Periodic Safety Reporting for Ongoing Clinical Trials: IND Annual Reports, DSURs and EU CTR Annual Safety Reports

Periodic reporting for ongoing clinical trials: IND annual reports, DSURs and EU CTR annual safety reports

Sponsors running multinational development programmes have to meet two layers of reporting. The first is expedited reporting of individual cases, such as IND safety reports and SUSARs. The second is periodic aggregate reporting, which is the subject of this article. Since ICH E2F, the Development Safety Update Report (DSUR) has served as the common format for the second layer. FDA accepts it in place of the IND annual report, the EU requires its format for the annual safety report (ASR) under Regulation (EU) No 536/2014, and the MHRA requires it by name. The details still differ by jurisdiction: who receives the report, when the obligation starts and stops, which trials and products it covers, and whether a routine submission is required at all.

Key points

• ICH E2F DSUR: an annual report keyed to the Development International Birth Date (DIBD). It is due no later than 60 calendar days after the data lock point ²⁴⁵²⁴⁷.
• FDA: 21 CFR 312.33 requires an IND annual report within 60 days of the IND anniversary date ¹⁷³. FDA will accept a DSUR prepared under E2F to meet that requirement ³³⁵.
• EU CTR: Article 43 requires an annual safety report for each investigational medicinal product (IMP) other than placebo, submitted to EMA through the EU database ¹⁵¹⁶. It must follow ICH E2F format and is submitted via CTIS ³⁶⁶³⁶⁹.
• UK: the sponsor submits a DSUR for each IMP to the MHRA (not to the ethics committee) within 60 calendar days of the end of the reporting year ²⁹⁰³⁰¹.
• Canada and Australia: neither regulator states a routine annual DSUR filing to the regulator in the passages reviewed. Australia's TGA receives annual safety reports on request ¹⁵³. In Health Canada's guidance, DSURs appear as standalone documents that may be provided to the review directorates, and Health Canada can request safety information at any time ⁴²⁰¹⁰⁷.
• Switzerland: the annual safety report goes to the ethics committee, and also to Swissmedic for Category B and C trials ⁴²⁵⁴²⁶.

ICH E2F: the harmonised DSUR

Purpose and scope

ICH E2F defines the DSUR as an annual report on the safety of a drug under development, including a marketed drug that is still being studied ¹⁶⁷. Its purpose is to review the safety information collected during the reporting period and assess it against what was already known. It should identify new issues that affect the protection of trial subjects and update the understanding and management of risks ²⁴¹²⁴². The report focuses on interventional clinical trials of investigational drugs and biologicals, whether or not they are marketed. It also takes in relevant post-marketing information and other significant safety findings ²⁴³²⁴⁴.

E2F was written as a common annual reporting standard for the ICH regions. US and EU regulators considered that an annually submitted DSUR would meet the requirements then met by the US IND Annual Report and the EU Annual Safety Report, and could replace them. Japan said it would consider its existing periodic safety reporting rules when implementing the DSUR ¹⁶⁷¹⁶⁸.

Periodicity, data lock point and deadline

• DIBD: the date of the sponsor's first authorisation to conduct a clinical trial anywhere in the world. Its month and day set the start of each annual reporting period. If the first trial runs where there is no formal authorisation process, the sponsor designates a date linked to the trial's start ²⁴⁵.
• Data lock point (DLP): normally the last day of the one-year period. For administrative convenience, the sponsor may instead use the last day of the month before the DIBD month ²⁴⁶.
• Deadline: no later than 60 calendar days after the DLP, to all concerned regulatory authorities ²⁴⁷.
• Duration: DSURs continue for as long as national or regional law requires. When a country or region no longer requires an annual report, the sponsor marks the DSUR as the final one for that jurisdiction and states whether trials are continuing elsewhere ²⁴⁸.

