Results on patient-reported outcomes are underreported in summaries of product characteristics for new drugs.

BACKGROUND: Summaries of product characteristics (SmPCs) are regulatory documents published upon drug approval. They should report all relevant study data and advise how to use drugs safely and effectively. Patient-reported outcomes (PROs) are increasingly used in clinical trials to incorporate the patient perspective-SmPCs should thus adequately report PROs. In Germany, new drugs undergo mandatory early benefit assessment. Pharmaceutical companies submit dossiers containing all evidence; the subsequent dossier assessments focus on patient-relevant outcomes and comprehensively report PROs. OBJECTIVE: The primary aim was to investigate to what extent PROs recorded as outcomes in clinical trials of new drugs are reported in SmPCs. METHODS: We analysed dossier assessments with randomized controlled trials (RCTs) of new drugs entering the market between 01/2014 and 07/2018 and the corresponding SmPCs, and compared PRO reporting in both document types. For this purpose, we evaluated dossier assessment characteristics (e.g. drug name, indication, disease category) and study characteristics (e.g. evaluable PROs available?). PROs were divided into symptoms and health-related quality of life (HRQoL). SmPCs were screened to identify RCTs. We conducted 3 main evaluation steps: (1) Did the RCT included in the dossier assessment contain evaluable PROs? (2) If yes, was the RCT included in the SmPC? (3) If yes, were the PROs reported in the SmPC? Results are presented descriptively. RESULTS: 88 dossier assessments including 143 RCTs on 72 drugs were considered: 109 (76.2%) RCTs included evaluable PROs, of which 89 were included in SmPCs. 38 RCTs (42.7%) investigated oncologics, 18 (20.2%) anti-infectives, and 33 (37.1%) other drugs. The RCTs considered symptoms more often than HRQoL (82 vs. 66 RCTs). In SmPCs, PROs were reported for 41 RCTs (46.1%), with a slightly higher reporting rate for RCTs considering HRQoL (43.9%) than for RCTs considering symptoms (41.5%). In oncologic indications, PROs were reported for 36.7% of RCTs considering HRQoL and 33.3% of RCTs considering symptoms. In infectious diseases, the rates were 21.4% (symptoms) and 0% (HRQoL), and for other diseases about 60% (symptoms) to 70% (HRQoL). CONCLUSION: Even though a large amount of PRO data on new drugs is available from clinical trials included in SmPCs, the corresponding results are underreported.

Study filters for non-randomized studies of interventions consistently lacked sensitivity upon external validation.

BACKGROUND: Little evidence is available on searches for non-randomized studies (NRS) in bibliographic databases within the framework of systematic reviews. For instance, it is currently unclear whether, when searching for NRS, effective restriction of the search strategy to certain study types is possible. The following challenges need to be considered: 1) For non-randomized controlled trials (NRCTs): whether they can be identified by established filters for randomized controlled trials (RCTs). 2) For other NRS types (such as cohort studies): whether study filters exist for each study type and, if so, which performance measures they have. The aims of the present analysis were to identify and validate existing NRS filters in MEDLINE as well as to evaluate established RCT filters using a set of MEDLINE citations. METHODS: Our analysis is a retrospective analysis of study filters based on MEDLINE citations of NRS from Cochrane reviews. In a first step we identified existing NRS filters. For the generation of the reference set, we screened Cochrane reviews evaluating NRS, which covered a broad range of study types. The citations of the studies included in the Cochrane reviews were identified via the reviews' bibliographies and the corresponding PubMed identification numbers (PMIDs) were extracted from PubMed. Random samples comprising up to 200 citations (i.e. 200 PMIDs) each were created for each study type to generate the test sets. RESULTS: A total of 271 Cochrane reviews from 41 different Cochrane groups were eligible for data extraction. We identified 14 NRS filters published since 2001. The study filters generated between 660,000 and 9.5 million hits in MEDLINE. Most filters covered several study types. The reference set included 2890 publications classified as NRS for the generation of the test sets. Twelve test sets were generated (one for each study type), of which 8 included 200 citations each. None of the study filters achieved sufficient sensitivity (≥ 92%) for all of the study types targeted. CONCLUSIONS: The performance of current NRS filters is insufficient for effective use in daily practice. It is therefore necessary to develop new strategies (e.g. new NRS filters in combination with other search techniques). The challenges related to NRS should be taken into account.

