Clinical Trials Of Pharmacological Interventions Research Articles

Clinical trials of pharmacological interventions for SARS-CoV-2 published in leading medical journals report adherence but not how it was assessed.

Adherence to pharmacological interventions in clinical trials is crucial for accurate identification of beneficial and adverse outcomes. The ways in which adherence to interventions should be reported in trial publications are described in the Template for Intervention Description and Replication (TIDieR), a 12-item extension of the Consolidated Standards of Reporting Trials reporting guidelines. The objective of this study was to assess compliance with TIDieR Items 11 and 12 of randomized controlled trials (RCTs) of interventions in SARS-CoV-2 infection published in 5 selected journals during 2021. We assessed pharmacological interventions for SARS-CoV-2 infection reported in RCTs published in 2021 in the Annals of Internal Medicine, The BMJ, JAMA, The Lancet and The New England Journal for Medicine for compliance with TIDieR items addressing intervention adherence (Items 11 and 12). We calculated proportional adherence for pharmacological and comparator interventions where available. We found 75 eligible RCTs. Twenty-eight (37%) reported results of SARS-CoV-2 vaccinations. Compliance with Items 11 and 12 could be assessed in 71 of these 75. Of the 71 RCTs, 37 (52%) reported how adherence was assessed (Item 11), and 70 reported adherence rates (Item 12). Only 1 of the 71 RCTs (1.4%, 0-7.6%) fully complied with TIDieR Items 11 and 12. Half of RCTs of SARS-CoV-2 pharmacological interventions published in leading medical journals in 2021 complied with reporting of how adherence assessments were made and almost none complied with both TIDieR Items 11 and 12. The implications for interpretation, application and replication of findings based on these publications warrant consideration.

A Systematic Review of Pharmacological Treatments for Internet Gaming Disorder.

Internet gaming disorder (IGD) is an increasingly common behavioral addiction, with an estimated global prevalence of 3%. A variety of pharmacological treatments have been used to treat IGD, yet no review to date has synthesized clinical trials evaluating their efficacy. This systematic review therefore synthesized the literature reporting on clinical trials of pharmacological treatments for IGD. We reviewed articles from MEDLINE, Embase, PubMed Central, CINAHL, and PsycINFO that were published as of March of 2022. A total of 828 articles were retrieved for review and 12 articles were included, reporting on a total of 724 participants. Most participants were male (98.6%), and all were currently living in South Korea. The most common drugs used to treat IGD were bupropion, methylphenidate, and a range of selective serotonin reuptake inhibitors. The Young Internet Addiction Scale was the most frequently used to measure gaming-related outcomes. All studies reported reduced symptoms of IGD from pre- to post-treatment. Across all clinical trials, IGD symptom reductions following the administration of pharmacological treatments ranged from 15.4% to 51.4%. A risk of bias assessment indicated that only four studies had a low risk of bias. Preliminary results suggest that a wide array of pharmacological interventions may be efficacious in the treatment of IGD. Future studies using double-blind randomized controlled trial designs, recruiting larger and more representative samples, and controlling for psychiatric comorbidities are needed to better inform understanding of pharmacological treatments for IGD.

P164 - Quality assessment of randomized controlled clinical trials of pharmacological treatments in patients with rare diseases

P164 - Quality assessment of randomized controlled clinical trials of pharmacological treatments in patients with rare diseases

Sharing of Individual Patient-Level Data by Trialists of Randomized Clinical Trials of Pharmacological Treatments for COVID-19

This study describes access to individual patient-level data from randomized clinical trials during the COVID-19 pandemic to determine whether the intent to share what was reported in the registry, publication, or preprint was consistent with actual data access.

