Summary of recommendations for the design of clinical trials and the registration of drugs used in the treatment of asthma

With new drugs being introduced to treat asthma it is timely to review criteria that can be used to assess efficacy in clinical trials. Anti-asthma drugs are classified into symptoms-modifying, symptom preventers and disease modifying agents. Attention is drawn to the types of experimental evidence required in preclinical studies to support further clinical development of a new therapy. Clinical trials demand careful selection of patients to maximise the strength of the efficacy signal according to the type of trial being designed. While provocation tests are useful in suggesting efficacy, negative tests do not necessarily indicate lack of anti-asthma activity. Therapeutic trial designs need to take account of duration of treatment, dose-response relationships and confirmatory trials. Outcome measures include symptoms, lung function, reduction in concomitant medication, exacerbations, quality of life and measures of inflammation. Interpretation of results need to include the clinical relevance of any changes as well as statistical significance. Special consideration needs to be given to the evaluation of drugs for acute severe asthma, asthma in children and older people, co-morbidity such as rhinitis, and inhaler devices. As with all drugs introduced into practice, careful attention needs to be paid to both short- and long-term safety.     

Recent clinical trials: A critical appraisal

Conclusions The clear message from these trials from the 1990s is that crucial questions often are being addressed by studies that contain important flaws in design and data interpretation. Investigators involved in on-going studies in hypertension are urged to review critically aspects of their study design and plans for later analysis to avoid some of the problems outlined in this overview. It is hoped that large-scale outcome trials such as the Anglo-Scandinavian Cardiac Outcomes Trial (ACSOT) and the Antihypertensive and Lipid-Lowering Heart Attack Prevention Trial (ALLHAT) will provide definitive answers to the questions of optimal treatments for the prevention of coronary heart disease and other cardiovascular end points in hypertension in the millennium.     

A critical analysis of the methods used to develop explicit clinical criteria for use in older people

Older people are the biggest users of medications and with the majority of the population ageing it is important to ensure that their medications are managed properly. Many have developed explicit criteria in order to assist in making appropriate drugs choices in the older population. This paper explores whether the methods used to develop the currently available explicit criteria for appropriate prescribing in older people are applied appropriately, and if not, whether this invalidates the criteria themselves. The wide spread use of the Delphi technique to develop medical criteria indicates that the technique itself should be evaluated for its suitability in the development of criteria in older people before the criteria are themselves evaluated. A number of criteria have been reviewed and none fulfils the requirements for appropriate development. There is a need for new criteria, with transparent referencing of recommendations and rigorous final evaluation.     

Methods used in clinical development of novel anti-asthma therapies

In recent years, it has become increasingly important to get as much as possible information on clinical efficacy already in the early phases of drug development. For proof of concept (POC) studies testing novel anti-inflammatory drugs in asthma, there are several validated exacerbation models, inducing various aspects of the airway inflammation and airway responsiveness. The choice of the appropriate asthma model depends on the drug's targets within the inflammatory process. For adequate assessment of the drug's anti-inflammatory potential, it is crucial to choose adequate (surrogate) biomarkers. Ideally, these should include measures of airway response, central and peripheral airway inflammation and airway hyperresponsiveness. Overall, there are validated non-invasive sampling techniques for the measurement of inflammatory markers in asthma that can be applied as outcome parameters in early clinical trials. If adequately implemented, these measurements can provide early indication of proof of pharmacological and potential therapeutic efficacy-even in first administration to humans.     

Novel antithrombotic strategies for the treatment of coronary artery thrombosis: A critical appraisal

Summary Large-scale clinical trials have demonstrated that treatment of patients with acute myocardial infarction and unstable angina with antithrombotic agents significantly improves outcome. Despite the proven benefit of current therapies, there is a widespread perception that outcome could be enhanced further with novel antithrombotic agents. Enthusiasm for novel antithrombotic strategies has been stimulated by recent advances in the understanding of the mechanisms responsible for coronary artery thrombosis, which has led to the development of diverse inhibitors of platelet function and coagulation factors. In experimental models of coronary artery thrombosis, aspirin and heparin have been ineffective in preventing recurrent thrombosis after coronary thrombolysis and in preventing the progression of thrombosis in response to strong thrombogenic stimuli. In contrast, inhibitors of the platelet fibrinogen receptor, direct-acting thrombin inhibitors, and inhibitors of coagulation factors that promote elaboration of thrombin have been shown to be effective in attenuating arterial thrombosis in a variety of experimental preparations. Initial clinical trials with these agents have also documented efficacy in attenuating thrombotic events in patients treated with coronary thrombolysis and in those with unstable angina. However, optimal doses of novel antithrombotic agents, the degree to which combination antiplatelet and anticoagulant therapies are needed, and the risk/benefit ratio associated with specific novel antithrombotic drugs are still relatively undefined. With regard to the latter, it is possible that the large-scale clinical trials now in progress may show an increase in bleeding complications with novel anticoagulants compared with conventional therapy. Nonetheless, there are considerable data that suggest that treatment with aspirin and heparin is not completely effective in preventing the progression of thrombosis or its recurrence after interventions in high-risk subgroups of patients with coronary artery thrombosis and unstable coronary artery disease. Accordingly, continued investigation of a large variety of antithrombotic agents, both currently available and in development, should improve the treatment of highrisk patients with coronary disease if regimens with appropriate efficacy but without serious hemorrhagic effects can be designed.Supported in part by SCOR in Coronary and Vascular Diseases (grant HL-17646), National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD.     

