Use Of Response Rate Research Articles

Unique characteristics of regulatory approval and pivotal studies of orphan anticancer drugs in Japan.

The approval of orphan anticancer drugs has increased, with the number exceeding that of non-orphan drugs in Japan in recent years. Although orphan anticancer drugs may have unique characteristics due to their rarity, these have not been fully characterized. We investigated anticancer drugs approved in Japan between April 2004 and November 2017 to reveal the characteristics of regulatory approval and pivotal studies on orphan anticancer drugs compared to non-orphan drugs. The median regulatory review time and number of patients in pivotal studies on orphan anticancer drugs (281.0days [interquartile range, 263.3-336.0]; 222.5 patients [66.0-454.3]) were significantly lower than those on non-orphan drugs (353.0days [277.0-535.5]; 521.0 patients [303.5-814.5], respectively) (P < 0.001). Phase II, non-randomized and non-controlled designs were more frequently used in pivotal studies on orphan anticancer drugs (45.9%, 41.9% and 43.2%) than non-orphan drugs (17.2%, 14.1% and 14.1%, respectively). Response rate was more commonly used as a primary endpoint in pivotal studies on orphan anticancer drugs (48.6%) than non-orphan drugs (17.2%). Indications limited by molecular features, second or later treatment line, and accelerated approval in the United States were associated with the use of response rate in orphan anticancer drug studies. In conclusion, we demonstrated that orphan anticancer drugs in Japan have unique characteristics compared to non-orphan drugs: shorter regulatory review and pivotal studies frequently using phase II, non-randomized, or non-controlled designs and response rate as a primary endpoint, with fewer patients.

Selection Error in Single- and Mixed Mode Surveys of the Dutch General Population

SummaryThis study compares the extent of selection error (non-response and coverage error) evoked by the four major contemporary modes of data collection (face to face, telephone, mail and Web) and three sequential mixed mode designs (telephone, mail and Web with face-to-face follow-up) for the case of the Dutch Crime Victimization Survey. Sociodemographic characteristics and target variables from the survey serve as benchmark variables. A special two-wave experimental design allows studying design differences in selection error on Crime Victimization Survey variables independently from differences in measurement error. Despite large differences in response rates, only small or no differences in selection error between the four single-mode designs are found on both types of variable. We observe cases when the error is enlarged or mitigated in the mixed mode designs despite the fact that the designs yielded large response increases. Our results question the use of response rates to motivate the choice of mode and use of mixed mode surveys.

Assessment of tumor response as a surrogate endpoint of survival in recurrent/platinum-resistant ovarian carcinoma: A Gynecologic Oncology Group study

Purpose We investigated whether tumor response rate (TRR), disease control rate (DCR), or progression-free survival (PFS) was a valid surrogate for overall survival (OS) in phase II trials of second-line therapies for patients with platinum-resistant ovarian carcinoma (PROC). Methods We retrospectively evaluated data from 11 second-line phase II trials conducted for PROC by the Gynecologic Oncology Group (GOG). TRR included complete response and partial response (CR/PR) and DCR was defined as either tumor response or stable disease (CR/PR + SD). Survival by tumor response was analyzed using a landmark approach. Correlations of OS with TRR, DCR, and PFS were estimated. Results Among 407 patients analyzed the TRR was 13.8% (56/407) and DCR was 38.8% (158/407). Median OS was 10.2 months while median PFS was only 2.4 months. Median OS among patients with a best response of CR/PR, SD, and progressive disease (PD) was 13.3, 12.1 and 5.7 months, respectively, showing no difference between CR/PR and SD. From a protocol level, DCR correlated better with OS (Pearson r = 0.748; Tau-b r = 0.514) compared to TRR (Pearson r = 0.564; Tau-b r = 0.404). PFS rate at 6 months (Pearson r = 0.661; Tau-b r = 0.514) also correlated strongly with OS. Conclusions This study demonstrates the limitations of the use of response rate alone in PROC. Clinical benefit, as defined by OS, appeared similar for patients with an objective response and those with SD. The DCR, by including tumor response and SD may have utility as a surrogate endpoint for survival in phase II therapeutic trials in PROC.

FDA Drug Approval Summary: Bevacizumab (Avastin®) as Treatment of Recurrent Glioblastoma Multiforme