Non-abstinent treatment outcomes for cannabis use disorder

BackgroundAbstinence remains a standard outcome for potential treatment interventions for Cannabis Use Disorder (CUD). However, there needs to be validation of non-abstinent outcomes. This study explores reductions in self-reported days of use as another viable outcome measure using data from three completed randomized placebo-controlled clinical trials of pharmacological interventions for CUD. MethodsThe three trials tested the effect of quetiapine (QTP, n = 113); dronabinol (DRO, n = 156); and lofexidine + dronabinol (LFD, n = 122). Self-reported cannabis use was categorized into three use-groups/week: heavy (5–7 days/week), moderate (2–4 days/week) and light use (0–1 days/week). Multinomial logistic regressions analyzed the treatment by time effect on the likelihood of light and moderate use compared to heavy use in each study. ResultsAcross the three trials, there was no significant overall time-by-treatment interaction (QTP: p = .06; DRO: p = .15; LFD: p = .21). However, the odds of moderate compared to heavy use were significantly higher in treatment than in placebo groups starting around the midpoint of each trial. No treatment differences were found between the odds of light compared to heavy use. ConclusionsWhile study-end abstinence rates have been a standard treatment outcome for CUD trials, reduction from heavy to moderate use has not been standardly assessed. During the last several weeks of each trial, those on active medication were more likely to move from heavy to moderate use, which suggests that certain medications may be more impactful than previously assessed. Future studies should determine if this pattern is associated with less CUD severity and/or improved quality of life.

Current evidence for COVID-19 therapies: a systematic literature review.

Effective therapeutic interventions for the treatment and prevention of coronavirus disease 2019 (COVID-19) are urgently needed. A systematic review was conducted to identify clinical trials of pharmacological interventions for COVID-19 published between 1 December 2019 and 14 October 2020. Data regarding efficacy of interventions, in terms of mortality, hospitalisation and need for ventilation, were extracted from identified studies and synthesised qualitatively. In total, 42 clinical trials were included. Interventions assessed included antiviral, mucolytic, antimalarial, anti-inflammatory and immunomodulatory therapies. Some reductions in mortality, hospitalisation and need for ventilation were seen with interferons and remdesivir, particularly when administered early, and with the mucolytic drug, bromhexine. Most studies of lopinavir/ritonavir and hydroxychloroquine did not show significant efficacy over standard care/placebo. Dexamethasone significantly reduced mortality, hospitalisation and need for ventilation versus standard care, particularly in patients with severe disease. Evidence for other classes of interventions was limited. Many trials had a moderate-to-high risk of bias, particularly in terms of blinding; most were short-term and some included low patient numbers.This review highlights the need for well-designed clinical trials of therapeutic interventions for COVID-19 to increase the quality of available evidence. It also emphasises the importance of tailoring interventions to disease stage and severity for maximum efficacy.

32 Quantifying the Prevalence of Frailty in Drug Trials and the Relationship with Serious Adverse Events

Abstract Introduction Frailty is common in clinical practice, but trials rarely report on participant frailty. Consequently, clinicians and guideline-developers assume frailty is largely absent from trials and have questioned the relevance of trial findings to frail people. Therefore, we examined frailty in phase 3/4 industry-sponsored clinical trials of pharmacological interventions for three exemplar conditions: type 2 diabetes mellitus (T2DM), rheumatoid arthritis (RA), and chronic obstructive pulmonary disease (COPD). Methods We constructed a 40-item frailty index (FI) in 19 clinical trials (7 T2DM, 8 RA, 4 COPD, mean age 42–65 years) using individual-level participant data. Participants with a FI >0.24 were considered “frail”. Baseline disease severity was assessed using HbA1c for T2DM, Disease Activity Score-28 (DAS28) for RA, and % predicted FEV1 for COPD. Using generalised gamma regression, we modelled FI on age, sex and disease severity. In negative binomial regression we modelled serious adverse event rates on FI, and combined results for each index condition in a random-effects meta-analysis. Results All trials included frail participants: prevalence 7–21% in T2DM trials, 33–73% in RA trials, and 15–22% in COPD trials. Increased disease severity and female sex were associated with higher FI in all trials. Frailty was associated with age in T2DM and RA trials, but not in COPD. Across all trials, and after adjusting for age, sex, and disease severity, higher FI predicted increased risk of serious adverse events; the pooled incidence rate ratios (per 0.1-point increase in FI scale) were 1.46 (95% CI 1.21–1.75), 1.45 (1.13–1.87) and 1.99 (1.43–2.76) for T2DM, RA and COPD, respectively. Conclusion Frailty is identifiable and prevalent among middle aged and older participants in phase 3/4 drug trials and has clinically important safety implications. Trial data may be harnessed to better understand chronic disease management in people living with frailty.

