Update to RIFM fragrance ingredient safety assessment, 2,4-dimethylbenzyl acetate, CAS Registry Number 62346-96-7.

The MOE is greater than 100. Without adjustment for specific uncertainty factors related to inter-species and intra-species variation, the material exposure by inhalation at 0.0040 mg/day is deemed to be safe under the most conservative consumer exposure scenario.

The RIFM approach to evaluating Natural Complex Substances (NCS).

The Research Institute for Fragrance Materials, Inc. (RIFM) has evaluated safety data for fragrance materials for 55 years. The safety assessment of Natural Complex Substances (NCS) is similar to that of discrete fragrance materials; all of the same endpoints are evaluated. A series of decision trees, reflecting advances in risk assessment approaches of mixtures and toxicological methodologies, follows a tiered approach for each endpoint using a 4-step process with testing only as a last resort: 1) evaluate available data on NCS; 2) verify whether the Threshold of Toxicological Concern (TTC) can be applied; 3) verify whether the NCS risk assessment can be achieved on a component basis; and 4) determine whether data must be generated. Using in silico tools, RIFM examined NCS similarities based on the plant part, processing, and composition of materials across 81 plant families to address data gaps. Data generated from the Creme RIFM Aggregate Exposure Model for over 900 fragrance NCS demonstrate that dermal exposure is the primary route of human exposure for NCS fragrance uses. Over a third of materials are below the most conservative TTC limits. This process aims to provide a comprehensive Safety Assessment of NCS used as a fragrance ingredient.

Regulatory and clinical consequences of negative confirmatory trials of accelerated approval cancer drugs: retrospective observational study.

OBJECTIVES: To investigate the regulatory handling of cancer drugs that were granted accelerated approval by the US Food and Drug Administration (FDA) but failed to improve the primary endpoint in post-approval trials and to evaluate the extent to which negative post-approval trials changed the recommendations in treatment guidelines. DESIGN: Retrospective observational study. SETTING: FDA and National Comprehensive Cancer Network (NCCN) reports. INCLUDED DRUGS: Cancer drugs that received accelerated approval from the FDA and had negative post-approval trials. MAIN OUTCOME MEASURES: Regulatory outcomes, including withdrawal, conversion to regular approval, and no action. RESULTS: 18 indications for 10 cancer drugs that received accelerated approval but failed to improve the primary endpoint in post-approval trials were identified. Of these, 11 (61%) were voluntarily withdrawn by the manufacturer and one (bevacizumab for breast cancer) was revoked by the FDA. Of the 11 withdrawals, six occurred in 2021 alone. The remaining six (33%) indications remain on the label. The NCCN guidelines provide a high level of endorsement (category 1 endorsement for one and category 2A endorsement for seven) for accelerated approval drugs that have failed post-approval trials, sometimes even after the approval has been withdrawn or revoked. CONCLUSION: Cancer drug indications that received accelerated approval often remained on formal FDA approved drug labelling and continued to be recommended in clinical guidelines several years after statutorily required post-approval trials showed no improvement in the primary efficacy endpoint. Clinical guidelines should better align with the results of post-approval trials of cancer drugs that received accelerated approval.

[Study on endpoint determination method of tablet coating based on 3σ criteria and logic regression].

This paper explores the statistical distribution characteristics of coating film thickness, so as to present a new method for determining coating endpoint based on 3σ criterion and logic regression. Firstly, the spectrum and thickness of 4 batch samples were collected. Secondly, the spectral range of normal products was obtained by 3σ criterion, with the spectral feature NI as the number of test spectrum in the above range. Then, the model based on 3σ criterion and logic regression was built according to the best condition in K-fold cross-validation and the determined threshold of qualified rate in the coating endpoint. Finally, the qualified rate of test set samples at different time points was calculated by the above model, and the above change trend and the threshold value were combined to determine the coating endpoint. The results of KS analysis showed the distribution of thickness of the qualified products followed the normal distribution(P=0.081>0.05). The accuracy of the coating endpoint determination was as high as 100% by the model based on 3σ criterion and logic regression when the determined threshold of qualified rate was 90%. Therefore, the 3σ criterion was feasible to the research of coating eligibility. This paper reveals certain random phenomena in the coating process, and the method features a high accuracy, quick analysis and a good interpretability, which provides a reference for online detection and qualify evaluation in future.

