Germany – Regulatory Requirements and Considerations when Conducting Non-Interventional Studies (NIS)

Latest Regulatory Updates ()

  • June-2024-Germany-Single-REC-Approval

GERMANY | Single Ethics Committee Approval for Multi-Centre Studies

July 5, 2024|Categories: 2024, Germany, June 2024, Members-Only, Significant Update|Tags: , , , , , , |

RWR CONTEXT This procedural change by BÄK and AKEK represents a major advancement in streamlining the ethical review process for multi-centre non-interventional studies in Germany, transitioning from individual federal state ethics committee approvals [...]

GERMANY | AKEK Statement on the Secondary Use of Patient Data for Research Purposes in Germany

September 5, 2023|Categories: 2023, August 2023, Data Privacy and Data Protection, EHDS, GDPR, Germany, Members-Only, Minor Update, RWD to Support Reg Decisions, Secondary Use of Existing Data|Tags: , |

RWR CONTEXT A draft Health Data Use Act (GDNG) has been published this month with a view to supporting the implementation of the research aspects of European Health Data  Space in Germany. Germany’s [...]

GERMANY | New Version of the BfArM-PEI Joint NIS Recommendations

February 4, 2023|Categories: 2023, Germany, January 2023, Members-Only, Moderate Update|Tags: , , |

RWR CONTEXT The BfArM-PEI Joint NIS Recommendations have been revised to capture the clinical study definitions presented in the EU Clinical Trials Regulation. These recommendations provide detailed guidance on the approval and notification [...]

GERMANY | New AKEK Checklist for PMCF Study Submission Documents

January 6, 2023|Categories: 2022, December 2022, Germany, MDR, Medical Devices, Members-Only, Moderate Update|Tags: , , |

RWR CONTEXT This checklist is of interest to medical divide researchers, because it focuses on post-market clinical follow-up studies other than Article 74(1) MDR studies I.e., PMCF studies of CE marked medical devices [...]

GERMANY | BfArM Tightens Data Protection Requirements for DiGAs

November 14, 2022|Categories: 2022, Data Privacy and Data Protection, Germany, Medical Devices, Members-Only, October 2022|Tags: , , , , |

RWR CONTEXT BfArM is one of the first authorities in Europe to develop a special data protection certificate for class I and IIa digital health applications (DiGA) and thus specifically strengthen the rights of [...]

Regulatory Requirements ()

wdt_ID Country Study Type Approvals Other Start-Up Requirements Approval Timeframe
1 Germany Prospective NIS (Drug) 1. Research Ethics Committee (REC) of Lead Principal investigator (fee = approx. 200 to 1000 euro)
2. Local Research Ethics Committee(s) (fee = approx. 200 to 1000 euro)
1. Notify the Competent Authority (BfArM or PEI)
2. Notify the Federal Panel Doctors’ Association (KBV)
3. Notify the Central Federation Association of the Statutory Health Insurance Funds (GKV)
4. Notify the Association of Private Health Insurance Companies (PKV)
5. Publish the study on a Public Register (e.g., the HMA-EMA Catalogue of Real-World Data Studies)
6. Local legal representative needed if study sponsor not based in the EU
8 to 16 weeks
2 Germany Retrospective NIS (Drug) 1. Research Ethics Committee (REC) of Lead Principal investigator (fee = approx. 200 to 1000 euro)
2. Local Research Ethics Committee(s) (fee = approx. 200 to 1000 euro)
1. Publish the study on the HMA-EMA Catalogue of Real-World Data Studies (optional)
2. Local legal representative needed if study sponsor not based in the EU
8 to 16 weeks
3 Germany Voluntary PASS 1. Research Ethics Committee (REC) of Lead Principal investigator (fee = approx. 200 to 1000 euro)
2. Local Research Ethics Committee(s) (fee = approx. 200 to 1000 euro)
1. Notify the Competent Authority (BfArM or PEI)
2. Notify the Federal Panel Doctors’ Association (KBV)
3. Notify the Central Federation Association of the Statutory Health Insurance Funds (GKV)
4. Notify the Association of Private Health Insurance Companies (PKV)
5. Publish the study on a Public Register (e.g., the HMA-EMA Catalogue of Real-World Data Studies)
6. Local legal representative needed if study sponsor not based in the EU
8 to 16 weeks
4 Germany Multi-Country PASS 1. EMAs Pharmacovigilance Risk Assessment Committee (PRAC)
2. Research Ethics Committee (REC) of Lead Principal investigator (fee = approx. 200 to 1000 euro)
3. Local Research Ethics Committee(s) (fee = approx. 200 to 1000 euro)
1. Notify the Competent Authority (BfArM or PEI)
2. Notify the Federal Panel Doctors’ Association (KBV)
3. Notify the Central Federation Association of the Statutory Health Insurance Funds (GKV)
4. Notify the Association of Private Health Insurance Companies (PKV)
4. Publish the study on a Public Register (e.g., the HMA-EMA Catalogue of Real-World Data Studies) (Required)
6. Local legal representative needed if study sponsor not based in the EU
8 to 16 weeks (not including PRAC endorsement)
5 Germany Single-Country PASS 1. Competent Authority (BfArM or PEI) Approval
2. Research Ethics Committee (REC) of Lead Principal investigator (fee = approx. 200 to 1000 euro)
3. Local Research Ethics Committee(s) (fee = approx. 200 to 1000 euro)

