Clinical Assessment of Osteoarthritis Pain: Contemporary Scenario, Challenges, and Future Perspectives.

The multifaceted nature of osteoarthritis (OA) pain presents a challenge in understanding and managing the condition. The diverse pain experiences, progression rates, individual responses to treatments, and complex disease mechanisms contribute to heterogeneity in the clinical studies outcomes. The lack of a standardized methodology for assessing and classifying OA pain challenges healthcare practitioners. This complicates the establishment of universally applicable protocols or standardized guidelines for treatment. This article explores the heterogeneity observed in clinical studies evaluating OA pain treatments, highlighting the necessity for refined methodologies, personalized patient categorization, and consistent outcome measures. It discusses the role of the multidimensional nature of OA pain, underlying pain mechanisms, and other contributing factors to the heterogeneity in outcome measures. Addressing these variations is crucial to establishing a more consistent framework for evidence-based treatments and advancing care of the patient with OA pain.

Model-Based Assessment of the Liver Safety Profile of Acetaminophen to Support its Combination Use with Topical Diclofenac in Mild-to-Moderate Osteoarthritis Pain.

INTRODUCTION: The use of combination therapy of oral acetaminophen and topical diclofenac, having complementary mechanisms of action, is an attractive strategy to enhance the analgesic response in osteoarthritis (OA) pain. While topical diclofenac is considered as well tolerated due to its low systemic exposure, concerns of liver toxicity with acetaminophen at standard analgesic doses remain. Thus, this study aimed to assess the liver safety profile of acetaminophen, particularly in OA management, using a model-based meta-analysis (MBMA). METHODS: A literature review was conducted using the MEDLINE database to identify randomized clinical trials (RCTs) reporting liver toxicity on acetaminophen use. An MBMA was implemented to assess the deviation from the upper limit of normal (ULN) of alanine aminotransferase or aspartate aminotransferase, namely > 0-1 × ULN, > 1.5-2 × ULN, and > 3 × ULN representing mild, moderate, and severe risk of liver abnormality, respectively. RESULTS: A total of 15 RCTs were included in the MBMA, encompassing over 4800 subjects and exposure to acetaminophen ranging from 2 to 26 weeks. Of the 15 included studies, eight involved patients with OA pain, four involved healthy subjects and three were in patients with conditions such as asthma, glaucoma, chronic pain, and cardiovascular disease. Acetaminophen 1500-4000 mg/day was found to exhibit 23% (95% confidence interval (CI): 17.74-29.20), 1.35% (95% CI: 0.17-2.51) and 0.01% (95% CI: 0.00-0.32) increased risk for mild, moderate, and severe liver injury, respectively, versus placebo. Moreover, at therapeutic doses, no correlation was identified between acetaminophen intake and liver abnormality risk. CONCLUSIONS: Overall, our analysis shows that short-term (~ 8-16 weeks) acetaminophen use at therapeutically recommended doses is associated with a low risk of clinically relevant changes in liver enzymes. Given the good tolerability of topical diclofenac, the findings support the safety of the combination of acetaminophen and topical diclofenac, at least over the short term, as treatment for mild-to-moderate OA pain.

Moving Toward a Question-Centric Approach for Regulatory Decision Making in the Context of Drug Assessment.

The most intuitive question for market access for medicinal products is the benefit/risk (B/R) balance. The B/R assessment can conceptually be divided into subquestions related to establishing efficacy and safety. There are additional layers to the B/R ratio for medical products, including questions related to dose selection, clinical and nonclinical pharmacology, and drug quality. Explicitly stating the actual questions and how they contribute to the overall B/R provides a structure that fosters better informed cross-domain discussions. There is currently no systematic approach in the regulatory setting to assess and establish the acceptability of alternative methods and data sources. In most cases, the medicinal product sponsors tend to prioritize traditional data types and methods, which are well accepted by regulators for inclusion in regulatory submissions. This, in addition to the absence of rigor in the use and validation of new data types and methods, and the limited training of assessors in related fields can lead to increased regulatory skepticism toward new data types and methods. A data-knowledge backbone is needed to mitigate the uncertainty in efficacy and safety characterization. This white paper discusses the value of explicitly redefining and restructuring the regulatory scientific decision making around the scientific question to be addressed. The ecosystem proposed is based on three pillars: (i) a repository connecting questions, data, and methods; (ii) the development and validation of high-quality standards for data and methods; and (iii) credibility assessment. The ecosystem is applied to four use cases for illustration. The need for training and regulatory guidance is also discussed.

