Historical controls in clinical trials: a note on linking Pocock's model with the robust mixture priors.

Several Bayesian methods have been proposed to borrow information dynamically from historical controls in clinical trials. In this note, we identify key features of the relationship between the first method proposed, the bias-variance method, which is strongly related to the commensurate prior approach, and a more recent and widely used approach called robust mixture priors (RMP). We focus on the two key terms that need to be chosen to define the RMP, namely $w$, the prior probability that the new trial differs systematically from the historical trial, and $s_v^2$, the variance of the vague component of the RMP. The relationship with Pocock's prior reveals that different combinations of these two terms can express similar prior beliefs about the amount of information provided by the historical data. This demonstrates the value of fixing $s_v^2$, e.g., so the vague component is "worth one subject." Prior belief about the relevance of the historical data is then driven by a single value, the prespecified weight $w$.

Estimation of historical control rate for a single arm de-escalation study - Application to the POSITIVE trial.

BACKGROUND: Although randomized controlled clinical trials are optimal to evaluate the effect of an experimental therapy, single-arm trials are required whenever randomization is unethical or not feasible, such as de-escalation studies. We propose using prospectively identified historical controls to place results of single-arm, de-escalation trials into context. METHODS: POSITIVE is a prospective, single-arm study in young women with hormone-receptor-positive early breast cancer to determine if temporarily interrupting adjuvant endocrine therapy in order to become pregnant increases the risk of a breast cancer event. After 272 women enrolled in POSITIVE, we identified a cohort of 1499 SOFT/TEXT patients potentially eligible to enroll in POSITIVE who did not interrupt endocrine therapy. Method I used the SOFT/TEXT cohort to calculate annualized hazard rates by a piecewise exponential model. Method II used the SOFT/TEXT cohort to group-match SOFT/TEXT patients to POSITIVE patients; sample sets of SOFT/TEXT patients were randomly drawn 5000 times to obtain sets having patient, disease, and treatment characteristics more balanced with POSITIVE participants. RESULTS: Compared with SOFT/TEXT, POSITIVE participants were younger, less likely to be overweight/obese, had fewer positive nodes, and fewer received aromatase inhibitor or chemotherapy. The estimated 3-year breast cancer free interval event rates were 9.5% (95% CI: 7.9%,11.1%) for Method I and 9.4% (95% CI: 7.8%,10.9%) for Method II, compared with 5.8% initially assumed when POSITIVE was designed. CONCLUSION: External control datasets should be identified before launching single-arm, de-escalation trials and methods applied during their conduct to provide context for interim monitoring and interpretation of the final analysis.

Results after introduction of a hip fracture care pathway: comparison with usual care.

Background and purpose - We established a care pathway for hip fracture patients, a "Hip Fracture Unit" (HFU), aiming to provide better in-hospital care and thus improve outcome. We compared the results after introduction of the HFU with a historical control group.Patients and methods - The HFU consisted of a series of measures within the orthopedic ward, such as reducing preoperative waiting time, increased use of nerve blocks, early mobilization, and osteoporosis treatment. 276 patients admitted from May 2014 to May 2015 constituted the HFU group and 167 patients admitted from September 2009 to January 2012 constituted the historical control group. Patients were followed prospectively up to 12 months post fracture.Results - Mean preoperative waiting time was 24 hours in the HFU group and 29 hours in the control group (p = 0.003). 123 patients (47%) in the HFU were started on anti-osteoporosis treatment while in hospital. "Short Physical Performance Battery" score (SPPB) was mean 5.5 in the HFU group and 3.8 in the control group at 4 months (p < 0.001), and 5.7 vs. 3.6 at 12 months (p < 0.001). The mortality rate at 4 months was 15% in both groups. No statistically significant differences were found in readmissions, complications, new nursing home admissions, in Barthel ADL index or a mental capacity test at the follow-ups.

Group sequential design for historical control trials using error spending functions.

Group sequential designs using Lan-DeMets error spending functions are proposed for historical control trials with time-to-event endpoints. Both O'Brien-Fleming and Gamma family types of sequential decision boundaries are derived based on sequential log-rank tests, which follow a Brownian motion in a transformed information time. Simulation results show that the proposed group sequential designs using historical controls preserve the overall type I error and power.

