Therapeutic Innovation & Regulatory Science

Bootstrapping technique is distribution-independent, which provides an indirect way to estimate the sample size for a clinical trial based on a relatively smaller sample. In this paper, sample size estimation to compare two parallel-design arms for continuous data by bootstrap procedure are presented for various test types (inequality, non-inferiority, superiority, and equivalence), respectively. Meanwhile, sample size calculation by mathematical formulas (normal distribution assumption) for the identical data are also carried out. Consequently, power difference between the two calculation methods is acceptably small for all the test types. It shows that the bootstrap procedure is a credible technique for sample size estimation. After that, we compared the powers determined using the two methods based on data that violate the normal distribution assumption. To accommodate the feature of the data, the nonparametric statistical method of Wilcoxon test was applied to compare the two groups in the data during the process of bootstrap power estimation. As a result, the power estimated by normal distribution-based formula is far larger than that by bootstrap for each specific sample size per group. Hence, for this type of data, it is preferable that the bootstrap method be applied for sample size calculation at the beginning, and that the same statistical method as used in the subsequent statistical analysis is employed for each bootstrap sample during the course of bootstrap sample size estimation, provided there is historical true data available that can be well representative of the population to which the proposed trial is planning to extrapolate.

Monitoring the quality of clinical trial efficacy outcome data has received increased attention in the past decade, with regulatory guidance encouraging it to be conducted proactively, and remotely. However, the methods utilized to develop and implement risk-based data monitoring (RBDM) programs vary, and there is a dearth of published material to guide these processes in the context of central nervous system (CNS) trials. We reviewed regulatory guidance published within the past 6 years, generic white papers, and studies applying RBDM to data from CNS clinical trials. Methodologic considerations and system requirements necessary to establish an effective, real-time risk-based monitoring platform in CNS trials are presented. Key RBDM terms are defined in the context of CNS trial data, such as “critical data,” “risk indicators,” “noninformative data,” and “mitigation of risk.” Additionally, potential benefits of, and challenges associated with implementation of data quality monitoring are highlighted. Application of methodological and system requirement considerations to real-time monitoring of clinical ratings in CNS trials has the potential to minimize risk and enhance the quality of clinical trial data.

Risk-based monitoring (RBM) has disrupted the clinical trial industry, challenging conventional monitoring norms, business processes, and organizational structures. Endorsed by regulators and leading industry forums, and further driven by escalating drug development costs and enabling technology shifts making data available real time, the industry is moving from a mode of recalcitrance to acceptance. The effective implementation of RBM requires delicately interweaving changes in technology, processes, people, and perspectives. This article deliberates upon the multiple challenges that exist and proposes potential solutions.

Recent National Institutes of Health policy changes have expanded the number of research studies that must be registered in clinicaltrials.gov beyond the requirements of the Food and Drug Administration Amendments Act of 2007. The International Committee of Medical Journal Editors has also adopted a policy that requires registration of research in a public database. The goal was to increase the transparency of research by reporting the original endpoints of a study, and to discern whether primary endpoints were excluded in subsequent publications. Efforts to increase openness and accountability in clinical trials are likely to strengthen public trust. However, first investigators and study staff must be educated about the requirements, and staff must be prepared to offer support to researchers in navigating the clinicaltrials.gov system. For academic institutions, maintaining compliance requires continuous oversight so that problems can be identified centrally and addressed with investigators. At Wake Forest University Health Sciences, because researchers often did not realize they were out of compliance, we implemented a program to assist them and provide oversight. We introduced standard operating procedures, provided education and assistance to investigators, and engaged leadership about consequences of compliance, resulting in increased budget support for a full-time employee in this role. As a result of these changes, compliance increased from 22% to 92% over 4 months. These approaches may help other institutions become compliant with registration requirements more quickly.

Micro-, small-, and medium-sized enterprises (SMEs) have been considered as key players who can bring innovative medicinal products and/or technologies into the field. However, they may need much regulatory/scientific supports to provide their products, technologies, or services to the market in a timely way. Both the Pharmaceuticals and Medical Devices Agency (PMDA) and the European Medicines Agency (EMA), regulatory authorities for medicinal products in Japan and the EU, respectively, have prepared supportive measures for SMEs from the early phase of product/technology development to the postmarketing phase. With respect to supports for SMEs, both agencies have provided similar SME-specific supportive activities, including routine administrative assistance, consultations about product development strategy from an early phase, as well as specific regulatory/scientific issues and fee incentives. In addition, there is a system to register SME status in the EU, which can be a tool for regulators to know how much potential SME-driven activities have and with whom they should communicate to provide necessary supports. Furthermore, as new technologies and novel products from SMEs are not limited to the region where they are developed, close communication about these topics between the PMDA and the EMA will contribute to advancing patients’ access to necessary medicinal products.

The surging costs of health care in China is highly related to the high expenses in pharmaceutical costs. Since the Government of China launched the health care reform in 2009, the issue of growing pharmaceutical expenditure continues to grasp policy makers’ attention. Since 2015, an ongoing series of drug-related policies have been revised or developed, resulting in profound impact on the overall pharmaceutical market in China, and the dynamic is still evolving. As China has become the second largest pharmaceutical market in the world, any volatility in the Chinese pharmaceutical market may have great implications to multinational pharmaceutical markets that have had their products launched in China or plan to extend their business to the Chinese market. Based on a comprehensive analysis of the most recent health care reform policies in China, the objectives of this study were to identify the major opportunities appealed to and the challenges confronted by multinational pharmaceutical enterprises in the current Chinese pharmaceutical market.