Evaluation of the efficacy and safety of deferiprone compared with deferasirox in paediatric patients with transfusion-dependent haemoglobinopathies (DEEP-2): a multicentre, randomised, open-label, non-inferiority, phase 3 trial.

BACKGROUND: Transfusion-dependent haemoglobinopathies require lifelong iron chelation therapy with one of the three iron chelators (deferiprone, deferasirox, or deferoxamine). Deferasirox and deferiprone are the only two oral chelators used in adult patients with transfusion-dependent haemoglobinopathies. To our knowledge, there are no randomised clinical trials comparing deferiprone, a less expensive iron chelator, with deferasirox in paediatric patients. We aimed to show the non-inferiority of deferiprone versus deferasirox. METHODS: DEEP-2 was a phase 3, multicentre, randomised trial in paediatric patients (aged 1 month to 18 years) with transfusion-dependent haemoglobinopathies. The study was done in 21 research hospitals and universities in Italy, Egypt, Greece, Albania, Cyprus, Tunisia, and the UK. Participants were receiving at least 150 mL/kg per year of red blood cells for the past 2 years at the time of enrolment, and were receiving deferoxamine (<100 mg/kg per day) or deferasirox (<40 mg/kg per day; deferasirox is not registered for use in children aged <2 years so only deferoxamine was being used in these patients). Any previous chelation treatment was permitted with a 7-day washout period. Patients were randomly assigned 1:1 to receive orally administered daily deferiprone (75-100 mg/kg per day) or daily deferasirox (20-40 mg/kg per day) administered as dispersible tablets, both with dose adjustment for 12 months, stratified by age (<10 years and ≥10 years) and balanced by country. The primary efficacy endpoint was based on predefined success criteria for changes in serum ferritin concentration (all patients) and cardiac MRI T2-star (T2*; patients aged >10 years) to show non-inferiority of deferiprone versus deferasirox in the per-protocol population, defined as all randomly assigned patients who received the study drugs and had available data for both variables at baseline and after 1 year of treatment, without major protocol violations. Non-inferiority was based on the two-sided 95% CI of the difference in the proportion of patients with treatment success between the two groups and was shown if the lower limit of the two-sided 95% CI was greater than -12·5%. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with EudraCT, 2012-000353-31, and ClinicalTrials.gov, NCT01825512. FINDINGS: 435 patients were enrolled between March 17, 2014, and June 16, 2016, 393 of whom were randomly assigned to a treatment group (194 to the deferiprone group; 199 to the deferasirox group). 352 (90%) of 390 patients had ß-thalassaemia major, 27 (7%) had sickle cell disease, five (1%) had thalassodrepanocytosis, and six (2%) had other haemoglobinopathies. Median follow-up was 379 days (IQR 294-392) for deferiprone and 381 days (350-392) for deferasirox. Non-inferiority of deferiprone versus deferasirox was established (treatment success in 69 [55·2%] of 125 patients assigned deferiprone with primary composite efficacy endpoint data available at baseline and 1 year vs 80 [54·8%] of 146 assigned deferasirox, difference 0·4%; 95% CI -11·9 to 12·6). No significant difference between the groups was shown in the occurrence of serious and drug-related adverse events. Three (2%) cases of reversible agranulocytosis occurred in the 193 patients in the safety analysis in the deferiprone group and two (1%) cases of reversible renal and urinary disorders (one case of each) occurred in the 197 patients in the deferasirox group. Compliance was similar between treatment groups: 183 (95%) of 193 patients in the deferiprone group versus 192 (97%) of 197 patients in the deferisirox group. INTERPRETATION: In paediatric patients with transfusion-dependent haemoglobinopathies, deferiprone was effective and safe in inducing control of iron overload during 12 months of treatment. Considering the need for availability of more chelation treatments in paediatric populations, deferiprone offers a valuable treatment option for this age group. FUNDING: EU Seventh Framework Programme.

