How to Code Ambiguous Verbiage in MedDRA for Clinical Trials

Introduction to Ambiguous Verbiage in Adverse Event Reporting

In clinical trials, adverse events (AEs) are initially reported by investigators in verbatim language, often reflecting patient statements or clinical notes. These terms are not always precise. Ambiguous expressions such as “feeling unwell,” “stomach upset,” or “heart problem” pose significant challenges during MedDRA coding. Unlike clear terms like “myocardial infarction” or “rash,” ambiguous terms require coder interpretation, which increases the risk of misclassification and regulatory non-compliance.

Regulators including the FDA, EMA, and CDSCO emphasize that accurate and consistent MedDRA coding is critical for pharmacovigilance and safety signal detection. Incorrect coding due to ambiguity can distort safety analyses and undermine the validity of DSURs, PSURs, and IND safety reports. To address this challenge, sponsors must implement SOPs, coding conventions, and training programs that guide coders in interpreting and coding ambiguous terms consistently.

Examples of Ambiguous Verbiage in Clinical Trials

Ambiguity often arises because investigators record patient experiences in lay language. Below are common examples and potential MedDRA interpretations:

These examples highlight the complexity of coding ambiguous terms. Without adequate conventions, coders may apply different PTs across trials, leading to inconsistent datasets.

Risks of Incorrect Coding Due to Ambiguity

Ambiguous coding errors can have serious consequences:

• Signal distortion: Misclassification of AEs can mask or exaggerate safety signals.
• Regulatory findings: Inspectors often flag inconsistencies in coding of ambiguous terms.
• Data fragmentation: Similar events coded differently across trials prevent accurate pooling of safety data.
• Audit deficiencies: Lack of documentation on coding decisions may be cited as a GCP non-compliance.

For instance, if “fainting” is coded as “Loss of consciousness” in one trial and “Syncope” in another, regulators may question the reliability of cross-study safety analyses. Consistency is therefore paramount in ambiguous coding cases.

Strategies for Handling Ambiguous Verbiage

Sponsors and CROs can manage ambiguity by applying structured strategies:

• Request clarification: Where possible, query the investigator for more detail before final coding.
• Use general PTs: When specifics are lacking, coders may assign broader PTs such as “Malaise.”
• Follow SOP conventions: Coding conventions should define how ambiguous terms are consistently coded.
• Flag for review: Ambiguous cases should undergo medical review by safety physicians.
• Document rationale: Coders should record the reasoning for selected PTs in audit trails.

For example, a sponsor SOP may state: “All reports of ‘feeling unwell’ should be coded as PT ‘Malaise’ unless additional clinical details are available.” Such conventions reduce variability and inspection risks.

Regulatory Expectations and Inspections

Regulators expect coders to demonstrate traceability in coding decisions for ambiguous terms. Common inspection findings include:

• Inconsistent PT selection across similar events.
• Failure to query investigators for clarification.
• Lack of documentation explaining coding rationale.
• Use of auto-coding without manual review of ambiguous terms.

To meet expectations, sponsors should establish coding conventions, maintain training records, and conduct routine audits. Inspection readiness requires evidence that ambiguous coding decisions were consistent, justified, and traceable. Public registries such as the NIHR Be Part of Research platform highlight the importance of standardized terminology for global safety data consistency.

Best Practices for Coders

Best practices for handling ambiguous terms include:

• Maintain detailed coding conventions with common ambiguous terms and assigned PTs.
• Provide refresher training to coders on how to handle vague or incomplete terms.
• Ensure coders escalate complex cases to medical safety officers.
• Review ambiguous terms in coding quality audits.
• Update conventions after each MedDRA version release.

These practices ensure that ambiguous terms are consistently coded and that datasets remain reliable across trials and submissions.

Key Takeaways

Coding ambiguous terms in MedDRA requires coders to balance accuracy, consistency, and regulatory compliance. To achieve this, clinical teams must:

• Recognize common sources of ambiguity in investigator-reported terms.
• Develop SOPs and conventions for standardizing ambiguous coding decisions.
• Document rationale and maintain audit trails for inspection readiness.
• Train coders and escalate complex cases to medical experts.
• Perform quality reviews to ensure consistency across trials.

By following structured strategies, sponsors and CROs can minimize the risks of misclassification, ensure reliable pharmacovigilance data, and meet global regulatory expectations.

Understanding the Hierarchy of MedDRA Terms from LLT to SOC

Introduction to the MedDRA Hierarchical System

The Medical Dictionary for Regulatory Activities (MedDRA) is a standardized terminology used globally to code adverse events in clinical trials and post-marketing surveillance. One of its most powerful features is its hierarchical structure, which allows for flexible analysis of safety data. The hierarchy ranges from very specific patient-reported terms (Lowest Level Terms, LLTs) to broad categories used in regulatory summaries (System Organ Class, SOC).

