[Show abstract][Hide abstract] ABSTRACT: In noninferiority trials, acceptable efficacy of an experimental treatment is established by ruling out some defined level of reduced effect relative to an effective active control standard. Serial use of noninferiority trials may lead to newly approved therapies that provide meaningfully reduced levels of benefit; this phenomenon is called bio-creep. Simulations were designed to facilitate understanding of bio-creep risk when approval of an experimental treatment with efficacy less than some proportion of the effect of the active control treatment would constitute harm, such as when new antibiotics that are meaningfully less effective than the most effective current antibiotic would be used for treatment of Community-Acquired Bacterial Pneumonia. In this setting, risk of approval of insufficiently effective therapies may be great, even when the standard treatment effect satisfies constancy across trials. Modifiable factors contributing to this manifestation of bio-creep included the active control selection method, the noninferiority margin, and bias in the active control effect estimate. Therefore, when noninferiority testing is performed, the best available treatment should be used as the standard, and margins should be based on the estimated effect of this control, accounting for the variability and for likely sources of bias in this estimate, and addressing the importance of preservation of some portion of the standard’s effect.
No preview · Article · Jan 2015 · Statistics in Biopharmaceutical Research
[Show abstract][Hide abstract] ABSTRACT: Background
In pulmonary arterial hypertension (PAH), adding oral sildenafil to intravenous (IV) epoprostenol improved 6-minute walk distance (6MWD) and haemodynamics and delayed time to clinical worsening in a 16-week randomised, placebo-controlled trial (PACES-1).
Patients completing PACES-1 could receive sildenafil (titrated to 80 mg TID as tolerated) in an open-label extension study (PACES-2) for ≥3 years; additional therapy was added per investigator judgment. Survival and changes from PACES-1 baseline in World Health Organization functional class (FC) and 6MWD were captured.
In an open-label setting, an effort-dependent outcome measure, 6MWD, was known to have improved or to have been maintained in 59%, 44%, and 33% of patients at 1, 2, and 3 years, respectively; FC was known to have improved or to have been maintained in 73%, 59%, and 46%. At 3 years, 66% of patients were known to be alive, 24% were known to have died, and 10% were lost to follow-up. Patients with PACES-1 baseline 6MWD <325 m without 6MWD improvement during the first 20 weeks of sildenafil treatment subsequently had poorer survival.
While reliable assessments of safety and efficacy require a long-term randomised trial, addition of sildenafil to background IV epoprostenol therapy appeared generally to be well tolerated in PAH patients.
No preview · Article · Jul 2014 · The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation
[Show abstract][Hide abstract] ABSTRACT: Data monitoring committees (DMCs) have important roles in safeguarding patient interests and enhancing trial integrity and credibility. To effectively fulfill their responsibilities, DMCs should be independent of study sponsors, study investigators, and caregivers managing study participants. Unfortunately, in real-world settings where DMCs are in place, there are some practices that threaten to diminish the level of independence of these committees. To address this, some important approaches should be considered: A DMC charter should outline the roles and responsibilities of the DMC without appearing to be a legal contract; the meetings of the DMC should be led by its chair, ideally with a meeting format that ensures independence from the investigators and sponsor; the DMC and those having leadership roles in the monitoring process should have adequate training and experience; procedures should be in place to enable the DMC to have access to interim safety and efficacy data that are accurate, current, and comprehensive; these data should be presented to the DMC unblinded by treatment group, while being kept confidential from all others; DMC recommendations should be developed through consensus development rather than by casting votes; creative approaches are needed for the engagement of DMC members to increase the transparency such that they are neither employees of nor consultants to the sponsor of the trial; meaningful conflicts of interest should be identified and addressed; and finally, members of DMCs should have adequate indemnification that provides effective protection.
No preview · Article · Jun 2014 · Journal of Biopharmaceutical Statistics
[Show abstract][Hide abstract] ABSTRACT: To assess the efficacy and safety of enzyme replacement therapy (ERT) with BMN 110 (elosulfase alfa) in patients with Morquio A syndrome (mucopolysaccharidosis IVA).
