Advanced Methods for Dose and Regimen Finding During Drug Development: Summary of the EMA/EFPIA Workshop on Dose Finding (London 4-5 December 2014).

Inadequate dose selection for confirmatory trials is currently still one of the most challenging issues in drug development, as illustrated by high rates of late-stage attritions in clinical development and postmarketing commitments required by regulatory institutions. In an effort to shift the current paradigm in dose and regimen selection and highlight the availability and usefulness of well-established and regulatory-acceptable methods, the European Medicines Agency (EMA) in collaboration with the European Federation of Pharmaceutical Industries Association (EFPIA) hosted a multistakeholder workshop on dose finding (London 4-5 December 2014). Some methodologies that could constitute a toolkit for drug developers and regulators were presented. These methods are described in the present report: they include five advanced methods for data analysis (empirical regression models, pharmacometrics models, quantitative systems pharmacology models, MCP-Mod, and model averaging) and three methods for study design optimization (Fisher information matrix (FIM)-based methods, clinical trial simulations, and adaptive studies). Pairwise comparisons were also discussed during the workshop; however, mostly for historical reasons. This paper discusses the added value and limitations of these methods as well as challenges for their implementation. Some applications in different therapeutic areas are also summarized, in line with the discussions at the workshop. There was agreement at the workshop on the fact that selection of dose for phase III is an estimation problem and should not be addressed via hypothesis testing. Dose selection for phase III trials should be informed by well-designed dose-finding studies; however, the specific choice of method(s) will depend on several aspects and it is not possible to recommend a generalized decision tree. There are many valuable methods available, the methods are not mutually exclusive, and they should be used in conjunction to ensure a scientifically rigorous understanding of the dosing rationale.

Salpingoscopic and laparoscopic investigations in relation to fertility outcome.

STUDY OBJECTIVE: To evaluate the correlation between salpingoscopic and laparoscopic findings and their relation to reproductive outcomes. DESIGN: Prospective study (Canadian Task Force classification II-2). SETTING: University-affiliated hospital. PATIENTS: Ninety-one infertile women. INTERVENTION: Salpingoscopy and laparoscopy. MEASUREMENTS AND MAIN RESULTS: Salpingoscopic findings were expressed according to a widely used classification. Tubal morphology at laparoscopy was defined as regular (normal morphology), convoluted (any kind of distortion or adhesion), or hydrosalpinx. Laparoscopic and salpingoscopic findings did not correlate. Seventeen pregnancies occurred within 1 year from the procedures. According to life table analysis, the cumulative pregnancy rate was significantly higher in women with endotubal morphology showing minimal or no tubal damage, than in women with higher grades of endotubal damage. Conversely, tubal morphology at laparoscopy was not able to predict pregnancy outcome. CONCLUSION: Laparoscopy alone might not be sufficient to predict tubal integrity. Performing salpingoscopy with laparoscopy could significantly increase accuracy in predicting short-term fertility outcome. Given its low complication rate and brief duration, salpingoscopy should have a primary role in management of infertility.

Recurrent spontaneous abortion. Etiologic factors.

BACKGROUND: Spontaneous abortion is the most common complication of pregnancy. It may be unique, remaining random and having no consequences on the reproductive process, or it can repeat itself, starting a clinical picture known as recurrent spontaneous abortion or habitual abortion. The term of RSA syndrome is used to define the repetition of three or more consecutive abortions before the 24th week. METHODS: A population of 195 couples with recurrent spontaneous abortion were screened for genetic, metabolic, infective, morphological, endocrine and autoimmune factors. Eighty-five completed the investigation, 44 are being tested and 66 did not complete the diagnostic course. Causes of recurrent abortion were evaluated in relation to the period of abortion and number of embryo losses. RESULTS: Forty-six percent of patients who completed the investigation turned out to be sine causa, which is in accordance with the findings in literature. CONCLUSIONS: Couple with RSA require accurate counselling and it is fundamental to eliminate any pathologies that can be discovered so as to improve the likelihood of the pregnancy's reaching term.

The use of intravenous immunoglobulin in sine causa or alloimmune recurrent spontaneous abortion (RSA).

BACKGROUND: Recurrent spontaneous abortion (RSA) has an incidence of 0.5%-1%. It is thought that immune reaction disorders in the mother may evolve in unexplained RSA, which has a higher incidence in women over 40 years old. METHODS: Twenty-three patients with recurrent spontaneous abortion of unknown origin and two autoimmune cases were treated with intravenous specific immunoglobulins at the 5th-6th week of pregnancy and fifteen days later. RESULTS: After treatment, nineteen patients brought their pregnancy to term, five aborted, one is pregnant at present. CONCLUSIONS: The use of immunoglobulins seems to be efficacious in recurrent spontaneous abortion of unknown origin. Our results support the theory that this treatment is able to passively transfer the sparking off factor that allows the pregnancy to evolve.