On May 5, 2009, the U.S. Food and Drug Administration granted accelerated approval to bevacizumab injection (Avastin; Genentech, Inc., South San Francisco, CA) as a single agent for patients with glioblastoma multiforme (GBM) with progressive disease following prior therapy. The approval was based on durable objective responses (independent radiologic review with stable or decreasing corticosteroid use). Two trials evaluating bevacizumab, 10 mg/kg by i.v. infusion every 2 weeks, were submitted. One trial also randomized patients to bevacizumab plus irinotecan treatment. All patients had received prior surgery, radiotherapy, and temozolomide. Patients with active brain hemorrhage were excluded. One trial enrolled 78 independently confirmed GBM patients. Partial responses were observed in 25.9% (95% confidence interval [CI], 17.0%-36.1%) of the patients. The median response duration was 4.2 months (95% CI, 3.0-5.7 months). The second trial enrolled 56 GBM patients. Partial responses were observed in 19.6% (95% CI, 10.9%-31.3%) of the patients. The median response duration was 3.9 months (95% CI, 2.4-17.4 months). Safety data were provided for the first study. The most frequently reported bevacizumab adverse events of any grade were infection, fatigue, headache, hypertension, epistaxis, and diarrhea. Grade 3-5 bevacizumab-related adverse events included bleeding/hemorrhage, central nervous system (CNS) hemorrhage, hypertension, venous and arterial thromboembolic events, wound-healing complications, proteinuria, gastrointestinal perforation, and reversible posterior leukoencephalopathy. The attribution of certain adverse events (e.g., CNS hemorrhage, wound-healing complications, and thromboembolic events) to either bevacizumab, underlying disease, or both could not be determined because of the single-arm, noncomparative study design.

Phase II Trials in Journal of Clinical Oncology

Phase II Trials in <i>Journal of Clinical Oncology</i>

Evolution of the Randomized Controlled Trial in Oncology Over Three Decades

The randomized controlled trial (RCT) is the gold standard for establishing new therapies in clinical oncology. Here we document changes with time in design, sponsorship, and outcomes of oncology RCTs. Reports of RCTs evaluating systemic therapy for breast, colorectal (CRC), and non-small-cell lung cancer (NSCLC) published 1975 to 2004 in six major journals were reviewed. Two authors abstracted data regarding trial design, results, and conclusions. Conclusions of authors were graded using a 7-point Likert scale. For each study the effect size for the primary end point was converted to a summary measure. A total of 321 eligible RCTs were included (48% breast, 24% CRC, 28% NSCLC). Over time, the number and size of RCTs increased considerably. For-profit/mixed sponsorship increased substantially during the study period (4% to 57%; P < .001). There was increasing use of time-to-event measures (39% to 78%) and decreasing use of response rate (54% to 14%) as primary end point (P < .001). Effect size remained stable over the study period. Authors have become more likely to strongly endorse the experimental arm (P = .017). A significant P value for the primary end point and industry sponsorship were each independently associated with endorsement of the experimental agent (odds ratio [OR] = 19.6, 95% CI, 8.9 to 43.1, and OR = 3.5, 95% CI, 1.6 to 7.5, respectively). RCTs in oncology have become larger and are more likely to be sponsored by industry. Authors of modern RCTs are more likely to strongly endorse novel therapies. For-profit sponsorship and statistically significant results are independently associated with endorsement of the experimental arm.

Evolution of the randomized controlled trial (RCT) in oncology over three decades

6515 Background: The RCT is the gold standard for establishing new therapies in oncology. Here we document changes with time in design, results, author conclusions and sponsorship. Methods: Reports of RCTs evaluating systemic therapy for breast, colorectal (CRC) and non-small cell lung cancer (NSCLC) published 1975–2004 in 6 major journals were reviewed. Two authors independently abstracted data regarding trial design, effect size and author conclusions. Author conclusions were assigned a score from 1 to 7: 4/7 for a neutral statement, 7/7 and 1/7 for strong endorsement of experimental and control arm respectively. For each study the effect size for the primary endpoint was converted to a summary measure: hazard ratio [HR] for survival endpoints and relative risk [RR] for response rate. Descriptive statistics were used to analyze trends over time. Results: 326 eligible RCTs were included (48% breast, 24% CRC, 28% NSCLC). There was a significant increase in the number and size of RCTs (see Table ). Median rate of accrual increased from 7 patients/month in 1975–84 to 14 patients/month in 1995–2004 (p&lt;0.001). There was an increase in multicenter (55 to 95%, p&lt;0.001), international trials (26 to 52%, p&lt;0.001) and for-profit sponsorship over time (6 to 57%, p&lt;0.001). There was increasing use of survival (13 to 48%,) and decreasing use of response rate (32 to 14%) as primary endpoint (p&lt;0.001). Authors have become more likely to strongly endorse the experimental arm despite no change in effect size over time (p=0.005). Studies sponsored by for-profit organizations were more likely to strongly endorse the experimental agent than studies not sponsored by for-profit groups (median author score 6/7 vs. 4/7, p&lt;0.001). Conclusions: RCTs in oncology have become more common, larger, and are more likely to be sponsored by industry. Authors of modern RCTs are more likely to strongly endorse novel therapies despite no increase in the relative benefit of interventions. For-profit sponsorship is associated with stronger endorsement of the experimental arm. No significant financial relationships to disclose. [Table: see text]

The molar view of behavior and its usefulness in behavior analysis.

