scholarly journals Chemical Composition and Petrogenetic Implications of Eudialyte-Group Mineral in the Peralkaline Lovozero Complex, Kola Peninsula, Russia

Minerals ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1036
Author(s):  
Lia Kogarko ◽  
Troels F. D. Nielsen
Keyword(s):  
Magma Chamber ◽  
Phase Ii ◽  
Phase Iii ◽  
Magma Flow ◽  
Eudialyte Group ◽  
Compositional Evolution ◽  
World Class ◽  
Bulk Content ◽  
Phase Ii And Iii ◽  
Convective Volume

Lovozero complex, the world’s largest layered peralkaline intrusive complex hosts gigantic deposits of Zr-, Hf-, Nb-, LREE-, and HREE-rich Eudialyte Group of Mineral (EGM). The petrographic relations of EGM change with time and advancing crystallization up from Phase II (differentiated complex) to Phase III (eudialyte complex). EGM is anhedral interstitial in all of Phase II which indicates that EGM nucleated late relative to the main rock-forming and liquidus minerals of Phase II. Saturation in remaining bulk melt with components needed for nucleation of EGM was reached after the crystallization about 85 vol. % of the intrusion. Early euhedral and idiomorphic EGM of Phase III crystalized in a large convective volume of melt together with other liquidus minerals and was affected by layering processes and formation of EGM ore. Consequently, a prerequisite for the formation of the ore deposit is saturation of the alkaline bulk magma with EGM. It follows that the potential for EGM ores in Lovozero is restricted to the parts of the complex that hosts cumulus EGM. Phase II with only anhedral and interstitial EGM is not promising for this type of ore. Nor is the neighboring Khibiny complex despite a bulk content of 531 ppm of Zr. Khibiny only has interstitial and anhedral EGM. The evolution of the Lovozero magma is recorded in the compositions EGM up through a stratigraphy of 2400 m in Phase II and III of the complex, and distinct in elements like rare earth elements (REE), Sr, Ba, Th, U, Rb, Mn, Fe. The compositional evolution reflects primarily fractional crystallization processes within the magma chamber itself in combination with convective magma flow and layering by precipitation of minerals with different settling velocities. The suggested mechanism for the formation of the EGM deposits is flotation of very small, suspended EGM crystals in the convective magma and concentration below the roof of the magma chamber. Phase III EGM is enriched in total REE (1.3%) and in HREE (Ce/Yt = 8.8) and constitutes a world class deposit of REE in the million tons of Phase III eudialyte lujavrites.

Tildrakizumab: A Review of Phase II and III Clinical Trials

2018 ◽  
Vol 53 (4) ◽  
pp. 413-418 ◽  
Author(s):  
Sree S. Kolli ◽  
Sarah D. Gabros ◽  
Adrian Pona ◽  
Abigail Cline ◽  
Steven R. Feldman
Keyword(s):  
Clinical Trial ◽  
Phase Ii ◽  
Biological Therapy ◽  
Common Adverse Effect ◽  
Clinical Trial Data ◽  
Trial Data ◽  
Severe Psoriasis ◽  
Phase Iii ◽  
Physician Global Assessment ◽  
Phase Ii And Iii

Objective: Tildrakizumab, an inhibitor of the p19 subunit of interleukin (IL)-23, was recently Food and Drug Administration (FDA) approved for patients with moderate to severe psoriasis. This article will review the phase II and III clinical trial data of tildrakizumab. Data Sources: A PubMed search from January 2000 to September 2018 was done with the search terms tildrakizumab, guselkumab, risankizumab, p19, interleukin-23, and psoriasis. Study Selection and Data Extraction: Articles discussing phase II and III clinical trial data for tildrakizumab were selected. Data Synthesis: In phase II and phase III trials, tildrakizumab was safe and efficacious compared with placebo and etanercept. More patients achieved Psoriasis Area and Severity Index 75 receiving tildrakizumab (200 mg, 62%-74%; 100 mg, 61%-66%; 25 mg, 64%; 5 mg, 33%) compared with placebo (4%-6%, P < 0.0001) and etanercept (48%, P = 0.01). More patients achieved Physician Global Assessment (PGA) response of “clear” or “minimal” receiving tildrakizumab (200 mg, 59%; 100 mg, 55%-58%) than the placebo group (4%-7%, P < 0.0001). 59% of patients who received tildrakizumab 200 mg achieved a PGA response of “clear” or “minimal” compared with etanercept (48%, P = 0.0031). The most common adverse effect was infection. Relevance to Patient Care and Clinical Practice: Tildrakizumab is a new, FDA-approved, physician-administered biological therapy for patients with moderate to severe psoriasis. It appears to be efficacious and safe so far. Conclusion: Tildrakizumab is efficacious and safe for the treatment of patients with moderate to severe psoriasis. IL-23/p19 inhibitors are a promising class of biological therapy.

