Discovery and validation of biomarkers to aid the development of safe and effective pain therapeutics: challenges and opportunities

Abstract

Pain medication plays an important role in the treatment of acute and chronic pain conditions, but some drugs, opioids in particular, have been overprescribed or prescribed without adequate safeguards, leading to an alarming rise in medication-related overdose deaths. The NIH Helping to End Addiction Long-term (HEAL) Initiative is a trans-agency effort to provide scientific solutions to stem the opioid crisis. One component of the initiative is to support biomarker discovery and rigorous validation in collaboration with industry leaders to accelerate high-quality clinical research into neurotherapeutics and pain. The use of objective biomarkers and clinical trial end points throughout the drug discovery and development process is crucial to help define pathophysiological subsets of pain, evaluate target engagement of new drugs and predict the analgesic efficacy of new drugs. In 2018, the NIH-led Discovery and Validation of Biomarkers to Develop Non-Addictive Therapeutics for Pain workshop convened scientific leaders from academia, industry, government and patient advocacy groups to discuss progress, challenges, gaps and ideas to facilitate the development of biomarkers and end points for pain. The outcomes of this workshop are outlined in this Consensus Statement.

Fig. 1. Preclinical and human pain biomarkers.

a | Development of preclinical pain biomarkers starts with induction of different modalities of pain that are clinically relevant. In the absence of a ground truth for pain in animals, a critical first step relies on converging lines of evidence from behavioural, electrophysiological and other overt signs. The next step is to demonstrate reversal of these signs using analgesic compounds with proven efficacy in humans. b | Development of human pain biomarkers starts with the individual’s self-report, also known as the ground truth (asterisks), and a set of signs and symptoms, with the goal of defining objective methods and criteria, as well as end points for assessing, predicting and/or classifying pain and analgesia. Thus, biomarkers are obtained to indicate chronic pain predisposition, pain mechanisms, diagnostic stratification, chronification, recovery and treatment outcome (response or failure).

Fig. 2. Steps to identify and develop biomarkers for clinical use.

The process starts with recognition of the need for a biomarker followed by discovery of candidate biomarkers. Assay development ensues. The type of assay selected is based on the properties of the biomarker or analyte. Specific detection of the analyte is required to move forward to the assay development phase. The analyte must be measurable and the detection method must be reliable and reproducible. During development, a prototype assay is tested with a test set of samples, including both positive and negative controls. As the assay is developed, conditions are optimized, and the prototype assay is then refined, tested and retested to ensure reliable, reproducible results. For an omics assay, this process may include optimizing the pH, reducing the background signal or filtering the biological fluid to remove signal interference (for example, from haemoglobin). Once the prototype assay is optimized and produces reliable, verifiable results on test sets of samples, it must be validated using a naive sample set. Validation must be performed without knowledge of patient status to eliminate any bias in interpretation of results. If specific detection of the analyte is demonstrated, prospective validation is performed. Reproducible, reliable, sensitive and specific biomarker detection positions a biomarker for clinical use.