The prevalence and incidence of medical conditions in healthypharmaceutical company employees who volunteer toparticipate in medical research

S. D. Singh & A. J. WilliamsClinical Pharmacology Unit, Zeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG

Aims Although clinical research in healthy volunteers is commonly performed therehave been few studies of the value of the medical screening of subjects. The aim ofthis study was to investigate the prevalence and incidence of medical conditionsfound during the medical screening of ‘healthy’ subjects employed in a pharmaceuticalcompany who volunteered to participate in medical research.Methods This was a retrospective study of the medical notes of all the subjects whovolunteered for membership of the Zeneca Clinical Pharmacology Unit’s healthyvolunteer panel over a 4 year period from 1990 to 1994. The prevalence of medicalconditions found at presentation was determined. The incidence of medicalconditions during the 4 year observation period was also ascertained. Medicalscreening included a full medical history and examination, clinical chemistry,haematology and urinalysis screens, pulmonary function tests, ECGs, 24 h ambulatorycardiac monitoring and a request for information from the volunteer’s GeneralPractitioner.Results Prevalence-1293 subjects volunteered to join the panel of which 156subjects (12%) were not accepted at presentation including 141 (10.9%) for medicalreasons. The most medical common reasons were; previously diagnosed medicalconditions (3.3%), cardiovascular abnormalities (1.9%), abnormal liver function tests(1.9%), anaemia (1.2%), hyperlipidaemia (1.1%), excess alcohol intake (0.6%) andthyroid disease (0.5%). Incidence—36 of the 1137 volunteers (0.8% per year)accepted onto the panel subsequently developed medical conditions of which themost common were; anaemia (0.29% per year), cardiovascular abnormalities (0.13%per year) and vasovagal syncope (0.13% per year).Conclusions This study demonstrates the importance of medical screening beforehealthy volunteers participate in clinical research.

Keywords: healthy, incidence, medical conditions, prevalence, screening, volunteer

Watson & Wyld found that medical screening (includ-Introduction

ing electrocardiogram, clinical chemistry and haematologyand urinalysis screens) of volunteers led to 28.5% ofClinical research in healthy volunteers is commonly

undertaken, but there have been few studies of the value applications being rejected for all reasons including 14%on clinical grounds [4]. There has been no other studyof medical screening of subjects. Such studies are

important because serious and even life threatening events of the prevalence of medical conditions in healthy subjectswho volunteer to participate in medical research.are known to occur during clinical research in healthy

subjects [1]. Additionally volunteers have died during [2] Additionally, many industrial and academic clinicalpharmacology units operate ‘healthy volunteer panels’or after [3] participation in research involving thera-

peutic agents. including their own employees in which panel membersparticipate regularly in clinical research. The value ofhealth screening in this population has not been studied.

Correspondence: Dr S. D. Singh, Clinical Pharmacology Unit, ZenecaWe have undertaken a retrospective epidemiologicalPharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG.

Received 7 October 1998, accepted 23 February 1999. study to assess the prevalence of medical conditions in

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S. D. Singh & A. J. Williams

healthy subjects who volunteer to participate in medical the type and prevalence of cardiac arrythmias on ACMrecordings in healthy volunteers.research and the incidence of such conditions in a ‘healthy

volunteer panel’. Laboratory values from 1000 subjects screened formembership of the healthy volunteer panel in the 4 yearsbefore November 1990 were used to establish reference

Methodsranges for the population who volunteer to participate inthis Clinical Pharmacology Unit’s studies. Normal rangesThis was a retrospective study of the medical notes of all

the subjects who volunteered for membership of the for laboratory investigations usually cover 95% of thepopulation [7]. Our reference ranges covered 98% ofZeneca healthy volunteer panel over a 4 year period

from November 1990 to November 1994. The period subjects, which avoids classifying 5% of previously healthyindividuals as having laboratory abnormalities (i.e. weprevalence over 4 years of medical conditions found in

1293 subjects who volunteered to join the healthy would anticipate 2% of our healthy volunteers beingoutside the reference range for any reason found onvolunteer panel was obtained (the period prevalence of a

disease is defined as the proportion of a population that screening). An abnormal test result was repeated andvolunteers were not excluded from the panel for isolatedare cases at any time within a stated period [5]).