Patients with Morquio A aged ≥5 years (N = 176) were randomised (1:1:1) to receive elosulfase alfa 2.0 mg/kg/every other week (qow), elosulfase alfa 2.0 mg/kg/week (weekly) or placebo for 24 weeks in this phase 3, double-blind, randomised study. The primary efficacy measure was 6-min walk test (6MWT) distance. Secondary efficacy measures were 3-min stair climb test (3MSCT) followed by change in urine keratan sulfate (KS). Various exploratory measures included respiratory function tests. Patient safety was also evaluated.
At week 24, the estimated mean effect on the 6MWT versus placebo was 22.5 m (95 % CI 4.0, 40.9; P = 0.017) for weekly and 0.5 m (95 % CI -17.8, 18.9; P = 0.954) for qow. The estimated mean effect on 3MSCT was 1.1 stairs/min (95 % CI -2.1, 4.4; P = 0.494) for weekly and -0.5 stairs/min (95 % CI -3.7, 2.8; P = 0.778) for qow. Normalised urine KS was reduced at 24 weeks in both regimens. In the weekly dose group, 22.4 % of patients had adverse events leading to an infusion interruption/discontinuation requiring medical intervention (only 1.3 % of all infusions in this group) over 6 months. No adverse events led to permanent treatment discontinuation.
Elosulfase alfa improved endurance as measured by the 6MWT in the weekly but not qow dose group, did not improve endurance on the 3MSCT, reduced urine KS, and had an acceptable safety profile.
Full-text · Article · May 2014 · Journal of Inherited Metabolic Disease
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: To assess the efficacy and safety of enzyme replacement therapy (ERT)
with BMN 110 (elosulfase alfa) in patients with Morquio A syndrome
METHODS: Patients with Morquio A aged ≥5 years (N = 176) were randomised (1:1:1)
to receive elosulfase alfa 2.0 mg/kg/every other week (qow), elosulfase alfa
2.0 mg/kg/week (weekly) or placebo for 24 weeks in this phase 3, double-blind,
randomised study. The primary efficacy measure was 6-min walk test (6MWT)
distance. Secondary efficacy measures were 3-min stair climb test (3MSCT)
followed by change in urine keratan sulfate (KS). Various exploratory measures
included respiratory function tests. Patient safety was also evaluated.
RESULTS: At week 24, the estimated mean effect on the 6MWT versus placebo was
22.5 m (95 % CI 4.0, 40.9; P = 0.017) for weekly and 0.5 m (95 % CI -17.8, 18.9;
P = 0.954) for qow. The estimated mean effect on 3MSCT was 1.1 stairs/min (95 %
CI -2.1, 4.4; P = 0.494) for weekly and -0.5 stairs/min (95 % CI -3.7, 2.8;
P = 0.778) for qow. Normalised urine KS was reduced at 24 weeks in both regimens.
In the weekly dose group, 22.4 % of patients had adverse events leading to an
infusion interruption/discontinuation requiring medical intervention (only 1.3 %
of all infusions in this group) over 6 months. No adverse events led to permanent
CONCLUSIONS: Elosulfase alfa improved endurance as measured by the 6MWT in the
weekly but not qow dose group, did not improve endurance on the 3MSCT, reduced
urine KS, and had an acceptable safety profile.
Full-text · Article · May 2014 · Journal of Inherited Metabolic Disease
[Show abstract][Hide abstract] ABSTRACT: Pulmonary hypertension (PH) is a rare disease in newborns, infants, and children that is associated with significant morbidity and mortality. In the majority of pediatric patients, PH is idiopathic or associated with congenital heart disease and rarely is associated with other conditions such as connective tissue or thromboembolic disease. Incidence data from the Netherlands has revealed an annual incidence and point prevalence of 0.7 and 4.4 for idiopathic pulmonary arterial hypertension and 2.2 and 15.6 for pulmonary arterial hypertension, respectively, associated with congenital heart disease (CHD) cases per million children. The updated Nice classification for PH has been enhanced to include a greater depth of CHD and emphasizes persistent PH of the newborn and developmental lung diseases, such as bronchopulmonary dysplasia and congenital diaphragmatic hernia. The management of pediatric PH remains challenging because treatment decisions continue to depend largely on results from evidence-based adult studies and the clinical experience of pediatric experts.
