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\begin{document}
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\title{Do Data Monitoring Committees Scale with Clinical Trial Risk? A Large-Scale Evaluation of Oversight Gaps in ClinicalTrials.gov}
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\titlerunning{Supplementary Material}
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\author{Francis Osei\inst{1}}

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\authorrunning{Do Data Monitoring Committees Scale with
Clinical Trial Risk?}
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\institute{Bayezian Limited\\
\email{francis@bayezian.com}}

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%\begin{abstract}
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%\section*{Supplementary Material}


This supplementary material provides additional methodological detail, validation summaries, extended therapeutic-area results, regression outputs, and secondary figures supporting the main manuscript. The material is directly relevant to the article conclusions and is provided to support transparency and reproducibility.

\subsection{Supplementary Tables}

\begin{table}[htbp]
\centering
\begin{threeparttable}
\caption{Dataset structure and extracted ClinicalTrials.gov variables.}
\label{tab:supp_dataset_structure}
\begin{tabular}{p{0.28\textwidth} p{0.62\textwidth}}
\toprule
\textbf{Variable domain} & \textbf{Extracted variables} \\
\midrule
Trial identifiers & NCT identifier, brief title, official title \\
Trial status and dates & Overall status, reason stopped, start date, primary completion date, completion date \\
Oversight & ClinicalTrials.gov Data Monitoring Committee field, registry-reported DMC presence \\
Study design & Study type, phase, allocation, intervention model, masking, primary purpose \\
Population & Enrolment, minimum age, maximum age, sex \\
Sponsor & Sponsor class \\
Clinical context & Conditions, keywords, therapeutic area \\
Interventions & Intervention types, intervention names \\
Outcomes & Primary outcomes, secondary outcomes, outcome time frames \\
Derived variables & Trial duration, late-phase status, serious-condition flag, serious-endpoint flag, vulnerable age population flag, large-enrolment flag, long-duration flag, regulated-intervention flag, DMC-indicated status \\
Secondary analysis variables & Termination category, termination category confidence, LLM adjudication flag where applicable \\
\bottomrule
\end{tabular}
\begin{tablenotes}[flushleft]
\footnotesize
\item \textit{Note:} DMC, Data Monitoring Committee; LLM, large language model. The registry-reported DMC variable was derived from the ClinicalTrials.gov DMC oversight field and was not independently verified against protocols, statistical analysis plans, DMC charters, or regulatory submissions.
\end{tablenotes}
\end{threeparttable}
\end{table}

\begin{table}[htbp]
\centering
\begin{threeparttable}
\caption{DMC-indicated risk proxy definitions.}
\label{tab:supp_risk_proxy}
\begin{tabular}{p{0.24\textwidth} p{0.66\textwidth}}
\toprule
\textbf{Component} & \textbf{Definition used in analysis} \\
\midrule
Late phase & Trial reported as Phase III or Phase IV. \\
Serious condition & Trial condition, keyword, therapeutic area, brief title, or official title indicated a serious or life-threatening disease context using prespecified rule-based terms. \\
Serious endpoint & Primary or secondary outcome measures or time frames included terms related to mortality, survival, serious adverse events, dose-limiting toxicity, hospitalisation, intensive care, ventilation, stroke, myocardial infarction, major adverse cardiovascular events, organ failure, transplantation, or disability. \\
Vulnerable age population & Eligibility included children or was restricted to older adults. Older-adult restriction was defined as a minimum eligible age of at least 65 years. \\
Large enrolment & Planned or actual enrolment of at least 500 participants. \\
Long duration & Trial duration of at least 24 months from start date to completion date or primary completion date. \\
Regulated intervention & Intervention type included drug, biological, device, genetic, radiation, or combination-product intervention. \\
Primary DMC-indicated definition & Interventional trials meeting at least one tiered criterion: Tier 1, serious condition, serious endpoint, or vulnerable age population; Tier 2, Phase III or IV plus at least one additional risk feature; or Tier 3, regulated intervention plus large enrolment or long duration. Phase III or IV status alone and regulated intervention alone were not sufficient. \\
Broad DMC-indicated definition & Interventional trials with at least one of the seven predefined risk features. \\
Strict DMC-indicated definition & Interventional trials meeting a Tier 1 criterion plus either Tier 2 or Tier 3 compound risk evidence. \\
\bottomrule
\end{tabular}
\begin{tablenotes}[flushleft]
\footnotesize
\item \textit{Note:} DMC, Data Monitoring Committee. The DMC-indicated variable was used as a regulatory-risk proxy for research purposes and was not interpreted as a legal determination that a DMC was required.
\end{tablenotes}
\end{threeparttable}
\end{table}

