reveal intervention effect
- Moderators: variables that change the size or direction of the effect of the intervention
- Confounders: variables that correlate either positively or negatively with both the intervention and the outcome (a nuisance variable)
- Covariates: variables that influence the outcome but are not associated with the intervention
Interactions among interventions are complex. The hope is that the intervention has a direct effect on the outcome, but sometimes the intervention goes through a mediator or a moderator, which influences the size of the effect, before affecting the outcome. Other times the intervention goes through a confounder before affecting the outcome, which is not beneficial. And sometimes a covariate affects the outcome, independent of the intervention.
For example, in SCI physical activity is known to have powerful effects. In a given intervention, activity might act as a mediator, moderator, or covariate, so it can have many different roles.
Dr. Field-Fote used a study of reach training in spinal cord-injured mice to show the influence of activity. Training alone was found to be highly effective in restoring pellet-reaching function. Another study found that combining reaching training with a chondroitinase injection significantly improved outcomes over chondroitinase injection alone. However, when the investigators combined chondroitinase with ladder walking, this combination of interventions did not have an effect on pellet-reaching success, although it did improve accuracy of stepping in ladder walking. The point is that even if a biologic intervention has value, it must be combined with the right type of activity to show improvement in the outcome of interest.
To illustrate confounding effects in multimodal interventions, Dr. Field-Fote described a pre-clinical study that informed clinical practice using methylprednisolone (MP), a potent anti-inflammatory. GM1 gangliosides are natural substances that have been shown to promote axonal regeneration but had also been shown to block the neuroprotective effects of MP when given concurrently in pre-clinical studies. In a clinical trial undertaken when MP was the standard of care for chronic spinal injuries, administration of GM1 did not provide a statistically-significant beneficial effect, perhaps because administration of GM1 was delayed for hours after MP administration. Therefore, even when two substances are beneficial, putting them together does not necessarily result in a synergistic or additive beneficial effect.
Dr. Field-Fote cited a systemic review that searched the literature looking for intervention studies with the strongest evidence of beneficial effects on functional outcomes in persons with SCI. The study found that a large number of studies had a high risk of bias, which shows the need for stronger clinical trials in SCI. The systemic review assessed the reported studies in terms of whether they were phase I, II, or III, and found that the strongest evidence for beneficial effects was for phase III studies multi-modal interventions that contained a rehabilitation component with some other intervention. Recognizing this, an international workgroup has been formed to develop an International SCI Rehabilitation Dataset so that investigators leading intervention studies for persons with SCI can track the rehabilitation interventions participants are receiving along with the experimental interventions.
Dr. Field-Fote discussed the powerful effects of time on studies, noting that time may be necessary to reveal treatment effects (as a mediator), influence the size or direction of the intervention effect (as a moderator,) or be more beneficial for recovery than the intervention of interest (as a covariate). Age, time from injury, treatment duration and frequency, and assessment timing are all important temporal factors. She described one of her own studies of the effects of whole-body vibration on stretch reflex excitability, which looked at how time after intervention influenced he outcome measure in different ways. Understanding how the effects of an intervention change in the post-intervention period informs clinical practice, for example, it may indicate the window of time to intervene with activity depending whether spasticity helps or hinders the activity. Mechanisms underlying intervention effects may be time-dependent, and consideration should be given to time issues such as time since injury, the duration of the intervention, and the timing of combination treatment. Dr. Field-Fote provided examples of time-related influences in studies of neuromodulation, using either gating (which involves applying the stimulation concurrently with the intervention) or homeostatic plasticity (which involves applying the stimulation prior to the activity).
Dr. Field-Fote said that dose also has powerful effects. It may be necessary to reveal treatment effects (as a mediator) or influence the size or direction of the intervention effect (as a moderator). Dr. Field-Fote described a pre-clinical study published this year that found that the optimal dose needed may depend on injury severity and that dose has a significant effect on identifying and influencing outcomes. The doses provided in pre-clinical studies often far exceed those that are provided in clinical trials.
To recap, multimodal interventions are best used when the effects of each intervention in isolation have been characterized, have been characterized in the study population of interest, have indications that the effects will be cumulative, and have no evidence for negative interactions between interventions. Identifying confounders, mediators, and moderators can be done by starting with pre-clinical trials to test the effect of possible confounders, moving to phase I trials to look at potential interactions between various interventions, moving to phase II trials to make comparisons, using phase III trials to work out the details and comparative benefits, and possibly undertaking phase IV pragmatic trials to look at long-term effects.
