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Janet Wittes

Publications and source records attributed to Janet Wittes.

29 records · Page 2Linked to original sources
PubMed2004

Forming your phase III trial's data and safety monitoring board: a perspective on safety.

A data safety monitoring board (DSMB) established in a phase III trial to monitor the safety of participants in a clinical trial views itself as protecting participants and ensuring the integrity of the study. The DSMB should operate under a clear charter, with expectations understood by all members of the Board, the sponsor, and the investigators. Sponsors must trust their DSMBs. The sponsor must give the DSMB the tools and the data that it needs to operate effectively in protecting the safety of the participants.

Biometry↗
PubMed2004

Liability issues for data monitoring committee members.

In randomized clinical trials, a data monitoring committee (DMC) is often appointed to review interim data to determine whether there is early convincing evidence of intervention benefit, lack of benefit or harm to study participants. Because DMCs bear serious responsibility for participant safety, their members may be legally liable for their actions. Despite more than three decades of experiences with DMCs, the issues of liability and indemnification have yet to receive appropriate attention from either government or industry sponsors. In industry-sponsored trials, DMC members are usually asked to sign an agreement delineating their responsibilities and operating procedures. While these agreements may include language on indemnification, such language sometimes protects only the sponsor rather than the DMC members. In government-sponsored trials, there has been even less structure, since typically there are no signed agreements regarding DMC activities. This paper discusses these issues and suggests sample language for indemnification agreements to protect DMC members. This type of language should be included in DMC charters and in all consulting agreements signed by DMC members.

Clinical Trials Data Monitoring Committees↗
PubMed2003

Efficacy trial of live, cold-adapted and inactivated influenza virus vaccines in older adults with chronic obstructive pulmonary disease: a VA cooperative study.

We assessed whether trivalent live, cold-adapted influenza virus (CAIV-T) vaccine provides added protection when co-administered with trivalent inactivated influenza virus vaccine (TVV) in patients with chronic obstructive pulmonary disease (COPD). Subjects (N=2215) were randomly assigned to receive either TVV intramuscularly (IM) and CAIV-T intranasally (TC), or TVV and placebo (TP). The vaccines were well-tolerated. Efficacy of TC compared to TP was not statistically significant and was 0.16 for any influenza virus strain (95% confidence limit (CL): -0.22, 0.43), 0.26 for A (H3N2) virus (95% CL: -0.17, 0.53), and -0.05 for type B virus (95% CL: -1.13, 0.48). However, there was a possible advantage for TC over TP in reducing respiratory consequences of an influenza season measured by pulmonary function and symptoms at end of study.

Administration, Intranasal↗
PubMed2003

Toward protecting the safety of participants in clinical trials.

It is a widely held belief that the current system of oversight of clinical research, particularly the means of assessing risks and minimizing harms to participants in clinical trials, could be improved. In particular, the system is inefficient with overemphasis on the monitoring ability of some groups such as research ethics review boards and investigators, underemphasis on others such as data monitoring committees (DMCs) and sponsors, confusion about responsibilities for safety and imperfect communication between these different groups. Research ethics review boards are not able to perform safety monitoring by review of individual adverse events and are often burdened by duplicative reviews of large multicenter studies. There are no standards for DMCs to ensure they can reliably identify safety issues. Sponsors may be overreliant on data audits and slow to disseminate safety data in a coherent summary. Investigators, their staffs and clinical sites may not fully appreciate all the nuances of good clinical practice or may be inattentive to the daily conduct of studies. Regulators, particularly those in the United States, have failed to completely harmonize their policies with each other or with international regulatory agencies. We recommend well-designed monitoring plans for all studies that are appropriate to their scope and risk, more centralized review of large multisite studies and closer local scrutiny of single-institution studies. In addition, sponsors should pay greater attention to monitoring adverse events and keeping up-to-date databases or investigator's brochures emphasizing safety issues. A minimal standard of education or expertise in good clinical practice should be established for investigators, their staffs and research ethics review board members. DMC composition and functions should be standardized and regulations should be harmonized nationally and internationally. Finally, there should be a concerted effort to study the efficacy of various components of the system.

Clinical Trials Data Monitoring Committees↗
PubMed2002

On changing a long-term clinical trial midstream.

Clinical triallists are often reluctant to alter the protocol or the design of an ongoing study in part because of concern that changes may affect the integrity of the study. This paper encourages considering changes in long-term clinical trials when the medical environment changes or when the accruing data from the trial lead to questioning the assumptions underlying the original design. One must make such changes in a way that will not cast doubt on the integrity of the trial. An important aspect of the design is choice of sample size. Methodology for sample size recalculation has matured over the decade. Several techniques are now available for the usual types of endpoints - continuous, discrete and time-to-failure - as well as for longitudinal analysis. Published papers describe the choices of variance at the time of recalculation, approaches to estimation and testing at the end of the study, and the time of recalculation. In a study with a sponsor, a Data Safety Monitoring Board (DSMB) and an Executive Committee, one or more of these three groups is responsible for recommending increases in sample size when the accruing data indicate that the assumed variance underestimated the true variance. Sometimes a statistician independent of all three bodies performs the relevant calculations and sends the recommendation to the sponsor. This paper argues that the DSMB should not generally be the responsible body because knowledge of treatment effect can place it in an uncomfortable position.

