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Background Mantle cell lymphoma (MCL) is an aggressive lymphoma with a dismal prognosis because of numerous relapses. Because the most promising results have been obtained with immunochemotherapy followed by autologous cell stem transplantation (ASCT), we evaluated the efficacy of yttrium-90 ibritumomab ( 90 Y-IT) consolidation after such an intensive treatment. Patients and Methods We retrospectively assessed 57 patients affected by intermediate or high-risk MCL in complete remission (CR) or partial remission (PR) after 3 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [Oncovin], prednisolone) plus 3 cycles of R-DHAP (dexamethasone, cytarabine [Ara-C], cisplatin [platinum]) followed by ASCT and additional consolidation treatment with 90 Y-IT in 28 cases. All patients underwent 2 years of rituximab maintenance. Results After ASCT, 94% achieved CR and 4% achieved PR. The median follow-up was 6.2 years (range, 1.8-9.7 years). Treatment intensification was well tolerated and led to a significantly longer response duration in comparison to standard treatment. In contrast to the historical cohort, the addition of 90 Y-IT seems to overcome important risk factors such as Mantle Cell Lymphoma International Prognostic Index (MIPI) score and bone marrow infiltration. Conclusion In the present retrospective analysis, immunochemotherapy followed by ASCT resulted in a very high response rate, and subsequent 90 Y-IT consolidation significantly reduced the number of relapses and increased survival, suggesting that 90 Y-IT consolidation might be a valid option in first-line treatment. However, a prospective confirmatory trial is warranted.

Introduction. BC is a potentially curable cancer condition, with more favorable outcomes with avoidance of CIN. Peg is the standard of care for the prevention of CIN, but does not fully prevent CIN (Masuda 2015). Plin is a novel, small molecule, non-G-CSF agent, given as a single dose per cycle, by 30 min IV infusion, 30 min after Chemotherapy (Chemo), on the same day of Chemo. In contrast to Peg, Plin does not cause bone pain or thrombocytopenia (Blayney JAMA Onc in press). The mechanism of action (MoA) of Plin exerts its CIN preventive effects predominantly in week 1 of the cycle, whereas Peg primarily in week 2. This was the rationale to combine these two agents, to obtain superior CIN protection throughout the entire cycle (Blayney ASCO 2019). Data from Phase (Ph) 2 portion of PROTECTIVE-2 (NCT0329457) with the Plin/Peg combination demonstrated superiority in CIN protection vs Peg alone, with a favorable safety/tolerability profile (Blayney, St Gallen 2019). Additionally, the addition of Plin to Peg almost eradicated the Peg-induced bone pain. The Ph 3 portion of PROTECTIVE-2 aims to confirm superiority of the Plin/Peg combination vs Peg standard of care for avoidance of CIN and Bone Pain-prevention. Trial Design PROTECTIVE-2 is a global, multicenter, randomized, double-blind Study to Evaluate Plin 40 mg + Peg 6mg (Arm 1) versus Peg 6mg + Placebo (Arm 2) in preventing Severe Neutropenia (defined as Absolute Neutrophil Count (ANC) of ANC (Covance Central Laboratory) was assessed before and after during Cycle 1 on D 1, 2, 3, 6, 7, 8, 9, 10, 11, 12, 13, and 15. Bone Pain was assessed by a validated at regular timepoints in Cycle 1 with a validated PRO questionnaire. The Primary objective was to compare the percentage of pts with a Duration of Severe Neutropenia (DSN) of 0 days in treatment Cycle 1 between the Plin/Peg vs Peg alone. Secondary objectives in Cycle 1 included mean DSN, mean ANC NADIR, average change in Bone Pain from baseline, the rate of composite risk (infection, FN, hospitalization, significant disability, life threatening and death), and over 4 Cycles, the percentage of patients with Relative Dose Intensity (RDI) < 85%. Following the pre-planned Interim Analysis, the DSMB recommended the trial to continue without modifications. Current Status: Patient accrual has been completed. Disclosures Blayney: BeyondSpring Pharma: Other: Research Funding to Institution. Mohanlal:BeyondSpring Pharma: Current Employment, Current equity holder in publicly-traded company. Huang:BeyondSpring Pharma: Current Employment, Current equity holder in publicly-traded company.

Case series Patients:— Final Diagnosis: Breast cancer • ovarian cancer Symptoms: Thrombocytopenia Medication: — Clinical Procedure: — Specialty: Oncology Objective: Unusual or unexpected effect of treatment Background: Thrombocytopenia is a potentially treatment-limiting adverse event of particular interest with the PARP inhibitor niraparib. This adverse event may necessitate niraparib dose reduction or treatment discontinuation, resulting in suboptimal treatment outcomes. Here, we report on niraparib dose optimization in 2 patients with breast cancer and 4 patients with ovarian cancer through concurrent administration of the thrombopoietin receptor stimulating agent avatrombopag to mitigate thrombocytopenia, enabling niraparib reescalation and improved clinical response. Case Reports: Three of 6 patients received niraparib 300 mg daily, the highest recommended dose, for a sustained period. Avatrombopag therapy enabled niraparib dose escalation that led to reductions in biomarkers associated with disease progression. Before initiation of avatrombopag, increases in CA-125 levels, a marker for ovarian cancer, were observed in association with niraparib dose interruption, and in 2 patients with ovarian cancer CA-125 levels fell in response to niraparib dose escalation enabled by concurrent avatrombopag therapy. Further, in 2 patients with metastatic breast cancer, intracranial response was observed in association with avatrombopag-enabled niraparib therapy. In 1 patient with metastatic breast cancer, niraparib induced an intracranial response, while previous use of talazoparib had not, confirming preclinical findings of superior blood-brain-barrier penetrance with niraparib. Conclusions: Avatrombopag is currently approved for use in chronic immune thrombocytopenia and thrombocytopenia associated with chronic liver disease in patients undergoing a surgical procedure. A clinical trial of avatrombopag for chemotherapy-induced thrombocytopenia is ongoing. Preliminary results in these 6 patient cases demonstrate the need for a confirmatory trial of avatrombopag for optimizing the dose of niraparib.

Importance Pathologic complete response (pCR) is a known prognostic biomarker for long-term outcomes. The I-SPY2 trial evaluated if the strength of this clinical association persists in the context of a phase 2 neoadjuvant platform trial. Objective To evaluate the association of pCR with event-free survival (EFS) and pCR with distant recurrence–free survival (DRFS) in subpopulations of women with high-risk operable breast cancer treated with standard therapy or one of several novel agents. Design, Setting, and Participants Multicenter platform trial of women with operable clinical stage 2 or 3 breast cancer with no prior surgery or systemic therapy for breast cancer; primary tumors were 2.5 cm or larger. Women with tumors that were ERBB2 negative/hormone receptor (HR) positive with low 70-gene assay score were excluded. Participants were adaptively randomized to one of several different investigational regimens or control therapy within molecular subtypes from March 2010 through 2016. The analysis included participants with follow-up data available as of February 26, 2019. Interventions Standard-of-care neoadjuvant therapy consisting of taxane treatment with or without (as control) one of several investigational agents or combinations followed by doxorubicin and cyclophosphamide. Main Outcomes and Measures Pathologic complete response and 3-year EFS and DRFS. Results Of the 950 participants (median [range] age, 49 [23-77] years), 330 (34.7%) achieved pCR. Three-year EFS and DRFS for patients who achieved pCR were both 95%. Hazard ratios for pCR vs non-pCR were 0.19 for EFS (95% CI, 0.12-0.31) and 0.21 for DRFS (95% CI, 0.13-0.34) and were similar across molecular subtypes, varying from 0.14 to 0.18 for EFS and 0.10 to 0.20 for DRFS. Conclusions and Relevance The 3-year outcomes from the I-SPY2 trial show that, regardless of subtype and/or treatment regimen, including 9 novel therapeutic combinations, achieving pCR after neoadjuvant therapy implies approximately an 80% reduction in recurrence rate. The goal of the I-SPY2 trial is to rapidly identify investigational therapies that may improve pCR when validated in a phase 3 confirmatory trial. Whether pCR is a validated surrogate in the sense that a therapy that improves pCR rate can be assumed to also improve long-term outcome requires further study. Trial Registration ClinicalTrials.gov Identifier:NCT01042379

The majority of people receiving treatment for their heroin addiction, are prescribed methadone; for which there is an extensive evidence base. When treatment starts, people take their daily dose of methadone under supervision at a community pharmacy. Supervision guarantees methadone is taken as directed by the individual for whom it has been prescribed, helps to ensure individuals take their correct dose every day, and safeguards against diversion and overdose. However, individuals often fail to attend the pharmacy to take their methadone. Each missed dose is of concern. If a patient misses their daily dose of methadone, they will start to experience opiate withdrawal and cravings and are more likely to use heroin. If they miss three days dose, there are concerns that they may lose tolerance to the drug and may be at risk of overdose when the next dose is taken. Hence there is an urgent need to develop effective interventions for medication adherence. Research suggests that incentive-based medication adherence interventions may be very effective, but there are few controlled trials and the provision of incentives requires time and organisational systems which can be challenging in pharmacies. The investigators have developed the technology to deliver incentives by mobile telephone. This cluster randomised trial will test the feasibility of conducting a future trial evaluating the clinical and cost effectiveness of using telephone delivered incentives (praise and modest financial rewards via text messaging) to encourage adherence with supervised consumption of methadone in community pharmacies. Three drug services (each with two or three community pharmacies supervising methadone consumption that will enrol 20 individuals, a total of 60 participants) will be recruited and randomly allocated to deliver either i) telephone delivered incentives, ii) telephone delivered reminders or iii) no telephone system. Acceptability, recruitment, follow-up, and suitable measures of clinical and cost effectiveness will be assessed. Findings from this feasibility study will be assessed against stated progression criteria and used to inform a future confirmatory trial of the clinical and cost effectiveness of telephone delivered incentives to encourage medication adherence. Trial registration: ISRCTN58958179 (retrospectively registered). Keywords: Opiate substitution treatment, Methadone, Supervised consumption, Pharmacies, Contingency management, Medication adherence, Financial incentives, Behavioural reinforcement, Heroin use

