Navigating Post-Market Clinical Investigations for Medical Device

Throughout my career, I’ve had the unique opportunity to work in both the medical device and pharmaceutical industries. This experience has highlighted the unique challenges and specific nuances of medical devices—areas often overlooked but crucial for ensuring patient safety and advancing healthcare innovation. With the rapid growth of artificial intelligence (AI), there’s an increasing need to understand how these technologies will be regulated, especially as software becomes a medical device.

In this blog post, I want to share insights into post-market clinical investigations for medical devices, exploring complexities, best practices, and real-world examples to help others better understand these important topics.

The Unique Landscape of Medical Device Clinical Investigations

While pharmaceuticals and medical devices share foundational regulations to ensure safety, efficacy and quality—like risk management, Good Clinical Practice (GCP), and post-market surveillance—their paths diverge significantly in practice.

Medical devices, especially Class III devices, evolve rapidly due to technological advancements and require significant user interaction. Innovations such as implantable technologies, advanced diagnostics, and software as medical devices (including AI applications) continually reshape the field. This rapid evolution poses unique challenges in regulation and clinical investigations compared to pharmaceuticals.

A distinct aspect of medical devices is the nature of clinical investigations, particularly in the post-market setting. Unlike pharmaceuticals, where post-approval changes are relatively infrequent, medical devices often undergo iterative enhancements after they enter the market. Software updates, design modifications, and new usage parameters necessitate ongoing clinical evaluations to ensure continued safety and performance.

Pre-Market vs. Post-Market Investigations

In the pre-market phase, clinical investigations aim to demonstrate that a new device is safe and effective for its intended use. These studies typically involve controlled environments and predefined endpoints, focusing on regulatory approval requirements.

In contrast, post-market clinical investigations are essential for monitoring real-world performance and uncovering issues not evident in pre-market studies. They help understand device functionality across diverse patient populations and varied clinical settings. Given the rapid evolution of medical devices—especially with the integration of AI and software applications—these investigations are critical to capture data on long-term safety, effectiveness, and potential unforeseen risks.

Navigating Regulatory Submissions and Requirements

Understanding and navigating regulatory requirements is the first crucial step of conducting successful post-market clinical investigations for medical devices. Compliance with these regulations not only ensures the legality of the study but also upholds patient safety and data integrity. The general principles have been discussed in my previous blog post, Clinical Trials Safety Reporting 101: A Practical, Industry-Wide Overview. Here, I’ll focus on the key points and specific considerations for medical devices.

Understanding the Investigator’s Brochure (IB)

A key component of regulatory submissions is the Investigator’s Brochure (IB). The IB provides comprehensive information about the medical device, including pre-clinical and clinical data, safety information, and instructions for use.

Whether an IB is required can depend on local regulations and the specifics of the study:

• Interventional Studies: If the post-market study involves additional procedures or interventions beyond normal clinical practice, an IB may be necessary.
• Non-Interventional Studies: When the device is used within its approved labeling without additional interventions, the approved labeling and instructions for use might suffice.

It’s important to consult local regulations in each country where the study will take place. Even if an IB isn’t explicitly required, having one prepared can facilitate discussions with regulatory authorities and ethics committees, and it can be valuable if questions arise during the study.

Planning Regulatory Submissions

Thorough planning for regulatory submissions is essential to avoid delays and ensure a smooth study launch. Requirements can vary significantly:

• Mandatory Submissions: Some countries require submissions to regulatory authorities for all post-market studies, regardless of their nature.
• Ethics Committees Only: Others may only require approval from ethics committees or institutional review boards.
• No Formal Submissions: In certain regions, non-interventional studies may proceed without formal submissions to regulatory authorities.

To navigate these differences, it’s advisable to assess regulatory requirements early in the planning phase

Sourcing Investigational Medical Devices (IMD)

With regulatory approvals secured and documentation prepared, the focus shifts to the practical aspects of conducting the study. A vital step in this process is obtaining the investigational medical device needed for the investigation. Understanding the options and considerations for sourcing the IMD ensures that the study can proceed efficiently and in compliance with all regulations. There are two otions for obtaining the IMD as explained following.

Commercial Sources

Applicability: Both interventional and non-interventional post-market clinical investigations can often obtain the IMD from commercial sources.

Advantages:

• Consistency: Using commercially available devices ensures that the study uses the same devices as those in routine clinical practice.
• Simplified Logistics: Procurement processes are generally more straightforward when sourcing from existing commercial channels.

