Novel bioequivalence approach for narrow therapeutic index drugs.

Narrow therapeutic index drugs are defined as those drugs where small differences in dose or blood concentration may lead to serious therapeutic failures and/or adverse drug reactions that are life-threatening or result in persistent or significant disability or incapacity. The US Food and Drug Administration proposes that the bioequivalence of narrow therapeutic index drugs be determined using a scaling approach with a four-way, fully replicated, crossover design study in healthy subjects that permits the simultaneous equivalence comparison of the mean and within-subject variability of the test and reference products. The proposed bioequivalence limits for narrow therapeutic index drugs of 90.00%-111.11% would be scaled based on the within-subject variability of the reference product. The proposed study design and data analysis should provide greater assurance of therapeutic equivalence of narrow therapeutic index drug products.

The use of large loop excision of the transformation zone in management problems of cervical intraepithelial neoplasia.

We studied 2 groups of women whose management is controversial: those with cervical intraepithelial neoplasia (CIN) grade 2 or 3 on smear, but only CIN grade 1 or no abnormality on target biopsy (Group 1), and those with persistent CIN grade 1 on smear and up to CIN 1 on biopsy (Group 2). We set out to assess whether large loop excision of the transformation zone (LLETZ) was an acceptable method of treating these 2 groups of women. A review of 100 consecutive patients was undertaken. There were 71 women in Group 1 and 29 women in Group 2. The LLETZ procedures were performed under local analgesia and no immediate problems were encountered. Delayed haemorrhage requiring vaginal packing and admission to hospital occurred in 1 patient. In Group 1, histopathology of the LLETZ biopsies showed CIN 2 or 3 in 29 (40.8%) of the women, CIN 1 in 24 (33.8%) and no CIN in 18 (25.3%), and in Group 2, CIN 2 or 3 was seen in 5 (17.2%) of the women, CIN 1 in 11 (37.9%) and no CIN in 13 (44.8%). At 12 months completed follow-up, 4 patients in Group 1 had recurrent CIN 1 or equivocal CIN 1 and 1 patient from Group 2 had recurrent CIN 1, giving an overall recurrence rate of 5 of the 94 patients who completed follow-up (5%). We concluded that LLETZ was a useful procedure in both groups. In Group 1 the provision of a histological diagnosis on the LLETZ biopsy was a check on the accuracy of the cervical smear report. In Group 2, LLETZ offered the advantage of rapidly returning the smear to normal in most patients, and the diagnosis and treatment of those women who actually had a high-grade lesion.