US Clinical and Pre-Clinical Regulations for Medical Devices

Good Clinical Practices (GCPs)

  • Definition: Internationally accepted scientific and ethical quality standards for designing, conducting, recording, and reporting clinical trials involving human subjects.
  • Scope: Includes design, conduct, performance, auditing, recordkeeping, analysis, and reporting.
  • Application: When local GCP regulations don't address an issue, consult company procedures, Ethics Committees, IRBs, and Regulatory Authorities.
  • ISO 14155:2020: Specific to clinical investigations of medical devices for human subjects; recognized by FDA and international agencies.

Purpose of GCPs

  • Subject Rights: Ensures the protection of human subjects' rights to safety, confidentiality, and well-being.
    • Rights include being informed, choosing not to participate, withdrawing at any time, and having privacy respected.
  • Data Integrity: Guarantees the high quality, credibility, accuracy, and reliability of collected data.
  • Roles and Responsibilities: Defines the roles and responsibilities of groups involved in clinical research.

Historical Overview of GCPs

GCPs were developed in response to tragic events where individual rights and safety were compromised:

  • Sulfanilamide Disaster
  • World War II Experiments
  • Tuskegee Syphilis Study

Clinical Trials for Medical Devices

  • Requirement: Not all submissions require clinical trials.
  • Factors: Depends on:
    • Device development stage.
    • Risk class (Class I, II, or III).
    • Market entry mechanism (510(k) or PMA).
  • PMA: PMA applications typically require clinical trials.
  • 510(k): Only some 510(k) applications require clinical or preclinical trials.
  • HUD: Humanitarian Use Devices may enter the market via a Humanitarian Device Exemption (HDE) application, with special exceptions.

Types of Medical Device Clinical Trials

1. Preclinical Trials and Bench Testing
  • Requirement: May be required based on the new device's risk level before human testing.
  • Use: Can provide evidence for substantial equivalence in the 510(k) process, potentially removing the need for clinical trials.
2. Early Feasibility Studies (Pilot Trials)
  • Definition (FDA): Limited clinical investigation early in development, before the device design is finalized for a specific indication.
  • Focus: Prototype development, including first-in-human (FIH) studies.
  • IDE: For nonsignificant risk devices eligible for an Investigational Device Exemption (IDE), trials may be iterative.
  • Timing: Can run concurrently with traditional feasibility or pivotal trials.
3. Traditional Feasibility Study
  • Definition (FDA): Clinical investigations to gather preliminary safety and effectiveness data on a near-final or final device design to plan an appropriate pivotal study.
  • Timing: Conducted later in the device development process, with a final or near-final device configuration.
4. Pivotal Study
  • Purpose: To collect definitive safety and effectiveness evidence for a device's intended use.
  • Requirement: Required for some 510(k) and all PMA submissions.
  • Similarity: Analogous to Phase 3 pharmaceutical studies, needing a statistically justified subject number.
5. Postmarket Surveillance Studies
  • Also Known As: Post-Approval Studies (PAS) in the US.
  • Requirement: May be required upon PMA/HDE approval or PDP application.

Drug and Biologic Clinical Trial Phases

  • Each phase gathers specific information about a new treatment's dose, safety, and efficacy.
Pre-Clinical
  • Animal Testing
Phase 1
  • Subjects: Healthy volunteers, typically 20-100.
  • Focus: Safety and dosage determination; first-in-human trials.
Phase 2
  • Subjects: Patient population, several hundred.
  • Focus: Efficacy and side effects.
Phase 3 (Pivotal)
  • Subjects: Patient population, 300-3,000 volunteer patients.
  • Focus: Efficacy and monitoring of adverse reactions (ARs).
Phase 4 (Post Marketing)
  • Subjects: Approved patient population, several thousand patients.
  • Focus: Safety and efficacy in long-term use.

Phase 1 Trials

  • First-in-human Trials: Initial human exposure to evaluate metabolism, pharmacologic action, safe dosage range, side effects, and early effectiveness.
  • Protocol Submission: Sponsors must submit a study protocol to the FDA before starting.
  • Group Size: Small, 10-80 subjects.