Use of a historical control group in a noninferiority trial assessing a new antibacterial treatment: A case study and discussion of practical implementation aspects.

When recruitment into a clinical trial is limited due to rarity of the disease of interest, or when recruitment to the control arm is limited due to ethical reasons (eg, pediatric studies or important unmet medical need), exploiting historical controls to augment the prospectively collected database can be an attractive option. Statistical methods for combining historical data with randomized data, while accounting for the incompatibility between the two, have been recently proposed and remain an active field of research. The current literature is lacking a rigorous comparison between methods but also guidelines about their use in practice. In this paper, we compare the existing methods based on a confirmatory phase III study design exercise done for a new antibacterial therapy with a binary endpoint and a single historical dataset. A procedure to assess the relative performance of the different methods for borrowing information from historical control data is proposed, and practical questions related to the selection and implementation of methods are discussed. Based on our examination, we found that the methods have a comparable performance, but we recommend the robust mixture prior for its ease of implementation.

A comprehensive intervention following the clinical pathway of eating and swallowing disorder in the elderly with dementia: historically controlled study.

BACKGROUND: Eating problems in patients with advanced dementia are strongly associated with their deteriorating survival. Food and drink intake in people with dementia may be supported by specific interventions, but the effectiveness of such interventions is backed by almost no evidence. However, comprehensive geriatric assessment (CGA) might potentially clarify the etiology of decreased oral intake in people with dementia; thus improving their clinical outcomes. METHODS: This study was a single-arm, non-randomized trial that included historically controlled patients for comparison. We defined elderly patients with both severely decreased oral intake depending on artificial hydration and/or nutrition (AHN) and dementia as "Eating and Swallowing Disorder of the Elderly with Dementia (ESDED)". In the intervention group, participants received CGA through the original clinical pathway with multidisciplinary interventions. This was followed by individualized therapeutic interventions according to assessment of the etiology of their eating problems. RESULTS: During the intervention period (between 1st April 2013 and 31st March 2015), 102 cases of ESDED were enrolled in the study and 90 patients had completed receiving CGA. Conversely, 124 ESDED patient controls were selected from the same hospital enrolled during the historical period (between 1st April 2011 and 31st March 2012). Most participants in both groups were bedridden with severe cognitive impairment. For the intervention group, an average of 4.3 interventional strategies was recommended per participant after CGA. Serological tests, diagnostic imaging and other diagnostic examinations were much more frequently performed in the intervention group. Recovery rate from ESDED in the intervention group was significantly higher than that in the historical group (51% v.s. 34%, respectively, P = 0.02). The 1-year AHN-free survival in the intervention group was significantly higher than that in the historical group (28% v.s. 15%, respectively, P = 0.01). No significant difference between the two groups was found for 1-year overall survival (37% v.s. 28%, respectively, P = 0.08). CONCLUSIONS: Use of CGA with multidisciplinary interventions could improve the functional status of eating and allow elderly patients with severe eating problems and dementia to survive independently without the need for AHN. TRIAL REGISTRATION: ISRCTN57646445 , this trial was retrospectively registered on 8th December 2015.

Quality of life, mood and seizure control in patients with brain tumor related epilepsy treated with lacosamide as add-on therapy: A prospective explorative study with a historical control group.