Laparoscopy-assisted distal gastrectomy (LADG) for gastric cancer is safe and feasible. In contrast, no prospective study evaluating the safety and efficacy of laparoscopy-assisted total gastrectomy (LATG) or laparoscopy-assisted proximal gastrectomy (LAPG) has been completed. We conducted a single-arm confirmatory trial to evaluate the safety of LATG/LAPG for clinical stage I (T1N0/T1N1/T2N0) proximal gastric cancer. The extent of lymphadenectomy was selected based on the Japanese Gastric Cancer Treatment Guidelines. The mini-laparotomy incision was required to be ≤ 6 cm. The primary endpoint was the proportion of grade 2–4 (CTCAE ver. 4.0) esophagojejunal anastomotic leakage. The planned sample size was 245 considering a threshold of 8% and one-sided alpha of 2.5%. Between April 2015 and February 2017, 244 eligible patients were enrolled. LATG/LAPG was performed in 195/49. The proportion of conversions was 1.7%. Clinical T1N0/T1N1/T2N0 was 212/9/23. The extents of lymphadenectomy were as follows: D1+: 229; D2: 15. The median operation time was 309 min (IQR 265–353). The median blood loss was 30 ml (IQR 10–86). Grade 2–4 esophagojejunal anastomotic leakage was 2.5% (6/244; 95% CI 0.9–5.3). The overall proportion of in-hospital grade 3–4 adverse events was 29% (71/244). The proportions of intraabdominal abscess and pancreatic fistula were 3.7% and 2.0%, respectively. There were no treatment-related deaths. This trial confirmed the safety of LATG/LAPG. After the non-inferiority of LADG is confirmed in our phase III trial (JCOG0912), LATG/LAPG is expected to be established as one of the standard treatments for clinical stage I gastric cancer.

The authors consider a statistically valid method that has little concern caused by down weighting in stage 2 or slight loss in efficiency and possibly improves power performance for a trial design that allows for adaptation of statistical information. In addition to the need for a priori sound data-based planning that accounts for limited uncertainty, the criteria for statistical information adaptation are scientifically sound and can foster transparent trial logistics that are necessary for such adaptation in confirmatory trials. A major rationale of the proposed conditional adaptive weighted test method is to increase the probability of success of an adequate and well-controlled confirmatory trial that may otherwise fall short of statistical significance despite initial rigorous planning for statistical information.

Objective To evaluate the safety of hypofractionated whole breast irradiation in Japanese women after breast-conserving surgery. Methods Japanese women who had invasive breast cancer with a clinical tumor size ≤3 cm, pN0-1c and a negative inked margin were enrolled. Hypofractionated whole breast irradiation (42.56 Gy/16 fractions) was delivered, adding boost irradiation (10.64 Gy/4 fractions) when the surgical margin was ≤5 mm. The treatment course was meant to be completed within 29 days or 33 days (plus boost irradiation). The primary endpoint was the proportion of grade ≥2 of pre-specified late adverse reactions, including telangiectasia, ulceration, fibrosis, fracture, pneumonitis, cardiac ischemia/infarction, pericardial effusion and breast pain, within 3 years. A sample size of 310 patients was set, with one-sided alpha of 0.05, beta of 0.1, threshold value of 8% and expected value of 4%. Secondary endpoints included the proportion of treatment completion within the recommended period and early adverse events within 90 days. Adverse events/adverse reactions were evaluated using CTCAE-3.0. Results Between 2010 and 2012, 312 women were enrolled; 306 received hypofractionated whole breast irradiation, but 6 chose conventional fractionated WBI, with 301 patients (96.5%) treated within the recommended period. Grade 2 early adverse events were found in 38 patients (12.4%); none had grade 3/4. Among the 303 evaluable patients, 13 (4.3%; 90% CI 2.6-6.7) had grade 2/3 late adverse reactions, including one with grade 3 pneumonitis, which was under the threshold value. Conclusion Hypofractionated whole breast irradiation is considered to be safe and one of the standard treatments for Japanese women with margin-negative invasive breast cancer after breast-conserving surgery.

We analytically obtain the average success probability (ASP) and the contemplated average success probability (CASP) for normally distributed observed differences in the treatment group and the placebo group means of the early trial and the confirmatory trial, assuming a uniform noninformative prior for the population treatment effect and a common known variance of the observations from both groups. For the CASP optimization problem with a fixed subtotal sample size of the early trial and the confirmatory trial of one arm larger than a threshold, we obtain the optimal plan of the sample sizes in a theorem. Moreover, in the theorem, we obtain the analytical formula of the optimal CASP as an increasing function of the subtotal sample size. After that, we calculate and compare the numerical values of the ASP with those in Table 1 of Chuang-Stein (2006). Finally, we investigate the numerical features of the CASP and find the optimal plan of the sample sizes for a given subtotal sample size.

ObjectiveTreatment options for severe, enduring anorexia nervosa (SE-AN) are limited. Non-invasive neuromodulation is a promising emerging intervention. Our study is a feasibility randomised controlled trial of repetitive transcranial magnetic stimulation (rTMS) in individuals with SE-AN, which aims to inform the design of a future large-scale trial.DesignDouble-blind, parallel group, two-arm, sham-controlled trial.SettingSpecialist eating disorders centre.ParticipantsCommunity-dwelling people with anorexia nervosa, an illness duration of ≥3 years and at least one previous completed treatment.InterventionsParticipants received 20 sessions (administered over 4 weeks) of MRI-guided real or sham high-frequency rTMS to the left dorsolateral prefrontal cortex in addition to treatment-as-usual.OutcomesPrimary outcomes were recruitment, attendance and retention rates. Secondary outcomes included body mass index (BMI), eating disorder symptoms, mood, quality of life and rTMS safety and tolerability. Assessments were conducted at baseline, post-treatment and follow-up (ie, at 0 month, 1 month and 4 months post-randomisation).ResultsThirty-four participants (17 per group) were randomly allocated to real or sham rTMS. One participant per group was withdrawn prior to the intervention due to safety concerns. Two participants (both receiving sham) did not complete the treatment. rTMS was safe and well tolerated. Between-group effect sizes of change scores (baseline to follow-up) were small for BMI (d=0.2, 95% CI −0.49 to 0.90) and eating disorder symptoms (d=0.1, 95% CI −0.60 to 0.79), medium for quality of life and moderate to large (d=0.61 to 1.0) for mood outcomes, all favouring rTMS over sham.ConclusionsThe treatment protocol is feasible and acceptable to participants. Outcomes provide preliminary evidence for the therapeutic potential of rTMS in SE-AN. Largest effects were observed on variables assessing mood. This study supports the need for a larger confirmatory trial to evaluate the effectiveness of multi-session rTMS in SE-AN. Future studies should include a longer follow-up period and an assessment of cost-effectiveness.Trial registration numberISRCTN14329415; Pre-results.

On September 2, 2017, the U.S. Food and Drug Administration approved gemtuzumab ozogamicin (GO; Mylotarg; Pfizer, New York City, NY) for treatment of relapsed or refractory (R/R) CD33-positive acute myeloid leukemia (AML) in patients 2 years of age and older. GO is a CD33-directed antibody drug conjugate linked to the cytotoxic antibiotic calicheamicin. It originally received accelerated approval for treatment of older patients with relapsed CD33-positive AML in 2000, but it was withdrawn from the market in 2010 when the confirmatory trial failed to demonstrate clinical benefit among safety concerns, such as a higher rate of induction fatalities on the GO combination arm compared with chemotherapy alone. In addition, GO was associated with hepatic veno-occlusive disease (VOD), which has substantial morbidity and mortality. Pharmacokinetic analyses suggested a lower maximum concentration of GO would result in less VOD without affecting target saturation or efficacy. A meta-analysis across dose schedules of GO in patients with R/R AML showed that a lower-dose “fractionated” schedule of 3 mg/m2 days 1, 4, and 7 was associated with less early mortality, hemorrhage, and VOD, without an apparent decrease in complete remission (CR) rate. MyloFrance 1 was a single-arm study evaluating response rates in patients with relapsed CD33-positive AML treated with the lower-dose fractionated GO regimen. The CR rate was 26% (95% confidence interval 16%–40%). Common adverse reactions were fever, infections, nausea, vomiting, constipation, bleeding, increased liver enzymes, and mucositis. There were no cases of VOD. These results supported the approval of GO as monotherapy for R/R CD33-positive AML using the lower-dose fractionated regimen. Implications for Practice Gemtuzumab ozogamicin (GO) 3 mg/m2 days 1, 4, and 7 is an active regimen for induction of remission when used to treat patients with relapsed or refractory CD33-positive acute myeloid leukemia without curative intent. The risks of hepatic veno-occlusive disease and early mortality with this regimen appear to be lower than reported previously for GO 9 mg/m2 days 1 and 15. The data were not sufficient to enable conclusions about the safety of GO in children younger than 2 years of age.

As biomarker information from early-phase trials can be unreliable due to high variability, it is logical to take a prospective two-stage approach when designing a late-phase confirmatory trial, ie, refining the target population at the first stage and performing the hypothesis testing at the second stage. The use of a reliable intermediate endpoint at the first stage can further improve the trial efficiency from both time and cost perspectives. Nevertheless, there are needs for expanding such two-stage confirmatory designs to more stages for monitoring efficacy on the refined population. There is limited literature on this matter, particularly for two popular designs with population selection midway, ie, the biomarker enrichment design and the basket design. In this manuscript, we focus on these two popular designs and discuss how to implement the interim efficacy analyses after population refinement while controlling type I error. Power and stopping probability are also explored for the two designs.