In discussing control and comparison groups, Dr. Field-Fote indicated that it is no longer permissible to have control groups that do nothing, because expectations can influence outcomes. Expectations may include the placebo effect (effects arising from the subjects’ beliefs about the intervention rather than the intervention itself), the Hawthorne effect (alteration of subjects’ behavior as a consequence of being observed), and the Pygmalion effect (subjects perform at the level they believe others expect of them). Moreover, even well-controlled trials can be affected by unexpected individual differences, such as level of subject engagement within training sessions or potential reinforcing or competing activities performed outside of formal training sessions.
Dr. Field-Fote provided some alternatives to randomized controlled trial designs that might be valuable to work out issues of mediators, moderators, and confounders:
- Delayed-intervention design: One group receives the intervention immediately and the other group has a delayed start. The delay provides a baseline comparison group. The delayed group may start on placebo, but eventually all subjects receive the same intervention. This design is useful only for clinical conditions that are non-progressive. Enrollment may suffer if subjects are unwilling to wait, and the delayed group may be at higher risk for dropout.
- Crossover design: Each subject receives in sequence each contrasting treatment, with the order of treatment randomized. This design controls inter-subject variability and allows within-subject comparisons. This design requires a sufficient washout period between interventions to prevent any potential carryover of effects into the second treatment period. (For drug trials, the FDA recommends a washout period that is equivalent to at least three times the half-life of the drug.) Although this is an efficient design for smaller sample sizes and for studies of symptom control, it would not be appropriate for an intervention that significantly resolves the condition.
- Run-in (wash-in) design: When using subjects who have been inactive, any intervention is likely to result in change. In this design, all participants receive the same initial treatment. For example, in one study Dr. Field-Fote was interested in the effect of transcranial direct stimulation (TDS) on hand function, and she suspected that TDS is more likely to be beneficial when combined with training. Being able to separate those two interventions out is important. She used a run-in design where subjects had just the hand training for 3 weeks, then 3 weeks of stimulation combined with hand training. The investigators then determined whether the trend lines in those two phases differed This design is valuable for assessing stability at baseline, identifying placebo responders and trends in response to the intervention, acquiring multiple baseline measures, and withdrawing non-adherers.
- N of 1 randomized design: This is a form of single-subject research design with one dependent variable (outcome) and independent variables (interventions). It involves repeated observations across time and may have an unblinded run-in period. Using this design requires that the health condition be chronic and stable, the intervention effect rapid, the clinically relevant effect measurable, optimal treatment duration achievable within the study period, and the effect reversible with withdrawal of the intervention.
- Multiple baseline design: This is a variation on the delayed intervention design that allows for investigation of the effects of multiple measures and separating out effect of potential confounds that may occur during the study. It is especially valuable when effects are not reversible.
Dr. Nitkin thanked Dr. Field-Fote for outlining key variables, noting that for timing and dosing it is important to ensure that the “sweet spot” for each potential treatment has been optimized, because otherwise potentially contradictory results could be found. Dr. Field-Fote agreed that many factors, some unexpected, can affect the optimal dose, citing as an example the amount of the subject’s hair when receiving TDS.
A Board member observed that the selection of assessment could influence outcomes from the intervention. For example, if the outcome is fall frequency and the intervention promotes activity, participants might fall more frequently because of the increased activity. Dr. Field-Fote agreed that it is very important to keep track of interactions like this. If an intervention changes the ability to move and interact with the environment and people apply it in the real world, they could actually be set up for greater risk for a number of issues. Similarly, for all participants who are very sedentary, just participating in frequent assessments could be increased activity.
A Board member, noting that considerable animal literature looks at neurobiological influences, observed that skilled and unskilled activity have different effects. Skilled interventions are task specific and may not generalize to other types of behaviors, so the specificity of the intervention and the specificity of the outcome measures are important aspects of generalizability. Dr. Field-Fote said that in a skilled activity, attention and focus are critical, which is why skilled behavior training has a larger effect. In terms of how specific to be, science is not close to answering that question yet, but it is important that the investigator consider the training activities in the context of real-world movement. She recounted a hand-function study where participants practiced fine motor control of the hand and researching activities, to promote salience of the practice activities participants had the opportunity to choose activities from each of five categories. One participant wanted to focus on fine motor control and so did not choose reaching activities. She got very good at fine motor activity but was not able to move her arm away from her body. It is important to experience the whole range of activity with skilled activities as part of the design of the intervention.
