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Background: Following marketing authorization in Japan, for almost all new drugs or new indications, postmarketing studies (PMS) are a regulatory requirement. These PMS focus on accrual of a defined number of cases with data being collected for a predetermined period after approval to confirm efficacy/effectiveness, safety, and quality in the Japanese population. In contrast to other regions where PMS are only required to address a specific scientific uncertainty, in Japan, PMS are often required regardless of any specific scientific uncertainty, and therefore, their scientific value is unclear., Objectives: To determine the contribution to the understanding of benefit/risk of PMS conducted by Pfizer in Japan over 2000-2020 for Pharmaceuticals and Medical Devices Agency (PMDA) reexamination., Methods: A retrospective analysis of all Pfizer Japan postmarketing studies (PMS) during 2000-2020 was performed. Available Pfizer clinical study reports (CSRs) and PMDA reexamination reports (RERs) were reviewed for key safety findings. The primary analysis was conducted on the subset of PMS that had both an English CSR and a discussion of that PMS in the relevant RER issued by the PMDA, which was subsequently translated into English by a professional translation vendor. Reexamination outcome is included in each RER and served to demonstrate the impact of the study of the benefit/risk profile of the drug., Results: A total of 79 PMS for 43 different drug products across therapy areas enrolled a total of 98,035 patients. The 79 PMS comprised 34 general drug use investigation (GDUI) studies and 45 special investigation (SI) studies. The primary analysis involved 37 PMS with a CSR and RER available in English (40,470 patients); all of which were observational in design. For 31 of 37 PMS, the RER concluded the overall adverse drug reaction (ADR) rate in the PMS was nominally lower than in the phase 3 program. Unlabeled ADRs were reported in 28 of 37 PMS; however, no new safety concerns requiring regulatory action arose from any PMS. The PMDA did not require additional risk minimization measures for any of the 43 drug products studied in any of the 79 PMS assessed. Japan PMS data were consistent with prior global data with no evidence of clinically meaningful differences in safety in Japanese patients. In all cases, the reexamination outcome was category 1 ("usefulness is confirmed")., Conclusions: The reexamination process did not result in regulatory changes for any of the examined drugs. The Japan new-drug application (J-NDA) review and approval process, including implementation of the initial Japan product label, assures acceptable benefit/risk at the time of approval such that mandatory GDUI or SI studies for all products should be reconsidered. In the case of genuine scientific uncertainty to the extent that the benefit/risk of the product is not clear, a PMS is warranted., (© 2024. The Author(s).)

Objective: Demonstrate how benefit-risk profiles of systemic treatments for moderate-to-severe osteoarthritis (OA) can be compared using a quantitative approach accounting for patient preference., Study Design and Setting: This study used a multimethod benefit-risk modelling approach to quantifiably compare treatments of moderate-to-severe OA. In total four treatments and placebo were compared. Comparisons were based on four attributes identified as most important to patients. Patient Global Assessment of Osteoarthritis was included as a favourable effect. Unfavourable effects, or risks, included opioid dependence, nonfatal myocardial infarction and rapidly progressive OA leading to total joint replacement. Clinical data from randomized clinical trials, a meta-analysis of opioid dependence and a long-term study of celecoxib were mapped into value functions and weighted with patient preferences from a discrete choice experiment., Results: Lower-dose NGFi had the highest weighted net benefit-risk score (0.901), followed by higher-dose NGFi (0.889) and NSAIDs (0.852), and the lowest score was for opioids (0.762). Lower-dose NGFi was the highest-ranked treatment option even when assuming a low incidence (0.34% instead of 4.7%) of opioid dependence (ie, opioid benefit-risk score 808) and accounting for both the uncertainty in clinical effect estimates (first rank probability 46% vs 20% for NSAIDs) and imprecision in patient preference estimates (predicted choice probability 0.26, 95% confidence interval [CI] 0.25-0.28 vs 0.21, 95% CI 0.19-0.23 for NSAIDs)., Conclusion: The multimethod approach to quantitative benefit-risk modelling allowed the interpretation of clinical data from the patient perspective while accounting for uncertainties in the clinical effect estimates and imprecision in patient preferences., (© 2022 Pfizer Inc. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Abstract: Chronic pain clinical trials have historically assessed benefit and risk outcomes separately. However, a growing body of research suggests that a composite metric that accounts for benefit and risk in relation to each other can provide valuable insights into the effects of different treatments. Researchers and regulators have developed a variety of benefit-risk composite metrics, although the extent to which these methods apply to randomized clinical trials (RCTs) of chronic pain has not been evaluated in the published literature. This article was motivated by an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus meeting and is based on the expert opinion of those who attended. In addition, a review of the benefit-risk assessment tools used in published chronic pain RCTs or highlighted by key professional organizations (ie, Cochrane, European Medicines Agency, Outcome Measures in Rheumatology, and U.S. Food and Drug Administration) was completed. Overall, the review found that benefit-risk metrics are not commonly used in RCTs of chronic pain despite the availability of published methods. A primary recommendation is that composite metrics of benefit-risk should be combined at the level of the individual patient, when possible, in addition to the benefit-risk assessment at the treatment group level. Both levels of analysis (individual and group) can provide valuable insights into the relationship between benefits and risks associated with specific treatments across different patient subpopulations. The systematic assessment of benefit-risk in clinical trials has the potential to enhance the clinical meaningfulness of RCT results., (Copyright © 2021 International Association for the Study of Pain.)