We describe the development of an intervention strategy for the indicated prevention of depression in older adults living in Goa, India. Of particular novelty, the intervention is deliverable by lay health counselors and is grounded in problem solving therapy for primary care and brief behavioral treatment for insomnia. We have named the intervention “DIL” (the Hindi word for “heart” and an acronym for “depression in late life.”) Additional DIL strategies include psychoeducation in self-management of co-occurring medical disorders such as diabetes mellitus, together with assistance in navigation to needed social and economic resources. We present the results of a preliminary open-trial case series involving 21 participants with subsyndromal symptoms of depression, demonstrating feasibility, acceptability, and benefit to participants. We then present the design of a larger confirmatory trial into which 181 participants have been enrolled. “DIL” is a novel and large depression prevention trial conducted with lay health counselors in a low-resource country. Its results are likely to have implications for depression prevention in older adults in other low- and middle-income countries and to inform contemporary models of the staging of depressive illness in later life.

A personalized medicine in oncology may benefit a subpopulation of patients with certain predictive biomarker signatures or certain disease types. However, there is great uncertainty about drug activity in a subpopulation when designing a confirmatory trial in practice and it is logical to take a two-stage adaptive approach. The first stage de-selects (or prunes) non-performing subpopulations at an interim analysis, and the second stage pools the remaining subpopulations in the final analysis. A critical statistical issue of the adaptive design is Type I error control of the primary endpoint in the final analysis. The endpoints used at the two stages can be different in general. In this chapter, we discuss Type I error control under this general setting by treating the treatment effect of the intermediate endpoint as a nuisance parameter to provide the most conservative Type I error control. The methodology is applied to two previously studied designs. In the first design, patients with different biomarker levels are enrolled in a study and the treatment effect is assumed to be in ascending order of the biomarker level (a biomarker enrichment design). The goal of the interim analysis is to de-select non-performing biomarker subpopulations. In the second design, patients with different tumor types but the same biomarker signature are included in a trial (a basket design). The goal of the interim analysis is to identify a subset of tumor types in the absence of order in treatment effect. Pruning tends to inflate Type I error, which implies that the naive estimator of the treatment effect in the final analysis is biased. Bias correction is also discussed. Hypothetical examples are provided for illustration purpose.

Background: This comparison of PRAsugrel and clopidogrel in Japanese patients with ischemic STROke (PRASTRO)-I trial investigates the noninferiority of prasugrel to clopidogrel sulfate in the prevention of recurrence of primary events (ischemic stroke, myocardial infarction, and death from other vascular causes), and the long-term safety of prasugrel in Japanese patients with non-cardioembolic stroke. Research design and methods: This was an active-controlled, randomized, double-blind, double-dummy, parallel-group study conducted between July 2011 and March 2016 at multiple centers around Japan. Patients had to meet eligibility criteria before receiving 3.75 mg prasugrel or 75 mg clopidogrel orally once daily for a period of 96–104 weeks. Results: A total of 3747 patients were included in this trial; 1598 in the 3.75 mg prasugrel group and 1551 in the 75 mg clopidogrel group completed the study. During the study period, 287 (15.2%) patients in the prasugrel group and 311 (16.7%) in the clopidogrel group discontinued treatment. Baseline characteristics, safety, and efficacy results are forthcoming and will be published separately. Conclusions: This article presents the study design and rationale for a trial investigating the noninferiority of prasugrel to clopidogrel sulfate with regards to the inhibitory effect on primary events in patients with non-cardioembolic stroke.

Background A single-arm confirmatory trial (JCOG1101) is now on follow-up, which is to evaluate the efficacy of modified radical hysterectomy for FIGO Stage IB1 uterine cervical cancer patients (pts) with clinical maximal tumor diameter (MTD) estimated 2 cm or less (UMIN-CTR: UMIN000009726). It is needed to evaluate whether application of modified radical hysterectomy is feasible or not. Methods From Jan 2013 to Aug 2017, 240 pts were enrolled. We analyzed the data of 224 eligible pts who underwent modified radical hysterectomy to elucidate the relationship between clinical maximal tumor diameter (cMTD) and pathological MTD (pMTD), degree of tumor extension and adverse events (AEs). Results In 224 eligible pts, median pMTD was 1.5 cm (range, 0-4.5), and. pMTD were Conclusions Though cMTD does not always correspond to pMTD on stage IB1 cervical cancer, low incidence of parametrial involvement and lymph node metastasis indicate that cMTD is useful as presurgical diagnosis. In addition, there was low frequency of AEs by modified radical hysterectomy, which was presumed to be less invasive than radical hysterectomy. Modified radical hysterectomy will be a standard surgery if the efficacy of modified radical hysterectomy in overall survival is confirmed by the primary analysis planned in 2022. Clinical trial identification UMIN-CTR: UMIN000009726, 08/Jan/2013. Legal entity responsible for the study JCOG (Japan Clinical Oncology Group). Funding National Cancer Center Research and Development Funds. Disclosure All authors have declared no conflicts of interest.

Background Tobacco dependence remains the leading preventable cause of death in the developed world. Smokers are disproportionately from lower socioeconomic groups, and may use the hospital emergency department (ED) as an important source of care. A recent clinical trial demonstrated the efficacy of a multicomponent intervention to help smokers quit, but the independent contributions of those components is unknown. Methods This is a full-factorial (16-arm) randomized trial in a busy hospital ED of 4 tobacco dependence interventions: brief motivational interviewing, nicotine replacement therapy, referral to a telephone quitline, and a texting program. The trial utilizes the Multiphase Optimization Strategy (MOST) and a novel mixed methods analytic design to assess clinical efficacy, cost effectiveness, and qualitative participant feedback. The primary endpoint is tobacco abstinence at 3 months, verified by participants' exhaled carbon monoxide. Results Study enrollment began in February 2017. As of April 2017, 52 of 1056 planned participants (4.9%) were enrolled. Telephone-based semi-structured participant interviews and in-person biochemical verification of smoking abstinence are completed at the 3-month follow-up. Efficacy and cost effectiveness analyses will be conducted after follow-up is completed. Discussion The goal of this study is to identify a clinically efficacious, cost-effective intervention package for the initial treatment of tobacco dependence in ED patients. The efficacy of this combination can then be tested in a subsequent confirmatory trial. Our approach incorporates qualitative feedback from study participants in evaluating which intervention components will be tested in the future trial. Trial registration: Trial ( NCT02896400 ) registered in ClinicalTrials.gov on September 6, 2016.

A sample size re-estimation (SSR) design is a flexible, adaptive design with the primary purpose of allowing sample size of a study to be reassessed in the mid-course of the study to ensure adequate power. In real world drug product, biologic, and device development, there may be large uncertainty in key factors that drive the sample size estimation for a confirmatory clinical trial. For example, early phase studies may have encouraging results but could be of shorter duration, or use a different endpoint than what is required for confirmatory phase clinical trials. The negative impact of high uncertainty at design stage for a confirmatory trial can be mitigated by an SSR design. Recent surveys have reported an encouraging upward trend in the use of SSR designs in clinical trials since the release of the draft guidance for adaptive design clinical trials for drugs and biologics by the U.S. Food and Drug Administration in 2010 (U.S. Food and Drug Administration (FDA) (February, 2010), Draft Guidance for In...

Aims The aim of this study was to confirm the efficacy and safety of adjunctive levetiracetam in adult Japanese patients with uncontrolled partial-onset seizures. Methods In a double-blind, placebo-controlled, confirmatory trial, eligible patients were randomized to receive levetiracetam 500, 1000, 2000, or 3000 mg/day or placebo for 16 weeks. The primary end-point was percentage reduction from baseline in seizure frequency/week over a 12-week evaluation period. Tolerability assessments were also conducted. Findings of this and a previous randomized, double-blind trial were compared. Results Of 401 patients screened, 352 were randomized and 316 completed the study. Median percentage reduction in seizure frequency/week from baseline was 12.92%, 18.00%, 11.11% and 31.67% in the levetiracetam 500, 1000, 2000 and 3000-mg groups, respectively, compared with 12.50% in the placebo group. Unlike the previous trial, the primary efficacy analysis between the levetiracetam 1000 and 3000-mg and placebo groups did not reach statistical significance (P = 0.067). Exploratory analyses demonstrated that the difference in seizure reduction versus placebo was 14.93% (95% confidence interval, 1.98–27.64; P = 0.025) for the levetiracetam 3000-mg group. All levetiracetam doses were well tolerated. The main difference between the two trials was a high placebo response in the present trial. Conclusions The primary efficacy analysis did not reach statistical significance, a finding that could be attributed to an unexpectedly high placebo response. Nonetheless, exploratory analysis suggests that levetiracetam at 3000 mg/day may, at least marginally, be beneficial for patients with uncontrolled partial-onset seizures.

Goal Dysphagia is a major stroke complication but lacks effective therapy that can promote recovery. Noninvasive brain stimulation with and without peripheral sensorimotor activities may be an attractive treatment option for swallowing recovery but has not been systematically investigated in the stroke population. This article describes the study design of the first prospective, single-center, double-blinded trial of anodal versus sham transcranial direct current stimulation (tDCS) used in combination with swallowing exercises in patients with dysphagia from an acute ischemic stroke. The aim of this study is to gather safety data on cumulative sessions of tDCS in acute–subacute phases of stroke, obtain information about effects of this intervention on important physiologic and clinically relevant swallowing parameters, and examine possible dose effects. Methods Ninety-nine consecutive patients with dysphagia from an acute unilateral hemispheric infarction with a Penetration and Aspiration Scale (PAS) score of 4 or more and without other confounding reasons for dysphagia will be enrolled at a single tertiary care center. Subjects will be randomized to either a high or low dose tDCS or a sham group and will undergo 10 sessions over 5 consecutive days concomitantly with effortful swallowing maneuvers. The main efficacy measures are a change in the PAS score before and after treatment; the main safety measures are mortality, seizures, neurologic, motor, and swallowing deterioration. Conclusions The knowledge gained from this study will help plan a larger confirmatory trial for treating stroke-related dysphagia and advance our understanding of important covariates influencing swallowing recovery and response to the proposed intervention.

