Changes to Clinical Trials Research
Impact On You
Neural Control Funding
NIA Approved Concepts
Welcome to the November Clinical and Translational Neuroscience newsletter, this month we update you on some things to keep in mind with the NIH’s definition of a clinical trial, approved concepts from the NIA, new funding opportunities, and let you know about upcoming neuroscience events. Please visit our program area pages of the IHSI website for the latest news and grant opportunities. And as always, if you have an item to share with the neuroscience community at Illinois, we would be happy to feature it. Items can be submitted to Gillian Snyder, IHSI research development manager.
Clinical Trials Definition | CHANGES AT THE NIH
Policies at the NIH about the definition of clinical trials have gone through considerable changes over the last few months, the reason is that the NIH believes that NIH-funded scientists are not publicizing in a timely manner nearly half of the trials they conduct and complete. The agency believes that this is an unacceptable state of affairs, and that the purpose in defining clinical trials as they do is to improve dissemination and transparency. The bottom line: if public money is going to be spent to conduct experiments on people, scientists are expected to report the results.
Clinical trials are clinical research studies involving human participants assigned to an intervention in which the study is designed to evaluate the effect(s) of the intervention on the participant and the effect being evaluated is a health-related biomedical or behavioral outcome. But does your research fall within this category? The NIH has developed a tool to help you determine whether your study now falls within the category of a clinical trial. In addition, they have provided a series of case studies and FAQ’s that might help you decide.
The following questions should be used to determine whether a study meets the NIH clinical trial definition:
- Does the study involve human participants?
- Are the participants prospectively assigned to an intervention?
- Is the study designed to evaluate the effect of the intervention on the participants?
- Is the effect being evaluated a health-related biomedical or behavioral outcome?
If the answers are all “yes,” the study is a clinical trial.
If any answers are “no,” the study is not a clinical trial.
Does the primary outcome of a study need to be a health-related outcome in order for a study to be considered a clinical trial?
If any outcome is health-related and the answers to the four questions are all yes, then the study meets the clinical trial definition. You should note, though, that all NIH-funded research investigating biomedical or behavioral outcomes is considered to be health-related. Hence, if the outcome is biomedical or behavioral, the study may be a clinical trial (if the answers to the other three questions are “yes”). Many clinical trials are “mechanistic” or “exploratory” falling outside the realm of efficacy or effectiveness trials.
What is the sub-definition of "intervention"?
An intervention is defined as a manipulation of the subject or subject’s environment for the purpose of modifying one or more health-related biomedical or behavioral processes and/or endpoints. Examples include: drugs/small molecules/compounds; biologics; devices; procedures (e.g., surgical techniques); delivery systems (e.g., telemedicine, face-to-face interviews); strategies to change health-related behavior (e.g., diet, cognitive therapy, exercise, development of new habits); treatment strategies; prevention strategies; and, diagnostic strategies.
Note that studies that involve secondary research with biological specimens or health information are not clinical trials.
NIH will continue to update case studies, FAQs, tools, and resources to clarify guidance around the NIH clinical trial definition. See resources at: https://grants.nih.gov/policy/clinical-trials.html
Additionally, NIH staff are prepared to help researchers determine whether their studies meet the NIH clinical trial definition.
Effective for application due dates on/after January 25, 2018, refer to "Section II. Award Information" of the funding opportunity announcement (FOA) to ensure you are responding to a FOA that accepts clinical trial applications.
Follow the application instructions carefully, as well as all NIH policies related to clinical trial applications and awards.
For more information, please consult the NIH website.
Changes To Clinical Trials Research | WHAT DOES THIS MEAN FOR YOU?
The changes to the NIH’s definition of a clinical trial is likely to have a time-intensive impact on your future NIH applications (assuming that your study falls within the boundary of a clinical trial). Outlined below are the areas that are likely to impact your submission process:
Good Clinical Practice Training
Effective January 1, 2017, NIH expects all NIH-funded clinical investigators and clinical trial staff who are involved in the design, conduct, oversight, or management of clinical trials to be trained in Good Clinical Practice (GCP). The principles of GCP help assure the safety, integrity, and quality of clinical trials by addressing elements related to the design, conduct, and reporting of clinical trials. GCP training describes the responsibilities of investigators, sponsors, monitors, and IRBs in the conduct of clinical trials.
GCP training aims to ensure that:
- The rights, safety, and well-being of human subjects are protected
- Clinical trials are conducted in accordance with approved plans with rigor and integrity
- Data derived from clinical trials are reliable
Training in GCP may be achieved through a class or course, academic training program, or certification from a recognized clinical research professional organization. NIH also offers GCP training. See their FAQ on this topic.
Clinical Trial-Specific Funding Opportunities
For due dates on or after January 25, 2018, NIH will require that all applications involving one or more clinical trials be submitted through a Funding Opportunity Announcement (FOA) specifically designed for clinical trials. The purpose of this policy is to improve the NIH’s ability to identify proposed clinical trials, ensure that key pieces of trial-specific information are submitted with each application, and uniformly apply trial-specific review criteria.
