Draft Guidance Research Articles

New draft guidance evaluates safety of new antihyperglycaemics

New draft guidance evaluates safety of new antihyperglycaemics

Adaptation for Regulatory Application: A Content Analysis of FDA Risk Evaluation and Mitigation Strategies Assessment Plans (2014-2018) Using RE-AIM.

Background: Risk Evaluation and Mitigation Strategies (REMS) are safety programs that U.S. Food and Drug Administration can require to ensure a drug's benefits outweigh its risks and can be considered public health interventions. FDA's 2019 draft Guidance for Industry on REMS Assessments encourages the development of “novel methods for assessing REMS [to] help advance the science of post-market assessment of effectiveness of risk mitigation strategies.”Objective: To characterize REMS assessment plans using RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework and identify areas for advancing methods for evaluating REMS programs. RE-AIM was selected for its wide application evaluating the translation of scientific advances into practice for public health impact.Methods: A content analysis of REMS assessment plans (N = 18) and measures(n = 540) was conducted for REMS programs approved by FDA between 1/1/2014–12/31/2018. Eligibility criteria were: a new drug application or biologic license application, included FDA-mandated mitigation strategies called elements to assure safe use (ETASU), and represented a single product REMS program. Assessment plans were collected from publicly available regulatory approval letters from REMS@FDA website. Blinded reviewers categorized each REMS assessment measure to a RE-AIM dimension, adjudicated their application (average IRR 75%), and refined the adapted dimensions' definitions. Dimensions were also mapped to REMS Assessment guidance categories.Results: The median number of assessment measures per REMS assessment plan was 31 (IQR: 21–36). Frequency of measures per RE-AIM criteria per REMS program was: Reach (median = 2; IQR: 2–4); Effectiveness (median = 2.5; IQR:1–4); Adoption (median = 3.5; IQR: 2–5); Implementation (median = 18; IQR: 15–24); Maintenance (median = 0; IQR: 0–1). Adoption (among prescriber, health system agents of implementation) was more commonly assessed than Reach (population-attributable number of patients affected). Assessment of heterogeneity of Adoption and Reach was generally absent. Implementation assessment measures were most common among drugs requiring evidence of safe-use conditions before dispensing or administering the drug. Patient-level Effectiveness and Maintenance assessments were most common among drugs requiring patient monitoring.Discussion: Implementation science frameworks, such as RE-AIM, can be applied to characterize REMS assessment measures and identify opportunities for standardizing and strengthening their evaluation. Methods to measure Maintenance are needed to provide real-world evidence of REMS integration into the healthcare system.

Some thoughts on the QR method for analytical similarity evaluation

ABSTRACTAs indicated in a recent published draft guidance on comparative analytical assessment, the United States (US) Food and Drug Administration (FDA) seems to suggest the use of quality range (QR) method for analytical similarity evaluation. It is a concern that the use of QR method for analytical similarity evaluation could potentially approve biological products which are not deemed biosimilar to the reference biological products. In this article, the limitations and potential risk for the use of the QR method for analytical similarity evaluation are discussed. Alternatively, two modified versions of the QR method, which are referred to as effect size (ES) mQR and plausibility interval (PI) mQR methods are suggested. The performance and statistical properties of the mQR methods are evaluated via extensive clinical trial simulation under various scenarios. The results indicate that the modified versions of the QR method not only overcome the limitations of the QR method for analytical similarity evaluation, but also can potentially help in detecting reference product changes during manufacturing process.

Protocol for the development of guidance for stakeholder engagement in health and healthcare guideline development and implementation

BackgroundStakeholder engagement has become widely accepted as a necessary component of guideline development and implementation. While frameworks for developing guidelines express the need for those potentially affected by guideline recommendations to be involved in their development, there is a lack of consensus on how this should be done in practice. Further, there is a lack of guidance on how to equitably and meaningfully engage multiple stakeholders. We aim to develop guidance for the meaningful and equitable engagement of multiple stakeholders in guideline development and implementation.MethodsThis will be a multi-stage project. The first stage is to conduct a series of four systematic reviews. These will (1) describe existing guidance and methods for stakeholder engagement in guideline development and implementation, (2) characterize barriers and facilitators to stakeholder engagement in guideline development and implementation, (3) explore the impact of stakeholder engagement on guideline development and implementation, and (4) identify issues related to conflicts of interest when engaging multiple stakeholders in guideline development and implementation.DiscussionWe will collaborate with our multiple and diverse stakeholders to develop guidance for multi-stakeholder engagement in guideline development and implementation. We will use the results of the systematic reviews to develop a candidate list of draft guidance recommendations and will seek broad feedback on the draft guidance via an online survey of guideline developers and external stakeholders. An invited group of representatives from all stakeholder groups will discuss the results of the survey at a consensus meeting which will inform the development of the final guidance papers.Our overall goal is to improve the development of guidelines through meaningful and equitable multi-stakeholder engagement, and subsequently to improve health outcomes and reduce inequities in health.

