Placebo washout in trials of antipsychotic drugs

For antipsychotic phase 3 clinical trials, we compare the relative merits of a placebo washout period with an alternate design strategy using a low-dose antipsychotic treatment. Evaluations are made with respect to the achievement of specific clinical trial design goals including the effect on power for detecting between-treatment and within-treatment pre-post differences. The relative merits of these two designs are discussed separately for those patients who enter the initial leadin period after withdrawal from previous antipsychotic medication and for those not on medication immediately before that period.     

Reporting of gender-related information in clinical trials of drug therapy for myocardial infarction

The genomic RNA of Hepatitis A virus (HAV), a picornavirus of the hepatovirus group, is a single-stranded molecule, ca. 7.5 kb in length of positive polarity. Translation of this uncapped RNA starts at the 10th (or 11th) AUG triplet (position 734-36), by a mechanism of internal initiation of translation. The long sequences extending between the uncapped 5'-end and the translation initiation site contain two (instead of just one) pyrimidine-rich tracts (PRTs) spanning nucleotides 94-140 and 711-724, respectively. The latter lies only 11 nucleotides upstream from the initiation site of translation, and the question arose as to whether the notoriously poor replication ability of HAV was a consequence of a down regulation of translation due to the too short "spacer" sequence intervening between the 3'-PRT and the initiation of the main open reading frame. To address this issue, a series of full-length HAV cDNA clones were constructed in which the "spacer" sequence (normally 11 nts) was brought to 45 nts. Following transfection of COS-1 cells with these constructs, the amount of HAV (+)-strand RNA was determined by dot hybridization using a strand-specific RNA probe. HAV cDNA clones carrying a 45-nt "spacer" increased two-fold the rate of (+)-strand viral RNA synthesis, suggesting that the poor translation ability of HAV RNA may be one of the mechanisms responsible for the lengthy replication cycle of HAV.     

Self-designing clinical trials

I present a method of sequential analysis for randomized clinical trials that allows use of all prior data in a trial to determine the use and weighting of subsequent observations. One continues to assign subjects until one has 'used up' all the variance of the test statistic. There are many strategies to determine the weights including Bayesian methods (though the proposal is a frequentist design). I explore further the self-designing aspect of the randomized trial to note that in some cases it makes good sense (i) to change the weighting on components of a multivariate endpoint, (ii) to add or drop treatment arms (especially in a parallel group dose ranging/efficacy/safety trial), (iii) to select sites to use as the trial goes on, (iv) to change the test statistic and (v) even to rethink the whole drug development paradigm to shorten drug development time while keeping current standards for the level of evidence necessary for approval.     

Placebo effects. Issues for clinical practice in psychiatry and medicine

Placebo effects are integral to everyday clinical practice; therefore, they should be well understood by all health care practitioners. Despite the rich literature on the topic, placebo effects receive only passing mention in major textbooks of psychiatry and medicine. The authors clarify the placebo construct and offer a selective review of its history, definitions, mechanisms, and relation to experimental methodology and statistics. Also considered are the concept of nocebo, variation in placebo response rates, and some economic and ethical problems with placebos in clinical trials. Directions are suggested for future research.     

Placebo

At this time innovation in general practice service delivery is being extensively explored and critically examined as a means of improving efficiency. It is important that general practitioners are actively involved in the debate and utilise techniques that allow detailed, logical and robust judgments to be formulated. Economic analysis is one important tool that can contribute to these judgments. The aim of this article is to provide a brief overview of the concepts and methods used.     

Therapy and clinical trials

Little is know about intraosseous migration of nonerupting teeth, a rare natural condition of horizontal tooth movement and impaction. It occurs only in the mandible and involves primarily the second premolar or the canine. When the second premolar is the affected tooth, it always is found distal to its normal position. The origins of the second premolar intraosseous migration phenomenon are obscure and usually no treatment is recommended. Intraosseous migration involving the canine is commonly called transmigration because the affected canine moves mesially across the mandibular symphysis to the opposite side of the mandible. Analysis of 50 published cases of canine transmigration indicated higher occurrence in women and no sidedness preference. In over 80% of the studied cases, the canine remained nonerupted and, of the 24 cases receiving some treatment, all but two underwent extraction of the anomalous canine. The canine transmigration phenomenon appears to show signs of having some genetic determinants.