molar view of behavior contrasts with the older, molecular view. difference is paradigmatic, not theoretical. No experiment can decide between them, because they interpret all the same phenomena, but in different terms. molecular view relies on the concepts of discrete, momentary events and contiguity between them, whereas the molar view relies on the concepts of temporally extended patterns of activity and correlations. When dealing with phenomena such as avoidance, rule-governed behavior, and choice, the molar view has the advantage that it requires no appeal to hypothetical constructs. molecular view always appeals to hypothetical constructs to provide immediate reinforcers and stimuli when none are apparent. As a result, the explanations offered by the molar view are straightforward and concrete, whereas those offered by the molecular view are awkward and implausible. usefulness of the molar view for applied behavior ties in the flexibility and conceptual power it provides for talking about behavior and contingencies over time. ********** molar view of behavior is relatively new. Although its origins may be traced back earlier, its first partial articulation was by Baum and Rachlin (1969), in a paper called Choice as time allocation. It was presented more fully in a paper by Baum (1973), The correlation-based law of effect. Rachlin (1994) offered a book-length presentation, and Baum (2002) elaborated on his 1973 paper in another paper, From molecular to molar: A paradigm shift in behavior analysis and some papers in-between (Baum, 1995a; 1997). molar view contrasts with an older view that behavior inherited from nineteenth-century psychology. I call this older view molecular, because it is based on the notion explanations of behavior may be constructed by thinking of small discrete units being joined together into larger units, like the joining together of atoms into molecules in chemistry. difference between the molecular and molar views of behavior is paradigmatic, not theoretical. No data, no experiment can decide between the two views, because no matter what behavioral phenomenon one chooses, a proponent of either view is able to construct an account of it. difference between the two lies in the concepts each brings to bear in such an account. molecular view relies on momentary events and momentary causation, which leads to postulating hypothetical momentary events and causes when none are apparent, whereas the molar view relies on extended activities and extended causation, avoiding postulation of hypothetical constructs. Replacing the concept of momentary response with the concept of extended activity requires one to become familiar with thinking in more continuous terms-that is, in terms of extended patterns that cannot be seen at a moment in time. A familiar example is the concept of probability. An unbiased coin, when flipped, comes up heads with a probability of .50. What does this mean? On any particular flip, the coin comes up heads or tails; nothing more can be observed. Only for a long series of flips can one observe the probability of .50. If one says that on a particular flip the probability is .50, all one means is that in a long series of such flips about half would show heads. same is true of response rate. At any particular moment, an activity (lever pressing) is occurring or not. One can only observe the response rate over some substantial time period. A response that occurs 60 times per minute cannot occur 60 times per minute at a moment. Although Skinner advocated the use of response rate as a dependent variable, he was a molecularist. In his well-known paper on superstition, Skinner (1948) proposed a snapshot view of reinforcement, in which delivery of a reinforcer strengthens whatever behavior happens to be occurring at the moment. molecularity of his approach is perhaps nowhere clearer than in a short piece he wrote called Farewell, My Lovely! …

The role of chemotherapy in the treatment of children with neuroblastoma stage IV: The GPO (German Pediatric Oncology Society) experience

340 consecutive patients with neuroblastoma stage IV were analyzed for the possible impact of chemotherapy on general condition, remission status, event free survival and survival. The children entered the trials NB 79, NB 82 and NB 85 of the German Pediatric Oncology Society (GPO). The patients did benefit from chemotherapy by considerable improvement of the general condition, by achievement of 30-40% complete and 60-70% partial remissions. The event free survival (EFS) rate 5-8 years after diagnosis was 13% for all 299 protocol patients, the survival (S) rate 10%. The median/mean EFS time were 11.6/23.8 months, the median/mean S time 17.0/29.4 months. The use of response rates as early predictors for long term survival is challenged. Addition of PCVm (cisplatinum, cyclophosphamide, Vm 26) to ACVD (adriamycine, cyclophosphamide, vincristine, dacarbazine) in trial NB 82 resulted in an improvement of the long term EFS rate from 5% to 18% (S rates 7----21%). The introduction of IVp (ifosfamide, VP16) and increase of doses (cisplatinum, Vm 26) did not further improve the results. Maintenance therapy (NB 82) revealed a positive influence on the outcome. Shorter intervals for realization of chemotherapy were associated with a trend for better EFS (NB 85). Although the group of children with bone marrow transplantation showed better EFS and S data compared to the unselected chemotherapy group, the advantage was less clear if matched pairs (remission status at the time of BMT) were compared.(ABSTRACT TRUNCATED AT 250 WORDS)

Behavioral augmentation of tolerance to alcohol and the response measure

The differential effects upon behavior of alcohol in tolerance acquisition were examined. Consistent with earlier findings using a treadmill and temporal maze, tolerance as assessed by changes in operant response duration was transferable to another operant task, and tolerance as measured by operant response duration was augmented by drug-related practice only in the rate of tolerance acquisition, not in the level of tolerance attained. However, with the use of response rate as the acquisition index, tolerance was not completely transferable to a different operant and drug-related practice augmented rate of acquisition as well as final level of tolerance attained. It is suggested that the response measure employed is a variable in the determination of the behavioral augmentation of alcohol tolerance in the rat.