Full Summary — Development of Safe, Effective, and Non-Addictive Pain Treatments

June 16, 2017

As part of a government-wide effort to address the opioid crisis, NIH is initiating a public-private collaborative research initiative on (1) new and innovative medications and biologics to treat opioid addiction and for overdose prevention and reversal; (2) safe, effective, and non-addictive strategies to manage chronic pain; and (3) neurobiology of chronic pain.

To identify the scientific strategies with the greatest potential for solutions to the opioid problem, NIH is bringing together innovative experts from government, industry, and academia for a series of three cutting-edge science meetings. NIH seeks to pursue new approaches and recruit additional expertise with the aim of developing new safe and effective therapeutics for opioid abuse and chronic pain in half the time it currently takes.

The first of these meetings was held on June 5, entitled Medications Development for Opioid Use Disorders and Overdose Prevention and Reversal. The second, summarized here, was held on June 16^th, entitled Development of Safe, Effective, Non-Addictive Pain Treatments. These will be followed by a meeting on July 7^th, entitled Understanding the Neurobiological Mechanisms of Pain.

Dr. Francis Collins, Director of the National Institutes of Health (NIH), highlighted the urgency of the opioid crisis, and the high priority agencies throughout the federal government have placed on ending this crisis. This meeting is the second of three that are being convened to identify areas for a public private partnership recently initiated by NIH to address the opioid crisis. Dr. Collins and Dr. Nora Volkow, Director, National Institute on Drug Abuse (NIDA), published a Special Report in the New England Journal of Medicine to describe the initiative which focuses on three scientific areas:

1. developing better overdose-reversal and prevention interventions to reduce mortality, saving lives for future treatment and recovery;
2. finding new, innovative medications and technologies to treat opioid addiction; and
3. finding safe, effective, nonaddictive interventions to manage chronic pain.

The goal of this initiative is to develop public-private partnerships to cut in half the time to develop new treatments. NIH has successfully used this model to address other scientific priority areas. For example, the Accelerating Medicine Partnership with NIH, FDA, Foundation for NIH, and 10 pharmaceutical companies aims to develop treatments for three disease areas, with 50/50 contributions from government and industry for a total of $230 million over 5 years.

Over-prescription of opioid analgesics has been a key driver of the opioid crisis. This, in part, has resulted from a lack of effective alternative treatments for chronic pain. An estimated 50 million Americans are suffering from significant chronic or severe pain. We cannot hope to end the opioid crisis without addressing the treatment needs of people with moderate to severe chronic pain. The goal for the day is to develop a draft workplan for partnerships that will accelerate development of safer, more effective medications for treating pain.

Penney Cowan: Patient Perspectives on Chronic Pain and Its Treatment

Penny Cowan, the founder and CEO of the American Chronic Pain Association (ACPA), shared the perspective of patients and families affected by chronic pain. She emphasized how chronic pain impacts one’s ability to function in everyday life. Pain can become so limiting that it impacts all other facets of life. She highlighted some aspects of the experience of living with chronic pain:

• Patients feel a strong desire to know the cause of their pain.
• Patients are frustrated when their providers do not believe them about their pain; objective measure of pain would help them get the treatment they need;
• Patients should not be defined by their pain. Prefers the terminology ‘people or patients with pain’ as opposed to ‘pain patient’.
• Pain often fluctuates in intensity and the fear of pain can be just as debilitating as the actual pain; people with pain will avoid making plans because they don’t know when the pain will hit.
• Chronic pain also has significant impacts on family and caregivers.
• Many people believe that medicine should be able to take away their pain; we need to reset expectations for what is an achievable outcome. The goal is improved quality of life.
• Each patient is unique. They need personalized, comprehensive pain treatment plans that are developed through coordination between the patient and clinician.
• People with pain need a better understanding of clinical trials to encourage greater, more diverse participation.

Ms. Cowan also emphasized the importance of including patients in efforts to address chronic pain, asking the assembled group to remember the role of people with pain, and reminding them: “nothing about us without us”.

Two case studies were presented to highlight the major challenges experienced in the medication development pipeline.