This article reviews the benefit‐risk assessment of osimertinib that led to approval of osimertinib for the treatment of patients with metastatic EGFR T790M mutation‐positive non‐small cell lung cancer whose disease had progressed after EGFR tyrosine kinase inhibitor therapy., On March 30, 2017, the U.S. Food and Drug Administration (FDA) approved osimertinib for the treatment of patients with metastatic, epidermal growth factor receptor (EGFR) T790M mutation‐positive, non‐small cell lung cancer (NSCLC), as detected by an FDA‐approved test, whose disease has progressed following EGFR tyrosine kinase inhibitor (TKI) therapy. Approval was based on demonstration of a statistically significant difference in the primary endpoint of progression‐free survival (PFS) when comparing osimertinib with chemotherapy in an international, multicenter, open‐label, randomized trial (AURA3). In this confirmatory trial, which enrolled 419 patients, the PFS hazard ratio for osimertinib compared with chemotherapy per investigator assessment was 0.30 (95% confidence interval 0.23–0.41), p 20%) in patients treated with osimertinib were diarrhea, rash, dry skin, nail toxicity, and fatigue. Herein, we review the benefit‐risk assessment of osimertinib that led to regular approval, for patients with metastatic NSCLC harboring EGFR TKI whose disease has progressed on or after EGFR TKI therapy. Implications for Practice. Osimertinib administered to metastatic non‐small cell lung cancer (NSCLC) patients harboring an EGFR T790M mutation, who have progressed on or following EGFR TKI therapy, demonstrated a substantial improvement over platinum‐based doublet chemotherapy as well as durable intracranial responses. The ability to test for the T790M mutation in plasma using the FDA‐approved cobas EGFR Mutation Test v2 (Roche, Basel, Switzerland) identifies patients with NSCLC tumors not amenable to biopsy. Since a 40% false‐negative rate has been observed with the circulating tumor DNA test, re‐evaluation of the feasibility of tissue biopsy is recommended to identify patients with a false‐negative plasma test result who may benefit from osimertinib.

Background The National Institute for Health and Care Excellence (NICE) recommends evidence-based parenting programmes as a first-line intervention for conduct disorders (CD) in children aged 5–11 years. As these are not effective in 25–33% of cases, NICE has requested research into second-line interventions. Child and Adolescent Psychotherapists (CAPTs) address highly complex problems where first-line treatments have failed and there have been small-scale studies of Psychoanalytic Child Psychotherapy (PCP) for CD. A feasibility trial is needed to determine whether a confirmatory trial of manualised PCP (mPCP) versus Treatment as Usual (TaU) for CD is practicable or needs refinement. The aim of this paper is to publish the abridged protocol of this feasibility trial. Methods and design TIGA-CUB (Trial on improving Inter-Generational Attachment for Children Undergoing Behaviour problems) is a two-arm, pragmatic, parallel-group, multicentre, individually randomised (1:1) controlled feasibility trial (target n = 60) with blinded outcome assessment (at 4 and 8 months), which aims to develop an optimum practicable protocol for a confirmatory, pragmatic, randomised controlled trial (RCT) (primary outcome: child’s behaviour; secondary outcomes: parental reflective functioning and mental health, child and parent quality of life), comparing mPCP and TaU as second-line treatments for children aged 5–11 years with treatment-resistant CD and inter-generational attachment difficulties, and for their primary carers. Child-primary carer dyads will be recruited following a referral to, or re-referral within, National Health Service (NHS) Child and Adolescent Mental Health Services (CAMHS) after an unsuccessful first-line parenting intervention. PCP will be delivered by qualified CAPTs working in routine NHS clinical practice, using a trial-specific PCP manual (a brief version of established PCP clinical practice). Outcomes are: (1) feasibility of recruitment methods, (2) uptake and follow-up rates, (3) therapeutic delivery, treatment retention and attendance, intervention adherence rates, (4) follow-up data collection, and (5) statistical, health economics, process evaluation, and qualitative outcomes. Discussion TIGA-CUB will provide important information on the feasibility and potential challenges of undertaking a confirmatory RCT to evaluate the effectiveness and cost-effectiveness of mPCP. Trial registration Current Controlled Trials, ID: ISRCTN86725795. Registered on 31 May 2016. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2166-2) contains supplementary material, which is available to authorized users.

Although clinical trials have investigated thrombolytic therapies such as streptokinase, urokinase, and desmoteplase in acute ischemic stroke treatment, only trials assessing intravenous (IV) tissue plasminogen activator (tPA) and intraarterial prourokinase were successful in showing efficacy. Since a confirmatory trial with prourokinase was not performed, it has not been approved for treatment and IV tPA remains the standard of care. Advances in fluoroscopic imaging led to additional research in endovascular therapies as performing interventional cerebrovascular procedures became more feasible. After years of device development, enhanced acute stroke imaging, and improvements in systems of care, endovascular therapy has now shown efficacy in acute stroke treatment in randomized trials as well. Trials have shown the efficacy of stent retrievers compared to medical therapy alone in patients with anterior circulation large vessel occlusions. This has resulted in a paradigm shift in the management of acute ischemic stroke.

Introduction Surgical treatment of maxillary tumours is often highly complex. The three-dimensional anatomy of the mid-face renders both correct intraoperative orientation and adequate oncological safety difficult to obtain. Recently, computer-assisted techniques and intraoperative navigation have been applied to oncological surgery treating head and neck cancer. However, only a few studies have explored whether preoperative virtual resection planning and intraoperative control of resection margins allow assessment of the surgical margins of the tumour. In our present feasibility study, we developed a protocol for preoperative mapping of tumour margins using computed tomography and/or magnetic resonance imaging, virtual planning of the surgical resection, and intraoperative navigation during actual resection of advanced maxillary tumours. Materials and methods Twenty patients were included in this feasibility study. We prospectively selected ten patients requiring surgery to treat malignant maxillary tumours. A control group of ten patients was retrospectively selected. The simulation protocol featured the following steps: 1. “Contouring” of the tumour: identification of the tumour and the borders thereof on the axial, sagittal, and coronal planes; 2. Definition of the resection margins by positioning “landmarks” at least 1 cm from the tumour edges on the axial, sagittal, and coronal planes; 3. Simulation of osteotomy lines passing through the landmarks, and evaluation of the bony defects to be reconstructed. Tumour margins were controlled by using a pointer to identify mobilised regions and then checking the overlap between the planned resection (shown on the LCD screen of the navigation system) and the real anatomical situation. Results A total of 127 margins were pathologically assessed in the test group, and 85 were assessed in the control group. Overall, 9% of surgical margins were positive in the test group, and 16% were positive in the control group (p = 0.0047). A significant difference was apparent in terms of deep margin evaluation: in test patients, 87% of margins were clear; this figure was 75% for the control group (p = 0.0038). No significant difference in either mucosal or bone margin clearance was evident. The preoperative planning errors were

A personalized medicine may benefit a subpopulation with certain predictive biomarker signatures or certain disease types. However, there is great uncertainty about drug activity in a subpopulation when designing a confirmatory trial in practice, and it is logical to take a two-stage approach with the study unless credible external information is available for decision-making purpose. The first stage deselects (or prunes) non-performing subpopulations at an interim analysis, and the second stage pools the remaining subpopulations in the final analysis. The endpoints used at the two stages can be different in general. A key issue of interest is the statistical property of the test statistics and point estimate at the final analysis. Previous research has focused on type I error control and power calculation for such two-stage designs. This manuscript will investigate estimation bias of the treatment effect, which is implicit in the adjustment of nominal type I error for multiplicity control in such two-stage designs. Previous work handles the treatment effect of an intermediate endpoint as a nuisance parameter to provide the most conservative type I error control. This manuscript takes the same approach to explore the bias. The methodology is applied to the two previously studied designs. In the first design, patients with different biomarker levels are enrolled in a study, and the treatment effect is assumed to be in an order. The goal of the interim analysis is to identify a biomarker cut-off point for the subpopulations. In the second design, patients with different tumour types but the same biomarker signature are included in a trial applying a basket design. The goal of the interim analysis is to identify a subset of tumour types in the absence of treatment effect ordering. Closed-form equations are provided for the estimation bias as well as the variance under the two designs. Simulations are conducted under various scenarios to validate the analytic results that demonstrated that the bias can be properly estimated in practice. Worked examples are presented. Extensions to general adaptive designs and operational considerations are discussed. Copyright © 2017 John Wiley & Sons, Ltd.

On September 30, 2013, the FDA granted accelerated approval to pertuzumab (Perjecta; Genentech, Inc.) for use in combination with trastuzumab and docetaxel as neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer. The approval was based in part on a randomized multicenter trial in the indicated population that allocated 417 patients to neoadjuvant treatment with trastuzumab–docetaxel (TD), pertuzumab–trastuzumab–docetaxel (PTD), pertuzumab–trastuzumab, or pertuzumab–docetaxel. PTD was administered preoperatively every 3 weeks for four cycles. Following surgery patients received three cycles of 5-fluorouracil, epirubicin, and cyclophosphamide every 3 weeks and trastuzumab every 3 weeks to complete 1 year of therapy. The pathologic complete response rates by the FDA-preferred definition [absence of invasive cancer in the breast and lymph nodes (ypT0/is ypN0)] were 39.3% and 21.5% in the PTD and the TD arms, respectively (P = 0.0063). The most common adverse reactions with PTD were alopecia, diarrhea, nausea, and neutropenia. This approval was based on the totality of evidence, particularly improved survival in the metastatic breast cancer trial, and a fully accrued confirmatory trial. Clin Cancer Res; 20(21); 5359–64. ©2014 AACR.