Content

The E2F structure has 20 sections. The early sections cover worldwide marketing approval status, actions taken for safety reasons, changes to the reference safety information, the inventory of ongoing and completed trials, and estimated cumulative exposure ²⁰⁶²⁰⁷. The middle sections cover line listings and summary tabulations; significant findings from clinical trials, non-interventional studies and marketing experience; non-clinical data; literature; and lack of efficacy ^207208209. The report closes with region-specific information, late-breaking information, an overall safety assessment that includes benefit-risk considerations, a summary of important risks, and conclusions ^209210211212.

Regional appendices carry national requirements. For the US IND these include cumulative serious adverse reaction tabulations, lists of subjects who died or dropped out, significant Phase 1 protocol modifications, significant manufacturing changes, the general investigational plan for the coming year, and an optional log of outstanding IND business ¹⁷¹²¹⁴. Sponsors should check the applicable national or regional requirements to decide which sections to include and which trials to cover ¹⁶⁹.

FDA

IND annual report (21 CFR 312.33)

The regulation requires a brief progress report within 60 days of the anniversary of the date the IND went into effect ¹⁷³. The required contents are:

1. Individual study information: for each study in progress or completed during the year, its status, purpose and population; enrolment to date by age group, gender and race; dropouts; and any available results ¹⁷⁴.
2. Summary information: the most frequent and most serious adverse experiences by body system, all IND safety reports, deaths and their causes, dropouts associated with adverse experiences, preclinical findings, and significant manufacturing or microbiological changes ¹⁷⁵.
3. General investigational plan for the coming year ¹⁷⁶.
4. Investigator's brochure: a description of any revision and a copy of the new brochure ¹⁷⁷.
5. Phase 1 protocol modifications not previously reported in a protocol amendment ¹⁷⁸.
6. Foreign marketing developments, such as approvals, withdrawals or suspensions ¹⁷⁹.
7. Outstanding business log (optional) ¹⁸⁰.

Using the DSUR in place of the IND annual report

FDA's guidance on E2F describes the DSUR as a common standard for annual reporting that can take the place of the US IND annual report ³³⁴. FDA's IND safety reporting guidance confirms that the safety reporting rule did not change § 312.33. It also states that FDA will accept a DSUR prepared as described in E2F to meet the IND annual report requirement ³³⁵. In that case, the US-specific § 312.33 elements (Phase 1 protocol changes, the investigational plan, and the outstanding business log) go in the E2F regional appendices ¹⁷¹²¹⁴.

Aggregate safety review between annual reports

Annual reporting does not replace ongoing aggregate review under the IND safety reporting rule:

• Expedited reports: IND safety reports are due within 15 calendar days of the sponsor determining that information qualifies for reporting, and within 7 calendar days for unexpected fatal or life-threatening suspected adverse reactions ³⁸¹³⁸².
• Aggregate findings: an aggregate analysis showing that events occur more often in the drug group than in a control group can trigger reporting. So can pooled findings that suggest a significant risk ³⁸³³⁸⁴.
• FDA's recommended approach: FDA's final guidance on sponsor safety responsibilities recommends a prospective safety surveillance plan, with accumulating SAE data reviewed at regular intervals across the whole programme ⁶⁴⁶⁵⁶⁶. Where no specific concern exists, it gives every six months as an example interval, adjusted to data volume, accrual and event rates ⁷⁰.

Devices: IDE progress reports (21 CFR 812.150)

Device sponsors working under an IDE have a different set of periodic obligations:

• Sponsor progress reports: to all reviewing IRBs at least yearly, and also to FDA for significant-risk devices ²²⁴.
• Treatment IDEs: semi-annual progress reports to IRBs and FDA, in addition to annual reports ²²⁵.
• Investigator list: a current list of investigators to FDA every six months ²²⁹.
• Investigator reports: progress reports to the sponsor, monitor and IRB no less often than yearly, and a final report within 3 months of completion ^216217222.

European Union: annual safety report under the CTR

Legal requirement (Article 43 and Annex III)

Article 43 of Regulation (EU) No 536/2014 makes the sponsor submit a safety report every year, through the EU database, to EMA. One report is required for each IMP other than placebo used in the sponsor's trials, and it contains only aggregate, anonymised data ¹⁵¹⁶. The obligation starts with the first authorisation of a trial under the Regulation. It ends when the sponsor's last trial with that IMP ends ¹⁷. Where a single trial uses more than one IMP, one report covering all of them is allowed if the protocol provides for it and gives the reasons ¹⁸¹⁹.