In-line monitoring and endpoint determination of percolation process of herbal medicine using ultraviolet spectroscopy combined with convolutional neural network.

OBJECTIVES: As a common step in the herbal medicine production process, percolation usually lacks effective process monitoring methods and is often conducted with fixed process parameters. In this study, an in-line ultraviolet (UV) spectroscopy was used for monitoring the Caulis Sinomenii percolation process. METHODS: The spectra and concentration data of 156 percolation samples from five batches were collected. Convolutional neural networks (CNNs) were used to develop quantitative calibration models. The mean squared error (MSE), mean absolute percentage error (MAPE) and mean absolute error (MAE) were compared to select the proper loss function for developing the CNN models. Meanwhile, partial least square regression (PLSR) was also used to develop calibration models for performance comparison. KEY FINDINGS: The CNN models with MAPE or MAE as the loss function could provide accurate predictions for all samples. However, CNN models adopting MSE as the loss function tended not to predict low-concentration samples accurately. The CNN models mostly achieved satisfactory results without any preprocessing techniques and surpassed PLSR models in all the performance metrics. CONCLUSIONS: An in-line UV spectroscopy system combining the CNN algorithm was implemented to monitor the percolation process of Caulis Sinomenii. The system can accurately determine the endpoint of the percolation process.

Methods for development of a core outcome set for clinical trials integrating traditional Chinese medicine and Western medicine.

Clinical trial outcome reporting differs between studies integrating traditional Chinese medicine (TCM) and Western medicine, so that some clinical trials are not eligible for inclusion in a systematic review. The excluded studies are therefore less widely disseminated, and even valid studies are less likely to yield impact. This problem may be addressed by developing core outcome sets (COSs) for integrative medicine in specific healthcare areas. The first stage of development is to define the scope of the COS for integrative medicine, the second stage is to establish the need for such a COS, and the third stage is to develop a protocol and register the COS. The final stage involves three steps: (i) development of a comprehensive list of outcomes (including efficacy outcomes and safety outcomes and TCM syndromes) using systematic review, qualitative or cross-sectional research, and reviews of package inserts and medical records; (ii) merging and grouping of outcomes within domains; (iii) conducting two rounds of Delphi survey and consensus meetings with a range of stakeholders. The final COS will include a general COS and core TCM syndrome- set. Development of COSs for clinical trials of integrative medicine may help to standardize outcome reporting and reduce publication bias in the future.

Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial.

BACKGROUND: COVID-19 is associated with a prothrombotic state leading to adverse clinical outcomes. Whether therapeutic anticoagulation improves outcomes in patients hospitalised with COVID-19 is unknown. We aimed to compare the efficacy and safety of therapeutic versus prophylactic anticoagulation in this population. METHODS: We did a pragmatic, open-label (with blinded adjudication), multicentre, randomised, controlled trial, at 31 sites in Brazil. Patients (aged ≥18 years) hospitalised with COVID-19 and elevated D-dimer concentration, and who had COVID-19 symptoms for up to 14 days before randomisation, were randomly assigned (1:1) to receive either therapeutic or prophylactic anticoagulation. Therapeutic anticoagulation was in-hospital oral rivaroxaban (20 mg or 15 mg daily) for stable patients, or initial subcutaneous enoxaparin (1 mg/kg twice per day) or intravenous unfractionated heparin (to achieve a 0·3-0·7 IU/mL anti-Xa concentration) for clinically unstable patients, followed by rivaroxaban to day 30. Prophylactic anticoagulation was standard in-hospital enoxaparin or unfractionated heparin. The primary efficacy outcome was a hierarchical analysis of time to death, duration of hospitalisation, or duration of supplemental oxygen to day 30, analysed with the win ratio method (a ratio >1 reflects a better outcome in the therapeutic anticoagulation group) in the intention-to-treat population. The primary safety outcome was major or clinically relevant non-major bleeding through 30 days. This study is registered with ClinicalTrials.gov (NCT04394377) and is completed. FINDINGS: From June 24, 2020, to Feb 26, 2021, 3331 patients were screened and 615 were randomly allocated (311 [50%] to the therapeutic anticoagulation group and 304 [50%] to the prophylactic anticoagulation group). 576 (94%) were clinically stable and 39 (6%) clinically unstable. One patient, in the therapeutic group, was lost to follow-up because of withdrawal of consent and was not included in the primary analysis. The primary efficacy outcome was not different between patients assigned therapeutic or prophylactic anticoagulation, with 28 899 (34·8%) wins in the therapeutic group and 34 288 (41·3%) in the prophylactic group (win ratio 0·86 [95% CI 0·59-1·22], p=0·40). Consistent results were seen in clinically stable and clinically unstable patients. The primary safety outcome of major or clinically relevant non-major bleeding occurred in 26 (8%) patients assigned therapeutic anticoagulation and seven (2%) assigned prophylactic anticoagulation (relative risk 3·64 [95% CI 1·61-8·27], p=0·0010). Allergic reaction to the study medication occurred in two (1%) patients in the therapeutic anticoagulation group and three (1%) in the prophylactic anticoagulation group. INTERPRETATION: In patients hospitalised with COVID-19 and elevated D-dimer concentration, in-hospital therapeutic anticoagulation with rivaroxaban or enoxaparin followed by rivaroxaban to day 30 did not improve clinical outcomes and increased bleeding compared with prophylactic anticoagulation. Therefore, use of therapeutic-dose rivaroxaban, and other direct oral anticoagulants, should be avoided in these patients in the absence of an evidence-based indication for oral anticoagulation. FUNDING: Coalition COVID-19 Brazil, Bayer SA.

