Women and babies are dying from inertia: a collaborative framework for obstetrical drug development is urgently needed.

Obstetrical complications, often referred to as the "great obstetrical syndromes," are among the most common global causes of mortality and morbidity in young women and their infants. However, treatments for these syndromes are underdeveloped compared with other fields of medicine and are urgently needed. This current paucity of treatments for obstetrical complications is a reflection of the challenges of drug development in pregnancy. The appetite of pharmaceutical companies to invest in research for obstetrical syndromes is generally reduced by concerns for maternal, fetal, and infant safety, poor definition, and high-risk regulatory paths toward product approval. Notably, drug candidates require large investments for development with an unguaranteed return on investment. Furthermore, the discovery of promising drug candidates is hampered by a poor understanding of the pathophysiology of obstetrical syndromes and their uniqueness to human pregnancies. This limits translational extrapolation and de-risking strategies in preclinical studies, as available for other medical areas, compounded with limited fetal safety monitoring to capture early prenatal adverse reactions. In addition, the ethical review committees are reluctant to approve the inclusion of pregnant women in trials, and in the absence of regulatory guidance in obstetrics, clinical development programs are subject to unpredictable regulatory paths. To develop effective and safe drugs for pregnancy complications, substantial commitment, and investment in research for innovative therapies are needed in parallel with the creation of an enabling ethical, legislative, and guidance framework. Solutions are proposed to enable stakeholders to work with a common set of expectations to facilitate progress in this medical discipline. Addressing this significant unmet need to advance maternal and possibly perinatal health requires the involvement of all stakeholders and specifically patients, couples, and clinicians facing pregnancy complications in the dearth of appropriate therapies. This paper focused on the key pharmaceutical research and development challenges to achieve effective and safe treatments for obstetrical syndromes.

Shortcomings of protocols of drug trials in relation to sponsorship as identified by Research Ethics Committees: analysis of comments raised during ethical review.

BACKGROUND: Submission of study protocols to research ethics committees (RECs) constitutes one of the earliest stages at which planned trials are documented in detail. Previous studies have investigated the amendments requested from researchers by RECs, but the type of issues raised during REC review have not been compared by sponsor type. The objective of this study was to identify recurring shortcomings in protocols of drug trials based on REC comments and to assess whether these were more common among industry-sponsored or non-industry trials. METHODS: Retrospective analysis of 226 protocols of drug trials approved in 2010-2011 by three RECs affiliated to academic medical centres in The Netherlands. For each protocol, information on sponsorship, number of participating centres, participating countries, study phase, registration status of the study drug, and type and number of subjects was retrieved. REC comments were extracted from decision letters sent to investigators after review and were classified using a predefined checklist that was based on legislation and guidelines on clinical drug research and previous literature. RESULTS: Most protocols received comments regarding participant information and consent forms (n = 182, 80.5%), methodology and statistical analyses (n = 160, 70.8%), and supporting documentation, including trial agreements and certificates of insurance (n = 154, 68.1%). Of the submitted protocols, 122 (54.0%) were non-industry and 104 (46.0%) were industry-sponsored trials. Non-industry trials more often received comments on subject selection (n = 44, 36.1%) than industry-sponsored trials (n = 18, 17.3%; RR, 1.58; 95% CI, 1.01 to 2.47), and on methodology and statistical analyses (n = 95, 77.9% versus n = 65, 62.5%, respectively; RR, 1.18; 95% CI, 1.01 to 1.37). Non-industry trials less often received comments on supporting documentation (n = 72, 59.0%) than industry-sponsored trials (n = 82, 78.8%; RR, 0.83; 95% CI, 0.72 to 0.95). CONCLUSIONS: RECs identified important ethical and methodological shortcomings in protocols of both industry-sponsored and non-industry drug trials. Investigators, especially of non-industry trials, should better prepare their research protocols in order to facilitate the ethical review process.

Recommendations for a uniform assessment of publication bias related to funding source.

BACKGROUND: Numerous studies on publication bias in clinical drug research have been undertaken, particularly on the association between sponsorship and favourable outcomes. However, no standardized methodology for the classification of outcomes and sponsorship has been described. Dissimilarities and ambiguities in this assessment impede the ability to compare and summarize results of studies on publication bias. To guide authors undertaking such studies, this paper provides recommendations for a uniform assessment of publication bias related to funding source. METHODS AND RESULTS: As part of ongoing research into publication bias, 472 manuscripts on randomised controlled trials (RCTs) with drugs, submitted to eight medical journals from January 2010 through April 2012, were reviewed. Information on trial results and sponsorship was extracted from manuscripts. During the start of this evaluation, several problems related to the classification of outcomes, inclusion of post-hoc analyses and follow-up studies of RCTs in the study sample, and assessment of the role of the funding source were encountered. A comprehensive list of recommendations addressing these problems was composed. To assess internal validity, reliability and usability of these recommendations were tested through evaluation of manuscripts submitted to journals included in our study. CONCLUSIONS: The proposed recommendations represent a first step towards a uniform method of classifying trial outcomes and sponsorship. This is essential to draw valid conclusions on the role of the funding source in publication bias and will ensure consistency across future studies.

