Absence Of Efficacy Data Research Articles

Immunogenicity against wild-type and Omicron SARS-CoV-2 after a third dose of inactivated COVID-19 vaccine in healthy adolescents.

Two doses of inactivated SARS-CoV-2 vaccine CoronaVac cannot elicit high efficacy against symptomatic COVID-19, especially against the Omicron variant, but that can be improved by a third dose in adults. The use of a third dose of CoronaVac in adolescents may be supported by immunobridging studies in the absence of efficacy data. With an immunobridging design, our study (NCT04800133) tested the non-inferiority of the binding and neutralizing antibodies and T cell responses induced by a third dose of CoronaVac in healthy adolescents (N=94, median age 14.2 years, 56% male) compared to adults (N=153, median age 48.1 years, 44% male). Responses against wild-type (WT) and BA.1 SARS-CoV-2 were compared in adolescents. Safety and reactogenicity were also monitored. A homologous third dose of CoronaVac further enhanced antibody response in adolescents compared to just 2 doses. Adolescents mounted non-inferior antibody and T cell responses compared to adults. Although S IgG and neutralizing antibody responses to BA.1 were lower than to WT, they remained detectable in 96% and 86% of adolescents. T cell responses to peptide pools spanning only the mutations of BA.1 S, N and M in adolescents were preserved, increased, and halved compared to WT respectively. No safety concerns were identified. The primary vaccination series of inactivated SARS-CoV-2 vaccines for adolescents should include 3 doses for improved humoral immunogenicity.

Nonhuman primate to human immunobridging to infer the protective effect of an Ebola virus vaccine candidate

It has been proven challenging to conduct traditional efficacy trials for Ebola virus (EBOV) vaccines. In the absence of efficacy data, immunobridging is an approach to infer the likelihood of a vaccine protective effect, by translating vaccine immunogenicity in humans to a protective effect, using the relationship between vaccine immunogenicity and the desired outcome in a suitable animal model. We here propose to infer the protective effect of the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen with an 8-week interval in humans by immunobridging. Immunogenicity and protective efficacy data were obtained for Ad26.ZEBOV and MVA-BN-Filo vaccine regimens using a fully lethal EBOV Kikwit challenge model in cynomolgus monkeys (nonhuman primates [NHP]). The association between EBOV neutralizing antibodies, glycoprotein (GP)-binding antibodies, and GP-reactive T cells and survival in NHP was assessed by logistic regression analysis. Binding antibodies against the EBOV surface GP were identified as the immune parameter with the strongest correlation to survival post EBOV challenge, and used to infer the predicted protective effect of the vaccine in humans using published data from phase I studies. The human vaccine-elicited EBOV GP-binding antibody levels are in a range associated with significant protection against mortality in NHP. Based on this immunobridging analysis, the EBOV GP-specific-binding antibody levels elicited by the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen in humans will likely provide protection against EBOV disease.

Colonoscopy and colorectal cancer mortality: both sides of the story

Colonoscopy and colorectal cancer mortality: both sides of the story

Reduced susceptibility to chlorhexidine in staphylococci: is it increasing and does it matter?

Antiseptic agents are increasingly used for hand hygiene and skin decolonization as key tools for the prevention of healthcare-associated infections. Chlorhexidine, a divalent, cationic biguanide, has a broad spectrum of activity and is one of the most frequently used topical antiseptic agents. Notably, there are an increasing number of prevalence studies that report reduced levels of susceptibility to chlorhexidine. In contrast to bacterial resistance to antibiotics, using parameters such as the MIC to define resistance to antiseptics, including chlorhexidine, is not straightforward. A range of methods have been used for the detection of reduced susceptibility to chlorhexidine, but, importantly, there is no standardized method and no consensus on the definition of chlorhexidine 'resistance'. In this review we have assessed the methods available for the detection of reduced susceptibility to chlorhexidine and the prevalence of coresistance to other antimicrobial agents. We have focused on the development of reduced susceptibility to chlorhexidine and the presence of efflux-mediated resistance genes in staphylococci, and have reviewed the clinical significance of this phenomenon. Lastly, we have identified unanswered questions to further our understanding of this emergent threat. We anticipate that clinical use of chlorhexidine will continue to increase, and it will be important to be alert to the possibility that this may lead to the emergence of new clones with reduced susceptibility. Indiscriminate chlorhexidine use in the absence of efficacy data should be discouraged.

Critical Appraisal of the Guidelines for the Management of Ankylosing Spondylitis: Disease-Modifying Antirheumatic Drugs

Surprisingly, little data are available for the use of diseasemodifying antirheumatic drugs in ankylosing spondylitis. Sulfasalazine has been the best studied. Efficacy data for individual agents (including pamidronate) and combinations of agents are detailed in this review. Intriguingly, these agents continue to be used with some frequency, even in the absence of efficacy data. To answer these questions, additional systematic studies of these agents in ankylosing spondylitis are needed and will likely need to be done by interested collaborative groups such as SPARTAN.