Applying available knowledge and resources to alleviate familial and sporadic neurodegenerative disorders.

Here I present the scientific rationale and implementation strategies for elimination of early-onset neurodegenerative disorders (EONDD) from future generations, and for risk reduction and treatments for the more common late-onset neurodegenerative disorders (LONDD). Young adults with a family history of an EONDD should be educated on the genetics and familial burden of EONDD. They can then be genotyped and, if positive for the mutation, counseled as to how they can ensure that none of their children will be affected by choosing either adoption or in vitro fertilization and preimplantation genetic testing. LONDD risk reduction will require education of physicians and patients on the benefits of regular intermittent bioenergetic and cognitive challenges (exercise, intermittent fasting, intellectual challenges and social engagement) for brain health, and on specific risk-reduction regimens. Regulations will be required to counteract the disease-promoting mercenary practices of the processed food and pharmaceutical industries. Clinical trials of pharmacological interventions should shift to small trials of agents that substantially mimic mechanisms of action of exercise and intermittent fasting to bolster neuronal bioenergetics and stress resistance.

Identifying frailty in trials: an analysis of individual participant data from trials of novel pharmacological interventions

BackgroundFrailty is common in clinical practice, but trials rarely report on participant frailty. Consequently, clinicians and guideline-developers assume frailty is largely absent from trials and have questioned the relevance of trial findings to frail people. Therefore, we examined frailty in phase 3/4 industry-sponsored clinical trials of pharmacological interventions for three exemplar conditions: type 2 diabetes mellitus (T2DM), rheumatoid arthritis (RA), and chronic obstructive pulmonary disease (COPD).MethodsWe constructed a 40-item frailty index (FI) in 19 clinical trials (7 T2DM, 8 RA, 4 COPD, mean age 42–65 years) using individual-level participant data. Participants with a FI > 0.24 were considered ‘frail’. Baseline disease severity was assessed using HbA1c for T2DM, Disease Activity Score-28 (DAS28) for RA, and % predicted FEV1 for COPD. Using generalised gamma regression, we modelled FI on age, sex, and disease severity. In negative binomial regression, we modelled serious adverse event rates on FI and combined results for each index condition in a random-effects meta-analysis.ResultsAll trials included frail participants: prevalence 7–21% in T2DM trials, 33–73% in RA trials, and 15–22% in COPD trials. The 99th centile of the FI ranged between 0.35 and 0.45. Female sex was associated with higher FI in all trials. Increased disease severity was associated with higher FI in RA and COPD, but not T2DM. Frailty was associated with age in T2DM and RA trials, but not in COPD. Across all trials, and after adjusting for age, sex, and disease severity, higher FI predicted increased risk of serious adverse events; the pooled incidence rate ratios (per 0.1-point increase in FI scale) were 1.46 (95% CI 1.21–1.75), 1.45 (1.13–1.87), and 1.99 (1.43–2.76) for T2DM, RA, and COPD, respectively.ConclusionThe upper limit of frailty in trials is lower than has been described in the general population. However, mild to moderate frailty was common, suggesting trial data may be harnessed to inform disease management in people living with frailty. Participants with higher FI experienced more serious adverse events, suggesting screening for frailty in trial participants would enable identification of those that merit closer monitoring. Frailty is identifiable and prevalent among middle-aged and older participants in phase 3/4 drug trials and has clinically important safety implications.

A Call to Action: A Systematic Review Examining the Failure to Include Females and Members of Minoritized Racial/Ethnic Groups in Clinical Trials of Pharmacological Treatments for Alcohol Use Disorder.