All existing FOAs will be updated in Fall 2017 with the following changes:
- All FOAs will specify the allowability of clinical trials in Section II. Award Information
- All clinical trial FOAs will specify allowability of clinical trials in the FOA title
- FOAs that accept clinical trials will incorporate specific review criteria to ensure that reviewers appropriately consider clinical trial-related information
Applicants should check the online version of the FOA within 8 weeks of the due date to ensure it is still appropriate for their application. Keep in mind that there are specific considerations for training, fellowship, and career development awards.
New Human Subjects and Clinical Trial Information Form
A primary component of NIH’s initiative to enhance the stewardship of clinical trials is the creation of a new application form that consolidates all Human Subjects and Clinical Trial related information into one place, and also expands the information required for studies that meet the NIH definition of a clinical trial. This new form will be included in the new FORMS-E Application Packages and will be required for all applications with due dates on or after January 25, 2018. Other key dates:
- September 25, 2017 – New FORMS-E Application Instructions available on the How to Apply - Application Guide website
- October 25, 2017 – FORMS-E Application Packages will start being published for FOAs with due dates on or after January 25, 2018
- Note that all new application packages will be published at least 60 days ahead of the first due dates
- January 25, 2018 – First due dates for new FORMS-E Application Packages
During the transition period from FORMS-D to FORMS-E, both form packages will be available for some FOAs. It is important that applicants pay close attention and choose the announcement specific for their due date.
The most significant change with the new FORMS-E Application Package is the addition of a new PHS Human Subjects and Clinical Trials Information form. This form consolidates human subjects, inclusion enrollment, and clinical trial information previously collected across multiple agency forms. The form collects information on human subjects and clinical trials at the study level.
Single IRB Policy for Multi-site Research
Historically, in many multi-site studies, each site has its own IRB which conducts an independent review of studies involving human research participants. The use of a single IRB of record for multi-site studies that are conducting the same protocol will help streamline the IRB review process by eliminating the unnecessary repetition of those reviews across sites.
The goal of this policy is to enhance and streamline the IRB review process for multi-site research so that research can proceed as quickly as possible without compromising ethical principles and protections for human research participants.
Clinical Trials Protocol Template
To facilitate the development of clinical trial protocols that require a Food and Drug Administration (FDA) Investigational New Drug (IND) or Investigational Device Exemption (IDE) Application, the NIH and FDA collaboratively developed a Phase 2/3 Clinical Trial Protocol Template and an electronic protocol-writing tool to help investigators think through the scientific basis of their assumptions, minimize uncertainty in the interpretation of outcomes, and prevent loss of data.
Requirements for Registering & Reporting NIH-funded Clinical Trials in ClinicalTrials.gov
All NIH-funded clinical trials are expected to register and submit results information to Clinicaltrials.gov, as per the "NIH Policy on Dissemination of NIH-Funded Clinical Trial Information" for competing applications and contract proposals submitted on or after 1/18/2017. This website provides resources for understanding and complying with this NIH policy and the federal regulations in Section 801 of the Food and Drug Administration Amendments Act (FDAAA 801) as implemented by 42 CFR Part 11 (Final Rule).
Peripheral Proteostasis, Brain Aging and Alzheimer's Disease | APPLY NOW
A failure of proteostasis is a hallmark of aging, and aging is a major risk factor for AD and many other proteinopathies. It has been hypothesized that one reason why AD is an age-related disease is that, as the proteostatic machinery fails, protein quality control can no longer be assured, leading to the accumulation of damaged proteins which, during adulthood, were kept at bay by adequate proteostasis. Since aging is a biological process that affects the entire body, it is possible that the rate of decline in proteostatic function in peripheral tissues might be informative of the risk of developing proteinopathies, including AD. Therefore, one goal of this FOA is to ascertain whether changes in proteostasis in the periphery can be used as an informative risk factor for brain dementias including AD. Because aging affects the entire body, and the age-related decrease in proteostasis is not limited to the brain, research funded under this FOA does not need to include AD models explicitly, though proposals must include a suitable cognitive readout for “aging brain”, such as loss of cognitive function or other AD-related cognitive or behavioral measurement.
This FOA invites applications to advance understanding of the role of peripheral proteostasis and its loss during aging in the etiology and development of late onset AD. Proposals are expected to make a connection between the area of study and AD, but there is no need to include AD models explicitly in the application. Areas to be considered include, but are not limited to:
- tissue-specific regulation of proteostasis mechanisms during aging;
- tissue cross-talk regarding proteotoxic challenges;
- development of tools to assess the cross-talk of proteostatic signals between the brain and the periphery;
- mechanisms of cellular import and export of misfolded proteins, peptides and oligomers in aging tissues;
- determination of mechanisms by which peripheral proteostasis signals cross the blood-brain barrier; and
- strategies to ameliorate the impact of dysregulated proteostasis in aging peripheral tissues on the brain and on Alzheimer’s Disease.
As the novel and interdisciplinary nature of the research area necessitates a broad range of expertise in aging, Alzheimer’s and proteostasis biology, applicants may seek to collaborate as a research strategy to address the topics in this FOA. Therefore, multidisciplinary teams of investigators are encouraged to apply.
For more information see the FOA.