Antifungal Susceptibility Testing and Identification.

The requirement for antifungal susceptibility testing is increasing given the availability of new drugs, increasing populations of individuals at risk for fungal infection, and emerging multiresistant fungi. Rapid and accurate fungal identification remains at the forefront of laboratory efforts to guide empiric therapy. Antifungal susceptibility testing methods have greatly improved, but are subject to variation in results between methods. Careful standardization, validation, and extensive training of users is essential to ensure susceptibility results are clinically useful and interpreted appropriately. Interpretive criteria for many drugs and species are still lacking, but this will continue to evolve.

Creatine Supplementation for Patients with Inflammatory Bowel Diseases: A Scientific Rationale for a Clinical Trial

Based on theoretical considerations, experimental data with cells in vitro, animal studies in vivo, as well as a single case pilot study with one colitis patient, a consolidated hypothesis can be put forward, stating that "oral supplementation with creatine monohydrate (Cr), a pleiotropic cellular energy precursor, is likely to be effective in inducing a favorable response and/or remission in patients with inflammatory bowel diseases (IBD), like ulcerative colitis and/or Crohn's disease". A current pilot clinical trial that incorporates the use of oral Cr at a dose of 2 × 7 g per day, over an initial period of 2 months in conjunction with ongoing therapies (NCT02463305) will be informative for the proposed larger, more long-term Cr supplementation study of 2 × 3-5 g of Cr per day for a time of 3-6 months. This strategy should be insightful to the potential for Cr in reducing or alleviating the symptoms of IBD. Supplementation with chemically pure Cr, a natural nutritional supplement, is well tolerated not only by healthy subjects, but also by patients with diverse neuromuscular diseases. If the outcome of such a clinical pilot study with Cr as monotherapy or in conjunction with metformin were positive, oral Cr supplementation could then be used in the future as potentially useful adjuvant therapeutic intervention for patients with IBD, preferably together with standard medication used for treating patients with chronic ulcerative colitis and/or Crohn's disease.

Quantifying noxious-evoked baseline sensitivity in neonates to optimise analgesic trials.

Despite the high burden of pain experienced by hospitalised neonates, there are few analgesics with proven efficacy. Testing analgesics in neonates is experimentally and ethically challenging and minimising the number of neonates required to demonstrate efficacy is essential. EEG (electroencephalography)-derived measures of noxious-evoked brain activity can be used to assess analgesic efficacy; however, as variability exists in neonate's responses to painful procedures, large sample sizes are often required. Here, we present an experimental paradigm to account for individual differences in noxious-evoked baseline sensitivity which can be used to improve the design of analgesic trials in neonates. The paradigm is developed and tested across four observational studies using clinical, experimental, and simulated data (92 neonates). We provide evidence of the efficacy of gentle brushing and paracetamol, substantiating the need for randomised controlled trials of these interventions. This work provides an important step towards safe, cost-effective clinical trials of analgesics in neonates.