Editorial: Case series and efficacy

Costalat et al.2 present a retrospective case series of 60 patients undergoing angioplasty and stent treatment with the Wingspan stent system and Gateway percutaneous transluminal angioplasty (PTA) balloon for refractory symptomatic intracranial stenosis. Their study population reflects the approved indication for the device under the FDA Humanitarian Device Exemption (HDE) guidelines specifying its use for patients with ≥ 50% intracranial stenosis who experience recurrent ischemic events while receiving antithrombotic therapy. The study aimed to evaluate the efficacy and safety of intracranial angioplasty and stent insertion in this population. The authors conclude that this treatment may be considered the first alternative for cases of failed medical therapy. Do their data justify their recommendation? The authors have chosen as historical comparators the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) and Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina (GESICA) studies, in which the event rates for patients with symptomatic intracranial stenoses treated medically included a 19% risk of recurrent events within 1 year and a 38.2% risk of ipsilateral ischemic recurrent events at 2 years.1,5 The statistics reported by Costalat et al.2 include a technical success rate of 95.2%; a total procedural complication rate of 20.6%, including 4.8% of patients with permanent morbidity and death; and a combined rate of in-stent restenosis and occlusion of 17.4%. Although at face value these numbers look favorable, the authors are comparing apples to oranges. When the combined rate of stroke and vascular death at 30 days is calculated, it is 16.7% (10 of 60) in their series, which is practically identical to the rate of stroke and vascular death at 1 year with aspirin (15%) or warfarin (17%) in the WASID trial. Do retrospective case series add to our understanding of efficacy for a medical device? Although FDA approval of a drug is based on randomized clinical trials demonstrating both safety and efficacy, a medical device can be approved under an HDE in the absence of efficacy data when clinical investigation is deemed infeasible due to the low prevalence of the condition in the population. Since the FDA approval of the Wingspan stent system and Gateway PTA balloon in August 2005, there has been a proliferation of small case series reflecting the growth in enthusiasm for this therapy as well as the growth in the number of neurointerventionalists. The majority of reported case series are gleaned from procedural data bases, lack any contemporary comparator group, and assess efficacy by comparing the authors’ results to historical controls. Although the collective volume of treated patients now number in the thousands, and the therapy has become a standard of care at many neurointerventional centers, volume and practice patterns do not constitute evidence of efficacy. This caveat is underscored by the recent negative results in 2 randomized clinical trials for secondary stroke prevention, “CLOSURE 1” and the Carotid Occlusion Surgery Study (COSS). In the CLOSURE trial,4 an endovascular device for closing a patent foramen ovale (PFO) was not superior to medical therapy alone, and trial recruitment was hampered by the off-label practice of PFO closure in tens of thousands of potentially eligible patients.3 In the COSS trial, extracranial-intracranial bypass surgery failed to provide an additional benefit to aggressive medical therapy alone, due to the much lower than expected stroke rate in the nonsurgical group (http://clinicaltrials.gov/ct2/show/ NCT00029146?term=coss&rank=2 [Accessed June 7, 2011]). In April 2011, the NIH-funded Stenting versus Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial (http:// clinicaltrials.gov/ct2/show/NCT00576693?term=sammp ris&rank=1 [Accessed June 7, 2011]) halted further recruitment when the 30-day rate of stroke and death of 14% in patients receiving angioplasty and stent placement was significantly greater than the 5.8% rate with aggressive medical therapy alone. Long-term follow-up will continue, but unless safety and efficacy can be established, “the usefulness of angioplasty and/or stent placement is unknown and is considered investigational.”3