Annex III, section 3 requires the reference safety information (RSI) in effect at the start of the reporting period to be appended to the report. That RSI applies for the whole period. If it changes significantly during the period, the report lists the changes and appends the revised RSI as well ⁴⁷⁵⁴⁷⁶.

Format, timing and submission (CTR Q&A)

The Commission's CTR Q&A sets out the following:

• Format and language: content and format follow ICH E2F and Annex III section 3, written in English. The ASR is an annual review and is not the way to notify significant new safety information for the first time ^366367368.
• Route: the ASR goes through CTIS. Individual SUSARs go to EudraVigilance. Separate submissions to ethics committees are not foreseen ³⁶⁹³⁷⁰.
• Timing: the reporting period runs from the DIBD. The DLP is the last day of the one-year period, or the last day of the month before the DIBD month, and the ASR is due within 60 days of the DLP ⁵⁴⁸⁵⁴⁹.
• PSUR synchronisation: the ASR may be aligned with a PSUR using the PSUR International Birth Date, provided the next ASR covers no more than one year ⁵⁵⁰.

Simplified ASRs

CTR Q&A question 7.43 allows simplified content only for non-commercial sponsors, in two cases:

• Single trial with authorised IMPs: a single trial using authorised IMPs, with SmPC section 4.8 as the RSI. A CTCG template applies ⁵³⁸.
• Inactive trials: trials that have not started, or that have all been halted for more than a year with no administration of the IMP. A short statement is enough. It must cover the trial status, a literature and IB/SmPC review, the benefit-risk ratio, and whether the protocol or consent materials need updating ⁵³⁹⁵⁴⁰.

A full E2F-compliant ASR is required in all other cases, including when the criteria are only partly met ⁵⁴¹. A separate Commission quick guide for sponsors describes simplified reporting for low-intervention trials and trials with authorised IMPs ⁵⁴². In practice, sponsors should check eligibility against the Q&A wording.

Related CTR reporting obligations

• SUSARs (Article 42): fatal or life-threatening SUSARs within 7 days and others within 15 days ³¹. An incomplete initial fatal or life-threatening report may be completed within a further 8 days ³²³³.
• Summary of results (Article 37): due in the EU database within one year of the end of the trial in all Member States concerned, with a lay summary ³⁵.
• Clinical study report: where the trial supported a marketing authorisation application, the CSR is due within 30 days of the authorisation, completion of the procedure, or withdrawal ³⁷.

Trials still running under Directive 2001/20/EC fall under the CT-3 guidance. CT-3 also refers to ICH E2F, but there the report goes to the national competent authority and the ethics committee, and it is submitted in a Member State only while subjects are being treated there ^373374375.

United Kingdom (MHRA)

MHRA guidance on the UK Clinical Trials Regulations (regulations A32 and 35) sets the following requirements:

• Scope: the sponsor provides an annual safety report in DSUR form for each IMP tested in a UK trial, including notifiable trials. One DSUR may cover several trials of the same IMP ²⁹⁰²⁹¹.
• Exceptions: non-IMPs, and an IMP used in a single trial that lasts less than a year and ends before the reporting year closes ²⁹².
• Timing and recipient: the DSUR goes to the licensing authority, not the ethics committee, within 60 calendar days of the day after the reporting year ends. Annual submissions continue until no UK trials of the IMP remain ongoing ²⁹³³⁰¹.
• Content: the DSUR follows the E2F section 3 headings ²⁹⁵. It must include safety data from non-UK trials of the same IMP run by the same sponsor, a sponsor in the same corporate group, or a co-development partner ²⁹⁷. SAR line listings are strongly recommended, and may be omitted only with justification ²⁹⁸³⁹⁰. The RSI in effect at the start of the period goes in an appendix ²⁹⁹.
• Other reports: the MHRA no longer accepts annual progress reports and directs sponsors to the relevant DSUR sections instead ²⁷⁶. End-of-trial notification is due within 90 days, or within 15 days if the trial ends early ²⁷⁸. Summary results are expected within one year of the end of the trial ²⁸⁰.

