Literature Review

A literature review in the medical device context is a systematic process of identifying, evaluating, and analyzing all relevant published scientific and clinical data to support the safety and performance claims of a medical device. This is a fundamental component of clinical evaluation required by regulations worldwide, particularly under EU MDR.

Regulatory requirements:

EU MDR Clinical Evaluation (Annex XIV):
- Literature review is mandatory for all medical devices
- Must follow systematic methodology per MEDDEV 2.7/1 Rev 4
- Required to demonstrate equivalence to similar devices
- Updates necessary throughout device lifecycle
- Critical for devices without clinical investigations

FDA Premarket Submissions:
- Literature data can support 510(k) substantial equivalence
- Required for PMA scientific justification
- Important for De Novo classification requests
- Supports safety and effectiveness determination

ISO 14155 Clinical Investigations:
- Literature review informs clinical investigation design
- Background for investigational plan
- Supports sample size and endpoint selection
- Identifies known risks and benefits

MEDDEV 2.7/1 Rev 4 methodology:

This European guidance document provides the framework for conducting clinical evaluations through systematic literature review:

Stage 0: Planning
- Define scope and objectives
- Establish search strategy and criteria
- Develop literature review protocol
- Define appraisal criteria
- Assign qualified personnel

Stage 1: Identification of Relevant Data
- Comprehensive literature search
- Multiple database searches
- Hand searching of relevant journals
- Review of regulatory databases
- Consultation with clinical experts

Stage 2: Appraisal of Relevant Data
- Assess scientific validity of each publication
- Evaluate methodological quality
- Determine relevance to subject device
- Weight evidence based on study design
- Identify biases and limitations

Stage 3: Analysis of Clinical Data
- Extract relevant data systematically
- Synthesize findings across studies
- Assess consistency of results
- Identify gaps in evidence
- Determine adequacy for supporting claims

Stage 4: Clinical Evaluation Report
- Comprehensive documentation of process
- Conclusions on safety and performance
- Identification of residual risks
- Post-market surveillance plan
- Recommendations for additional studies

Literature search methodology:

Database Selection:
Primary medical databases to search:
- PubMed/MEDLINE - Comprehensive biomedical literature
- EMBASE - European pharmaceutical and medical database
- Cochrane Library - Systematic reviews and clinical trials
- Web of Science - Cross-disciplinary research
- IEEE Xplore - For software and electronic devices
- Google Scholar - Broad academic search

Specialized databases:
- ClinicalTrials.gov - Ongoing and completed clinical trials
- MAUDE - FDA adverse event database
- EUDAMED - European device vigilance data
- Manufacturer websites - Instructions for use and technical documentation

Search Strategy Development:

1. PICO Framework:
- Population - Target patient group
- Intervention - Device or technology being evaluated
- Comparator - Alternative treatments or predicate devices
- Outcome - Clinical endpoints and safety measures

2. Search Terms:
- Medical Subject Headings (MeSH) terms
- Free-text keywords and synonyms
- Device-specific terminology
- Boolean operators (AND, OR, NOT)
- Truncation and wildcard symbols

3. Inclusion/Exclusion Criteria:
- Publication date ranges
- Language restrictions
- Study types (RCTs, observational, case reports)
- Patient populations
- Relevant outcomes
- Quality thresholds

Example Search String:
("total knee replacement" OR "knee arthroplasty" OR "TKR") AND ("clinical outcomes" OR "safety" OR "complications") AND ("randomized controlled trial" OR "cohort study") AND (2015:2025[pdat])

Appraisal of literature quality:

Study Design Hierarchy (strongest to weakest evidence):
1. Systematic reviews and meta-analyses - Synthesis of multiple studies
2. Randomized controlled trials (RCTs) - Gold standard for efficacy
3. Prospective cohort studies - Follow patients over time
4. Case-control studies - Compare cases with controls
5. Cross-sectional studies - Snapshot at single timepoint
6. Case series - Multiple patient cases
7. Case reports - Individual patient experiences
8. Expert opinions - Clinical consensus