\begin{table}[htbp]
\centering
\begin{threeparttable}
\caption{Full therapeutic-area coverage among DMC-indicated trials, ordered from lowest to highest coverage.}
\label{tab:supp_therapeutic_area}
\begin{tabular}{lrrr}
\toprule
\textbf{Therapeutic area} & \textbf{DMC-indicated trials} & \textbf{With DMC (\%)} & \textbf{Coverage index} \\
\midrule
Dermatology & 1,092 & 24.63 & 0.656 \\
Endocrine/Metabolic & 5,640 & 31.93 & 0.850 \\
Respiratory & 4,336 & 33.16 & 0.883 \\
Rheumatology/Immunology & 2,632 & 33.21 & 0.885 \\
Neurology & 6,398 & 33.53 & 0.893 \\
Psychiatry & 4,421 & 33.84 & 0.901 \\
Other/Unclassified & 54,874 & 34.47 & 0.918 \\
Ophthalmology & 634 & 35.02 & 0.933 \\
Obstetrics/Gynaecology & 969 & 37.25 & 0.992 \\
Cardiovascular & 10,089 & 39.41 & 1.050 \\
Gastroenterology & 1,587 & 42.16 & 1.123 \\
Infectious disease & 11,357 & 42.49 & 1.132 \\
Oncology & 28,662 & 43.80 & 1.167 \\
Haematology & 2,066 & 47.58 & 1.267 \\
Genetic/Rare & 358 & 55.59 & 1.481 \\
\bottomrule
\end{tabular}
\begin{tablenotes}[flushleft]
\footnotesize
\item \textit{Note:} DMC, Data Monitoring Committee. The coverage index is the therapeutic-area DMC coverage divided by overall DMC coverage among DMC-indicated trials. Values below 1.00 indicate below-average coverage, while values above 1.00 indicate above-average coverage.
\end{tablenotes}
\end{threeparttable}
\end{table}


\begin{table}[htbp]
\centering
\scriptsize
\begin{threeparttable}
\caption{Logistic regression outputs for registry-reported DMC use among interventional trials.}
\label{tab:supp_regression}
\begin{tabular}{llrrrr}
\toprule
\textbf{Model} & \textbf{Predictor} & \textbf{OR} & \textbf{95\% CI lower} & \textbf{95\% CI upper} & \textbf{p-value} \\
\midrule
Primary & Academic sponsor & 2.84 & 2.44 & 3.30 & $<0.001$ \\
Primary & NIH sponsor & 0.72 & 0.63 & 0.81 & $<0.001$ \\
Primary & Other sponsor & 1.32 & 1.29 & 1.36 & $<0.001$ \\
Primary & DMC-indicated & 2.13 & 2.08 & 2.19 & $<0.001$ \\
Primary & Start year, centred & 0.96 & 0.95 & 0.96 & $<0.001$ \\
\midrule
Broad sensitivity & Academic sponsor & 3.16 & 2.72 & 3.67 & $<0.001$ \\
Broad sensitivity & NIH sponsor & 0.82 & 0.72 & 0.92 & 0.001 \\
Broad sensitivity & Other sponsor & 1.40 & 1.36 & 1.44 & $<0.001$ \\
Broad sensitivity & Broad DMC-indicated & 2.07 & 2.00 & 2.14 & $<0.001$ \\
Broad sensitivity & Start year, centred & 0.95 & 0.95 & 0.96 & $<0.001$ \\
\midrule
Strict sensitivity & Academic sponsor & 2.78 & 2.38 & 3.25 & $<0.001$ \\
Strict sensitivity & NIH sponsor & 0.65 & 0.58 & 0.74 & $<0.001$ \\
Strict sensitivity & Other sponsor & 1.50 & 1.46 & 1.54 & $<0.001$ \\
Strict sensitivity & Strict DMC-indicated & 2.89 & 2.81 & 2.98 & $<0.001$ \\
Strict sensitivity & Start year, centred & 0.97 & 0.97 & 0.97 & $<0.001$ \\
\midrule
Component-based & Academic sponsor & 2.98 & 2.55 & 3.49 & $<0.001$ \\
Component-based & NIH sponsor & 0.68 & 0.60 & 0.77 & $<0.001$ \\
Component-based & Other sponsor & 1.80 & 1.74 & 1.85 & $<0.001$ \\
Component-based & Late phase & 1.36 & 1.31 & 1.41 & $<0.001$ \\
Component-based & Large enrolment & 1.51 & 1.44 & 1.58 & $<0.001$ \\
Component-based & Regulated intervention & 1.75 & 1.71 & 1.81 & $<0.001$ \\
Component-based & Long duration & 1.63 & 1.59 & 1.67 & $<0.001$ \\
Component-based & Serious condition & 1.47 & 1.43 & 1.51 & $<0.001$ \\
Component-based & Vulnerable population & 1.27 & 1.23 & 1.31 & $<0.001$ \\
Component-based & Serious endpoint & 1.63 & 1.58 & 1.68 & $<0.001$ \\
Component-based & Start year, centred & 0.99 & 0.99 & 1.00 & $<0.001$ \\
\bottomrule
\end{tabular}
\begin{tablenotes}[flushleft]
\footnotesize
\item \textit{Note:} DMC, Data Monitoring Committee; OR, odds ratio; CI, confidence interval; NIH, National Institutes of Health. Industry sponsor was the reference category in all models. Each model included 145,201 interventional trials. Results are interpreted as associations and not causal effects.
\end{tablenotes}
\end{threeparttable}
\end{table}