1. Notify the Federal Panel Doctors’ Association (KBV)
2. Notify the Central Federation Association of the Statutory Health Insurance Funds (GKV)
3. Notify the Association of Private Health Insurance Companies (PKV)
4. Publish the study on a Public Register (e.g., the HMA-EMA Catalogue of Real-World Data Studies) (Required)
5. Local legal representative needed if study sponsor not based in the EU
8 to 16 weeks
Country Study Type Approvals Other Start-Up Requirements Approval Timeframe

BfArM – Federal Institute for Drugs and Medical Devices;NIS = Non-Interventional Study; PASS = Post-Authorisation Safety Study; PEI  = Paul-Ehrlich-Institute (PEI) = The Federal Institute for Vaccines and Biomedicines

Note – Numerical listings in the “Approvals” and “Other Start-Up Requirements” are not an indication of chronological order

Submission Documents ()

wdt_ID Study Conduct Requirements and Considerations Details References
24 Submission Documents - BfArM/ PEI 1. Notification form
2. Time and Location of Study (Provide site list and timeframe for study)
3. Protocol (Observation plan) (In English)
4. Case Report Forms (CRF) or questionnaires, indicating the reference number of the version and the date of the last version (CRF and questionnaires are part of the observational observation plan).
5. PRAC Endorsement (Requirement for multi-country imposed PASS)

Additional Recommended Documents:
i. REC approvals
ii. Statistical Analysis Plan (SAP)
iii. Summary of Product Characteristics (SPC)
Section 2.2.1 of BfArM/PEI Joint NIS Recommendations (2022)
Link: https://www.pei.de/SharedDocs/Downloads/DE/regulation/klinische-pruefung/awb-nis-pass-empfehlungen.pdf?__blob=publicationFile&v=4
25 Submission Documents - Lead Principal Investigator Ethics Committee 1. Submission Form (In German)
2. Cover Letter (In English or German)
3. Protocol Signature Pages (Signed by Sponsor and PI(s))
4. Protocol (In English)
5. Protocol Synopsis (In German)
6. CRF (In English)
7. Patient Information/ Informed Consent (In German and adapted to local requirements)
8. Any Patient Facing Documents (In German)
9. List of Participating Investigators and Sites (Required for ethics submission 
Is also part of the documentation to provide to German KBV, GKV, PKV related to obligations in § 63, 67 AMG (German Drug Act))
10. CV of Principal Investigators (PIs)
11. Contract between Sponsor, Investigator and/or Institution (Not executed. Including the financial aspects of the planned project)
12. Time and Location of Study (Provide site list and timeframe for study)
26 Submission Documents - Local Ethics Committee(s) 1. Submission Form (In German)
2. Cover Letter (In English or German)
3. Protocol Signature Pages (Signed by Sponsor and PI(s))
4. Protocol (In English)
5. Protocol Synopsis (In German)
6. CRF (In English)
7. Patient Information/ Informed Consent (In German and adapted to local requirements)
8. Any Patient Facing Documents (In German)
9. List of Participating Investigators and Sites (Required for ethics submission 
Is also part of the documentation to provide to German KBV, GKV, PKV related to obligations in § 63, 67 AMG (German Drug Act))
10. CV of Principal Investigators (PIs)
11. Contract between Sponsor, Investigator and/or Institution (Not executed. Including the financial aspects of the planned project)
12. Time and Location of Study (Provide site list and timeframe for study)
27 Submission Documents - GKV, KBV, PKV 1. Submission Form (In German)
2. Cover Letter (In English or German)
3. Protocol (In English)
4. List of Participating Investigators and Sites (Required for ethics submission 
Is also part of the documentation to provide to German KBV, GKV, PKV related to obligations in § 63, 67 AMG (German Drug Act))
5. Contract between Sponsor, Investigator and/or Institution (Not executed. Including the financial aspects of the planned project)
6. Time and Location of Study (Provide site list and timeframe for study)
Study Conduct Requirements and Considerations Details References

Regulatory Assumptions ()

