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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.

The randomized phase III trial EGF100151 demonstrated that the combination of lapatinib plus capecitabine (L + C) significantly improved time to progression (TTP) compared with capecitabine alone (C) in heavily pretreated patients with HER2+ (ErbB2+) advanced or metastatic breast cancer. This analysis assessed the effects of study treatments on quality of life (QOL) among patients in EGF100151. Quality of life was assessed using the Functional Assessment of Cancer Therapy-Breast (FACT-B) and EuroQoL (EQ-5D) questionnaires. Patients completed questionnaires during efficacy and safety assessment visits (i.e., at screening visit, every 6 weeks for the first 24 weeks, every 12 weeks thereafter, and at discontinuation of study treatment). Primary analyses compared the treatment groups based on change from baseline QOL. Exploratory analyses compared proportion of patients achieving minimum important differences (MID) in QOL scores and the relationship between QOL and tumor status. Quality of life for patients in both treatment groups was maintained during 24 weeks of follow-up. Adjusted mean changes from baseline in all QOL scores for the L + C arm were comparable to those for the C arm. The between-group differences ranged from 0.7 to 2.2 (FACT-B total) and 0.3 to 1.8 (EQ-5D visual analog scale) and were consistently in favor of the L + C arm, although not statistically significant. Patients with an objective tumor response or stable disease showed clinically meaningful differences in QOL scores compared to patients with progressive disease. A greater proportion of patients receiving L + C versus C achieved the MID for all five QOL scores, although differences were not statistically significant. The addition of lapatinib to capecitabine significantly increases TTP without any evidence of a deleterious effect on patients’ QOL, confirming its clinical benefit in this heavily pretreated patient population with advanced HER2+ breast cancer that has progressed on trastuzumab therapy.

9532 Background: In a phase III randomized open-label multicenter trial, L+C improved time to progression and progression free survival vs C alone in women with ErbB2+ MBC who had received prior th...

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).

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.