Phase 2 Trials

  • Purpose: To study effectiveness and further evaluate safety after dose establishment.
  • Group Size: Medium, 100-300 subjects.

Phase 3 Trials

  • Purpose: Confirm effectiveness, monitor side effects, compare to common treatments, and collect safety information.
  • Design: Often randomized, multicenter trials with long durations (several years).
  • Group Size: Large, hundreds to thousands of subjects.
  • Timing: Regulatory review occurs around this phase.

Phase 4 Trials

  • Purpose: Postmarket studies to gather information on long-term effectiveness and side effects.
  • Conduct: In compliance with the investigational plan, signed agreement, federal regulations, and IRB conditions.

FDA Protocol Review

  • Requirement: Device studies must be conducted under an IDE.
  • Class II and III Devices: Sponsors must submit the protocol in the investigational plan to the FDA and IRB for approval.
  • Nonsignificant Risk Devices: Only IRB approval is required.
  • IRB Disagreement: If IRB disagrees with nonsignificant risk determination, it must be reported to FDA within five working days.

Clinical Investigation Plan (Protocol)

  • Synonymity: "Protocol" and "Clinical Investigation Plan (CIP)" are synonymous per ISO GCP.
  • Contents: Detailed in ISO 14155:2020.

Protocol Amendments and Changes

  • ISO 14155:2020: Requires controlled version numbers, dates, and rationales for amendments.
  • FDA Submission: Changes impacting an IDE application should be submitted to FDA within five business days.

Protocol Deviations

  • Definition (ISO 14155:2020): Any failure to follow CIP or protocol requirements, intentional or unintentional.
  • US GCP: Special documentation requirements, with a mandatory five-day reporting window for emergency deviations.

Informed Consent Process

  • Elements: Providing sufficient information, facilitating understanding, allowing questions, and obtaining voluntary agreement.
  • Ongoing Information: Continue providing information as the investigation progresses.

Informed Consent Form

  • Purpose: Provides information about the drug/biologic and trial; documents voluntary agreement.
  • Required Elements: (1) Description of the clinical investigation, (2) Risks and discomforts, (3) Benefits, (4) Alternative procedures, (5) Confidentiality, (6) Compensation, (7) Medical treatment for injury, (8) Contacts and voluntary participation.

Institutional Review Board (IRB)

  • Definition: A group of at least five members with varied backgrounds, including scientific and non-scientific members, and someone unaffiliated with the institution, designated to review and monitor biomedical research involving human subjects to ensure their rights and welfare are protected.

Types of IRB Review

  • 1. Exempt from IRB Review: For emergency use.
  • 2. Expedited Review
  • 3. Full Board (convened) Review
    *Based on study type and risk.

Regulatory Oversight (January 2009 FDA Ruling)

  • All US IRBs reviewing FDA-regulated clinical studies must register through an HHS system.
  • Facilitates FDA inspections and educational information dissemination.

Responsibilities

  • Review clinical investigations.
  • Approve sponsor's nonsignificant risk determination.

Multi-Center Study

  • An institution's IRB can:
    • Serve as a central IRB.
    • Rely on a centralized IRB's review.
    • Conduct its own study review.

Sponsor and Contract Research Organization (CRO)

  • Sponsor Definition: A person who takes responsibility for and initiates a clinical investigation; can be an individual or a company.

Record Keeping & Retention

  • Drug and biologic sponsors must retain all records associated with a clinical study, including:
    • Correspondence with sponsors, monitors, investigators, IRBs, and FDA.
    • Investigational product receipt, shipment, and disposition.
    • Signed investigator agreements and financial disclosure information.

Regulatory Oversight (Sponsor Inspections)

  • Used to confirm subject rights, safety, and welfare; determine data accuracy; and assess compliance with FDA regulations.

Responsibilities

  • All trial operational aspects, ensuring:

    • Clinical studies are conducted properly for FDA submission.
    • Clinical subject rights and welfare are protected.