  • Study involves a medicinal product
  • Observational (non-interventional) study design
  • Lead and local ethics committee approval required
  • Prospective drug observation studies (AWBs) need to be notified to the competent authority (either BfArM or the PEI), as well as to (1) The Central Federation Association of the Statutory Health Insurance Funds (GKV), (2) The Federal Panel Doctors’ Association (KBV), and (3) The Association of Private Health Insurance Companies (PKV)
  • Publishing the study data on a public register (e.g., HMA-EMA Catalogue of Real-World Data Studies) is mandatory for Prospective drug observation studies (AWBs) and post-authorisation safety studies (PASS)
  • Retrospective drug observation studies (AWBs) and disease registries DO NOT need to be notified to the competent authority (either BfArM or the PEI), as well as to (1) The Central Federation Association of the Statutory Health Insurance Funds (GKV), (2) The Federal Panel Doctors’ Association (KBV), and (3) The Association of Private Health Insurance Companies (PKV)
  • Publishing the study data on a public register (e.g., HMA-EMA Catalogue of Real-World Data Studies) is optional for Retrospective drug observation studies (AWBs)
  • Other approvals required for imposed post-authorisation safety studies (PASS)
  •  

Regulatory Classification Decision Tree ()

Start-Up Roadmap – Prospective NIS (AWB) ()

Start-Up Roadmap – Retrospective NIS (AWB) ()

Start-Up Roadmap – Voluntary Post-Authorisation Safety Study (PASS) ()

Start-Up Roadmap – Multi-Country Imposed Non-Interventional Post-Authorisation safety Study (PASS) ()

Start-Up Roadmap – Single Country Imposed Non-Interventional Post-Authorisation safety Study (PASS) ()

Study Conduct Considerations ()

wdt_ID Study Conduct Requirements and Considerations Details References
6 Competent Authority Notification 1. Notify BfArM if the study involves drugs or PEI if the study involves vaccines or biological medicinal products.
2. Costs are approx. 260€.
3. The invoice may be issued late by the CA, in our experience up to 1 year after the notification.
4. Notification of the appropriate CA is an online procedure: to PEI, refer to the following webpage in German, the notification to BfArM can be performed here.
Ref1: BfArM - Nichtinterventionelle Prüfungen (Anwendungsbeobachtungen, Unbedenklichkeitsprüfungen) [Non-Interventional Studies (Drug Observation Studies (AWB), PASS)
Link: https://www.bfarm.de/DE/Arzneimittel/Klinische-Pruefung/Nichtinterventionelle-Studien/_node.html

Ref2: PEI - An­wen­dungs­be­ob­ach­tun­gen (AWBs)
Link: https://www.pei.de/DE/regulation/klinische-pruefung/anwendungsbeobachtungen/awb-node.html
7 Competent Authority Study Registration (occurs as part of the notification process) 1. Study protocols and final reports are published in BfArM’s database for marketing surveillance (AWB Datenbank).
2. The database includes information on title, objective, start and end of non-interventional studies (Anwendungsbeobachtung), as well as the medicinal product under surveillance.
3. The database is limited to AWB (drug utilization observation) studies.
4. Voluntary PASS or mandated PASS are not published in the database and do not get assigned a NIS number.
5. For registration of Voluntary or Imposed PASS, see EU PAS register
Ref1: BfArM AWB Database
Link: https://awbdb.bfarm.de/ords/r/awb/awb_pub/home
8 Study Registration - ‘Other Considerations’ Within 21 days of the start of patient recruitment, information about the intended study (study title, objectives, name of the director of studies, planned number of study centers and the targeted number of cases) must be entered in a publicly accessible register Ref: Section 19 of the FSA HCP Code of Conduct
Link: https://www.fsa-pharma.de/wp-content/uploads/2023/06/fsa_code_of_conduct_hcp-_final_new.pdf
9 Ethics Committee Approval 1. Observational studies involve a number of possible conflicts of interest, especially in the area of tension between data protection, patient protection, protection and liability of medical persons and health professionals and the interest of the sponsor/ researcher.
2. It should be ensured that, prior to an observational study commencing, consultation is provided by an independent ethics committee established under state law. A drug observational study should only be started after a positive vote of an independent ethics committee.
3. Reference is made to the Declaration of Helsinki and the corresponding provisions in the health profession laws of the Länder and the professional codes of the State Medical Associations.
Ref: Section 2.7.5 of the BfArM/PEI Joint NIS Recommendations (2022)
Link: https://www.pei.de/SharedDocs/Downloads/DE/regulation/klinische-pruefung/awb-nis-pass-empfehlungen.pdf?__blob=publicationFile&v=4
10 Exceptions to the BfArM/PI Notification Requirements The following types of studies do not fall under the concept of observational study and are exempt from the obligation to notify the competent higher federal authorities pursuant to § 67 paragraph 6 AMG:
- Retrospective studies i.e., only retrospective data are collected and evaluated that were already available when patients were included.
- Secondary data analysis i.e., Studies evaluate the data that were not primarily collected to answer the study question. This includes, for example, the analysis of health insurance data or the retrospective evaluation of patient files.
- Cross-sectional studies in which an empirical study or data collection is carried out once; there is therefore no prospective observation of patients or forward-looking data collection.
- Disease registers without specific requirements regarding the registration of certain drugs or groups of active substances e.g., Cancer registries, which are primarily concerned with the collection of data on the disease and for which the monitoring plan has not specified that largely persons with a defined drug therapy should be included.
Section 2.3 of the BfArM/PEI Joint NIS Recommendations (2022)
Link: https://www.pei.de/SharedDocs/Downloads/DE/regulation/klinische-pruefung/awb-nis-pass-empfehlungen.pdf?__blob=publicationFile&v=4
Study Conduct Requirements and Considerations Details References

