Clinical data warehouse analysis of clinical laboratory test results of Korean healthy volunteers: does “not clinically significant” range of healthy volunteers need modification?

Abstract

This study analyzed clinical laboratory test results of healthy Korean volunteers screened for Phase 1 clinical trials at Chungnam National University Hospital. Data from 53 trials conducted between 2019 and 2023 were extracted from the Clinical Data Warehouse and included tests such as white blood cell count, hemoglobin, aspartate aminotransferase, alanine aminotransferase, and creatinine. The study aimed to evaluate whether current ranges for “not clinically significant (NCS)” values need modification. Results showed that NCS values often varied between studies, with temporary deviations from normal ranges being common among healthy volunteers, especially those engaged in activities such as heavy weight training or recent dietary excess. Comparative pharmacokinetics and bioequivalence studies made up the majority of trials. The analysis highlighted discrepancies in laboratory criteria application, with implications for screening failure rates. The findings suggest that stricter guidelines might exclude otherwise eligible participants unnecessarily. Establishing consistent NCS criteria could optimize screening and reduce variability across clinical sites. This is the first study to provide insights into clinical lab results for healthy Korean volunteers, emphasizing the need for tailored NCS guidelines in Phase 1 trials.

INTRODUCTION

In Phase 1 clinical trial screening, clinical laboratory tests are essential components of the basic evaluation of volunteers. The clinical laboratory test items typically include white blood cell count, hemoglobin concentration, platelet count, aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine, and urine dipstick analysis. These items have well-established normal ranges.

However, a slight deviation from the normal range does not necessarily indicate an abnormal condition in volunteers. The determination of an abnormal condition or eligibility for participation in a clinical trial requires a comprehensive evaluation of various factors, including clinical laboratory test results, physical examination, medical history, and blood pressure. Laboratory test values may temporarily fall outside the normal range. Therefore, if the abnormal values are deemed not clinically significant (NCS), volunteers may still be allowed to participate in the Phase 1 clinical trial. The Common Terminology Criteria for Adverse Events (CTCAE) grading system is internationally recognized as the standard evaluating adverse events [1,2]. However, applying the CTCAE laboratory criteria directly to the screening of healthy adult volunteers in Phase 1 clinical trials remains controversial. Among healthy adults, it is common for individuals who engage in heavy weight training to present for screening when their creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) levels have not fully returned to baseline. There are also cases where individuals undergo screening when their triglyceride (TG) and AST/ALT levels have not returned to baseline following a single episode of excessive consumption of fatty foods and alcohol.

The NCS range for healthy participants in a Phase 1 clinical trial can be determined with a certain degree of discretion by the investigator, depending on the study. As a result, the NCS range may vary slightly between institutions and studies.

There are limited studies on the clinical laboratory test results of volunteers in Phase 1 clinical trials. Sibille et al. [3] analyzed laboratory data from 927 healthy male volunteers to establish reference values, reference changes, and limits for screening and laboratory adverse events (LAE) in Phase 1 clinical trials. The research highlighted the importance of specific inclusion limits and LAE thresholds to differentiate between normal variations and significant abnormalities during trials. Deiteren et al. [4] retrospectively analyzed data from 3,365 healthy volunteers who participated in 9,670 screening visits for Phase 1 clinical trials to assess how predefined eligibility criteria impact screen failure rates. It was found that strict ranges for cardiovascular, renal, liver, and coagulation parameters often led to high screen failure rates, suggesting that many healthy individuals were excluded unnecessarily.

A retrospective study was considered necessary to establish minimum criteria for setting the NCS range. Accordingly, clinical laboratory test data of healthy Korean adults who volunteered for clinical trials at Chungnam National University Hospital were extracted and analyzed using the hospital’s Clinical Data Warehouse (CDW). This study is the first to examine the clinical laboratory test results of Korean volunteers screened for Phase 1 clinical trials conducted in Republic of Korea.

METHODS

Ethics review

This study was reviewed and approved by the Institutional Review Board (IRB) of Chungnam National University Hospital (IRB No. 2024-10-039).