OBJECTIVE: Brain tumor-related epilepsy (BTRE) is often drug resistant and patients can be forced to take polytherapy that can adversely affect their quality of life (QoL). Lacosamide (LCM) is a new antiepileptic drug (AED) used as adjunctive therapy in patients with partial seizures with or without secondary generalization, with a favorable pharmacokinetic profile that seems to be effective and well tolerated. Therefore it represents a possible therapeutic choice for patients with BTRE. We propose a prospective study with a historical control group to evaluate the effect of LCM as add-on therapy on seizure control and quality of life in patients with BTRE. This study has been designed to test the superiority of Lacosamide over Levetiracetam as an add-on. We compared a prospective cohort of 25 patients treated with Lacosamide with a historical control group (n=19) treated with Levetiracetam as an add-on. METHODS: We recruited 25 adult patients (M 18, F 7; mean age 41.9) affected by BTRE with uncontrolled partial-onset seizures treated with AED polytherapy. We added LCM as an add-on. Patients were evaluated at baseline, after 3months and at 6months. This population has been compared with a historical control group of 19 BTRE adult patients (M 13, F 6; median age 48.0, range: 28-70) with uncontrolled partial-onset seizures treated with LEV as add-on. The patients underwent QoL, mood and adverse events tests (Adverse Event Profile-AEP) and evaluation of seizure frequency. RESULTS: Twelve patients had high grade gliomas, and thirteen had low grade gliomas. During follow-up, thirteen patients underwent chemotherapy, three radiotherapy and five patients had disease progression. Nine patients had simple partial seizures, eight had complex partial seizures, and eight had secondary generalized seizures. Fifteen patients were in monotherapy and ten in polytherapy with AEDs. LCM was added up to reach the maximum dosage of 400mg/die (mean final dose 300mg/die). Four patients dropped out due to poor compliance and 1 for inefficacy. In the historical control group treated with LEV (mean final dose 2000mg/die) 12 patients had high-grade gliomas, and 7 had low grade gliomas. Thirteen patients were in monotherapy and 6 in polytherapy with AEDs. In the 22 patients evaluable of 25 patients treated with LCM, we observed at final follow-up 7 patients seizure free, 12 with a significant reduction of seizures≥50%, 2 stable and 1 patient with number of seizures increased. Mean seizure frequency at baseline compared with baseline period: the mean number of seizures significantly decreased from baseline (9.4) to final follow-up (1.2) (P=0.005). The Responder Rate was 86.4%. Comparing responder rate of 22 evaluable patients with LCM with responder rate of 19 patients with LEV we didn't observe significant differences (p=0.31). In our patients treated with LCM we didn't observe significant difference at 3 and 6months in QoL tests results; we observe a significant reduction in the mean score of Karnofsky Performance Status (KPS) and Barthel Index (BI) between baseline and 6months of follow-up (KPS p=0.003; BI p=0.007). No clinical side effects were observed. CONCLUSION: Comparing the LCM with the historical group treated with LEV in add-on, we observed that LCM seems to have a higher clinical efficacy than LEV. In our patients, we did not observe any significant changes in QoL tests, indicating stability in all quality of life domains explored, despite the objective worsening in their functional status. Although this is a small series with a relatively short follow-up, our data indicates that LCM in add-on in patients with BTRE appears to be as effective as LEV in add-on, without impact on mood and quality of life.

A Bayesian analysis of quantal bioassay experiments incorporating historical controls via Bayes factors.

This paper addresses model-based Bayesian inference in the analysis of data arising from bioassay experiments. In such experiments, increasing doses of a chemical substance are given to treatment groups (usually rats or mice) for a fixed period of time (usually 2 years). The goal of such an experiment is to determine whether an increased dosage of the chemical is associated with increased probability of an adverse effect (usually presence of adenoma or carcinoma). The data consists of dosage, survival time, and the occurrence of the adverse event for each unit in the study. To determine whether such relationship exists, this paper proposes using Bayes factors to compare two probit models, the model that assumes increasing dose effects and the model that assumes no dose effect. These models account for the survival time of each unit through a Poly-k type correction. In order to increase statistical power, the proposed approach allows the incorporation of information from control groups from previous studies. The proposed method is able to handle data with very few occurrences of the adverse event. The proposed method is compared with a variation of the Peddada test via simulation and is shown to have higher power. We demonstrate the method by applying it to the two bioassay experiment datasets previously analyzed by other authors. Copyright © 2017 John Wiley & Sons, Ltd.

Sample size calculation based on efficient unconditional tests for clinical trials with historical controls.