Background: To evaluate if early improvements in pain and function with subcutaneous tanezumab are meaningful and sustained over 24 weeks., Methods: Patients with moderate-to-severe osteoarthritis (hip or knee) in Europe and Japan were randomized to placebo, tanezumab 2.5 mg or tanezumab 5 mg (baseline, Week 8 and Week 16). Outcomes included: average daily index joint pain score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) subscales, rescue medication use, WOMAC responders (within-patient ≥30% reduction in WOMAC Pain or Physical Function), Outcome Measures in Rheumatology-Osteoarthritis Research Society International (OMERACT-OARSI) responders (within-patient) and Patient-reported Treatment Impact Assessment-Modified questionnaire., Results: Patients received placebo (n = 282), tanezumab 2.5 mg (n = 283) or tanezumab 5 mg (n = 284). Changes from baseline in average daily index joint pain (within the first week) and WOMAC subscales (Week 2 through Week 24) were greater for each tanezumab group versus placebo (least squares [LS] mean, unadjusted p ≤ .05). Rescue medication use (days/week) was lower for each tanezumab group versus placebo from Week 2 through Week 12 (LS mean, unadjusted p ≤ .05) but not at Week 16 or 24. A higher proportion of each tanezumab group than placebo achieved ≥30% reduction from baseline in WOMAC Pain or Physical Function, or OMERACT-OARSI response (Week 2 through Week 24, unadjusted p ≤ .05), or were satisfied with treatment at Week 24 (unadjusted p ≤ .05)., Conclusions: Subcutaneous tanezumab, compared with placebo, reduced pain within the first week, and pain and function were improved throughout 24 weeks. The proportions of responders and patients satisfied were higher with tanezumab than placebo. ClinicalTrials.gov:NCT02709486., Significance: This exploratory analysis of data from a placebo-controlled, Phase 3 study of patients with moderate-to-severe osteoarthritis of the hip or knee for whom standard analgesics were not effective or could not be taken, found that onset of efficacy of subcutaneous tanezumab was within the first week, and efficacy was maintained through the 24-week treatment period. Tanezumab was effective in those patients with the most radiologically severe osteoarthritis., (© 2021 Pfizer Inc. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFICA®.)

Interpreting randomized clinical trials (RCTs) is crucial to making decisions regarding the use of analgesic treatments in clinical practice. In this article, we report on an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus meeting organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks, the purpose of which was to recommend approaches that facilitate interpretation of analgesic RCTs. We review issues to consider when drawing conclusions from RCTs, as well as common methods for reporting RCT results and the limitations of each method. These issues include the type of trial, study design, statistical analysis methods, magnitude of the estimated beneficial and harmful effects and associated precision, availability of alternative treatments and their benefit-risk profile, clinical importance of the change from baseline both within and between groups, presentation of the outcome data, and the limitations of the approaches used.

