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PubMed2026

Efficacy and Safety of the Dual Glucagon-Like Peptide-1 and Glucagon Receptor Agonist Mazdutide in Predominantly Chinese Adults With Obesity and/or Type 2 Diabetes: A Systematic Review and Meta-Analysis.

AIM: To assess the effects of mazdutide on body weight, HbA1c, metabolic outcomes, and adverse events in adults with overweight/obesity and/or type 2 diabetes (T2D). METHODS: This systematic review and meta-analysis included randomized controlled trials (RCTs) comparing mazdutide with placebo or active comparators in adults with overweight/obesity and/or T2D, identified through PubMed, Scopus, Web of Science, and ClinicalTrials.gov to 20 February 2026. Co-primary outcomes were percent change in body weight and change in HbA1c. Secondary outcomes included other weight-related and metabolic outcomes, as well as safety. Random-effects models were used to generate pooled mean differences (MDs) or risk ratios with 95% confidence intervals, and the certainty of the evidence (COE) was assessed using GRADE. RESULTS: Nine RCTs (N = 2292; most with low risk of bias) were included. In overweight/obesity without diabetes, mazdutide 3, 4, and 6 mg reduced body weight more than placebo (MDs -6.56%, -9.92%, and -11.1%, respectively; very low COE due to substantial heterogeneity and few trials). In T2D, mazdutide 4 and 6 mg reduced body weight and HbA1c versus placebo (moderate COE) and also outperformed dulaglutide for both outcomes. Mazdutide also improved waist circumference, lipids, liver enzymes, and uric acid levels. Gastrointestinal adverse events were more frequent, but serious adverse events and treatment discontinuation rates were comparable with those of the comparators. CONCLUSIONS: Mazdutide was associated with dose-dependent reductions in body weight and HbA1c, with broader metabolic benefits in predominantly Chinese adults with obesity and/or T2D. Longer-term, multi-ethnic studies are needed to confirm durability, generalizability, and cardiovascular safety.

Humans↗

PubMed2026

Early Analgesia for the Management of Acute Pancreatitis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: We aimed to evaluate the efficacy and safety of early analgesic interventions, particularly NSAIDs versus opioids, in reducing pain and improving clinical outcomes among adults with AP. METHODS: A systematic literature search was conducted across PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, Scopus, and ClinicalTrials.gov from database/registry inception to December 2025 to obtain relevant data. Randomized controlled trials involving adults aged 18 years or older diagnosed with AP, irrespective of the etiology and severity, who were administered analgesics (opioids, nonsteroidal anti-inflammatory drugs, cyclooxygenase-2 inhibitors, epidural anesthesia, local anesthesia, and paracetamol) and compared with placebo, conventional treatment, or another analgesic modality were included in this review. The primary outcome assessed was pain reduction. The secondary outcomes assessed were the need for rescue analgesia, length of hospital stay, complications (local and/or systemic), mortality, and adverse drug effects. Risk of bias was assessed using the Cochrane Risk of Bias tool 2.0. Effect estimates were pooled using a random-effects meta-analysis (DerSimonian-Laird approach), while nonpooled outcomes were summarized narratively. RESULTS: A total of 13 studies were included in the analysis. NSAIDs provided pain relief comparable to opioids, with a lower incidence of local complications (RR: 0.59, 95% CI: 0.37-0.94). No significant differences in the need for rescue analgesia (OR: 0.88, 95% CI: 0.33-2.35), length of hospital stay (MD: -2.68 d, 95% CI: -6.27 to 0.91), mortality (RR: 0.76, 95% CI: 0.19-3.05), and adverse drug effects (RR: 0.55, 95% CI: 0.17-1.76) were observed. However, the findings are limited by study bias and heterogeneity. CONCLUSION: Early analgesia with NSAIDs has efficacy and safety comparable to opioids in adults with AP, with the advantage of reducing local complications.

Humans↗

PubMed1992

[European Organization for Research and Treatment of Cancer (EORTC): objectives, realizations and future perspectives].

The objectives and realizations of the EORTC are described. The activities of the treatment branch are centralized at the EORTC Data Center located in Brussels. Approximately 6000 patients are included every year within clinical trials run by EORTC, involving active participation of more than 2000 physicians distributed in 350 institutions in Europe. 80% of patients included in EORTC trials are located in EC countries. Recently, new cooperative groups have been created in order to study cancers in elderly, tumors related to AIDS as well as invasive fungal infections in cancer patients. New perspectives and further developments include cost evaluations of new therapeutic modalities in oncology as well as quality of life of cancer patients. Furthermore, EORTC promotes the creation of a meta-analysis unit. A fellowship program to allow training of medical doctors and statisticians at the EORTC Data Center including scientists coming from Eastern and Central Europe is also encouraging. Every year, EORTC activities lead to at least 40 publications and more than 80 scientific communications allowing rapid diffusion of the results of researches performed.