Alcohol use disorder (AUD) presents a significant public health concern given the high prevalence estimates and numerous deleterious-associated consequences. The FDA currently has approved 3 pharmacological treatments for alcohol use disorder: acamprosate, naltrexone, and disulfiram. Previous research suggests that there may exist differences in the prevalence of and outcomes related to AUD across sex and racial/ethnic groups. Other work indicates that there may be differences in the efficacy of existing pharmacological treatments for AUD across demographic groups. The purpose of the present study was to examine the inclusion of women and members of minoritized racial/ethnic groups in published randomized clinical trials of pharmacological treatments for alcohol use disorder since 1994, in accordance with the NIH Revitalization Act of 1993. PubMed was systematically searched using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The initial search located 842 articles. After exclusion of ineligible articles, 102 remained for analysis. Of those included in the review, only 11.8% reported full sex and racial/ethnic characteristics of their study participants. Of the total sample, 6 articles were specifically examining 1 racial/ethnic group, and 11 were specifically examining 1 sex. Two articles (2.2%) did not report information regarding the sex breakdown of their participants, while 47 (49.0%) did not report any information regarding the racial/ethnic breakdown of their sample. Despite guidelines set forth by NIH, only 5.9% of articles conducted subgroup analyses to examine differences in treatment outcomes by sex or race/ethnicity, and only 16.7% of articles included considerations related to cultural inclusion when discussing study limitations. These results varied by medication type. Results suggest that considerably greater efforts must be put forth by the larger scientific community regarding the inclusion, analysis, and reporting of data focused on women and non-White racial and ethnic groups.

Identification, collection, and reporting of harms among non-industry-sponsored randomized clinical trials of pharmacologic interventions in the critically ill population: a systematic review

BackgroundPrescribing pharmacologic therapies for critically ill patients requires a careful balancing of risks and benefits. Defining, monitoring, and reporting harms that occur in clinical trials conducted in critically ill populations, however, is challenging given that the natural history of most critical illnesses includes progressive multiple organ failure and death. In this study, we assessed harms reporting in clinical trials performed in critically ill populations.MethodsRandomized, non-industry-sponsored, human clinical trials of pharmacologic interventions in adult critically ill populations published between 2015 and 2018 in high-impact journals were included in this systematic review. Harms data, adherence to Consolidated Standards of Reporting Trials (CONSORT) harms reporting guidelines, and restrictions on harms reporting were recorded.ResultsA total of 707 abstracts were screened with 40 trials ultimately being included in the analysis. Included trials represent 28,636 randomized patients with a median of 292 (IQR 100–546) patients per trial. The most common disease states were general critical care (33%) and sepsis (28%). Of 18 included CONSORT items, the median number met was 12 (IQR 9, 14). The most commonly missed items were adverse event (AE) severity grading definitions and AE attribution (relationship of AE to study drug), which were only reported in 35 and 38% of manuscripts, respectively. Half of the manuscripts (48%) provided definitions for recorded AEs. There were 5 studies investigating the effects of corticosteroids in sepsis, with the number of AEs reported per analyzed patient ranging from 0.01 to 1.89. AE definitions in studies of similar/equivalent interventions often varied substantially. Study protocols were available for 30/40 (75%) of studies, with 13 (43%) of those not providing any guidance regarding AE attribution.ConclusionsRandomized trials of pharmacologic interventions conducted in critically ill populations and published in high impact journals often fail to adequately describe AE definitions, severity, attribution, and collection procedures. Among trials of similar interventions in comparable populations, variation in AE collection and reporting procedures is substantial. These factors may limit a clinician’s ability to accurately balance the potential benefits and harms of an intervention.

Detection of endophenotypes associated with neuropsychiatric deficiencies in a mouse model of tuberous sclerosis complex using diffusion tensor imaging.

