On confidence bounds for the ratio of net differences in the "gold standard" design with reference, experimental, and placebo treatment

The three-arm clinical study including a placebo has been recommended to be the preferred study design for the comparison of an experimental treatment relative to a reference treatment. In a confirmatory three-arm study multiplicity issues arise that are not present in two-arm studies. In the past a successful demonstration of superiority of the reference over placebo has been regarded a prerequisite validation step for the demonstration of superiority of the experimental treatment over placebo. However, for an investigator this last comparison is the most critical one. In a clinical study the demonstration of superiority of the experimental treatment over placebo is a result of its own value and this should therefore not be made dependent on tests that are of higher priority in a hierarchical test procedure. This can be achieved through a symmetrical formulation of Fieller's method for constructing confidence intervals for ratio of the expected values from normally distributed variables. In the symmetrical formulation the different meanings of nominator and denominator disappear, and simultaneous statements for comparisons between the experimental treatment and placebo, reference treatment and placebo, and reference and experimental treatment can be made. This is accomplished by moving the discussion on confidence sets from the line of real numbers to the unit circle which allows representing confidence sectors always as connected sets, gives always simple geometrical interpretations, and is easy to be transformed back to the real numbers if the traditional calculations behave well. The proposed procedures provides additional insight in existing methods but does obviously not answer the clinical question whether or not the demonstration of superiority of the reference treatment over placebo is a necessary validation step for further comparisons.     

Re‐Formulating Non‐inferiority Trials as Superiority Trials: The Case of Binary Outcomes

Non‐inferiority trials are conducted for a variety of reasons including to show that a new treatment has a negligible reduction in efficacy or safety when compared to the current standard treatment, or a more complex setting of showing that a new treatment has a negligible reduction in efficacy when compared to the current standard yet is superior in terms of other treatment characteristics. The latter reason for conducting a non‐inferiority trial presents the challenge of deciding on a balance between a suitable reduction in efficacy, known as the non‐inferiority margin, in return for a gain in other important treatment characteristics/findings. It would be ideal to alleviate the dilemma on the choice of margin in this setting by reverting to a traditional superiority trial design where a single p ‐value for superiority of both the most important endpoint (efficacy) and the most important finding (treatment characteristic) is provided. We discuss how this can be done using the information‐preserving composite endpoint (IPCE) approach and consider binary outcome cases in which the combination of efficacy and treatment characteristics, but not one itself, paints a clear picture that the novel treatment is superior to the active control (© 2009 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)     

Note on simultaneous inferences about non-inferiority and superiority for a primary and a secondary endpoint

In their review of challenges to multiple testing in clinical trials, Hung and Wang (2010) considered the situation where a treatment is to be compared with an active comparator and the aim is to show non-inferiority and (if possible) superiority with respect to a primary and a secondary endpoint. This note extends their discussion of this particular situation, taking the sequentially rejective procedure they used for illustration as a starting point. Some alternative multiple testing procedures (MTPs) are considered, and corresponding simultaneous confidence regions are discussed that provide additional information "for free". The choice may then be based on the properties of these MTPs and corresponding confidence regions.     

Phytotherapy for functional dyspepsia: A review of the clinical evidence for the herbal preparation STW 5

Functional gastrointestinal disorders such as functional (or non-ulcer) dyspepsia are characterized by a broad spectrum of symptoms referred to the upper abdomen without a detectable cause utilizing routine diagnostic measures. It is now believed that disordered gut function (including abnormalities like disturbances of motility such as postprandial fundic relaxation, gastric emptying and disturbed visceral sensory function) play a key role for the manifestation of these disorders. The underlying pathophysiology is not yet fully understood. However, the available data suggest that a number of factors may contribute to the manifestation of symptoms. These factors include environmental factors such as acute infections as trigger event, psychological stressors that may precede acute exacerbations and a genetic predisposition. Considering the large number of mechanisms, a treatment targeting a single mechanism is unlikely to be effective in all patients. Indeed, chemically defined treatments usually gain a 10–15% superiority over placebo. In recent years placebo-controlled studies have demonstrated superiority of a commercial multicomponent herbal preparation, STW 5, with the trade name Iberogast^® for the treatment of patients with functional dyspepsia and irritable bowel syndrome. This phytopharmacon is a combination of nine plant extracts each with a number of different active constituents. Pharmacological studies have shown different effects of the single plant extracts on the (molecular) mechanisms which are discussed as underlying the manifestation of symptoms. Various well-controlled clinical trials have independently confirmed clinical efficacy and safety.The clinically efficacy of this multicomponent herbal preparation questions the current trend of highly targeted drug molecules that usually target one single receptor population while it has not been shown that a single receptor group plays a pivotal role for the control of symptoms. Herbal medicines are obtained from various plants and contain complex extracts with a large number of different active substances. While there are only limited head-to-head comparisons with conventional chemically defined medications, the combination of extracts with various gastrointestinal active ingredients appears to be advantageous for a heterogenous condition such as functional dyspepsia.     