Full-text · Article · Dec 2013 · Journal of the American College of Cardiology
[Show abstract][Hide abstract] ABSTRACT: A greater understanding of the epidemiology, pathogenesis, and pathophysiology of pulmonary artery hypertension (PAH) has led to significant advances, but the disease remains fatal. Treatment options are neither universally available nor always effective, underscoring the need for development of novel therapies and therapeutic strategies. Clinical trials to date have provided evidence of efficacy, but were limited in evaluating the scope and duration of treatment effects. Numerous potential targets in varied stages of drug development exist, in addition to novel uses of familiar therapies. The pursuit of gene and cell-based therapy continues, and device use to help acute deterioration and chronic management is emerging. This rapid surge of drug development has led to multicenter pivotal clinical trials and has resulted in novel ethical and global clinical trial concerns. This paper will provide an overview of the opportunities and challenges that await the development of novel treatments for PAH.
No preview · Article · Dec 2013 · Journal of the American College of Cardiology
[Show abstract][Hide abstract] ABSTRACT: Evaluation of non-inferiority is based on ruling out a threshold for what would constitute unacceptable loss of efficacy of an experimental treatment relative to an active comparator "Standard". This threshold, the "non-inferiority margin", is often based on preservation of a percentage of Standard's effect. To obtain an estimate of this effect to be used in the development of the "non-inferiority margin", data are needed from earlier trials comparing Standard to placebo if the non-inferiority trial does not have a placebo arm. This approach often provides a biased over-estimate of Standard's true effect in the setting of the current non-inferiority study. We describe two commonly used non-inferiority margin methods that adjust for this bias, the two-confidence interval (95-95) and the Synthesis margins. However, the added 'variance inflation' adjustment made by 95-95 margin diminishes with increasing information from historical trial(s), and the Synthesis margin is based on a strong assumption that the relative bias is known. We introduce an alternative "Bias-adjusted" margin addressing vulnerabilities of each by attenuating the estimate and by accounting for uncertainty in the true level of bias. Examples and asymptotic estimates of non-inferiority hypothesis rejection rates in the proportional hazards setting are used to compare methods.
No preview · Article · Aug 2013 · Statistics in Biopharmaceutical Research
[Show abstract][Hide abstract] ABSTRACT: Background:
The development of interventions for systemic pre-exposure prophylaxis (PrEP) faces several significant challenges following the US Food and Drug Administration's approval of emtricitabine/tenofovir (FTC/TDF) for HIV prevention. This development is particularly complex because of inconsistency of efficacy results of FTC/TDF PrEP trials for HIV prevention.
Possible designs for a PrEP phase 3 efficacy trial are obtained by considering scenarios for potential experimental PrEP and control regimens, including consideration of placebo and active controls, longer acting PrEP and alternate dosing schedules.
Noninferiority (NI) trials with hazard ratio NI margins ranging from 1.10 to 1.25 can be justified in the contexts of the 3 PrEP trials demonstrating efficacy of FTC/TDF. However, these HIV endpoint trials may require extremely large number of participants, particularly in settings where FTC/TDF has been shown to reduce the risk of HIV acquisition. NI trials also are often difficult to interpret because they depend on previous placebo-controlled efficacy results. Superiority trials for PrEP are plausible in settings where FTC/TDF efficacy is not yet established, possibly due to low adherence (ie, women at risk as in FemPrEP and VOICE): a new product with potential for higher adherence and potency would be a promising candidate in this setting.
Following Food and Drug Administration's approval of FTC/TDF for PrEP, trials to establish efficacy of new PrEP regimens require stringent design standards, together with rigorous debate about adherence within study populations and many important ethical issues.