This structure ensures that data can be reviewed at varying levels of detail. For example, a regulatory reviewer may focus on SOC-level summaries such as “Nervous system disorders,” while a safety physician may need PT-level data on “Convulsions” to understand case-level safety implications. Without this hierarchy, harmonized signal detection and cross-study comparisons would be impossible.

MedDRA’s hierarchy is applied across regulatory submissions, including FDA IND safety reports, EMA EudraVigilance submissions, and DSURs. Its standardized nature ensures global consistency in how adverse events are categorized and reported.

The Five Levels of MedDRA Terms

MedDRA’s structure is comprised of five interconnected levels. Each level rolls up into a broader category, enabling flexibility in data analysis.

1. Lowest Level Term (LLT): The most specific level, often the exact wording used by investigators. Example: “Heart attack.”
2. Preferred Term (PT): A distinct descriptor representing a single medical concept. Example: “Myocardial infarction.”
3. High Level Term (HLT): Groups of related PTs that share a common medical concept. Example: “Ischaemic coronary artery disorders.”
4. High Level Group Term (HLGT): Broader groups of related HLTs. Example: “Coronary artery disorders.”
5. System Organ Class (SOC): The highest level, grouping terms by organ system or etiology. Example: “Cardiac disorders.”

This structured roll-up allows sponsors and regulators to analyze adverse events at different levels of granularity. Investigators may use patient language (“chest pain”), but regulators require consistency across submissions, which MedDRA provides by coding these terms into PTs and SOCs.

Example of Hierarchical Mapping

Below is an illustrative example showing how terms map through the MedDRA hierarchy:

This example demonstrates how LLTs used by investigators are standardized into PTs and then progressively grouped into SOCs for high-level regulatory analysis.

Application of the Hierarchy in Clinical Trials

The MedDRA hierarchy is critical for both operational and regulatory purposes:

• Case-level analysis: Coders assign PTs to investigator terms for precise classification.
• Aggregate analysis: Regulators and safety teams review SOC-level data to detect system-wide toxicity patterns.
• Signal detection: Aggregated PTs under HLTs and HLGTs allow statistical analysis for safety signal identification.
• Regulatory submissions: IND safety reports, DSURs, and PSURs require tabulations at SOC and PT levels.

For example, in oncology trials, individual reports of “low platelets” coded as “Thrombocytopenia” (PT) roll up to the SOC “Blood and lymphatic system disorders,” enabling regulators to quickly assess hematologic toxicity across trials.

Challenges in Using the MedDRA Hierarchy

Despite its strengths, applying MedDRA’s hierarchy presents challenges:

• Ambiguity at LLT level: Investigator terms like “felt unwell” require careful coding to avoid misclassification.
• Overlapping SOCs: Certain PTs may link to multiple SOCs (primary and secondary linkages), complicating analysis.
• Version updates: Twice-yearly MedDRA updates may alter mappings, requiring database reconciliation.
• Consistency issues: Different coders may choose different LLTs for similar investigator terms.

These issues highlight the need for SOPs, coding conventions, and periodic coding reviews. Training coders on version updates and providing case-based examples reduces inconsistency and ensures compliance.

Regulatory Expectations and Audit Readiness

Regulatory agencies such as the FDA, EMA, and CDSCO expect sponsors to demonstrate traceability in their coding practices. During inspections, common findings include:

• Incorrect LLT or PT assignment for investigator terms.
• Failure to reconcile coding after MedDRA version updates.
• Inconsistent mapping of similar events across different studies.
• Lack of coding conventions documentation.

To avoid findings, sponsors must maintain coding guidelines, training logs, and reconciliation records. Regular audits and mock inspections can strengthen inspection readiness. Reference resources such as the EU Clinical Trials Register demonstrate regulatory emphasis on standardized coding practices.

Key Takeaways

The MedDRA hierarchy provides a structured approach to adverse event coding, ensuring accuracy, consistency, and global harmonization. Clinical teams must:

• Understand the five levels of MedDRA: LLT → PT → HLT → HLGT → SOC.
• Apply coding conventions consistently to avoid misclassification.
• Maintain updated databases aligned with new MedDRA versions.
• Document coding decisions for inspection readiness.
• Train coders and CRAs to navigate the hierarchy effectively.

By mastering the MedDRA hierarchy, sponsors and CROs can ensure high-quality safety data, meet regulatory expectations, and protect patients through accurate pharmacovigilance practices.