We present a Bayesian adaptive design for a confirmatory trial to select a trial's sample size based on accumulating data. During accrual, frequent sample size selection analyses are made and predictive probabilities are used to determine whether the current sample size is sufficient or whether continuing accrual would be futile. The algorithm explicitly accounts for complete follow-up of all patients before the primary analysis is conducted. We refer to this as a Goldilocks trial design, as it is constantly asking the question, "Is the sample size too big, too small, or just right?" We describe the adaptive sample size algorithm, describe how the design parameters should be chosen, and show examples for dichotomous and time-to-event endpoints.

Background Clinical trials supporting approval for new drugs often evaluate surrogate endpoints, and data on meaningful outcomes like OS or QoL may not be available. Here, we evaluated changes in the magnitude of clinical benefit, OS and QoL after approval. Methods We examined data on pivotal trials supporting FDA accelerated (AA) and regular (RA) cancer drug approvals between January 2006, and December 2015. For AA drugs, if conversion to RA was granted, only the confirmatory trial was analysed. To determine any new evidence on OS and QoL in the postmarketing period (PMP) we performed a systematic search of Pubmed and ClinicalTrials.gov. European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) grades were applied for trials at approval and in the PMP. Substantial clinical benefit was defined as a grade of A or B for trials of curative intent and 4 or 5 for those of palliative intent. Results We identified 96 pivotal trials supporting the approval of 47 drugs for 94 solid tumour indications. Of these indications, 22 (23%) were granted AA and 21 (22%) were converted to RA. At time of approval, 45 (48%) trials showed improved OS, 15 (16%) improved QoL and 33 (34%) had substantial clinical benefit. With a median PMP of 3.7 years, 50 (52%) trials reported OS data and 27 (28%) on QoL. Of these, 48 could be graded by the ESMO-MCBS. Of the updated 51 trials approved based on surrogate endpoints, only 7 (14%) showed an improvement in OS. In advanced disease, out of 74 trials for which there was no evidence on QoL at the time of approval, 12 (16%) showed improved QoL subsequently. Updated results led to changes in clinical benefit in 11 trials (10 upgrades, 1 downgrade) with 30 (62%) showing substantial clinical benefit. Among all trials, 52 (54%) showed improved OS, 27 (28%) improved QoL and 42 (44%) met the threshold for substantial clinical benefit. Conclusions After 3.7 years of post-marketing time, 54% of FDA approved cancer drugs showed statistically significant improvement in OS and 28% in QoL. Less than a half of trials supporting FDA approval met the threshold for substantial clinical benefit using ESMO-MCBS. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure E. Amir: Speaker Bureau / Expert testimony: Genentech/Roche; Advisory / Consultancy: Apobiologix; Advisory / Consultancy: Agendia; Advisory / Consultancy: Myriad Genetics. All other authors have declared no conflicts of interest.

Background Plin is a novel non-G-CSF small molecule, in development for the prevention of Chemo-Induced Neutropenia (CIN) and is differentiated from Peg: Plin has anticancer activity, does not cause bone pain or an immune-suppressive Neutrophil profile (i.e NLR>5; Blayney ASC0 2018, ESMO 2018, SITC 2018). For Intermediate (10-20%) Risk for Febrile Neutropenia (FN) induced by Doc 75mg/m2, single agent (SA) Plin alone was equally effective vs SA Peg standard dose (6mg) for CIN. For High (> 20%) Risk FN induced by TAC, the combination of Plin with Peg 6mg was superior vs SA Peg 6mg, and Plin combined with half-dose Peg (3 mg) was non-inferior, with respect to CIN (Blayney ASCO 2019; St Gallen 2019). Adding Plin to any dose of Peg eradicated Peg-induced bone pain (Blayney St Gallen 2019). Here we evaluated effects of Peg and Plin on absolute platelet count by analyzing thrombocytopenia frequency (T). Methods We analyzed T Grade (Gr by CTCAE 4.03 criteria) in 4 treatment arms of BC patients receiving 4 cycles of TAC and Peg doses of either 0 mg (N = 15), 1.5 mg (N = 14), 3 mg (N = 21) or 6 mg (N = 16) in the phase (Ph) II Study BPI-2358-106 (NCT03294577). All pts in these 4 arms also received Plin 20 mg/m2. A 5th arm (N = 22) with SA Peg 6mg (without Plin) was also evaluated for T in study 106. Results Increasing Peg doses caused a statistically significant dose-dependent increase in T (Table below). T frequency with SA Plin was generally low (Table below) and not different from reported T frequency with TAC use (Any Gr T = 39% and Gr3/4 T = 2%; Taxotere Product Label). With SA Peg 6 mg (arm 5), Gr 1 (46%), Gr 2 (5%) and Gr 3 (9%), T was not significantly (P = 0.2) different vs Plin+Peg 6mg. Gr 4 T was not observed. Table . 1813P Thrombocytopenia Frequency Plin+ Peg 0 mg Plin+ Peg 1.5 mg Plin+ Peg 3 mg Plin+ Peg 6 mg P-Value of Peg Dose effect on T T Any Grade 26.7% 35.7% 52.4% 93.8% P T Grade 1 20% 35.7% 28.6% 56.3% P = 0.03 T Grade 2 6.68% 0% 23.8% 18.8% P = 0.056 T Grade 3 0% 0% 0% 18.8% P Conclusions Plin 20mg/m2 did not induce T. Peg caused a statistically and clinically significant dose-dependent increase in T. A ph III confirmatory trial is underway. Clinical trial identification BPI-2358-106. Legal entity responsible for the study BeyondSpring Pharmaceuticals, Inc. Funding BeyondSpring Pharmaceuticals, Inc. Disclosure D.W. Blayney: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BeyondSpring Pharmaceuticals, Inc. I. Bondarenko: Honoraria (self): BeyondSpring Pharmaceuticals, Inc. Y. Shi: Honoraria (self), Advisory / Consultancy: BeyondSpring Pharmaceuticals, Inc. S. Ogenstad: Advisory / Consultancy, Travel / Accommodation / Expenses: BeyondSpring Pharmaceuticals, Inc. L. Du: Leadership role, Travel / Accommodation / Expenses, Full / Part-time employment, Officer / Board of Directors: Wanchun Bulin Pharmaceuticals, Inc; Shareholder / Stockholder / Stock options: BeyondSpring, Inc. L. Huang: Leadership role, Travel / Accommodation / Expenses, Full / Part-time employment, Officer / Board of Directors: BeyondSpring Pharmaceuticals, Inc; Shareholder / Stockholder / Stock options: BeyondSpring, Inc. R. Mohanlal: Leadership role, Travel / Accommodation / Expenses, Full / Part-time employment, Officer / Board of Directors: BeyondSpring Pharmaceuticals, Inc; Shareholder / Stockholder / Stock options: BeyondSpring, Inc.

104 Background: JCOG0909, a single-arm confirmatory trial of definitive chemoradiotherapy (dCRT) including salvage treatment, demonstrated promising efficacy and safety for cStage II/III (UICC-TNM 6th) esophageal cancer (EC) (Ito Y, ASCO 2018). Radiation (RT) fields included the elective regional lymph node during initial 41.4 Gy, such as bilateral supraclavicular fossae and superior mediastinal lymph nodes for upper thoracic (Ut), and mediastinal and perigastric lymph nodes for middle thoracic (Mt)/lower thoracic (Lt) EC. It is unclear whether the safety and efficacy are associated with the tumor location in patients with cStage II/III EC treated with dCRT. Methods: Patients who were enrolled in JCOG0909 and underwent dCRT were analyzed. Patients were categorized into three groups according to primary tumor location (Ut/Mt/Lt). We compared adverse events during dCRT, complete response (CR) rate, progression-free survival (PFS) and overall survival (OS) among groups. Results: Ninety-four patients (Ut/Mt/Lt: 16/59/19) were analyzed. The proportions of cStage IIA/IIB/III were 31%/44%/25% in Ut group, 20%/42%/37% in Mt group, and 21%/32%/47% in Lt group, respectively. The summary of safety and efficacy was listed in Table 1. Grade 3-4 leukopenia, neutropenia and thrombocytopenia were more frequently observed in Mt and Lt groups than in Ut group. CR rate was 63% in Ut, 63% in Mt, and 42% in Lt, respectively. 3-year PFS in Ut/Mt/Lt was 60%/59%/47% and 3-year OS was 73%/78%/58%, respectively. Conclusions: The RT field by the tumor location might be associated with efficacy and safety of dCRT for cStage II/III esophageal cancer. [Table: see text]

Objective To use novel statistical methods for analyzing the effect of lesion set on (long-standing) persistent atrial fibrillation (AF) in the Cardiothoracic Surgical Trials Network trial of surgical ablation during mitral valve surgery (MVS). Methods Two hundred sixty such patients were randomized to MVS + surgical ablation or MVS alone. Ablation was randomized between pulmonary vein isolation and biatrial maze. During 12 months postsurgery, 228 patients (88%) submitted 7949 transtelephonic monitoring (TTM) recordings, analyzed for AF, atrial flutter (AFL), or atrial tachycardia (AT). As previously reported, more ablation than MVS-alone patients were free of AF or AF/AFL at 6 and 12 months (63% vs 29%; P Results Estimated freedom from AF/AFL/AT on any transmission trended higher after biatrial maze than pulmonary vein isolation (odds ratio, 2.31; 95% confidence interval, 0.95-5.65; P = .07) 3 to 12 months postsurgery; estimated AF/AFL/AT load (ie, proportion of TTM strips recording AF/AFL/AT) was similar (odds ratio, 0.90; 95% confidence interval, 0.57-1.43; P = .6). Within 12 months, estimated prevalence of AF/AFL/AT by TTM was 58% after MVS alone, and 36% versus 23% after pulmonary vein isolation versus biatrial maze (P Conclusions Statistical modeling using TTM recordings after MVS in patients with (long-standing) persistent AF suggests that a biatrial maze is associated with lower AF/AFL/AT prevalence, but not a lower load, compared with pulmonary vein isolation. The discrepancy between AF/AFL/AT prevalence assessed at 2 time points by Holter monitoring versus weekly TTM suggests the need for a confirmatory trial, reassessment of definitions for failure after ablation, and validation of statistical methods for assessing atrial rhythms longitudinally.