Effectiveness and Cost-Effectiveness of Tuina for Chronic Neck Pain: A Randomized Controlled Trial Comparing Tuina with a No-Intervention Waiting List.

OBJECTIVE: To evaluate whether tuina is more effective and cost-effective in reducing pain compared to no intervention in patients with chronic neck pain. DESIGN: Single-center randomized two-armed controlled trial. SETTING: University outpatient clinic specialized in Integrative Medicine. SUBJECTS: Outpatients with chronic neck pain were randomly allocated to tuina or no intervention. INTERVENTION: Six tuina treatments within 3 weeks. OUTCOME MEASURES: The primary outcome was the mean neck pain intensity during the previous 7 days on a visual analogue scale after 4 weeks (VAS, 0-100 mm, 0 = no pain, 100 = worst imaginable pain). Secondary outcomes included Neck Pain and Disability Scale (NPDS), Neck Disability Index (NDI), health-related quality of life (12-item quality-of-life questionnaire [SF-12]), medication intake, and cost-effectiveness after 4 and 12 weeks. Statistical analysis included analysis of covariance adjusted for baseline values and a full economic analysis from a societal perspective. RESULTS: Altogether, 92 outpatients were included (46 in both groups, 87% female, mean age 45.4 [standard deviation ±9.7], and mean VAS 57.7 ± 11.5). Tuina treatment led to a clinically meaningful reduction in neck pain intensity (group differences, 4 weeks: -22.8 mm [95% confidence interval, -31.7 to -13.8]; p < 0.001 and 12 weeks: -17.9 mm [-27.1 to -8.8], p < 0.001). No serious adverse events were observed. Total costs as well as quality-adjusted life years (QALYs) did not differ significantly between the groups. When taking group differences into account independently from their statistical significance, costs per QALY gained (incremental cost-effectiveness ratio) would range within a cost-effective area from €7,566 (for costs €10.28 per session) to €39,414 (cost €35 per session). CONCLUSION: An additional treatment with six tuina sessions over 3 weeks was effective, safe and relatively cost-effective for patients with chronic neck pain. A future trial should compare tuina to other best care options.

Effectiveness of app-based self-acupressure for women with menstrual pain compared to usual care: a randomized pragmatic trial.

