The idea for this special issue arose shortly after attending one of several expert meetings convened in 2014 that brought industry and academic statisticians together with regulators to discuss challenges in drug development. This particular meeting was focused on challenges in the development of new antibacterial agents to treat resistant pathogens and was the 2nd Statistical Think Tank on Antibacterial Drug Development, held November 19, 2014 and organized by the U.S. Food and Drug Administration (FDA) and the Clinical Trials Transformation Initiative (CTTI). Earlier meetings included a think tank convened by FDA and the Cardiac Safety Research Consortium at the American College of Cardiology headquarters in Washington, DC on February 19, 2014. The purpose of this meeting was to discuss the use of cardiovascular outcome trials to assess the cardiac safety of new medications under development. Through a cooperative agreement with FDA, the Engelberg Center for Health Care Reform at the Brookings Institution assembled an expert workshop to discuss statistical approaches to accelerate cancer drug development through adaptive trial designs on March 27, 2014. On August 11, 2014, FDA held a Part 15 public hearing on the confidentiality of interim results from cardiovascular outcome trials used to assess safety of therapies for Type 2 diabetes mellitus. The European Medicines Agency (EMA) workshop on the role of subgroup analyses and subgroup findings in clinical trials submitted for marketing authorization took place on November 7, 2014.
Each of the meetings listed above represents regulators’ taking the initiative to collaborate with external stakeholders to address important public health challenges. Statisticians from industry, academia, and government with expertise in therapeutic clinical trials are well positioned to provide solutions to complex problems through innovative thinking and, as such, played a key role at each meeting. The collegial and often lively discussion of ideas at the expert meetings motivated the creation of a special journal issue, and many of the challenges and proposed solutions that were discussed are captured in the articles appearing in the issue.
There are several interesting features of the special issue: (i) seven original manuscripts are written on six topics: oncology drug development, antibacterial drug development, assessment of cardiovascular risk in clinical trials in patients with Type 2 diabetes mellitus, equivalence of generic locally acting drug products, subgroup analysis in clinical trials, and sample size reestimation; (ii) four of the seven original manuscripts are written by FDA statisticians and three by industry statisticians representing scientific working groups, the American Statistical Association (ASA) Biopharmaceutical Section Working Group on Safety, the Drug Information Association (DIA), Adaptive Design Scientific Working Group (ADSWG) on Sample Size Re-estimation (SSR), and the Society for Clinical Trials (SCT) Quantitative Sciences in the Pharmaceutical Industry (QSPI) Working Group on Subgroup Analysis; (iii) each original article is accompanied by a commentary written by an expert or experts on the same topic; (iv) the articles and commentaries represent contributions from the three sectors, regulatory (FDA and EMA), industry, and academia.
Rajeshwari Sridhara et al. discuss challenges in the regulatory review of cancer therapies as a result of new paradigm shifts and also describe innovative ideas that might improve the evaluation of novel agents for treating cancer in clinical trials. Price et al. outline some critical design, conduct, and analysis elements that impact clinical trials of new antibiotics and discuss scientific challenges unique to antibacterial product development. Grosser et al. outline statistical approaches used in clinical equivalence studies, illustrate the approach with a discussion of studies of nasal spray products for allergic rhinitis, and describe a new statistical approach for evaluating bioequivalence of topical locally acting dosage forms studied in vitro. Alosh et al. report for the FDA working group of statisticians from the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), and the Center for Devices and Radiological Health (CDRH) on major statistical issues underlying subgroup analysis in clinical trials. Their article provides a regulatory perspective on the interpretation of subgroup findings and on the design and analysis of a clinical trial that aims to establish efficacy in a targeted subgroup and for the overall population. Other aspects of subgroup analysis highlighted in the article include Bayesian subgroup analysis, subgroup considerations for noninferiority trials, personalized medicine, subgroup misclassification, and subgroup analysis for safety assessments. Mayer et al., writing for the QSPI Working Group on Subgroup Analysis, give a summary of the results of a recent survey in the pharmaceutical and device industry on the current practice and common issues in the identification and analysis of subgroups. Marchenko et al., writing for the ASA Biopharmaceutical Section Working Group on Safety, review drugs approved by the FDA to treat Type 2 diabetes mellitus during 2002–2014 with an objective to understand the impact of FDA guidance on assessment of CV risk in anti-diabetes development programs. The authors discuss the advantages and disadvantages of different CV assessment strategies and raise some emerging questions that might stimulate further research on the topic. Finally, Pritchett et al., writing for the ADSWG on SSR, summarize statistical methods pertaining to SSR designs, including recent developments in the field, and discuss design alternatives among blinded and unblinded options, including conventional group sequential designs. Their objective is to support broad understanding and acceptance of SSR designs in confirmatory trial settings. The authors make recommendations for operational logistics and provide points to consider for final data analysis and reporting of studies where the sample size has been increased through either blinded or unblinded SSR methods. Commentaries accompanying all of the articles were written by expert statisticians from the U.S. FDA, the EMA, the pharmaceutical industry, and academia and provide engaging discussions and complimentary viewpoints on the topics.
We thank the authors of the original articles and of the commentaries for their informative and interesting contributions to this special issue. We believe these contributions, taken together, will provide readers with new insights and perspectives on current challenges, trends, and innovations in clinical trial statistics. Additionally, we thank Dr. José Pinheiro, the Editor of Statistics in Biopharmaceutical Research, for the opportunity to organize this special issue and for his help during its preparation, and editorial coordinator, Jina Lee, for her assistance.
Additional information
Notes on contributors
Olga Marchenko
Olga V. Marchenko is Vice President, Quantitative Decision Strategies and Analytics, Quintiles, Durham North Carolina (E-mail: [email protected]). Lisa M. LaVange is Director of the Office of Biostatistics, Office of Translational Sciences CDER FDA, Silver Spring Marylan (E-mail: [email protected]). Olga Marchenko Lisa and M. LaVange are Guest Co-Editors.
Lisa M. LaVange
Olga V. Marchenko is Vice President, Quantitative Decision Strategies and Analytics, Quintiles, Durham North Carolina (E-mail: [email protected]). Lisa M. LaVange is Director of the Office of Biostatistics, Office of Translational Sciences CDER FDA, Silver Spring Marylan (E-mail: [email protected]). Olga Marchenko Lisa and M. LaVange are Guest Co-Editors.