The incidence of medical conditions occurring over or spurious abnormalities in laboratory values.GPs were informed of the reason for volunteers notthe 4 years observation period, in those subjects who

were accepted on to the healthy volunteer panel, was being accepted onto the panel and where appropriatespecialist referral was made for further investigationdetermined (the incidence of a disease is defined as the

rate at which new cases occur in a population during a and/or treatment.specified period [5]). Volunteers were all employees ofZeneca Pharmaceuticals who had been recruited byadvertising within the workplace. All were aged between

Results18 and 62 years.Screening of subjects for membership of the healthy Prevalence

volunteer panel was carried out by the physicians of theZeneca Clinical Pharmacology Unit. All volunteers are One thousand two hundred and ninety-three subjects

volunteered to join the healthy volunteer panel and ofrequired to undergo a medical screening process for panelmembership. Medical screening consists of the following these a total of 156 subjects (12%) were not accepted;

141 (10.9%) were rejected for medical reasons and 15stages:1 medical history and examination (1.1%) were rejected for non medical reasons. Table 1

lists the medical reasons. Previously diagnosed medical2 cardiac investigation with a computerized 12 leadECG and 2 lead 24 h ambulatory cardiac monitoring conditions, cardiovascular abnormalities, abnormal liver

function tests, anaemia, hyperlipidaemia, excess alcoholusing a Schiller ECG recording and analysing machine3 lung function assessment with spirometry and flow intake and thyroid disease all occurred with a prevalence

greater than 0.5% (1 in 200 subjects). Of the 16 subjectsvolume loop.4 laboratory investigations—clinical biochemistry found to be anaemic 13 were female and 3 were male.

Details of the previously undiagnosed medical con-including electrolytes, liver function, lipids and thyroidfunction. ditions found at medical screening (that is all the above

groups excluding previously diagnosed conditions) are—clinical haematology including full blood count andcoagulation. given in Table 2. These 99 volunteers’ ages are presented

in Figure 1a which shows the percentage of subjects with—hepatitis B virology—urinalysis medical conditions stratified by age. Figure 1b shows the

percentage of the total volunteers stratified by age. These5 request for information from the subjects GeneralPractitioner (GP). distributions have different modal values; 41–45 years for

Figure 1a and 31–35 years for Figure 1b. Additionally,The previously reported guidelines [6] for the manage-ment of 24 h ambulatory cardiac monitor (ACM) the percentage of volunteers in each age band after

35 years is higher in Figure 1a than Figure 1b. Thisrecording abnormalities in healthy volunteer studies werefollowed. The guidelines detail the appropriate manage- indicates that the prevalence of previously undiagnosed

medical conditions is greater in the older age groups.ment for healthy subjects with cardiac arrhythmias. Theseguidelines were derived from studies undertaken in our The most common non medical reason for rejection

was difficulty in obtaining blood samples by venepunctureunit on ACM recordings which showed that only 13%of these in healthy subjects are entirely normal (i.e. sinus at medical screening, since this would present difficulties

in obtaining blood samples for research purposes.rhythm throughout). The report deals extensively with

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Medical conditions in volunteers

Table 1 Prevalence (1990–1994).Medical conditions at presentation in 141volunteers rejected for panelmembership.

Number of % of 1293 volunteersMedical condition volunteers screened

Previously diagnosed chronic medical conditions 42 3.25Cardiovascular abnormality 25 1.93Abnormal liver function tests1 24 1.86Anaemia1 16 1.23Hyperlipidaemia1 14 1.08Excess alcohol intake with normal liver function2 8 0.62Thyroid dysfunction1 7 0.54Overweight3 3 0.23Underweight4 3 0.23Haematuria 2 0.15Tattoos5 2 0.15Raised creatinine1 1 0.08Pancytopenia1 1 0.08Eosinophilia1 1 0.08b-thalassaemia trait 1 0.08Visual field defect 1 0.08Chronic obstructive airways disease 1 0.08Breast lump 1 0.08Neurological disorder 1 0.08Irritable bowel syndrome 1 0.08Dermatitis 1 0.08Anxiety 1 0.08

14 volunteers had two simultaneous medical conditions.1 volunteer had three simultaneous medical conditions.1Normal reference ranges: Hb (M)12.5–16.9 g dl−1 (F)11–15.2 g dl−1, WCC 3.6–11.7(109 l−1), Eosinophils 0–0.44 (109 l−1), Plt 142–368 (109 l−1), Alk Phos 85–274 IU l−1, ALT9–61 IU l−1, AST 12–45 IU l−1, GGT 7–96 IU l−1, Creatinine 65–120 mmol l−1, Cholesterol<6.5 mmol l−1, Thyroxine (T4) 60–174 nmol l−1, TSH 0.25–4.2 mU l−1.2Defined as greater than 21 units per week for men and 14 units per week for women [8].3Weight greater than 20% of ideal weight using metropolitan height and weight tables.4Weight less than 20% of ideal weight using Metropolitan height and weight tables.5There was no screen for Hepatitis C so tattoos were considered a risk factor. Screening is nowcarried out.