This paper presents a review of the literature, including government legislations, policies, guidelines, and recommendations available in the European Union, the United States of America, and Australia pertaining to the availability, development, and distribution of written medicine information (WMI) for prescription medicines. The online databases searched were Embase, International Pharmaceutical Abstracts, Medline, and PubMed, together with Google as the Internet search engine. The design and content of WMI documents have similarities and differences across all the 3 geographical regions. All the 3 regions have legislations in place to evaluate and regulate WMI documents for health care professionals (HCPs) and, to some degree, for patients; however, the degree of regulation varies between the 3 regions. The regulations around the content and information design of WMI impacts how well the WMI performs and consequently influences patients’ knowledge and medication-taking behavior. Legislation in certain areas could be seen as more beneficial and can be implemented across the 3 regions. Furthermore, the required legislation on the evaluation of the content of WMIs can be seen in some areas to be more stringent and comprehensive, which when taken onboard across the 3 regions can be valuable when creating WMIs for both patients and HCPs.

Data quality is critical for clinical trials to obtain robust conclusions about drug safety and efficacy evaluation. Effective data quality evaluation has been one of the major obstacles to new drug approvals in China, which hinders innovation in drug discovery and development ultimately. To improve the data quality submitted for regulatory drug approval, the China Food and Drug Administration (CFDA) has issued serial official announcements and industry guidelines regarding improvement of the clinical trial data integrity and quality since 2015. These announcements and follow-up measures are shaping up the entire pharmaceutical industry in China. While data quality is being strongly emphasized more than ever at the trial conduction phase, it is still an open question about how to assess data quality effectively at the review stage. Thus, this article describes the authors’ standpoints to assess the quality and integrity of submitted clinical data via statistical review methods including advanced risk-based approaches, which may bring significant impact to new drug applications and motivate sustainable development of innovative medicines in China.

Globalization of the pharmaceutical industry has continued over the past few decades, and various regulatory authorities have put considerable effort into harmonizing and standardizing drug regulations. However, the regulatory practices of each regulatory authority, in addition to local differences in ethnic, social, and cultural backgrounds, create discrepancies in risk/benefit assessments, regulatory decisions, and drug label information in various countries. This study examines discrepancies in the label information for direct oral anticoagulants approved in the US, Europe, Korea, and Japan and reviews the causes of those discrepancies, focusing on regulatory practices. Although the label information for each direct oral anticoagulant in all 4 regions was supported by the same global, pivotal clinical data, it differed depending on regulatory authorities’ judgments about the risk/benefit balance, which were based on their own requirements, regulations, perspectives on making regulatory decisions, and regulatory approval experiences, in addition to their review of the scientific data. In particular, the Korean Ministry of Food and Drug Safety and Japanese Pharmaceuticals and Medical Devices Agency have taken a comparatively conservative stance, with more emphasis on safety than on efficacy compared with regulatory authorities in western countries, because of the double threshold in their regulatory practice. Our findings suggest that drug label information in various regions will not be equal as long as differences in regulatory practice and non-regulatory factors exist among regulatory authorities. Also, those differences should be considered in order to streamline global drug discovery, development, and approval.

The US Food and Drug Administration’s (FDA’s) generic drug program has dramatically increased the availability of affordable, high quality generic drugs. The foundation of generic drug approvals is a two-tiered regulatory framework of pharmaceutical equivalence and bioequivalence. Intrinsic to both of these is consideration of the clinical relevance of formulation and bioequivalence data to support an inference of therapeutic equivalence, based on clear evidence that there are no significant differences between the generic drug and the brand name drug. These analyses allow FDA to determine that the generic drug will perform in the patient in the same way, with the same safety and efficacy profiles, as the brand name drug. Allowable differences and the precise definition of what is meant by equivalence are critical to maintaining the quality, efficacy, and safety of generic drugs. The FDA Office of Generic Drugs’ (OGD’s) Clinical Safety Surveillance Staff (CSSS) has developed investigative processes that complement the broader FDA safety efforts that focus on the potential impact of allowable differences and equivalence determinations for generic drugs. Two recent examples of the CSSS’s processes include a clonidine transdermal system and lansoprazole oral disintegrating tablet. Ongoing efforts of the CSSS result in improvements to the FDA’s review processes and the quality of generic drugs in the US market.

Although outcomes for children with cancer have significantly improved over the past 40 years, there has been little progress in the treatment of some pediatric cancers, particularly when advanced. Additionally, clinical trial options and availability are often insufficient. Improved genomic and immunologic understanding of pediatric cancers, combined with innovative clinical trial designs, may provide an enhanced opportunity to study childhood cancers. Master protocols, which incorporate the use of precision medicine approaches, coupled with the ability to quickly assess the safety and effectiveness of new therapies, have the potential to accelerate early-phase clinical testing of novel therapeutics and which may result in more rapid approval of new drugs for children with cancer. Designing and conducting master protocols for children requires addressing similar principles and requirements as traditional adult oncology trials, but there are also unique considerations for master protocols conducted in children with cancer. The purpose of this paper is to define the key challenges and opportunities associated with this approach in order to ensure that master protocols can be adapted to benefit children and adolescents and ensure that adequate data are captured to advance, in parallel, the clinical development of investigational agents for children with cancer.