  • 21 CFR 312.52: Sponsors may transfer responsibilities to a CRO, except for overall study oversight. CROs assuming obligations must comply with applicable regulations and are subject to the same regulatory actions as sponsors.

Clinical Investigators

  • Definition (21 CFR 312.3): An individual who conducts the clinical investigation, under whose direction the drug is administered or dispensed. If a team is involved, the investigator is the responsible leader.

Record Keeping & Retention

  • (1) Disposition of the drug or biologic.
  • (2) Adequate and accurate case histories.
  • (3) Annual clinical trial progress reports.
  • (4) Safety Reports.
  • (5) Final report upon completion.
  • (6) Financial disclosure reports.
  • Retention Period: Investigators must retain all relevant records for 2 years following the date the drug/biologic marketing application is approved for the indication under investigation.

Regulatory Oversight (Investigator Inspections)

  • FDA inspects investigator sites for compliance with regulations.
  • FDA may impose a clinical hold if subjects face unreasonable risk of illness or injury.
  • Medical device investigations are conducted under 21 CFR part 812 and ISO 14155:2020 10.

Responsibilities

  • (1) Protecting subject rights, safety, and welfare.
  • (2) Controlling investigational products.
  • (3) Ensuring informed consent.
  • (4) Ensuring trials are conducted according to the investigator statement, investigational plan, and regulations.
  • Clinical investigators must ensure IRB complies with FDA regulations and conducts ethical reviews.

Clinical Trial Monitoring and Auditing

Purpose of Monitoring

  • To protect human subjects, collect complete, accurate data, and conduct high-quality, compliant studies.

FDA Requirement

  • Sponsors must monitor their clinical investigation’s conduct and progress.

Monitor Qualifications

  • Appropriate training.
  • Scientific and/or clinical knowledge.
  • Familiarity with the investigational product, documentation, SOPs, GCPs, and regulations.

Monitor Responsibilities

  • Acts as the main communication line between sponsor and investigator.
  • Verifies investigator qualifications and resources.
  • Verifies investigational product storage, supply, receipt, use, and disposition.
  • Checks case report form accuracy and completeness and AEs reporting.

Monitoring Activities

On-Site (In Person) Monitoring
  • Important early in the study.
  • Verifies subject enrollment, study documentation, identifies data entry errors, assess the site’s consenting process familiarity/compliance with protocol and procedures.
Remote (Off Site) or Centralized Monitoring
  • Supplements or reduces on-site monitoring.
  • Monitors data quality through routine data review, statistical analysis to identify data trends, analyzes performance metrics.
Risk-Based Monitoring
  • Identifies and analyzes risks and determines whether they need to be modified by implementing controls.
  • Focus on preventing/mitigating important and likely sources of error in conduct, collection, and reporting of critical data.
  • FDA recommends sponsors proactively identify critical data/processes and perform risk assessments.

Monitor Reports

  • Monitors submit written reports to the sponsor after each site visit or communication, including the date, site, monitor name, investigator name, concerns, findings and recommended actions.

Monitoring and Data Monitoring Committee (DMC)

  • For medical device trials, monitoring differs from oversight by a DMC, which provides additional oversight of clinical trial data.

Quality Assurance (Auditing)

  • Per FDA's Compliance Program Guidance Manual 7348.810, clinical trial quality assurance departments/units are not required by regulation to perform independent audits or data verifications.
  • Auditing personnel should be independent and separate from routine monitoring and quality control functions.
  • Per ICH E6, Section 5.19 (Audit), sponsors should select qualified auditors who have written audit procedures.
  • All audit observations and findings must be documented.

Reporting Adverse Events/Adverse Device Effects

  • UADE (in medical device clinical trial): Any serious adverse effect on health or safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the investigational plan or application.
  • Investigators must submit UADE reports to the IRB and sponsor as soon as possible, but no later than 10 working days after discovery.
  • Sponsors must evaluate UADEs and report results to FDA and IRBs within 10 working days of receipt.