Data extraction

The analysis included all healthy volunteer clinical trials screened at the Clinical Trial Center of Chungnam National University Hospital between January 1, 2019, and December 31, 2023. Only trials with an approved protocol, a protocol number, and a completed database lock were included in the analysis. All trials were conducted with the approval of Institutional Review Board of Chungnam National University Hospital and in accordance with the Helsinki Declaration.

The data extraction algorithm from the CDW was configured using search criteria based on the intersection of outpatient visit dates (January 1, 2019 to December 31, 2023), department code, and the principal investigator’s name.

The output items were set as follows: reception ID, gender, date of birth, date of visit, age at the time of visit, department at the time of visit, attending physician, test code, test name, test form detail item ID, test result (numeric value), test result (positive/negative), and overall test result.

Data cleaning and statistical analysis software

The whole process was conducted in R (version 4.4.1; R Foundation for Statistical Computing, Vienna, Austria) and R Studio (RStudio 2024.04.2+764 "Chocolate Cosmos" Release [e4392fc9ddc21961fd1d0efd47484b43f07a4177, 2024-06-05] for windows, Mozilla/5.0 [Windows NT 10.0; Win64; x64] AppleWebKit/537.36 [KHTML, like Gecko] RStudio/2024.04.2+764 Chrome/120.0.6099.291 Electron/28.3.1 Safari/537.36, Quarto 1.4.555). To isolate screening tests among those performed in the outpatient setting, only data where the order date and test date of the anti-human immunodeficiency virus antibody matched were remained. Follow-up tests conducted after the initial screening were not considered in the analysis.

RESULTS

The 53 Phase 1 clinical trials included in the analysis were further categorized and detailed in Table 1. Comparative pharmacokinetics and bioequivalence studies accounted for 64.1% of the total clinical trials.

Table 1. Detailed overview of clinical trials in the data.

Detailed type of Phase 1 clinical trial	No. of trials (%)
Comparative pharmacokinetics	19 (35.8)
Bioequivalence test	15 (28.3)
Drug-drug interaction	8 (15.1)
Food effect	4 (7.5)
First-in-human (single ascending dose and/or multiple ascending dose)	3 (5.7)
Exploratory/proof-of-concept	3 (5.7)
Bridge	1 (1.9)
Total	53 (100)

The data cleaning process is depicted in Fig. 1. Clinical laboratory test results were analyzed for 1,378 male and 203 female volunteers.

Figure 1. Description of the data cleaning process following the extraction of raw data from the Clinical Data Warehouse at Chungnam National University Hospital.

HIV, human immunodeficiency virus.

The demographics of the volunteers are presented in Table 2. Continuous variables are summarized in Tables 3 and 4, while categorical variables are detailed in Table 5. The number of volunteers counted for each variable in Tables 3, 4, 5 varies because the tests included in the screening differ between studies. Due to the significant difference in the mean age between males and females, all statistical analyses were conducted separately for each genderr.

Table 2. Demographics of healthy volunteer population at screening.

Variables	Male (n = 1,378)	Female (n = 203)	Total (n = 1,581)
Age (yr)	25.7 ± 5.8	44.7 ± 16.6	28.3 ± 10.4
Height (cm)	175.2 ± 6.5	158.1 ± 4.8	169.2 ± 10.1
BMI (kg/m2)	24.1 ± 3.4	23.4 ± 3.3	23.9 ± 3.4

BMI, body mass index.

Table 3. Descriptive statistics of continuous laboratory test variables for healthy male volunteers and their corresponding reference ranges.