Objectives We evaluated the safety and effectiveness of the Resolute™ zotarolimus-eluting stent (R-ZES) in real-world clinical practice through 3 years. Background A randomized comparison of the R-ZES and the XIENCE V™ everolimus-eluting stent showed no difference in any outcomes through 3-year follow-up in high-volume academic centers. RESOLUTE International is a confirmatory trial designed to evaluate the R-ZES in real-world clinical practice. Methods RESOLUTE International is a single arm, observational trial that enrolled 2,349 patients from 88 centers with only a few inclusion and exclusion criteria. The primary end-point was the composite of cardiac death and target vessel myocardial infarction (TV-MI) at 1 year. Secondary end-points include target lesion failure (TLF), target vessel revascularization (TVR), and their components, and stent thrombosis (ST). Results At 3 years 97.2% of patients completed clinical follow-up. The mean age was 63.4 ± 11.2 years, 77.8% were male, and 30.4% had diabetes. The average number of stents per patient was 1.6 ± 1.0; and mean stent length was 30.9 ± 20.5 mm. Dual antiplatelet therapy was used in 91.1% of patients at 1 year, 43.0% at 2 years, and 34.6% at 3 years. Cardiac death and TV-MI occurred in 161 patients (7.0%). There were 6 (0.3%) very late ST events for a total ST rate of 1.1% through 3 years. The rates of clinically driven target lesion revascularization (TLR), TVR, and TLF were 5.7%, 7.4%, and 11.4%, respectively. Conclusions The safety and effectiveness of the R-ZES through 3 years in this real-world all-comer study was consistent with previously reported all-comer trials. (J Interven Cardiol 2013;26:515-523)

Motivated by a complex study design aiming at a definitive evidential setting, a panel forum among academia, industry, and US regulatory statistical scientists was held at the 7th International Conference on Multiple Comparison Procedures (MCP) to comment on the multiplicity problem. It is well accepted that studywise or familywise, type I error rate control is the norm for confirmatory trials. But, it is an uncharted territory regarding the criteria beyond a single confirmatory trial. The case example describes a Phase III program consisting of two placebo-controlled multiregional clinical trials identical in design intended to support registration for treatment of a chronic condition in the lung. The case presents a sophisticated multiplicity problem in several levels: four primary endpoints, two doses, two studies, two regions with different regulatory requirements, one major protocol amendment on the original statistical analysis plan, which the panelists had a chance to study before the forum took place. There were differences in professional perspectives among the panelists laid out by sections. Nonetheless, irrespective of the amendment, it may be arguable whether the two studies are poolable for the analysis of two primary endpoints prespecified. How should the study finding be reported in a scientific journal if one health authority approves while the other does not? It is tempting to address the Phase III program level multiplicity motivated by the increasing complexity of the partial hypotheses framework posed that are across studies. A novel thinking of the MCP procedures beyond individual-study level (studywise or familywise as predefined) and across multiple-study level (experimentwise and sometimes programwise) will become an important research problem expected to face with scientific and regulatory challenges.

Screening trials are small trials used to decide whether an intervention is sufficiently promising to warrant a large confirmatory trial. Previous literature examined the situation where treatments are tested sequentially until one is considered sufficiently promising to take forward to a confirmatory trial. An important consideration for sponsors of clinical trials is how screening trials should be planned to maximize the efficiency of the drug development process. It has been found previously that small screening trials are generally the most efficient. In this paper we consider the design of screening trials in which multiple new treatments are tested simultaneously. We derive analytic formulae for the expected number of patients until a successful treatment is found, and propose methodology to search for the optimal number of treatments, and optimal sample size per treatment. We compare designs in which only the best treatment proceeds to a confirmatory trial and designs in which multiple treatments may proceed to a multi-arm confirmatory trial. We find that inclusion of a large number of treatments in the screening trial is optimal when only one treatment can proceed, and a smaller number of treatments is optimal when more than one can proceed. The designs we investigate are compared on a real-life set of screening designs. Copyright © 2013 John Wiley & Sons, Ltd.

Angiogenesis is one of the classic and diagnostic features of glioblastoma. These newly formed blood vessels are typically tortuous, forming vascular glomeruli, and they are notable for the lack of the tight junctions and complete pericyte coverage. This leads to peritumoral edema and extravasation of intravenous contrast on computed tomography or magnetic resonance imaging. Because angiogenesis is such an important aspect of glioblastoma biology, targeting this process has been considered a therapeutic priority. Vascular endothelial growth factor A is the most prominent and common mediator of angiogenesis, although there are a variety of other factors that have been identified in glioblastoma. Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor A, showed activity in a variety of solid tumors. However, brain tumors were excluded from early studies of bevacizumab because of concerns regarding the risk of intracranial hemorrhage. A presentation in 2005 of a small number of patients with recurrent glioblastoma who were safely treated with bevacizumab led to larger formal clinical trials. These initial studies combined bevacizumab with irinotecan, emulating the successful treatment regimen in colorectal cancer, and demonstrated imaging response rates in the 30% to 40% range. These studies confirmed that the rate of intracranial hemorrhage was low and that the systemic toxicities were on par with this treatment regimen in other cancers. Two subsequent trials solidified these early results. The BRAIN Trial was a multicenter, randomized, noncomparative phase II study that treated patients with recurrent glioblastoma with bevacizumab either as a single agent or in combinationwith irinotecan. A parallel study was done at the National Institutes of Health, where patients were treated with bevacizumab in a single arm but at progression, irinotecan could be added. The results of these two studies were quite consistent with objective response rates ranging from 28% to 38%. The median overall survival (OS), measured from entry onto these studies, was similar. However, in the absence of a treatment arm without bevacizumab, assessment of the impact on OS was difficult. On the basis of the response rates, bevacizumab was granted accelerated approval by the Food and Drug Administration for treatment of patients with recurrent glioblastoma. Bevacizumab was then tested in newly diagnosed glioblastoma in two international placebo-controlled, double-blinded randomized phase III trials, AVAGlio and RTOG 0825. These studies added bevacizumab to the standard first-line treatment of glioblastoma, which combines external beam radiationwith concurrent daily temozolomide followed by six to 12 cycles of single-agent temozolomide. Both studies demonstrated prolonged progression-free survival (PFS) with bevacizumab; although because of differences in statistical design, the PFS difference was statistically significant in AVAGlio but not in RTOG 0825. However, neither study showed a difference in OS. A subsequent three-arm phase II trial in patients with recurrent glioblastoma, BELOB, randomly assigned patients to single-agent lomustine, single-agent bevacizumab, or the combination of lomustine and bevacizumab. This study enrolled approximately 50 patients per arm and was designed to look for a survival signal, designating the 9-month survival rate as the metric of success. Only the combination arm of bevacizumab and lomustine surpassed the preset threshold of a 9-month survival rate of 55%. The EORTC 26101 phase III trial was designed as the confirmatory trial. Patients with recurrent glioblastoma were randomized to either lomustine or the combination of lomustine with bevacizumab. The results were recently presented at the annual meeting of the Society for NeuroOncology. No survival difference was noted between the two treatment arms, although there was a difference in PFS. The article accompanying this editorial has the results of the GLARIUS trial, an open-label, randomized study that compared the standard treatment for newly diagnosed glioblastoma (chemoradiation with temozolomide, followed by maintenance temozolomide) with radiation followed by the combination of bevacizumab and irinotecan. Eligibility was restricted to patients with centrally confirmed glioblastoma that on molecular testing demonstrated that the promoter region of the O6-methylguanine DNA methyltransferase (MGMT) gene was unmethylated. These patients have a worse prognosis and the benefit of temozolomide is modest at best, allowing temozolomide to be excluded from the experimental arm. The primary end point of the trial was the progression-free rate at 6 months, a metric more commonly used for clinical trials for recurrent glioblastoma where statistical parameters are well established. The results did demonstrate a statistically significant difference in this metric, but the secondary end point of OSwas not different between the two treatment arms. There were, however, a high percentage of crossovers, with patients on the control (temozolomide) arm receiving bevacizumab at progression and, conversely, patients on the experimental (bevacizumab and irinotecan) arm receiving temozolomide at recurrence. How do we interpret this large composite of clinical trials? The gold standard benchmark of efficacy in cancer clinical trials is

The discovery of numerous molecular subtypes of common cancers leads to the investigation of biomarkers potentially predictive of treatment effect of an experimental treatment in multiple histologies. However, the prevalence of a putative predictive biomarker within a histology is often low, which makes it challenging to enroll adequate number of patients in a conventional histology-based confirmatory trial. An alternative approach is to study patients with a common biomarker signature in a “basket” trial across multiple histologies. This study design has previously been used to explore experimental therapies with potentially transformative effects. We present a general design concept of a Phase 3 basket trial broadly applicable to any effective therapy. The trial is designed with scientific and statistical rigor to enable the approval of an experimental treatment in multiple tumor indications based on the outcome from a single study. Given the difficulty in indication selection, the basic idea is to prune the inactive indications at an interim analysis and pool the active indications in the final analysis. A critical statistical issue of the basket design is Type I error control for the pooled analysis after pruning. While pruning may be seen as cherry-picking which tends to inflate the Type I error, it also shares similarity with a binding futility analysis which tends to deflate the Type I error if all indications are pruned. The net impact of pruning is complicated. The use of different endpoints for pruning and pooling further complicates the issue. This paper will provide statistical details on Type I error control for the general basket design concept under three sample size adjustment strategies after pruning. Power and sample size calculations are also provided. Comparisons are made to a straightforward design without pruning. Supplementary materials for this article are available online.

