Therapeutic Innovation & Regulatory Science

Patient-facing digital technologies (also called “Patient Technology” [PT]) have the potential to serve a variety of functions in clinical trials, such as capturing clinical endpoints, engaging patients, and facilitating remote study conduct. However, these technologies are not yet accepted as mainstream research tools, and the opportunities, challenges, and facilitators associated with their implementation in clinical trials have not been fully characterized.

In order to understand the factors affecting PT adoption, the TransCelerate Patient Technology Initiative conducted a series of surveys, interviews, and focus groups with approximately 600 subject matter experts, including pharmaceutical company representatives, clinical trial investigators at a number of trial sites worldwide, and clinical trial participants. All interview and survey responses were blinded and aggregated by a third-party consultant and themes were extracted.

There was general consensus around the potential value of patient-facing technology as a clinical research tool, though a variety of challenges faced by each stakeholder were discussed. Detailed accounts of opportunities (improved patient experience, compliance, and engagement; clinical trial efficiencies; improved data quality and insights) and barriers (organizational and corporate cultural challenges, business-related challenges, user willingness and burden, and regulatory challenges) are reported.

While the barriers to PT adoption explored here were numerous, they were also generally consistent. A number of proposals for establishing more holistic, collaborative, and strategic approaches to PT implementation in clinical trials are discussed. Such approaches could facilitate more effective, widespread adoption of PT, and thereby a more patient-centric clinical trial paradigm.

The concept of the risk-based approach has been introduced as an effort to secure the quality of clinical trials. In the risk-based approach, identification and evaluation of risk in advance are considered important. For recently completed clinical trials, we investigated the relationship between study characteristics and protocol deviations leading to the exclusion of subjects from Per Protocol Set (PPS) efficacy analysis.

New drugs approved in Japan in the fiscal year 2014-2015 were targeted in the research. The reasons for excluding subjects from the PPS efficacy analysis were described in 102 trials out of 492 in the summary of new drug application documents, which was publicly disclosed after the drug’s regulatory approval. The author extracted these reasons along with the numbers of the cases and the study characteristics of each clinical trial. Then, the direct comparison, univariate regression analysis, and multivariate regression analysis was carried out based on the exclusion rate.

The study characteristics for which exclusion of subjects from the PPS efficacy analysis were frequently observed was multiregional clinical trials in study region; inhalant and external use in administration route; Anti-infective for systemic use; Respiratory system, Dermatologicals, and Nervous system in therapeutic drug under the Anatomical Therapeutic Chemical Classification. In the multivariate regression analysis, the clinical trial variables of inhalant, Respiratory system, or Dermatologicals were selected as study characteristics leading to a higher exclusion rate.

The characteristics of the clinical trial that is likely to cause protocol deviations that will affect efficacy analysis were suggested. These studies should be considered for specific attention and priority observation in the trial protocol or its monitoring plan and execution, such as a clear description of inclusion/exclusion criteria in the protocol, development of training materials to site staff, and/or trial subjects as specific risk-alleviating measures.

Research coordinators (or teams) are usually assigned to multiple studies of varying complexity at any one time, each with different and ever-changing workloads. As a result, determining the impact of protocol complexity on productivity is not easily accomplished. Standard methods of effort tracking typically require oversight or create additional workload to the site staff under study; they are time-consuming, expensive, intrusive, and usually incomplete.

This article describes a novel method for determining the impact of protocol complexity on clinical research coordinator (CRC) or team productivity by using proxy variables in place of effort tracking. A protocol assessment tool that quantitates complexity is used to determine cumulative workload.

Productivity graphs are generated for each CRC per month and can be followed over time to assess trends or for comparative analysis.

The data provide managers with unique insights into the functional capacity of study coordinators and support staff. The goal is to optimize efficiency by applying a systematic decision process from performance and productivity trends. In addition to exploring the theory behind the method, this article begins a discussion on the use of this information in clinical research site management.

The objective of this report is to summarize common deficiencies identified in the filing reviews of abbreviated new drug applications (ANDAs) with clinical endpoint bioequivalence studies and skin irritation, sensitization, and adhesion (I/S/A) studies received by the US Food and Drug Administration (FDA) between 2007 and 2017, to help applicants avoid common deficiencies, minimize “refuse-to-receive” (RTR) actions, “information requests,” and ANDA approval delays.

Multiple internal FDA databases were searched to evaluate and summarize common deficiencies identified in ANDA submissions containing clinical endpoint studies and skin I/S/A studies that required review by the Division of Clinical Review. A total of 275 ANDA submissions with filing reviews from January 2007 to June 2017 were analyzed in this report.

Two hundred eighteen (79.3%) filing reviews contained one or more deficiencies. Seventy-nine (28.7%) ANDAs were issued RTR letters because of major clinical deficiencies, specifically bioequivalence and clinical deficiencies, accounting for 9% of overall identified deficiencies. Twenty-two other categories of deficiencies are summarized into 4 main categories: missing information related to the clinical studies other than data sets (38%), missing data sets (35%), formulation issues (12%), and organization/format issues (6%).