Reporting Device Deficiencies

  • Any inadequacy of a medical device with respect to its identity, quality, durability, reliability, safety or performance, even if it did not lead to an adverse event.
  • Device deficiencies should be documented and reported to the sponsor.

Good Documentation Practice (GDP)

  • All clinical trial personnel are responsible for maintaining complete and accurate records.
  • Regulatory agency approvals depend on data accuracy and integrity.

ALCOA

  • Attributable: Clear indication of who and when recorded the information.
  • Legible: Information is easily understood and permanently recorded.
  • Contemporaneous: Information recorded at the time of occurrence.
  • Original: Source information is accessible and preserved in its original form.
  • Accurate: Recorded information clearly and without error describe the documented study events.

Recordkeeping (Medical Device)

  • Must comply with 21 CFR and ISO GCP requirements.
  • ISO GCP requires printed versions of electronic source documents to contain a signature, date, and a statement indicating that contents represent a true reproduction of the original source date and the use of a delegation log.

Device Accountability

  • The control of investigational devices used in the clinical investigation, which should be only those in the protocol or CIP.
  • ISO GCP requires sponsors to keep records of all investigational devices’ physical locations, from shipment to return/disposal.

Essential Clinical Investigation Documents and Archival (Medical Devices)

  • ISO 14155:2020 requires the sponsor and principal investigator to take measures to prevent the accidental or premature destruction of documents and transfer changes of custody for records at both the site and sponsor facilities.
  • US law requires essential documents be retained for two years, and the manufacturer has 10 working days to notify FDA of applicable record transfers.

Quality Assurance and BIMO

  • CDRH’s Division of Bioresearch Monitoring (DBM or BIMO) is responsible for inspections as well as EIR reviews for IDE, PMA, PDP, HDE, 510(k), routine surveillance of IRBs and nonclinical laboratories conducting animal research with medical devices.

Harmonized Medical Device GCPs (ISO-GCP)

  • By the 1970s and 1980s, drug and device clinical trials had advanced dramatically. To reduce the burden of repetition to meet various regulatory standards across the globe, GCP standards were developed to establish harmonized global clinical trial requirements.

Development

  • In 1996, ICH convened to produce harmonized GCP guidelines for drugs, and an international initiative was undertaken to specify harmonized guidelines for medical device clinical trials.
  • ISO 10993-8 Biological testing of medical and dental materials and devices: Clinical investigations was developed. ( Based on EN 540-:1993 Clinical Investigation of Medical Devices for Human Subjects)

Predecessors of ISO-GCP

  • ISO 10993 and BS EN 540

ISO GCP (ISO 14155)

  • ISO’s GCP: ISO 14155-1:2003 Clinical investigation of medical devices for human subjects – Part 1: General requirements was introduced in 2003 but was deemed to not be as rigorous as ICH’s GCP.
  • Second version: ISO 14155-1: 2011 Clinical investigation of medical devices for human subjects – Good clinical practice (Combines Part 1 and 2 of ISO 14155-1:2003 and reflects alignment with ICH’s GCP)
  • Third version ISO 14155:2020 aligns more closely with other international standards to ensure the standard remains globally acceptable. ( Emphasizes the role of ISO 14971 risk management principles at all stages of clinical investigation )

FDA Recognition of ISO-GCP for Medical Device Trials

  • FDA formally recognized ISO 14155 in 2012 – added to Federal Register in 2012.
  • In January 2014, ISO 14155 has been listed in FDA’s Recognized Consensus Standards database.

ISO-GCP for Non-US Trials Supporting US Submissions

  • April 28, 2008 – FDA issued a ruling that modified 21 CFR 312.120 to state that FDA will accept foreign clinical study involving a medical device not conducted under an IDE study if it adheres to the Declaration of Helsinki (1983 version) ethical principles or the laws and regulations of the country where the clinical trial was conducted.

US CFR and ISO GCP

  • US and EU formally recognize ISO 14155, but not all global member bodies recognize and enforce the same for medical devices.
  • ISO GCP is not mandated by US law, so US medical device clinical trials must comply with ISO 14155 and applicable sections of 21 CFR.