Clinical Trials as Topic↗

PubMed1990

The existence of publication bias and risk factors for its occurrence.

Publication bias is the tendency on the parts of investigators, reviewers, and editors to submit or accept manuscripts for publication based on the direction or strength of the study findings. Much of what has been learned about publication bias comes from the social sciences, less from the field of medicine. In medicine, three studies have provided direct evidence for this bias. Prevention of publication bias is important both from the scientific perspective (complete dissemination of knowledge) and from the perspective of those who combine results from a number of similar studies (meta-analysis). If treatment decisions are based on the published literature, then the literature must include all available data that is of acceptable quality. Currently, obtaining information regarding all studies undertaken in a given field is difficult, even impossible. Registration of clinical trials, and perhaps other types of studies, is the direction in which the scientific community should move.

American Medical Association↗

PubMed1990

Format and conduct of consensus development conferences. Multi-nation comparison.

The consensus development conference method developed by the National Institutes of Health in the United States has been adopted and modified by a number of countries. Based on published articles and communication with representatives from each country, we examined whether the organization and conduct of these conferences in nine countries (United States, Canada, Denmark, Finland, the Netherlands, Norway, Sweden, Switzerland, and the United Kingdom) enhanced or detracted from achieving the stated conference goals and objectives. We conclude that improvements in the process by which consensus conferences are conducted may be warranted. More scientific methods for synthesizing literature, such as meta-analysis, should be used in developing inputs for the conference panel. Formalizing the decision-making processes through polling or other methods that allow for structured disagreement with parts of a consensus statement would potentially expand the range and type of issues that can be addressed in such conferences. Finally, countries should consider having the consensus statement written over a longer period of time than the traditional overnight session, which seems unlikely to promote clear thinking.

Consensus Statements as Topic↗

PubMed1990

[Critical study of gastroduodenal complications of corticotherapy].

Contrary to a still widely held belief, there is no explicative or clinical evidence that corticosteroid therapy has undesirable effects on the digestive tract causing, in particular, gastric or duodenal ulcers. From a meta-analysis of all published randomized, double-blind trials comparing corticosteroids with placebos, it appeared that the prevalence of peptic ulcers was 0.4% in the steroid group (n = 3335) and 0.3% in the placebo group (n = 3267), the difference being non-significant. Although a weak cause-effect relationship cannot be definitely excluded, these data demonstrate that it is unnecessary in practice to prescribe preventive anti-ulcer treatments to all patients receiving corticosteroids.

Adrenal Cortex Hormones↗

PubMedDate not supplied

[The role of beta-blockers in the preventive treatment of rupture of esophageal varices].

beta-blockers, mainly propranolol, have dramatically modified the treatment of portal hypertension. It has been demonstrated that it was possible to decrease portal pressure over a long period and to modify the natural history of gastrointestinal bleeding in cirrhosis. The prevention of first bleeding, or primary prophylaxis, should be distinguished from prevention of rebleeding, or secondary prevention, as these two situations pertain to different events. Concerning primary prophylaxis, at least five randomized controlled trials, (RCT), comparing beta-blockers and placebo, have been published. All the results are homogenous and their meta-analysis suggests that the incidence of first bleeding is significantly decreased but not that of death rate. Results of studies comparing propranolol and sclerotherapy are also available but we know that the results of more than 15 RCT testing sclerotherapy are debated. In secondary prevention, there are more than 10 RCT comparing beta-blockers versus placebo. Results of these RCT are heterogeneous. Meta-analysis suggests that the incidence of rebleeding is significantly decreased but not that of death rate. The results of 5 RCT comparing propranolol versus sclerotherapy are available. Whatever the trial, there was no significant differences between these two treatments. However, meta-analysis suggests that the bleeding incidence is decreased by sclerotherapy but this does not reach statistical significance. Finally, there are RCT with combined treatments: it seems that sclerotherapy plus propranolol is superior to sclerotherapy alone; however this result should be confirmed. In conclusion beta-blockers seem to bring about real changes in the prevention of digestive bleeding in cirrhosis. Their contribution is particularly appreciable in primary prevention of cirrhotic patients with large oesophageal varices.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗

PubMed1991

[Intermediary and substitution criteria in the development of anti-arrhythmia agents].

