A course in constructing effective displays of data for pharmaceutical research personnel.

Interpreting data and communicating effectively through graphs and tables are requisite skills for statisticians and non-statisticians in the pharmaceutical industry. However, the quality of visual displays of data in the medical and pharmaceutical literature and at scientific conferences is severely lacking. We describe an interactive, workshop-driven, 2-day short course that we constructed for pharmaceutical research personnel to learn these skills. The examples in the course and the workshop datasets source from our professional experiences, the scientific literature, and the mass media. During the course, the participants are exposed to and gain hands-on experience with the principles of visual and graphical perception, design, and construction of both graphic and tabular displays of quantitative and qualitative information. After completing the course, with a critical eye, the participants are able to construct, revise, critique, and interpret graphic and tabular displays according to an extensive set of guidelines.

Raltegravir with optimized background therapy for resistant HIV-1 infection.

BACKGROUND: Raltegravir (MK-0518) is an inhibitor of human immunodeficiency virus type 1 (HIV-1) integrase active against HIV-1 susceptible or resistant to older antiretroviral drugs. METHODS: We conducted two identical trials in different geographic regions to evaluate the safety and efficacy of raltegravir, as compared with placebo, in combination with optimized background therapy, in patients infected with HIV-1 that has triple-class drug resistance in whom antiretroviral therapy had failed. Patients were randomly assigned to raltegravir or placebo in a 2:1 ratio. RESULTS: In the combined studies, 699 of 703 randomized patients (462 and 237 in the raltegravir and placebo groups, respectively) received the study drug. Seventeen of the 699 patients (2.4%) discontinued the study before week 16. Discontinuation was related to the study treatment in 13 of these 17 patients: 7 of the 462 raltegravir recipients (1.5%) and 6 of the 237 placebo recipients (2.5%). The results of the two studies were consistent. At week 16, counting noncompletion as treatment failure, 355 of 458 raltegravir recipients (77.5%) had HIV-1 RNA levels below 400 copies per milliliter, as compared with 99 of 236 placebo recipients (41.9%, P<0.001). Suppression of HIV-1 RNA to a level below 50 copies per milliliter was achieved at week 16 in 61.8% of the raltegravir recipients, as compared with 34.7% of placebo recipients, and at week 48 in 62.1% as compared with 32.9% (P<0.001 for both comparisons). Without adjustment for the length of follow-up, cancers were detected in 3.5% of raltegravir recipients and in 1.7% of placebo recipients. The overall frequencies of drug-related adverse events were similar in the raltegravir and placebo groups. CONCLUSIONS: In HIV-infected patients with limited treatment options, raltegravir plus optimized background therapy provided better viral suppression than optimized background therapy alone for at least 48 weeks. (ClinicalTrials.gov numbers, NCT00293267 and NCT00293254.)

Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection.

BACKGROUND: We evaluated the efficacy of raltegravir and the development of viral resistance in two identical trials involving patients who were infected with human immunodeficiency virus type 1 (HIV-1) with triple-class drug resistance and in whom antiretroviral therapy had failed. METHODS: We conducted subgroup analyses of the data from week 48 in both studies according to baseline prognostic factors. Genotyping of the integrase gene was performed in raltegravir recipients who had virologic failure. RESULTS: Virologic responses to raltegravir were consistently superior to responses to placebo, regardless of the baseline values of HIV-1 RNA level; CD4 cell count; genotypic or phenotypic sensitivity score; use or nonuse of darunavir, enfuvirtide, or both in optimized background therapy; or demographic characteristics. Among patients in the two studies combined who were using both enfuvirtide and darunavir for the first time, HIV-1 RNA levels of less than 50 copies per milliliter were achieved in 89% of raltegravir recipients and 68% of placebo recipients. HIV-1 RNA levels of less than 50 copies per milliliter were achieved in 69% and 80% of the raltegravir recipients and in 47% and 57% of the placebo recipients using either darunavir or enfuvirtide for the first time, respectively. At 48 weeks, 105 of the 462 raltegravir recipients (23%) had virologic failure. Genotyping was performed in 94 raltegravir recipients with virologic failure. Integrase mutations known to be associated with phenotypic resistance to raltegravir arose during treatment in 64 patients (68%). Forty-eight of these 64 patients (75%) had two or more resistance-associated mutations. CONCLUSIONS: When combined with an optimized background regimen in both studies, a consistently favorable treatment effect of raltegravir over placebo was shown in clinically relevant subgroups of patients, including those with baseline characteristics that typically predict a poor response to antiretroviral therapy: a high HIV-1 RNA level, low CD4 cell count, and low genotypic or phenotypic sensitivity score. (ClinicalTrials.gov numbers, NCT00293267 and NCT00293254.)