BACKGROUND: Primary dysmenorrhea is common among women of reproductive age. Nonsteroidal anti-inflammatory drugs and oral contraceptives are effective treatments, although the failure rate is around 20% to 25%. Therefore additional evidence-based treatments are needed. In recent years, the use of smartphone applications (apps) has increased rapidly and may support individuals in self-management strategies. OBJECTIVE: We aimed to investigate the effectiveness of app-based self-acupressure in women with menstrual pain. MATERIALS AND METHODS: A 2-armed, randomized, pragmatic trial was conducted from December 2012 to April 2015 with recruitment until August 2014 in Berlin, Germany, among women aged 18 to 34 years with self-reported cramping pain of 6 or more on a numeric rating scale (NRS) for the worst pain intensity during the previous menstruation. After randomization, women performed either app-based self-acupressure (n = 111) or followed usual care only (n = 110) for 6 consecutive menstruation cycles. The primary outcome was the mean pain intensity (NRS 0-10) on the days with pain during the third menstruation. Secondary outcomes included worst pain intensity during menstruation, duration of pain, 50% responder rates (reduction of mean pain by at least 50%), medication intake, sick leave days, and body efficacy expectation assessed at the first, second, third, and sixth menstruation cycles. RESULTS: We included 221 women (mean age, 24.0 years; standard deviation [SD], 3.6 years). The mean pain intensity difference during the third menstruation was statistically significant in favor of acupressure (acupressure: 4.4; 95% confidence interval [CI], 4.0-4.7; usual care 5.0; 95% CI, 4.6-5.3; mean difference -0.6; 95% CI, - 1.2 to -0.1; P = .026). At the sixth cycle, the mean difference between the groups (-1.4; 95% CI, -2.0 to -0.8; P < .001) reached clinical relevance. At the third and sixth menstruation cycles, responder rates were 37% and 58%, respectively, in the acupressure group, in contrast to 23% and 24% in the usual care group. Moreover, the worst pain intensity (group difference -0.6; 95% CI, -1.2 to -0.02; and -1.4; 95% CI, -2.0 to -0.7), the number of days with pain (-0.4; 95% CI, -0.9 to -0.01; and -1.2; 95% CI, -1.6 to -0.7) and the proportion of women with pain medication at the third and sixth menstruation cycles (odds ratio [OR], 0.5; 95% CI, 0.3-0.9] and 0.3 (95% CI, 0.2-0.5) were lower in the acupressure group. At the third cycle, hormonal contraceptive use was more common in the usual care group than in the acupressure group (OR, 0.5; 95% CI, 0.3-0.97) but not statistically significantly different at the sixth cycle (OR, 0.6; 95% CI, 0.3-1.1]). The number of sick leave days and body efficacy expectation (self-efficacy scale) did not differ between groups. On a scale of 0 to 6, mean satisfaction with the intervention at the third cycle was 3.7 (SD 1.3), recommendation of the intervention to others 4.3 (1.5), appropriateness of acupressure for menstrual pain 3.9 (1.4), and application of acupressure for other pain 4.3 (1.5). The intervention was safe, and after the sixth cycle, two-thirds of the women (67.6%) still applied acupressure on all days with pain. CONCLUSION: Smartphone app-delivered self-acupressure resulted in a reduction of menstrual pain compared to usual care only. Effects were increasing over time, and adherence was good. Future trials should include comparisons with other active treatment options.

Association of individual and neighbourhood socioeconomic status with physical activity and screen time in seventh-grade boys and girls in Berlin, Germany: a cross-sectional study.

OBJECTIVES: Few studies have explored the impact of neighbourhood socioeconomic status (SES) on health behaviours in youths in Germany. Our aim was to investigate the association of individual and neighbourhood SES with physical activity (PA) and screen time (ST) in students aged 12-13 years in Berlin. DESIGN: Cross-sectional study. SETTING: Secondary schools (high schools and integrated secondary schools) in Berlin, Germany. PARTICIPANTS: A total of 2586 students aged 12-13 years (seventh grade). MAIN OUTCOME MEASURES: Sociodemographics, anthropometric data and health behaviours were assessed by self-report during classes. Primary outcome was the association of individual and neighbourhood SES with meeting daily PA and exceeding daily ST recommendations. Students' characteristics were described with means or percentages. Comparisons were performed using generalised linear mixed model yielding ORs with 95% CIs. RESULTS: Mean (±SD) age was 12.5±0.5 years, 50.5% were girls and 34.1% had a migrant background. When adjusting for individual covariates, associations of low versus high individual SES were 0.85 (0.48; 1.52) for PA and 2.08 (1.26; 3.43) for ST. Associations of low versus high neighbourhood SES were 1.76 (1.12; 2.75) for PA and 1.54 (1.10; 2.17) for ST. After additional adjustment for school type and school neighbourhood SES, associations comparing low versus high individual and neighbourhood SES were attenuated for PA (individual SES 0.74 (0.41; 1.33) and neighbourhood SES 1.51 (0.93; 2.46)) and ST (individual SES 1.88 (1.12; 3.14) and neighbourhood SES 1.40(0.98; 2.00). CONCLUSIONS: Lower individual and neighbourhood SES were associated with higher ST. Lower neighbourhood but not individual SES was associated with higher PA. After consideration of school type and school neighbourhood SES associations were attenuated and became insignificant for the relationship between neighbourhood SES, PA and ST. Further research is warranted to unravel the complex relationships between individual SES, neighbourhood SES and school environment to develop more targeted health promotion strategies in the future.