For a drug to be clinically useful, physicians must know the optimal conditions for its application, including dose, timing of administration, and route of delivery. Typically, these conditions are discovered over the course of early phase clinical testing. In what follows, we describe a conceptual tool—“ensemble space”—for understanding scientific decision-making in the early phases of clinical development. Briefly, we liken each condition to a dimension that can assume an optimal value for clinical utility. Early stages of intervention development can thus be described as a process of exploring a multi-dimensional landscape of conditions, with the aim of identifying necessary and sufficient conditions (i.e. effective “intervention ensembles”) to unlock the clinical utility of a drug. We then show how the concept of ensemble space can be used to address and resolve perennial scientific and ethical debates in clinical development, such as how aggressively to design early phase studies, when to initiate randomized trials, and reporting requirements for early phase studies. We close by discussing some limitations of the concept of ensemble space.

Although acupuncture researchers have conducted studies using rats for decades, there is no established method for controlling the animals while performing acupuncture. Some choose to use general anesthesia [1]; some prefer light sedation [2]; many opt to use tools such as tubes, bags [3, 4], or clothing holders [5]; while others simply immobilize them by hand [6]. In 2013, a study by Zhang et al. [7] further compared the analgesic effects of electroacupuncture (EA) in rats using a novel nonrestraining method that was developed by one of the coauthors in 2011 [8]. Their results showed that the nonrestraining method had similar analgesic effects to the restraining model but reduced stress on rats while also giving researchers greater access to treatment intensities and acupuncture points. However, one acupuncture point that they did not explore was PC6, which is the most frequently stimulated treatment point in cardiovascular studies. Unlike other parts of the rat's body (outer part of the forearm, hind leg, or back), PC6 is located on the inner part of the forearm that frequently sweeps the ground, is open to a wide range of motion, and consists of thin muscle layers, resulting in difficulty with needle insertion and increased risk of bent or pulled-out needles. Furthermore, previous cardiovascular studies recommend performing EA on PC6 with a frequency of 2 Hz and verifying motor threshold response based on visible muscle twitches on the stimulated area [9–11], making the nonrestraining method even more challenging. Since we could not use the nonrestraining method and there were no studies exploring optimal experimental methods for cardiovascular rat models utilizing EA on PC6, we looked at the protective effects of EA in the restrained rat model and the anesthetized rat model of myocardial ischemia-reperfusion (IR) injury. Thirty-two male Sprague-Dawley rats were randomly divided into an anesthetized (AN) group and a restrained (RS) group, which were further divided into four subgroups each (n = 4 for all subgroups) consisting of (1) the sham subgroup, which had their chest opened and the heart exposed but were sutured without further intervention; (2) the IR subgroup; (3) the IR + EA subgroup (EA on PC6, ST36 for 30 min); and (4) the IR + placebo subgroup (EA on nonacupoints without conduction of electricity). On the first day, IR injury was induced in all rats (except the sham subgroups) by placing a slipknot (5-0 silk) around the left anterior descending coronary artery and releasing it after 40 min of ischemia. During the whole process, rats were anesthetized with ketamine (75 mg/kg) and xylazine (2 mg/kg) and mechanically ventilated (Harvard Apparatus, MA, USA). On the first day, the IR + EA subgroups in both AN and RS groups were anesthetized prior to surgery and preconditioned with EA on the left PC6 and ST36 starting 20 min after ischemia was induced to 10 min after the snare was loosened. The IR + placebo subgroups were treated with EA on nonacupoints without conduction of electricity. From the second day to the fifth day, the IR + EA subgroup in the AN group received EA for 30 min every day under anesthesia, with additional anesthesia administered intramuscularly if needed (but to a minimum degree); the IR + EA subgroup in the RN group received the same treatment immobilized in the restrainers. Similarly, placebo EA was conducted in the IR + placebo subgroups in both the AN and RS groups. All EA stimulation was administered with acupuncture needles (0.20 × 30 mm, Dongbang Acuneedle Co, Gyeonggi-Do, Korea) with a frequency of 2 Hz for 30 min. To evaluate LV function, rats were anesthetized on the last day, and cardiac function was measured using two-dimensional transthoracic echocardiography (Vivid Q; GE Medical Systems, Milwaukee, WI, USA) with a 12 MHz probe. M-mode echocardiography of the LV was performed at the papillary muscle level, guided by two-dimensional short-axis images. LV cavity size was measured during at least three beats in each projection and averaged. The m-mode images yielded systolic and diastolic wall thicknesses (anterior and posterior), and LV end-systolic and end-diastolic diameters. LV fractional shortening was calculated as (LVEDD − LVESD)/LVEDD∗100. All values are expressed as mean ± SE. Results were analyzed using the Kruskal-Wallis nonparametric test for multiple comparisons, and p values less than 0.05 were considered statistically significant. In our findings, improvement in cardiac function was similar in the IR + EA subgroups of both AN and RS groups, but there were different results in the placebo subgroups. While the LVEF of the AN placebo subgroup did not improve (IR, 60.30 ± 5.49; IR + EA, 70.56 ± 4.42; IR + placebo, 54.88 ± 2.12, p 0.05). Among many possible factors that could have produced the additional effects, we believe frequent reinsertion of acupuncture needles was a significant factor. In the restrained group, the rats frequently flexed their muscles to try to escape from the restrainers, which made the acupuncture needles fall out. Although the needles at ST36 mostly stayed intact, the ones at PC6 were a problem, as the needles were inserted to a shallower depth of approximately 5 mm. Every time the needles fell out, the researchers had to stick them back in, which increased stress and produced additional somatosensory stimulation. Unlike the RS placebo subgroup, the AN placebo subgroup (which did not require reinsertions) showed no significant improvement in LVEF, and in a confirmatory trial that limited the number of reinsertions per session to less than three, the LVEF of the RS placebo subgroup did not improve. Our observation is noteworthy because in the study by Zhang et al. [7], the authors also report that they had to reinsert the needles several times when using the novel nonrestraining method. However, based on our findings, frequent reinsertion itself can contribute significantly to the final treatment effect and should be controlled regardless of how quickly and conveniently it can be performed. Much more experiments to standardize and optimize research methods in acupuncture-related preclinical studies should be conducted. Novel methods to control rats must be continuously explored and researchers should know that differences in handling techniques can unwittingly expose well-designed studies to confounding factors, reproducibility failures, and limitations. Both of the chosen methods in our study do have their limitations, sedating animals prior to every acupuncture session is not feasible, and restraining rats also induces high levels of stress [12–14]. Using anesthesia for one or two days may be harmless, but results can be different when anesthetics are accumulated for several days. Furthermore, the difference between our study and the study by Zhang et al. [7] may be due to the different pathological rat models used and the different endpoints defined. For now, however, unless an improved nonrestraining method is developed that can be used for needling PC6, in acupuncture-related cardiovascular studies, researchers should try to minimize needle fall-outs, limit the number of reinsertions per session, or use general anesthesia if all factors cannot be adequately controlled.

Adaptive designs allow the investigator of a confirmatory trial to react to unforeseen developments by changing the design. This broad flexibility comes at the price of a complex statistical model where important components, such as the adaptation rule, remain unspecified. It has thus been doubted whether Type I error control can be guaranteed in general adaptive designs. This criticism is fully justified as long as the probabilistic framework on which an adaptive design is based remains vague and implicit. Therefore, an indispensable step lies in the clarification of the probabilistic fundamentals of adaptive testing. We demonstrate that the two main principles of adaptive designs, namely the conditional Type I error rate and the conditional invariance principle, will provide Type I error rate control, if the conditional distribution of the second-stage data, given the first-stage data, can be described in terms of a regression model. A similar assumption is required for regression analysis where the dis...

