Therapeutic Innovation & Regulatory Science

To raise awareness and promote dialogue leading to action, this article provides proceedings on ethical and legal considerations associated with medicine use during pregnancy discussed during the 2014 DIA Medicines and Pregnancy Forum. A key focus of discussion at the forum was “When is it ethically appropriate to include or unethical not to include pregnant patients in clinical studies, and how can ethical barriers be addressed?” Also debated was the question “What are the most appropriate methods to collect and share data on medication use in pregnancy, and what is the best process for sharing such information?” Goals of the forum were to gain participant alignment on answers to these ethical questions, offer rationale for the answers, and provide insight into which stakeholders might be needed to facilitate discussion and action. Participants felt that under the right circumstances, drug research in pregnant women is justified and necessary. Multiple ideas and opinions on the handling of pregnant patients in clinical research, treating pregnant women in clinical practice, and communicating data to physicians and patients are presented.

Previous research has demonstrated that profits are a key requirement in private pharmaceutical development. We sought to examine the extent that pressure of financial incentives exerted by investors and the board of directors, including senior management financial rewards, have on regulatory decisions made by senior management. Our selected case study involved Aveo Pharmaceuticals Inc (Aveo). The specific question was to what extent the terms of financing, particularly the corporate governance goals which determined executive bonus compensation, may have dictated Aveo’s regulatory approach in the drug application process for tivozanib. These corporate governance goals emphasized quantitative over qualitative goals for the executive team. Aveo did not conduct the second arm of the randomized crossover trial, whose results could possibly have demonstrated a favorable clinical profile or a superior competitor’s product. Arguably, as a result of this decision, the participating research subjects were denied an opportunity for improvement, and progress in the study of renal cell cancer was curtailed.

In the field of health care, researchers and decision makers are increasingly turning toward retrospective observational studies of administrative claims and electronic health record databases to improve outcomes for patients. For many important questions, randomized studies have not been conducted, and even when they have been, such studies often inadequately reflect the realities of patients’ lives or care. However, use of retrospective studies not only increases methodological complexity but also requires more subjectivity for those attempting to perform statistical analysis. The hurdles for establishing the reproducibility of such research to ensure accuracy and generalizability are therefore also higher, as are the requirements for transparency to limit the impact of bias. The ethical statistical practitioner will therefore need to take additional steps to enable results to be interpreted and acted upon with confidence. These include increased transparency regarding the impact of database selection, database quality, database content, and design decisions on the robustness of statistical conclusions. A number of approaches to increase the reproducibility of retrospective health care research are also presented, along with some discussion regarding responsibilities of data owners, statistical practitioners, publishers, and users of results.

Expanded access is a regulatory mechanism by which an investigational drug can be made available outside of a clinical trial to treat patients with serious or life-threatening conditions for which there are no satisfactory treatment options. An expanded access program (EAP) is the formal plan under which preapproval access to an investigational drug can be provided to a group of patients. Although an EAP is a regulated program, the decision to authorize an EAP is the responsibility of the biopharmaceutical sponsor. Because of the significant impact an EAP can have on current patients, drug development, and future patients, we propose that a sponsor’s decision must be based not only on regulatory criteria but also on ethical and practical considerations regarding implementation of an EAP. Such an approach will help ensure that decisions and plans uphold ethical precepts such as fairness, promoting good, and minimizing risk of harm.

Off-label promotion has attracted intense scrutiny from regulators in recent decades, resulting in many pharmaceutical companies paying hefty penalties for illegal marketing practices. At the same time, the pharmaceutical industry has accused governments of applying double standards by encouraging the use of cheaper off-label alternatives to registered treatments, and defended their “right” to promote off-label drugs on freedom of speech grounds. However, the debate about off-label promotion and the prescribing that results has largely failed to address the issue that really matters—what impact does off-label promotion and prescribing have on patients and the health system? This paper explores the benefits and problems with off-label prescribing to determine whether off-label promotion is ever justified and, if so, under what conditions.

Many health care systems globally provide publicly subsidized access to prescribed medicines. Decisions about which medicines to fund affect a range of stakeholders, and it is not reasonable to expect that medicines funding decisions are supported by all stakeholder groups all the time. A more realistic aim may be for decisions to be understood and accepted as legitimate by stakeholders; however, several shortcomings of existing processes make it difficult to achieve this aim. To date, the main strategy to address these shortcomings has been to increase stakeholder involvement in decision making, either by eliciting stakeholder values or increasing stakeholder participation in decision making. Despite these efforts, there is growing evidence that decision makers are falling short when it comes to the perceived legitimacy of their resource allocation processes and decisions. As such, there is a pressing need for decision makers to think seriously and creatively about ways to increase the legitimacy of their processes and to make them more acceptable to a wider range of stakeholders. In this article we summarize and critique existing literature on the legitimacy of public resource allocation processes, and we make some practical suggestions for those who are concerned about this issue.

Safety assessment and monitoring are critical throughout the life cycle of drug development. The evaluation of safety information, specifically adverse events, from clinical trials has always been challenging for a number of reasons, such as the unexpectedness and rarity of some important adverse events, the fact that some events can recur, and the events’ variability in duration and severity. To accurately characterize and communicate the risk profile of a drug, the choice of metrics is critical. However, there seems to be a lack of consistency, clear guidance, and comprehensive recommendations on choosing metrics for assessing adverse events in clinical trials. This article reviews the common metrics and provides some recommendations.

In recent years, concern has been growing that traditional research and development models in the life sciences are unsustainable. Productivity, especially in pharmaceuticals, has plummeted, and too many of the products emerging from increasingly lengthy and costly clinical development offer marginal benefit to patients. Although the phenomenon is global, there are specific and important features of European life sciences that impede the translation of an ever more penetrating understanding of biology into effective treatments. This article analyzes these issues in the context of European biopharmaceutical innovation, describes the actions that Europe is already taking, and suggests what more needs to be done.

Pharmaceutical drugs and devices are increasingly evaluated by quantitative tools that combine benefit and risk. These tools vary by their limitations and desirable properties, which may confuse the decision-making process. Experts from the Food and Drug Administration (FDA) and industry shared their perspectives at the 2012 American Statistical Association (ASA) Biopharmaceutical Section FDA-Industry Statistics Workshop, and these insights are presented here. First, benefit-risk terminology is given to better understand subtle distinctions. Next, pragmatic considerations in endpoint selection are given that distinguish between benefit-risk assessment and analysis of clinical trials. Then the strengths of weighting methods, including ranking, utilities, and risk tolerance for assessing the trade-off between benefits and risks, are compared. The last topic presented is summarizing information to ease the interpretation, transparency, and ability to support decisions. Benefit-risk methods are moving towards a unified paradigm to make selection of endpoints, weights, and metrics easier and more structured. This will lead to better decision-making based on a transparent assessment and clear interpretability.