Development Safety Update Report Research Articles

Assessment of pharmacovigilance guidelines in the Southern African Development Community: A document review.

Lack of harmonization in pharmacovigilance (PV) practice in resource-limited states in Africa has led to differentiation and marginalization, thus creating an environment where weak or absent PV systems may benefit from regional guidelines. To compare the PV guidelines of Southern African Development Community (SADC) member states to international guidelines and identify areas for improvement for aligning PV practice within the SADC region. We utilized a 73-item checklist to assess the PV guidelines of the SADC member states. Checklist parameters were rated using binary scoring. Only seven (Botswana, Mauritius, Namibia, South Africa, Tanzania, Zambia, and Zimbabwe) of the 16 SADC member states had guidelines to assess. Of these, only four had supporting legislation. All seven national medicines regulatory authorities (NMRA)'s guidelines required reporting of local serious adverse drug reactions (ADRs). Four NMRAs implemented device vigilance; none specified submission timelines for ADRs associated with substandard or falsified medicines. Only three NMRAs required electronic transmission of individual case safety reports in the E2B format. Five NMRAs mandated safety monitoring during interventional clinical trials. Five NMRAs required aggregate reporting through periodic safety update reports. Only two NMRAs required submission of the development safety update report. Regarding risk management, four NMRAs required notification of actions taken by foreign NMRAs and four NMRAs expected to review Dear Healthcare Professional Letters before distribution by the marketing authorization holder. Areas for improvement of guidelines to establish common process standards and allow for synchronized submissions of comparable data to SADC NMRAs are provided.

Increasing Efficiency and Cost-Effectiveness by Automating the Authoring of the Development Safety Update Report.

A Development Safety Update Report (DSUR) is a comprehensive review of safety information collected during an annual reporting period for an investigational drug. The creation of a DSUR is a resource-intensive process, requiring effective communication among, and collaboration with, various functional stakeholders. To increase the efficiency and cost-effectiveness of generating a DSUR with the use of an electronic authoring platform. This computerized platform auto-populates the DSUR template using available source data. Requirements for the DSUR authoring tool were developed, and available data sources were mapped to respective sections of a company DSUR template. The DSUR authoring tool, mined, scanned, and extracted the relevant data from multiple-input source documents using Natural Language Processing logic. The data were then auto-populated into the template, as required by regulatory guidance ICH-E2F, with different text options based on questions and answers. The time- and cost-savings gained through automation were analyzed for DSURs authored during 2017-2019. The DSUR contains 31 sections (20 main sections and 11 sub-sections), of which 9 were fully automated, 12 were partially automated, and 10 were not automated in this release of the automation tool. Use of the DSUR automation tool resulted in a time-savings of approximately 25% per report, corresponding to a cost saving of US$4550 per report. Deployment of the automation tool reduced the time and cost required to manually produce DSURs, as well as improved the quality, compliance, and consistency of company-prepared DSURs. This tool enhanced the potential of the organization to generate larger volumes of DSURs in a timely manner, without requiring additional resources or compromising quality. This or a similar authoring automation tool could be employed in the future to generate other regulatory submission documents, which also require various source documents and cross-functional contributions.

Authoring a periodic adverse drug experience report…here's what you need to know!

Aggregate reporting involves preparation and submission of safety reports for a given medicinal product to worldwide regulatory agencies and constitutes an essential part of safety monitoring of a medicinal product. There are specific aggregate safety reports required for a molecule in development called development safety update reports while Periodic Adverse Drug Experience Reports (PADERs) and Periodic Safety Update Reports/Periodic Benefit-risk Evaluation Reports (PBRERs) are submitted for products with marketing authorization. Based on the periodic analysis of worldwide safety reports, product label is updated to optimize safe use of a medicinal product. PADERs are aggregate safety reports to be submitted to the Food and Drug Administration (FDA) for products approved for marketing in the United States (US). PADER submission starts once marketing authorization approval is received for a medicinal product by the sponsor. Quarterly and annual PADERs should be submitted within 30 and 60 days of data lock point, respectively. PADERs mainly involve presentation of case reports with serious unlisted events (15-day alert reports) in the form of narratives or in a tabular format. The present article focuses on the background, scope, structure of a PADER, and its submission timelines; lists differences between PADER and PBRER; and describes the knowledge, skills, and attitudes required for a PADER writer.