Hospitalized newborns often undergo medical procedures, like blood tests, without pain relief. This can cause the baby to experience short-term distress that may have negative consequences later in life. However, testing the effects of pain relief in newborns is challenging because, unlike adults, they cannot report how much pain they are experiencing. One way to overcome this is to record the brain activity of newborns during a painful procedure and to see how these signals are modified following pain relief. Randomized controlled trials are the gold standard for these kinds of medical assessments, but require a high number of participants to account for individual differences in how babies respond to pain. Finding ways to reduce the size of pain control studies could lead to faster development of pain relief methods. Here, Cobo, Hartley et al. demonstrate a way to reduce the number of newborns needed to test potential pain-relieving interventions. In the experiments, the brain activity of nine babies was measured after a gentle poke and after a painful clinically required procedure. Cobo, Hartley et al. found that the babies' response to the gentle poke correlated with their response to pain. Further data analysis revealed that this information can be used to predict the variability in pain experienced by different newborns, reducing the number of participants needed for pain relief trials. Next, Cobo, Hartley et al. used this new approach in two pilot tests. One showed that gently stroking an infant's leg before blood is drawn from their heel reduced their brains' response to pain. The second showed that giving a baby the painkiller paracetamol lessened the brain's response to immunisation. The new approach identified by Cobo, Hartley et al. may enable smaller studies that can more quickly identify ways to reduce pain in babies. Furthermore, this work suggests that gentle brushing and paracetamol could provide pain relief for newborns undergoing hospital acute procedures. However, more formal clinical trials are needed to test the effectiveness of these two strategies.

Sjogren's syndrome in clinical trials of traditional Chinese medicine: protocol for the development of a core outcome set.

BACKGROUND: Sjogren's syndrome (SS) is a chronic autoimmune rheumatic disease with an incidence of 0.03 to 0.3%. In recent years, there are an increasing number of randomized controlled trials of traditional Chinese medicine (TCM) for SS. However, there are generally some problems in these published clinical trials: lack of reporting primary or long-term outcomes and the heterogeneous in different clinical trials' outcome. Our study aims to determine the priority outcomes and standard TCM syndromes for all stakeholders and reach agreement on the COS and syndromes to be measured and reported in all future TCM trials in patients with SS. METHODS AND ANALYSIS: A phase-wise refinement approach will be used, consisting of three phases, yet complementary, sub-work phases, whereby each phase will inform the next coming phases. The following are the three phases: (I-a) identifying of a long initial list of outcomes through systematic literature review and semi-structured qualitative interviews and (I-b) identifying an initial list of TCM syndromes through (1) systematic literature review, (2) referencing ancient Chinese medical books, and (3) retrospective studies of medical records; (II) prioritization of outcomes using Delphi survey with different stakeholders, such as health professionals and patients; and (III) through consensus meetings with patients and professionals to agree on the final COS and TCM syndromes. DISCUSSION: We summarized the actions of COS into three points: direct action, indirect action, and final action. After the final COSs is completed, we will publish this research in a journal to promote communication. TRIAL REGISTRATION: Core Outcome Measures in Effectiveness Trials Initiative (COMET) number 1429 . Registered on 01 December 2019.

[Analysis of RCT outcome indicators of traditional Chinese medicine for essential hypertension in recent two years].

To find the status of outcome indicators reported in published randomized controlled trial(RCT) of traditional Chinese medicine(TCM) for essential hypertension in the past two years, we searched for relevant information from four Chinese databases, three English databases and two clinical trial registries in this study, from January 2018 to September 2019. The outcome indicators of RCT were extracted and categorized from trials and the risk of bias was assessed by ROB tools from the Cochrane Collaboration. A total of 125 RCTs and 15 RCT protocols were finally included after study screening. The results showed that the RCT outcomes mainly included efficacy and safety outcomes. Efficacy indicators mainly included blood pressure measurement, quality of life assessment, blood biochemical indicators, urine analysis, arterial ultrasound, vascular endothelial function indicators, hematocrit, hemorheology indicators and other indicators. The safety indicators mainly included general physical examination items, heart, liver and kidney function tests, blood, urine, and stool routine examinations as well as adverse drug reactions/events. The current RCTs cannot distinguish primary and secondary outcomes, and the RCT protocols didn't report efficacy criteria clearly. They both didn't report health economic indicators and the methodological qualities were relatively low. In view of the current status on outcome indicators reported in TCM RCTs, constructing a core outcome set of TCM for essential hypertension and improving the methodology quality of RCTs will help to accurately reflect the actual efficacy of TCM intervention.