Objective: Tanezumab, a nerve growth factor inhibitor, was investigated for osteoarthritis (OA) of the hip or knee in a study with 24-week treatment and 24-week safety follow-up., Methods: This double-blind, randomised, phase III study enrolled adults in Europe and Japan with moderate-to-severe OA who had not responded to or could not tolerate standard-of-care analgesics. Patients were randomised to tanezumab 2.5 mg or 5 mg subcutaneously or matching placebo every 8 weeks (three doses). Co-primary end points were change from baseline to week 24 in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain and Physical Function, and Patient's Global Assessment of OA (PGA-OA). Joint safety and neurological assessments continued throughout the 48-week study., Results: From March 2016 to December 2017, 849 patients were randomised and evaluated (placebo n=282, tanezumab 2.5 mg n=283, tanezumab 5 mg n=284). At week 24, there was a statistically significant improvement from baseline for tanezumab 5 mg compared with placebo for WOMAC Pain (least squares mean difference±SE -0.62±0.18, p=0.0006), WOMAC Physical Function (-0.71±0.17, p<0.0001) and PGA-OA (-0.19±0.07, p=0.0051). For tanezumab 2.5 mg, there was a statistically significant improvement in WOMAC Pain and Physical Function, but not PGA-OA. Rapidly progressive osteoarthritis (RPOA) was observed in 1.4% (4/283) and 2.8% (8/284) of patients in the tanezumab 2.5 mg and tanezumab 5 mg groups, respectively and none receiving placebo. Total joint replacements (TJRs) were similarly distributed across all three treatment groups (6.7%-7.8%). Tanezumab-treated patients experienced more paraesthesia (5 mg) and hypoaesthesia (both doses) than placebo., Conclusion: Tanezumab 5 mg statistically significantly improved pain, physical function and PGA-OA, but tanezumab 2.5 mg only achieved two co-primary end points. RPOA occurred more frequently with tanezumab 5 mg than tanezumab 2.5 mg. TJRs were similarly distributed across all three groups., Trial Registration Number: NCT02709486., Competing Interests: Competing interests: FB reports personal fees from Boehringer, Bone Therapeutics, Expanscience, Galapagos, Gilead, GSK, Merck Sereno, MSD, Nordic, Novartis, Pfizer, Regulaxis, Roche, Sandoz, Sanofi, Servier, UCB, Peptinov, TRB Chemedica, 4P Pharma, outside the submitted work. FJB reports grants and personal fees from Pfizer, and grants from AbbVie, UCB, Bristol-Meyers Squibb, Roche, Servier, Bioiberica, Sanofi, Grunenthal, GlaxoSmithKline, Lilly, Janssen, Regeneron, Amgen and TRB Chemedica, outside the submitted work. AG reports personal fees from Merck Serono, Pfizer, TissueGene, Roche, Galapagos, AstraZeneca, personal fees from Boston Imaging Core Lab, LLC, outside the submitted work. KM reports personal fees from Merck, Pfizer, Lilly, Ayumi, Mundi Pharma, Janssen, Nippon Zok, outside the submitted work. LV reports personal fees and other from Eli Lilly and Company, outside the submitted work. TY reports personal fees and other from Pfizer outside the submitted work. RJ reports personal fees and other from Pfizer outside the submitted work. WC reports personal fees and other from Pfizer outside the submitted work. MTB reports personal fees and other from Pfizer outside the submitted work, and has a patent pending (Tanezumab Method of Treatment). CRW reports personal fees and other from Pfizer outside the submitted work, and has a patent pending (Tanezumab Method of Treatment). KMV reports personal fees and other from Pfizer outside the submitted work., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC-ND. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Osteoarthritis (OA) causes substantial pain and reduced health-related quality of life (HRQL). Although opioid analgesics are commonly used, the relative benefits of different opioids are poorly studied. Transdermal buprenorphine (TDB) offers an alternative to oral opioids for the treatment of moderate-to-severe chronic pain. This observational study of people with OA pain assessed satisfaction, HRQL and medication adherence., Methods: Patients in the UK with self-reported knee and/or hip OA who had been receiving one or more of TDB, co-codamol (an oral paracetamol/codeine combination) and tramadol for at least 1 month completed an online or telephone questionnaire. Medication satisfaction scores, HRQL scores (Short-Form 36 [SF-36]), medication adherence (Morisky Medication Adherence Scale [MMAS™]), adverse events and treatment discontinuations were recorded. Linear and logistic regression models were used to compare the treatment effect of TDB with co-codamol or tramadol., Results: Overall, 966 patients met the inclusion criteria; 701 were taking only one of the target medications (TDB: 85; co-codamol: 373; tramadol: 243). The largest age group was 50-59 years and 76.0 % of patients were female. The TDB group was younger, with more male patients, therefore the statistical models were adjusted for age and sex. Medication satisfaction scores were significantly higher in the TDB group than the other two groups (TDB vs. co-codamol: 3.56, 95 % confidence interval [CI] 1.90-6.68, p < 0.0001; TDB vs. tramadol: 3.22, 95 % CI 1.67-6.20, p = 0.0005). Physical Component Summary scores for HRQL and mean adherence were also higher in the TDB group, while Mental Component Summary HRQL scores were similar across the three groups., Conclusions: Patients with knee and/or hip OA pain treated with TDB were more satisfied and more adherent with their medication, and reported higher Physical Component Summary HRQL scores than those treated with co-codamol or tramadol, although demographic differences were observed between groups.

