Preclinical Research in Pain Treatments: Discovery and Validation of Targets for Pain, Animal and Human-Based Screening Platforms
Walter J. Koroshetz, M.D., Director, NINDS
Dr. Koroshetz said NIH’s strength lies in discovering new targets; he reiterated that some new research will emphasize validation in various settings and species, followed by generalizability, with the goal of lowering the risk of adopting new targets into translational projects. Some interesting areas of research include new ways to design and interact with receptors that can be evaluated in silico. The Brain Research through Advancing Innovative Technologies Initiative is heavily invested in developing ways to turn cell types on and off, possibly through chemical measures. A recent study found a method for turning off neurons in the basal amygdala so that animals feel pain but do not respond to it, opening up new capacity to dissect the circuits.
Preclinical Screening Platform for Pain (PSPP)
Amir Tamiz, Ph.D., Director, Division of Translational Research, NINDS
The PSPP aims to accelerate discovery and preclinical development of nonaddictive pain treatments, de-risk assets so they can be made available for research quickly, and generate high-quality data using pain models to advance promising treatments into trials. NIH will incorporate industry-standard protocols and work with industry to generate robust data.
The PSPP will include a public database where all findings and protocols will be published. Dr. Tamiz anticipates the PSPP will have a catalytic impact on the field. Development began in 2018, and the platform is already testing some compounds. In 2023, NIH will evaluate the platform to see whether it achieved useful, meaningful milestones, then identify the next steps. Anyone can submit ideas for assets to evaluate through the PSPP.
Developing Drugs and Testing Platforms for Pain, Addiction, and Overdose
Joni L. Rutter, Ph.D., Deputy Director, NCATS
NCATS’ role in the HEAL Initiative includes intramural and extramural work, with a number of intramural collaborations. Some efforts are developing human-based platforms for testing treatments for pain, addiction, and overdose, and they range from simple, single cell-based assays to three-dimensional fabricated tissue models and multi-organ models. Other efforts are putting compounds through the preclinical regulatory requirements, with the goal of accelerating novel compounds toward testing. Some have developed new chemical structures to modulate novel targets, while others are combining artificial intelligence with synthetic chemicals to assess compounds better, faster, and more cheaply.
The NCATS in-house chemistry program can help assess compounds and conduct toxicology testing. NCATS can also help develop drugs for clinical testing by providing capability (such as pharmacokinetic or safety evaluation) or assisting with scaling up to a Good Manufacturing Practices (GMP) production facility.
Among the extramural opportunities is an FOA to support creation of tissue models/chips and another for developing innovative, specialized platforms to help solve the opioid crisis. Intramural collaboration does not include funding but enables investigators to use NCATS resources and expertise for free. It also allows investigators to fail fast, ensuring that work that proceeds to the next milestone has a high likelihood of success. Dr. Rutter pointed out that NCATS can create on-ramps into the product pipeline—as well as off-ramps—to get to approval and commercialization.
Discussion
Asked about the status of models in development, Dr. Koroshetz said that some models are specific to certain types of pain, and some types of pain may require more relevant models. For validation studies, he and his colleagues will try to match the asset to the best population and animal model to evaluate the asset and refine the model.
Models
- Models should account for sex as a biological variable, even at the cellular level. Some research is already demonstrating different pain responses between male and female cells.
- The field lacks models for centralized pain, which represents a huge gap that cuts across diseases. Centralized pain occurs with many diseases for which the pain was initially caused by nociceptive input and then transforms into chronic pain (e.g., fibromyalgia, irritable bowel syndrome, pelvic pain, and sickle cell disease).
- NCATS is supporting development of human cell models that can last as long as 60 days so that researchers can evaluate longer-term exposure to interventions.
- The field is beginning to realize that animal models may be measuring sensitization to input, not spontaneous pain.
- Some work on animal models aims to assess outcomes related to functional performance.
- Research should explore new territory in animal models, such as the use of marmosets, which have neurological components similar to humans.
Other Topics
- Working with industry may be a means to gather information from the preclinical and animal model data about products that failed clinical testing—information that is not in the public domain.
- The research community has indicated that focusing on validating endpoints that better predict human response can provide insights that allow for reverse engineering to develop new models. Biomarkers may help identify efficacy and predict validity.
- Some research is seeking new analgesics that are not addictive, looking at the potential use of cannabinoids, for example. NCATS may be able to help by providing researchers with tetrahydrocannabinol manufactured in a GMP setting and developing tests of the addictive, analgesic, and anti-inflammatory properties of the product.
EPPIC-Net
Clinton Wright, M.D., Director, NINDS Division of Clinical Research
EPPIC-Net will create an infrastructure that draws on existing expertise and facilitates learning and training, allowing for innovative trial design and iterative learning approaches to speed up research. EPPIC-Net will also establish a pool of well-phenotyped patient cohorts and incorporate biomarkers and endpoints that demonstrate target engagement or proof of principle.