Laboratory parameter		Male (n = 1,378)
		No. of tests	Arithmetic mean	Standard deviation	Minimum	Median	Maximum	2.5th percentile	97.5th percentile	Reference range
Complete blood count
	White blood cell (103/μL)	1,704	6.6	1.6	3.2	6.3	16.5	4.2	10.3	3.8–10
	Red blood cell (106/μL)	422	5.1	0.3	4.2	5.1	6.2	4.5	5.7	4.2–6
	Hemoglobin (g/dL)	422	15.4	0.9	10.1	15.4	18.3	13.5	16.9	13.5–17.5
	Hematocrit (%)	422	45.1	2.6	31.2	45.2	51.5	40.0	49.5	39–53
	Platelets (103/μL)	422	259.5	50.8	108	254	588	173.5	370.8	130–400
	Segmented neutrophil (%)	1,704	57.3	8.3	29.1	57	84.6	42.0	74.5	35–74
	Lymphocyte (%)	1,704	31.8	7.3	10.1	31.8	59.4	17.1	45.8	20–51
	Monocyte (%)	1,704	7.5	1.9	2.3	7.3	25.2	4.4	11.7	3–11
	Eosinophil (%)	1,704	2.7	2.2	0	2.2	23.9	0.4	8.4	0–10
	Basophil (%)	1,704	0.8	0.4	0	0.7	10.6	0.3	1.5	0–2
Blood chemistry
	Total protein (g/dL)	1,704	7.3	0.4	5.9	7.2	10.4	6.6	8.0	6.5–8
	Albumin (g/dL)	422	4.5	0.3	3.6	4.5	5.3	4.0	5.1	4.0–5.0
	Total cholesterol (mg/dL)	422	186.6	35.5	116	185	342	125	266.5	125–220
	Aspartate transaminase (U/L)	422	23.1	12.8	8	21	155	11	52	13–33
	Alanine transaminase (U/L)	422	28.1	20.7	7	23	190	9.5	93.4	8–42
	Alkaline phosphatase (U/L)	422	65.1	16.7	27	63	133	40	104	40–130
	Lactate dehydrogenase (U/L)	422	374.8	88.5	195	361.5	708	241	592.8	200–400
	Gamma-glutamyl transferase (U/L)	421	31.1	31.6	7	22	334	9.6	86.5	10–47
	Creatine phosphokinase (U/L)	422	190.2	543.3	39	114.5	9,445	60	602.6	56–244
	Total bilirubin (mg/dL)	1,702	1.0	0.4	0.2	0.9	4.4	0.4	2	0.2–1.2
	Urea nitrogen (mg/dL)	422	12.3	3.3	3.8	12	25	6.8	19.7	8–20
	Creatinine (mg/dL)	422	0.9	0.2	0.5	0.9	1.3	0.6	1.2	0.6–1.1
	Estimated glomerular filtration rate (MDRD) (mL/min/1.73 m2)	416	111.3	25.6	60	106	214	73.4	174.2	≥ 90
	Estimated glomerular filtration rate (CKD-EPI) (mL/min/1.73 m2)	403	116.3	15.6	67	118	156	82	143	≥ 90
	Phosphorus (mg/dL)	422	3.7	0.5	2.2	3.6	5.3	2.8	4.9	2.5–4.7
	Uric acid (mg/dL)	422	6.2	1.5	0.5	6.2	16.9	3.7	9.3	3.5–7.2
	Glucose (mg/dL)	1,704	95	8.8	59	95	232	80	110	70–115
	Sodium (mEq/L)	422	140	2.4	133	140	158.1	135.7	145	135–150
	Potassium (mEq/L)	422	4.3	0.3	3.4	4.3	5.3	3.7	5.0	3.4–5
	Chloride (mEq/L)	422	103.1	2.8	92	103	115.7	97.9	108.6	98–110
Urinalysis
	Specific gravity	422	1.0199	0.0087	1.0010	1.0210	1.0390	1.0030	1.0335	1.005–1.03
	pH	422	6.1	0.7	5.0	6.0	8.5	5.0	7.7	5–9
Coagulation
	PT (%)	153	95.9	10.2	71	96	122	77.6	114.8	70–130
	PT (INR)	153	1.03	0.07	0.89	1.03	1.25	0.93	1.18	0.80–1.23
	aPTT (sec)	153	32.7	2.6	26.7	32.5	40.8	28.2	38.5	25.1–39.7

MDRD, Modification of Diet in Renal Disease; CKD-EPI, Chronic Kidney Disease Epidemiology; INR, international normalized ratio; PT, prothrombin time; aPTT, activated partial thromboplastin time.

Table 4. Descriptive statistics of continuous laboratory test variables for healthy female volunteers and their corresponding reference ranges.

