Equivalence trials/studies

Equivalence trials are, of course, routinely used in the evaluation of bioequivalence and the methodology there is well established, both European and FDA guidelines exist. More recently we have seen the need to establish therapeutic equivalence and Ebbutt and Frith (1998) provide a detailed case study in the development of an alternative propellant for the asthma inhaler. More usually,... 

This chapter introduces basic concepts in statistical analysis that are of relevance to describing and analyzing the data that are collected in clinical trials, the hallmark of new drug development. (Statistical analysis in nonclinical studies was addressed earlier in Chapter 4.) This chapter therefore sets the scene for more detailed discussion of the determination of statistical significance via the process of hypothesis testing in Chapter 7, evaluation of clinical significance via the calculation of confidence intervals in Chapter 8, and discussions of adaptive designs and of noninferiority/equivalence trials in Chapter 11. 

Staszewski S, Keiser P, Montaner J, Raffi F, Gathe J, Brotas V, Hicks C, Hammer SM, Cooper D, Johnson M, TorteU S, CutreU A, Thorborn D, Isaacs R, Hetherington S, Steel H, Spreen W CNAAB3005 International Study Team. Abacavir-lamivudine-zidovudine vs indinavir-lamivudine-zidovudine in antiretroviral-naive HIV-infected adults A randomized equivalence trial. JAMA 2001 285(9) 1155-63. 

Interchangeability Multisource (generic) bioequivalence study. Bioequivalence of all oral preparations except aqueous solutions. Orally or parenterally administered aqueous solutions chemical-pharmaceutical characteristics. Comparative clinical trial using clinical or pharmacodynamic end-points can be presented. End-points justified and validated for the compound and trial should be designed to show equivalence. Trial showing the absence of significant difference cannot be accepted Bioequivalence study report included ... 

Phase III studies can be tested against a placebo control with the intent of showing superiority over placebo. Another type of study design is to show equivalence or noninferiority to an approved therapy. An equivalence trial is intended to show that the response to two or more treatments differs by an amount which is clinically unimportant. A noninferiority trial demonstrates that the response to the investigational product is not clinically inferior to a comparative agent. 

Equivalence trials Useful when superiority is unlikely to be demonstrated Scientific problem of proving a negative Large sample sizes Standards of care not previously studied... 

Reifart, N., Morice, M.C., Silber, S., Benit, E., Hauptmann, K.E., de Sousa, E., et al. The NUGGET study NIR ultra gold-gilded equivalency trial. Catheter Cardiovasc. Interv. 62,18-25 (2004)... 

Compared to streptokinase, urokinase has been less extensively studied because of its high cost, ie, about 10 times that of a comparable treatment with streptokinase. In addition to the indications described for streptokinase, urokinase is indicated for use in patients with prior streptokinase treatment, or prior Streptococcal infection. Urokinase is commonly used at a loading dose of 4400 units /kg, with a maintenance intravenous infusion dose of 4400 units/kg/h for thromboses other than acute myocardial infarction. In the latter case, a much larger dose, ie, 0.5—2.0 million units/h or a bolus dose of 1.0 million units followed by a 60-min infusion with 1.0 million units, has been found optimal (106). An intracoronary dose of 2000 units/min for two hours was used in one comparative study with intracoronary streptokinase (107). In this study, urokinase exhibited efficacy equivalent to streptokinase with fewer side effects. Other studies with intracoronary urokinase have adrninistered doses ranging from 2,000 to 24,000 units/min with a reperfusion efficacy of 60—89% (108—112). In another urokinase trial, 2.0 million units were adrninistered intravenously, resulting in a thrombolytic efficacy of 60% (113). Effectiveness in terms of reduction in mortaUty rate has not been deterrnined because of the small number of patients studied. 

In capillary shear studies involving M. citrifolia, the extent of cell damage was found to increase with the prevailing level of shear stress (Fig. 2). Trials involving capillary tubes of different lengths yielded similar levels of viability loss at equivalent exposure times, indicating that the death rate is determined by the shear stress alone. 

Our studies do not resolve the question of phytate vs fiber for the effect of wheat bran on dietary calcium bioavailability. Phytate level clearly affected apparent absorption of calcium in HS-II in the presence of an amount of the water insoluble fraction of dephytinized bran equivalent to 12 g of untreated bran and the phytate supplied as sodium phytate. An additional trial using untreated bran and the same amount of fiber as the water insoluble fraction with sodium phytate could resolve the question of fiber vs phytate. In HS-I, the balances were positive when a relatively large amount of bran, 36 g/day, was consumed. Calcium intakes were possibly higher than most men consume, but under the dietary conditions imposed for 15 days, the phytate and fiber of 36 g of bran did not express an adverse effect on calcium balance. 

In Japan, if there are no Phase II clinical trials of equivalent duration to the planned Phase III trials, conduct of longer duration toxicity studies is recommended as given in Table 2. 

Clinically, it has been confirmed that the drug is an effective bronchodilator with very little cardiovascular activity it does not appear to increase hypoxaemia [439]. A more detailed study [440], comparing salbutamol with isoprenaline and orciprenaline, demonstrated that 200 jug of salbutamol provided effective bronchodilation for at least three hours without detectable cardiac stimulation. Equivalent bronchodilator doses of isoprenaline and orciprenaline were 1000 /ag and 1500 jUg respectively. The bronchial effects of isoprenaline, though initially intense, waned within one hour and cardiac effects were noted. In this trial little objective difference could be detected between salbutamol and orciprenaline at the dose levels used, though most patients expressed preference for salbutamol. 

In Japan and the United States, the clinical duration for Phase I, II and III trials can equal the duration of toxicity studies (Table 3.1). In Europe, a more conservative approach is adopted as longer duration studies, equivalent to those expected for marketing, are needed for Phase III trials (Table 3.2). 

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