Quality Assessment Tools:
- GRADE (Grading of Recommendations Assessment, Development and Evaluation)
- Cochrane Risk of Bias Tool for RCTs
- Newcastle-Ottawa Scale for observational studies
- ROBINS-I for risk of bias in non-randomized studies
- CASP (Critical Appraisal Skills Programme) checklists

Data extraction and synthesis:

Structured Data Extraction:
Create standardized forms to capture:
- Study design and methodology
- Patient demographics and sample size
- Device specifications and comparators
- Primary and secondary endpoints
- Adverse events and complications
- Follow-up duration
- Statistical analyses and results
- Study limitations and biases
- Relevance to subject device

Evidence Synthesis Approaches:
- Qualitative synthesis - Narrative summary of findings
- Quantitative synthesis (meta-analysis) - Statistical pooling when appropriate
- Subgroup analyses - Examination of specific populations or configurations
- Sensitivity analyses - Testing robustness of conclusions

Demonstrating equivalence:

For EU MDR, literature review often supports equivalence claims:

Technical Equivalence:
- Same materials, design, and specifications
- Similar manufacturing processes
- Identical intended purpose
- Comparable performance characteristics

Biological Equivalence:
- Same tissue contact
- Similar duration of contact
- Identical chemical composition
- Comparable biocompatibility profile

Clinical Equivalence:
- Same clinical indications and contraindications
- Comparable patient populations
- Similar clinical outcomes
- Equivalent safety profile

Challenges in literature review:

Publication Bias:
- Positive results more likely to be published
- Industry-sponsored studies may favor products
- Small studies with null results often unpublished
- Mitigation: Search grey literature, trial registries

Heterogeneity:
- Different study designs and methodologies
- Varying patient populations
- Non-standardized outcome measures
- Different follow-up durations

Limited Literature:
- Novel devices may lack published data
- Rare indications with small patient populations
- Proprietary devices without public data
- Recent devices with insufficient long-term data

Relevance Assessment:
- Devices may differ in important ways from subject device
- Changing medical practice and standards of care
- Different regulatory environments
- Generalizability to target population

Documentation requirements:

Literature Review Protocol:
- Search strategy and rationale
- Database and date ranges
- Inclusion/exclusion criteria
- Appraisal methodology
- Data extraction plan
- Analysis approach

Literature Search Record:
- Search strings and results
- Number of hits per database
- Screening and selection process
- PRISMA flow diagram
- Reasons for exclusion

Appraisal Documentation:
- Quality assessment for each study
- Risk of bias evaluation
- Relevance justification
- Evidence tables
- Critical analysis

Clinical Evaluation Report:
- Comprehensive analysis of all data
- Integration with clinical investigation data
- Safety and performance conclusions
- Risk-benefit analysis
- Post-market surveillance plan
- Updates and addendums

Updating literature reviews:

Literature reviews are living documents requiring regular updates:

EU MDR Requirements:
- Annual update for implantable devices
- Updates when new safety information emerges
- Integration of post-market clinical follow-up data
- Revision for design changes or new indications

Triggers for Updates:
- Adverse event trends or recalls
- New clinical studies published
- Regulatory actions on similar devices
- Changes to standards of care
- Expansion to new markets or indications

Best practices for literature review:

1. Develop detailed protocol before beginning searches
2. Use multiple databases to ensure comprehensiveness
3. Document everything including search strategies and excluded studies
4. Involve clinical experts in appraisal and interpretation
5. Assess quality rigorously using validated tools
6. Be transparent about limitations and gaps
7. Update regularly to maintain current evidence base
8. Integrate with other clinical data for complete evaluation
9. Maintain objectivity and avoid cherry-picking favorable studies
10. Plan for post-market surveillance to address evidence gaps