Purpose: The objective of this systematic review was to assess the clinical efficacy, safety, tolerability, and health-related quality of life outcomes associated with management of moderate-to-severe chronic pain with oxycodone/naloxone and tapentadol, focusing on the effect of these treatments on patients' daily functioning., Methods: Literature from a wide range of sources, including Embase, MEDLINE, MEDLINE In-Process, and the Cochrane Central Register of Controlled Trials, was searched to identify randomized controlled trials investigating tapentadol or oxycodone/naloxone for the treatment of patients with chronic pain. A network meta-analysis was conducted to determine the relative efficacy and safety profiles of these treatments., Findings: Oxycodone/naloxone was significantly better than tapentadol with respect to the Patient Assessment of Constipation Symptoms total score (risk ratio = -3.60; 95% credible interval, -5.36 to -2.11) and revealed a significantly lower risk of dizziness (risk ratio = 0.72; 95% credible interval, 0.42-0.98). Oxycodone/naloxone was directionally favored, although not significantly superior to tapentadol for headache, fatigue, dry mouth, dyspepsia, and withdrawals due to lack of efficacy. For the AE outcomes of constipation, nausea, and vomiting, as well as pain efficacy and all-cause withdrawals from studies, tapentadol was directionally favored without any statistical difference from oxycodone/naloxone. However, the two treatments were not wholly comparable for the evaluation of pain efficacy because of differences in on-study rescue medication and a higher baseline pain severity in the tapentadol studies., Implications: Oxycodone/naloxone offers significant improvements in Patient Assessment of Constipation Symptoms total score and dizziness and was directionally favored for fatigue and headache compared with extended-release tapentadol, which may translate to improved patient daily functioning and health-related quality of life., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Assessing and mitigating the abuse liability (AL) of analgesics is an urgent clinical and societal problem. Analgesics have traditionally been assessed in randomized clinical trials (RCTs) designed to demonstrate analgesic efficacy relative to placebo or an active comparator. In these trials, rigorous, prospectively designed assessment for AL is generally not performed. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) convened a consensus meeting to review the available evidence and discuss methods for improving the assessment of the AL of analgesics in clinical trials in patients with pain. Recommendations for improved assessment include: (1) performing trials that include individuals with diverse risks of abuse; (2) improving the assessment of AL in clinical trials (eg, training study personnel in the principles of abuse and addiction behaviors, designing the trial to assess AL outcomes as primary or secondary outcome measures depending on the trial objectives); (3) performing standardized assessment of outcomes, including targeted observations by study personnel and using structured adverse events query forms that ask all subjects specifically for certain symptoms (such as euphoria and craving); and (4) collecting detailed information about events of potential concern (eg, unexpected urine drug testing results, loss of study medication, and dropping out of the trial). The authors also propose a research agenda for improving the assessment of AL in future trials., (Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

A critical component in development of opioid analgesics is assessment of their abuse liability (AL). Standardization of approaches and measures used in assessing AL have the potential to facilitate comparisons across studies, research laboratories, and drugs. The goal of this report is to provide consensus recommendations regarding core outcome measures for assessing the abuse potential of opioid medications in humans in a controlled laboratory setting. Although many of the recommended measures are appropriate for assessing the AL of medications from other drug classes, the focus here is on opioid medications because they present unique risks from both physiological (e.g., respiratory depression, physical dependence) and public health (e.g., individuals in pain) perspectives. A brief historical perspective on AL testing is provided, and those measures that can be considered primary and secondary outcomes and possible additional outcomes in AL assessment are then discussed. These outcome measures include the following: subjective effects (some of which comprise the primary outcome measures, including drug liking; physiological responses; drug self-administration behavior; and cognitive and psychomotor performance. Before presenting recommendations for standardized approaches and measures to be used in AL assessments, the appropriateness of using these measures in clinical trials with patients in pain is discussed., (Published by Elsevier B.V.)

A number of pharmacologic treatments examined in recent randomized clinical trials (RCTs) have failed to show statistically significant superiority to placebo in conditions in which their efficacy had previously been demonstrated. Assuming the validity of previous evidence of efficacy and the comparability of the patients and outcome measures in these studies, such results may be a consequence of limitations in the ability of these RCTs to demonstrate the benefits of efficacious analgesic treatments vs placebo ("assay sensitivity"). Efforts to improve the assay sensitivity of analgesic trials could reduce the rate of falsely negative trials of efficacious medications and improve the efficiency of analgesic drug development. Therefore, an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus meeting was convened in which the assay sensitivity of chronic pain trials was reviewed and discussed. On the basis of this meeting and subsequent discussions, the authors recommend consideration of a number of patient, study design, study site, and outcome measurement factors that have the potential to affect the assay sensitivity of RCTs of chronic pain treatments. Increased attention to and research on methodological aspects of clinical trials and their relationships with assay sensitivity have the potential to provide the foundation for an evidence-based approach to the design of analgesic clinical trials and expedite the identification of analgesic treatments with improved efficacy and safety., (Copyright © 2012 International Association for the Study of Pain. All rights reserved.)