The traditional view that the suppression of arrhythmias (risk factor) after myocardial infarction can only be beneficial, has been queried by the results of the Cardiac Arrhythmia Suppression Trial (CAST) which showed increased mortality in two treatment groups. The methodology of trials of secondary prevention of myocardial infarction by antiarrhythmic agents partially explains why the reduction of anti-arrhythmias has come to be considered as a substitute for mortality in the assessment of drug efficacy. The authors define substitutive criteria and describe their three advantages (facility, correspondence, estimation). A meta-analysis of 6 trials of secondary prevention of myocardial infarction by Class I antiarrhythmics, in which the antiarrhythmic effect was evaluated (Holter monitoring) in parallel with mortality, shows that anti-arrhythmias were significantly reduced by nearly 60% (p = 10-8) whereas mortality remained unchanged (p = 0.41). A special graphic presentation of the results of these 6 trials shows that, even before the results of the CAST, it was clear that the suppression of antiarrhythmics was not a suitable substitutive end point for mortality.

Anti-Arrhythmia Agents↗

PubMed2026

Isometric Exercises for Tendinopathies: A Systematic Literature Review.

PURPOSE: Musculoskeletal disorders are among the most common reasons for medical consultation, with tendinopathies accounting for up to 30% of such presentations. Although exercise remains the cornerstone of management, the most effective modality continues to be debated. Eccentric exercise has long been the mainstay, but the role of isometric exercise in pain modulation and functional recovery remains unclear. This systematic review aims to evaluate the current evidence on the efficacy of isometric exercises in the management of tendinopathies across various anatomic sites. METHODS: A systematic search was conducted in PubMed, MEDLINE, Embase, and the Cochrane Library from inception to August 1, 2025. Eligible studies included randomized controlled trials and prospective or retrospective cohort studies assessing isometric exercise interventions for tendinopathy, with or without comparator groups. Case series and case reports were excluded. Data extracted included participant demographic characteristics, site of tendinopathy, symptom duration, treatment duration, adherence, and outcome measures such as Victorian Institute of Sports Assessment (A, P, or G), visual analog scale, Patient-Specific Functional Scale, 36 item short form health survey (SF-36), and EuroQol 5-Dimension questionnaires. Imaging outcomes (ultrasound or magnetic resonance imaging) were recorded where available. Methodological quality and risk of bias were assessed using the Cochrane Risk of Bias tool in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. FINDINGS: The search identified 304 articles, of which 13 randomized controlled trials met the inclusion criteria, encompassing 336 participants (40% female). Tendinopathy sites included the patellar (n = 4), Achilles (n = 3), lateral elbow (n = 2), rotator cuff (n = 2), wrist extensor (n = 1), and gluteal (n = 1) tendons. Median symptom duration was 23 months (interquartile range, 3-51 months). Intervention periods ranged from a single 45-minute session to 4-month exercise programs. Treatment adherence was high initially (nearly 100%) but declined over time, with 70% of participants in the isometric and 58% in the control (isotonic) groups completing ≥80% of sessions. Pain reduction and functional improvement were statistically significant in only 3 studies. Imaging-based outcomes were inconsistently reported, and study heterogeneity precluded meta-analysis. Overall methodological quality was rated as good in 3 studies and poor in 10. IMPLICATIONS: Current evidence provides limited support for the superiority of isometric exercise in tendinopathy management. Although isometric regimens appear tolerable and may confer short-term analgesic benefits, their long-term efficacy relative to eccentric or isotonic protocols remains uncertain. Future research should prioritize standardized outcome measures, longer follow-up, and uniform diagnostic criteria to strengthen the evidence base for exercise prescription in tendinopathies.

Humans↗

PubMed1991

Advances in data assessment. Application to the etiology of nausea reported during chemotherapy, concerns about significance testing, and opportunities in clinical trials.