Rofecoxib in patients with mild cognitive impairment: further analyses of data from a randomized, double-blind, trial.

A recent clinical trial in patients with Mild Cognitive Impairment (MCI) found an increased rate of possible or probable Alzheimer's disease (AD) diagnoses in patients assigned to rofecoxib compared to placebo. This unexpected finding was difficult to interpret due to methodological issues and a lack of confirmation on secondary endpoints, as well as a lack of confirmation in trials in related populations. We performed additional post hoc analyses to explore explanations for the finding based on possible neuropathological, cardiovascular/cerebrovascular, or cognitive effects of rofecoxib. 1) Neuropathological hypothesis: Of the 189 incident cases of possible or probable AD, 154 were probable AD. In probable AD patients, the treatment hazard ratio was reduced compared to the primary analysis -- a concordant finding would have strengthened a conclusion that rofecoxib accelerated the underlying neuropathology of AD. The treatment hazard ratio was increased in the remaining 35 patients with less certain diagnoses, but there was no single predominant reason for the reduced certainty of diagnosis. 2) Cardiovascular hypothesis: Neither cardiovascular risk status nor mean arterial blood pressure had an overall effect on AD diagnosis or modified the treatment difference. 3) Cognitive side-effects hypothesis: The percentages of patients with non-specific NSAID-type central nervous system adverse events were similar between the treatment groups. In summary, the present analyses are limited by their post hoc nature but provided little support for any of the possible explanations explored. The significance of the observation that rofecoxib increased the rate of conversion from MCI to AD remains uncertain.

A randomized, double-blind, study of rofecoxib in patients with mild cognitive impairment.

Inflammatory mechanisms have been implicated in Alzheimer's disease (AD) and might be mediated via the COX-2 enzyme. Previous studies with the selective COX-2 inhibitors, rofecoxib and celecoxib, have shown that they do not alter the progression of AD. We conducted a double-blind study to investigate whether rofecoxib could delay a diagnosis of AD in patients with mild cognitive impairment (MCI), a group with an expected annual AD diagnosis rate of 10-15%. MCI patients > or =65 years were randomized to rofecoxib 25 mg (N=725) or placebo (N=732) daily for up to 4 years. The primary end point was the percentage of patients with a clinical diagnosis of AD. The estimated annual AD diagnosis rate was lower than the anticipated 10-15%: 6.4% in the rofecoxib group vs 4.5% in the placebo group (rofecoxib : placebo hazard ratio=1.46 (95% CI: 1.09, 1.94), p=0.011). Analyses of secondary end points, including measures of cognition (eg the cognitive subscale of the AD Assessment Scale (ADAS-Cog)) and global function (eg the Clinical Dementia Rating (CDR)), did not demonstrate differences between treatment groups. There was also no consistent evidence that rofecoxib differed from placebo in post hoc analyses comparing ADAS-Cog and CDR-sum of boxes scores in overlapping subgroups of patients who had Mini Mental State Exam scores of 24-26 in the present MCI study and in a previous AD treatment study with a similar design. The results from this MCI study did not support the hypothesis that rofecoxib would delay a diagnosis of AD. In conjunction with the lack of effects observed in previous AD studies, the findings suggest that inhibition of COX-2 is not a useful therapeutic approach in AD.

Treatment comparisons for a partially categorical outcome applied to a biomarker with assay limit.

The plasma level of HIV-RNA has been shown to be a strong prognostic biomarker for clinical progression and death in HIV infected patients and is widely used as the primary outcome in clinical trials to evaluate antiretroviral treatments. Currently approved assays to measure HIV-RNA levels have a lower limit of reliable quantification (LoQ). Current regulatory guidelines recommend using the proportion of patients achieving HIV-RNA levels below the assay limit at a certain time point (e.g. 24 or 48 weeks) as the primary endpoint for regulatory approval. However, a substantial decrease in HIV-RNA that does not go below the LoQ still is considered clinically beneficial for patients with advanced diseases who have failed many other therapies and are unlikely to maximally suppress the virus and achieve HIV-RNA levels below the LoQ. An experimental treatment may not be distinguishable from a control solely in terms of the proportions of patients whose HIV-RNA levels fall below the LoQ. The sensitivity of the comparison between the experimental treatment and the control could be increased by considering as well the difference between the treatments with respect to the HIV-RNA reductions of patients not achieving HIV-RNA levels below the LoQ. In this paper, we introduce a best-rank analysis which assigns the best rank to patients who achieve the HIV-RNA levels below the LoQ and applies the Mann-Whitney-Wilcoxon rank test to compare the two treatment groups. The Mann-Whitney-Wilcoxon statistic is shown to be a weighted sum of two statistics: one to compare the proportions of patients achieving the HIV-RNA levels below the LoQ and one to compare the viral reductions in patients with HIV-RNA levels above the LoQ. The corresponding statistical null and alternative hypotheses and the clinical interpretations of this best-rank test procedure are also discussed. An example is used to illustrate this approach and a simulation study is used to compare this approach with other methods.