The Placement of DPP-4 Inhibitors in Clinical Practice Recommendations for the Treatment of Types 2 Diabetes

ObjectiveTo review the most recent clinical data on the safety and efficacy of dipeptidyl peptidase-4 (DPP-4) inhibitors and to evaluate their position in current treatment guidelines and algorithms.MethodsPubMed searches were performed to identify published data regarding both the safety and efficacy of DPP-4 inhibitors approved for use in the United States and clinical guidelines describing recommendations for their use.ResultsIn the past 2 years, more than 100 publications have added clinical trial data on DPP-4 inhibitors to the medical literature. Since becoming available in 2006, these agents have demonstrated an excellent safety/tolerability profile, and as add-on to metformin, DPP-4 inhibitors may have comparable glycemic efficacy as other oral agents. As a result, DPP-4 inhibitors have assumed roles in clinical practice guidelines and treatment algorithms that are comparable to the sulfonylurea class. Advantages of DPP-4 inhibitors include an oral route of administration, a mechanism of action based on glucose-stimulated insulin secretion, and a low risk of hypoglycemia. The main disadvantage associated with this class is a relatively high cost. There is also less clinical experience with DPP-4 agents than classes of agents that have been in use for decades; however, long-term data on the safety and efficacy of DPP-4 agents will be available in the near future to refine their place in therapy. From 2 large clinical trials recently reported, EXAMINE and SAVOR, this class of agents does not increase overall adverse cardiovascular outcomes nor the risk of pancreatitis or pancreatic cancer.ConclusionBased on comparisons of nonglycemic effects such as risk of hypoglycemia, weight gain, and durability, DPP-4 inhibitors may be considered as an alternative to sulfonylureas. However, direct cost may be a determining factor in the choice of therapy. (Endocr Pract. 2013;19:1050-1061)     

Probiotics: time for a dose of realism

There is already a long research and retail history of probiotics, but progress in the scientific and medical validation of these products has been extremely slow. Even now, adequate information by which the consumer and health professional can judge the efficacy and safety of retailed probiotics is lacking. Probiotic products have not been subjected to large scale trials of efficacy that are used in the pharmaceutical industry. Without these trials and subsequent approval by fastidious regulatory agencies such as the FDA (USA), probiotics continue to languish in the self-care health market. Optimistically, a new generation of probiotics may be developed that have medical validity with respect to the prevention or treatment of atopic and inflammatory bowel diseases. These new products, however, will need to be targeted at the alleviation of specific medical conditions, and the mechanistic basis of their effectiveness will need to be provided.     

Plant Derived Antimalarial Agents: New Leads and Challenges

New treatments for malaria are urgently needed due to the increasing problem of drug-resistance in malaria parasites. The long-established use of quinine and the more recent introduction of artemisinin and its derivatives as highly effective antimalarials demonstrates that plant species are an important resource for the discovery of new antimalarial agents. Furthermore, many plant species continue to be used in traditional medicines for the treatment of malaria and many people depend on such remedies as they cannot afford and/or do not have access to effective antimalarial drugs. In this paper the potential of plant species to yield new leads to antimalarial drugs will be illustrated with reference to cryptolepine, the main alkaloid present in the species, Cryptolepis sanguinolenta. In addition to this approach, there is currently increasing interest in the use and development of traditional herbal remedies for the treatment of malaria as these may have the potential to provide affordable antimalarial treatment for many who cannot afford the drugs needed to treat chloroquine-resistant Plasmodium falciparum infections. However, little is known with respect to the efficacy and safety of traditional antimalarials and clinical studies are urgently needed to establish their value. Some of the issues pertinent to this area will be briefly reviewed and it is hoped that this will stimulate further discussion and research on this important topic.     