Deriving meaningful insights from clinical trial and postmarketing safety data: Perspectives from India.

Today, drug safety data collection in India is both manual and electronic with reporting of potential overlapping and duplicate data, which is likely incomplete for further review and analysis. Furthermore, standardized data collection and timelines are not aligned with international standards. Complete coverage of safety data from all sources throughout the life of the drug cannot be ensured. There is no requirement to submit periodic safety data in clinical trials to regulatory authority. There is clearly a lack of emphasis on deriving meaningful safety data insights for ensuring patient safety. Efforts toward the early detection of drug safety issues are minimal. There is no mandate to publicly disclose drug safety findings. Benefit-risk evaluation of investigational and marketed products cannot be assured merely through annual status reports and periodic safety update reports, respectively. Focused initiatives involving stakeholders from regulatory, health-care, and pharmaceutical industries are required to change the current situation and enable derivation of meaningful insights from safety data. Equal emphasis on assessing real-time safety of the drugs and protection of patients' rights, safety, and well-being is required. Periodic safety data reporting in clinical trials, proactive safety data collection related to potential safety concerns, electronic medical records, electronic expedited reporting, collection of targeted data from stakeholders, and standardized and harmonized data collection aligned to the International Council for Harmonization guidelines are required. The Central Drugs Standard Control Organization should implement requirements to submit Development Safety Update Reports, Periodic Benefit-Risk Evaluation Reports, and Risk Management Plans. Access to clinical trials and postmarketing safety data through central repository would enable researchers to explore the data for application in clinical practice.

PHARMACOVIGILANCE IN CLINICAL RESEARCH: PAST, PRESENT AND FUTURE

The growing clinical research after the product patents rights for the pharmaceutical industries as per the trade related aspects of intellectual property rights agreement and adverse drug reaction monitoring of the marketed drugs have raised many ethical and regulatory issues regarding the promotion of new drugs in Indian markets. It becomes vital to understand the history, growth and evolution of the regulatory aspects of drugs which are handled by multiple Ministries and Departments of the Government of India. Although amendment to Schedule Y, registration of Ethics committee, registration of Clinical Trials, Speeding up review process, Pharmacovigilance (PhV) programme for India and Inspection of clinical trial sites have been started by the various regulatory agencies. India’s growing partaking in multinational trials, this artifact explores potential areas of Indian pharmacovigilance, requiring reform and provides recommendations for building a robust safety reporting system. (1) Despite global focus on Development Safety Update Report, local regulators are not yet insistent on real-time update of a drug's cumulative safety profile. Issues like reporting requirements for generic trials, pregnancy reporting and lenient timeline for death/life-threatening events need attention. (2)

Statistical Analysis of Cumulative Serious Adverse Event Data From Development Safety Update Reports.

Monitoring safety in clinical trials by regulatory authorities and sponsors involves the clinical review, often subjectively, of large data sets of different types of safety information which may require considerable resources. This study investigated a means of statistically guided clinical review of safety data provided in the Cumulative Table of Serious Adverse Events of a Development Safety Update Report (DSUR). A simple statistical approach that treats every adverse event as independent of all others and uses a reference prior, which avoids infinite estimates of relative risk but does not unduly influence posterior inferences, was used with fixed rules of relative risk to identify a serious adverse event preferred term as a potential risk. This simple model, using cumulative serious adverse event (SAE) data from 5 DSURs, identified a small group of potential risks that included some not reported by the sponsor as well as most of those reported by the sponsor in the DSUR Summary of Important Risks. The method provides a systematic and objective approach to analysis of cumulative SAE data that could help to identify potential risks that need further investigation by a regulatory authority or sponsor.