Dose optimization of piperacillin/tazobactam in critically ill children.

Objectives: To characterize the population pharmacokinetics of piperacillin and tazobactam in critically ill infants and children, in order to develop an evidence-based dosing regimen. Patients and methods: This pharmacokinetic study enrolled patients admitted to the paediatric ICU for whom intravenous piperacillin/tazobactam (8:1 ratio) was indicated (75 mg/kg every 6 h based on piperacillin). Piperacillin/tazobactam concentrations were measured by an LC-MS/MS method. Pharmacokinetic data were analysed using non-linear mixed effects modelling. Results: Piperacillin and tazobactam blood samples were collected from 47 patients (median age 2.83 years; range 2 months to 15 years). Piperacillin and tazobactam disposition was best described by a two-compartment model that included allometric scaling and a maturation function to account for the effect of growth and age. Mean clearance estimates for piperacillin and tazobactam were 4.00 and 3.01 L/h for a child of 14 kg. Monte Carlo simulations showed that an intermittent infusion of 75 mg/kg (based on piperacillin) every 4 h over 2 h, 100 mg/kg every 4 h given over 1 h or a loading dose of 75 mg/kg followed by a continuous infusion of 300 mg/kg/24 h were the minimal requirements to achieve the therapeutic targets for piperacillin (60% f T >MIC >16 mg/L). Conclusions: Standard intermittent dosing regimens do not ensure optimal piperacillin/tazobactam exposure in critically ill patients, thereby risking treatment failure. The use of a loading dose followed by a continuous infusion is recommended for treatment of severe infections in children >2 months of age.

Pharmacology-based toxicity assessment: towards quantitative risk prediction in humans.

Despite ongoing efforts to better understand the mechanisms underlying safety and toxicity, ~30% of the attrition in drug discovery and development is still due to safety concerns. Changes in current practice regarding the assessment of safety and toxicity are required to reduce late stage attrition and enable effective development of novel medicines. This review focuses on the implications of empirical evidence generation for the evaluation of safety and toxicity during drug development. A shift in paradigm is needed to (i) ensure that pharmacological concepts are incorporated into the evaluation of safety and toxicity; (ii) facilitate the integration of historical evidence and thereby the translation of findings across species as well as between in vitro and in vivo experiments and (iii) promote the use of experimental protocols tailored to address specific safety and toxicity questions. Based on historical examples, we highlight the challenges for the early characterisation of the safety profile of a new molecule and discuss how model-based methodologies can be applied for the design and analysis of experimental protocols. Issues relative to the scientific rationale are categorised and presented as a hierarchical tree describing the decision-making process. Focus is given to four different areas, namely, optimisation, translation, analytical construct and decision criteria. From a methodological perspective, the relevance of quantitative methods for estimation and extrapolation of risk from toxicology and safety pharmacology experimental protocols, such as points of departure and potency, is discussed in light of advancements in population and Bayesian modelling techniques (e.g. non-linear mixed effects modelling). Their use in the evaluation of pharmacokinetics (PK) and pharmacokinetic-pharmacodynamic relationships (PKPD) has enabled great insight into the dose rationale for medicines in humans, both in terms of efficacy and adverse events. Comparable benefits can be anticipated for the assessment of safety and toxicity profile of novel molecules.

The role of concentration-effect relationships in the assessment of QTc interval prolongation.