\clearpage
\subsection{Supplementary Figures}
The following supplementary figures provide extended descriptive analyses that support, but do not replace, the primary risk-coverage findings in the main manuscript. These figures examine DMC reporting by sponsor and therapeutic area, oversight gaps among DMC-indicated trials, documented termination reasons, and temporal patterns in DMC prevalence by phase and sponsor type.


\begin{figure}[htbp]
\centering
\includegraphics[width=0.95\textwidth]{fig_oversight_gap_heatmap.png}
\caption{Oversight gap among DMC-indicated trials by sponsor type and therapeutic area. The heatmap shows the percentage of DMC-indicated trials without registry-reported DMC oversight across sponsor and therapeutic-area strata. Higher values indicate larger reporting gaps. This figure extends the main oversight-gap analysis by showing that under-reporting or non-use of DMC oversight is patterned by both sponsor type and therapeutic area.}
\label{fig:supp_oversight_gap_heatmap}
\end{figure}


\begin{figure}[htbp]
\centering
\includegraphics[width=0.95\textwidth]{fig_termination_by_dmc.png}
\caption{Termination category rates by registry-reported DMC status among stopped trials with a documented reason. Bars show the percentage of stopped trials in each structured termination category, stratified by DMC reporting status. Trials reporting DMC use had higher proportions of safety-related and futility-related stopping categories, whereas trials without reported DMC use had a higher proportion of administrative stopping categories. This analysis is exploratory and descriptive; it does not imply that DMC presence caused trial termination or determined the recorded stopping reason.}
\label{fig:supp_termination_by_dmc}
\end{figure}


\begin{figure}[htbp]
\centering
\includegraphics[width=0.95\textwidth]{fig_trend_by_phase_year.png}
\caption{Annual registry-reported DMC prevalence by trial phase, excluding trials with phase recorded as not applicable. Lines show the percentage of trials reporting DMC use by start year and phase category. This figure provides temporal context for DMC reporting patterns across trial phases. It is secondary to the main risk-coverage analysis because annual estimates may be influenced by changes in trial mix and by small numbers in some phase-year strata.}
\label{fig:supp_trend_phase_year}
\end{figure}


\begin{figure}[htbp]
\centering
\includegraphics[width=0.95\textwidth]{fig_trend_by_sponsor_year.png}
\caption{Annual registry-reported DMC prevalence by sponsor type. Lines show the percentage of trials reporting DMC use by start year and sponsor category. This figure provides descriptive temporal context for sponsor-level differences in DMC reporting. It should be interpreted as a descriptive trend analysis rather than evidence of causal change over time.}
\label{fig:supp_trend_sponsor_year}
\end{figure}


\newpage
\subsection*{Supplementary Methods: LLM-assisted adjudication and audit checks}
This supplementary section provides additional detail on the limited LLM-assisted adjudication used in the analysis pipeline. The main manuscript describes the rule-based DMC-indicated proxy, the extracted ClinicalTrials.gov variables, and the main statistical analyses. The purpose of this section is therefore restricted to documenting where LLM review was available in the pipeline, how it was controlled, and how often it contributed to final structured outputs.

\subsubsection*{Scope of LLM-assisted adjudication}
The analysis was designed as a rule-first pipeline. Prespecified deterministic rules were used to classify trial-risk features, DMC-indicated status, and structured termination categories wherever possible. LLM-assisted adjudication was available only as a fallback procedure for unresolved or ambiguous cases.\\
For DMC-indicated classification, the LLM fallback was restricted to unresolved assessment of serious-condition and serious-endpoint flags in interventional trials. For the secondary \texttt{whyStopped} analysis, the LLM fallback was restricted to records classified by the rule-based pipeline as ambiguous, mixed, uncertain, unclear, or low confidence.\\
The LLM was not used to determine registry-reported DMC status, to extract trial records from ClinicalTrials.gov, to calculate descriptive statistics, to fit regression models, to generate figures, or to interpret the primary study findings.

