Non-Interventional Studies (NIS): PMCF & Regulatory Compliance

Non-interventional studies (NIS) play a central role in collecting clinical data for Post-Market Clinical Follow-up (PMCF) and meeting regulatory requirements under the Medical Device Regulation (EU) 2017/745 (MDR) and ISO 14155. In recent years, interest in NIS has increased significantly as manufacturers of medical devices and pharmaceuticals are increasingly required to provide reliable clinical evidence for the safety and performance of their products.

But what exactly defines an NIS? What regulatory frameworks must be considered? And how can a non-interventional study be implemented efficiently and in compliance with regulations? This article explains the criteria an observational study must meet, the relevant ethical and legal aspects, and how to leverage NIS effectively for your Regulatory Compliance Management.

Retrospective: The Development of the NIS Definition

Non-interventional studies (NIS) are not a new concept but have evolved over time from a regulatory perspective. As early as the 2000s, a distinction was made at the European level between clinical trials and purely observational studies. In Germany, the term “Anwendungsbeobachtung” (application observation) was established, primarily used in the field of pharmaceutical studies.

With the increasing importance of clinical data for medical devices, specific guidelines were also developed for medical technology. The currently applicable requirements for distinguishing non-interventional studies are found in ISO 14155 (currently ISO 14155:2020) and the MDR. Essential criteria for an NIS include:

• The medical device is used according to its intended purpose.
• The decision to use a specific product is made independently of the study and follows clinical routine.
• No additional burdensome or invasive procedures are involved beyond regular treatment.
• The collected data are analyzed using epidemiological methods.

In short: An NIS serves to observe medical products under real-life conditions, without the treatment being influenced by a predetermined study protocol.

Your 10-Point Program for Becoming an NIS Expert

(1) Study Participant or Patient?

In the context of an NIS, we no longer speak of study participants but rather of patients. According to MDR Article 2 (50), study participants are those who take part in a clinical trial. Since NIS are conducted in clinical practice, this term does not apply here.

(2) Plan: Yes or No?

According to Annex A of ISO 14155, certain requirements for the Clinical Investigation Plan (CIP) must also be met for an application observation or NIS. However, some aspects may be omitted since many details are already specified in the product's approval documentation.

(3) Additional Burdens or Invasive Procedures?

In 2016, the Working Group on Medical Ethics Committees in Germany published an exemplary list of potentially burdensome or invasive procedures, including ultrasound examinations, blood sampling, provocation tests, and any radiation applications. MDCG 2021-6 (Questions & Answers regarding clinical investigation) defines burdensome procedures (Point 13) as those “which may cause pain, discomfort, fear, potential risks or complications/side effects, disturbances of lives or personal activities, or otherwise unpleasant experiences.” Invasive procedures are defined as those involving “penetration inside the body through the surface of the body, including through mucous membranes or body orifices, or penetration of a body cavity via a body orifice.” Additionally, it is noted that the definition of what is considered invasive or burdensome may evolve over time.

Therefore, the CIP should explicitly discuss whether a procedure should be classified as burdensome or invasive.

(4) Finding Motivated Study Physicians

A committed study physician is essential for the success of an NIS. Ideally, a physician who has an interest in scientific research or publication, as this can improve data quality and increase the study's acceptance in the medical community.

ISO 14155:2020 (Annex I.7d) makes it clear that the same requirements for study physicians do not apply for an NIS as they do for a clinical trial under MDR Article 62. However, certain minimum requirements must still be met:

Requirements for the Principal Investigator
The principal investigator must:

• hold a recognized profession in an EU member state that qualifies them to be the investigator. They must have expertise in the relevant medical field and experience in patient care (MDR Article 62 (6));
• be qualified through education, training, and experience to be responsible for the proper conduct of the study in accordance with the requirements of ISO 14155. This qualification must be demonstrated through a current CV or other relevant documents (ISO 14155:2020, Chapter 10.2);
• have experience with the investigational product and be trained in its use;
• disclose any potential conflicts of interest (e.g., financial incentives) that could influence the conduct or interpretation of the study;
• be familiar with the informed consent process.

Requirements for the Study Site
The study site must:

• have a sufficiently large patient base to recruit enough study participants within the planned timeframe;
• have a qualified team with appropriate evidence (CVs, training);
• possess the necessary technical and spatial resources for the study.

Practical Tip

• Choose study physicians who are specialists with a high patient volume to ensure good recruitment.
• Physicians with a scientific motivation or interest in publications can act as multipliers.
• A preliminary discussion with potential investigators can help identify their expectations and possible challenges early on.

Important Note: These requirements refer to clinical trials, which are defined under both MDR and ISO 14155 as systematic investigations involving one or more participants to assess the safety or performance of a product. For an application observation, these requirements should be interpreted appropriately based on the study type.

(5) Discuss Clinical Practice with Physicians in Advance

Discuss with medical professionals how clinical practice for your medical device looks. This ensures that the observational plan is practical and realistic.

(6) Define Study Objectives (Endpoints) and Create the Observation Plan

A structured observation helps capture relevant clinical data systematically, ensuring no important information is lost.

(7) Pre-discuss Additional Procedures

If additional procedures (e.g., vision tests, questionnaires, gait tests) are necessary, they should be discussed in advance regarding risks and burdens for the patients. Questionnaires are usually unproblematic.

(8) IMPORTANT: What Is NOT an Observational Study!

• Use of a medical device beyond its intended use – this requires a clinical trial under MDR Article 74(2).
• Use of a non-CE-marked product – this does not align with clinical practice. (Observational studies are, by definition, always post-market studies.)
• Randomized studies – these are not considered NIS, as they are no longer "observational" (see ISO 14155:2020, I.4.4).
  
  

(9) NIS = Post-Market Clinical Follow-Up Study Without Additional Burdens

A non-interventional study counts as a Post-Market Clinical Follow-Up (PMCF) study where no additional burdensome or invasive procedures are performed.

• There is no requirement for notification or approval by ethics committees or national authorities.
• However, investigators must consult with the responsible ethics committee according to professional regulations (§ 15).
• Reporting serious adverse events (SAEs) in application observations is not required, but the obligation to report occurrences remains.
  
  

(10) Registration Requirements

Register your NIS in a public study database (e.g., ClinicalTrials.gov or DRKS) before the study begins. This registration is also recommended by MDCG 2021-6. If registration is forgotten, it should be done retroactively – better late than never!

PMCF studies under Article 74 MDR, which involve additional burdensome or invasive procedures and thus are not NIS, must also be notified to national authorities (see § 85 No. 6 MPDG). This notification must be made at least 30 days before the trial begins. This requirement does not affect the obligation for involved investigators to consult with the ethics committee as per professional law.

Conclusion

Conducting a non-interventional study requires a solid understanding of regulatory requirements, ISO 14155, the MDR, and national regulations. Careful planning, the right study methodology, and close coordination with the relevant authorities and ethics committees are critical for successful implementation.

As experienced consultants in regulatory compliance, we support medical device manufacturers in strategically planning and conducting NIS in compliance with regulations. From study design to documentation to clinical evaluation – we help you generate your clinical data efficiently and fulfill your regulatory obligations.

If you have questions about implementing a non-interventional study or would like individual advice, feel free to contact us. We look forward to the exchange!