Acupuncture in Patients with Allergic Asthma: A Randomized Pragmatic Trial.

BACKGROUND: Although the available evidence is insufficient, acupuncture is used in patients suffering from chronic asthma. The aim of this pragmatic study was to investigate the effectiveness of acupuncture in addition to routine care in patients with allergic asthma compared to treatment with routine care alone. METHODS: Patients with allergic asthma were included in a randomized controlled trial and randomized to receive up to 15 acupuncture sessions over 3 months or to a control group receiving routine care alone. Patients who did not consent to randomization received acupuncture treatment for the first 3 months and were followed as a cohort. All trial patients were allowed to receive routine care in addition to study treatment. The primary endpoint was the asthma quality of life questionnaire (AQLQ, range: 1-7) at 3 months. Secondary endpoints included general health related to quality of life (Short-Form-36, SF-36, range 0-100). Outcome parameters were assessed at baseline and at 3 and 6 months. RESULTS: A total of 1,445 patients (mean age 43.8 [SD 13.5] years, 58.7% female) were randomized and included in the analysis (184 patients randomized to acupuncture and 173 to control, and 1,088 in the nonrandomized acupuncture group). In the randomized part, acupuncture was associated with an improvement in the AQLQ score compared to the control group (difference acupuncture vs. control group 0.7 [95% confidence interval (CI) 0.5-1.0]) as well as in the physical component scale and the mental component scale of the SF-36 (physical: 2.5 [1.0-4.0]; mental 4.0 [2.1-6.0]) after 3 months. Treatment success was maintained throughout 6 months. Patients not consenting to randomization showed similar improvements as the randomized acupuncture group. CONCLUSIONS: In patients with allergic asthma, additional acupuncture treatment to routine care was associated with increased disease-specific and health-related quality of life compared to treatment with routine care alone.

Long-term effectiveness of a combined student-parent and a student-only smoking prevention intervention among 7th grade school children in Berlin, Germany.

BACKGROUND AND AIMS: In Germany, the smoking prevalence among adolescents is among the highest in Europe. Our aim was to evaluate the long-term effectiveness of a combined student-parent and a student-only smoking prevention programme to reduce the smoking prevalence among 7th grade students in Berlin. DESIGN: Three-armed cluster-randomized controlled trial (RCT). Schools as cluster units were randomized into (i) student intervention, (ii) combined student-parent intervention or (iii) control group, with follow-up after 12 and 24 months. SETTING: High schools and integrated secondary schools in Berlin, Germany. PARTICIPANTS: Seventh grade students aged 11-16 years. We included 47 schools, 161 classes and 2801 students [50.1% girls, mean age ± standard deviation (SD) = 13.0 ± 0.6 years]. MEASUREMENTS: The primary outcome was self-reported regular smoking (at least one cigarette per day) after 24 months (point prevalence). Further self-reported outcomes were other smoking behaviours as well as parental rules and attitudes towards smoking. Comparisons were calculated as odds ratios (OR) with 95% confidence intervals (CI). FINDINGS: At baseline, 2.3% of the students reported that they smoked regularly. After 24 months, 7.8% and 7.0% were regular smokers in the student-only intervention and the student-parent intervention, respectively, compared with 10.1% in the control group. The OR for being a regular smoker was 0.81 (0.34-1.92) for the student-parent intervention versus control, 0.95 (CI = 0.41-2.22) for the student-only intervention versus control and 0.85 (0.38-1.89) for student-parent intervention versus student-only intervention. CONCLUSION: A combined student-parent smoking prevention intervention delivered via secondary schools in Berlin, Germany did not result in a statistically significant reduction in regular smoking compared with a control group or a student-only intervention. The student-only intervention did not result in a significant reduction in regular smoking compared with the control group.

