The new article explains the approach to be applied with respect to clinical investigations.

MDCG Guidance on Legacy Devices Under the MDR: Non-Conformity and Timelines

The Egyptian Drug Authority (EDA), the country’s regulatory agency in the sphere of healthcare products, has published a guidance document dedicated to preclinical testing and clinical investigation for medical devices. The document provides an overview of the applicable regulatory requirements, as well as additional clarifications and recommendations to be taken into consideration by medical device manufacturers and other parties involved in order to ensure compliance. 

At the same time, it is important to mention that provisions of the guidance are non-binding in their legal nature, nor are they intended to introduce new rules or impose new obligations. Moreover, recommendations provided in the guidance could be subject to changes, should such changes be reasonably necessary to reflect corresponding amendments to the underlying legislation.

Clinical Evaluation

Clinical evaluation involves the ongoing assessment of clinical data using scientifically sound methods to ensure the safety, clinical performance, and effectiveness of a medical device as intended by the manufacturer.

Timing of Clinical Evaluation:  

  • Conducted throughout the lifecycle of a medical device, beginning in the development phase.
  • Identifies regulatory data needs and determines the necessity of new clinical investigations.
  • Updated periodically with new data obtained during post-market use.
  • Feeds into risk management processes (ISO 14971), potentially leading to changes in risk assessments, clinical documents, and post-market activities.
FDA Guidance on Distinguishing Medical Device Recalls from Enhancements: Key Concepts and Definitions

Clinical Investigation

A clinical investigation, also known as a clinical trial or study, is a systematic evaluation of a medical device in human subjects to assess safety, clinical performance, and effectiveness for specific indications.

Clinical investigations are conducted when existing data are insufficient to address the following:

  • New questions regarding safety, clinical performance, or effectiveness.
  • Regulatory requirements for high-risk or novel devices.
  • Establishing benefit-risk profiles for devices not supported by literature or prior data.

For established technologies, published literature and existing clinical experience may suffice if no new risks or changes in intended use exist.

Considerations for Clinical Investigations

  1. Risk Management  

Risk analysis helps identify residual risks and gaps in clinical performance that require further investigation. Residual risks must be balanced against anticipated benefits, particularly for high-risk devices.

  1. Clinical Evaluation and Data Sources  

Clinical evaluations utilize data from literature, prior studies, post-market reports, and comparable devices to determine whether new investigations are necessary.

  1. Discussions with Regulatory Bodies  

Uncertainty about data sufficiency or conformity to essential principles should prompt discussions with authorities.

Stages of Clinical Development

According to the guidance, medical device clinical development is divided into three stages:

  1. Exploratory Stage  
  • Purpose: Evaluate device limitations, preliminary safety, and performance.
  • Activities: Includes first-in-human and feasibility studies to refine device design and plan pivotal investigations.
  • Focus: Understanding device functionality and preparing for rigorous pivotal studies.
  1. Pivotal Stage  
  • Purpose: Conduct confirmatory investigations to establish safety, performance, and effectiveness.
  • Activities: Requires a predefined hypothesis, statistical analysis, and rigorous evaluation of clinical endpoints.
  1. Post-Market Stage  
  • Purpose: Evaluate broader population safety and effectiveness.
  • Activities: Includes observational studies to identify rare adverse events and long-term outcomes.

Types of Clinical Investigations

  1. Exploratory Investigations  
  • Early-stage evaluations, often without pre-specified hypotheses.
  • Includes first-in-human and feasibility studies to guide device modifications.
  1. Confirmatory Investigations  
  • Controlled studies with predefined hypotheses and statistical methods.
  • Focus on verifying device claims and establishing clinical safety and performance.
  1. Observational Studies  

Non-interventional studies to gather real-world data on device safety and effectiveness under normal conditions.

Descriptors of Clinical Investigations

  1. The document further elaborates on descriptors related to clinical investigations. 

    1. First-in-Human Studies  

    Initial evaluation of a device’s safety and performance in human subjects.

    1. Early Feasibility Studies  
    • Conducted early in development, often for innovative devices or novel applications.
    • Evaluates clinical safety, delivery, and operator challenges to guide design refinements.
    1. Traditional Feasibility Studies  
    • Focused on near-final or final device designs.
    • Provides preliminary performance data for planning pivotal investigations.
    1. Pivotal Studies  
    • Designed to collect definitive data on safety and effectiveness.
    • Usually conducted in statistically justified populations.
    1. Registries  

    Observational systems collecting clinical data under normal use to evaluate outcomes and inform scientific or clinical policies.

Study Design Based on Subject Burden

  1. Interventional Investigations  
  • Subjects assigned to specific device use with procedures beyond standard clinical practice.
  • Pre- or post-market studies requiring additional diagnostic or monitoring procedures.
  1. Non-Interventional Investigations  
  • Devices used per approved labeling without additional procedures.
  • Focus on collecting data from routine clinical practice.

Importance of Exploratory Studies

The EDA additionally emphasizes the importance of exploratory studies. According to the document, they are intended to ensure:

  • Device design is refined before pivotal studies.
  • Key endpoints for pivotal studies are well-defined.
  • Early identification of potential issues, reducing costs and time in later stages.

These studies may overlap with pivotal studies to provide continuous data collection, especially for long-term evaluations like implants or pediatric applications.

Determining the Appropriate Clinical Investigation Stage

Factors influencing the choice of study type include:

  1. Device Novelty: Innovative devices may require feasibility studies to explore unknown factors.
  2. Intended Clinical Use: Early studies assess safety and functionality in specific contexts.
  3. Design Stability: Early studies accommodate modifications; stable designs progress to pivotal investigations.
  4. Previous Data: Nonclinical and clinical data from prior studies inform investigation needs.

Early Feasibility Study Benefits

Early feasibility studies are suitable for:

  • Assessing initial safety and performance in small populations.
  • Refining device design, procedure, or operator techniques.
  • Addressing unknown risks and challenges specific to novel devices.

Compared to later-stage studies, early feasibility studies require less nonclinical data and allow for device adjustments during the investigation.

Conclusion

In summary, clinical investigations are essential for establishing the safety, performance, and effectiveness of medical devices across their lifecycle. A structured approach involving exploratory, pivotal, and post-market stages ensures robust data generation, regulatory compliance, and continuous device improvement.

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