PrabotulinumtoxinA-xvfs for the Treatment of Moderate-to-Severe Glabellar Lines

2020 ◽  
pp. 106002802094352
Author(s):  
Mary B. Gadarowski ◽  
Rima I. Ghamrawi ◽  
Sarah L. Taylor ◽  
Steven R. Feldman
Keyword(s):  
Clinical Trials ◽  
Phase Ii ◽  
Data Extraction ◽  
Botulinum Toxin Type A ◽  
Botulinum Toxin Type ◽  
Phase Iii ◽  
Phase Iii Clinical Trials ◽  
Study Selection ◽  
Pubmed Database ◽  
Phase Ii And Iii

Objective: PrabotulinumtoxinA-xvfs (Jeuveau), a botulinum toxin type A, was approved by the Food and Drug Administration for the temporary improvement in the appearance of moderate-to-severe glabellar lines in February 2019. This article will review phase II and III clinical trials to assess the efficacy, safety, and clinical application of this novel, aesthetic-only drug. Data sources: A systematic literature review was performed using the terms “glabellar lines AND prabotulinumtoxinA” in the PubMed database. ClinicalTrials.gov was searched to identify nonpublished studies. Study Selection and Data Extraction: Articles written in English between November 2019 and June 2020 discussing phase II and phase III clinical trials were evaluated. Data Synthesis: By the primary efficacy end point on day 30, more patients achieved a greater than 2-point improvement on the Glabellar Line Scale (GLS) at maximum frown compared with baseline on day 0. The proportions of participants who responded to treatment with prabotulinumtoxinA were 67.5% and 70.4% versus 1.2% and 1.3% in placebo groups across 2 identical clinical trials ( P < 0.001). Patients receiving prabotulinumtoxinA experienced greater improvement in GLS at maximum frown on day 30 (87.2%) compared with onabotulinumtoxinA (82.8%) and placebo (4.2%; P < 0.001). PrabotulinumtoxinA was well tolerated across all studies. Relevance to Patient Care and Clinical Practice: This review provides a detailed analysis of the safety and efficacy of prabotulinumtoxinA-xvfs and includes special considerations to help guide patients and clinicians. Conclusion: PrabotulinumtoxinA is a safe and effective new addition to the repository of available treatments for the appearance of glabellar lines.

Treating Psoriasis With Halobetasol Propionate and Tazarotene Combination: A Review of Phase II and III Clinical Trials

2020 ◽  
Vol 54 (9) ◽  
pp. 872-878
Author(s):  
Vignesh Ramachandran ◽  
Brooke Bertus ◽  
Arjun M. Bashyam ◽  
Steven R. Feldman
Keyword(s):  
Clinical Trials ◽  
Phase Ii ◽  
Plaque Psoriasis ◽  
Patient Adherence ◽  
Treatment Success ◽  
Phase Iii ◽  
Global Assessment Scale ◽  
Once Daily ◽  
Psoriasis Treatment ◽  
Phase Ii And Iii