Effect of treatment guidelines on the initial management of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disease with no known aetiology and no proven treatment. Despite the absence of efficacy data, many physicians treat IPF with corticosteroids either as monotherapy or in combination with a cytotoxic agent. Specialty society guidelines published in 1999 and 2000 recognize that treatment may not be appropriate for all patients with IPF, but recommend that if treatment is to be initiated, a combination of corticosteroids with a cytotoxic agent is preferred over corticosteroids alone. It is not known how the use of corticosteroids and cytotoxic agents in the treatment of IPF has changed over time and whether published guidelines have altered prescribing practices. The results of this study demonstrate a modest but statistically significant reduction in the overall use of corticosteroids since the publication of treatment guidelines. At the same time, there was a more pronounced increase in the combined use of corticosteroids and cytotoxic agents consistent with recommendations. Even with the increase in the use of combination therapy, corticosteroid monotherapy remained the most commonly prescribed regimen among treated patients. Given the lack of established benefit and the risks associated with corticosteroid therapy, the reasons for the continued use of corticosteroid monotherapy in the majority of treated patients warrant further investigation. To assess the impact of specialty society guidelines on the use of corticosteroids and cytotoxic agents in the initial management of patients with idiopathic pulmonary fibrosis. A retrospective cohort study of 941 patients with an incident diagnosis of IPF was conducted using a large medical records database. The primary outcome was a new prescription for corticosteroids with or without a cytotoxic agent within 30 days of diagnosis. The primary exposure was whether diagnosis occurred before or after the publication of treatment guidelines. Logistic regression was used to control for changes in population demographics and disease characteristics across time. In total, 187 patients (19.9%) received a new corticosteroid prescription within 30 days of diagnosis. Fewer patients received corticosteroids after the publication of guidelines (22.2% vs. 17.7%; adjusted OR for steroid use after the publication of guidelines 0.65, 95% confidence interval 0.46, 0.92, P = 0.014). Among the 187 patients treated with corticosteroids, 22 (11.8%) also received a cytotoxic agent. The use of cytotoxic agents among users of corticosteroids increased significantly after the publication of guidelines (5.1% vs. 19.3%) with a fully adjusted OR = 4.71 (95% CI 1.56, 14.21, P = 0.006). Since the publication of treatment guidelines, there has been a small reduction in the overall use of corticosteroids. Consistent with these guidelines, the use of cytotoxic agents among those prescribed corticosteroids has increased significantly; however, the use of these agents remains uncommon.

Anal use of the female condom: does uncertainty justify provider inaction?

Despite limited safety data and the absence of efficacy data, several studies have reported that the female condom is being used for anal sex by men who have sex with men. We describe providers’ awareness of female condom use during anal sex among their clients and their experiences in counseling clients. We conducted semi-structured interviews with 78 health-care providers recruited from various health-care delivery systems in New York City: a family planning agency, a sexually transmitted infection agency, a hospital-based obstetrics and gynecology clinic, and two community-based AIDS service organizations. While two-thirds of providers reported that they were uncertain as to whether the female condom could or should be used for anal intercourse, nearly one-third believed that anything is better than nothing to prevent HIV/sexually transmitted infections during anal sex. Few providers had actually talked with clients about anal use of the female condom, and clients themselves had seldom mentioned nor asked for information about such use. Our findings highlight providers’ uncertainty about anal use of the female condom. Lacking guidelines regarding the safety and efficacy of female condom use during anal sex, health-care providers are left to make their own well-intentioned recommendations (or not) to potential users. The dearth of information on female condom use during anal sex could encourage individuals to use the female condom for anal sex, which may increase HIV transmission risk or represent a missed opportunity for protecting non-condom users. There is a need for a series of harm-reduction, acceptability, and efficacy studies and, in the interim, for the development of a carefully qualified safety set of guidelines regarding anal use of the female condom for health-care providers.

Efficacy or effectiveness?

