Clinical trials randomization

In general, according to EU law, applicants are expected to carry out controlled clinical trials, randomized and as appropriate against a placebo and an established medicinal product (an active comparator) of proved therapeutic value. However, applicants may justify use of other trial design. The treatment of the control groups will vary from case to case and also will depend on ethical consideration and therapeutic area. In some cases it may be more justified to compare the efficacy of a new medicinal product with that of an established medicinal product of proved therapeutic value rather than with a placebo. 

A clinical trial to evaluate misoprostol as a protector of normal tissue during a course of XRT in cancer patients suggests a reduction in acute normal tissue injury (215). A randomized, prospective, double-blind study indicates that topical misoprostol, administered as an oral rinse 15-20 min before irradiation using conventional 2-Gy (200 rad) fractions, five days a week over 6—7 weeks, significantly protects the oral mucosa from radiomucositis, a frequently observed normal tissue complication during XRT for head and neck cancer (215). 

Several clinical trials have been conducted with streptokinase adrninistered either intravenously or by direct infusion into a catheterized coronary artery. The results from 33 randomized trials conducted between 1959 and 1984 have been examined (75), and show a significant decrease in mortaUty rate (15.4%) in enzyme-treated patients vs matched controls (19.2%). These results correlate well with an ItaUan study encompassing 11,806 patients (76), in which the overall reduction in mortaUty was 19% in the streptokinase-treated group, ie, 1.5 million units adrninistered intravenously, compared with placebo-treated controls. The trial also shows that a delay in the initiation of treatment over six hours after the onset of symptoms nullifies any benefit from this type of thrombolytic therapy. Conversely, patients treated within one hour from the onset of symptoms had a remarkable decrease in mortaUty (47%). The benefits of streptokinase therapy, especially in the latter group of patients, was stiU evident in a one-year foUow-up (77). In addition to reducing mortahty rate, there was an improvement in left ventricular function and a reduction in the size of infarction. Thus early treatment with streptokinase is essential. 

Moore, M., Burak Jr., W., Nelson, E., Kearney, T., Simmons, R., Mayers, L. and Spotnitz, W., Fibrin sealant reduces the duration and amount of fluid drainage after axillary dissection A randomized prospective clinical trial. J. Am. Coll. Surg., 192. 591-599 (2001). 

The clinical trial that resulted in FDA approval of bevacizumab (February 2004) was a randomized, double-blind, phase III study in which bevacizumab was administered in combination with bolus-IFL (irinotecan, 5FU, leucovorin) chemotherapy as first-line therapy for previously untreated metastatic colorectal cancer [3]. Median survival was increased from 15.6 months in the bolus-IFL + placebo arm to 20.3 months in the bolus-IFL + bevacizumab arm. 

A key element in planning and conducting clinical trials is to ensure that they have scientific validity and objectivity. This is particularly relevant with respect to Phase II and III studies, where it is desired to demonstrate a positive benefit to risk outcome. Responses to a drug among a patient population are rarely homogeneous and clear-cut. Thus, sound statistical principles must be applied in order to be able to distinguish significant effects from random events. 

Kranzler HR, Wesson DR, Billot L Naltrexone depot for treatment of alcohol dependence a multicenter, randomized, placebo-controlled clinical trial. Alcohol Clin... 

Reoux JP, Saxon AJ, Malte CA, et al Divalproex sodium in alcohol withdrawal a randomized douhle-hlind placeho-controlled clinical trial. Alcohol Clin Exp Res 25 1324-1329,2001... 

Ling W, Weiss DG, Charuvastra VC, et al Use of disulfiram for alcoholics in methadone maintenance programs. Arch Gen Psychiarry 40 851—854, 1983 Ling W, Charuvastra C, Collins JF, er al Buprenorphine maintenance treatment of opiate dependence a multi-center, randomized clinical trial. Addiction 93 475-486, 1998... 

Oncken CA, Hatsukami DK, Lupo VR, et al Effects of short-term use of nicotine gum in pregnant smokers. Clin Pharmacol Ther 59 654-61, 1996 Pomerleau OF, Pomerleau CS Neuroregulators and the reinforcement of smoking towards a biobehavioral explanation. Neurosci Biobehav Rev 8 503—513, 1984 Prochazka AV, Weaver MJ, Keller RT, et al A randomized trial of nortriptyline for smoking cessation. Arch Intern Med 158 2035-2039, 1998 Puska P, Korhonen HJ, Vartiainen E, et al Combined use of nicotine patch and gum compared with gum alone in smoking cessation a clinical trial in North Karelia. Tob Control 4 231-235, 1995... 