Objective: To review phase II and III clinical trial data to evaluate the efficacy and safety of the halobetasol propionate/tazarotene (HP/TAZ) combination lotion (Duobrii), a medication approved by the Food and Drug Administration in April 2019 for adults with plaque psoriasis. Data Sources: A systematic search (January 2005 to July 2019) of MEDLINE (PubMed) and EMBASE databases was performed using the terms halobetasol, tazarotene, halobetasol/tazarotene, Duobrii, and IDP-118. Study Selection and Data Extraction: Relevant English-language articles reporting on phase II and phase III clinical trials were included. Data from the individual trials were extracted independently and then cross-checked to ensure accuracy. Data Synthesis: HP/TAZ was safe and efficacious compared with HP alone, TAZ alone, or vehicle. More patients achieved treatment success, described as a ≥2-grade improvement on Investigator Global Assessment Scale, over 8 weeks of treatment and at the 4-week follow-up after treatment cessation. The most common adverse events were dermatitis, pain, and pruritus, which occurred more often in the TAZ groups compared with the HP/TAZ cohorts. Relevance to Patient Care and Clinical Practice: The once-daily HP/TAZ combination lotion simplifies psoriasis treatment and may facilitate adherence, which may improve psoriasis outcomes. Conclusions: HP/TAZ combination lotion is efficacious and safe for plaque psoriasis treatment, with more patients achieving end points and fewer side effects than in HP, TAZ, or vehicle-treated controls. Drug synergy may play a role. Importantly, patient adherence to a once-daily combinational therapy is likely to contribute to efficacy.

Evolution of statistical methodology and design of phase II/III clinical trials in non-small cell lung cancer (NSCLC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7108-7108 ◽  
Author(s):  
R. K. Bagai ◽  
A. Dowlati
Keyword(s):  
Clinical Trials ◽  
Survival Time ◽  
Phase Ii ◽  
Response Rate ◽  
Phase Iii ◽  
Type I ◽  
Phase Ii Trials ◽  
Improvement In Survival ◽  
Phase Ii And Iii ◽  
Phase Iii Studies

7108 Background: A significant heterogeneity exists in the design and reporting of phase II and III therapeutic clinical trials in NSCLC. This has led to difficulty in interpretation of these trials leading to over- or underestimation of therapeutic efficacy. We set out to investigate the statistical methodology and design reporting of chemotherapeutic trials in NSCLC published in the Journal of Clinical Oncology (JCO) over 20 years. Methods: We identified all phase II and III NSCLC chemotherapy trials published in the JCO from January 1983 to August 2005. All manuscripts were reviewed to evaluate components of statistical design that were reported, including: sample size calculation, power, type I error, single or multiple drug trials, relative response sought in phase II trials and improvement in survival time or response rate sought in phase III trials. Results: One hundred forty eight trials were identified. 52% of studies were phase III and 48% were phase II. The majority (78%) were conducted in advanced stage NSCLC. Sample size calculations were reported for only 58% of phase III studies and 31% of phase II studies. Power was reported in 66% of phase III studies and 13% of phase II trials. Type I error was reported in 47% of phase III studies and 17% in phase II studies. 60% of phase III trials defined endpoints (percentage improvement in survival time, improvement in survival time in months or increase in response rate). 41% of phase II trails defined the target response rate, ranging from response rates of 15% to 70%. The frequency of adequate reporting of statistical design was shown to increase from 31% in 1990–1995 to 64% in 2000–2005 ( table ). Conclusions: Significant heterogeneity exists in trial design and reporting of phase II and III trials in NSCLC. This impacts the ability to adequately interpret these studies. More widespread application of statistical methods in planning and reporting of lung cancer clinical trials are necessary to increase reliability of data. [Table: see text] No significant financial relationships to disclose.