Dear Sir, Seemingly similar in meaning, ‘efficacy’ and ‘effectiveness’ express distinctly different concepts. A medical intervention is ‘efficacious’ if it works under strictly controlled (laboratory) conditions and it is considered ‘effective’ if it works under ‘real life’ conditions. Efficacy (or fastidious) trials test for efficacy and effectiveness (pragmatic) studies for effectiveness of a therapy. Discussion continues over which of the two approaches are more valuable. The main characteristics of the two types of clinical investigation are summarized in Table 1. The typical efficacy study tests whether the experimental therapy generates specific therapeutic effects, while the typical effectiveness study is aimed at quantifying the sum of specific effects and other contributors to the total therapeutic effect. In theory therefore, the effect size measured in an efficacy study is a pure product of the specific effect of the experimental treatment, while that of an effectiveness study can be due to additional factors such as placebo- or context effects, effects of undeclared concomitant therapies and social desirability (Fig. 1). Thus causal attribution between the treatment and the clinical outcome is usually possible in efficacy trials, while this is rarely the case in effectiveness studies. Schematic difference between effects captured by efficacy and effectiveness studies. *Example: a placebo-controlled, double-blind, randomized trial with two parallel groups. OExample: a randomized trial of the experimental treatment versus usual care. 1 = Effect of natural history of disease, 2 = Hawthorn effect, 3 = Regression towards the mean, 4 = Effect of concomitant treatments, 5 = Social desirability, 6 = Placebo effect, 7 = Specific effect of experimental treatment, ES = Effect size measured as difference between experimental and control group. Efficacy trials will tell us whether a treatment works in principle and under optimal, ‘laboratory’ conditions. In some cases, however, ‘real life situations’ might differ from the ideal. For instance, a drug that normalizes cholesterol levels might not be acceptable to ‘real life’ patients if it causes adverse events. Similarly, an anti-hypertensive drug might work for a very narrowly defined homogenous group of patients (e.g. those who have no other risk factors and take no other medication), but in ‘real life’ where patients are heterogenous the effect could be smaller or totally lost. Whenever there is reason to suspect that this could be the case, effectiveness trials are required to test whether the results of efficacy trials also hold true in practice. Would it then make sense to rely on the findings of effectiveness studies in the absence of efficacy data? If the results of effectiveness trials suggest a therapeutic benefit of the experimental therapy, we would not normally be able to be sure whether this is due to the treatment itself or whether it was caused by one of the many other factors that could have contributed to the overall therapeutic effect (Fig. 1). Effectiveness trials are therefore most valuable to test whether the results of efficacy trials are applicable to ‘real life’. In the absence of efficacy data, the results of effectiveness trials can be difficult to interpret and may therefore be of little value. What if both efficacy and effectiveness data are available but do not agree with each other? In many conventional settings, this would correspond to situations similar to the ones outlined above: a treatment is efficacious yet in ‘real life’ there are obstacles, e.g. due to problems with compliance. It is, however, also conceivable that an effectiveness trial shows a benefit while an efficacy trial does not. This scenario is frequently encountered in the area of complementary/alternative medicine. The most logical explanation would then be that the experimental treatment is devoid of specific effects but generates benefit through context effects. Such a treatment would be associated with positive outcomes without directly causing them. An example could be homoeopathy, which seems to help many patients [1, 2] while rigorous trials of homoeopathic remedies have repeatedly been shown them to be no different from placebos [3, 4]. Is this sufficient justification for adopting such a (placebo) treatment into routine health care? We don't think so. We do not need a placebo to generate a placebo effect: even treatments with specific effects generate placebo- or context effects. In most instances, the debate about the relative value of efficacy and effectiveness trials distracts from the fact that both address different research questions. Both types of study undoubtedly have their place. We should, however, be vigilant that effectiveness trials are not (mis)used (in the absence of convincing efficacy data) to convince policy makers of the value of treatments which have no specific effects at all.

Anxioselective compounds acting at the GABA(A) receptor benzodiazepine binding site.

With the exception of obsessive compulsive disorder, benzodiazepines (BZs) remain a major first line treatment for anxiety disorders. However, as well as being anxiolytic, BZs also cause sedation acutely, related to the fact that BZs are also used as hypnotics, and chronically may have abuse potential as well as cause physical dependence which manifests itself as the demonstration of a number of adverse events upon discontinuation. The molecular mechanisms of BZs are now well defined in that they enhance the actions of the inhibitory neurotransmitter GABA by binding to a specific recognition site on GABA(A) receptors containing alpha1, alpha2, alpha3 and alpha5 subunits. Compounds that bind at this modulatory site and enhance the inhibitory actions of GABA are classified as agonists, those that decrease the actions of GABA are termed inverse agonists whereas compounds which bind but have no effect on GABA inhibition are termed antagonists. The clinically used BZs are full agonists and between the opposite ends of the spectrum, i.e. full agonist and full inverse agonist, are a range of compounds with differing degrees of efficacy, such as partial agonists and partial inverse agonists. Attempts have been made to develop compounds which are anxioselective in that they retain the anxiolytic properties of the full agonist BZs but have reduced sedation and dependence (withdrawal) liabilities. Such compounds may interact with all four (i.e. alpha1-, alpha2-, alpha3- and alpha5-containing) GABA(A) receptor subtypes and have partial rather than full agonist efficacies. Examples of nonselective partial agonists include bretazenil, imidazenil, FG 8205, abecarnil, NS 2710, pagoclone, RWJ-51204 and (S)-desmethylzopiclone. Alternatively, a compound might have comparable binding affinity but different efficacies at the various subtypes, thereby preferentially exerting its effects at subtypes thought to be associated with anxiety (alpha2- and/or alpha3-containing receptors) rather than the subtype associated with sedation (alpha1-containing receptors). Examples of efficacy selective compounds include L-838417, NGD 91-3 and SL651498. For each compound, preclinical and where available clinical data will be reviewed. Emerging themes include the lack of definitive intrinsic efficacy data for certain compounds (e.g. abecarnil, ocinaplon, pagoclone) and the difficulty in translating robust anxiolysis and a separation between anxiolytic and sedative doses of non-selective partial agonists in preclinical species into consistent clinical benefit in man (e.g. bretazenil, abecarnil, pagoclone). With respect to efficacy selective compounds, NGD 91-3 was not anxiolytic in man but in the absence of efficacy data, these results are difficult to interpret. Nevertheless, efficacy selective compounds represent a novel approach to targeting specific subtypes of the GABA(A) receptor, the ultimate test of which will be evaluation in the clinic.

Medication Labeling for Children: Where is it Going?

Medication Labeling for Children: Where is it Going?