Simultaneous One-Sided Pairwise Comparisons in a Two-Way Design

Cheung and Chan (1996) provided a procedure for simultaneous two-sided pairwise comparisons of treatment means in a two-way design. Expanding on this earlier work, we develop a procedure where all such comparisons are instead one-sided. The new procedure is appropriate in situations where the treatment means are a priori ordered. The overall type I error rate for the simultaneous inferences is controlled at a designated level. Tables of upper percentage points of the test statistic are given to facilitate the implementation of our method. The application of the testing procedure is illustrated with an example from a medical study.     

The Role of Bromocriptine-Qr in the Management of Type 2 Diabetes Expert Panel Recommendations

ObjectiveTo review available data on the efficacy and safety of bromocriptine-QR (BQR) and to consider its role in the management of Type 2 diabetes mellitus (T2DM).MethodsPublished literature reporting the efficacy and safety of BQR in the treatment of T2DM was reviewed, including peer-reviewed abstracts and poster presentations.ResultsBQR is an oral hypoglycemic agent with a novel mechanism of action that appears to involve enhancement of morning central nervous system (CNS) dopaminergic activity, resulting in improved insulin sensitivity and reduced hepatic glucose output. Adjunctive treatment with BQR in the dosing range of 1.6 to 4.8 mg/d may result in a mean (95% confidence interval [CI]) reduction in glycated hemoglobin (A1c) levels of 0.69% (0.97%, 0.41%). Treatment with BQR appears to be associated with minimal intrinsic risk of hypoglycemia, and does not appear to be associated with clinically significant adverse effects on weight, triglycerides, free fatty acids, or blood pressure.ConclusionThe favorable cardiovascular risk profile of BQR suggests that it may be useful in the treatment of patients with T2DM with a history of cardiovascular disease (CVD) or who have significant risk factors for CVD. However, knowledge of the efficacy and safety of BQR is limited by the relatively small clinical trials database. As a result, there is currently insufficient information on the safety and efficacy of adjunctive BQR in T2DM patients being treated with several common diabetes regimens (e.g., thiazolidinediones, insulin). (Endocr Pract. 2013;19:100-106)     

Multiple Testing for Identifying Effective and Safe Treatments

In the literature various multiple test procedures to compare k treatments with a control have been investigated. They can be applied to establish either treatment efficacy or treatment safety. In this paper we propose procedures which control the multiple level α with respect to efficacy and safety simultaneously. On the one hand we consider a method with stagewise rejective adjustments of local levels applied to appropriately defined subfamilies of null hypotheses. When order restrictions are assumed to hold among the parameters of interest we can alternatively split the multiple level between the families of efficacy and safety null hypotheses. If either all treatments are declared to be safe or all are declared to be effective then the other family can be tested at the full multiple level α, respectively. The methods are compared in a simulation study.     

Vaccine trials

This article reviews some of the issues involved in evaluating vaccines in humans. Vaccine trials are required for licensure and are essential for demonstrating a vaccine's safety and protective efficacy. The formal framework of phase I, II, and III trials is described, with particular emphasis on the choice of hypotheses, trial design, and biases that arise in the context of vaccine trials. However, some aspects of a vaccine's performance cannot be evaluated in clinical trials owing to their relatively small size. Thus, vaccine evaluation must continue after licensure, for example, to evaluate the vaccine with respect to rare reactions, duration of protection, and ecological effects. The article reviews some of the methods commonly used for post-licensure studies of vaccine efficacy and safety.     

A summary of second-line randomized studies of aromatase inhibitors

The new generation of selective aromatase inhibitors (anastrozole, letrozole and exemestane) offer a significant efficacy and safety advantage over both older agents in this class (aminoglutethimide) and the progestins (megestrol acetate (MA)), as second-line treatment for postmenopausal women with advanced hormone-dependent breast cancer who have failed on tamoxifen therapy. Exemestane, a steroidal aromatase inhibitor, has been shown to have activity after failure with the non-steroidal aromatase inhibitors, anastrozole and letrozole, and could be used as third-line treatment. Although the newer aromatase inhibitors belong to the same class and appear, from indirect comparisons, to have similar efficacy compared with the older therapies, they have different pharmacokinetic and pharmacodynamic profiles, suggesting the potential for clinical differences. Compared with exemestane and letrozole, anastrozole shows greater selectivity for aromatase, as it lacks any evidence of an effect on adrenal steroidogenesis and has no androgenic effects. Therefore, it is clear that these agents should not be considered to be similar in all respects. In summary, the introduction of the aromatase inhibitors represents a significant step forward in the treatment of advanced breast cancer in postmenopausal women. Studies in the adjuvant setting will ultimately determine whether the differences in pharmacokinetics and phamacodynamics will be of clinical relevance.     