The Weight of Evidence From Electrophysiology, Observational, and Cardiovascular End Point Studies Demonstrates the Safety of Azithromycin.

Increased use of azithromycin (AZ) in treating infections associated with coronavirus disease 2019 (COVID-19) and reports of increased incidence of prolonged corrected QT (QTc) interval associated with AZ used with hydroxychloroquine prompted us to review the latest evidence in the literature, present additional analyses of human cardiovascular (CV) electrophysiology studies, and to describe sequential steps in research and development that were undertaken to characterize the benefit-risk profile of AZ. Combined QTc findings from electrocardiograms taken during oral and i.v. pharmacokinetic-pharmacodynamic studies of AZ suggest that clinically meaningful QTc prolongation is unlikely. Findings from several observational studies were heterogeneous and not as consistent as results from at least two large randomized controlled trials (RCTs). The QTc findings presented and observational data from studies with large numbers of events are not consistent with either a proarrhythmic action of AZ or an increase in frequency of CV deaths. Well-powered RCTs do not suggest a presence of increased risk of CV or sudden cardiac death after short-term or protracted periods of AZ usage, even in patients at higher risk from pre-existing coronary disease.

Multiple-endpoint in vitro carcinogenicity test in human cell line TK6 distinguishes carcinogens from non-carcinogens and highlights mechanisms of action.

Current in vitro genotoxicity tests can produce misleading positive results, indicating an inability to effectively predict a compound's subsequent carcinogenic potential in vivo. Such oversensitivity can incur unnecessary in vivo tests to further investigate positive in vitro results, supporting the need to improve in vitro tests to better inform risk assessment. It is increasingly acknowledged that more informative in vitro tests using multiple endpoints may support the correct identification of carcinogenic potential. The present study, therefore, employed a holistic, multiple-endpoint approach using low doses of selected carcinogens and non-carcinogens (0.001-770 µM) to assess whether these chemicals caused perturbations in molecular and cellular endpoints relating to the Hallmarks of Cancer. Endpoints included micronucleus induction, alterations in gene expression, cell cycle dynamics, cell morphology and bioenergetics in the human lymphoblastoid cell line TK6. Carcinogens ochratoxin A and oestradiol produced greater Integrated Signature of Carcinogenicity scores for the combined endpoints than the "misleading" in vitro positive compounds, quercetin, 2,4-dichlorophenol and quinacrine dihydrochloride and toxic non-carcinogens, caffeine, cycloheximide and phenformin HCl. This study provides compelling evidence that carcinogens can successfully be distinguished from non-carcinogens using a holistic in vitro test system. Avoidance of misleading in vitro outcomes could lead to the reduction and replacement of animals in carcinogenicity testing.

Analysis of RCT outcome indicators of traditional Chinese medicine for essential hypertension in recent two years / 中国中药杂志

To find the status of outcome indicators reported in published randomized controlled trial(RCT) of traditional Chinese medicine(TCM) for essential hypertension in the past two years, we searched for relevant information from four Chinese databases, three English databases and two clinical trial registries in this study, from January 2018 to September 2019. The outcome indicators of RCT were extracted and categorized from trials and the risk of bias was assessed by ROB tools from the Cochrane Collaboration. A total of 125 RCTs and 15 RCT protocols were finally included after study screening. The results showed that the RCT outcomes mainly included efficacy and safety outcomes. Efficacy indicators mainly included blood pressure measurement, quality of life assessment, blood biochemical indicators, urine analysis, arterial ultrasound, vascular endothelial function indicators, hematocrit, hemorheology indicators and other indicators. The safety indicators mainly included general physical examination items, heart, liver and kidney function tests, blood, urine, and stool routine examinations as well as adverse drug reactions/events. The current RCTs cannot distinguish primary and secondary outcomes, and the RCT protocols didn't report efficacy criteria clearly. They both didn't report health economic indicators and the methodological qualities were relatively low. In view of the current status on outcome indicators reported in TCM RCTs, constructing a core outcome set of TCM for essential hypertension and improving the methodology quality of RCTs will help to accurately reflect the actual efficacy of TCM intervention.