Typical inferential statistical procedures, such as the t-test and analysis of variance, compare differences in mean values of variables. This approach can sometimes obscure rather than illuminate research data. Here we present and discuss alternative data analytic techniques. Potential advantages of box plots over conventional t-tests for understanding data are shown by comparing the area under high and low frequencies from spectral curves of autonomic changes following chemotherapy treatment. Typical t-tests provide information regarding statistical significance in terms of the differences in group means; box plots and related exploratory techniques provide information regarding the characteristics of the distributions within the groups as well as examination of potential outliers. Multivariate analysis of variance (MANOVA) and other multivariate techniques are commonly used to deal with potentially complex data sets with multiple outcome measures. The potential advantages of visual clustering techniques such as star plots, Chernoff faces, and Andrew's Function Plots are demonstrated by examining changes in facial pallor caused by chemotherapy-induced nausea and vomiting. Typical MANOVA approaches can identify potential differences in mean values between groups; visual clustering approaches do this by graphically presenting complex interrelationships for individual cases. This approach enhances the visual interpretation of potential interactions that would be obscured by simply focusing on overall mean values. Preliminary data from a meta-analysis on the effect of metoclopramide on chemotherapy-induced vomiting demonstrates the potential uses and advantages of this summary technique over simple tabular summaries. We found significant relationships between the effect size of the drug and variables such as the year of study publication and whether the publication was an article or an abstract. While none of these techniques are meant to replace traditional inferential statistics, they offer advantages in terms of data exploration and understanding relationships within data sets that are not clearly addressed by other methods. They are potentially valuable alternatives worthy of exploration. Finally, we discuss issues of interim analyses and multiple endpoint assessment for clinical trials.

Antineoplastic Agents↗

PubMed2026

Effects of Family-Based Intervention for Childhood Obesity on Parental and Offspring Outcomes: A Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVES: Childhood obesity is a global public health issue with strong familial and intergenerational transmission. However, existing syntheses often overlook the active role of parents and fail to assess outcomes beyond the child. This systematic review and meta-analysis specifically investigate the effects of family-based interventions, which position parents as active co-agents of change, on health outcomes for both children with obesity and their parents. METHODS: A systematic review and meta-analysis were conducted. Six databases were searched for randomized controlled trials (RCTs) targeting children with obesity and at least one family member. Primary outcomes were children's BMI z-score and parental BMI; secondary outcomes included other adiposity measures and dietary behaviors. Outcomes for both children and parents were synthesized. Subgroup analyses were conducted based on intervention characteristics. Risk of bias was assessed using RoB 2, and evidence certainty was evaluated using GRADE. RESULTS: Twenty RCTs with 1740 participants were included in the meta-analysis. The interventions demonstrated a significant reduction in children's BMI z-score. Additional benefits were observed for long-term BMI z-score and percentage of total body fat. The most effective interventions commonly integrate health education, behavioral strategies, and motivational support. Subgroup analyses indicated that interventions positioning parents as active co-participants, rather than mere supporters, yielded larger effects. However, no significant effects were found on parental BMI. CONCLUSION: This study demonstrates that family-based interventions can confer significant benefits for children with obesity. Their success hinges on strategically framing parents as active co-agents and integrating motivational strategies.

Humans↗

PubMed1985

Clinical trials of patient education for chronic conditions: a comparative meta-analysis of intervention types.

Results are reported of a quantitative synthesis of 70 published evaluations of educational programs for people with long-term health problems and regimens that include drugs. Study methods and interventions are rated according to methodological and educational principles, respectively. The differential effects achieved by seven types of educational techniques are compared. The largest effect-size values (in standard deviation units) for knowledge were in three empirically distinct and homogeneous groups of studies--those testing one-to-one counseling, group education, and one or both of these strategies in combination with audiovisual materials (range = 0.73-1.13). Homogeneous subgroups of behavioral studies (grouped according to type of intervention) were found within the studies measuring drug utilization errors, but the overall group was homogeneous. The absence of significant differences among the subgroups precluded subgroup comparison. The overall effect size was 0.37, indicating substantially decreased drug errors. Analyses of study and other intervention characteristics found the educational rating score to be the strongest predictor of effect size for both knowledge and drug errors. Patient package inserts were predictors of lower effect sizes.

Audiovisual Aids↗

PubMed1991

Ambulatory blood pressure monitoring in clinical trials.