Laboratory parameter		Female (n = 203)
		No. of tests	Arithmetic mean	Standard deviation	Minimum	Median	Maximum	2.5th percentile	97.5th percentile	Reference range
Complete blood count
	White blood cell (103/μL)	231	6.5	1.6	3.3	6.2	12.5	4.0	10.6	3.5–10
	Red blood cell (106/μL)	103	4.3	0.3	3.2	4.3	5.2	3.8	4.9	4–5.4
	Hemoglobin (g/dL)	103	13.1	0.9	10.4	13.2	15.1	11	14.5	12–16
	Hematocrit (%)	103	38.7	2.5	31.4	38.5	43.5	33.4	42.9	36–46
	Platelets (103/μL)	103	268.8	60.5	158	264	424	175	383.2	130–400
	Segmented neutrophil (%)	231	54.6	9.9	29.2	54.4	83.9	35.7	73.8	35–74
	Lymphocyte (%)	231	36	9.2	10.7	36.5	58.3	20.1	54.6	20–51
	Monocyte (%)	231	6.3	1.6	2.9	6.2	11.2	3.7	9.6	3–11
	Eosinophil (%)	231	2.3	2.2	0.1	1.6	17.1	0.5	7.9	0–10
	Basophil (%)	231	0.8	0.4	0.1	0.7	2.7	0.3	1.7	0–2
Blood chemistry
	Total protein (g/dL)	231	7.1	0.4	6.1	7.1	8.2	6.5	7.9	6.5–8
	Albumin (g/dL)	103	4.2	0.3	3.3	4.2	5.1	3.7	4.8	4.0–5.0
	Total cholesterol (mg/dL)	103	200.9	35.5	124	198	292	137.6	261.8	125–220
	Aspartate transaminase (U/L)	103	23.4	11.9	8	21	95	10.1	51.5	13–33
	Alanine transaminase (U/L)	103	22.1	16.8	6	17	112	7	69.6	6–27
	Alkaline phosphatase (U/L)	102	66.4	19.7	36	63	127	38.5	108.8	35–105
	Lactate dehydrogenase (U/L)	103	419.7	98.9	253	411	698	277.6	644.2	200–400
	Gamma-glutamyl transferase (U/L)	103	22.2	15.2	7	17.6	118.7	7.5	59.6	10–47
	Creatine phosphokinase (U/L)	103	96.5	46.3	36	86	301	46.6	227.6	43–165
	Total bilirubin (mg/dL)	228	0.8	0.3	0.2	0.7	2.1	0.3	1.4	0.2–1.2
	Urea nitrogen (mg/dL)	103	12.1	3.8	5.3	11.4	24	6.7	20.5	8–20
	Creatinine (mg/dL)	103	0.6	0.1	0.3	0.6	0.9	0.4	0.8	0.4–0.8
	Estimated glomerular filtration rate (MDRD) (mL/min/1.73 m2)	103	121.3	34.2	67	117	294	77	197.6	≥ 90
	Estimated glomerular filtration rate (CKD-EPI) (mL/min/1.73 m2)	103	115.3	18.7	76	114	167	80.6	144	≥ 90
	Phosphorus (mg/dL)	103	3.8	0.5	2.4	3.8	5.2	2.7	4.8	2.5–4.7
	Uric acid (mg/dL)	103	4.4	1.2	1.9	4.3	8.1	2.5	7.3	2.6–6
	Glucose (mg/dL)	231	94.9	8.1	78	95	126	81	115	70–115
	Sodium (mEq/L)	103	139.6	2.6	134	139.6	145	134.4	144	135–150
	Potassium (mEq/L)	103	4.2	0.3	3.5	4.2	5.1	3.6	4.7	3.4–5
	Chloride (mEq/L)	103	105	2.5	97.5	105.3	110	99.6	109	98–110
Urinalysis
	Specific gravity	103	1.0161	0.0080	1.0020	1.0160	1.0340	1.0030	1.0319	1.005–1.03
	pH	103	6.0	0.8	5.0	6.0	7.5	5.0	7.5	5–9
Coagulation
	PT (%)	24	94.5	8.1	83	95	112	84.2	112	70–130
	PT (INR)	24	1.04	0.05	0.94	1.04	1.13	0.94	1.12	0.80–1.23
	aPTT (sec)	24	32.9	3.3	27.5	32.8	41.2	27.7	39.4	25.1–39.7

MDRD, Modification of Diet in Renal Disease; CKD-EPI, Chronic Kidney Disease Epidemiology; INR, international normalized ratio; PT, prothrombin time; aPTT, activated partial thromboplastin time.