Methods for development of a core outcome set for clinical trials integrating traditional Chinese medicine and Western medicine / 中西医结合学报

Clinical trial outcome reporting differs between studies integrating traditional Chinese medicine (TCM) and Western medicine, so that some clinical trials are not eligible for inclusion in a systematic review. The excluded studies are therefore less widely disseminated, and even valid studies are less likely to yield impact. This problem may be addressed by developing core outcome sets (COSs) for integrative medicine in specific healthcare areas. The first stage of development is to define the scope of the COS for integrative medicine, the second stage is to establish the need for such a COS, and the third stage is to develop a protocol and register the COS. The final stage involves three steps: (i) development of a comprehensive list of outcomes (including efficacy outcomes and safety outcomes and TCM syndromes) using systematic review, qualitative or cross-sectional research, and reviews of package inserts and medical records; (ii) merging and grouping of outcomes within domains; (iii) conducting two rounds of Delphi survey and consensus meetings with a range of stakeholders. The final COS will include a general COS and core TCM syndrome- set. Development of COSs for clinical trials of integrative medicine may help to standardize outcome reporting and reduce publication bias in the future.

[Study on endpoint determination and process analysis of tablet coating based on near infrared spectroscopy].

To conduct endpoint determination of tablet coating and analyze coating process by near-infrared spectroscopy(NIRS). Firstly, the layered k-fold cross validation was used to discuss the optimal combination of spectral interval and preprocessing method, and the optimal result was used as the modeling condition. Secondly, in above condition, the qualitative model was proposed based on the throught of principal component analysis(PCA) and confidence interval, this model and the conformity test model were established respectively in this study, and the discrimination performance of coating eligibility was calculated. Then, the internal cross validation was used to obtain the coating end-point conforming rate as the threshold for determining the endpoint of tablet coating. Finally, the results of predicted conforming rate and discrimination parameters for the test samples of different batches were calculated with the above models, which were then further used for end-point detection and process analysis. As compared with the conformity test, this method proposed in this study was more accurate and stable in determining the coating conformity, and the coating endpoint can be accurately determined when 95% of the eligibility rate was used as the discriminant threshold. Meanwhile, in the process analysis, the change trend of the process parameters(model discrimination parameters, prediction conforming rate) was basically consistent with that in the conformity test. The results indicate that the method proposed in this study has a good and stable performance, which can be used to determine the endpoint of coating and analyze the process. It is of great significance to reduce the difference between batches and improve the product consistency. Meanwhile, this research method also lays a foundation for the future researches by online near infrared measurements.

Frontiers in translational systemic sclerosis research: A focus on the unmet 'cutaneous' clinical needs (Viewpoint).

This viewpoint considers four cutaneous unmet clinical needs of patients with systemic sclerosis (SSc), namely the rapidly progressive skin thickening (scleroderma) which occurs early on in diffuse cutaneous disease; digital (finger and toe) ulcers; calcinosis; and cutaneous telangiectases. All four problems cause pain, disability and/or disfigurement, all impact on quality of life, and for each, we require effective treatments. For each unmet need, we give a brief description of the clinical problem (including clinical burden), pathophysiology and current treatment, followed by a personal viewpoint of the key questions which research must address. For the painful, debilitating skin thickening of early diffuse cutaneous SSc, studies are required to decide whether corticosteroids are effective and safe (current opinion is divided) and whether phototherapy approaches have a role. Also, we need to develop and validate reliable outcome measures for clinical trials of promising new therapies: these could be composite indices, novel non-invasive imaging methods and patient-reported outcome measures, possibly in combination as they provide complementary information. For digital ulcers, again we require validated outcome measures for clinical trials. We also need to explore local (including topical) treatments, which are free from systemic adverse effects, and preventative strategies for high-risk patients. For calcinosis, we need to better understand pathophysiology, to validate outcome measures and to develop topical treatments. For telangiectases, we need to "use" these highly accessible lesions to help unravel the vascular pathophysiology of SSc and explore their different properties as potential biomarkers.