Population pharmacokinetic and pharmacokinetic-pharmacodynamic (PKPD) modelling has been widely used in clinical research. Yet, its application in the evaluation of cardiovascular safety remains limited, particularly in the evaluation of pro-arrhythmic effects. Here we discuss the advantages of disadvantages of population PKPD modelling and simulation, a paradigm built around the knowledge of the concentration-effect relationship as the basis for decision making in drug development and its utility as a guide to drug safety. A wide-ranging review of the literature was performed on the experimental protocols currently used to characterize the potential for QT interval prolongation, both pre-clinically and clinically. Focus was given to the role of modelling and simulation for design optimization and subsequent analysis and interpretation of the data, discriminating drug from system specific properties. Cardiovascular safety remains one of the major sources of attrition in drug development with stringent regulatory requirements. However, despite the myriad of tests, data are not integrated systematically to ensure accurate translation of the observed drug effects in clinically relevant conditions. The thorough QT study addresses a critical regulatory question but does not necessarily reflect knowledge of the underlying pharmacology and has limitations in its ability to address fundamental clinical questions. It is also prone to issues of multiplicity. Population approaches offer a paradigm for the evaluation of drug safety built around the knowledge of the concentration-effect relationship. It enables quantitative assessment of the probability of QTc interval prolongation in patients, providing better guidance to regulatory labelling and understanding of benefit/risk in specific populations.

Integrative knowledge management to enhance pharmaceutical R&D.

Information technologies already have a key role in pharmaceutical research and development (R&D), but achieving substantial advances in their use and effectiveness will depend on overcoming current challenges in sharing, integrating and jointly analysing the range of data generated at different stages of the R&D process.

Lack of compliance of European Public Assessment Reports to guidelines for paediatric drug development before the introduction of paediatric investigation plans.

BACKGROUND: According to the International Conference on Harmonisation (ICH) and Food and Drug Administration (FDA) guidelines for paediatric clinical trials, bridging procedures can be used if disease progression, exposure-response relationships, and clinical endpoints are similar in adults and children. In these circumstances, confirmatory efficacy trials are not necessary; the evaluation of pharmacokinetics and safety ought to be sufficient for drug approval. PURPOSE: The aim of this study was to assess whether the clinical trials and strategy for market approval authorisation (MAAs) in paediatric indications reflect the guidelines for bridging of adult data. METHODS: A total of 95 European Public Assessment Reports (EPARs) published between 1995 and 2007 were reviewed. From every report, data extraction was performed according to the phase of development, scope of analysis, number of dose levels, dosage form, and demographics of the subjects enrolled in the trial. Data analysis consisted of an initial grouping of the studies by the degree of compliance to bridging guidelines. RESULTS: Our analysis reveals that only 66% of the trials (n = 174) can be classified as needed, while 22% of the trials (n = 59) could have been designed and performed differently from the approved protocol (partially required). Moreover, 12% (n = 30) of the studies were deemed completely unnecessary. LIMITATIONS: A potential limitation in our study was that the dates of start and completion of the clinical studies were not available. Therefore, some EPARs have been included that may reflect common practice in the period that precedes the introduction of the ICH E11 guidelines. Yet, this should not obscure the points identified with regard to the lack of compliance to guidelines before the introduction of the paediatric legislation and the requirements for a paediatric investigation plan. CONCLUSIONS: Paediatric trials are desirable and necessary to address important unmet medical needs. However, the types of studies supporting regulatory approval do not always reflect the recommendations available in paediatric guidelines, which allow for extrapolation and bridging approaches. This situation may be explained by the lack of awareness about the prerequisites for the use of bridging concepts and of a clear process for evaluating different strategies in paediatric development.

Development of paediatric medicines: concepts and principles.