Capecitabine and irinotecan (XELIRI) in first-line treatment of metastatic colorectal cancer (mCRC): A systematic review of controlled clinical trials

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15100-e15100
Author(s):  
S. Sukumaran ◽  
N. Pavlakis ◽  
K. B. Pittman ◽  
K. Patterson ◽  
T. J. Price
Keyword(s):  
Phase Ii ◽  
Phase Iii ◽  
Line Treatment ◽  
Phase Ii Trials ◽  
First Line ◽  
Hand Foot Syndrome ◽  
Phase Iii Trials ◽  
Grade 3 ◽  
Phase Ii And Iii ◽  
First Line Treatment

e15100 Background: Irinotecan and 5-Fluorouracil based combination is an effective regimen for mCRC. Capecitabine, an oral fluoropyrimidine, is a convenient alternative to intravenous 5- Fluorouracil. This study aims to systematically review all published and unpublished controlled phase II and III trials of XELIRI combination, used in first line treatment of mCRC, reported from 2000–2008, to describe its efficacy and safety. Methods: A literature search of MEDLINE, EMBASE, CINAHL and proceedings from ASCO, ESMO and WGIC was conducted. The primary end point was response rate (RR), secondary endpoints include: time to progression (TTP), overall survival (OS) and toxicity. Results: Thirty non-randomised phase II trials (n = 1380) along with 6 randomised phase II and 3 phase III trials, were included (pooled n = 1478). The daily dose of capecitabine ranged from 1,800 mg/m2 to 2,500 mg/m2 for 7 to 14 days per cycle and the dose of irinotecan varied from 180mg/m2 to 350 mg/m2, over a 3 week period per cycle. Amongst the non-randomised studies, the median patient age was 61 years (53–72).The median RR was 46.75% (25–78%). The median reported TTP was 7.9 months (mo) (5- 9.9 mo) and the median OS was 15.6 months (7–24.8 mo). Grade 3–4 toxicity incidence was: diarrhoea (21.5%), neutropenia (12%), vomiting (12.5%), fatigue (6%) and Hand-foot syndrome (6%). The pooled incidence of febrile neutropenia was 2.5%. Amongst the randomised trials, the comparator regimens were XELOX or FOLFIRI. Median age was 65 years (61–74). RR for XELIRI was 39% (34–56%) compared to 47% (27–61.8%) for the non XELIRI comparator arms. Median reported TTP was 8.2 mo (5.7–12.5 mo) for the XELIRI arms and 9.2 mo for the comparator arms. Conclusions: XELIRI is an effective and feasible regime in the first line management of mCRC. However the optimal role of this combination remains to be established. No significant financial relationships to disclose.

Combinations of drugs

1996 ◽  
Vol 1 (6) ◽  
pp. 400-403 ◽  
Author(s):  
Ludwig Kappos
Keyword(s):  
Phase Ii ◽  
Theoretical Background ◽  
Phase Iii ◽  
Mri Findings ◽  
Recombinant Interferon ◽  
Therapeutic Trials ◽  
Phase Ii Studies ◽  
Proven Efficacy ◽  
Phase Ii And Iii ◽  
Combination Regimens

As a result of recent therapeutic trials, recombinant Interferon beta (r/FNβ)-1b and-1a as well as Copolymer 1 (COP 1) and to some extent unspecific immunosuppressants have been accepted as partially efficient treatments of relapsing-remitting MS. In view of partially effective single treatments, the question arises if combination of two or even more agents could improve efficacy without increasing side effects. The theoretical background of possible combinations is discussed. The selection of combination partners should be based on their proven efficacy as Singh treatment, on their mode of action and their distinct target in the pathogenetic cascade of events and on their specific side effect prof ile. Combination regimens selected in this way should undergo evaluation in short term early phase II studies and if the results are positive enter phase III studies. The use of surrogate markers (especially MRI-findings) may help to accelerate this process. Combinations that could enter phase II and III studies in the near future are r/FNβ with unspecific immunosuppressants, e.g. Azathioprine or Methotrexate and r/FNβ with COP I. Combinations including agents just entering phase I and II studies as a single treatment may be more promising for the future.

Phase II trial of gemcitabine, carboplatin, and bevacizumab in chemotherapy-naive patients (Pts) with advanced/metastatic urothelial carcinoma (UC).