Monitoring ambulatory blood pressure, instead of taking pressure readings in hospital, avoids the so-called white-coat effect and allows more readings to be obtained over a longer period of time. It improves the accuracy of the blood pressure estimate and increases the statistical power of therapeutic trials for hypertension. Subjects with white-coat or office hypertension can be detected by ambulatory blood pressure monitoring and excluded from clinical trials. In 23 studies, including a total of 3304 normotensive subjects, the 24-h ambulatory blood pressure averaged 118/72 mmHg; the daytime and night-time pressures were 123/76 mmHg and 106/64 mmHg, respectively. If the mean plus two standard deviation (s.d.) interval is considered the upper limit of normal, the meta-analysis suggested that hypertension may be suspected if the 24-h pressure exceeds 129/87 mmHg, or if the daytime or night-time pressures are higher than 146/91 mmHg or 127/79 mmHg, respectively. On balance, most studies suggest that placebo effects on blood pressure are not observed when blood pressure is measured with ambulatory recorders. If confirmed, this observation indicates that it is possible to simplify the design of trials in the field of hypertension. Ambulatory blood pressure readings should be obtained with properly validated monitors. If the recordings are of sufficient quality, editing does not increase the precision of the subsequent statistical analyses. The statistical analyses should account for diurnal rhythms, and subject and treatment effects.

Antihypertensive Agents↗

PubMed2026

Physical therapy for urinary incontinence in older women: A systematic review.

BACKGROUND: Urinary incontinence is highly prevalent among older women, affecting more than one-third of this population and significantly impairing quality of life, independence, and healthcare utilization. Older women often present with complex needs that may require broader rehabilitation strategies. METHODS: This systematic review evaluated randomized controlled trials of physical therapy interventions for urinary incontinence in older women. PubMed, Embase, and Scopus were searched to October 2025. Eligible studies included women ≥60 years and assessed interventions such as Pelvic floor muscle training (PFMT), bladder training, Yoga, Pilates, general resistance training, electrical stimulation, or multimodal programs. Methodological quality was appraised using the PEDro scale, and random-effects meta-analysis was performed where appropriate. RESULTS: Twenty studies involving 2002 women across 13 countries were included. Eleven trials were rated as good quality and nine as fair. Meta-analysis demonstrated that PFMT significantly reduced urinary incontinence severity compared with usual care (SMD = -1.27, 95% CI: -2.18 to -0.36, p = 0.006). Multimodal programs combining PFMT with mobility, strength, or fall-prevention training also showed significant benefits (SMD = -0.98, 95% CI: -1.60 to -0.36, p = 0.002). Comparative studies indicated that PFMT was similarly effective to Yoga and Pilates, while adjuncts such as general resistance training or tibial nerve stimulation provided additional improvements. CONCLUSION: Physical therapy interventions, particularly PFMT and multimodal programs, are effective in reducing urinary incontinence severity and improving functional outcomes among older women. These findings support prioritizing physical therapy as an important management strategy, with multimodal approaches offering added value for enhancing functional independence and fall prevention.

Humans↗

PubMed1988

Prevention of venous thromboembolism in general surgical patients. Results of meta-analysis.

The results of randomized clinical trials evaluating commonly used methods of deep vein thrombosis (DVT) prophylaxis in moderate- and high-risk general surgery patients were pooled to obtain an unbiased estimate of efficacy and risks. Low-dose heparin (LDH), dextran, heparin-dihydroergotamine (HDHE), intermittent pneumatic compression (IPC), and graded elastic stockings significantly reduced the incidence of DVT; aspirin was ineffective. In contrast to other methods, elastic stockings have not been adequately studied to determine their value in reducing DVT in high-risk patients, such as those with malignancy. Only LDH and dextran were studied in numbers of patients sufficient for demonstrating a clear reduction in pulmonary embolism (PE). In comparison studies, LDH was superior to dextran in preventing DVT, but the two agents were equivalent in protecting against PE. Although HDHE was marginally better than LDH in preventing DVT, it appeared to have no advantage in preventing PE--at least in moderate-risk patients. The incidence of major hemorrhage was not increased with any of the prophylactic agents. However, wound hematomas occurred significantly more frequently with LDH, an effect noted in the pooled data from double-blind and open trials. In comparison trials with LDH, both dextran and HDHE had significantly fewer wound hematomas. LDH administered every 8 hours appeared more effective in reducing DVT than LDH administered every 12 hours; the incidence of wound hematomas was equivalent with both regimens.

Adult↗

PubMed1991

Update on calcium antagonists in cerebrovascular diseases.