Pharmacovigilance in Clinical Trials: Current Practice and Challenges

ABSTRACTIn view of the MENA increasing participation in multinational trials and the increasing number of national/regional trials, this article explores potential areas of pharmacovigilance, requiring reform and provides recommendations for building a robust safety reporting system. Regulatory silence on expedited reporting requirements creates confusion for local sites that are part of multinational trials. Not allowing waiver for serious adverse events that are protocol specified or are study endpoints, along with lack of emphasis on causality as reporting criteria, adds substantial burden of uninformative cases for regulatory review. Despite global focus on Development Safety Update Report, local regulators are not yet insistent on real-time update of a drug’s cumulative safety profile. Issues like reporting requirements for generic trials, pregnancy reporting and lenient timeline for death/life-threatening events need attention. Finally, the need to formulate an all-encompassing local pharmacovigilance guideline, in sync with global practice cannot be overemphasized.

Analysis of safety reporting requirements during medical device clinical trials in Japan

Regulatory convergence in safety reporting requirements for medical device clinical trials has not yet been achieved. The Global Harmonization Task Force (GHTF) issued new guidance, GHTF/SG5/N5, on this topic in August 2012. First, we compared current reporting requirements for drug and medical devices in Japan with the international guidelines International Conference on Harmonization (ICH)-E2A/E2F and GHTF/SG5/N5. As a result, we confirmed that Japan's expedited reporting requirements are nearly the same for drugs and medical devices and that these requirements are similar to those described in ICH-E2A. We also found that GHTF/SG5/N5 differs from the ICH-E2A in several ways. We sorted these differences into three categories: reportable events, reporting time frame, and definitions of terms. Although there are several equivalent terms between the ICH and GHTF guidelines, the terms Serious Health Threat and Device Deficiency are only defined in GHTF/SG5/N5. The reporting time frame for a Serious Adverse Event is either 10 or 30days for medical devices; expedited reporting is not required according to ICH-E2A, but it is covered in the annual Development Safety Update Report in ICH-E2F. GHTF/SG5/N5 recommends substantially stricter requirements than the current requirements in Japan. Therefore, the Ministry of Health, Labour and Welfare (MHLW) seemed to have prioritized the introduction of consistent definitions of terms while maintaining the current reporting time frame, rather than introducing GHTF guidance as it is. This policy is in accordance with the draft proposal on the revision of safety reporting requirements issued by MHLW in October 2012.

Using Resources for Scientific-Driven Pharmacovigilance

Current regulations require a description of the overall safety profile or the specific risks of a drug in multiple documents such as the Periodic and Development Safety Update Reports, Risk Management Plans (RMPs) and Signal Detection Reports. In a resource-constrained world, the need for preparing multiple documents reporting the same information results in shifting the focus from a thorough scientific and medical evaluation of the available data to maintaining compliance with regulatory timelines. Since the aim of drug safety is to understand and characterize product issues to take adequate risk minimization measures rather than to comply with bureaucratic requirements, there is the need to avoid redundancy. In order to identify core drug safety activities that need to be undertaken to protect patient safety and reduce the number of documents reporting the results of these activities, the author has reviewed the main topics included in the drug safety guidelines and templates. The topics and sources that need to be taken into account in the main regulatory documents have been found to greatly overlap and, in the future, as a result of the new Periodic Safety Update Report structure and require-ments, in the author’s opinion this overlap is likely to further increase. Many of the identified inter-document differences seemed to be substantially formal. The Development Safety Update Report, for example, requires separate presentation of the safety issues emerging from different sources followed by an overall evaluation of each safety issue. The RMP, instead, requires a detailed description of the safety issues without separate presentation of the evidence derived from each source. To some extent, however, the individual documents require an in-depth analysis of different aspects; the RMP, for example, requires an epidemiological description of the indication for which the drug is used and its risks. At the time of writing this article, this is not specifically required by other documents. The author has identified signal detection (intended not only as adverse event disproportionate reporting, but including non-clinical, laboratory, clinical analysis data and literature screening) and characterization as the basis for the preparation of all drug safety documents, which can be viewed as different ways of presenting the results of this activity. Therefore, the author proposes to merge all the aggregate reports required by current regulations into a single document — the Drug Safety Master File. This report should contain all the available information, from any source, regarding the potential and identified risks of a drug. It should be a living document updated and submitted to regulatory authorities on an ongoing basis.

