The new article pays special attention to combination products as a separate category of medical devices, and also highlights the key points related to ethical considerations.

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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 they are 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.

Combination Products

Combination products integrate drugs, devices, and biological products in various forms, including:

  1. Single-Entity Combination Products: Components physically or chemically combined (e.g., drug-eluting stents, prefilled syringes).
  2. Co-Packaged Combination Products: Separate components packaged together (e.g., vaccine vials with delivery devices, first-aid kits).
  3. Cross-Labelled Combination Products: Separate components specifically labeled for joint use (e.g., photosensitizing drug with an activating laser).

The Primary Mode of Action (PMOA) determines regulatory oversight based on the component providing the most important therapeutic action. For instance, a device-biological combination is reviewed as a biological product if the biological component drives its PMOA.

Clinical trials for combination products must address specific safety and efficacy considerations tailored to the product type. For example, drug-eluting stents may require human toxicity studies to establish safety thresholds (e.g., no observed adverse effect levels).

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Ethical Considerations for Clinical Investigations

Ethical principles in clinical investigations are guided by the Declaration of Helsinki and other regulatory standards, focusing on:

  1. Subject Protection:  Rights, safety, and well-being of participants are paramount.   Investigations must be ethically justified and generate meaningful data without unnecessary risks.
  2. Balancing Experimentation and Public Health: Clinical studies should address unanswered safety, performance, and efficacy questions. Risk mitigation is essential to avoid undue harm while obtaining essential data for public health benefits.
  3. Trial Design:  Proper trial design ensures scientific validity and ethical conduct, minimizing discomfort or harm to participants.

Risk Management for Medical Devices

According to the guidance, risk management is a comprehensive, lifecycle-long process for identifying, analyzing, and mitigating risks associated with medical devices. It ensures patient and user safety and complies with standards like ISO 14971 and ISO 10993-1 for risk assessment and biological evaluation.

Key Phases:  

  1. Preclinical Assessment: Biological evaluation identifies potential hazards and evaluates their acceptability.  
  2. Clinical Evaluation: Risks associated with investigational devices and related procedures are assessed before designing clinical investigations.  
  3. Ongoing Monitoring:  Risks are continually evaluated and controlled throughout the device’s lifecycle, including production and post-market phases.

Components of the Risk Management Process

  1. Risk Analysis:  
  • Identifying hazards and estimating associated risks.  
  • Evaluating risks against acceptable thresholds.
  1. Risk Control:  
  • Implementing measures to reduce risks to acceptable levels.  
  • Monitoring the effectiveness of these measures.
  1. Risk Management Report:  
  • Documentation of benefit-risk analysis outcomes.  
  • Demonstrates the device’s safety.
  1. Iterative and Lifecycle Approach  

Risk management activities are revisited and adjusted at different stages of the product lifecycle.

Benefit-Risk Determination

  1. Assessing Benefits  

Factors include:  

  • Type of Benefit: Improved clinical management, quality of life, reduced morbidity.  
  • Magnitude: Scale or endpoint-based evaluation of improvements.  
  • Probability: Likelihood of patient benefit across populations.  
  • Duration: Longevity of benefits, from temporary relief to curative outcomes.
  1. Assessing Risks  

Factors include:  

  • Severity and Types of Harm: From minor to debilitating or permanent injuries.  
  • Probability: Likelihood of harm occurring in the intended population.  
  • Duration of Harm: Temporary, reversible harm versus long-term or irreversible injury.  
  1. Additional Considerations:  
  • Uncertainty: Poor trial design or analysis can reduce data reliability.  
  • Patient Perspectives: Varying risk tolerance and preferences influence decisions.  
  • Disease Characterization: Severity, natural progression, and treatability of the condition.  
  • Patient-Centric Assessments: Use of validated outcomes like quality of life scores to gauge device impact.

Ethical and Risk Management Integration in Clinical Investigations

The guidance further explains how the above two important aspects should be integrated into clinical investigations in order to ensure the accuracy of the results while also ensuring the safety of patients. 

  1. Ethical Safeguards:  
  • Trials must ensure scientific validity and minimize undue risks.  
  • Ethical considerations guide risk assessments and influence trial design.  
  1. Risk Monitoring in Trials:  
  • Hazards identified during clinical investigations are evaluated and managed through iterative assessments.  
  • Immediate suspension or termination is mandated for unmanageable risks.
  1. Final Outcomes:  
  • A comprehensive risk management report integrates findings into the clinical evaluation process.  
  • Ensures that all risks are appropriately balanced against potential benefits.

Conclusion

n summary, combination products and medical devices require robust frameworks for ethical and risk-based assessments. The manufacturers or other parties responsible for clinical investigations can ensure the safety, effectiveness, and ethical integrity of clinical investigations by integrating risk management principles throughout the product lifecycle. Clear benefit-risk determinations, coupled with patient-centric and disease-specific considerations, support the highest standards of public health protection and innovation, ensuring they are properly balanced.

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