Ken Verburg recounted Pfizer experiences in developing therapeutics for pain. In the 1980’s they developed NSAIDs; trials took just a few years and involved only a few hundred patients. Trials today take significantly longer and require tens of thousands of patients. From 2005-2015 only one of 16 compounds made it through the pipeline. Most compounds failed in Phase 2. Dr. Verburg discussed the development of Tanezumab, an IgG2 monoclonal antibody specific to nerve growth factor (NGF) that has been in development for 13 years – compared to Celebrex which only took 3 years to develop in the 1990s. Clinical trials were conducted on over 11,000 participants. They experienced two clinical holds, one as a result of an increased rate of rapidly progressing osteoarthritis leading to joint replacement in patients receiving higher doses of Tanezumab in combination with NSAIDs. The second hold was in response to animal studies that found reductions in neuron size and count in the sympathetic ganglia. They have since demonstrated that these reductions do not increase with time, are not associated with loss of function, and are reversible after cessation of treatment. In 2015, the clinical hold was released and they started Phase 3 trials on another 7000 patients.

John Dunlop then discussed Amgen’s experiences developing sodium channel blockers. Ion channels historically have not made great targets for treating pain because of their complexity. However, recent advances in screening technology have led to progress in the design of compounds with greater subtype specificity. The combination of subtype selectivity and restricted bioavailability may allow for the identification of more effective analgesics with reduced side effects. A screening platform with higher predictive validity would speed research in this area. More research is also needed on the blood-nerve barrier which has significant impacts on bio-availability.

There has been a disproportionate shift in investment towards NaV 1.7 specific molecules because of human genetic findings in this area. However, more investment is needed research on other subtypes and mixed inhibitors and other novel mechanisms.

Dr. Walter Koroshetz, Director of the National Institute on Neurological Disorders and Stroke, summarized participant feedback solicited prior to the meeting related to compounds in development and future research directions, challenges, and partnership opportunities for developing safer opioids, novel/repurposed non-opioid medications, and drug combinations.

Key Themes

• There has been significant progress in target identification and structure based drug development; there are many therapeutics in the pipeline.
• There is a need to reset expectations of what is achievable with pain treatment. Complete relief may not be attainable for all patients. The goal of chronic pain treatment may be to reduce pain so that the patient can be aggressively rehabilitated so the underlying causes of pain can be addressed.
• Heterogeneity—in both underlying pathology and confounding factors—among patients with chronic pain poses significant challenges in clinical trials.
• A panel of objective biomarkers is needed to improve the speed, efficiency, and quality of clinical trials.
• Better animal models with predictive validity are needed.
• There is a need for more basic research on a diverse range of pain conditions to develop a foundation for future clinical trials.
• Advances in neuroscience technologies are poised to accelerate the development of treatments targeted to the neurobiological substrates of pain.
• There is significant potential value in coordination of efforts across both pharmaceutical and academic research to facilitate more efficient use of limited resources.
  • Significant overlap in the targets being pursued by different companies but the lessons learned are not readily shared.
  • Common technical challenges that everyone is working on independently, such as development of biomarkers and animal models.
• Patient advocacy groups have a valuable perspective that should inform the research agenda.

Challenges

There are many challenges faced in conducting clinical trials for pain therapeutics including:

• Heterogeneity among patients with pain – pain sensitivity, underlying causes of pain, responses to treatment, etc.
• Pain has a complex pathophysiology with a strong placebo effect.
• Many conditions that cause pain have a downward clinical trajectory (e.g. osteoarthritis, multiple sclerosis, etc.); endpoints that include a slowed rate of decline are needed.
• There is a lack of objective measures for pain.
• Clinical trials don’t reflect the way pain is treated in the real world
  • Longest trials are about 12 weeks while patients with chronic pain may take medications for years; however, there are ethical concerns about keeping patients on placebo for an extended period or discontinuing other treatments during the trials.
  • Daily dosing during trials vs. real world episodic dosing in response to exacerbation of pain.
• Trials often focus on endpoints relevant to acute pain as opposed to chronic pain; need more focus on meaningful clinical endpoints such as improved function and quality of life.
• Trials often compare medications to placebo without incorporating a multidisciplinary treatment plan that reflects the standard of care.
  • Clinicians often base their practice on what is successful in clinical trials, these trials should reflect the best available care.
  • Randomized trials are needed to determine whether there are synergistic effects between the medications and other treatment modalities (e.g. behavioral therapies, physical therapy, acupuncture, etc.); This is common in trials of medications for behavioral health disorders (e.g. depression, addiction).
  • For industry, this would likely be cost prohibitive. They currently try to minimize ancillary therapy to maximize the signal on the medication’s effects.
• Clinical trials often focus on common pain conditions; however, FDA has minimal tolerance for risk when low prevalence adverse effects could impact thousands of people. Focusing on narrower indications could reduce costs and speed clinical trials.
• Many clinical trials are conducted with poor quality, leading to a waste of resources.
  • Common problems include:
    • Flaws in the implementation of the study protocol
    • Research misconduct; current profit motive causes misaligned incentives
    • Non-compliant patients and patients who misrepresent their condition because they want to participate
    • Professional subjects (there are networks of brokers that coach non-subjects on how to pretend to have a specific condition)
      • Biomarkers for pain and treatment response would help address this problem
    • Poorly trained site-investigators
  • FDA noted that they sometimes discard data from entire sites because of the poor-quality trial implementation – this is more common than most people realize
    • Trained trial centers could lead to considerable savings in the long run
• There is a need for objective biomarkers for pain; the visual analog scale (VAS) is not sufficient; there is significant heterogeneity in patient responses on this scale
  • A diverse set of biomarkers is needed for research and clinical practice that reflect:
    • Analgesic target engagement (molecular and circuitry)
    • Functional impairment (e.g. sleep, activity level, quality of life)
      • Accelerometers built into mobile health devices can be leveraged
    • Pain sensitivity
    • Severity of pain
    • Predicted and actual treatment response
    • Risk of developing chronic pain
    • Safety (e.g. abuse potential or risk for respiratory depression)
    • Predictors of patients who can discriminate pain and treatment response
  • Relevant biomarkers may vary based on pain condition, and need to be validated for diverse modalities including MRI, PET, peripheral imaging, EEG, plasma markers, genotype, etc.
  • Biomarkers need to be translatable back to animal models.