Optimizing the gonadotrophin dose regimen.

The starting dose of gonadotrophin for controlled ovarian stimulation (COS) or ovulation induction (OI) must be individualized and has considerable impact on outcomes (pregnancy and adverse events). Five large randomized, controlled trials have compared fixed doses of recombinant follicle-stimulating hormone (rFSH) for COS for assisted reproductive technology (ART). Among young women, a fixed dosage of 200 IU/day (versus 100 IU/day) yielded more oocytes and more transferable embryos. Thus, if surplus embryos can be cryopreserved, it could result in a higher cumulative pregnancy rate. However, no clear dose-response relationship was evident among older women receiving either 150 or 250 IU/day. Another randomized, controlled trial showed that a low-dose step-up OI protocol with weekly increments of 25 IU/day of rFSH was more effective and more efficient than a regimen with 50-IU/day increments. Research to develop a normogram for the optimal starting dose of rFSH for individual patients is under way.

Recombinant follicle-stimulating hormone: gold standard or not?

Recombinant follicle stimulating hormone has been available now for almost 10 years and many couples have benefited from its use. Its clinical efficacy, purity and safety profile have been extensively documented in numerous publications. Because of growing public concerns on the safety of gonadotrophins extracted from human urine, the future will lie in the recombinant technology, which will also enable the design of more convenient tailor-made gonadotrophins.

A randomized, double-blind, multicentre clinical trial comparing starting doses of 150 and 200 IU of recombinant FSH in women treated with the GnRH antagonist ganirelix for assisted reproduction.

BACKGROUND: Studies with the GnRH antagonist ganirelix in assisted reproduction have indicated that compared with traditional GnRH agonist downregulation protocols, slightly fewer oocytes are retrieved. In this study it was investigated whether an increase in the starting dose of recombinant FSH (rFSH) could compensate for this loss. METHODS: A randomized, double-blind, multicentre clinical trial comparing a starting dose of 150 and 200 IU of rFSH (follitropin beta), in women undergoing treatment with the GnRH antagonist ganirelix. RESULTS: In total, 257 women were treated with rFSH, of whom 131 received 150 IU and 126 women 200 IU. Overall, 10.3 oocytes were retrieved in the 150 IU group and 11.9 in the 200 IU group (P=0.051). This difference became significant when women with cycle cancellation before HCG administration were excluded. Nearly 500 IU of additional rFSH was given in the high-dose group (2014 versus 1541 IU). In the low-dose group, 4.6 high-quality embryos were obtained compared with 4.5 in the high-dose group. Vital pregnancy rates were similar (31 and 25% in the 150 and 200 IU-treated women, respectively). Serum concentrations of FSH, estradiol and progesterone were significantly higher in the high-dose group at day 6 of rFSH treatment and on the day of HCG administration. In the high-dose group, serum LH concentrations were higher at day 6 of rFSH treatment but lower at the day of HCG administration. CONCLUSION: By increasing the starting dose from 150 to 200 IU of rFSH, slightly more oocytes can be retrieved in GnRH antagonist protocols for assisted reproduction. However, because this did not translate into a higher number of high quality embryos, the clinical relevance of such a dose increase may be questioned.

The gonadotrophin-releasing hormone antagonist ganirelix--history and introductory data.

The gonadotrophin-releasing hormone antagonist ganirelix has recently become available to clinicians. Its indication, prevention of premature luteinizing hormone surges in assisted reproduction programmes, has been investigated extensively in numerous studies. This article summarizes the major results from pharmacokinetics studies, a double-blind dose-finding trial and three large-scale phase III randomized clinical trials, comparing ganirelix and the most commonly used gonadotrophin-releasing hormone agonists, buserelin,leuprolide and triptorelin, in a long protocol. It is concluded that controlled ovarian hyperstimulation with ganirelix offers significant advantages in terms of convenience of treatment as reflected in a considerably reduced treatment period.Safety and tolerance as well as overall clinical outcome are good.