Bilastine: new insight into antihistamine treatment

Bilastine is a new second generation H1-antihistamine recently approved for the symptomatic treatment of allergic rhinitis (AR) and chronic urticaria (CU). Bilastine epitomizes the evolution of research on antihistamines concerning both efficacy and safety. In AR treatment, a number of large controlled clinical trials documented its efficacy, as assessed by improvement of all nasal and ocular symptoms and quality of life. These outcomes show that bilastine meets current EAACI/ARIA criteria for medications used in the treatment of AR. Also in CU, the review of the literature indicates that once-daily treatment with bilastine 20 mg was effective in managing symptoms and improving patient’s quality of life. Concerning safety and tolerability, the profile of bilastine is very similar to placebo and in particular the adverse effects on central nervous system are insignificant. The balance of efficacy and safety of bilastine is particularly helpful when dosages higher than standard are needed to control the symptoms, as frequently occurs in patients with urticaria, in whom antihistamines doses up to four times the standard dose may be administered.     

Recombinant therapeutic proteins: production platforms and challenges

Since the approval of insulin in 1982, more than 120 recombinant drug substances have been approved and become available as extremely valuable therapeutic options. Exact copying of the most common human form is no longer a value per se, as challenges, primarily related to the pharmacokinetics of artificial recombinant drugs, can be overcome by diverging from the original. However, relatively minor changes in manufacturing or packaging may impact safety of therapeutic proteins. A major achievement is the development of recombinant proteins capable of entering a cell. Such drugs open up completely new opportunities by targeting intracellular mechanisms or by substituting intracellularly operating enzymes. Concerns that protein variants would cause an intolerable immune response turned out to be exaggerated. Although most recombinant drugs provoke some immune response, they are still well tolerated. This knowledge might result in a change in attitude towards antibody formation, i.e., neutralizing antibody activity (in vitro) may be overcome by dosing consistently on the basis of antibody titers and not only on body weight. As with other drugs, efficacy and safety of therapeutic proteins have to be demonstrated in clinical studies, and superiority over available products has to be proven instead of just claimed.     

Coronary artery bypass grafting (CABG): reassessing efficacy,safety, and cost

Based on randomized clinical trials begun in the 1970s showing the superiority of coronary artery bypass grafting (CABG) to medical management for patients with coronary artery disease (CAD), CABG has been routinely used to reduce angina and improve chances of survival in patients with CAD. Since CABG became a recognized standard treatment of CAD, considerable evidence has accumulated concerning the pathogenesis of CAD; the efficacy, risks, and costs of CABG; and the effectiveness of CAD risk factor reduction. To re-evaluate efficacy, safety, and cost of CABG, a MEDLINE search was performed to locate randomized trials comparing CABG vs nonsurgical management, CAD pathogenesis studies, and articles evaluating efficacy of coronary artery risk factor reduction behaviors. The extent of revascularization with CABG bore no relationship to relief of angina or survival. Randomized CABG vs medical management studies revealed that only patients with the most advanced CAD had improved survival, and this advantage vanished after 12 years. Researchers kept little coronary risk factor reduction data in the original CABG vs medical management randomized trials. However, in the Bypass Angioplasty Revascularization Intervention (BARI) study, surgically treated patients adopted lifestyles associated with lower coronary risk significantly more than patients treated with angioplasty. Factors other than revascularization cause the improvement in angina associated with CABG. Temporary survival advantages of CAD high-risk subgroups after CABG may be better explained by risk factor reduction rather than by revascularization. Using the BARI data, including lifestyle factors, a multivariate analysis of the influences determining survival and quality-of-life end points would test this hypothesis.     

