Reporting of serious adverse events (SAEs) and device deficiencies (DDs) for clinical investigations

SAE and DD reporting obligations according to MDR and MPDG

Since the MDR comes applicable on 26.05.2021, the reporting of serious adverse events (SAEs) and device deficiencies (DDs) must be carried out in accordance with the European Regulation 2017/745 (MDR) in conjunction with the Medical Devices Law Implementation Act (“Medizinprodukterecht-Durchführungsgesetz”, MPDG) for all clinical investigations that must be applied for or notified to the federal higher authority.

This also applies to clinical investigations that were commenced under the legal framework of the MPG (MDD) and are considered to have been initiated within the meaning of Section 99 (3) - (5) MPDG when the MDR came applicable on 26.05.2021 and for which SAEs were previously to be reported to the federal higher authority in accordance with the MPSV.

Only performance studies of in vitro diagnostic medical devices are excluded from this regulation.

Which reporting forms are to be used for serious adverse events (SAE) and device deficiencies (DD) from 26.05.2021?

Until reporting via the central European database EUDAMED or the German Medical Devices Information System (DMIDS) is possible, the following requirements apply:

From the date of application of the MDR on 26.05.2021, the MDCG-SAE reporting table (see appendix of the MDCG guideline "Guidance on safety reporting in clinical investigations") is to be used as a replacement for the MEDDEV-SAE reporting table. The guideline also contains important information, e. g. on reporting deadlines and how to complete the table.

For SAEs or device deficiencies (DD) from German trial sites, the SAE / DD individual notification form of the BfArM must still be used.

In addition, the BfArM continues to expect the quarterly summary SAE / DD assessment. (Further details can be found in the overview table on reporting obligations in Germany.)

All SAE / DD reports are to be sent to the functional mailbox mpsae@bfarm.de .

What are the reporting deadlines for serious adverse events (SAE) and device deficiencies (DD) from the date of application of the MDR?

The reporting deadlines are based on the requirements of the MDCG guideline "Guidance on safety reporting in clinical investigations":

• For all reportable events according to Article 80 MDR or § 64 paragraph 1 MPDG which indicate an imminent risk of death, serious injury, or serious illness and that requires prompt remedial action for other patients/subjects, users or other persons or a new finding to it:
  Immediately, but not later than 2 calendar days after awareness by sponsor of a new reportable event or of new information in relation with an already reported event.
  This includes events that are of significant and unexpected nature such that they become alarming as a potential public health hazard. It also includes the possibility of multiple deaths occurring at short intervals.
  These concerns may be identified by either the NCA or the manufacturer.
• Any other reportable events as described Article 80 MDR or § 64 paragraph 1 MPDG or a new finding / update to it:
  Immediately, but not later than 7 calendar days following the date of awareness by the sponsor of the new reportable event or of new information in relation with an already reported event.

Note:
For performance evaluations, the previous reporting deadlines as specified in the MPSV remain valid until the date of application of the IVDR on 26.05.2022.

Condition for reporting to BfArM	Country in which the SAE / DD occurred	Timeline for reporting to BfArM	Form
(a) any serious adverse event that has a causal relationship with the investigational device, the comparator or the investigation procedure or where such causal relationship is reasonably possible; (b) any device deficiency that might have led to a serious adverse event if appropriate action had not been taken, intervention had not occurred, or circumstances had been less fortunate; (c) any new findings in relation to any event referred to in points (a) and (b).	Germany	immediately	Individual report German SAE Report Form PDF, 983KB, File does not meet accessibility standards Please send to mpsae@bfarm.de
	all other countries where the clinical investigation is performed	immediately	Summary table MDCG SAE Report Table Please document all SAE cumulatively in the same Excel spreadsheet. Please send to mpsae@bfarm.de
all reportable SAEs / DDs* and in addition SAEs / DDs* that are included in Endpoints according to the CIP *In the case of clinical investigations according to Art. 74 (1) MDR incidents instead of DDs have to be reported.	all	quarterly	Summary evaluation of SAEs / DDs or incidents Evaluation DOCX, 25KB, File does not meet accessibility standards Annex 3.1 complication rates XLSX, 43KB, File does not meet accessibility standards Please send to mpsae@bfarm.de Please observe our Notes PDF, 485KB, File does not meet accessibility standards

What changes with regard to the SAE / DD reporting obligations in comparison of the MDR to the MPG / MPSV?

