2.1 Introduction
When a company or academic institution is granted permission to test a yet to be authorized medicinal product on human subjects (or an authorized medicinal product in a new patient population/indication), the sponsor of the said clinical study undertakes a legally binding obligation to provide annually to the regulatory authority, an aggregated analysis of all serious adverse drug reactions (SARs), as well as serious adverse events (SAEs) and events leading to subject withdrawal in the US, recorded from the clinical study. This is in addition to standard reporting of individual reactions in accordance with the mandated timelines. The requirement for submission of these annual reports continues until completion of the clinical studies, and is intended as an opportunity for the clinical study sponsor, ethics committees, or institutional review boards, and regulatory authorities to review and monitor the safety of subjects participating in the clinical studies.
Up until August 2011, these documents, their content, and purpose differed between the EU and US regions, with submission of the EU Annual Safety Report (ASR) and US Investigational New Drug (IND) Annual Report, respectively. The EU ASR served as an annual benefit-risk assessment exercise, and thus differed from the US IND Annual Report, which essentially functioned as an annual progress report to the Food and Drug Administration (FDA). A comparative summary of the EU ASR and US IND Annual Report is presented in Table 2.1.
Table 2.1 The EU ASR and US IND Annual Report.
| EU ASR | US IND Annual Report |
| Functions as benefit-risk assessment | Functions as progress report of the clinical program |
| Only SARs included in analysis | Includes SAEs, AEs leading to study withdrawal, and expedited safety reports |
| Covers all EU-based clinical studies and clinical studies undertaken by an EU sponsor in non-EU countries | Only covers US-based clinical studies |
| AE = adverse event; ASR = Annual Safety Report; EU = European Union; SAE = serious adverse event; SAR = serious adverse reaction; US = United States; IND = Investigational New Drug | |
However, it is no secret, that pharmacovigilance medical writing during clinical development is currently undergoing a period of transition. The EU ASR and US IND Annual Report have both been replaced by the Development Safety Update Report (DSUR), a single harmonized document that integrates both jurisdictional requirements for annual reporting of clinical trial safety data. This removes the duplication of reports to be prepared by multinational companies simultaneously sponsoring clinical studies for the same medicinal product in both regions.
In addition to integration of EU and US requirements for annual reporting from clinical studies, the DSUR also extends the scope of reviewed safety data, with the inclusion of safety information from sources not included in the EU ASR and US IND Annual Report (e.g. data from observational and epidemiological studies, patient registries, and compassionate use programs), and thereby allowing for a more comprehensive assessment of the medicinal product’s safety profile.
In the EU, guidelines regarding the DSUR were adopted by the Committee for Medicinal Products for Human Use (CHMP) in September 2010 and came into effect in EU countries on 1 September 2011, after which submission of the ASR was replaced by the DSUR in that jurisdiction. Similarly, the FDA issued notice in August 2011, indicating that the DSUR could be submitted in place of the IND Annual Report.
Accordingly, discussion of the EU ASR and US IND Annual Report in this chapter is kept to a minimum, intended only to provide a historical perspective, thereby offering the PV Medical Writer some insight into how these documents have evolved into the DSUR. Therefore, the emphasis is placed on the DSUR and the practicalities of preparing this report.
2.2 The EU Annual Safety Report and US IND Annual Report – A Historical Look at Reporting from Clinical Studies
2.2.1 The EU Annual Safety Report
The EU ASR was born out of the Clinical Trials Directive of 2001 [1], which came into effect on 1 May 2004, and sought to standardize the conduct of clinical trials throughout the EU. This directive had a wide ranging impact on pharmacovigilance functions, including the introduction of annual safety reporting for medicinal products in clinical development (including authorized medicinal products investigated in new indications). The EU ASR was intended to function as a mechanism through which regulatory authorities, ethics committees, and institutional review boards could periodically monitor the safety of subjects participating in clinical trials.
As a document, the ASR presented a concise summary of all relevant new safety information for the clinical trials in question and, in accordance with guidance from the European Commission [2], was generally structured to consist of three parts, as summarized in Table 2.2.
Table 2.2 Structure of the EU ASR.
| ASR Part | Data Component |
| Part 1 | Analysis of the subjects’ safety in the concerned clinical studies |
| Part 2 | Appendix – a line listing of all suspected SARs (including SUSARs) reported from the clinical studies |
| Part 3 | Appendix – an aggregate/cumulative summary tabulation of suspected SARs reported from the clinical trial(s) |
| ASR = Annual Safety Report; EU = European Union; SAR = serious adverse reaction; SUSAR = suspected unexpected serious adverse reaction | |
Submission of ASRs to the relevant regulatory authority (e.g. the Medicines and Healthcare products Regulatory Agency [MHRA] in the UK) and ethics committees was required 60 days after the annual cut-off date, which was the anniversary of the Clinical Trials Authorization (CTA; i.e. permission to conduct clinical investigations). For clinical studies involving products that were also marketed, the annual cut-off date was synchronized to the International Birth Date (IBD) used for Periodic Safety Update Reports (PSURs; see Chapter 5: Pharmacovigilance Medical Writing for Marketed Products), although the authorities required that the PSUR and ASR remained as separate and stand-alone documents. If the clinical study sponsor was conducting several studies with the same investigational medicinal product (IMP) in a number of different EU Member States, a single ASR was used for all concerned clinical studies.