Measurement of ß-hydroxybutyrate in cats with nonketotic diabetes mellitus, diabetic ketosis, and diabetic ketoacidosis.

Diabetic ketoacidosis (DKA) is a life-threatening complication of diabetes mellitus (DM). The standard method of detection of ketone bodies is the dipstick method, which detects semiquantitatively acetoacetate, but not ß-hydroxybutyrate (ß-HB). The objectives of the current study were to assess the diagnostic utility of ß-HB to diagnose diabetic ketosis (DK) and DKA in cats and to establish a cut-off value for the diagnosis of DKA. Sixty-two cats were included in the study. Eleven cats were healthy (group 1); in the remainder of cats (51), a diagnosis of DM was based on hyperglycemia, glucosuria, and increased fructosamine concentrations. Nineteen of 51 cats suffered from nonketotic diabetes mellitus (group 2). In 11 cats, plasma ketone bodies were detected with the dipstick method (diabetic ketosis, group 3). In 21 cats, plasma ketone bodies and metabolic acidosis were present (DKA, group 4). Plasma ß-HB was measured in all cats by an enzymatic method (spectrophotometry). A cut-off value for the diagnosis of DKA was calculated based on the receiver operating characteristic curve. In healthy cats, the ß-HB concentration ranged from 0 to 0.1 mmol/l; in cats of group 2, from 0 to 0.9 mmol/l (median: 0.1 mmol/l); in cats of group 3, from 0.6 to 6.8 mmol/l (median: 1.7 mmol/l); and in cats of group 4, from 3.8 to 12.2 mmol/l (median: 7.9 mmol/l). A cut-off value of 2.4 mmol/l revealed 100% sensitivity and 87% specificity to diagnose DKA. Beta-hydroxybutyrate is a useful parameter for the diagnosis of diabetic ketosis and DKA in cats.

Validation of a portable hand-held whole-blood ketone meter for use in cats.

BACKGROUND: Urinary dipsticks are the most frequent method used for screening of ketones in animals, but this method has many drawbacks. In human medicine, portable meters that measure ketones in whole blood have largely replaced urinary dipsticks. OBJECTIVE: The aim of this prospective study was to validate a portable whole-blood ketone meter for use in cats. METHODS: Sixty-two cats (11 clinically healthy, 51 with diabetes mellitus) were included in the study. The concentration of ß-hydroxybuyrate (ß-HB) was measured in venous and capillary blood with a hand-held ketone meter (Precision Xceed; assay range 0-8 mmol/L) and compared with a spectrophotometric method. Precision, accuracy, and the effects of hematocrit and anticoagulants were evaluated. RESULTS: Between-run precision using low- and high-concentration control solutions was 8.1% and 2.6%, respectively; within-run coefficient of variation determined using 12 feline blood samples was 2.8%. In the 62 cats, ß-HB concentrations measured with the portable ketone meter ranged from 0-7.4 mmol/L (median 0.9 mmol/L). When ß-HB concentrations measured by the portable meter were < 4.0 mmol/L there was good agreement with the reference method, but concentrations > 4.0 mmol/L were lower than those obtained by the reference method in 20 of 24 cats (83%). There was good correlation between capillary and venous measurements. Results were not affected by hematocrits from 0.17 to 0.50 L/L, but EDTA was not a suitable anticoagulant. CONCLUSION: Measurement of ß-HB concentration in peripheral or capillary blood by an easy-to-use portable ketone meter was suitable for detecting ketonemia in cats. Underestimation of ß-HB concentration was observed at higher values, but results were sufficiently high to aid in diagnosing diabetic ketoacidosis.