Definitions
When the MDR comes applicable, its definition of a serious adverse event applies and replaces the definition from the MPSV that was valid in Germany until then. The following definitions apply from 26.05.2021:

Article 2, point (57):
‘adverse event’ means any untoward medical occurrence, unintended disease or injury or any untoward clinical signs, including an abnormal laboratory finding, in subjects, users or other persons, in the context of a clinical investigation, whether or not related to the investigational device;

Article 2, point (58):
‘serious adverse event’ means any adverse event that led to any of the following:

a) death,
b) serious deterioration in the health of the subject, that resulted in any of the following:

i) life-threatening illness or injury,
ii) permanent impairment of a body structure or a body function,
iii) hospitalisation or prolongation of patient hospitalisation,
iv) medical or surgical intervention to prevent life-threatening illness or injury or permanent impairment to a body structure or a body function,
v) chronic disease,

c) foetal distress, foetal death or a congenital physical or mental impairment or birth defect;

Article 2, point (59):
‘device deficiency’ means any inadequacy in the identity, quality, durability, reliability, safety or performance of an investigational device, including malfunction, use errors or inadequacy in information supplied by the manufacturer;

Which reporting obligations apply to which clinical investigation?

• Clinical investigations subject to authorisation pursuant to Article 70(7) MDR:

  • SAE / DD reporting obligations according to Article 80 MDR and § 63 MPDG

• PMCF investigation according to Article 74(1) MDR (with additional invasive and / or burdensome procedures):

  • Incident reporting requirements
    According to Article 80 (5) MDR, post-marketing clinical investigations are subject to the vigilance provisions (Articles 87 - 90 MDR).
  • SAEs where a causal relationship between the serious adverse event and the preceding investigational procedure has been established (Article 80 (6) MDR).
    This includes SAEs related to the application procedure of the investigational device or any of the additional invasive and/or burdensome procedures.

• PMCF investigation for one of the purposes referred to in Article 62 MDR without additional invasive and / or burdensome procedures

  • The provisions on vigilance apply
    (SAEs / DDs do not have to be reported to the federal higher authority.)

• Other clinical investigation according to Section 3 Number 4 MPDG:

  • SAE / DD reporting obligations according to Section 64 MPDG
    (Corresponding to the SAE / DD reporting obligations under Article 80(2) and (3) MDR)

• Other clinical investigation according to Section 3 Number 4 MPDG, which fulfils the criteria of Section 47(3) MPDG (investigational device with CE marking, use within the intended purpose, no additional invasive and / or burdensome procedures):

  • The provisions on vigilance apply
    (SAEs / DDs do not have to be reported to the federal higher authority [Section 64(4) MPDG].)

Note:
For performance evaluation tests, the reporting obligations according to MPSV must continue to be applied until the date of application of the IVDR on 26.05.2022!

Important notes on the SAE / DD summary assessment

The assessment can be sent at the same time as an SAE / DD reporting table (MDCG - Clinical Investigation Summary Safety Reporting Form) and should be updated regularly at 3-month intervals. For further information, please refer to the associated information sheet.

BfArM expects significant comparative data from scientific literature or other sources for all serious complications that may be related to the use of an investigational medical device, including adverse events associated with the medical procedures involved, to be included in the quarterly summary evaluation of serious adverse events. In addition to literature data, data derived from the risk analysis or comparable sources may be used. Such comparative data is to be provided in the Excel spreadsheet "complication rates" or, where needed, in other chapters of the summary evaluation report.

A restriction to unexpected events related to the investigational device (USADEs) or events that represent endpoint criteria is not acceptable in this context.

The criteria used by the sponsor in the course of the investigation to assess whether a positive risk-benefit balance for the clinical investigation persists shall be described.

The safety of the subjects during treatment with the medical device shall be assessed with regard to the entire application procedure. Complications that occur during the access procedure must be considered as well as risks due to concomitant diseases (possible contraindications), complications when interacting with other medical devices or other conditions that may lead to an increased risk.

A benefit-risk evaluation in a clinical investigation means comprehensive evaluation of all events with relevance for the safe use of the medical device, irrespective of the relation to the investigational device, the medical procedure involved or any other factor and regardless of whether they are anticipated or not.

In the case of a notifiable clinical investigation according to Article 74(1) of Regulation (EU) 2017/745 (MDR), the reportable incidents shall be listed instead of the device deficiencies.

Important notes on completing the MDCG SAE / DD reporting table

The MDCG table must be kept consecutively. Please always provide as complete information as possible. New information relevant to the assessment can be added to already reported events at any time. The data record must then be marked as "modified".

Please enter only pure date values in columns for date information in the format "dd/mm/yyyy" according to the MDCG specification. Please avoid empty cells if the information is available.

However, please avoid making changes of a formal nature, such as:

• correcting spelling errors, including punctuation
• adding or removing spaces or line breaks
• format changes

Such modifications will result in duplication in the SAE / DD assessment process. Please note that assessment of duplicate records may incur additional charges.

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German individual SAE Report