IND综合评价的逻辑结构及成药性评价

基于各学科信息作出安全性、有效性和质量可控性方面的综合评价是新药研究评价的灵魂,是一个多学科、多组织参与的综合决策过程。根据新药评价研究的实际工作经验,介绍一个新药临床试验综合评价的逻辑性、结构性的工作思考模式,有助于将不同专业的技术信息和技术结论有机整合,作出科学决策。     

A mixed approach for proving non-inferiority in clinical trials with binary endpoints

When a new treatment is compared to an established one in a randomized clinical trial, it is standard practice to statistically test for non-inferiority rather than for superiority. When the endpoint is binary, one usually compares two treatments using either an odds-ratio or a difference of proportions. In this paper, we propose a mixed approach which uses both concepts. One first defines the non-inferiority margin using an odds-ratio and one ultimately proves non-inferiority statistically using a difference of proportions. The mixed approach is shown to be more powerful than the conventional odds-ratio approach when the efficacy of the established treatment is known (with good precision) and high (e.g. with more than 56% of success). The gain of power achieved may lead in turn to a substantial reduction in the sample size needed to prove non-inferiority. The mixed approach can be generalized to ordinal endpoints.     

Evolutionarily stable strategy and invader strategy in matrix games

In this paper, we consider the concepts of evolutionarily stable strategy (ESS), neighborhood invader strategy (NIS) and global invader strategy (GIS) in single species with frequency-dependent interactions. We find some general relationships among the three concepts in matrix games. The main conclusion is that ESS and NIS are equivalent to each other and are both equivalent to local superiority; a strategy with global superiority must be a GIS; a GIS may not be equivalent to its global superiority in games with more than two players; and in any two-player matrix game a GIS is just equivalent to its global superiority. In two-player games, globally asymptotic stability in the replicator dynamics has also been shown. Equivalent conditions for the three concepts stated by payoff comparisons are given and are applied to examples involved.     

Physiological basis for novel drug therapies used to treat the inflammatory bowel diseases. I. Immunology and therapeutic potential of antiadhesion molecule therapy in inflammatory bowel disease

Adhesion molecules regulate the influx of leukocytes in normal and inflamed gut. They are also involved in local lymphocyte stimulation and antigen presentation within the intestinal mucosa. In intestinal inflammation, many adhesion molecules are upregulated, but alpha4-integrins most likely hold a key position in directing leukocytes into the inflamed bowel wall. Therapeutic compounds directed against trafficking of leukocytes have been designed and are being developed as a novel class of drugs in the treatment of Crohn's disease and ulcerative colitis. This review deals with the immunological aspects of leukocyte trafficking focused on gut homing of T cells. Second, the changes in adhesion molecules and T cell trafficking during intestinal inflammation are discussed. Finally, we review the clinical data that have been gathered with respect to the therapeutic potential and the safety of antiadhesion molecule treatment. Antegren, or natalizumab, a humanized anti-alpha4 integrin IgG4 antibody, has been most extensively evaluated and may be close to registration. A more specific humanized alpha4beta7-integrin MLN-02 has shown preliminary clinical efficacy in ulcerative colitis, and both antergren and MLN-02 appear to be very safe. Trials with the anti-ICAM-1 antisense oligonucleotide ISIS-2302 in steroid refractory Crohn's disease have provided conflicting efficacy data. In the near future, some of these novel biological agents may prove valuable therapeutic tools in the management of refractory inflammatory bowel disease, although it is too early to define the patient population that will benefit most from these agents.     

Drain the lysosome: Development of the novel orally available autophagy inhibitor ROC-325

Although macroautophagy/autophagy is a key contributor to malignant pathogenesis and therapeutic resistance, there are few FDA-approved agents that significantly affect this pathway. We used medicinal chemistry strategies to develop ROC-325, an orally available novel inhibitor of lysosomal-mediated autophagy. Detailed in vitro and in vivo studies in preclinical models of renal cell carcinoma demonstrated that ROC-325 triggered the hallmark features of lysosomal autophagy inhibition, was very well tolerated, and exhibited significant superiority with respect to autophagy inhibition and anticancer activity over hydroxychloroquine. Our findings support the clinical investigation of the safety and preliminary efficacy of ROC-325 in patients with autophagy-dependent malignancies and other disorders where aberrant autophagy contributes to disease pathogenesis.