Pharmacovigilance for clinical trials in India: Current practice and areas for reform

Keeping in mind India’s increasing participation in multinational trials, this article explores potential areas of Indian pharmacovigilance, requiring reform and provides recommendations for building a robust safety reporting system. Internal discrepancies exist between Schedule Y and Central Drugs Standard Control Organisation approval letter regarding what to report. Schedule Y’s silence on expedited reporting requirements creates confusion for Indian sites that are part of multinational trial. Not allowing waiver for serious adverse events that are protocol specified or are study endpoints, along with lack of emphasis on causality as reporting criteria, adds substantial burden of uninformative cases for regulatory review. Despite global focus on Development Safety Update Report, Indian regulators are not yet insistent on real-time update of a drug’s cumulative safety profile. Issues like reporting requirements for generic trials, pregnancy reporting and lenient timeline for death/life-threatening events need attention. Finally, the need to formulate an all-encompassing pharmacovigilance guideline for India, in sync with global practice cannot be overemphasized.

The Development Safety Update Report

This article provides a critical review of the Step 2/3 International Conference on Harmonisation (ICH) E2F guidance on the Development Safety Update Report (DSUR) and examines its contents in relation to current requirements in the US and EU. The DSUR will provide a yearly update on the safety information for compounds in clinical development in addition to providing information on total exposure in the clinical trial programme, actions taken for managing safety risks and statements on the benefit-risk balance for clinical trials undertaken in the clinical development programme. The proposedDSURwill essentially cover all requirements of the existing periodic reports required during clinical development in the US and EU. The organization of the DSUR is similar to that of the postmarketing Periodic Safety Update Report but the DSUR will require additional fields and sources of data and it makes use of several region-specific appendices. Special attention is given in this article to challenges in implementing the DSUR concept including the varieties of data required, the amount of information from the DSUR to be provided to Ethics Committees and the impact of the incomplete international harmonization proposed by the ICH E2F guidance.

Development Safety Update Reports and Proposals for Effective and Efficient Risk Communication

The periodic safety reporting to regulatory authorities is globally harmonized for postmarketing medicinal products by the International Conference on Harmonisation (ICH) guidelines, and is being extended for investigational drugs. To facilitate effective safety risk communication regarding investigational drugs, and to reduce duplicate periodic reporting to the US and EU by sponsors during development programmes, standardized Development Safety Update Reports (DSURs) are to be implemented in the near future. In this current opinion article, after extensively reviewing the relevant report from the CIOMS VII Working Group and the ICH draft guideline regarding DSURs, we discuss an effective and efficient approach to its application. To ensure effective risk communication, we recommend that DSURs be made available to all the ethics committees and participating investigators around the world for the purpose of continuing review during ongoing clinical trials. Furthermore, in order to maintain the consistency and integrity of safety information throughout the life-cycle of a drug, we believe it would be substantially more prudent and efficient to start a single, integrated, life-cycle periodic safety report covering both development and postmarketing, as proposed by the CIOMS VII Working Group, rather than maintain separate DSURs and Periodic Safety Update Reports, which can overlap considerably in content. To this end, we believe that the international regulatory community should undertake the new initiative for integrated periodic reporting immediately.

The Development Safety Update Report

This article gives an overview of the current status of the development safety update report (DSUR) guideline, provides a rationale for some of the key sections of the report and highlights the practical implications of its implementation for clinical trial sponsors and other parties. The DSUR aims to provide a periodic analysis of the evolving safety profile of an investigational drug, and actions proposed or being taken to address safety concerns during the clinical development of an investigational drug. The draft guideline, published for consultation in mid-2008 in the International Conference on Harmonisation regions of Europe, Japan and the US, is intended to be the common standard for the format, content and timing of annual safety reports to regulators, replacing existing reports such as the US investigational new drug annual report and the EU annual safety report.