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 248-248 ◽  
Author(s):  
A. V. Balar ◽  
M. I. Milowsky ◽  
A. B. Apolo ◽  
I. Ostrovnaya ◽  
A. Iasonos ◽  
...  
Keyword(s):  
Phase Ii ◽  
Stable Disease ◽  
Response Rate ◽  
Unmet Need ◽  
Phase Iii ◽  
Risk Scores ◽  
Primary Endpoints ◽  
Grade 3 ◽  
Phase Ii And Iii ◽  
To Receive

248 Background: Effective treatment for pts with advanced UC unfit to receive cisplatin-based therapy remains an unmet need. A recent phase III study showed limited benefit of gemcitabine-carboplatin (GC) alone (median OS 9.3 months) (DeSantis ASCO 2010). We recently identified the VEGF-axis as a viable pathway for UC treatment (JCO 2010;Mar 10). We propose that bevacizumab, a monoclonal antibody against VEGFR, may be safely added to GC and improve time to progression (TTP) in pts with advanced UC. Methods: Primary endpoints (N=47 planned enrollment) were median TTP, to test an improvement of 50% over a 4.8 months median TTP seen with GC alone (Urology 2004;64:479), and safety. Secondary endpoints were response rate (RR) and overall survival (OS). Pts first received a single dose of bevacizumab 10 mg/kg. 2 weeks later they received 6 cycles of gemcitabine 1,000 mg/m2 on day(D) 1 and D 8, and both carboplatin AUC 4.5 and bevacizumab 15 mg/kg on D1 every 21 days. Pts who achieved at least stable disease were eligible to receive maintenance bevacizumab at 15 mg/kg q21 days for 18 additional doses. Restaging evaluations were performed after every 3 cycles of therapy. Results: 51 pts (37 M, 14 F; median age 67 (Range 42-83)) were enrolled from 6/06 to 6/10. Primary tumor sites include bladder (31), renal pelvis (17) and ureter (2). 38 pts (74.5%) had visceral disease including lung (22), liver (13), bone (9) and adrenal (2). 13 pts had LN only disease. 46 of 51 pts were evaluable for response rate (RR) and TTP, 51 for toxicity. RR by RECIST was 46% (21 pts; PR 18, CR 3). 12 achieved stable disease; 1 too early to assess. Responses by MSKCC Risk Scores of 0, 1 and 2 were seen in 8/11(73%), 10/29 (35%), and 3/6 (50%) pts, respectively. 39% of pts had grade 3/4 toxicity, notably vascular thromboembolic events (VTE) in 18%. Conclusions: Bevacizumab can be safely added to GC in the treatment of advanced UC. The 16% VTE rate is similar to the 17% rate seen at MSKCC with GC alone. (JCO 2009;27:15s). Addition of bevacizumab does not improve the RR seen with GC alone in phase II and III studies (Bellmunt Eur J Cancer 2001; DeSantis ASCO 2010). Analysis of bevacizumab's impact on TTP and OS is ongoing and will be updated. [Table: see text]

scholarly journals The Role of Checkpoint Inhibitors in Adults with Classical Hodgkin Lymphoma; A Systematic Review and Meta-Analysis of Phase II and III Clinical Trials

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 25-26
Author(s):  
Yazan Samhouri ◽  
Muhammad Yasir Anwar ◽  
Ali Younas Khan ◽  
Urwat Til Vusqa ◽  
Iqraa Ansar ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase Ii ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Pooled Analysis ◽  
Phase Iii ◽  
Classical Hodgkin Lymphoma ◽  
Programmed Death ◽  
Phase Ii And Iii