\subsubsection*{Model settings and acceptance rule}
The LLM fallback used \texttt{gpt-4o-mini} with temperature set to 0. Outputs were requested in structured JSON format using fixed schemas. For DMC-indicated classification, the schema required binary fields for serious condition and serious endpoint, a confidence score from 0 to 1, and a short rationale. For termination-reason classification, the schema required one category from the prespecified termination schema, a confidence score from 0 to 1, and a short rationale.\\
LLM outputs were accepted only when the confidence score was at least 0.75. Outputs below this threshold were not accepted. Where LLM adjudication was not applied or not accepted, the final classification was retained from the prespecified rule-based pipeline.

\subsubsection*{Termination-reason audit by DMC reporting status}
The secondary termination reason analysis classified stopped trials with documented \texttt{whyStopped} text into prespecified categories. Table~\ref{tab:supp_termination_llm_audit} summarises the resulting termination categories by registry-reported DMC status and records the number of cases flagged as requiring LLM review, the number ultimately classified by LLM, and the number classified by rules.\\
This audit supports transparency by showing that LLM use was concentrated in ambiguous or low-confidence termination-reason records. The primary analyses of DMC prevalence, DMC-indicated coverage, therapeutic-area variation, high-risk subgroup gaps, and regression-based associations did not depend on LLM-generated interpretation.

\begin{table}[htbp]
\centering
\scriptsize
\begin{threeparttable}
\caption{Structured termination categories by registry-reported DMC status and LLM audit status.}
\label{tab:supp_termination_llm_audit}
\begin{tabular}{llrrrrrr}
\toprule
\textbf{DMC status} & \textbf{Termination category} & \textbf{Trials} & \textbf{Rate (\%)} & \textbf{Mean confidence} & \textbf{Needed LLM} & \textbf{LLM-classified} & \textbf{Rule-classified} \\
\midrule
No DMC & Safety & 786 & 3.45 & 0.864 & 298 & 107 & 679 \\
No DMC & Efficacy & 72 & 0.32 & 0.902 & 1 & 56 & 16 \\
No DMC & Futility & 781 & 3.42 & 0.897 & 71 & 280 & 501 \\
No DMC & Recruitment failure & 7,588 & 33.26 & 0.864 & 876 & 796 & 6,792 \\
No DMC & Administrative & 6,546 & 28.69 & 0.878 & 0 & 1,221 & 5,325 \\
No DMC & Business decision & 3,018 & 13.23 & 0.877 & 112 & 876 & 2,142 \\
No DMC & Mixed reasons & 212 & 0.93 & 0.786 & 109 & 103 & 109 \\
No DMC & Uncertain & 3,701 & 16.22 & 0.350 & 3,699 & 2 & 3,699 \\
No DMC & Unclear & 110 & 0.48 & 0.320 & 0 & 21 & 89 \\
\midrule
With DMC & Safety & 708 & 5.19 & 0.867 & 255 & 83 & 625 \\
With DMC & Efficacy & 71 & 0.52 & 0.892 & 4 & 60 & 11 \\
With DMC & Futility & 839 & 6.15 & 0.900 & 87 & 214 & 625 \\
With DMC & Recruitment failure & 4,663 & 34.20 & 0.865 & 502 & 428 & 4,235 \\
With DMC & Administrative & 3,441 & 25.24 & 0.878 & 0 & 633 & 2,808 \\
With DMC & Business decision & 1,677 & 12.30 & 0.877 & 61 & 453 & 1,224 \\
With DMC & Mixed reasons & 167 & 1.22 & 0.786 & 89 & 78 & 89 \\
With DMC & Uncertain & 2,010 & 14.74 & 0.350 & 2,010 & 0 & 2,010 \\
With DMC & Unclear & 58 & 0.43 & 0.284 & 0 & 8 & 50 \\
\bottomrule
\end{tabular}
\begin{tablenotes}[flushleft]
\footnotesize
\item \textit{Note:} DMC, Data Monitoring Committee; LLM, large language model. Percentages are calculated within DMC reporting strata among stopped trials with documented \texttt{whyStopped} text. \textit{Needed LLM} indicates records flagged by the rule-first classifier as potentially requiring LLM review because they were ambiguous, mixed, uncertain, unclear, or low confidence. \textit{LLM-classified} indicates records for which the final structured category was assigned by the LLM under the prespecified schema and confidence threshold.
\end{tablenotes}
\end{threeparttable}
\end{table}

\subsubsection*{Interpretation}
The LLM fallback was included to improve classification robustness for ambiguous free-text termination reasons and unresolved risk-feature adjudication. Its use was constrained by fixed schemas, deterministic model settings, and a confidence acceptance threshold. The primary study findings were generated from registry-reported DMC status, predefined risk features, descriptive statistics, and regression models, and were not dependent on LLM interpretation.
\end{document}