EPPIC-Net will be similar to current CTNs but provide more flexibility and nimbleness to pave the way for more partnerships with industry researchers. It will include a data coordination center, a clinical coordination center, and specialized hubs and spokes set up around different pain conditions. The data coordination center will facilitate data sharing and allow programs to put their data in a repository that others can use.
Anyone can propose an asset for testing by completing an online template that enables NIH to screen the proposals. Selected assets will be reviewed independently, on a rolling cycle, according to traditional NIH review procedures. If the asset appears promising, NIH will solicit more information, and the asset will undergo extensive review and prioritization. NIH will then work with the asset holder to develop a study protocol and with the clinical coordination center to identify a site with the expertise to conduct the research. EPPIC-Net will store data and biosamples from trials or from industry partners that can be used by others.
Discussion
In response to Dr. Collins, Dr. Wright explained that some sites will likely have capacity to set up trials quickly for common pain conditions (e.g., back pain or diabetic neuropathy); for other conditions, EPPIC-Net will seek out new partners. Dr. Wright and Dr. Koroshetz clarified that NIH partners with FDA; asset holders can communicate with FDA when they face hurdles or bottlenecks. NIH will prioritize assets for which Phase I and safety research are already completed. NIH can learn from assets that failed testing and build on existing work for which more evidence is needed. Key points of discussion follow:
- EPPIC-Net will be set up to incorporate phenotype data. A trans-NIH discussion is needed about how pain conditions are phenotyped. Phenotype data are very important to understanding who will respond to treatment.
- NIH should let the field know that the HEAL Initiative offers an opportunity to prioritize assets focusing on pain or OUD and facilitate their inclusion in, for example, the NIH Blueprint for Neuroscience Research. NCATS can provide resources for early toxicology studies, manufacturing, and meaningful Phase I trials, among others. Such opportunities will be attractive to smaller companies that are working on high-risk discovery.
- At present, no reliable biomarkers have been identified for chronic pain, which represents a significant unmet need.
- The current FOA does not include genotyping, but it may be considered, as costs are coming down.
- One barrier to pain research is the problem of secondary data analysis. The lack of biomarkers and the use of limited outcomes measures (e.g., VAS) stymies advances. Imaging, such as functional magnetic resonance imaging correlated with pain, could elevate efforts, but it is expensive. In addition, pain may not be the same, neurobiologically, across individuals. It is possible that imaging could reveal categories related to prediction of pain.
- Some research is exploring what happens in the brain as individuals transition from acute to chronic pain. Work is underway to advance potential biomarkers and to refine imaging technology for use in clinical trial settings.
- Little is known about chronic pain when it is not triggered by an acute event. Because pain draws on neurological and musculoskeletal systems, dynamic imaging may yield understanding about the transition from acute to chronic pain.
Pain Management Effectiveness Research Network (Pain ERN)
Jane Atkinson, D.D.S., Director, Trial Innovation Network, NCATS
The Pain ERN, a trans-NIH initiative co-led by NINDS and NCATS, will compare the effectiveness of existing therapies or novel delivery approaches to prevent or manage pain while reducing the risk of addiction. It will strengthen and inform current clinical guidelines, address pain management across diverse communities, develop a suite of effective pain strategies for patients and providers, and improve patients’ and families’ QoL.
The Pain ERN will build on the infrastructure of the NCATS Clinical and Translational Science Awards (CTSA) program, allowing NIH to address multiple conditions through one network that has access to millions of patients. The NCATS Trial Innovation Network, part of the CTSA program, will provide clinical and biostatistical coordination and expertise in pain and support the development of recruitment and retention plans before trial launch to ensure stakeholders are engaged in advance and the trial goals are meaningful to participants.
NIH staff who oversee HEAL trials meet regularly to discuss standardization across CTNs using validated patient-reported clinical outcomes, common data elements, common data standards (e.g., Clinical Data Interchange Standards Consortium [CDISC]), and common adverse event coding. The Pain ERN studies will use CDISC data standards, which aligns with FDA’s needs. Data and biospecimens will be stored in the EPPIC-Net central data repository for public use.
Discussion
Dr. Atkinson said trial data are typically available about 5 to 6 years after the trial begins, which gave rise to the suggestion that some metadata, such as recruitment variables, could be made available sooner if doing so would not interfere with the integrity of the analysis. Investigators generally agree that they would like to maintain the confidentiality of their data for about a year to allow for publication before the data are shared broadly. (All NIH-funded research findings must be published in ClinicalTrials.gov within 1 year of the conclusion of data collection.)
New technology may help speed up patient recruitment and data collection—for example, by enabling oversight from a distance. Dr. Atkinson agreed but underscored the need to maintain the quality of the research processes and to avoid overwhelming the data and clinical coordination centers. She added that NIH can use electronic methods to identify which sites to visit and support web-based training of study personnel. Dr. Atkinson clarified that collecting biosamples is optional, but NCATS could consider asking sites to collect and submit DNA samples.