Introduction The ability of the neoplastic cells to escape from immune surveillance has been considered as a hallmark of cancer. The upregulation of programmed death-1 (PD-1) and programmed death ligand-1/2 (PDL-1) axis is a major immune escape pathway in multiple malignancies including classical hodgkin lymphoma (cHL). Disruption of PD1-PDL1/2 pathway using checkpoint inhibitors (CPIs) leads to reactivation of immune cells to attack malignant cells. CPIs have been studied in cHL in different settings. Here in, we did a systematic review and meta-analysis of phase II and III clinical trials that looked at the efficacy of CPIs in cHL Methods We did a comprehensive literature search, using 4 major databases (pubmed, embase, chocrane, and clinialtrials.gov). We used MeSH terms and related keywords that included all CPIs in generic and trade names, and cHL. We included phase II and III prospective clinical trials in patients &gt; 18 year-old. We excluded case reports, case series, review articles, retrospective and observational studies, and phase I clinical trials. Initial search resulted in 1647 articles. After applying the inclusion and exclusion criteria, we had 13 articles that we explored in details. We stratified the articles according to CPIs and did a pooled-analysis of the complete response (CR) rate. Medcalc was used to do the statistical analysis. Results Of those 13 clinical trials, we had 12 phase II trials and 1 phase III trial. Nivolumab was studied in 7 trials (n=568), pembrolizumab in 5 trials (n=427), and camrelizumab in 1 trial (n=86). Table 1 shows the characteristics of these trials. (table 1) Four studies evaluated the efficacy of nivolumab in the relapsed/refractory (RR) setting. Armand et al (2018) evaluated the efficacy of nivolumab after autologous hematopoietic stem cell transplantation (auto-HSCT), the cohort in this study was divided into 3 groups: patients who received brentuximab vedotin (BV) after auto-HSCT, patients who are BV naïve, and patients who received BV before and/or after auto-HSCT. Overall response rate (ORR) and CR were 68% and 13%, 65% and 29%, 73% and 12%, respectively. Maruyama et al (2017) reported ORR and CR of 81.3% and 25%, in 16 Japanese patients received nivolumab in combination with BV. The ORR and CR in the remaining 2 trials were: 82% and 59%, and 85% and 67%. In the frontline setting, nivolumab showed ORR and CR of 84% and 67% (Ramchandren et al, 2019), 96%-100% and 53-85% (Brockelmann et al, 2019 in 2 different dosing regimens), and 100% and 72% (Yasenchack et al, 2019). Pooled analysis of all nivolumab trials showed CR rate of 47.4 % (95% CI 29.0-66.1) (figure 1) Pembrolizumab was evaluated in 4 clinical trials in the RR setting. Armand et el (2019) reported CR rate of 83% in 25 patients. Chen et al (2019) reported ORR and CR of 76.8 % and 26.1% in patients who relapsed after auto-HSCT and BV, 66.7% and 25.9% in patients ineligible for HSCT, and 73.3% and 31.7% in patients who relapsed after auto-HSCT with no prior exposure to BV. In combination with gemcitabine, vinorelbone , and doxorubicin, pembrolizumab showed ORR and CR of 100% and 93%, respectively. The only phase III clinical trial compared pembrolizumab vs BV in the RR setting showed ORR of 65.6% vs 54% and CR of 24.5% vs 24%, respectively. Only one study evaluated pembrolizumab in the frontline setting, ORR and CR of 100% in 30 patients received 3 cycles of pembolizumab followed by 4-6 cycles of doxorubicin, vinblastine, and dacarbazine. Pooled analysis of all pembrolizumab trials showed CR rate of 54.4% (95% CI 32.6-77.2) (figure 2) Only one trial evaluated the role of camrelizumab as monotherapy or in combination with decitabine. The combination regimen showed ORR and CR of 95% and 71% in CPIs naïve patients, and 52% and 28% in patients previously received CPIs. Camrelizumab monotherapy showed ORR and CR of 90% and 32% in CPIs naïve patients. Conclusion CPIs in cHL have showed high rates of response in the frontline and RR settings, with fairly acceptable toxicity profile. Their efficacy was studied post HSCT and BV, in BV naïve patients, and in HSCT-ineligible patients. Pembrolizumab and nivolumab were the 2 most studied CPIs. Future direction should focus on more studies in the frontline setting, the role of combined CPIs with other CPIs or with novel agents, to spare this relatively young population the long term toxicity of chemotherapy. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.Fazal:Jansen:Speakers Bureau;Jazz Pharma:Consultancy, Speakers Bureau;Stemline:Consultancy, Speakers Bureau;Glaxosmith Kline:Consultancy, Speakers Bureau;Gilead/Kite:Consultancy, Speakers Bureau;Amgen:Consultancy, Speakers Bureau;Novartis:Consultancy, Speakers Bureau;Agios:Consultancy, Speakers Bureau;BMS:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Celgene:Speakers Bureau;Karyopham:Speakers Bureau;Incyte Corporation:Consultancy, Honoraria, Speakers Bureau;Takeda:Consultancy, Speakers Bureau.

