A Model Based Meta-Analysis (MBMA) to support development of medicines for treatment of DPN, PHN and Fibromyalgia.
Leticia Arrington (1)*, Han Witjes (2)*, Akshita Chawla (1), Richard Franzese (2), Mark Lovern (2) and Sreeraj Macha (1)
(1) MSD (2) Certara
Objectives:
The objective of the analysis was to develop a MBMA comparator model for neuropathic pain to provide a quantitative framework for comparison of drugs commonly used for the treatment of diabetic peripheral neuropathy (dpn), post herpetic neuralgia (phn) and fibromyalgia. The following drug classes were included in the analysis: antiepileptics (AEDs), a2δ, benzodiazepine, cannabinoids, opioids, Nav 1.7, serotonin-noradrenaline reuptake inhibitors (SNRI) and selective serotonin reuptake inhibitors (SSRI) antidepressants, and tricyclic antidepressants. Specific objectives include development of a joint response MBMA model describing the proportion of subjects who achieved 30% (PID30) and 50% (PID50)1,2reduction from baseline in pain score. This MBMA platform is envisioned to help develop better neuropathic pain (NP) therapies.
Methods:
A systematic review of the literature was conducted using a predefined inclusion/exclusion criteria. The database captures publically available, summary-level clinical trial data from 121 placebo and/or active controlled randomized trials. The analysis dataset for PID30 and PID50 contained 75 trials with 22 drugs and 3 combined therapies across 9 drug classes. Model development, evaluation and simulations were performed using R 3.3.2. The models were developed using the generalized nonlinear least squares (gnls) and nonlinear mixed-effects (nlme) functions provided in R. The response in the MBMA model was described as the sum of a trial specific non-parametric (unstructured) placebo effect and a parametric drug effect depending on indication, dose, time, model parameters and covariates. Dose-response was estimated where possible, with drug specific treatment effects within indication using a shared Emax within a drug class and drug-specific potency (ED50). Fixed-effect estimates for the mean shift in placebo response on the logit scale from 50% reduction to 30% reduction and trial-specific random effects accounted for trial heterogeneity. The correlation between multiple observations within one treatment arm was accounted for by assuming a compound symmetry correlation structure for all observations within one arm within a trial. Model appropriateness was assessed using goodness of fit plots and additional simulations. Covariates were graphically explored and age, black race and baseline score were tested for statistical significance. Treatment effect estimates with associated 95% confidence intervals were derived as the mean and 2.5th - 97.5th percentile intervals across 3000 simulated data sets with parameter values sampled from the multivariate normal variance-covariance matrix of the estimates.
Results:
The final MBMA model shows that the magnitude of placebo response differs between indications. The estimated placebo response for PID30 is 42%, 37% and 30% for dpn, phn and fibromyalgia respectively and that for PID50 is 26%, 22% and 17%, respectively. Age was identified as a significant covariate as the PID30 and PID50 rates increased with increasing age for dpn and phn patients. All other covariates (baseline pain score, disease duration, sex, BMI, race etc) were evaluated but were not found to be significant. Treatment effects (mean, 95% CI) were estimated from the final MBMA model and presented in forest plots to compare treatment effects of common NP drugs in DPN, PHN and Fibromyalgia.
Conclusions:
The available PID30/50 data were well described by an Emax model. Placebo response and drug effects differed markedly across indications. The model derived from this analysis will provide a quantitative framework for benchmarking new investigational compounds to SOC and improve understanding of D-R relationship for compounds used in treatment of pain.
References:
[1] Finnerup NB, Attal N, Haroutounian S, et al., Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis, Lancet Neurol 2015; 162-73.
[2] European Medicines Agency - Committee for Medicinal Products for Human Use (CHMP). Guideline on the clinical development of medical products intended for the treatment of pain. 2016. from http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/12/WC500219131.pdf [Accessed June 26 2017]