Table 5. Descriptive statistics of categorical laboratory test variables for healthy volunteers and their corresponding reference values.

Laboratory parameter		Male (n = 1,378)			Female (n = 203)
		No. of tests	No. of tests by outcome	Reference value	No. of tests	No. of tests by outcome	Reference value
Urinalysis
	Protein	1,704	Negative: 1,506	Negative	231	Negative: 214	Negative
			+/−: 154			+/−: 11
			1+: 35			1+: 4
			2+: 7			2+: 2
			3+: 1
			4+: 1
	White blood cell (/HPF)	1,667	0–2: 1,591	0–2	231	0–2: 160	0–2
			3–5: 51			3–5: 33
			6–10: 13			6–10: 15
			11–20: 4			11–20: 15
			21–50: 5			21–50: 6
			Many: 3			Many: 2
	Red blood cell (/HPF)	1,667	0–2: 1,624	0–2	231	0–2: 204	0–2
			3–5: 23			3–5: 17
			6–10: 5			6–10: 4
			11–20: 6			11–20: 3
			21–50: 5			21–50: 1
			Many: 4			Many: 2
	Squamous epithelial cell (/HPF)	1,667	0–2: 6	0–5	231	0–5: 203	0-5
			0–5: 1,657			6–10: 14
			3–5: 1			11–20: 9
			6–10: 1			21–30: 3
			11–20: 2			Many: 2
	Glucose	1,704	Negative: 1,696	Negative	231	Negative: 231	Negative
			+/−: 4
			1+: 2
			2+: 1
			3+: 1
	Ketone	1,704	Negative: 1,361	Negative	231	Negative: 196	Negative
			+/−: 297			+/−: 25
			1+: 33			1+: 7
			2+: 6			2+: 1
			3+: 6			3+: 2
			4+: 1
	Bilirubin	1,704	Negative: 1,612	Negative	231	Negative: 228	Negative
			1+: 88			1+: 3
			2+: 4
	Erythrocyte	1,704	Negative: 1,636	Negative	231	Negative: 181	Negative
			+/−: 40			+/−: 25
			1+: 14			1+: 9
			2+: 9			2+: 12
			3+: 5			3+: 4
	Nitrite	1,704	Negative: 1,704	Negative	231	Negative: 229	Negative
						Positive: 2
	Urobilinogen	1,704	Negative: 4	+/−	231	+/−: 231	+/−
			+/−: 1,696
			1+: 4
	Leukocyte	1,704	Negative: 1,551	Negative	231	Negative: 120	Negative
			+/−: 112			+/−: 51
			1+: 32			1+: 27
			2+: 9			2+: 25
						3+: 8
	Bacteria	176	Few: 160	Not applicable	58	Few: 45	Not applicable
			Moderate: 16			Moderate: 12
						Many: 1
Serology
	Rapid plasma reagin antibody (RU)	1,702	Negative: 1,701	Negative	231	Negative: 230	Negative
			Gray zone: 1			Positive: 1
	Anti human immunodeficiency virus antibody (Signal-to-cutoff ratio)	1,703	Negative: 1,702	Negative	231	Negative: 231	Negative
			Positive: 1

The results were presented exactly as reported by the Department of Laboratory Medicine at Chungnam National University Hospital.

DISCUSSION

This study is significant as it is the first to analyze clinical laboratory tests conducted during the screening of healthy Korean volunteers participating in Phase 1 clinical trials. The ranges of clinical laboratory test results deemed “NCS” vary slightly between institutions and studies. Therefore, the findings of this study can provide valuable guidance for establishing criteria for what is considered “NCS.”