Definitions ()

Term wdt_ID Definition Reference Link
Retrospective Studies 2 Retrospective studies i.e., only retrospective data are collected and evaluated that were already available when patients were included. Section 2.3 of the BfArM/PEI Joint NIS Recommendations (2022) https://www.pei.de/SharedDocs/Downloads/DE/regulation/klinische-pruefung/awb-nis-pass-empfehlungen.pdf?__blob=publicationFile&v=4
Non-Interventional Study (NIS) 3 A non-interventional study within the meaning of Article 2 paragraph 2 number 4 of Regulation (EU) No. 536/2014 is not a clinical trial. Section 4(23) of the German Drug Law (AMG) https://www.gesetze-im-internet.de/amg_1976/__4.html
Safety Study 4 A safety study is any study on an authorized medicinal product that is carried out to identify, characterize or quantify a safety risk, to confirm the safety profile of a medicinal product or to measure the effectiveness of risk management measures. Section 4(34) of the German Drug Law (AMG) https://www.gesetze-im-internet.de/amg_1976/__4.html
Clinical Trial 5 A clinical trial is one within the meaning of Article 2 paragraph 2 number 2 of Regulation (EU) No. 536/2014 of the European Parliament and of the Council of April 16, 2014 on clinical trials on medicinal products for human use and repealing Directive 2001/ 20/EC Section 4(23) of the German Drug Law (AMG) https://www.gesetze-im-internet.de/amg_1976/__4.html
Side Effects 6 Side effects are harmful and unintended reactions to the drug. Serious adverse reactions are adverse reactions that are fatal or life-threatening, require hospitalization or prolonged hospitalization, result in permanent or severe disability, disability, congenital abnormalities, or birth defects. Unexpected side effects are side effects whose type, extent or result differ from the prescribing information for the medicinal product. Section 4(13) of the German Drug Law (AMG) https://www.gesetze-im-internet.de/amg_1976/__4.html
Term Definition Reference Link

Useful Links ()

wdt_ID Resource Link
1 Law on the Sale of Medicinal Products (Arzneimittelgesetz - AMG) https://www.gesetze-im-internet.de/amg_1976/BJNR024480976.html
2 The Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte, BfArM) https://www.bfarm.de/DE/Home/_node.html
3 BfArM - Non-Interventional Studies (AWB, PASS) https://www.bfarm.de/DE/Arzneimittel/Klinische-Pruefung/Nichtinterventionelle-Studien/_node.html
4 BfArM - NIS FAQs https://www.bfarm.de/DE/Arzneimittel/_FAQ/Klinische-Pruefung/Klinik/Anwendungsbeobachtungen/faq-liste.html?nn=596372
5 BfArM AWB Database https://awbdb.bfarm.de/ords/r/awb/awb_pub/home
Resource Link

History of Changes to this Page ()

wdt_ID Date Impact Category Details
4 21/08/2021 Not Applicable New Webpage New webpage
5 14/10/2021 Minor Impact - Has little or no impact on the regulatory requirements for conducting real world research studies in the country of interest Updated URL Updated the download URL for the NIS Considerations report
6 15/10/2021 Minor Impact - Has little or no impact on the regulatory requirements for conducting real world research studies in the country of interest Editorial Changes RWR-Regs branding added to images
7 06/04/2022 Not Applicable Editorial Change Reformatted webpage
8 06/04/2022 Minor Impact - Has little or no impact on the regulatory requirements for conducting real world research studies in the country of interest Editorial Change Added details of the submission documents for:
1. BfArM/ PEI
2. Ethics Committee of the Lead Principal Investigator
3. Local Ethics Committees
4. GKV,KBV, PKV