Aspirin↗
PubMed2002

Cost-effectiveness of gemfibrozil for coronary heart disease patients with low levels of high-density lipoprotein cholesterol: the Department of Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial.

BACKGROUND: Although numerous clinical trials and economic analyses have established the efficacy and cost-effectiveness of lowering cholesterol for the prevention of coronary heart disease, there are few data on the role of raising high-density lipoprotein cholesterol (HDL-C) levels and lowering triglyceride levels. The US Department of Veterans Affairs (VA) Cooperative Studies Program HDL-C Intervention Trial (VA-HIT) was a multicenter, randomized trial of gemfibrozil, an agent that raised HDL-C levels and lowered triglyceride levels, yet had no effect on low-density lipoprotein cholesterol (LDL-C) levels. The study showed that gemfibrozil therapy significantly reduced major cardiovascular events (cardiovascular death, myocardial infarction, and stroke) in patients with coronary heart disease, low HDL-C levels, and low LDL-C levels. OBJECTIVE: To report the results of a cost-effectiveness study based on the results of the VA-HIT. METHODS: The cost per year of life gained with gemfibrozil therapy was calculated. Hazard functions were estimated, and the resulting probabilities were used in a Markov model simulation to estimate the effect of gemfibrozil on life expectancy and costs over a simulated lifetime. Sensitivity analyses were used to account for uncertainty. RESULTS: Using the prices of gemfibrozil that were negotiated by the VA, gemfibrozil was cost saving. Using drug prices found outside the VA, a quality-adjusted life-year saved by gemfibrozil therapy cost between $6300 and $17 100. CONCLUSIONS: Gemfibrozil reduces major cardiovascular events in male coronary heart disease patients with low levels of HDL-C and low levels of LDL-C and would result in cost saving at annual drug costs of $100 or less in 1998 dollars. Even at the higher drug prices represented by the average wholesale price in the United States, the cost of a life-year saved is well below the threshold that would be deemed cost-effective. To our knowledge, this is the first economic analysis based on clinical trial data to assess the cost-effectiveness of raising HDL-C levels and lowering triglyceride levels in a setting in which LDL-C levels were not lowered.

Aged↗
PubMed2001

Baseline Characteristics and Early Blood Pressure Control in the CONVINCE Trial.

-Blood pressure (BP) control rates around the world are suboptimal. Part 2 of the National Health and Nutrition Educational Survey (NHANES) III indicates that only 27.4% of hypertensive Americans aged 18 to 74 years have a BP of <140/90 mm Hg. We wanted to assess BP control during the first 2 years and to describe the baseline characteristics of patients enrolled in the Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints (CONVINCE) Study, an international clinical trial that compares outcomes in hypertensive patients randomized to initial treatment with either controlled-onset extended-release verapamil or the investigator's choice of atenolol or hydrochlorothiazide. At randomization, BP was <140/90 mm Hg in only 20.3% of the 16 602 subjects (average+/-SD age 65.6+/-7.4 years; 56% women, 84% white/7% black/7% Hispanic). The average BP at enrollment was 148/85 mm Hg for patients taking BP medications (n=13 879) and 161/94 mm Hg for previously untreated patients (n=2723). After medication titration, with a transtelephonic computer that recommended an increase in the dose or number of antihypertensive agents whenever the BP was 140/90 mm Hg, 84.8% of the subjects attained the goal BP. During 2 years of treatment, BP control was maintained in 67% to 69% of the subjects (69% to 71% for systolic BP of <140 mm Hg and 90% for diastolic BP of <90 mm Hg). These data suggest that the control of systolic BP is more difficult than the control of diastolic BP. The US national goal of having 50% of hypertensives with a BP of <140/90 mm Hg may be achievable if a forced titration strategy is used. Interested investigators, free care and medications, and well-educated subjects may make the attainment of such a goal easier in the CONVINCE study than in the general population.

Journal Article↗
PubMed2001

Experience collecting interim data on mortality: an example from the RALES study.

INTRODUCTION: The Randomized Aldactone Evaluation Study (RALES) randomized 822 patients to receive 25 mg spironolactone daily and 841 to receive placebo. The primary endpoint was death from all causes. Randomization began on March 24, 1995; recruitment was completed on December 31, 1996; follow-up was scheduled to continue through December 31, 1999. Evidence of a sizeable benefit on mortality emerged early in the RALES. The RALES data safety monitoring board (DSMB), which met semiannually throughout the trial, used a prespecified statistical guideline to recommend stopping for efficacy. At the DSMB's request, its meetings were preceded by an 'endpoint sweep', that is, a census of all participants to confirm their vital status. METHODS: We used computer simulation to evaluate the effect of the sweeps. RESULTS: The sweeps led to an estimated 5 to 8% increase in the number of reported deaths at the fourth and fifth interim analyses. The data crossed the statistical boundary at the fifth interim analysis. If investigators had reported all deaths within the protocol-required 24-h window, the DSMB might have recommended stopping after the fourth interim analysis. DISCUSSION: Although endpoint sweeps can cause practical problems at the clinical centers, sweeps are very useful if the intervals between patient visits or contact are long or if endpoints require adjudication by committee, reading center, or central laboratory. CONCLUSION: We recommend that trials with interim analyses institute active reporting of the primary endpoints and endpoint sweeps.