Tuberous sclerosis complex (TSC) is a rare hereditary disease, which results from the mutation of either TSC1 or TSC2, and its clinical features include benign tumors and dysfunctions in numerous organs, including the brain. Many individuals with TSC manifest neuropsychiatric symptoms, such as learning impairments, cognitive deficits and anxiety. Current pharmacological treatment for TSC is the use of mTOR inhibitors. However, they are not effective in treating neuropsychiatric symptoms. We previously used curcumin, a diet‐derived mTOR inhibitor, which possesses both anti‐inflammatory and antiproliferative properties, to improve learning and memory deficits in Tsc2 +/− mice. Diffusion tensor imaging (DTI) provides microstructural information in brain tissue and has been used to study the neuropathological changes in TSC. In this study, we confirmed that the impaired recognition memory and increased anxiety‐like behavior in Tsc2 +/− mice can be reversed by curcumin treatment. Second, we found altered fractional anisotropy and mean diffusivity in the anterior cingulate cortex and the hippocampus of the Tsc2 +/− mice, which may indicate altered circuitry. Finally, the mTOR complex 1 hyperactivity was found in the cortex and hippocampus, coinciding with abnormal cortical myelination and increased glial fibrillary acidic protein expression in the hippocampal CA1 of Tsc2 +/− mice, both of which can be rescued with curcumin treatment. Overall, DTI is sensitive to the subtle alterations that cannot be detected by conventional imaging, suggesting that noninvasive DTI may be suitable for longitudinally monitoring the in vivo neuropathology associated with the neuropsychiatric symptoms in TSC, thereby facilitating future clinical trials of pharmacological treatments.

The ACTTION Guide to Clinical Trials of Pain Treatments: standing on the shoulders of giants.

The ACTTION Guide to Clinical Trials of Pain Treatments: standing on the shoulders of giants.

Pharmacological Treatments for Neonatal Abstinence Syndrome

Incidence of neonatal abstinence syndrome is rising rapidly, and optimal pharmacotherapy may meaningfully reduce length of treatment. To compare pharmacological therapies for neonatal abstinence syndrome. Systematic review and network meta-analysis of Medline (1946-June 2018), Embase (1974-June 2018), Cochrane CENTRAL (1966-June 2018), Web of Science (1900-June 2018), and ClinicalTrials.gov (June 2018). Randomized clinical trials of pharmacological treatments for neonatal abstinence syndrome alone or in combination with adjuvant treatments. Abstract, title, and full-text screening were conducted independently by 2 reviewers (T.D. and C.G.). Data extraction was conducted independently by 2 reviewers (T.D. and C.G.) according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)-Network Meta-Analyses guidelines. Quality was assessed with the Cochrane Risk of Bias tool and data were pooled with fixed-effect models as a result of the low number of trials that were included in the analysis. The primary outcome was the length of treatment. The length of stay, need for adjuvant therapy, and adverse events were considered as secondary outcomes. Eighteen trials (N = 1072) were eligible for inclusion. The treatments that were included in the length of treatment analysis were buprenorphine, clonidine, diluted tincture of opium and clonidine, diluted tincture of opium, morphine, methadone, and phenobarbital. Sublingual buprenorphine was considered the optimal treatment for a reduction in the length of treatment (days: mean difference vs morphine, -12.75 [95% CI, -17.97 to -7.58]; median rank, 1 [3-1]) and length of stay (days: mean difference vs morphine, -11.43 [95% CI, -16.95 to -5.82]; median rank, 1 [3-1]) but not the need for adjuvant treatment (odds ratio vs morphine, 1.23 [95% CI, 0.46-3.44]; median rank, 3 [5-1]). The results were robust to bias but sensitive to imprecision. The current evidence suggests that buprenorphine is the optimal treatment for neonatal abstinence treatment, but limitations are considerable and wide-scale adoption requires a large multisite trial. Morphine, which is considered standard of care in most hospitals, was the lowest-ranked opioid for length of treatment and length of stay.

Improving recruitment to pharmacological trials for illicit opioid use: findings from a qualitative focus group study.