Critical appraisal of commonly used treatment for genital warts

Genital warts are one of the most commonly reported sexually transmitted diseases worldwide. A variety of treatment options are available but few have been assessed in large-scale, randomized, placebo-controlled trials. Provider-applied surgical and non-surgical treatments have traditionally been the therapies of choice. Surgical therapies, including cryotherapy, electrotherapy, laser surgery and surgical excision, are generally equivalent in terms of wart clearance rates, but are associated with high rates of wart recurrence. Trichloroacetic acid is a widely used non-surgical therapy, but little is known about its efficacy, and it is associated with unpleasant side-effects. The patient-applied treatments imiquimod and podophyllotoxin are newer therapy choices which are more acceptable to both patients and practitioners. The wart clearance rates for these two treatments are similar, although imiquimod is associated with lower recurrence rates. In the face of increasing pressures on genitourinary clinic services, patient-applied home therapy represents an attractive option for the treatment of genital warts.     

Advances in methods used in evaluation of occupational asthma

PURPOSE OF REVIEW: Diagnosing occupational asthma (OA) is a complex undertaking, the primary goal of which is to demonstrate a causal relation between exposure to a specific agent encountered at work and asthmatic responses. Recent development or refinement of diagnostic tools may improve the diagnostic accuracy, which may have important economic and social consequences for both employers and workers. RECENT FINDINGS: Although specific inhalation challenge (SIC) testing is the gold standard for diagnosis of OA, these tests are not widely available in many countries. Thus, new less invasive techniques used in the measurement of airway inflammation, such as exhaled nitric oxide and induced sputum are highlighted as are recent developments in both in vivo and in vitro immunologic testing. SUMMARY: Although new perspectives are being evaluated, the diagnosis of occupational asthma still relies mostly on specific inhalation challenge. Further studies are required to confirm the utility of these new techniques in the diagnosis of OA.     

Anti-IgE as novel therapy for the treatment of asthma

Immunoglobulin-E (IgE) is believed to be the central effector antibody reacting to allergen in patients with allergic asthma. Clinical manifestations of allergic asthma result from the release of chemical mediators from mast cells and basophils on exposure to allergen. A humanized murine monoclonal antibody to IgE, rhuMAb-E25, recognizes the specific Fc epsilon3 portion of circulating IgE that binds to the high-affinity IgE receptor, Fc epsilonRI. In clinical studies, single and multiple doses of subcutaneous and intravenous rhuMAb-E25 have been shown to reproducibly reduce the serum free IgE concentrations in a dose-dependent manner. Clinical trials conducted in aeroallergen bronchoprovocation laboratories demonstrated that decreasing circulating IgE resulted in significant attenuation of the early and late asthmatic responses. Studies completed in moderate to severe allergic asthmatics have extended the safety and efficacy of rhuMAb-E25. Significant improvements in asthma symptoms, meaningful reductions in corticosteroid agents while decreasing reliance on bronchodilator rescue drugs, decreased asthma exacerbations, and improved quality of life have been documented. Because of the remarkable protein engineering and the humanization technology now available, rhuMAb-E25 therapy has elicited no antibody responses and has been safely administered to atopic subjects. rhuMAb-E25 as a novel monoclonal antibody, the first to be applied to lung diseases, holds promise for the control of many IgE-mediated diseases.     

Nephrotoxicity of common drugs used in clinical practice

Drug-induced nephrotoxicity is an increasingly recognized complication of a wide variety of therapeutic agents. The nephrotoxicity of three of the most commonly used drug groups are reviewed in this article. They include antibiotics, radiocontrast agents, and nonsteroidal anti-inflammatory drugs. Since the clinical spectrum of drug-induced nephrotoxicity is broad, it is imperative that the clinician recognize these nephrotoxic syndromes while they are reversible with discontinuation of the offending drug.     

Drugs used in the treatment of asthma: a review of clinical pharmacology and aerosol drug delivery

The selection and titration of pharmacologic agents are essential in the treatment of asthma. This Article focuses on the primary medications used in the treatment of reactive airway disease. The recent advances in the technology of devices used to administer aerosolized medications are also reviewed.