Other regulators

Health Canada

In the Health Canada guidance reviewed, DSURs appear among documents that may be provided to the review directorates as standalone documents outside a submission ⁴²⁰. The clinical trial guidance says Health Canada may request safety information at any time during a trial. A requested report could include a listing of all serious and other adverse drug reactions ¹⁰⁷. The Investigator's Brochure should be reviewed at least once a year, and sectional reports should not be submitted unless Health Canada asks for them ¹⁰⁶. Expedited reporting under C.05.014 applies to serious unexpected ADRs, whether they occur inside or outside Canada. Fatal or life-threatening cases are due within 7 days, with a complete report within a further 8 days. Other serious unexpected ADRs are due within 15 days ⁵²⁴.

Australia (TGA and HRECs)

The Australian clinical trial handbook lists DSURs or other annual safety reports for all therapeutic goods as documents provided to the TGA on request ¹⁵³. The main periodic obligation is to ethics review bodies:

• National Statement reporting: researchers report to the reviewing HREC and the institution at least annually and at project completion ⁴³⁹.
• Condition of approval: for clinical trials, continued ethics approval depends on providing progress and safety reports as indicated by NHMRC guidance ⁴⁴³.
• Urgent safety measures: for trials under the CTN or CTA schemes, significant safety issues involving an urgent safety measure are reported to the TGA within 72 hours ⁴⁶⁰.

Switzerland

ClinO Article 43 requires an annual report on participant safety, sent to the responsible ethics committee. It contains:

• a list of events, product deficiencies and adverse reactions, with an assessment of severity, causality and implications for safety;
• a description of the trial's general progress;
• relevant events abroad where the same protocol is used outside Switzerland ⁴²⁵.

For Category B and C trials, the report also goes to Swissmedic ⁴²⁶.

ClinO-MD sets a parallel annual safety report for device investigations. It covers serious adverse events and device deficiencies ⁴⁴⁶. For Category C investigations it also covers events abroad and the trial's status in the EU or EEA ⁴⁴⁷⁴⁴⁸. Non-substantial modifications are notified together with the annual safety report ⁴⁴⁹.

Japan

Japan's implementing notification states that DSURs prepared under the guideline will be used for periodic reporting under Article 273(3) of the Enforcement Regulations of the Pharmaceutical Affairs Law ⁵¹¹⁵¹². Where national rules require an annual safety report to an ethics committee or IRB, the guideline calls for the DSUR executive summary, with a line listing of serious adverse reactions where warranted ⁵¹⁵.

Comparison at a glance

Practical considerations for sponsors

• One DIBD across jurisdictions. The US, EU, UK and Japan all key their reports to the E2F structure ^335366295511. A single DSUR on one DIBD-based cycle, with regional appendices, can usually meet the core requirement in each.
• Start and end dates differ. The EU obligation runs from the first trial authorised under the CTR to the end of the sponsor's last trial with the IMP ¹⁷. The UK obligation continues until no UK trials of the IMP remain ²⁹³. The US obligation follows the IND anniversary unless a DSUR is used in its place ¹⁷³³³⁵.
• Recipients differ. EU and UK reports go to the regulator, not ethics committees ³⁷⁰³⁰¹. Swiss and Australian frameworks put more weight on ethics committee reporting ⁴²⁵⁴³⁹.
• Annual reports do not replace prompt notification. The ASR is not the vehicle for new safety signals ³⁶⁸. FDA expects aggregate review on a regular cadence through the year ⁷⁰.
• Devices follow separate rules. IDE progress reports (21 CFR 812.150) and ClinO-MD annual safety reports have their own content and recipient requirements, outside the drug DSUR framework ²²⁴⁴⁴⁶.