Journal Article↗
PubMedDate not supplied

Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial.

CONTEXT: Hypertensive patients are often given a calcium antagonist to reduce cardiovascular disease risk, but the benefit compared with other drug classes is controversial. OBJECTIVE: To determine whether initial therapy with controlled-onset extended-release (COER) verapamil is equivalent to a physician's choice of atenolol or hydrochlorothiazide in preventing cardiovascular disease. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, randomized clinical trial conducted at 661 centers in 15 countries. A total of 16 602 participants diagnosed as having hypertension and who had 1 or more additional risk factors for cardiovascular disease were enrolled between September 1996 and December 1998 and followed up until December 31, 2000. After a mean of 3 years of follow-up, the sponsor closed the study before unblinding the results. INTERVENTION: Initially, 8241 participants received 180 mg of COER verapamil and 8361 received either 50 mg of atenolol or 12.5 mg of hydrochlorothiazide. Other drugs (eg, diuretic, beta-blocker, or an angiotensin-converting enzyme inhibitor) could be added in specified sequence if needed. MAIN OUTCOME MEASURES: First occurrence of stroke, myocardial infarction, or cardiovascular disease-related death. RESULTS: Systolic and diastolic blood pressure were reduced by 13.6 mm Hg and 7.8 mm Hg for participants assigned to the COER verapamil group and by 13.5 and 7.1 mm Hg for partcipants assigned to the atenolol or hydrochlorothiazide group. There were 364 primary cardiovascular disease-related events that occurred in the COER verapamil group vs 365 in atenolol or hydrochlorothiazide group (hazard ratio [HR], 1.02; 95% confidence interval [CI], 0.88-1.18; P =.77). For fatal or nonfatal stroke, the HR was 1.15 (95% CI, 0.90-1.48); for fatal or nonfatal myocardial infarction, 0.82 (95% CI, 0.65-1.03); and for cardiovascular disease-related death, 1.09 (95% CI, 0.87-1.37). The HR was 1.05 (95% CI, 0.95-1.16) for any prespecified cardiovascular disease-related event and 1.08 (95% CI, 0.93-1.26) for all-cause mortality. Nonstroke hemorrhage was more common with participants in the COER-verapamil group (n = 118) compared with the atenolol or hydrochlorothiazide group (n = 79) (HR, 1.54 [95% CI, 1.16-2.04]; P =.003). More cardiovascular disease-related events occurred between 6 AM and noon in both the COER verapamil (99/277) and atenolol or hydrochlorothiazide (88/274) groups; HR, 1.15 (95% CI, 0.86-1.53). CONCLUSIONS: The CONVINCE trial did not demonstrate equivalence of a COER verapamil-based antihypertensive regimen compared with a regimen beginning with a diuretic or beta-blocker. When considered in the context of other trials of calcium antagonists, these data indicate that the effectiveness of calcium-channel therapy in reducing cardiovascular disease is similar but not better than diuretic or beta-blocker treatment.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

Preclinical evaluation of a chimeric malaria vaccine candidate in Montanide ISA 720: immunogenicity and safety in rhesus macaques.

UNLABELLED: Several malarial antigens are in development as potential vaccine candidates as part of a concerted effort to control the disease, which kills more than one million people per year. Although some antigens have demonstrated an impact against the malaria parasite, Plasmodium falciparum, many researchers hypothesize that a combination of antigens will be required to generate high levels of efficacy against clinical disease. PfCP2.9 is a chimeric protein that includes MSP119 and domain III of AMA1 [AMA1 (111)] of Plasmodium falciparum in a single recombinant molecule. The antigen, formulated in Seppic's ISA 720 adjuvant, is approaching Phase I clinical testing in humans. The purpose of this study was to assess the safety of this vaccine and to explore possible dosage levels for clinical evaluation. Groups of five monkeys each were immunized i.m. with 25 microg, 50 microg, 100 microg and 200 microg of PfCP2.9/ISA 720 in 0.5 mL on days 0 and 112. The mean anti-PfCP2.9 titres to the 50 microg dose group were higher than the other dose groups; however, there was no statistically significant difference between the anti-CP2.9 titres of any of the groups, suggesting that the immune response to PfCP2.9 was saturated at 25 microg. One animal in the 100 microg dose group elicited a higher antibody and IFN-gamma response to PfCP2.9 than the rest of the cohort; this animal developed a small sterile abscess following the second vaccination, which spontaneously resolved within one week. IN CONCLUSION: (a) 50 microg is highly immunogenic, appears safe, and is likely to be an appropriate dose for clinical evaluation; and (b) a conservative trial design is warranted to avoid any unexpected reactogenicity with the PfCP2.9/ISA 720 formulation.

Alanine Transaminase↗