GC-PROM: validation of a patient-reported outcomes measure for Chinese patients with gastric cancer

BackgroundThere is increasing recognition that PROs are important in the estimation of the burden of long-term survival among patients with gastric cancer. The study aimed to develop a disease-specific instrument to assess patient-reported outcomes for Chinese patients with gastric cancer.MethodFollowing the FDA’s draft guidance for patient-reported outcome, conceptual framework and item pool were defined based on relevant existing work. A draft scale was formed after revising some items based on feedback from experts and Chinese patients with gastric cancer. The pre-survey and formal survey were conducted in eight different hospitals in Shanxi Province, and two item-selection process based on classical test theory and item response theory. Finally, the patient-reported outcomes measure for Chinese patients with gastric cancer (GC-PROM) was validated in terms of reliability, validity, and feasibility. The minimal clinically important difference was determined by distribution-based method.ResultsThe final GC-PROM consisted of 38 items, 13 subdomains, and 4 domains. Reliability was verified by Cronbach’s alpha coefficient for four domains and 13 subdomains respectively. The validity results showed that the multidimensional scale fulfilled expectations. In the formal survey, the completion rate was 96.16%, and the average filling time was less than half an hour. The values of the minimal clinically important difference were 4.14, 3.41, 3.37, and 3.28 in the four domains.ConclusionsThe GC-PROM had good reliability, validity, and feasibility and thus can be considered an effective clinical evaluation instrument for Chinese patients with gastric cancer.

Monarch Initiative's response to the RFI for the NIH Policy for Data Management and Sharing and Supplemental DRAFT Guidance

Monarch Initiative's response to the RFI for the NIH Policy for Data Management and Sharing and Supplemental DRAFT Guidance

A Systematic Approach for Post Hoc Subgroup Analyses With Applications in Clinical Case Studies.

The analysis of subgroups in clinical trials is essential to assess differences in treatment effects for distinct patient clusters, that is, to detect patients with greater treatment benefit or patients where the treatment seems to be ineffective. The software application subscreen (R package) has been developed to analyze the population of clinical trials in minute detail. The aim was to efficiently calculate point estimates (eg, hazard ratios) for multiple subgroups to identify groups that potentially differ from the overall trial result. The approach intentionally avoids inferential statistics such as P values or confidence intervals but intends to encourage discussions enriched with external evidence (eg, from other studies) about the exploratory results, which can be accompanied by further statistical methods in subsequent analyses. The subscreen application was applied to 2 clinical study data sets and used in a simulation study to demonstrate its usefulness. The visualization of numerous combined subgroups illustrates the homogeneity or heterogeneity of potentially all subgroup estimates with the overall result. With this, the application leads to more targeted planning of future trials. This described approach supports the current trend and requirements for the investigation of subgroup effects as discussed in the EMA draft guidance for subgroup analyses in confirmatory clinical trials (EMA 2014). The lack of a convenient tool to answer spontaneous questions from different perspectives can hinder an efficient discussion, especially in joint interdisciplinary study teams. With the new application, an easily executed but powerful tool is provided to fill this gap.

NICE reverses advice on exercise therapy for treatment of chronic fatigue syndrome in draft guidance

Graded exercise therapy should not be offered for the treatment of myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome, according to draft guidance from the National Institute for Health and Care Excellence.

Analysis: Intravascular Devices with a Higher Risk of Polymer Emboli: The Need for Particulate Generation Testing.