The term "off-label use of drugs in children" is common to current medical practice. A look into the historical context helps to elucidate the framework for the use of medicines in children. Proper drug labels are relatively new in history. They emerged half a century ago when U.S. legislation forced manufacturers to prove the safety and efficacy of drugs by adequate clinical trials. Today pharmaceutical progress is so obvious and well established that the discrepancy between its benefit for adults as compared to children started to be perceived by champions in different institutions. There is an increased understanding of the child's physiology during developmental growth, of the maturation of enzyme systems, of the pharmacokinetics and pharmacodynamics and of the differences in disease processes. The involved institutions include legislators, government, regulatory authorities, academic scientists, pharmaceutical companies, the WHO, to name just the most prominent ones, but there are many more. Driving forces for the improvement of medicines for children include societal priorities, the involvement of science, the mission of regulatory authorities the role of clinical pharmacologists, paediatricians, and the characteristics of our market-driven economy with its chaotic, contradictory and lively elements. We do not live in an ideal world, but there is progress, and children are likely to benefit from it.

Sensitivity of the Montgomery Asberg Depression Rating Scale to response and its consequences for the assessment of efficacy.

An increasing body of evidence is available suggesting that the Hamilton Depression Rating Scale (HAMD) is not a sensitive measure of treatment effect. In this investigation, we explore the sensitivity of the individual items of the Montgomery Asberg Depression Rating Scale (MADRS) and compare the consequences of selecting a different scale as primary endpoint in the analysis of efficacy. A graphical approach is proposed for the evaluation of the sensitivity of individual items to response, using data from randomised, placebo-controlled clinical trials in which HAMD and MADRS were measured concurrently. Subsequently, we illustrate the impact of differences in the sensitivity of the primary endpoint for the detection of statistical significance in treatment effect. In contrast to the HAMD, our item-by-item analysis of the MADRS reveals that all individual items are sensitive to response, irrespective of treatment type. However, some HAMD subscales still outperform MADRS in the detection of treatment effect. The selection of these subscales as primary endpoints in clinical trials could save over 1/3 in patients compared to the full HAMD whilst keeping the same statistical power.

Fit-for-purpose pharmacogenomic biomarkers in drug development: a project team case study with 'what-ifs'.

Over the past four years, the annual US FDA-DIA pharmacogenomic workshops have brought together attendees with wide-ranging expertise spanning industry, regulatory authorities and academia. This special report summarizes a breakout session using a novel, interactive case format as a way to engage participants, raise awareness and share diverse learnings via 'real life' decisions that project teams might face in developing a new medicine. This case was situated just prior to approval by a Regulatory Authority as a project team is finalizing a new medicine label. To effectively integrate new biomarkers such as pharmacogenomics into developing new medicines, this session highlighted the importance in considering medical practice implications as relevant (or not) to information or actions by a prescriber; progressing validation beyond assay to clinical; and fitting pharmacogenomics into context with other evidence often built over decades during a drug's development. All converge onto a label that must communicate evidence-based use of a new medicine that is effective and safe.

Sensitivity of the individual items of the Hamilton depression rating scale to response and its consequences for the assessment of efficacy.

The Hamilton depression rating scale (HAM-D(17)) has been the gold standard in depression trials since its introduction in 1960 by Max Hamilton. However, several authors have shown that the HAM-D(17) is multi-dimensional and that subscales of the HAM-D(17) outperform the total scale. In the current study, we assess the sensitivity of the individual HAM-D(17) items in differentiating responders from non-responders over the typical treatment period used in clinical efficacy trials. Based on data from randomised, placebo-controlled trials with paroxetine, a graphical analysis and a statistical analysis were performed to identify the items that are most sensitive to the rate and extent of response irrespective of treatment. From these analyses, two subscales consisting of seven items each were derived and compared to the Bech and Maier and Philip subscales using a linear mixed-effects modelling approach for repeated measures. The evaluation of two clinical trials revealed endpoint sensitivity comparable to the existing subscales. Using a bootstrap technique, we show that the subscales consistently yield higher statistical power compared to the HAM-D(17), although no subscale consistently outperforms the others. In conclusion, this study provides further evidence that not all items of the HAM-D(17) scale are equally sensitive to detect responding patients in a clinical trial. A HAM-D(7) subscale with higher sensitivity to drug effect is proposed consisting of the HAM-D(6) and the suicide item. This response-based subscale increases signal-to-noise ratio and could reduce failure rate in efficacy trials with antidepressant drugs.