scholarly journals Optimal designs for phase II/III drug development programs including methods for discounting of phase II results

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Stella Erdmann ◽  
Marietta Kirchner ◽  
Heiko Götte ◽  
Meinhard Kieser
Keyword(s):  
Drug Development ◽  
Sample Size ◽  
Phase Ii ◽  
Treatment Effect ◽  
Development Program ◽  
Phase Iii ◽  
Effect Estimate ◽  
Development Programs ◽  
Treatment Effect Estimate ◽  
Phase Ii And Iii

Abstract Background Go/no-go decisions after phase II and sample size chosen for phase III are usually based on phase II results (e.g., the treatment effect estimate of phase II). Due to the decision rule (only promising phase II results lead to phase III), treatment effect estimates from phase II that initiate a phase III trial commonly overestimate the true treatment effect. Underpowered phase III trials are the consequence. Optimistic findings may then not be reproduced, leading to the failure of potentially expensive drug development programs. For some disease areas these failure rates are described to be quite high: 62.5%. Methods We integrate the ideas of multiplicative and additive adjustment of treatment effect estimates after go decisions in a utility-based framework for optimizing drug development programs. The design of a phase II/III program, i.e., the “right amount of adjustment”, the allocation of the resources to phase II and III in terms of sample size, and the rule applied to decide whether to stop or to proceed with phase III influences its success considerably. Given specific drug development program characteristics (e.g., fixed and variable per patient costs for phase II and III, probable gain in case of market launch), optimal designs with respect to the maximal expected utility can be identified by the proposed Bayesian-frequentist approach. The method will be illustrated by application to practical examples characteristic for oncological studies. Results In general, our results show that the program set-ups with adjusted treatment effect estimate used for phase III planning are superior to the “naïve” program set-ups with respect to the maximal expected utility. Therefore, we recommend considering an adjusted phase II treatment effect estimate for the phase III sample size calculation. However, there is no one-fits-all design. Conclusion Individual drug development planning for a specific program is necessary to find the optimal design. The optimal choice of the design parameters for a specific drug development program at hand can be found by our user friendly R Shiny application and package (both assessable open-source via [1]).

scholarly journals Biological therapies and their clinical impact in the treatment of systemic lupus erythematosus

2019 ◽  
Vol 11 ◽  
pp. 1759720X1987430 ◽  
Author(s):  
Rosalie Magro
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Clinical Experience ◽  
Phase Ii ◽  
Lupus Erythematosus ◽  
Phase Iii ◽  
Biological Therapies ◽  
Phase Ii Trials ◽  
Systemic Lupus ◽  
Biological Drugs ◽  
Phase Ii And Iii

The development of biological therapies has had an impact on the management of several medical conditions. Their use in systemic lupus erythematosus (SLE), however, remains very limited. This review has summarized the evidence on the clinical effect of biologicals in SLE. Biological drugs with a number of targets have been studied in several phase II and III randomized controlled trials (RCTs). Positive results have been obtained in phase III RCTs with belimumab and this led to its license for active SLE. The clinical experience with belimumab has confirmed the efficacy and safety of belimumab in SLE. Promising results have been noted in phase II trials for blisibimod, sifalimumab, anifrolumab, and ustekinumab. Despite the fact that the RCTs with rituximab did not achieve their primary endpoint, clinical experience with rituximab is extensive and shows favorable clinical response in refractory renal and non-renal SLE. It is hoped that further ongoing phase III RCTs on a number of biological agents in SLE will highlight the potential role of other biologicals in the management of this challenging and heterogeneous condition.

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