Hydrophilic polymer coatings on intravascular devices lower friction between the device and vasculature, thereby reducing trauma during interventional procedures. Polymer coating embolism-the detachment and downstream embolism of polymer particles-has been reported as an iatrogenic complication of coated interventional devices affecting the vasculature and various organs. The Food and Drug Administration (FDA) acknowledges this complication and continues to work with stakeholders to close gaps in performance testing and standards related to polymer coating integrity. Recent innovations within interventional technologies have led to development of new hydrophilic-coated devices with expanded indications for use. The 2018 FDA draft guidance for intravascular guidewires expands the application of particulate generation testing to most devices and recommends labeling changes to increase industry awareness. This article highlights current procedural trends where the phenomenon of polymer coating embolism may be more prevalent. It describes the mechanisms of polymer separation, reported clinical sequelae, and risk factors for relevant indications. These procedural trends and associated risk factors articulate the need for particulate testing and support the FDA's draft guidance recommendations for performance testing of applied coatings. If standardized, particulate assessments may allow characterization and comparisons of coating integrity among devices from various manufacturers, and are an important foundation for setting particulate limits. As hydrophilic coatings enable endovascular treatment for a range of patient populations, setting particulate limits or finding alternative solutions without compromise to device function may be essential. Particulate testing is relevant to physicians, regulators, and manufacturers for the purposes of product development and quality improvement of interventional devices.

Aspirin, paracetamol and ibuprofen should not be prescribed for chronic pain syndromes, NICE draft guidance says

Aspirin, paracetamol and ibuprofen should not be prescribed for chronic pain syndromes, NICE draft guidance says

Post-approval Change Submission: ICH Q12 Impact Analysis on India and Japan

The present research provides a discussion on post approval change management of pharmaceuticals, biologics and drug device combinations, which is an important part of life cycle management. The present study focuses on understanding the existing post approval change management system in India and Japan. Comparison is then made with the elements and principles provided in draft ICH Q12 guideline. In November 2017 the draft guidance ICH Q12 entitled Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management has been published for comment. The discussion of this study would bring to light the key requirements, challenges and impact of future implementation of ICH Q12 in India and Japan. The initiative taken by ICH Q12 with this guideline focuses mainly on harmonizing the post approval system throughout the world which has the potential to reduce costs and time burdens for the regulators and industry.

Adaptive Designs: Results of 2016 Survey on Perception and Use.

The DIA Adaptive Designs Scientific Working Group has a devoted subteam to performing surveys, literature reviews, and registry reviews every 4 years to assess the perception and use of adaptive designs (ADs) in the development of drugs and biologics. A survey was distributed to pharmaceutical companies, academic institutions, and contract research organizations to collect information about the usage of ADs of different types and perception of challenges for their use. Literature and registry reviews were conducted to assess the prevalence of ADs of different types in drug and biologics development. These results were compared to previous surveys and reviews using summary statistics. ADs appear to be more widely considered in the last 4 years as compared to earlier 4-year periods. The most common types of ADs remain early stopping, treatment group adaptations, and sample size re-estimation. Both stopping early for safety and changing the endpoint of the analyses were rarely mentioned in literature prior to 2012 but are now appearing more frequently. The barriers of change management and negative experiences by some institutions with ADs remain a source of concern. Additional, consistent training would be helpful to choose the right adaptation(s) needed for specific clinical trials and for planning appropriately for operational efficiency such as for drug supply management and data management. The perceived barrier of regulatory acceptance also remains a concern, which could be alleviated by additional interaction with agencies and an update of the FDA draft guidance to industry on adaptive designs.

Food and Drug Administration Issues Device Classifications, Draft and Final Guidances, and New Product Approvals

Corresponding author: Jay Geller, JD, MBA, 121000 Wilshire Blvd, Ste 1250, Los Angeles, CA 20025 ([email protected]). The author declares no conflicts of interest.

Recording problems and diagnoses in clinical care: developing guidance for healthcare professionals and system designers

BackgroundAccurate recording of problems and diagnoses in health records is key to safe and effective patient care, yet it is often done poorly. Electronic health record systems vary in their...

Clinical translation of eye drops and complex drug products

AbstractEye drops constitute majority of ophthalmic drug products, with solutions, suspensions, ointments, and emulsions being the top formulations. While solutions are considered simple formulations, with biowaiver granted for qualitatively and quantitatively similar generic formulations, others are complex formulations, whose generic products are difficult to develop and translate. In particular, manufacturing processes as well as the grades of inactive ingredients used can affect drug product attributes and bioavailability. Thus, bioequivalence of complex generics is less certain. The US FDA issued some draft guidance documents to ease approval of complex generic drug products. One purpose of this presentation is to discuss the difficulties in clinical translation of complex generic eye drop products. In recent years, there has been significant effort in developing eye drops for back of the eye drug delivery, using either pure drug formulations or carrier‐drug composite formulations (e.g., polymeric nanoparticles), with little or no success to date. The second purpose of this presentation is to discuss translational gaps in advancing eye drops for back of the eye drug delivery and to further discuss the difficulties in manufacturing and stabilizing composite nanoparticle formulations for eye drop applications.