The NCS criteria can be influenced by various factors, including volunteers’ lifestyle and temporary physical conditions. Therefore, setting more flexible and context-appropriate standards may be necessary. For test results that significantly deviate from the reference range, a practical approach often involves re-testing. However, even if the results do not completely fall within the reference range after 2 or more re-tests, volunteers may still be allowed to participate in the clinical trial based on the investigator’s judgment and the healthy condition of the volunteer. Prior to the initiation of the clinical trial, it is crucial for the sponsor, clinical research organization, and investigators to collaboratively discuss and establish NCS ranges. This approach ensures that the clinical trial is conducted in a scientifically sound and ethically responsible manner.

Based on the statistical analysis results of this study, proposed NCS ranges for certain laboratory tests in male and female participants in clinical trials involving healthy subjects are presented in Table 6. For test items like white blood cell count or estimated glomerular filtration rate, where values outside the reference range may indicate infection or renal impairment, NCS ranges were not proposed in Table 6. NCS ranges were proposed only for test items deemed potentially controversial based on the authors’ expertise and judgment.

Table 6. Proposal for adjusted not clinically significant clinical laboratory test ranges in clinical trials involving healthy adults.

Laboratory parameter		Male		Female
		Reference	Proposed not clinically significant range/value	Reference	Proposed not clinically significant range/value
Blood chemistry
	Albumin (g/dL)	4.0–5.0	4.0–5.1	4.0–5.0	3.7–5.0
	Total cholesterol (mg/dL)	125–220	125–266.5	125–220	125–261.8
	Lactate dehydrogenase (U/L)	200–400	200–592.8	200–400	200–644.2
	Creatine phosphokinase (U/L)	56–244	56–602.6	43–165	43–227.6
	Total bilirubin (mg/dL)	0.2–1.2	0.2–2.0	0.2–1.2	0.2–1.4
	Urea nitrogen (mg/dL)	8–20	6.8–20	8–20	6.7–20.5
	Creatinine (mg/dL)	0.6–1.1	0.6–1.2	0.4–0.8	0.4–0.8 (same as reference)
	Phosphorus (mg/dL)	2.5–4.7	2.5–4.9	2.5–4.7	2.5–4.8
	Uric acid (mg/dL)	3.5–7.2	3.5–9.3	2.6–6.0	2.5–7.3
Urinalysis
	Protein	Negative	Negative, +/−, 1+	Negative	Negative
	White blood cell (/HPF)	0–2	0–2, 3–5	0–2	0–2, 3–5, 6–10, 11–20
	Red blood cell (/HPF)	0–2	0–2, 3–5	0–2	0–2, 3–5, 6–10
	Squamous epithelial cell (/HPF)	0–5	0–5 (same as reference)	0–5	0–5, 6–10
	Ketone	Negative	Negative, +/−, 1+	Negative	Negative, +/−
	Bilirubin	Negative	Negative, 1+	Negative	Negative (same as reference)
	Erythrocyte	Negative	Negative, +/−	Negative	Negative, +/−, 1+
	Leukocyte	Negative	Negative, +/−	Negative	Negative, +/−, 1+, 2+
	Bacteria	-	-	Not applicable	Few, Many, Moderate

Only laboratory test items deemed potentially controversial in clinical trials involving healthy subjects were presented. If the lower limit of the reference range was smaller than the 2.5th percentile value, the lower limit of the proposed range/value was suggested as the lower limit of the reference range. If the 97.5th percentile value exceeded the upper limit of the reference range, the upper limit of the proposed range/value was suggested as the 97.5th percentile value. The proposed range/value was suggested within a range/value where the number of tests did not exceed 2.5% of the number of tests for each laboratory test item in Table 5.

This study has several limitations. First, it utilizes volunteer data from a single clinical trial site. Second, the data include all subjects who participated in the screening, regardless of whether they passed or failed the screening criteria. Third, the use of anonymized data prevented the identification of duplicated participants. Additionally, this study is based on screening results from clinical trials involving healthy volunteers, making it challenging to directly apply these findings to clinical trials involving patient populations.