In historical clinical trials, the sample size and the number of success in the control group are often considered as given. The traditional method for sample size calculation is based on an asymptotic approach developed by Makuch and Simon (1980). Exact unconditional approaches may be considered as alternative to control for the type I error rate where the asymptotic approach may fail to do so. We provide the sample size calculation using an efficient exact unconditional testing procedure based on estimation and maximization. The sample size using the exact unconditional approach based on estimation and maximization is generally smaller than those based on the other approaches.

The development of a comprehensive multidisciplinary care pathway for patients with a hip fracture: design and results of a clinical trial.

BACKGROUND: Hip fractures frequently occur in older persons and severely decrease life expectancy and independence. Several care pathways have been developed to lower the risk of negative outcomes but most pathways are limited to only one aspect of care. The aim of this study was therefore to develop a comprehensive care pathway for older persons with a hip fracture and to conduct a preliminary analysis of its effect. METHODS: A comprehensive multidisciplinary care pathway for patients aged 60 years or older with a hip fracture was developed by a multidisciplinary team. The new care pathway was evaluated in a clinical trial with historical controls. The data of the intervention group were collected prospectively. The intervention group included all patients with a hip fracture who were admitted to University Medical Center Groningen between 1 July 2009 and 1 July 2011. The data of the control group were collected retrospectively. The control group comprised all patients with a hip fracture who were admitted between 1 January 2006 and 1 January 2008. The groups were compared with the independent sample t-test, the Mann-Whitney U-test or the Chi-squared test (Phi test). The effect of the intervention on fasting time and length of stay was adjusted by linear regression analysis for differences between the intervention and control group. RESULTS: The intervention group included 256 persons (women, 68%; mean age (SD), 78 (9) years) and the control group 145 persons (women, 72%; mean age (SD), 80 (10) years). Median preoperative fasting time and median length of hospital stay were significantly lower in the intervention group: 9 vs. 17 hours (p < 0.001), and 7 vs. 11 days (p < 0.001), respectively. A similar result was found after adjustment for age, gender, living condition and American Society of Anesthesiologists (ASA) classification. In-hospital mortality was also lower in the intervention group: 2% vs. 6% (p < 0.05). There were no statistically significant differences in other outcome measures. CONCLUSIONS: The new comprehensive care pathway was associated with a significant decrease in preoperative fasting time and length of hospital stay.

Proactive pharmaceutical care interventions decrease patients' nonadherence to osteoporosis medication.

UNLABELLED: Using a protocolled intervention program, pharmacists can decrease nonadherence to osteoporosis medication, by continuous monitoring and tailored counseling sessions, starting at treatment initiation. In the usual care group, 32.8% of patients initiating osteoporosis medication discontinued or were nonadherent, compared to 19.0% of patients in the intervention group. PURPOSE: While community pharmacies have been shown to offer a promising platform for osteoporosis management in patients with osteoporosis, more research is needed to determine pharmacists' effects on improving adherence. The aim of this study was to determine the effects of a community pharmacists' intervention program on the 1-year discontinuation and nonadherence rates of patients initiating osteoporosis medication. METHODS: This intervention study included 937 patients, recruited from 13 Dutch community pharmacies, initiating osteoporosis medication. The intervention group (N = 495), received the Medication Monitoring and Optimization (MeMO) intervention, comprising of continuous monitoring of patients' adherence to their osteoporosis medication and tailored counseling sessions with nonadherent patients. Results were compared to an internal (n = 442) reference group, receiving usual pharmacy care. Primary study outcomes were therapy discontinuation and nonadherence; results were adjusted for potential confounders using Cox proportional hazard analysis. Secondary outcome was patients' satisfaction. RESULTS: In the usual care group, 32.8% of patients initiating osteoporosis medication discontinued or were nonadherent, compared to 19.0% of patients in the intervention group (P < 0.001). Ninety-three percent of the respondents were satisfied with the pharmacies' services provided. Notably, 31% mentioned that the pharmacy was the only place where they received information on various aspects of administration and acting of their medication. CONCLUSION: Pharmacists can decrease nonadherence and discontinuation with osteoporosis medication by providing tailored counseling sessions and continuous monitoring of drug use. Pharmaceutical care programs, such as MeMO, contribute to more optimal use of osteoporosis medication.