Considerations:

• Regulatory Compliance: Even when obtaining devices commercially, it’s important to ensure that all regulatory requirements for device tracking and documentation are met.

Study-Specific Device Supply

When Necessary:

• If the device is modified for the study.
• If specific tracking or accountability measures are required beyond standard practice.

Implications:

• Coordination with Manufacturers: May require collaboration with the device manufacturer to secure the necessary devices.
• Additional Regulatory Steps: Might involve extra regulatory compliance steps, such as obtaining approvals for the modified device or ensuring proper labeling.

Practical Example:

Consider a post-market study evaluating an implantable device used within its approved labeling. If the study does not require any modifications to the device, it can likely be sourced from commercial suppliers. This approach aligns with the earlier multiple-choice question highlighting that both interventional and non-interventional studies can obtain the IMD from commercial sources.

However, if the study involves altering the device or requires stringent control over device distribution, a study-specific supply may be necessary. This scenario would entail additional coordination and compliance efforts.

Safety Reporting: Key Considerations in Medical Device Investigations

After securing the investigational medical device (IMD) and obtaining all necessary regulatory approvals, the next crucial step is to establish effective safety reporting mechanisms. While safety reporting is a fundamental aspect of all clinical research, medical device studies come with unique considerations that require special attention. For a detailed overview of general safety reporting practices, you may refer to my previous blog post. Here, I’ll focus on the specific nuances relevant to medical devices.

• Device Deficiencies: Issues like malfunctions, software errors, or design problems that could lead to adverse events must be reported and assessed, even if no harm occurred.
• User Interaction: The way users interact with medical devices can impact safety. Reporting must consider potential user errors or misuse.
• Technical Investigations: Device-related events often require technical evaluations to determine the root cause, involving collaboration between clinical and engineering teams.

Specific Roles and Responsibilities

While the safety reporting processes in medical device studies are generally similar to those in drug studies, the unique types of events—such as device deficiencies and malfunctions—and specific considerations of medical devices mean that the roles and responsibilities in medical device safety reporting differ from those in pharmaceutical development.

Let’s delve into the specific roles and responsibilities involved in medical device safety reporting:

1. Serious Adverse Event (SAE) Responsible

   • Primary Role: Ensure that all safety reports are complete and valid for processing. This involves verifying that each report contains necessary information like patient details, reporter information, device identification, and a clear description of the event.
   • Action on Missing Information: If any required information is missing, promptly contact the reporter (e.g., investigator or healthcare professional) to obtain the missing details.

2. Safety Medical Reviewer

   • Responsibilities: Perform medical assessments of all adverse events (AEs) and device deficiencies (DDs). Determine the seriousness, expectedness, and possible relationship to the device. This assessment is crucial for meeting regulatory obligations and ensuring patient safety.
   • Expertise Required: A thorough understanding of both clinical aspects and technical nuances of the medical device is essential.

3. Investigator

   • Reporting Obligations: Report all adverse events and device deficiencies to the sponsor within specified timelines, including both serious and non-serious events.
   • Specific to Devices: Must be vigilant in identifying and reporting device-related issues, including malfunctions or user errors that could impact safety.

Managing Significant Safety Concerns in Medical Device Studies

After establishing effective safety reporting mechanisms, it’s important to understand how to handle significant safety concerns—specifically, Serious Public Health Threats—that may arise during a medical device study. While regular monitoring of adverse events helps ensure participant safety, sometimes more serious issues emerge that require swift action.

A Serious Public Health Threat in the context of medical devices might involve:

• Multiple Serious Adverse Events: Clusters of serious adverse events occurring within a short period.
• Device Deficiencies with Severe Outcomes: Malfunctions or failures leading to serious injury or death.
• Widespread Impact Potential: Issues with devices that are widely used by many patients.

Unique Considerations in Medical Device Safety Management

• Rapid Impact

  Defective medical devices can affect many patients quickly due to widespread use.

  Example: A cardiac implant with a software error distributed globally could malfunction during critical heart rhythms, putting numerous patients at immediate risk before the issue is identified.

• Specific Regulatory Requirements

  Authorities have clear rules for reporting serious threats related to medical devices. Compliance with these regulations is essential.

  • European Union

    The European Union Medical Device Regulation (EU MDR) 2017/745 outlines requirements for reporting serious incidents and public health threats.