A Board member, noting the importance of getting optimal dosage around interventions, asked about strategies to optimize dosing. Dr. Field-Fote said attention to dose has greatly increased. Studies of cortical and neural excitability contribute to this change, and consideration is being given to augmenting plasticity in other ways. The issue of health care reimbursement also factors into how much therapy time people receive, and the dose of therapy they receive in the clinical setting is often limited because of the need to re-learn a broad range of functional activities, so programs that people can do at home should receive more research attention.
An attendee asked whether task difficulty beyond just dose has been considered in treatment design. Dr. Field-Fote noted that the motor-learning literature supports the idea that practice sessions need to be challenging but not frustrating. This requires constant attention, because there is so much variability among individuals. Another complexity is quantifying the challenge and intensity of a task and how engaged the participant is, as engagement/motivation have a substantive impact on the outcome of the practice. However, the intensity of training, levels of challenge, level of effort and motivation, etc. are difficult to quantify. For example, ratings of perceived exertion may be valuable for assessing effort in more aerobic, gross-motor types of activities, but are of little value for quantifying effort in performance of motor tasks. Dr. Field-Fote indicated that she would appreciate suggestions on how to quantify this.A Board member recalled developing a study that involved a series of home exercises and then asking participants to rate the difficulty of each exercise. The best predictor of who did better with the balance exercises was the participants’ rating of difficulty. Because participants were starting to do things they had not done in a long time, their balance confidence was actually rated lower as the study progressed. The only study outcome that was correlated with the amount of improvement was the rating of the difficulty of the exercises. Dr. Nitkin suggested that some of the difficulty might not be simply the physical challenge involved but also the personalities of the participants and how they respond to the challenge. The Board member said a colleague who is studying subjective effort found that energy does not necessarily predict what the effort is and suggested that mathematical modeling may be useful because it could allow for subjective differences, which are very hard to understand.
Comments from Retiring Members
Dr. Cernich thanked the retiring Board members and presented each with a certificate of appreciation. The retiring members each made remarks.
Dr. Bastian, a former NABMRR Chair, said she found the time on the Board so useful because of how the staff distilled information from across NIH that was helpful and important to take back to the community. The topics were carefully chosen to ensure they were trans-NIH issues and the discussions were invaluable. She said that this was one of the nicest groups of people that she had been associated with and that she appreciated the opportunity to get to know the Board members.
Dr. Camica said how much she appreciated the efforts to make membership on this Board meaningful and how grateful she was to be part of the development of the rehabilitation research plan. She said she was excited to see where the plan takes NCMRR and will be interested in the global ventures going forward. She thanked NCMRR for this opportunity to serve.
Dr. Hidler recalled meeting Dr. Nitkin in 1996 when he came to NIH for a workshop and he noted his admiration for Dr. Nitkin’s work. He said how much he appreciated the opportunity to serve on the Board and that his takeaways would always be both the hard work that the staff and leadership do and the lasting friendships he made on the Board.
Dr. Means said that Dr. Nitkin was a mentor and a role model. He was impressed with how much work NCMRR does, noting that he did not have an appreciation of the scope of the work is both domestic and global. The last 4 years involved many changes, including leadership changes as Dr. Cernich came in after Dr. Nitkin’s interim term. There had been an amazing volume of information presented to the Board in an accessible way. Dr. Means thanked the NCMRR leadership for keeping inclusion on the agenda and noted that there is more work to be done. He said it was rewarding to be part of the Board and of the group. He expressed how much he enjoyed meeting his fellow Board members and the NCMRR staff, noting that although service on the Board was a way for him to give back to the field, he felt that he had gotten more than he had given. Dr. Means said that this group would always have a special bond and that he was thankful for this opportunity.Dr. Nudo said the change and development of this Board over the years has been wonderful and that it has been exciting to see the field develop. He said that as a pre-clinical investigator, he learned a great deal from the clinical community. He admired the effort to bring a diverse panel to the Board and encouraged the NCMRR leadership to think about adding other basic scientists who are doing animal work to the Board, noting that they would bring a different perspective to the Board and would also learn a lot. He had enjoyed his experience serving on the Board.
Dr. Cernich invited the retiring members to keep in touch and requested that everyone send names of nominees for the Board. She noted that the Board should be diverse not only in ethnic and gender representation, but also in areas of science. She thanked the Board members for their efforts and time. Current Board chair, Dr. Hicks, added his thanks for such a productive meeting and for such illuminating perspectives.The meeting was adjourned at 11:40 a.m.