Standardizing Safety Assessment and Reporting for Neonatal Clinical Trials

Standardizing Safety Assessment and Reporting for Neonatal Clinical Trials

FDA Addresses Breast Cancer in Men

Research on breast cancer is rapidly progressing, leading to new therapies and treatment approaches, yet in men with the disease it continues to lag. Recently, the FDA released a draft guidance to address this disparity, outlining strategies to improve drug development for men such as including them in clinical trials and using nontraditional data sources.

Adverse Drug Reaction Case Safety Practices in Large Biopharmaceutical Organizations from 2007 to 2017: An Industry Survey.

Drug safety remains a top global public health concern. An increase in the number of data sources available has increased the complexity of pharmacovigilance operations, so the US FDA has created draft guidance focusing on optimizing drug safety data for well-characterized medicines. However, to date, no data demonstrating changes in reports have been presented. This study provided data assessing changes in individual case safety reports (ICSRs) and aggregate reports (ARs) for large biopharmaceutical companies from 2007 to 2017. This study also evaluated current trends on the use of advanced machine and deep learning in order to process all data captured for ICSRs as well as opinions from industry thought leaders on creating a sustainable case-processing operation. Using data captured from Navitas Life Science's annual pvnet® benchmark, we calculated workload indicators characterizing pharmacovigilance operations for large biopharmaceutical organizations. Workload indicators included the number of ICSRs by organization, the number of ARs, and the number and types of data sources used. We also conducted structured in-depth interviews with seven biopharmaceutical executives to discover the reasons for changes in workload indicators across time as well as current strategies for increasing efficiencies in drug safety reporting. The median number of ICSRs increased from 84,960 cases in 2007 to over 200,000 cases in 2017; this increase was largely attributable to an increase in both nonserious cases and follow-up cases. Member companies reported using 12 ± 3 data sources for case identification. The number of ARs also increased from a median of 70 reports in 2007 to 258 reports in 2017. To address these increases, 61% of the biopharmaceutical organizations we surveyed planned to adopt machine learning for full ICSR processing; however, as of 2018, none of the organizations surveyed had mechanisms in place. This study demonstrated that pharmacovigilance departments are currently burdened by ever-increasing case volumes. With increased guidance from regulatory agencies, as well as improvements in artificial intelligence and natural language processing, biopharmaceutical organizations must determine the most resource-efficient and sustainable methods to process the growing volume of cases.

PP 1/271 (3) Guidance on efficacy aspects of comparative assessment

Specific scopePlant protection products (PPP) may be subject to a process of comparative assessment (CA) to determine whether substitution by alternative PPPs or other control methods is possible. Substitution should only be made if, among the other alternatives, there are no significant economic or practical disadvantages. This Standard provides guidance and a decision support scheme to determine whether the substitution of a PPP is appropriate in view of agronomic considerations. This includes practical and economic impacts of identified alternatives (both chemical and non‐chemical), as well as resistance risk management. The Standard does not address comparative safety from the human and environmental perspective (for EU Member States, guidance is available covering human health and environmental aspects of CA: ‘Draft Guidance document on Comparative Assessment and Substitution of Plant Protection Products in accordance with Regulation (EC) No 1107/2009 SANCO/11507/2013 rev.12, 10 October 2014’. SANCO 11507/2013 recommends a stepwise approach with the agronomic assessment conducted first, for which specific reference is made to using this EPPO Standard. Expert judgment is required in answering the questions (which may include the need to seek specialist advice).Specific approval and amendmentFirst approved in 2011‐09.Minor revision approved in 2015‐09 (to harmonize requirements with DG SANCO Guidance Document 11507/2013.Revision approved in 2019‐09 following discussion in the EPPO Workshop on Comparative Assessment of Plant Protection Products (Lisbon, 2018‐10‐24/25)

The Universal Patient Language: A set of resources and tools to design patient communications that support better health literacy

Recently, pharmaceutical companies have increased their focus on engaging with patients, following trends toward patient centricity and delivering services around individual drugs. Meanwhile, the U.S. Food and Drug Administration has released draft guidance on disclosing risk information in consumer-directed materials that recommends against verbatim presentations of the risk-related sections within prescribing information, as this may be of limited value to consumers who lack medical or scientific training. In this context, Bristol-Myers Squibb set out to build an organizational capability to communicate complex health topics to patients called the Universal Patient Language™, or UPL. In this report, the authors explore health literacy considerations within the pharmaceutical industry; introduce the UPL; explain how human-centered service design methods were deployed to build the UPL; and present two UPL case studies.