Pursuant to Article 2 (2) (4) of Regulation (EU) No 536/2014, a non-interventional study is a clinical study that is not a clinical trial. This definition of the non-interventional study was also incorporated into the Medicinal Products Act (section 4 subsection 23 sentence 2 AMG). The obligation to notify the competent higher federal authorities applies when carrying out non-interventional studies in the following categories:

• non-interventional studies in accordance with section 67 subsection 6 of the AMG and
• non-interventional post-authorisation safety studies in accordance with section 63f of the AMG.

Updated: 31.01.2025

A non-interventional study is a study designed to gather insights into the use of authorised or registered medicinal products. Non-interventional studies (AWB) are a subset of non-interventional trials within the meaning of section 4 subsection 23 sentence 3 of the Medicinal Products Act (AMG), i.e. studies in which "findings from the treatment of persons with medicinal products are analysed using epidemiological methods; the treatment, including the diagnosis and monitoring, does not follow a predetermined trial protocol, but only medical practice; if a medicinal product is used that requires marketing authorisation or to approval pursuant to section 21a (1) of the Medicinal Products Act (AMG), the treatment shall be carried out according to the specifications regarding its use contained in the marketing authorisation or approval." The decision to include a patient in a non-interventional study is separate from the decision on the prescription of the medicinal product.

A non-interventional study is not a clinical trial in accordance with section 4 subsection 23 sentence 1 AMG and is therefore not subject to approval. However, pursuant to section 67 subsection 6 of the AMG, the following authorities must be immediately notified: the National Association of Statutory Health Insurance Physicians (Kassenärztlichen Bundesvereinigungen), the National Association of Statutory Health Insurance Funds (Spitzenverband Bund der Krankenkassen), the Association of Private Health Insurance Funds (Verband der Privaten Krankenversicherung e.V.) and the competent higher federal authority. Non-interventional studies are not studies in humans after the authorisation of a medicinal product. Such studies are intended to investigate or demonstrate the clinical or pharmacological effects of medicinal products, to detect side effects, or to investigate the absorption, distribution, metabolism or excretion and are to be carried out with the aim of proving the safety or efficacy of the medicinal products. The treatment of patients, including diagnosis and monitoring, goes beyond the usual medical practice in such studies. These studies are to be carried out as clinical trials in accordance with section 4 subsection 23 sentence 1 of the AMG. Characteristics of a clinical trial include a systematic, randomised allocation of patients to treatment arms and the use of medicinal products outside their authorised indication. These clinical trials must be approved by the competent higher federal authority before they begin and evaluated positively by the competent ethics committee. Approval by the competent higher federal authority and a favourable assessment by the competent ethics committee are also required for clinical trials conducted within the authorised indication, known as phase IV trials.

Updated: 31.01.2025

Non-intervention is characterised by the fact that the treatment, including diagnosis and monitoring, is carried out in accordance with the usual medical practice. If a medicinal product is used that is subject to authorisation or approval in accordance with section 21a subsection 1 of the AMG, the treatment shall be carried out according to the specifications regarding its use contained in the marketing authorisation or approval.

A medicinal product may not be prescribed for the purpose of including a patient in a non-interventional study. The prescription of a medicinal product and the inclusion of the patient in a non-interventional study must be separated. This separation can be realised if, for example, the patient is identified as a candidate for the non-interventional study after the decision regarding therapy has already been made.

The systematic observation necessary for gaining knowledge requires specifications for collecting data as well as for the nature and scope of the documentation and its control. Depending on the objective of the study, specifications for the treating medical personnel are indispensable in order to obtain sufficiently consistent observations and sufficiently high levels of quality and completeness of the data collected. However, systematic allocation of patients to treatment arms (randomisation) is not permitted. Treatment must be carried out exclusively in accordance with usual medical practice.

In addition, no supplemental diagnostic or monitoring procedures may be used for the patient.

Surveys can be used as a tool in an observational study if their contents do not go beyond the information that would be requested in the context of usual medical practice. The data protection concerns must be observed when conducting such surveys. Pursuant to section 21 subsection 4 of the AMG, the competent higher federal authority decides on the approval obligation of a clinical trial at the request of the competent state authority. This also applies to the differentiation of clinical trials from non-interventional trials. Corresponding differentiation issues must therefore first be addressed to the competent state authority in order to give it the opportunity to comment. The competent state authority will then, if necessary, submit an application for a decision to the competent higher federal authority.