A summary of source data for the EU ASR is presented in Table 2.3.
Table 2.3 Source data for the EU ASR.
| ASR Data | Data Source |
| Studies | Clinical Operations provide the following information on clinical studies: – Details of all clinical studies started, ongoing, or completed during the ASR review period (i.e. EU and non-EU) – Status update on each clinical study (i.e. number of subjects planned, recruited, and exposed to treatment) Non-clinical R&D provide the following information on non-clinical studies: – Details of any safety related findings from pharmacology and toxicology studies |
| Safety Data – Line listing – Summary tabulation | Drug Safety (Pharmacovigilance); the following line listings and summary tabulations of all SARs: – A line listing of all SARs (including SUSARs) from all relevant clinical studies (i.e. EU and non-EU) – An aggregate tabulation of all SARs (including SUSARs) from all relevant clinical studies (i.e. EU and non-EU) – CIOMS reports (for the PV Medical Writer’s information) |
| Changes to the RSI – IB – SmPC | Medical Writing for changes to the IB Drug Safety (Pharmacovigilance) for changes to the SmPC |
| Changes to Clinical Study Documentation – Protocol Amendments – IB/SmPC | Clinical Operations Medical Writing Drug Safety (Pharmacovigilance) |
| Other Data – Protocol Amendments – IB/SmPC | Clinical Operations Medical Writing Drug Safety (Pharmacovigilance) |
| ASR = Annual Safety Report; CIOMS = Council for International Organizations of Medical Sciences; EU = European Union; IB = Investigator’s Brochure; ICH = International Conference on Harmonisation; R&D = Research & Development; RSI = Reference Safety Information; SAR = serious adverse reaction; SmPC = Summary of Product Characteristics; SUSAR = suspected unexpected serious adverse reaction | |
2.2.1 The US IND Annual Report
Submission of a US IND Annual Report to the FDA and investigators was mandated in the FDA’s Code of Federal Regulations (CFR), namely 21CFR312.33 [3], and required annually from the first anniversary of the IND (i.e. authorization from the FDA to administer an IMP to clinical subjects) until withdrawal of the IND or submission of final clinical study reports for all trials filed to the IND.
The US IND Annual Report differed from the EU ASR in that it served as a progress report of the clinical development program for a given IMP, to the FDA and investigators, unlike the EU ASR, which functioned as a benefit-risk assessment for the ongoing clinical studies. Unlike the EU ASR that only presented data on SARs, the US IND Annual Report included data on all SAEs, deaths, expedited safety reports (ESRs), and adverse events (AEs) leading to withdrawal. In further contrast to the EU ASR, which required inclusion of AEs from studies with the same IMP that were ongoing globally (i.e. in the EU as well as third-party countries), the US IND Annual Report only required inclusion of AE data from US-based clinical studies. The US IND Annual Report comprised seven parts, as summarized in Table 2.4.
Table 2.4 Structure of the US IND Annual Report.
| IND Annual Report Part | Data Component |
| Part 1 | Individual Study Information, including: – study status – subject recruitment – demographics |
| Part 2 | Summary Information, including: – SAEs – deaths – AEs leading to withdrawal – submitted IND safety reports – non-clinical studies – significant manufacturing or microbiological changes |
| Part 3 | General Investigative Plan for the Next Year |
| Part 4 | IB (including a summary of changes with rationale) |
| Part 5 | Phase I Protocol Modifications Made |
| Part 6 | Summary of Foreign Marketing Developments |
| Part 7 | Outstanding Business |
| AE = adverse event; IB = Investigator’s Brochure; IND = Investigational New Drug; SAE = serious adverse event | |
Like the EU ASR, submission of the US IND Annual Report to the FDA was required 60 days after the annual cut-off date, which was the anniversary of the IND. A summary of source data for the US IND Annual Report, with the departments charged with provision of these data, is presented in Table 2.5.
Table 2.5 Source data for the US IND Annual Report.