Relevance of absorption rate and lag time to the onset of action in migraine.

OBJECTIVE: The objective of this analysis was to simulate the performance of oral triptan formulations with varying absorption characteristics and their impact on the onset and magnitude of the antimigraine effect using a Markov model for migraine attacks. ANALYSIS: Sumatriptan pharmacokinetic data were obtained from clinical pharmacology studies in which marketed solid formulations were administered. Based on a population pharmacokinetic model, mean concentration-time profiles were generated by varying the absorption rate constant and lag time. Subsequently, the simulated profiles were evaluated in a disease model of migraine to predict the onset and duration of the effect (the pain-free, pain-relief response). RESULTS: Based on a therapeutic dose of 50 mg of sumatriptan, a maximum gain in the pain-free response of 12% was achieved with an increased absorption rate. This gain in the response was reached approximately 0.5 hours after administration. A decrease only in the lag time with respect to the currently available formulations (i.e. 0.24 hours) resulted in a maximum gain of 5% in the pain-free response, which in contrast may not be interpreted as clinically relevant. CONCLUSION: Model-based predictions suggest that increases in the absorption rate of the currently marketed oral formulation of sumatriptan result in a gain in the pain-free response that is both clinically and statistically relevant.

Analysis of responses in migraine modelling using hidden Markov models.

Markov-type models have been used in the analysis of disease progression. Although standard errors of model parameters are usually estimated, available software often does not permit the construction of confidence intervals around predictions of the dependent or response variable. A method is presented to calculate means and confidence intervals of model-predicted responses in time governed by a non-homogeneous hidden Markov model in continuous time. The Kolmogorov equations serve as the basis for the calculations. The method is realised in S-Plus and is applied to the prediction of headache responses in clinical studies of anti-migraine treatment. Means and confidence intervals are calculated by numerically solving differential equations that are non-linear in the explanatory variable. Results indicate that uncertainty on predicted drug responses is larger than that on predicted placebo responses and that pain-free responses are less precisely predicted than pain-relief responses. This is due to the uncertainty in the drug-specific parameters which is not present in predicted placebo responses.

A model-based approach to treatment comparison in acute migraine.

AIMS: Currently, direct comparisons between 5-HT(1B/d) receptor agonists are used to assess differences and similarities in antimigraine response. Such comparisons depend on the selected sampling time and do not allow evaluation of entire response profiles. A thorough evaluation of drug properties requires that the time course of the response be taken into account. In this investigation we show the advantages of a model-based approach to compare the efficacy of two triptans (sumatriptan vs. naratriptan). METHODS: A Markov model was used to describe the course of a migraine attack over three clinically identified stages. Drug effects were modelled as concentration-dependent increases in transition rates and were parameterised as potency (EC(50)) and maximum effect (E(max)). Parameters were estimated using headache measurements from efficacy studies. Model estimates were then used to compare the pharmacodynamics of the two drugs in a time-independent manner. RESULTS: Efficacy parameters could be derived, allowing for comparison between compounds. The potency ratio (EC50(suma)/EC50(nara)) for headache relief was 3.3 (0.9, 12). The ratio of maximum effects (Emax(suma)/Emax(nara)) for this endpoint was 0.74 (0.55, 0.97). To interpret these efficacy measures and explore their value for the development of antimigraine drugs, results were evaluated against the reported in vitro potency at 5-HT(1B) and 5-HT(1D) receptors. CONCLUSIONS: Comparison of the effects of two or more drugs based on preset sampling times does not allow proper assessment of the antimigraine properties in vivo. Disease dynamics must be considered to evaluate treatment response adequately and optimise the dosing regimen in migraine.