  • United States

    The FDA Medical Device Reporting (MDR) Regulation mandates reporting of adverse events and device-related deaths or serious injuries.

Case Study: Managing a Device Deficiency in Radiotherapy Planning Software

In a post-market clinical investigation, a company evaluated the performance of their CE-marked radiotherapy treatment planning software used in cancer therapy. This software assists oncologists in creating precise radiation dose plans for patients, aiming to maximize tumor targeting while minimizing exposure to healthy tissues.

Incident Overview

During the study, clinicians at several sites reported discrepancies between the radiation doses calculated by the software and those actually delivered by the radiotherapy equipment. Over a two-week period, three cases emerged where patients received higher radiation doses than planned, leading to unexpected side effects such as severe skin reactions and fatigue.

Recognizing the potential for serious patient harm, investigators reported these incidents immediately to the sponsor, adhering to the required timelines for reporting device deficiencies as specified for such events in medical device studies.

Actions Taken

Specific steps were taken to address the issue, incorporating key learnings and regulatory requirements relevant to medical devices:

1. Immediate Safety Assessment

   • Classification of the Events: The incidents were identified as device deficiencies that could potentially lead to serious adverse events.
   • Causality Determination: The Safety Medical Reviewer evaluated the cases, determining a probable relationship between the software malfunction and the overdosing of radiation.
   • Severity Assessment: Considered whether the events constituted a Serious Public Health Threat due to the potential for widespread impact.

2. Technical Investigation

   • Root Cause Analysis: A multidisciplinary team involving software engineers, medical physicists, clinical experts, and quality assurance personnel conducted a thorough investigation.
   • Findings: Discovered that a recent software update introduced a calculation error in the dose planning algorithm, specifically miscalculating tissue density in certain imaging modalities.
   • Scope Assessment: Evaluated whether other clinical sites using the software were affected and identified all patients who might be at risk.

3. Regulatory Compliance

   • Verification of Report Validity: The Serious Adverse Event (SAE) Responsible ensured all reports were complete and valid, promptly obtaining any missing information.
   • Initial Reporting: Submitted detailed incident reports to relevant health authorities within mandated timeframes, complying with both local and international regulations.
   • Investigator’s Brochure (IB): Updated the IB to include new safety information, acknowledging that an IB may be required depending on local regulations.

4. Risk Mitigation

   • Communication with Clinical Sites: Notified all sites using the software about the issue. Provided instructions to verify dose calculations manually and, if necessary, revert to a previous software version.
   • Software Update Rollback: Withdrew the faulty software update and halted further distribution until a fix was implemented.
   • Patient Monitoring: Advised clinicians to monitor affected patients closely and manage any adverse effects promptly.

5. Regulatory Submissions and Approvals

   • Software Correction Submission: Recognizing the software modification as significant, the sponsor submitted a regulatory application for the corrected software, understanding that regulatory submissions may be required before initiating changes.
   • Awaiting Approval: Did not deploy the corrected software until receiving regulatory approval, ensuring compliance with applicable laws.

6. Final Reporting

   • Submission of Final Investigation Report: Provided a comprehensive report to health authorities within the required 90-day period, detailing root cause analysis, corrective actions, and preventive measures.
   • Post-Market Surveillance Enhancement: Updated the post-market clinical follow-up plan to include enhanced monitoring of software updates and user feedback.

Key Learnings

• Timely Reporting and Role Clarity: Prompt reporting by investigators and verification by the SAE Responsible are critical. The Investigator reported the incidents and the SAE Responsible ensured reports were valid, reflecting specific points from earlier discussions.

• Technical Expertise in Investigations: Collaboration between clinical teams and technical experts, such as software engineers and medical physicists, is essential to identify and resolve software-related issues.

• Regulatory Compliance for Software Changes: Significant software modifications require regulatory approval. Recognizing that an Investigator’s Brochure may be required depending on local regulations is vital for compliance.

• Managing Significant Safety Concerns: The potential for widespread patient harm due to software deficiencies underscores the importance of immediate action and communication, aligning with how to handle Serious Public Health Threats.

Conclusion

Post-market clinical investigations in the medical device industry are complex and require careful navigation of regulatory requirements, safety reporting, and device management. Understanding the unique aspects of medical devices—from rapid technological changes to specific safety concerns—is essential. I hope these insights help you better understand the post-market clinical investigations for medical devices. Whether you’re in the industry or simply interested, staying informed and proactive is key to success in this dynamic field.