| IND Annual Report Data | Data Source |
| Studies | Clinical Operations provide the following information on US clinical studies for the review period: – Details of all clinical studies ongoing or completed during the reporting period (including study title, protocol number, and study objectives) – Status update on each clinical study (i.e. number of subjects planned, recruited, and exposed to treatment) Clinical Operations also provide a summary of the investigative plan for the next year Non-clinical R&D provide the following information on non-clinical studies: – A list of all ongoing or completed non-clinical studies (including animal studies), with a summary of any significant findings |
| Safety Data | Data Management and Statistics provide the following line listing and summary tabulations for the concerned US studies and review period: – A tabulation of SAEs by PT frequency and by SOC and PT – A tabulation of all cases with a fatal outcome – A tabulation of all AEs leading to study withdrawal Drug Safety (Pharmacovigilance) provide the following line listing and summary tabulations for the concerned US studies and review period: – A line listing of all IND safety reports submitted to the FDA – CIOMS reports for all cases (for the PV Medical Writer’s information) |
| Significant Changes to Manufacturing/Microbiology | Manufacturing and Clinical Operations |
| Changes to the IB | Medical Writing |
| Phase I Protocol Modifications | Medical Writing and Clinical Operations |
| Significant Foreign Marketing Developments | Regulatory Affairs & Drug Safety (Pharmacovigilance) |
| AE = adverse event; CIOMS = Council for International Organizations of Medical Sciences; FDA = Food and Drug Administration; IB = Investigator’s Brochure; IND = Investigational New Drug; PT = preferred term; R&D = Research and Development; SAE = serious adverse event; SOC = System Organ Class; US = United States | |
2.3 The Development Safety Update Report
2.3.1 The DSUR – Regulatory Guidelines and General Principles
The genesis of the DSUR emanated from a desire to harmonize the content of the annual clinical development safety update reports for the EU (i.e. the EU ASR) and US (i.e. the US IND Annual Report), as well as provide scope for a more extensive analysis of the collated safety data.
Of particular note, the structure of the DSUR has been designed to mirror that of the PSUR, both in presentation and terminology, although it is somewhat more flexible and allows for the provision of EU- and US-specific information and appendices.
Unlike the EU ASR and US IND Annual Report, which were scheduled according to the date of first authorization of a clinical study in any EU Member State and IND anniversary date, respectively, the DSUR (akin to the PSUR) uses a single international birth date, referred to as the development international birth date (DIBD) to distinguish it from the PSUR international birth date, and has thus harmonized submission in all regions.
As a means of expanding the scope of safety information reviewed and reported to the authorities during clinical development, the DSUR includes analysis of the following data from sources not currently included in the EU ASR or US IND Annual Report:
- reports describing lack of efficacy for serious or life-threatening indications;
- relevant findings from observational and epidemiological studies;
- clinical and non-clinical studies from published literature (including conference abstracts and posters);
- safety findings relating to ‘therapeutic’ or ‘class effect;’
- relevant safety findings from licensing partner studies;
- safety findings from investigator led/initiated studies;
- solicited data from organized data collection schemes, including patient registries and compassionate use programs.
The content and structure of the DSUR was proposed by the CIOMS VII Working Group [4], and is described in ICH E2F [5] guidelines. The general principles of the DSUR are summarized in Table 2.6.
Table 2.6 General principles of the DSUR.
| Principle | Description |
| Scope of Data | The DSUR includes safety data from: – Interventional and post-marketing studies – Expanded access programs, compassionate use programs, and named patient use The DSUR includes significant findings relevant to safety from: – Observational or epidemiological studies – Non-clinical studies – DSURs for related products – Manufacturing or microbiological changes – Studies published in the literature – Studies reporting lack of efficacy – Products of the same therapeutic class and licensing partner trials (if permitted) |
| One DSUR One Active | A single DSUR is prepared for all dosage forms, and strengths of the IMP, regardless of the investigated indications and studied patient populations. Submission of a single DSUR is encouraged, even when development of the IMP is undertaken by more than one company. |
| RSI | The RSI for the DSUR is the IB in effect at the start of the reporting period. If an IB was not required as part of the IND submission documents, the local product label (e.g. SmPC or Package Insert) could be used in place of the IB. |
| DIBD | The date of the sponsor’s first authorization to undertake a clinical study with the IMP in any country. |
| DLP | The date of data cut-off for a DSUR review period, which should be the last day of the 1-year reporting period. When clinical development continues after the medicinal product is marketed, the DSUR can be prepared according to the PSUR IBD, which is the date of first marketing authorization, so that the preparation of both reports is synchronized; however, the review period for the DSUR would not be permitted to exceed 1 year. |
| DIBD = Development International Birth Date; DLP = Data Lock Point; DSUR = Development Safety Update Report; EU = European Union; IB = Investigator’s Brochure; IBD = International Birth Date; IMP = Investigational Medicinal Product; IND = Investigational New Drug; PSUR = Periodic Safety Update Report; RSI = Reference Safety Information; SmPC = Summary of Product Characteristics | |
2.3.2 Scheduling and Periodicity – When are DSURs Prepared?
The DSUR should be submitted to the relevant regulatory authorities within 60 days of the DSUR DLP (i.e. data cut-off date for a DSUR review period).
2.3.3 Data Sources for the DSUR
The data required for preparation of a DSUR and the sponsor functions charged with provision of these data to the PV Medical Writer are outlined in Table 2.7.
Table 2.7 Source data for the DSUR.
| DSUR Data | Data Source |
| Safety Data – Line listings – Summary tabulations | Drug Safety (Pharmacovigilance); the following line listings and summary tabulations are required for the EU region: – Line listing of SARs reported during the 1-year review period – Cumulative summary tabulation of SAEs reported since the DIBD Region-Specific Appendices – Cumulative summary tabulation of SARs reported since the DIBD < div class='tao-gold-member'>
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