Clinical management of patients affected by subarachnoid hemorrhage has been modified by the use of nimodipine. Although no differences in overall neurologic outcome and rates of symptomatic spasm have been observed between nimodipine and control patients, severity of permanent neurologic deficits consequent to cerebral vasospasm is reduced in the former. On the other hand, clinical trials with nimodipine in ischemic stroke did not substantiate the expected neurologic benefits. A meta-analysis of the two phase IV studies published thus far shows that of 350 patients examined, mortality rate was 11.5% and 19% in subjects given nimodipine and placebo, respectively (n.s.). Cerebral death accounted for 30% of cases in both groups, whereas a lower percentage of cardiac and pulmonary fatal events were observed among nimodipine-treated subjects. Moreover, neurologic outcome of survivors was not significantly different. These results may be associated with the notion that the voltage-operated channel blockade exerted by calcium antagonists is only a part of the complex events leading to the enhancement of calcium ion intracellular concentration as a "common final pathway." However, difficulties encountered in planning clinical trials in acute ischemic stroke also might explain the lack of conclusive results. The feasibility of randomization of an adequate sample of patients and of very early therapeutic intervention after stroke onset are discussed.

Brain Ischemia↗

PubMed2026

Efficacy and Safety of Mechanical Insufflation-Exsufflation in Invasively Ventilated Critically Ill Adults: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Mechanical insufflation-exsufflation (MI-E) is increasingly used in invasively ventilated adults in the intensive care unit (ICU), yet its therapeutic efficacy and safety remain uncertain due to inconsistent evidence. AIM: To synthesize evidence on the clinical efficacy and safety of MI-E in this population and to examine methodological and clinical heterogeneity underlying reported outcomes. STUDY DESIGN: A systematic review and meta-analysis of randomized studies (including RCTs and randomized crossover trials), conducted following PRISMA guidelines, with risk of bias assessed using the Cochrane risk-of-bias tool. RESULTS: Five randomized controlled trials involving 310 patients were included. Meta-analysis showed that mechanical insufflation-exsufflation (MI-E) significantly increased sputum clearance (SMD = 0.63, 95% CI, 0.32-0.93; p < 0.00011; I2 = 38%) without affecting oxygenation (MD = 0.28, 95% CI, -0.53 to 1.09; p = 0.50; I2 = 9%). Data on respiratory mechanics, ventilation duration and ICU stay could not be pooled. No serious adverse events were reported. CONCLUSIONS: MI-E significantly improves sputum clearance in invasively ventilated critically ill adults, with no severe adverse events reported in the included studies. Its effects on other outcomes remain inconclusive due to limited data and heterogeneity. Standardized protocols and larger trials are needed. RELEVANCE TO CLINICAL PRACTICE: Clinicians may consider MI-E as an adjunct for respiratory secretion management. Application should be guided by structured patient assessment and individualized parameter adjustment. Future research should standardize interventions and target well-defined patient subgroups to inform clear practice guidelines. TRIAL REGISTRATION: The review protocol was registered in the International Prospective Register of Systematic Reviews, with registration number CRD42023403299.

Humans↗

PubMed2026

Risk-Benefit of Phase 2 Monotherapy Trials in Adult Solid Cancers: A Systematic Review and Meta-Analysis.

Phase 2 (and phase 1 dose expansion, which we label phase 2 for the purposes of this study) cancer trials are the first direct tests of a new drug's efficacy. Because efficacy evidence is lacking, the therapeutic status of drug administration during ethical review is uncertain. We compared the efficacy and safety of cancer monotherapies in phase 2 with phase 3, where clinical equipoise underwrites a therapeutic status for drug administration. In this systematic review and meta-analysis, we searched Clinicaltrials.gov for phase 2 and 3 investigational monotherapy drug trials in six solid malignancies, with primary completion dates 2015-2020, inclusive. Two independent reviewers completed data extraction. Effects were estimated using an inverse-variance weighted random-effects model meta-analysis of proportions using the R package meta. We analyzed 130 phase 2 and 52 phase 3 trial arms, enrolling 6665 and 18,694 patients. The pooled objective response rate was 7% (95% CI 5%-11%) in phase 2 versus 24% in phase 3 (95% CI 17%-31%; p < 0.0001). The median PFS and OS were shorter in phase 2 compared to phase 3 (3.23 vs. 5.43 months, p < 0.0001; 9.46 vs. 14.44 months, p = 0.0001). The pooled rate of drug-related grade 3-4 adverse events was 30% (95% CI 23%-37%) in phase 2 and 25% (95% CI 19%-32%) in phase 3. Monotherapies delivered in phase 2 cancer trials present diminished risk-benefit compared with phase 3 and align with historic estimates for phase 1. Though there may be exceptions, risks for drug administration in phase 2 should generally be justified by appeals to research rather than therapeutic value.

Humans↗