Possible Opportunities

• Consider features of a research initiative to develop and validate a battery of biomarkers for pain and related endpoints for diverse types of pain.
  • Investigate the Alzheimer’s Disease Neuroimaging Initiative (ADNI) as a model
  • Validate biomarkers in animal models
  • Commission a comprehensive review of data – both published and unpublished – related to biomarker development
• Consider standardized tools for measuring:
  • Nociceptive response both at the level of the nerve fiber and at the level of the brain/circuit
  • Abuse liability
  • Respiratory depression
  • Threshold levels of response for diverse molecular targets predicting human clinical effects
• Consider methods for standardized phenotypic characterization of patients to identify biologically relevant patient sub-types that incorporate both biological and psychosocial factors (e.g. affective state, motivation).
  • Support research on relevant endophenotypes (e.g. sleep, mood disorders, etc.) to identify genotypic and phenotypic predictors of treatment response
  • Leverage mobile health tools
• Facilitate clinical trials for diverse pain conditions (e.g. chemotherapy-induced pain; post-surgical pain)
  • Support the foundational research needed to support clinical trials
    • Anticipated effect sizes and placebo response
    • Response rate and magnitude of current therapies
    • Measures of target engagement
  • Clinical trial design – active comparators, patient populations, define endpoints
• Engage CMS to get clarification on the data required by payers to reimburse for novel pain therapeutics.
• Support the development of better animal models.
  • Identify biomarkers with predictive validity for human pain.
  • The veterinary market is a largely untapped market for pain treatment.
• Consider enhanced support for basic research including:
  • Mapping brain circuitry that mediates pain and how it is impacted by chronic pain to drive target development.
  • Explore the role of opioids in the transition from acute to chronic pain. Support research to prevent or reverse this transition.
  • Mechanisms for extinguishing conditioned fear responses to pain
  • Natural history studies
  • Development and screening of compounds that provide state-dependent blockade of pain signals to reduce side effects associated with tonic activation or inhibition of molecular targets
• Support development and expansion of pain registries
  • To understand the impact of abuse deterrent formulations
  • Support precision medicine
• Address regulatory barriers to research on cannabinoids and other scheduled drugs.

NIH and FDA resources and programs with potential to speed medication development and clinical trials were discussed:

• The Clinical and Translational Science Awards (CTSA) Program Trial Innovation Network
• The National Center for Advanced Translational Studies (NCATS) Streamlined, Multisite, Accelerated Resources for Trials (SMART) IRB Platform
• The NCATS Pre-Clinical Research Toolbox
• The NCATS Therapeutic Uses Project
• The NIH Blueprint Therapeutics Network
• The NIH Common Fund
• The Epilepsy Therapy Screening Program
• The NIDA Clinical Trials Network
• The NeuroNEXT Network for Excellence in Clinical Trials
• The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (FDA)
• The NeuroMab antibody-generating resource (NINDS)
• FDA mechanisms
  • Fast tracking
  • Breakthrough designation
  • Rare disease program