The most common deficiency in the “missing information related to the clinical studies other than data sets” category was “missing clarification of information” (22%). We also noted that the Division of Filing Review has identified these same types of deficiencies since assuming responsibility of the filing assessment for ANDAs with clinical endpoint BE studies and skin I/S/A studies. In conclusion, to minimize “refuse-to-receive” actions, “information requests,” and approval of ANDA delays for generic drug products, applicants should submit full clinical study reports, including all data sets for drug products recommending clinical studies.

In this study we compared Swissmedic’s (SMC’s) regulatory marketing authorization decisions to those of the US Food and Drug Administration (FDA) and European drug regulatory authorities (EU). We investigated the overall similarity of the regulatory decisions, approval, and postmarketing withdrawal rates in the 3 jurisdictions. In case regulatory decisions diverged, we analyzed the reasons for rejection of marketing authorization applications (MAAs).

The study comprises 255 new molecular entity (NME) MAAs assessed by SMC by the EU and FDA between 2005 through 2014. Study parameters included the regulatory decision, postmarketing withdrawal rates, and the official reasons for rejection.

Regulatory decisions converged to a high degree among all 3 agencies (between 84% and 90%). SMC’s average approval rate (84%) was slightly lower than those of the FDA (87%) and the EU (91%). Postmarketing withdrawal rates were generally low (4%-5%) but were 3 to 5 times higher when decisions among the drug regulatory authorities (DRAs) diverged. SMC’s primary grounds for rejection were lack of efficacy (45%) and safety (40%).

The 3 investigated DRAs adhere largely to the same scientific principles and regulatory guidelines; therefore, remaining disparities ought to be considered in a cultural, legal and public health priority context.

Pharmacists are the part of the health care team who can counsel patients on the most appropriate use of medications. This study aims to measure patients’ experience with services provided by community pharmacists and their perceptions toward providing medication therapy management (MTM) services by community pharmacists in the Western Region of Saudi Arabia. In addition, this study aims to measure patients’ willingness to pay (WTP) for participating in the MTM program led by community pharmacists.

Using a cross-sectional research design, a prevalidated questionnaire was developed and posted to respondents through either face-to-face interviews or online social media. All data were analyzed using SPSS, version 22.0, and all alpha values less than 0.05 were considered significant.

A total of 953 responses were obtained in this study. Overall, 47.6% of the respondents always buy their medications from different community pharmacies, and 46.1% of respondents said that community pharmacists always respond to all of their questions. In addition, 96% of respondents perceived the MTM program to be beneficial for patient care. Moreover, 70.3% of respondents were willing to register in the MTM program if implemented at community pharmacies.

Residents in the Western Region of Saudi Arabia highly appreciate the additional values of the MTM program if implemented by community pharmacists. Decisions makers should encourage community pharmacists to plan for MTM services.

Print pharmaceutical advertisements in the United States require inclusion of a brief summary of side effects, warnings, precautions, and contraindications from the labeling. The full package insert, which sponsors have traditionally used to fulfill the brief summary requirement, does not adhere to health literacy best practices, limiting its value to consumers. This study compared the understandability and usability of brief summaries in 3 formats designed to be more consumer friendly.

Three brief summary formats were tested: (1) 2-column “Question and Answer”; (2) “Prescription Drug Facts Box,” similar to current US over-the-counter drug facts labeling; and (3) “Health Literacy,” based on clear communication principles. Researchers evaluated the formats using the Suitability Assessment of Materials (SAM) tool and conducted structured, scripted, one-on-one interviews (usability tests) with participants with estimated low to average education levels. This research was replicated across 2 therapeutic areas (type 2 diabetes and plaque psoriasis).

SAM scores showed that the Health Literacy format outperformed the Question and Answer format and the Prescription Drug Facts Box format in both therapeutic areas, with both Health Literacy brief summaries rated on the SAM as “superior.” Qualitative usability tests supported the SAM findings, with the Health Literacy format preferred consistently over the Question and Answer format, and more often than not over the Prescription Drug Facts Box format.

Sponsors can employ a user-tested Health Literacy format to improve the understandability and usability of brief summaries with patients.

The aim was to analyze safety data associated with the maternal use of antiepileptic drugs in pregnancy and to assess the risk of cleft lip and/or palate (CL/P) as an outcome in the neonate. A parallel objective was to assess the completeness of the safety information concerning pregnancy exposures in the Summary of Product Characteristics (SmPCs) and the Patient Information (PI) in the USA and the UK.