Composite endpoints in COPD: clinically important deterioration in the UPLIFT trial.

BACKGROUND: Assessments of lung function, exacerbations and health status are common measures of chronic obstructive pulmonary disease (COPD) progression and treatment response in clinical trials. We hypothesised that a composite endpoint could more holistically assess clinically important deterioration (CID) in a COPD clinical trial setting. METHODS: A composite endpoint was tested in a post hoc analysis of 5652 patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2-4 COPD from the 4-year UPLIFT study. Patients received tiotropium 18 µg or placebo. RESULTS: The composite endpoint included time to first confirmed decrease in trough forced expiratory volume in 1 s (FEV1) ≥100 mL, confirmed increase in St. George's Respiratory Questionnaire (SGRQ) total score ≥ 4 units, or moderate/severe exacerbation. Most patients (> 80%) experienced CID, with similar incidence among GOLD subgroups. Most confirmed trough FEV1 (74.6-81.6%) and SGRQ (72.3-78.1%) deteriorations were sustained across the study and in all GOLD subgroups. Patients with CID more frequently experienced subsequent exacerbation (hazard ratio [HR] 1.79; 95% confidence interval [CI] 1.67, 1.92) or death (HR 1.21; 95% CI 1.06, 1.39) by Month 6. CID was responsive to bronchodilator treatment. CONCLUSIONS: Composite endpoints provide additional information on COPD progression and treatment effects in clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT00144339 .

Preclinical Alzheimer Disease Drug Development: Early Considerations Based on Phase 3 Clinical Trials.

The number of people in the United States living with Alzheimer disease (AD) is growing, resulting in significant clinical and economic impact. Substantial research investment has led to drug development in stages of AD before symptomatic dementia, such as preclinical AD. Although there are no treatments approved for preclinical AD, there are currently 6 phase 3 clinical trials for preclinical AD treatments. In this article, we review these clinical trials and highlight considerations for future coverage decisions. In line with the definition of preclinical AD, enrollment in these trials focuses on cognitively unimpaired patients that are at high risk of AD because of family history and then genetic testing or brain imaging. Enrollment in most of these trials also allows for younger patients, including those aged under 65 years. Primary clinical trial endpoints focus on cognition often 4 or more years after treatment. Secondary endpoints include other measures of cognition and function, as well as biomarkers. Review of these trials brings to light a few potential considerations when covering these new medications in the future. First, novel and potentially costly approaches involving genetic testing and/or positron emission tomography imaging may be needed to identify appropriate patients and should be developed efficiently. Second, the long duration of these clinical trials suggest that there may be a need for alternative payment approaches in the United States that encourage early payers to pay for a medication for which the long-term benefits may not be realized until after the beneficiary is no longer with the health plan. Third, the value of AD treatments may differ across populations, creating a potential role for indication-based or population-based contracting. Finally, considering the potentially high budgetary impact and little real-world evidence for a new drug class, payers and manufacturers may want to consider outcomes-based payment approaches and coverage with evidence development to mitigate uncertainty about the value of the treatment demonstrated in well-defined populations in clinical trials versus more heterogeneous real-world settings. DISCLOSURES: This work was funded through a generous gift from the Global CEO Initiative on Alzheimer Disease. Hung reports grants from Agency for Healthcare Research and Quality and Pharmaceutical Research and Manufacturers of America outside the submitted work and past employment at CVS Health and BlueCross BlueShield Association. McClellan is an independent board member on the boards of Johnson & Johnson, Cigna, Alignment Healthcare, and Seer; co-chairs the Accountable Care Learning Collaborative and the Guiding Committee for the Health Care Payment Learning and Action Network; and receives fees for serving as an advisor for Cota and MITRE. Hamilton Lopez and Schneider have nothing to disclose. Part of this work was presented at the 2019 AMCP Nexus Meeting, October 29-November 1, 2019, in National Harbor, MD.