Possible Opportunities

Short Term

• Develop a data sharing cooperative across companies to share lessons learned to support more effective use of limited resources.
  • May include data relevant to:
    • Understanding why did specific drug targets fail?
    • The participant characteristics that predict a placebo response.
    • Identifying factors that differentiate responders from non-responders?
    • Research to inform biomarker development.
  • NIH can serve as a neutral broker in this process. Data shared can be considered an in-kind contribution to the public private partnership.
• Accelerate work on validated targets and compounds in late stage development (e.g. Cox2 inhibitors, mu opioid receptor biased agonists, NGF monoclonal antibodies)
• Coordinate development of a high-risk cohort(s) of patients with pain conditions with low prevalence, severe pain, and unmet needs that can tolerate high risk.
  • Support the foundational research to facilitate clinical trials.
• Initiate coordinated effort to repurpose compounds with potential for treating pain.
  • Rapidly screening compounds with known mechanisms of action

Medium Term

• Develop a clinical trial network for pain
  • Start with a high-risk cohort(s) and design to expand to broader cohort.
  • Facilitate coordination with FDA on trial design.
  • This could help recruit young investigators into the pain treatment field.
• Explore patient registries to facilitate precision medicine
  • Deep phenotyping to classify patient subtypes
  • Pharmacogenetics on treatment response as well as risk of overdose and addiction to improve opioid prescribing practices

• Develop tools to objectively measure pain and predict treatment response (e.g. “noci-ometer(s)”). 

• Including tools to support various stages of drug development for diverse pain conditions.
  • Phase 1: Predictive pharmaco-dynamic markers (for go/no go decisions)
  • Phase 2: Chemical, functional measures, patient stratification – human
  • Phase 3: Sensory measures: a short bedside Quantitative Sensory Testing (QST) human
  • Phase 4: (longer term) Tools to objectively measure pain in animal models that are translatable to human pain conditions.

Long term

• Develop new drug targets, including disease modifying drugs that address underlying pathophysiology
• Expand basic research to understand the etiology and progression of pain
• Strategies to prevent the transition from acute to chronic pain
• Develop patient registries to study the trajectory, pathogenesis and natural history of pain.
• Work collaboratively across companies to combine efforts on common targets, and increase transparency on successes and failures in the pipeline. 

Possible High-Impact Opportunities

Short Term (< 1 year)

• Data Sharing: Developing a consortium to share relevant data and lessons learned to improve coordination. NIH could act as an “neutral broker”.
• Repurposing Compounds: Explore the late stage pipeline to identify therapeutics to accelerate.
• “Rare disease strategy”: Focus on pain conditions with smaller populations with severe pain and unmet clinical needs to speed clinical trials and accelerate the regulatory process.
  • We need to facilitate recruitment of patients with rare pain conditions to participate in clinical trials
• Clinical Trials Networks: Develop a clinical trials infrastructure focused on a cohort with severe, unmet clinical needs (e.g. complex regional pain syndrome, chronic pancreatitis, chemotherapy induced pain).

Medium Term (1-5 years)

• “Noci-ometers”: Initiate a project to develop a set of objective measures to assess pain and predict treatment response
• Biomarkers: Conduct a systematic assessment and validation of biomarkers – similar to ADNI.
  • Deep phenotyping of patients with diverse pain syndromes.
  • May be able to leverage the Europain Innovative Medicines Initiative (IMI); need to validate a shortened version of their Quantitative Sensory Testing (QST) battery.
  • Validate meaningful clinical endpoints for clinical trials.
• Animal Models: Support research to better understanding the genetic and molecular mechanisms underlying pain, and develop new approaches to treating chronic pain.

Long term (> 5 years)

• New drug targets: Initiate public private partnerships to research new targets.
• Pathogenesis: Develop pharmacodynamic measures in animal models that translate to clinical efficacy in humans.
• Understanding of the transition from acute to chronic pain: Leverage the precision medicine initiative to identify factors that predict transition to chronic pain and treatment outcomes.

Possible Next Steps

Major areas for which a public-private partnership would be valuable for accelerating the development of safe, effective, and non-addictive pain treatments will be further discussed with meeting participants. NIH aims to consider opportunities to:

1. Develop a data sharing cooperative
2. Establish a clinical trials network with cohorts of patients with severe unmet treatment needs.
3. Initiate an effort to develop objective measures of pain (e.g. a “noci-ometer(s)” grand challenge).
4. Accelerate development of therapeutics including:  disease modifying drugs, compounds in late stage development, repurposed compounds, and validation of current and new targets.