Updated: 31.01.2025

A non-interventional study is a study designed to gather insights into the use of authorised or registered medicinal products (section 67 subsection 6 sentence 1 of the Medicinal Products Act). Therefore, only data on those medicinal products that are authorised or registered can be collected in a non-interventional study. Data on prescription medicinal products cannot be collected within a non-interventional study.

If a study on prescription medicinal products is planned, a clarification regarding the classification of the study should be made with the competent state authority. The state authorities are responsible for classifying a study as a clinical trial subject to approval and for distinguishing non-interventional studies from clinical trials.

Updated: 31.01.2025

The location, time, purpose and observation plan, and the non-interventional study case report forms must be included when submitting a notification. In addition, the current Summary of Product Characteristics of the medicinal product must be enclosed. A final report must be submitted to the competent higher federal authority within one year of the completion of data collection for studies with medicinal products intended for use in humans. This information must be submitted electronically via the AWB notification portal.

The following information must be submitted to the higher federal authorities:

1. Competent authority: Paul-Ehrlich-Institut, BfArM or both higher federal authorities
2. Type of study: PASS or non-interventional study
3. Type of notification: initial notification, notification of amendment, interim report, termination, other Report, or notification of a final report.
4. Title of the AWB/PASS: informative title with a common term to indicate the study design
5. Purpose of the AWB/PASS
6. Planned number of participating doctors for the study as a whole and in Germany.
7. Where applicable, whether the non-interventional study is carried out at the request of a European regulatory authority, the Federal Joint Committee (G-BA) or another domestic or foreign institution.
8. Location of study: Germany or multinational
9. Planned start of data collection: "Start of data collection" refers to the time from which information about the first subject is recorded in the study's data set for the first time.
10. Planned end of data collection: Indicates the time until which patients are to be observed, i.e. when patient registration forms are to be completed.
11. Study number of the AWB/PASS
12. Information about the notifier: institution, name, address (postal address as well as email address and telephone number), as well as the sponsor of the AWB/PASS, if the notification and AWB/PASS is carried out on behalf of another company, such as a pharmaceutical company.
13. Medicinal products involved as specified in the observation plan.
14. Observation plan and case report form (CRF) for the AWB stating the reference number of that version and the date of the last version (as an unprotected PDF document, please no scanned image files) as well as the Summary of Product Characteristics (if individual preparations or active substances are observed). The submitted observation plan is published by the higher federal authority in the joint database:
    
    - in the case of individual preparations, indication of the name of the medicinal product, the INN name(s) and the associated German 7-digit ATC code and the authorisation number,
    - when observing all authorised preparations for an active substance, indication according to the observation plan of the INN name(s) and the 7-digit ATC code,
    - when observing all authorised preparations of substance classes according to the observation plan, indication of the 5-digit ATC code(s) and the name of the substance class(es),
    - in the case of non-specific recording of data regarding all of a patient's prescribed medicinal products without recording of specific preparations or substance classes, information on the type of recording and the recorded medicinal products.
    
    
15. A statistical analysis plan (SAP), if applicable.
16. The final report of the observational study (as an unprotected PDF document, please no scanned image files), if applicable. The submitted final report is published by the Paul-Ehrlich-Institut or BfArM in the joint database.
17. Confirmation of the accuracy of the information, a confirmation that the notifier is entitled to make the notification and is aware of the publication of the information and submitted documents in an online portal.
18. When submitting the final report, a confirmation that the submitted final report is submitted in accordance with the requirements of section 42b subsection 3 sentences 1 and 4 of the AMG, if applicable. After that, the report must include all results, regardless of whether they are favourable or unfavourable. With the exception of the name and address of the pharmaceutical entrepreneur or the sponsor, as well as the name and the address of the consenting investigators pursuant to section 4a of the Federal Data Protection Act, no personal, and especially no patient-related data may be contained in the report.

Updated: 31.01.2025

The higher federal authorities publish the notifications in accordance with section 67 subsection 6 of the AMG via a joint online portal.

Database of the Paul-Ehrlich-Institut and the Federal Institute for Drugs and Medical Devices (BfArM)

Updated: 31.01.2025

Notifications, observation plans, and final reports submitted for non-interventional studies are made available to the public via the AWB and PASS notification portal. This also applies to the observation plans submitted with the initial notification of a non-interventional study. Observation plans and final reports are published in full in addition to the location, time, and purpose of the non-interventional study.