Incorporating durability information in the comparison of proportions of patients with HIV suppression.

In some HIV clinical trials, the proportion of patients who achieve treatment success at a clinically meaningful time point (e.g., 16 or 24 weeks) and the subsequent durability of the treatment success after that time point are collected from two exclusive followup intervals. Two treatments are usually compared in terms of the proportion of patients achieving treatment success at the pre-defined time point and the subsequent durability information is ignored. However, combining the failure/success proportion at the pre-defined time point and the subsequent durability information in one test statistic could be more powerful if the experimental treatment is more efficacious than the control in that either fewer patients fail the experimental treatment at this time point or the responding patients have longer duration of viral suppression. In this paper, we propose a time-to-event type potency/durability endpoint which captures the information from the two exclusive followup intervals. A linear rank statistic to compare the two treatments in terms of this potency/durability endpoint can be interpreted as a weighted statistic to incorporate the potency information at a clinically meaningful time point (e.g., 16 or 24 weeks) and the durability information after that time point. The statistical hypotheses being tested by using this potency/durability endpoint and their clinical interpretations are discussed. A clinical endpoint study in anti-retroviral treatment naive patients is used to illustrate this method. Simulation studies show that this method is more powerful than comparing the success rates alone when the experimental treatment is also more durable in maintaining long term success.

Randomized, double-blind trial comparing indinavir alone, zidovudine alone and indinavir plus zidovudine in antiretroviral therapy-naive hiv-infected individuals with CD4 cell counts between 50 and 250/mm3

Treatment with indinavir has been shown to result in marked decreases in viral load and increases in CD4 cell counts in HIV-infected individuals. A randomized double-blind study to evaluate the efficacy of indinavir alone (800 mg q8h), zidovidine alone (200 mg q8h) or the combination was performed to evaluate progression to AIDS. 996 antiretroviral therapy-naive patients with CD4 cell counts of 50-250/mm3 were allocated to treatment. During the trial the protocol was amended to add lamivudine to the zidovudine-containing arms. The primary endpoint was time to development of an AIDS-defining illness or death. The study was terminated after a protocol-defined interim analysis demonstrated highly significant reductions in progression to a clinical event in the indinavir-containing arms, compared to the zidovudine arm (<0.0001). Over a median follow-up of 52 weeks (up to 99 weeks), percent reductions in hazards for the indinavir plus zidovudine and indinavir groups compared to the zidovudine group were 70 percent and 61 percent, respectively. Significant reductions in HIV RNA and increases in CD4 cell counts were also seen in the indinavir-containing groups compared to the zidovudine group. Improvement in both CD4 cell count and HIV RNA were associated with reduced risk of disease progression. All three regimens were generally well tolerated

Acute pain management in patients with prior opioid consumption: a case-controlled retrospective review.

The patient with a history of current opioid consumption presenting in the acute postoperative setting presents a challenge for pain management. Standard treatment dosages and strategies are often ineffective in providing pain relief. This retrospective case-control study reviews 4 years' experience of the Acute Pain Service (APS) at our institution providing care for 202 chronic pain and opioid-consuming (CPOC) patients, 6.6% of 3058 patients undergoing urologic, gynecologic, orthopedic and general surgical procedures. Controls matched for age, gender, date and type of surgery, and postoperative pain relief modality were found for 180 (89%) of these patients. Patients were provided patient-controlled analgesia (PCA), or epidural opioid analgesia (EOA with boluses of preservative-free morphine or bupivacaine (1:16% + 2 micrograms/ml fentanyl (B/F)). Records were reviewed for patient demographics, diagnoses, surgical procedures, pre-operative opioid use, days-on-service, analgesic requirement, pain scores and incidence of moderate/severe side effects. Patient demographics were similar between CPOC and control groups. When considering PCA alone, mean 24-h usage in controls was 42.8 (32.0) mg morphine (MS) equivalents differing significantly from CPOC patients' use of 135.8 (68.5) mg MS equivalents (P = 0.0001). EOA and B/F case studies showed similar results. Moderate sedation was experienced by 50% of CPOC patients receiving PCA. Differences in opioid usage, side effects, pain scores, sedation and prescribed treatment with anxiolytics were shown between CPOC patients and matched controls.(ABSTRACT TRUNCATED AT 250 WORDS)