AimTo explore potential study participants’ views on willingness to join clinical trials of pharmacological interventions for illicit opioid use to inform and improve future recruitment strategies.DesignQualitative focus group study [six groups: oral methadone (two groups); buprenorphine tablets (two groups); injectable opioid agonist treatment (one group); and former opioid agonist treatment (one group)].SettingsDrug and alcohol services and a peer support recovery service (London, UK).ParticipantsForty people with experience of opioid agonist treatment for heroin dependence (26 males, 14 females; aged 33–66 years).MeasurementsData collection was facilitated by a topic guide that explored willingness to enrol in clinical pharmacological trials. Groups were audio‐recorded and transcribed. Transcribed data were analysed inductively via Iterative Categorization.FindingsParticipants’ willingness to join pharmacological trials of medications for opioid dependence was affected by factors relating to study burden, study drug, study design, study population and study relationships. Participants worried that the trial drug might be worse than, or interfere with, their current treatment. They also misunderstood aspects of trial design despite the researchers’ explanations.ConclusionsRecruitment of participants for clinical trials of pharmacological interventions for illicit opioid use could be improved if researchers became better at explaining clinical trials to potential participants, dispelling misconceptions about trials and increasing trust in the research process and research establishment. A checklist of issues to consider when designing pharmacological trials for illicit opioid use is proposed.

Dropout in clinical trials of pharmacological treatment for methamphetamine dependence: the role of initial abstinence.

High rates of loss to follow-up represent a significant challenge to clinical trials of pharmacological treatments for methamphetamine (MA) use disorder. We aimed to estimate and test the relationship between achieving and maintaining abstinence in the initial weeks of study participation and subsequent retention in such trials, hypothesizing that participants able to achieve early abstinence would be less likely to drop out. Data from four randomized controlled trials (RCTs) of pharmacological treatments for MA use disorder were pooled and analyzed using a random-effects approach. All trials were conducted in the greater Los Angeles, CA, USA area. A total of 440 participants were included; trials were conducted between 2004 and 2014. Participants' ability to achieve a brief period of initial abstinence was measured as the number of MA-negative urine screens completed in the first 2weeks of the trials. Outcomes were the likelihood of dropout, i.e. missing two consecutive weeks of scheduled urine drug screens, and the number of days participants were retained in the trials. Study participants achieved an average of three (of six possible) negative urine screens during the first 2 weeks of the trials, 51% dropped out and the average number of days retained was 60 (of 90 maximum). Each additional negative urine screen achieved during the first 2 weeks of the study reduced multiplicatively the odds of dropout by 41% [odds ratio (OR) =0.59, 95% confidence interval (CI)=0.53, 0.66]. Abstinence was also a significant predictor of retention time; the hazard ratio for non-completion was 0.75 per additional negative urine screen (95% CI=0.71, 0.80). Participants in randomized controlled trials of pharmacological treatments for methamphetamine use disorder who are able to achieve a brief period of early abstinence are retained longer in the trials and are less likely to drop out overall.

Reporting of cross-over clinical trials of analgesic treatments for chronic pain: Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks systematic review and recommendations.

Cross-over trials are typically more efficient than parallel group trials in that the sample size required to yield a desired power is substantially smaller. It is important, however, to consider some issues specific to cross-over trials when designing and reporting them, and when evaluating the published results of such trials. This systematic review evaluated the quality of reporting and its evolution over time in articles of cross-over clinical trials of pharmacologic treatments for chronic pain published between 1993 and 2013. Seventy-six (61%) articles reported a within-subject primary analysis, or if no primary analysis was identified, reported at least 1 within-subject analysis, which is required to achieve the gain in power associated with the cross-over design. For 39 (31%) articles, it was unclear whether analyses conducted were within-subject or between-group. Only 36 (29%) articles reported a method to accommodate missing data (eg, last observation carried forward, n = 29), and of those, just 14 included subjects in the analysis who provided data from only 1 period. Of the articles that identified a within-subject primary analysis, 21 (51%) provided sufficient information for the results to be included in a meta-analysis (ie, estimates of the within-subject treatment effect and variability). These results and others presented in this article demonstrate deficiencies in reporting of cross-over trials for analgesic treatments. Clearer reporting in future trials could improve readers' ability to critically evaluate the results, use these data in meta-analyses, and plan future trials. Recommendations for proper reporting of cross-over trials that apply to any condition are provided.

