PubMed · 11988991
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A Tarkkanen. 2000. [Refractive surgery].. https://pubmed.ncbi.nlm.nih.gov/11988991/
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To demonstrate in a clinical trial that a new or experimental therapy (et) is 'at least as good as' a standard therapy (st), a statistical test or confidence interval procedure must rule out clinical inferiority with a high probability. The term 'at least as good as' implies equivalent but not necessarily superior efficacy. As it is statistically impossible to demonstrate equivalence (that is, prove the null hypothesis of no difference), Blackwelder proposed a one-sided significance test to reject the null hypothesis that standard therapy is better than experimental therapy by a clinically acceptable amount, delta(BW). In this paper, Blackwelder's approach is redefined in terms of the ratio of two means (R(True)= mu(et)/mu(st)) based on a continuous variate with higher values denoting greater improvement. The ratio-based equivalents to Blackwelder's hypotheses will be shown. The ratio parameter has the benefit of being available as a dimensionless percentage, not tied to a specified difference in means. Thus, a study can be sized to assure, with high probability, that the experimental therapy is 'at least' (R(LB)x100) per cent 'as effective as' the standard therapy, where R(LB) is the selected lower bound on the percentage effectiveness. A practical rationale is given for defining non-inferiority as a high fraction or percentage of the standard drug's efficacy, both in terms of statistical efficiency and medical relevance. For most typical 'at least as good as' applications (when R(LB) or = delta(BW), thereby requiring smaller sample sizes to detect the directionally based non-null alternatives contained in H(1): mu(et)/mu(st)>R(LB) or, equivalently, mu(st) - mu(et) R(LB), is shown to be more efficient than excluding R(LB) from the lower limit of a 100(1-2alpha) per cent two-sided symmetric confidence interval centred by R. Relevant examples will be presented.
Treatment with Semple or suckling mouse brain rabies vaccines persists in many countries of Asia, Africa and South America. Its replacement depends on the immediate accessibility of effective affordable alternative treatment with tissue culture vaccines (TCVs). The use of the expensive European TCVs has been possible in Asia by means of economical intradermal (ID) post-exposure vaccine regimens. Implementation of this effective economical treatment has been delayed by the complexity and inconvenience of the regimens, and the reluctance to change prophylaxis against a fatal disease. Up to now, the ID regimens have been used only where passive immunisation with rabies immune globulin (RIG) is usually available. Rabies deaths despite optimal vaccine treatment have been attributed to lack of RIG. The ID regimens might soon be promoted in areas where RIG is not even available for severe exposure. It is therefore vital that economical vaccine regimens should be used which induce protective immunity rapidly. Improvements in rabies pet in developing countries could be made by: (i). publicising the urgency and efficacy of wound cleaning; (ii). facilitating the replacement of nervous tissue vaccines by economical ID treatment with TCVs; (iii). using an ID regimen with a large dose of vaccine on the first day of treatment especially when no RIG is available; and (iv). promoting pre-exposure prophylaxis to eliminate the need for RIG and provide better rabies prophylaxis.
Human papilloma virus (HPV) found in 99.7% of cervical cancers represents an attractive immunotherapeutic target for novel adjuvant dendritic cell (DC) immunotherapy. DC primed with HPV antigens have been shown to be capable of inducing CTL responses powerful enough to eradicate established murine tumours expressing HPV16 antigen. The use of tumour lysate has been found to be an effective means of priming DC with tumour associated antigens in animal models and in clinical trials leading to significant anti-tumour responses. Autologous DC primed with sonicated HPV expressing tumour lysate have been shown to be capable of inducing HPV specific classes I and II T-cell immunity in a pilot clinical study.Synthetic double stranded polyribonucleotides are effective in vitro activation/maturation agents capable of inducing a stable mature DC phenotype producing high levels of IL12. However, the prototype polymer poly [I]:poly [G] has proved to be clinically toxic. Preliminary in vitro data have demonstrated that a novel clinically non-toxic analogue polymer poly [I]:poly [C(12)U] (Ampligen R) can effectively induce in vitro maturation of human monocyte derived DC with sustained bioactive IL12 production. Human monocyte derived DC primed with tumour lysate and matured with synthetic dsRNA may therefore offer an effective way of optimising Th1 specific anti-cancer T-cell responses in cancer patients. This strategy is currently being tested in a clinical trial in patients with cervical cancer.