Carroll KM, Sinha R, Nich C, er al Conringency management to enhance naltrexone treatment of opioid dependence a randomized clinical trial of reinforcement magnitude. Exp Clin Psychopharmacol 10 5d—63, 2002 Carroll KM, Fenron LR, Ball SA, er al Efficacy of disulfiram and cognitive behavior rherapy in cocaine-dependenr ourparienrs. Arch Gen Psychiatry 61 264—272, 2004... 

Johnson A, Jasinski DR, Galloway GP, et al Ritanserin in the treatment of alcohol dependence a multi-center clinical trial. Psychopharmacol 128 206—215, 1996 Johnson BA, Roache JD, Javors MA, et al. Ondansetron for reduction of drinking among biologically predisposed alcoholic patients a randomized controlled trial. JAMA 284 963-971, 2000... 

Szeimies RM, Gerritsen MJ, Gupta G, Ortonne JP, Serresi S, Bichel J, Lee JH, Fox TL, Alomar A (2004) Imiquimod 5% cream for the treatment of actinic keratosis results from a phase III, randomized, double-blind, vehicle-controlled, clinical trial with histology. J Am Acad Dermatol 51 547-555... 

Haddad AL, Matos LF, Brunstein F, et al (2003) A clinical, prospective, randomized, double-blind trial comparing skin whitening complex with hydroqui-none vs. placebo in the treatment of melasma. Int J Dermatol 42 153-156... 

Prospective sources include encounter data, which may or may not be contained in EHRs patient data input and randomized, prospective clinical trials. Advantages of prospective sources to inform interactive software include the ability to control and monitor the circumstances of data collection reduction (as a result of randomization) of sources of bias potential minimization of missing data potential to modify design of data collection ability to verify data accuracy and ability to validate and further test assumptions and modify existing programs. 

Abdellatif M, Reda D. A Paradox-based data collection and management system for a multi-center randomized clinical trials. Comput Methods Prog Biomed 2004 73 145-64. 

Chen J, Meloro L, Eng H, Wisniewski S. Using SAS to create and e-mail individualized reports in a multi-center randomized clinical trial. Clin Trials 2005 2 S64. 

Abdellatif M. A SAS macro for generating randomization lists in clinical trials using permuted blocks randomization. SUGI29 Proceeding 2004 147-29. 

Swanson A. Computerized bedside randomization in a randomized clinical trial. Controlled Clin Trials 2003 24 3S 166S. 

Kiuchi T, Ohashi Y, Konishi M, Bandai Y, Kosuge T, Kakizoe T. A world wide web-based user interface for a data management system for use in multi-institutional clinical trials—development and experimental operation of an automated subjects registration and random allocation system. Controlled Clin Trials 1996 17 6 476-93. 

Figure 27.2 A display that summarizes the duration of treatment (black sqnares) and the timing of serious vascular events (circles) for the subset of patients who withdrew from treatment because of an adverse event. Each line represents a single patient s experience over time in days for the test (left panel) and the control drug (right panel). Patients are sorted by decreased duration of treatment. In this 1 1 randomized clinical trial there were 18 withdrawals due to a severe vascular adverse event with the test drug. This is in contrast with the control drug, with 11 withdrawals. Withdrawals with the test drug occurred sooner than with the control drug.

Only two randomized, controlled trials have been completed, and neither provides anything like compelling data (Table 2.6). Chouinard and Albright (1997) conducted a unique evaluation of a subset of patients from a previously conducted clinical trial. Subjects were categorized and profiled at baseline and end point according to clinical severity, and a group of psychiatric nurses were asked to rate various aspects of likely outcome and quality of life to each profile (mild, moderate or severe symptoms). Health state utilities were then calculated risperidone was found to provide more than double the number of quality-adjusted life years compared with haloperidol. Csernansky and Okamoto (1999) conducted a rather more conventional trial, but included no economic analyses. However, they did find that the use of risperidone substantially reduced relapse rates compared with haloperidol—an outcome likely to have a positive impact on cost-effectiveness. 

Edgell ET, Hamilton SH, Revicki DA, et al (1998). Costs of olanzapine treatment compared with haloperidol for schizophrenia results from a randomized clinical trial. Poster presented at the 21st CINP Congress, Glasgow, July 1998. 

Grainger DL, Edgell ET, Andersen SW (1998b). Resource use and quality of life of olanzapine compared with risperidone results from an international randomized clinical trial. Abstract presented at 11th European College... 

Data on antidepressant dmgs are available from a number of sources randomized, controlled clinical trials (RCTs) in both hospital and primary-care populations decision analytic models population-based naturalistic observational studies of usual... 

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