The U.S. Food and Drug Administration granted accelerated approval to pembrolizumab for the treatment of patients with metastatic non-small cell lung cancer whose tumors express programmed death-ligand 1. This work discusses the data supporting the approval decision, specifically highlighting the incorporation of a companion diagnostic in the key study and the optimal dose of pembrolizumab., On October 2, 2015, the U.S. Food and Drug Administration (FDA) granted accelerated approval for pembrolizumab, a breakthrough therapy-designated drug, for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express programmed death-ligand 1 (PD-L1), as determined by an FDA-approved test, and who have disease progression on or after platinum-containing chemotherapy or targeted therapy against anaplastic lymphoma kinase or epidermal growth factor receptor, if appropriate. This indication was approved concurrently with the PD-L1 immunohistochemistry 22C3 pharmDx, a companion diagnostic test for patient selection based on PD-L1 tumor expression. The accelerated approval was granted based on durable objective response rate (ORR) and an acceptable toxicity profile demonstrated in a multicenter, open-label trial enrolling 550 patients with metastatic NSCLC. The efficacy population comprised 61 patients with tumors identified as strongly positive for PD-L1, and the confirmed ORR as determined by blinded independent central review was 41% (95% confidence interval: 28.6%, 54.3%); all were partial responses. At the time of the analysis, responses were ongoing in 21 of 25 patients (84%), with 11 patients (44%) having response duration of ≥6 months. The most commonly occurring (≥20%) adverse reactions included fatigue, decreased appetite, dyspnea, and cough. The most frequent (≥2%) serious adverse drug reactions were pleural effusion, pneumonia, dyspnea, pulmonary embolism, and pneumonitis. Immune-mediated adverse reactions occurred in 13% of patients and included pneumonitis, colitis, hypophysitis, and thyroid disorders. The accelerated approval regulations describe approval of drugs and biologic products for serious and life-threatening illnesses based on a surrogate endpoint likely to predict clinical benefit. Under these regulations, a confirmatory trial or trials is required to verify and describe the benefit of pembrolizumab for patients with metastatic NSCLC. Implications for Practice: This report presents key information on the U.S. Food and Drug Administration (FDA) accelerated approval of pembrolizumab for the treatment of patients with metastatic non-small cell lung cancer whose tumors express programmed death-ligand 1, as determined by an FDA-approved test, and who have disease progression on or after platinum-containing chemotherapy or targeted therapy against anaplastic lymphoma kinase or epidermal growth factor receptor, if appropriate. The report discusses the data supporting the approval decision, specifically highlighting the incorporation of a companion diagnostic in the key study and the optimal dose of pembrolizumab.

Clinical trials in drug development are commonly divided into 3 categories or phases. The first phase aims to find the range of doses of potential clinical use, usually by identifying the maximum tolerated dose. The second phase aims to find doses that demonstrate promising efficacy with acceptable safety. The third phase aims to confirm the benefit previously found in the second phase using clinically meaningful end points and to demonstrate safety more definitively. Dose-finding trials—studies conducted to identify the most promising doses or doses to use in later studies—are a key part of the second phase and are intended to answer the dual questions of whether future development is warranted and what dose or doses should be used. If too high a dose is chosen, adverse effects in later confirmatory phase 3 trials may threaten the development program. If too low a dose is chosen, the treatment effect may be too small to yield a positive confirmatory trial and gain approval from a regulatory agency. A well-designed dose-finding trial is able to establish the optimal dose of a medication and facilitate the decision to proceed with a phase 3 trial. Selection of a dose for further testing requires an understanding of the relationships between dose and both efficacy and safety. These relationships can be assessed by comparing the data from each dose group with placebo, or with the other doses, in a series of pairwise comparisons. This approach is prone to both false-negative and false-positive results because of the large number of statistical comparisons and the relatively small number of patients receiving each dose. These risks can be mitigated by combining data from patients receiving multiple active doses into a single treatment group for comparison with placebo (“pooling”), but only if it is possible to reliably predict which doses are likely to be effective. In general, dose-response relationships are best examined through dose-response models that make flexible, justifiable assumptions about the potential dose-response relationships and allow the integration of information from all doses used in the trial. This can reduce the risk of both false-negative and false-positive results; incorporating all data into the estimates of efficacy and safety for each dose produces more accurate estimates than evaluating the response to each dose separately. In this issue of JAMA, Gheorghiade et al 1 report the results of

Background: The treatment of Acute Myeloid Leukemia (AML) in elderly patients remains unsatisfactory, with an expected survival time of about 1 year post diagnosis. In an attempt to improve outcome for these patients, the prospective open-label phase 3 LAMSA-2007 trial (Clinicaltrial.gov ID, NCT00590837) repeated, at decreasing doses in consolidation and reinduction courses, a standard induction regimen with cytarabine and idarubicin (IC), with or without the randomized addition of lomustine (ICL). This alkylating agent with significant anti-leukemic activity is widely used in France for AML therapy. This study was performed as a confirmatory trial, following our previous report of the French experience in which this compound stood out as a favorable factor of improved outcome for patients with non-unfavorable cytogenetics (Pigneux, JCO 2010). Methods: Eligible patients were adults 60 years old or more, with previously untreated AML, fit to receive intensive chemotherapy (ECOG and SORROR Results: From February 2008 to December 2011, 459 patients were enrolled and 424 were evaluable. The median age of analyzed patients was 68 yo (60-81), 58% were male. Cytogenetics was favorable (5.2%), intermediate (90.3%) or failure (4.5%). Overall, 26% of the patients had a favorable genotype based on NPM, CEBPa and FLT3 ITD mutational status. The two arms were comparable for pre-treatment characteristics. There were 3.7% induction deaths in the IC arm and 7.7% in the ICL arm (p=0.11). The rate of primary resistant AML was 21.4% after IC versus 7.7% after ICL (p Conclusion: Thisschedule using the same drugs at decreasing doses during induction, consolidation and reinductions provided unusually good results in the IC arm, further improved in the ICL arm by the addition of lomustine, in fit elderly AML patients without unfavorable cytogenetics, with acceptable toxicity. The higher rate of CR, reduced relapse incidence and improved EFS in the ICL arm support the anti-leukemic effect of lomustine in elderly AML patients, even if it does not translate in a significantly prolonged long term overall survival. New strategies for maintenance therapy remain to be improved in this setting to sustain this positive effect. Disclosures Vey: Janssen: Honoraria; Roche: Honoraria; Celgene: Honoraria.

Clinical trials across multiple regions of the world have become common practice, with the ultimate goal to bring good medical products to patients around the world, as fast as scientifically possible. While these trials offer access to diverse patient populations, they are not without logistical challenges, including issues related to the quality of trial conduct, data validity, and the relevance of a single large confirmatory trial. In September 2008, PhRMA sanctioned a Key Issue Team (KIT) to examine issues relevant to multiregional clinical trials (MRCTs). The MRCT KIT formed four work streams that have contributed the five articles in this special section of this issue of the journal. As guest editors for these articles, as well as cochairs of the PhRMA MRCT KIT, we provide this introductory overview of industry perspective on MRCT to serve as background for the more focused articles that follow.

In confirmatory clinical trials the Type I error rate must be controlled for claims forming the basis for approval and labeling of a new drug. Strong control of the familywise error rate is usually needed for hypotheses related to the primary endpoint(s). For hypotheses related to secondary endpoint(s) which are only of interest if the corresponding “parent” primary null hypotheses have been rejected, less strict error rate control might be sufficient. We review and extend procedures for families of primary and secondary hypotheses when either at least one of the primary hypotheses or all coprimary hypotheses must be rejected to claim success for the trial. Such families of hypotheses arise naturally from comparing several treatments with a control, combined noninferiority and superiority testing for primary and secondary variables, the presence of multiple primary or secondary endpoints or any combination thereof. We show that many of the procedures proposed in the literature follow a common underlying p...

controlled trials (RCTs) represent the gold standard of methodology in clinical research and maximize the validity of scientific data through eliminating systematic biases. However, for clinical investigators one of the major ethical weaknesses is the act of randomization itself [1]. Clinical-researchers face the dilemma of reconciling their duty as physicians to provide the best care for their patients with the preeminent scientific process of assigning research participants to competing therapies by chance alone. The concept of ‘clinical equipoise’has been utilized by ethicists and researchers to overcome this crisis of professional responsibility. The reigning definition was described by Freedman as “an ethically necessary condition in all cases of clinical research... [that exists when] there is no consensus within the expert clinical community about the comparative merits of the alternatives to be tested” [2]. Since the 1970s equipoise has been challenged, deconstructed, and reformulated in the ethics literature, and it remains open for interpretation. Contemporary ethicists caution against relying on equi

Pertuzumab injection was granted accelerated approval by the US Food and Drug Administration last fall for use in combination with trastuzumab plus docetaxel for neoadjuvant treatment of patients with HER2-positive locally advanced, inflammatory, or early-stage breast cancer (either > 2 cm in diameter or node-positive) as part of a complete treatment regimen for early breast cancer. The accelerated approval was based on improvement in pathologic complete response (pCR) rate in a phase 2 trial. Data showing improved event-free survival or overall survival are not yet available. Continued approval for this indication is contingent on demonstration of improvement in disease-free survival in a confirmatory trial.

Progestogens are the first drugs to demonstrate reproducibly a reduction in the rate of early preterm birth. The efficacy and safety of progestogens are related to individual pharmacologic properties of each drug within this class of medication and characteristics of the population that is treated. The synthetic 17-hydroxyprogesterone caproate and natural progesterone have been studied with the use of a prophylactic strategy in women with a history of preterm birth and in women with a multiple gestation. Evidence from a single large comparative efficacy trial suggests that vaginal natural progesterone is superior to 17-hydroxyprogesterone caproate as a prophylactic treatment in women with a history of mid-trimester preterm birth. Progestogen therapy is indicated for women with this highest risk profile based on evidence from 2 trials. A therapeutic approach based on the identification of a sonographic short cervix has been studied in several phase III trials. Independent phase III trials and an individual patient metaanalysis suggest that vaginal progesterone is efficacious and safe in women with a singleton and a short cervix. Two trials that tested 17-hydroxyprogesterone caproate in women with a short cervix showed no benefit. No consistent benefit for the prophylactic or therapeutic use of progestogens has been demonstrated in larger trials of women whose pregnancies were complicated by a multiple gestation (twins or triplets), preterm labor, or preterm rupture of membranes. Unfortunately, several large randomized trials in multiple gestations have identified harm related to 17-hydroxyprogesterone caproate exposure, and the synthetic drug is contraindicated in this population. The current body of evidence is evaluated by the Grading of Recommendations Assessment, Development, and Evaluation guidelines to derive the strength of recommendation in each of these populations. A large confirmatory trial that is testing 17-hydroxyprogesterone caproate exposure in women with a singleton pregnancy and a history of preterm birth is near completion. Additional study of the efficacy and safety of progestogens is suggested in well-selected populations based on the presence of biomarkers.