severe episodes with transient weakness and lightIncidence

headedness.The volunteer who developed multiple sclerosis wasDuring the 4 year observation period 36 of the 1137

volunteers (0.8% per year) accepted onto the panel diagnosed initially by her General Practitioner. Otherwiseall the other medical conditions which led to thesubsequently developed medical conditions which

excluded them from panel membership. Table 3 lists the exclusion of volunteers from the panel were diagnosed asa result of the medical screening procedures. All 13conditions found. Anaemia, cardiovascular abnormalities

and vasovagal syncope occurred with an incidence of volunteers who became anaemic had donated blood formedical research. Ten of these volunteers were femalegreater than 0.1% per year.

Six volunteers (0.13% per year) developed vasovagal and three were male.syncope at venepuncture during clinical studies—thisoccurred despite specific questioning at medical screeningabout fear of medical procedures and undergoing vene-

Discussionpuncture for blood samples. One of these volunteers hadan episode of loss of consciousness for approximately In our sample of 1293 subjects who volunteered to

participate in medical research the prevalence of medical2 min. He was hypotensive and his ECG showed a sinusbradycardia. He recovered without any medical inter- conditions was 10.9%. During the 4 year observation

period the incidence of medical conditions developing invention. In the other five volunteers there were less

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S. D. Singh & A. J. Williams

Table 2 Previously undiagnosed medicalconditions in 99 volunteers not acceptedonto panel.

Number ofMedical condition volunteers % of 99 volunteers

Cardiovascular abnormality 25 25—Hypertension1 16—ECG abnormality alone 5—ECG abnormality and murmur 2—cardiac murmur 1—Angina 1

Liver function test abnormalities 24 24—Raised gamma GT alone 15—Other enzyme abnormalities (ALT, 9

AST, ALK PHOS with or withoutgamma GT abnormality)

Anaemia (all microcytic) 16 16Hyperlipidaemia 14 14Excess alcohol intake with normal liver function 8 8Thyroid dysfunction 7 7

—Hypothyroidism 5—Raised T4, normal TSH 1—Raised TSH, normal T4 1

Others 21 21

1As diagnosed using the British Hypertension Society Guidelines [9].

the 1137 subjects accepted onto the healthy volunteer chronic obstructive airways disease. Thus the prevalenceof respiratory disease diagnosed by respiratory functionpanel was 0.8% per year.

These results indicate that medical screening for healthy testing was the same (one subject-0.08%) as that foundby screening for renal disease by blood urea, creatininevolunteers before they participate as subjects in clinical

research is important, both on health and safety grounds and electrolytes and similar (0.08% compared with 0.15%)to the prevalence of renal disease detected by urinalysisto ensure that subjects with undiagnosed medical con-

ditions are not put at risk, and also on scientific grounds and abnormalities of white blood cells detected by cellcounts. This is a surprising result as all medical screeningto ensure that the subject population studied is indeed

composed of ‘healthy volunteers’. The commonest of subjects before they take experimental drugs willinclude urine and blood tests of renal function and whiteundiagnosed medical conditions (with a prevalence of

greater than 0.5%—1 in 200) found in this study were blood cell counts but few (if any) will include respiratoryfunction testing.cardiovascular disease, liver disease, anaemia, hyperlipidae-

mia, excess alcohol consumption and thyroid dysfunction. Medical screening discovered previously undiagnosedmedical conditions in subjects at all ages from 18 toThese conditions accounted for approximately 80% of

the abnormalities detected. 62 years. The age stratification of these volunteers withpreviously undiagnosed medical conditions is different toScreening for renal disease by urinalysis and blood

urea, creatinine and electrolyte levels forms part of almost that of the total number of volunteers; there is a higherproportion of the former group above 35 years of ageall healthy volunteer screening procedures involving

studies of experimental drugs. In our sample only two compared with the proportion of the total volunteerpopulation above 35 years. This indicates that thesubjects (0.15%) were found to have haematuria on

urinalysis and only one subject (0.08%) was found to prevalence of previously undiagnosed medical conditionsin subjects who volunteer to participate in clinical studieshave an abnormal blood test (raised creatinine). Thus the

prevalence of renal conditions was 0.23%. Similarly, a increases at above 35 years of age.Cardiovascular abnormalities were the most preva-full blood count is almost always performed before studies

involving new drugs. In our series although 1.2% of lent undiagnosed medical condition found at medicalscreening. Hypertension was the commonest condition.subjects were found to have anaemia only two subjects

