Biopharmaceutical statistics in a pharmaceutical regulated environment: past, present, and future.

The practice of statistics in the pharmaceutical industry has changed markedly over the last 25 years. This paper examines the evolution of clinical trial statistics in relationship to advances in statistical methodology and computational power as well as the changing regulatory environment. The current role of the biopharmaceutical statistician is assessed along with the drivers for future change.

Oral acyclovir in the treatment of acute herpes zoster ophthalmicus.

Seventy-one nonimmunocompromised patients with herpes zoster ophthalmicus, presenting within seven days of onset of characteristic skin eruption, were enrolled in a prospective, longitudinal, randomized, double-masked, placebo-controlled trial with oral acyclovir. In a previous interim report we noted more prompt resolution of dermatomal signs and symptoms with acyclovir treatment. There was also a reduction of viral shedding in acyclovir-treated patients coupled with a trend to greater rate of microdissemination of the virus in placebo-treated patients (Cobo LM, et al. Ophthalmology 1985; 92:1574-83). While further substantiating these findings, we report that a ten-day course of treatment with oral acyclovir (600 mg, five times a day) is well-tolerated and significantly reduces the incidence and severity of the most common complications of herpes zoster ophthalmicus: dendritiform keratopathy, stromal keratitis, and uveitis. While this acyclovir treatment regimen reduces the zoster-related pain during the acute phase of the disease, especially in patients treated within 72 hours of onset of skin lesions, it has no evident effect on either incidence, severity, or duration of post-herpetic neuralgia in the patients studied.

Topical acyclovir treatment of herpes zoster in immunocompromised patients.

Topical acyclovir favorably influences the healing of localized herpes zoster in immunocompromised patients. This therapy, or placebo, was applied to forty-three patients in a random access, double-blind trial, four times daily for 10 days, beginning within 72 hours after the onset of skin lesions. The mean time to pustulation is decreased from 12.4 to 6.7 days and the mean time to crusting is decreased from 16.0 to 11.4 days (p = 0.038 and 0.086, respectively) by topical treatment. The mean time to 50% healing is decreased from 24.5 to 15.2 days and the mean time to 100% healing is decreased from 34.9 to 25.8 days (p = 0.023 and 0.033, respectively). Favorable effects in treated patients are not associated with a more rapid decline in lesion virus titer, but do accrue without any toxicity.

Acyclovir halts progression of herpes zoster in immunocompromised patients.

We conducted a placebo-controlled, double-blind study of acyclovir therapy for acute herpes zoster in immunocompromised patients. Of the 94 patients enrolled in the study, 52 had localized skin lesions at entry, and 42 had disseminated cutaneous zoster. A one-week course of intravenous acyclovir (1500 mg per square meter of body-surface area per day) halted progression of zoster in both groups, as determined by development or progression of cutaneous dissemination, development of visceral zoster, or proportion of cases deemed treatment failures. Significantly fewer patients treated with acyclovir within the first three days after the onset of exanthem had complications of zoster, as compared with patients treated with placebo (P = 0.02 by Fisher's exact test), but acyclovir also stopped progression of zoster in patients treated after three days of rash (P = 0.05 by Fisher's exact test). Acyclovir recipients with disseminated cutaneous zoster had a significantly accelerated rate of clearance of virus from vesicles, as compared with placebo recipients (P = 0.05 by the Breslow test).

Multicenter collaborative trial of intravenous acyclovir for treatment of mucocutaneous herpes simplex virus infection in the immunocompromised host.

Intravenous acyclovir was evaluated in the treatment of 97 immunocompromised patients with mucocutaneous herpes simplex virus infection in a randomized, double-blind, placebo-controlled trial. Acyclovir recipients had significantly shorter periods of virus shedding (p less than 0.0002) and lesion pain (p less than 0.01), and more rapid lesion scabbing (p less than 0.004) and lesion healing (p less than 0.04). The most common adverse reaction was a low incidence of peripheral vein irritation; no serious toxicity could be definitely attributed to acyclovir treatment even in these seriously ill patients. Intravenous acyclovir offers both safe and effective treatment for mucocutaneous herpes simplex virus infection in the immunocompromised host.

Estimation of the median lethal dose when responses within a little are correlated.

In the analysis of mortality experiments on neonatal animals, the presence of litter effects may prevent the use of probit analysis. This communication presents a method for estimating the median lethal dose, based on a modification of the beta-binomial distribution.

Effects of reduced regional or body temperatures on responses of pial arterioles.

We have investigated the effects of a reduced regional or a reduced body temperature, on pial arteriolar response to a variety of vasoactive stimuli. This has been done by studying the effects of these stimuli on groups of mice with different body temperatures, or with different temperatures of the artificial cerebrospinal fluid (CSF) irrigating the pial surface. Responses in mice with body temperatures of 30 degrees or 22 degrees C showed little or no difference from responses in mice with body temperatures of 37 degrees. This was so whether the surface irrigant was maintained at 37 degrees or at 23 degrees. On the other hand, significant reductions in pial vascular responses were observed when mice with "CSF" temperatures of 22 degrees were compared with those having "CSF" temperatures of 37 degrees. The data suggest that regional cooling is more effective than cooling the body in reducing the response of pial arterioles. The data also indicate that marked reductions in body temperature would have to occur before a detectable effect on pial vascular responses is produced, at least in mice anesthetized with urethane.