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.

Placebo use and outcome quality: A protocol for systematic review and meta-analysis.

BACKGROUND: The Pharmaceutical industry sponsorship, research outcome and quality has been already evaluated for clinical trials in order to analyze if this kind of sponsorship affects the results of clinical trials. In this sense, this study has the aim to investigate whether placebo use allows positive outcomes regarding efficacy and safety compared to synthetic medicines. METHODS: We designed and registered a study protocol for a systematic review for methodology data. We will only randomized clinical trials that use placebo as comparator. The main outcome will be the evaluation of placebo use regarding the tendency for positive results (efficacy and security) when comparing to synthetic medicines. PubMed, Cochrane, LILACS (BVS), Web of Science, Scopus, and Excerpta Medica dataBASE (EMBASE) databases will be searched. Gray literature will be identified through the databases Proquest (Dissertation and Theses), OpenGrey and Google Scholar. Two review authors will independently assess trial quality and will extract data in accordance with standard Cochrane methodology. If necessary, we will also contact authors for additional information. The Cochrane Collaboration's risk of bias tool will be used. If feasible, it means homogenous data, we will conduct random effects meta-analysis. Subgroup analyses will be conducted for different justifications for placebo use and for studies sponsored/not sponsored by the pharmaceutical industry. RESULTS: Our present findings will indicate the effects of placebo use as comparator regarding efficacy and safety of the oral synthetic medicines. DISCUSSION: This systematic review will identify, summarize, and analyze if there is a trend for positive efficacy and safety results for synthetic medicines in clinical trials when compared with placebo and if the justification for placebo use is considered ethically acceptable. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018110829.

Non-profit Drug Research and Development at a Crossroads.

In wealthy nations, non-profit drug R&D has been proposed to reduce the prices of medicines. We sought to review the ethical and economic issues concerning non-profit drug R&D companies, and the possible impact that their pricing strategy may have on the innovation efforts from for-profit companies targeting the same segment of the pharmaceutical market. There are two possible approaches to pricing drugs developed by non-profit R&D programs: pricing that maximises profits and "affordable" pricing that reflects the cost of manufacturing and distribution, plus a margin that ensures sustainability of the drug supply. Overall, the non-profits face ethical challenges - due to the lack of resources, they are unable to independently commercialize their products on a large scale; however, the antitrust law does not permit them to impose prices on potential licensees. Also, reduced prices for the innovative products may result in drying the for-profit R&D in the area.

[Advance directive of probands in pharmaceutical research : A medical ethics discussion]. / Probandenverfügung in der Arzneimittelforschung : Eine medizinethische Diskussion.

In the fourth Act on the amendment of pharmaceutical legal and other regulations in November 2016, the legislature has designated the proband advance directive based on the instrument of patient advance directive to enable group beneficial research with persons not capable of giving consent. This article describes the existing conditional need for group beneficial research and presents the problem of the decisive instrument for advance directives at the center of the considerations. The features of the proband advance directive concluded by the legislature stand in opposition to a successful implementation, particularly due to the necessary concrete clarification content far in advance for informed research participants. This article describes solution possiblities, which refer to the realization of the instrument of a proxy research authorization as well as the consideration of an advance research planning based on the advance care planning.

[The impact of the EU Regulation 536/2014 on the tasks and functioning of ethics committees in Germany]. / Die EU-Verordnung 536/2014 und ihr Einfluss auf die Aufgaben und Arbeitsweisen der Ethikkommissionen in Deutschland.

The EU Clinical Trial Regulation 536/2014 (CTR) and its implementation in Germany led to substantial changes of the established, well-accepted and effective system of reviewing clinical trial applications by ethics committees (ECs), which impair their independence. For the first time, the German federal legislator specified in detail the composition, functioning, tasks and responsibilities of ECs. ECs have to be registered with the federal drug authority BfArM and if an EC does not perform properly the registration can be withdrawn. In addition, the drug authorities may override the negative opinion expressed by an EC. The ECs will also lose their financial autonomy as the fees will be fixed by the federal government. The tasks and responsibilities of the ECs remain almost entirely unchanged, however. The ECs remain involved in the assessment of both parts of the application dossier. Part I is assessed together with the drug authorities, the drug authorities having the lead. The assessment of part II remains the sole responsibility of the EC. As the deadlines for the assessment became rather short, in particular for multinational trials, and the communication with the sponsor will be in writing only, the established procedures of ECs have to be modified. Up to now it was common to verbally discuss problematic issues with the sponsor. The CTR is focused on written communication with the sponsor via the EU portal. ECs, their office staff and chairpersons will need considerable professionalism and respective training. The future workflow requires substantial IT support. The ECs and the Association of Medical Ethics Committees in Germany will do their utmost to protect efficiently the research subjects and to promote Germany as a major destination for clinical research.

[Universal ethical principles and their application in clinical drug trials]. / Los principios éticos universales y su aplicación a los ensayos clínicos de medicamentos.

Since 1931, and especially since the Nuremberg Code of 1947, an increasing number of declarations, regulations, norms, guidelines, laws, resolutions, and rules intended to create conditions for better protection of subjects participating in research studies have been published, although some have meant setbacks in the human rights of vulnerable populations. As such, violations of the dignity of experimental subjects in clinical trials continue. What researchers investigate and how the research is done, the quality and transparency of the data, and the analysis and the publication of results (of both raw and processed data) respond to the financial interests of the pharmaceutical companies, coming into permanent tension with bioethical principles and the needs of society. The active participation of civil society is necessary to make it so that pharmaceutical research, results and applications subordinate economic benefits to the protection of human rights.

[The impact of researchers loyal to Big Pharma on the ethics and quality of clinical trials in Latin America]. / El impacto de los investigadores fieles a la industria farmacéutica en la ética y la calidad de los ensayos clínicos realizados en Latinoamérica.

This article explains the difficulties innovative pharmaceutical firms have in repaying shareholders with attractive dividends. The problem is the result of the expiration of the patents of blockbuster drugs and the difficulties that the firms have in bringing new blockbuster drugs to the market. One of the solutions companies have found has been to accelerate the implementation of clinical trials in order to expedite the commercialization of new drugs. Doing so increases the period in which they can sell drugs at monopoly prices. We therefore discuss how innovative pharmaceutical firms shorten the implementation time of clinical trials in Latin America and the consequences such actions have on the quality of the collected data, the protection of human rights of the subjects of experimentation, and compliance with the ethical principles approved in international declarations.