Summary: A phenomenon known as regression of seizure frequency toward the median was observed in a previous clinical study performed in patients with partial seizures. Regression of seizure frequency is a situation in which patients with a frequency of seizures above the median value for the group during an initial period have a tendency to have frequency of seizures decrease during a subsequent period, and other patients with a lower frequency of seizures during the initial period increase their frequency during a subsequent period. To investigate this further, eight published sets of clinical data obtained in epileptic patients with various seizure types were identified by a literature search. Three separate analyses were conducted for each data set. All three analyses clearly demonstrated that regression to the median was present in the studies evaluated. It was concluded that this phenomenon is a real effect in epilepsy and occurs in patients with a wide variety of seizure types. The implication of this phenomenon for physicians treating epileptic patients is that there is value in establishing pattern of seizure frequency for individual patients. This information can be used in assessing those patients whose seizure frequency has increased. The implications of this phenomenon for designing and evaluating antiepileptic drug studies are also discussed. RESUME Un phenomene connu comme regression de frequence des crises vers la mediane a ete observe dans une etude anterieure effectuee chez des malades ayant des crises partielles. La regression de frequence des crises est la situation des malades dont la frequence des crises, superieure a la valeur mediane du groupe pendant une periode initiale, a tendance a diminuer pendant la periode suivante; ou dont la frequence des crises, inferieure a cette valeur mediane pendant une periode initiale, a tendance a augmenter pendant la periode suivante. Pour continuer cette etude, on a recherche et identifie dans la litterature huit series de donnees cliniques publiees a propos de malades ayant des types de crises varies. Trois analyses ont ete effectuees separement pour chacune de ces series. Les trois analyses ont clairement demontre qu'il y avait une regression vers la mediane dans les etudes evaluees. On en a conclu qu'il s'agissait d'un phenomene existant reellement et survenant chez des patients ayant des types de crises tres varies. En consequence il est donc important pour le therapeute des malades epileptiques d'etablir la frequence des crises pour chaque patient. Cette information peut ětre utilisee pour evaluer la situation des malades dont la frequence des crises a augmente. Elle peut ětre utile aussi dans les etudes des medicaments anti-epileptiques. RESUMEN En un estudio previo, realizado en enfermos con ataques parciales, un fenomeno conocido como regresion de la frecuencia de ataques hacia la media, ha sido observado. La regresion de la frecuencia de ataques es una situacion en la cual los pacientes con una frecuencia de ataques por encima del valor medio para el grupo, durante el periodo inicial, tienen una tendencia a una reduccion de la frecuencia de ataques durante el periodo subsiguiente y, para los que tienen una baja frecuencia de ataques durante el periodo inicial, a aumentar durante el periodo subsiguiente. Para investigar este asunto con mayor intensidad se han identificado, mediante la revision de la literatura, ocho colecciones publicadas de informacion clinica sobre enfermos epilepticos con varios tipos de ataques. Se han realizado tres analisis distintos para cada bloque. Los tres analisis demuestran claramente que la regresion hacia la media se ha producido en los estudios evaluados. Se ha concluido que este fenomeno es un efecto real en la epilepsia y que ocurre en pacientes con una amplia variedad de tipos de ataques. La implicacion de este fenomeno para los medicos que tratan enfermos epilepticos es que el establecimiento del patron de la frecuencia de ataques para enfermos individuales, es muy valido. Esta informacion puede usarse para investigar los pacientes cuya frecuencia de ataques ha incrementado. Las implicaciones de este fenomeno para designar y valorar las medicaciones antiepilepticas han sido tambien discutidas en el trabajo. ZUSAMMENFASSUNG Das Phanomen einer Regression der Anfallsfrequenz zum Medianwert wurde in einer fruheren klinischen Untersuchung beobachtet, die bei Patienten mit Partialanfallen durchgefuhrt wurde. Unter der Regression der Anfallsfrequenz versteht man eine Situation, in der Patienten mit einer Anfallsfrequenz oberhalb des Medianwertes fur die Gruppe wahrend einer initialen Periode die Tendenz zeigen, wahrend der folgenden Periode eine Frquenzabnahme zu zeigen; solche, die in der Initialperiode eine niedrige Anfallsfrequenz haben, tendieren zu einem Anstieg derselben in der Folgeperiode. Um dieses Phanomen weiter zu untersuchen, wurden durch ein? Literaturrecherche 8 Sets klinischer Daten von epileptischen Patienten mit verschiedenen Anfallstypen identifiziert. Zwei getrennte Analysen wurden fur jede Gruppe von Daten durchgefuhrt. Aile 3 Analysen zeigten deutlich, das die Regression auf dem Medianwert in den Unter-suchungen nachzuweisen waren. Es wurde geschlossen, das dieses Phanomen eine echte Wirkung in der Epilepsie besitzt und bei Pateinten mit einer grosen Vielfalt von Anfallstypen zu beobachten ist. Die Bedeutung dieses Phanomens fur Arzte, die epileptische Patienten behandeln, liegt darin, das es sinnvoll ist. Das Anfallsfrequenzmuster fur die individuellen Patienten zu bestimmen. Diese Information kann dazu verwendet werden, Patienten herauszufinden, deren Anfallsfrequenz zugenommen hat. Es erfolgt eine Diskussion iiber die Bedeutung dieses Phanomens fur die Planung und Auswertung von Studien mit Antiepileptika.

A prospective, randomized, double-masked, placebo-controlled clinical trial was conducted to study the effects of oral acyclovir on 55 patients with acute herpes zoster ophthalmicus. Treatment with oral acyclovir resulted in more prompt resolution of signs and symptoms, particularly in patients treated within 72 hours after onset of skin rash ( P P = 0.03). Interim analysis of this longitudinal study suggests that the incidence and severity of secondary ocular inflammatory disease was reduced by acyclovir. Prolonged observation of these patients is ongoing to determine if oral acyclovir reduces post-herpes zoster neuralgia or the late ocular complications of ophthalmic zoster.

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.

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.