No preview · Article · Jun 2013 · JAIDS Journal of Acquired Immune Deficiency Syndromes
[Show abstract][Hide abstract] ABSTRACT: Multiregional randomized clinical trials often are conducted to evaluate interventions proposed for treatment or prevention of diseases, especially in clinical settings such as cardiovascular diseases where it is important to enroll a large number of patients in a timely manner. As outlined in the International Conference on harmonization E5 Ethnic Factors in the Acceptability of Foreign Clinical Data, an obvious interest when evaluating the results of such trials is the consistency of effects across regions. The purpose of this article is to review a recent example, a large cardiovascular outcomes trial known as "PLATO," where substantial evidence of regional heterogeneity emerged during the analysis. We present the statistical thinking and methodology that went into the evaluation of the results and the logic that led to the judgment that, while chance cannot be ruled out entirely, the appearance of the regional heterogeneity was likely a manifestation of an underlying interaction with concurrent aspirin dosage. This example may provide a useful reference point for the statistical evaluation of regional effects in future large outcomes trials. Supplementary materials for this article are available online.
No preview · Article · Apr 2013 · Statistics in Biopharmaceutical Research
[Show abstract][Hide abstract] ABSTRACT: The HIV Prevention Trial Network (HPTN) 052 Study is a Phase III, two-arm, controlled, open-labeled, randomized clinical trial designed to determine whether early antiretroviral therapy (ART) can prevent the sexual transmission of human immunodeficiency virus type 1 (HIV-1). A total of 1763 couples in which one partner was HIV-1-positive and the other was HIV-1-negative were enrolled in four continents, nine countries and thirteen study sites. The HIV-1-positive partner was randomly assigned to either of the two arms: "immediate" (early) therapy with ART initiated upon enrollment plus HIV primary care, or "delayed" therapy with HIV primary care but ART initiated when the index case would have two consecutive measurements of a CD4+ cell count within or below the range of 200-250cells/mm(3), or develop an AIDS-defining illness. In this paper, we describe several key statistical considerations for the design of this landmark study. Despite that the observed event rates were lower than expected, which might have compromised the study power, an early release of the trial results in May 2011 showed an overwhelming 96% risk reduction for the immediate therapy in the prevention of genetically linked HIV-1 incident transmissions. Nevertheless, the durability of its long-term effectiveness is yet to be assessed. The HPTN 052 Study is still ongoing and will not complete till 2015.
[Show abstract][Hide abstract] ABSTRACT: Efficacy endpoints for previous registrational trials of antimicrobials for acute bacterial skin and skin structure infections
(ABSSSIs) and community-acquired bacterial pneumonia (CABP) were based on nonstandardized, clinician-based observations and
decisions, as well as on patient reports. More quantifiable, reproducible, and externally verifiable endpoints could improve
the design of future noninferiority trials. At the request of the Food and Drug Administration, the Foundation for the National
Institutes of Health convened a broadly representative scientific project team to evaluate potential endpoints for such registrational
trials. Review of historical and modern data led to the conclusion that antimicrobial treatment effects are most apparent
early in therapy; later outcomes provide important supportive information. Although evidence is incomplete, early response
endpoints can anchor noninferiority hypotheses in ABSSSI and CABP registrational trials, thereby allowing evidence-based drug
development to continue. Further research is underway to establish which short- and long-term outcomes are well-defined, reliable,
and reflective of how patients feel, function, or survive.
Preview · Article · Jun 2012 · Clinical Infectious Diseases
[Show abstract][Hide abstract] ABSTRACT: Definitive evidence of clinical efficacy in a Phase 3 trial is best shown by a beneficial impact on a clinically meaningful endpoint-that is, an endpoint that directly measures how a patient feels (symptoms), functions (the ability to perform activities in daily life), or survives. In idiopathic pulmonary fibrosis (IPF), we believe the endpoints that best meet these criteria are all-cause mortality and all-cause nonelective hospitalization. There are no validated measures of symptoms or broader constructs such as health status or functional status in IPF. A surrogate endpoint is defined as an indirect measure that is intended to substitute for a clinically meaningful endpoint. Surrogate endpoints can be appropriate outcome measures if validated. However, validation requires substantial evidence that the effect of an intervention on a clinically meaningful endpoint is reliably predicted by the effect of an intervention on the surrogate endpoint. For patients with IPF, there are currently no validated surrogate endpoints.
Preview · Article · Apr 2012 · American Journal of Respiratory and Critical Care Medicine