Updated: 31.01.2025

Please use the joint notification portal of the Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte, BfArM) and the Paul-Ehrlich-Institut (PEI), Federal Institute for Vaccines and Biomedicines, to submit notifications regarding non-interventional studies.

Notification Portal for AWB and PASS

Updated: 31.01.2025

The observation plan should be submitted as a non-copy-protected PDF document in electronic form. Please upload the observation plan to the non-interventional study notification portal.

The observation plan should be drawn up in accordance with the applicable recommendations of known scientific or regulatory guidelines. Corresponding guidelines can be found in resources such as the "Guidelines for Good Pharmacoepidemiology Practices" (GPP) of the "International Society for Pharmacoepidemiology" (ISPE), the recommendations of the "ENCePP Guide on Methodological Standards in Pharmacoepidemiology", or the Guidelines for Good Epidemiological Practice (GEP) of the German Society for Epidemiology (DGEpi). The corresponding recommendations and models for protocols for non-interventional post-authorisation safety studies in accordance with GVP Module VIII or Commission Implementing Regulation (EU) No 520/2012 can also be used as a basis for protocol development.

Further Information

Notification Portal for AWB and PASS

Updated: 31.01.2025

Since the provisions of section 67 subsection 6 sentence 1 AMG are aimed at "conducting" studies, changes to the location, time, purpose, and observation plan made while the study is being conducted must also be implicitly reported to the competent higher federal authority.

A notification of a significant amendment is sufficient. This is understood to mean such amendments that are likely to affect the safety, physical health, or mental health of the participants or are likely to influence the study results or their interpretation, such as a change in primary or secondary target variables, changes in the study population, a significant change in the study scope (+/- 10%), changes in the definitions of the main exposure variables, the endpoints, disturbances or changes to the analysis plan. It should be noted that an amendment of the observation protocol must not violate the character of the non-interventional study.

The significant amendment to the initial notification should be specified in the new notification and an updated observation plan should be submitted via the notification portal, which reflects the changes.

Updated: 31.01.2025

The final report should be submitted as a non-copy-protected PDF document in electronic form within 12 months of the end of data collection via the notification portal.

When submitting the final report, the information provided for the study at the time of the initial notification must be updated based on the actual data from the completed study (for example, actual number of patients included, etc.).

The final report should be drawn up in accordance with the applicable recommendations of known scientific or regulatory guidelines. Corresponding guidelines can be found in resources such as the STROBE statement (STrengthening the Reporting of OBservational studies in Epidemiology). The corresponding recommendations and models for final reports for non-interventional post-authorisation safety studies in accordance with GVP Module VIII or Commission Implementing Regulation (EU) No 520/2012 can also be used as a basis for protocol development.

The reports must include all results, regardless of whether they are favourable or unfavourable. With the exception of the name and address of the executor, as well as the name and the address of the consenting investigators pursuant to section 4a of the Federal Data Protection Act, no personal, and especially no patient-related data may be contained in the reports. The final reports submitted will be made available to the public by the competent higher federal authority via an online portal.

Updated: 31.01.2025

A safety study for a medicinal product intended for use in humans is any study of an authorised medicinal product that is carried out to identify, describe or quantify a safety risk, to confirm the safety profile of a medicinal product or to measure the effectiveness of risk management measures. Further information on the definition of post-authorisation safety studies (PASS) can be found in the guidelines on good pharmacovigilance practice, or in the Good Vigilance Practice (GVP) Module VIII on PASS and in the GVP Module V on risk management plans based on Article 108a of Directive 2001/83/EC.

The concept of a safety study is primarily based on whether the study is originally initiated to address safety concerns. PASS are listed in the risk management plan (RMP) of the medicinal product as an additional pharmacovigilance measure.
Non-interventional safety studies carried out by the marketing authorisation holder are subject to a notification obligation in accordance with section 63f of the AMG and are not to a notification obligation in accordance with section 67 subsection 6 of the AMG.

Information, observation plans, and final reports on voluntary and ordered post-authorisation safety studies in accordance with section 63f of the AMG should be published in accordance with the requirements of GVP Module VIII in the EU-PAS register in accordance with Article 26 Regulation (EC) No. 726/2004 (see www.encepp.eu).

Updated: 31.01.2025