The pregnant women as a drug orphan: a global survey of registered clinical trials of pharmacological interventions in pregnancy.

To undertake a survey of the world's clinical trial registries to provide current data on the number, nature, funding source and geographical distribution of pregnancy drug trials (PDT). Comprehensive analysis of WHO-certified clinical trial registries. Sixteen registries containing 301538 trials (168826 active in 2013-2014) were analysed to identify the numbers, location, funding sources, and areas of interest/development of PDTs. The percentage of PDTs varied from 0 to 7.4% across registries. Overall, just 0.32% (534) of all active registered studies were PDTs. The US registry (Clinicaltrials.gov) was the largest database, but contributed just 14% of all active PDTs. The majority of PDTs focused on anaesthesia/analgesia, preterm birth/tocolysis, labour induction, endocrine and hypertensive disorders. Less than 6% of active PDTs focused on maternal or fetal health as a specific primary outcome, and only 4.4% included a preplanned pharmacokinetic analysis of the trial medications. A third of all active PDTs involved repurposing of existing medicines for applications in pregnancy, whereas only three new investigational drugs had been developed for a pregnancy indication. Seven percent of all active PDTs identified were pharmaceutical industry-funded. Inter-disease comparisons identified a ~50-fold disparity in trial activity between pregnancy and other comparable areas. This study demonstrates unequivocally the marked under-representation of medication development, evaluation and safety trials in pregnancy. The likelihood that the current pharmaceutical landscape in pregnancy will improve in the foreseeable future is slim. Advocacy and increased awareness of the issue is necessary to achieve positive change. Pregnant women are significantly under-represented in global clinical drug trials.

Meta-analysis of assay sensitivity and study features in clinical trials of pharmacologic treatments for osteoarthritis pain.

To identify patient, study, and site factors associated with assay sensitivity in clinical trials of pharmacologic treatments for osteoarthritis (OA) pain. We examined associations between study characteristics and the standardized effect size (SES) in a database of 171 publicly available randomized clinical trials of pharmacologic treatment for OA pain. The included trials 1) evaluated oral, topical, or transdermal treatments, 2) had treatment durations of ≥7 days, 3) used parallel-group or crossover designs, 4) included patients with OA of the knee, hip, and/or hand, and 5) were placebo controlled and double blind. Crossover trials were excluded, because complete information was available for only 2 of 20 treatment conditions. There was considerable heterogeneity in the SES among the examined trials. A multiple meta-regression analysis indicated that trials with shorter treatment period durations and those that did not permit concomitant analgesics had significantly greater assay sensitivity. In univariate analyses of efficacious treatments, trials conducted outside North America and those with a minimum baseline pain intensity score (as defined by the inclusion criterion) of ≥40 (0-100 scale) had a significantly larger SES, although these relationships were not significant in the multiple meta-regression analysis. The analyses examined potentially modifiable correlates of study SES and showed that longer treatment durations and allowing concomitant analgesics in randomized clinical trials of OA pain are associated with reduced assay sensitivity. These data provide a foundation for investigating strategies to improve assay sensitivity and thereby decrease the likelihood of false-negative outcomes in randomized clinical trials of efficacious treatments for OA pain.

Review of clinical trials of pharmacologic interventions for cancer-related fatigue: focus on psychostimulants and steroids.

Cancer-related fatigue (CRF) is the most common and debilitating symptom in patients with cancer. Currently, there are very limited pharmacological interventions to effectively treat CRF. In this article, the authors review various pharmacological interventions for CRF and propose future direction for further research. Methylphenidate is the most studied pharmacological agent for the treatment of CRF. Various pharmacological studies have suggested benefit of corticosteroids, especially in terminally ill patients for a short period. However, recent systematic reviews, meta-analyses, and guidelines recommend caution to using pharmacological agents for CRF as evidence points the use of psychostimulants only in patients with moderate to severe fatigue with advanced cancer or those receiving active cancer therapy, with no evidence in their use in cancer patients who have completed active cancer therapy. Further research is needed.