Enhancing Central Neural Control of Mobility | GET YOUR TEAM TOGETHER
The overall goal of this funding opportunity announcement is to encourage applications that will examine the central neural control of mobility in older adults without overt neurological diseases, an understudied area of critical importance. Applications addressing the interplay between the central and peripheral nervous systems to investigate mobility impairment are also welcome. Applications are invited from multidisciplinary scientific teams that include basic, clinical, and translational scientists; propose innovative and cutting-edge methods that are emerging in neuroscience, geriatrics and mobility-related fields that could be effectively applied within the design of interventions; and develop and validate a common set of terminologies and standards to improve mobility research. NIA is particularly encouraging applications in the following areas, although applications on other relevant areas are also welcome:
- Propose a team-science approach that assembles a network of scientists from different disciplines that will develop a framework to fulfill the objectives of this program announcement
- Operationalize and harmonize imaging protocols and techniques for quantifying dynamic gait and motor functions
- Develop and validate a common set of terminologies and standards to improve mobility research
- Design studies that address one or more of these specific topic areas:
- Understand the functions of brain regions and networks in the control of mobility and quantify the contributions of the CNS to mobility loss in older adults in the absence of overt neurologic diseases
- Develop models of mobility limitations in older adults that differentiate aging from disease-related processes and that fully integrate central and peripheral nervous system and musculoskeletal contributions.
- Understand the relationship between vascular disease and/or neuro-inflammation with altered brain networks, impaired voluntary neuromuscular activation, and compromised mobility and other motor functions
- Focus on deciphering preclinical CNS changes predictive of mobility impairment which may be amenable to intervention
- Examine mechanisms and pathways linking vascular function to mobility in normal biological aging
- Understand the sequence of events and causal pathways leading early cerebrovascular changes to mobility impairments
- Understand the mechanism and pathways linking early cerebrovascular and peripheral nerve changes as well as the sequence of events and causal pathways leading to structural damage and mobility issues, not only in the presence of disease but also in normal biological aging
- Studies of mechanistic connections between neuropathological changes, inflammation, genetic polymorphisms, gene expression and other biological processes in the brain and periphery that contribute to the development of mobility impairments in the elderly
- Study age-related changes in tissue maintenance, repair, and plasticity in the CNS and their effects on mobility
- Propose a combination of secondary data analysis and prospective design to accomplish the study goals
For more information see the FOA.
RESEARCH & OUTREACH
Approved Concepts from the NIA | GET YOUR TEAM TOGETHER NOW!
Below are some of the concepts approved at the most recent National Advisory Council on Aging (NACA) meeting. The NIA has posted the approved concepts here to give interested researchers maximal lead time to plan projects. Please note that not all concepts will necessarily end up converting to a Funding Opportunity Announcement.
- Evolving Implementations for Training Cognition in Aging: The proposed initiative consists of an RFA soliciting one or possibly two planning awards to develop and finalize protocols for well-powered cognitive training intervention trials to remediate or prevent age-related cognitive decline, as well as possibly prevent or delay the onset of dementia. Trial designs would need to include state-of-the-art outcome measures, including behavioral and biological markers, and perform pre-, post-, and maintenance structural and functional imaging.
- Collaboratory on Research Definitions for Cognitive Resilience and Reserve: Without greatly enhanced conceptual and definitional clarity concerning the definition of cognitive resilience and cognitive reserve, or how we could conclusively establish whether cognitive resilience or reserve are responsible for relatively favorable outcomes, we cannot make substantial progress in answering questions concerning what intervention strategies we could reasonably propose or how much benefit such interventions would provide.
- Sleep disorders and circadian clock disruption in Alzheimer’s disease and other dementias of aging: Older adults with Alzheimer’s disease (AD) often exhibit sleep disturbances and circadian clock disruptions. Although this has been interpreted as a consequence of AD, there is evidence that sleep disturbances may contribute to AD risk. For example, it has been demonstrated that preclinical signs of AD are often associated with poor sleep quality. Moreover, Aβ accumulation in the brain predicts and exacerbates sleep disruption in humans and in animal models; experimental manipulations to increase sleep result in decreased Aβ deposition. Such findings provide support for interventions that improve sleep in older adults to reduce the risk of developing AD. Effective interventions exist to improve sleep, and these could be tested as a possible means to prevent AD.
Neuroscience Program Seminars Wrapping Up For Semester | MARK YOUR CALENDAR
This year’s Neuroscience Program seminar series kicked off in September, and continues throughout the semester. December seminar speakers include:
NSP Holiday Party 12/5/2017 Join the NSP program to celebrate the holidays
Scott Junti 11/28/2017 Dissecting social behavior using genetics in cichlid fish
Seminars will resume again on January 23, 2018!
IMPORTANT DATES AND DEADLINES
- Devices RFI: 12/1/2017
- Neuroscience Prize: 12/15/2017
- Proteostasis: 1/9/2018 (LOI)
- Neural Control: 1/21/18 (LOI)
If you have something to share with the neuroscience community at Illinois, contact Gillian Snyder, IHSI research development manager in CTN, at (217) 300-6709 or firstname.lastname@example.org.