We analyzed individual case safety reports of CL/P associated with antiepileptic drugs in the FDA Adverse Event Reporting System. For the antiepileptic drugs with signals (EB05 ≥ 2), we reviewed Drug Analysis Prints for CL/P cases in the UK Medicines and Healthcare products Regulatory Agency (MHRA). We performed descriptive analyses of relevant SmPCs and PIs in the UK and the USA using a checklist of recommendations collected from the literature.

In total 817 CL/P reports were identified for 12 antiepileptic drugs in the FDA Adverse Event Reporting System. Ten of the 12 antiepileptic drugs were associated with 156 CL/P cases in the MHRA Sentinel. Safety information concerning pregnancy was found to be more comprehensive in UK SmPCs than in the US equivalents.

There is statistical disproportionality in individual case safety reports indicative of an increased risk of CL/P with 12 antiepileptic drugs studied. More studies are required to explore the association between in utero exposure to antiepileptic drugs and the risk of CL/P. There are inconsistencies between the UK and US safety labels. CL/P associated with antiepileptic drugs is an important topic and requires providing inclusive, unbiased, up-to-date information to prescribers and women of childbearing age.

Corticosteroids have been used in numerous medical conditions. Studying the pattern and causality of adverse drug reactions (ADRs) helps us gain greater insight into their prevention, detection, assessment, and treatment. This reduces cost of health care and increases compliance. The study aimed to evaluate the ADRs reported in patients receiving corticosteroids for age, type of reaction, duration of steroid therapy, treatment prescribed for the ADR, and causal relationship of the ADR with the prescribed steroid.

ADRs observed in the patients admitted to the hospital wards and reported from October 1, 2015, to January 1, 2016, were studied for age, type of reaction, seriousness of the reaction, duration of steroid therapy, and treatment prescribed for the ADR. Causality assessment was done using the WHO-UMC scale.

A total of 59 ADRs were reported. More than three-fourths (76.6%) were adults. The gastrointestinal system was the most common organ system affected (45.8%), followed by the cardiovascular system (18.6%). The other ADRs affected the psychiatric, dermatologic, musculoskeletal, endocrine, metabolic, and nervous systems. In addition, 3.4% of the ADRs were serious causing disability and prolongation of hospitalization respectively. More than half (57.4%) of the patients were on long-term steroids. Most (91.5%) of the ADRs showed a possible causal relationship, whereas 6.8% showed a probable causal relationship with the prescribed steroid. The causal relationship of one ADR with the prescribed steroid seemed unlikely.

The decision to initiate corticosteroids requires careful consideration of relative risks and benefits in each patient. Strategies such as low-dose and alternate day therapy may reduce the incidence of adverse effects.

To identify if proprietary names are used by health care practitioners when prescribing over-the-counter (OTC) drug products. These findings can inform evaluation of proposed proprietary names for both prescription and OTC drug products.

QuintilesIMS OTC International Market Tracking (QuintilesIMS OTCIMS) was used to identify top OTC drug products sold to the consumers from US retail store outlets in year 2011. QuintilesIMS’s Vector One: National (VONA) was used to identify prescribers’ use of proprietary names by examining drug use data from 2003 to 2011 for the top OTC products identified from QuintilesIMS OTCIMS.

Of the 29 OTC drug products that have drug utilization data available, the data showed prescribers’ use of proprietary names every year from 2003 to 2011 for 24 OTC drug products, and from 2004 to 2011 for 2 OTC drug products. The drug use data showed the use of proprietary name in some years but not all years from 2003 to 2011 for the remaining 3 OTC drug products. For the OTC drug products studied, prescribers used proprietary names for OTC products when prescribing them, and the use of proprietary names on prescriptions can vary during a 9-year period.

This research identified that prescribers do prescribe OTC drug products using proprietary names. This prescribing practice confirms the need for the pharmaceutical industry, industry consultants, and regulators to consider the proprietary names of OTC drug products when formulating and evaluating new proprietary names for drugs.

Drug lag (DL) in Japan has decreased in the last few years as a result of the globalization of drug development in the past decade, and new molecule entities (NMEs) with short DL are on the rise. The purpose of this study was to investigate the influence of DL on postmarketing safety of NMEs, by comparing the length of DL and the chronological trend of package insert revisions.

The number of label revisions occurring during 6 years after approval was investigated for 142 NMEs approved between 2000 and 2006. The NMEs were classified by the length of DL (2 years and 4 years), and the label revision trends by each label section and therapeutic categories were analyzed.

The cumulative number of level revisions in the “Drug Interactions” and “Clinically Significant Adverse Reactions” sections in the first year after approval in the DL <2 years group was significantly greater than in the DL ≥2 years group. In the chemotherapeutic category that showed the shortest DL, the first label revision occurred in 33.3% within the first year and in 66.7% by the second year, and label revisions were performed earlier than in any other therapeutic categories.

These results suggest that the package inserts of NMEs with a shorter DL tend to be revised earlier and more frequently, and it requires more careful monitoring of safety information after product launch.