(0.15%) had other haematological abnormalities (one Hypertension [10], hyperlipidaemia [11, 12] and hypothy-roidism [13] are all associated with increased mortality.subject with pancytopenia and one subject with eosino-

philia). Respiratory function testing in which flow volume The medical screening of volunteers in our study pickedup these potentially fatal conditions. Since these conditionsloops were obtained found one subject with undiagnosed

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Medical conditions in volunteers

are all treatable and the risks of participating in studieswith experimental drugs are small (0.04% of volunteersexperience serious adverse events [1] and there are onlytwo reported deaths [2, 3]) there may be a health benefitto certain individuals who volunteer to participate insuch studies because of medical screening.

The prevalence of medical causes for not acceptingsubjects onto the volunteer panel in our study (10.9%)was lower than that found by Watson & Wyld [4] intheir study of volunteers from the general population(14%). We also found a lower proportion of subjectsunsuitable for non medical reasons than in their study(1.1% compared with 14.5%). The reason for thesedifferences might be because our volunteers all workwithin the pharmaceutical industry and so would beexpected to have a greater knowledge of drug develop-ment and understanding of the requirements of phase 1studies which are intended only for healthy volunteers.

Abnormal liver function tests were found in 24volunteers of which 22 were considered to be due toexcess alcohol intake based on a history of alcohol use.None had clinical signs of liver disease or alcoholism. Inthe remaining two subjects the cause of liver functionabnormalities was considered to be due to oral contracep-tive use in one case and previous infective hepatitis inthe other case. A further eight volunteers with normalliver function tests were found to have an alcohol intakeAge (years)

18-20

b

% o

f vol

unte

ers

21-25 26-30 31-35 36-40 41-45 46-50 51-55 56-62

25

20

15

10

5

0

18-20

a

21-25 26-30 31-35 36-40 41-45 46-50 51-55 56-62

20

16

12

8

4

0

18

14

10

6

2

(obtained at medical history) above recognized safe limitsFigure 1 a) Age stratification of 99 subjects with previously[8]. Consequently 30 volunteers (2.3%) were excludedundiagnosed medical conditions and b) age stratification of totalfrom panel membership for probable alcohol relatednumber of subjects (1293) who volunteered to join the healthy

volunteer panel. reasons.

Table 3 Previously undiagnosed medical conditions in 36 volunteers previously accepted onto the panel.

% incidence of newmedical conditions

% of new medical per year in 1137New medical condition Number conditions panel members

Anaemia (all microcytic) 13 36.1 0.29Cardiovascular abnormality 6 16.7 0.13

—Hypertension 2—Pre–excitation syndrome 2

(Wolf Parkinson White syndrome)—Chest pain 1—Ventricular tachycardia during study 1

Vasovagal episodes 6 16.7 0.13Thyroid dysfunction (hypothyroidism) 2 5.6 0.05Liver function test abnormalities 2 5.6 0.05Haematuria 2 5.6 0.05Multiple sclerosis 1 2.8 0.02Abnormal creatinine 1 2.8 0.02Rectal bleeding 1 2.8 0.02Haematemesis 1 2.8 0.02Urticaria 1 2.8 0.02

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S. D. Singh & A. J. Williams

Screening for thyroid disease revealed hypothyroidism previously normal ECG’s and one volunteer at initialscreening (prevalence 0.08%). There were no associatedin 0.5% (1 in 200 subjects) while thyrotoxicosis was not

found in any volunteers. In a survey of the prevalence of dysrhythmias on their 24 h ambulatory ECG recordings.These findings are consistent with other reports of thethyroid disease in an English town (Whickham) hyper-

thyroidism was reported to be more common than incidence of the pre-excitation syndrome which varybetween 0.1 and 3.1 per thousand per annum [19]. Thehypothyroidism [14]. However, the majority of these

cases had been previously diagnosed and these patients term pre-excitation refers to the premature activation ofthe ventricle by an accessory pathway [20] which maywould not have been expected to volunteer for member-

ship of our volunteer panel. In the Whickham study lead to paroxysmal tachycardias as the AV node and His-Purkinje systems are by-passed [19]. The most commonpreviously undiagnosed clinical hypothyroidism (clinical

features and abnormal thyroid function tests) was found syndrome is the Wolf Parkinson White syndrome whichis characterized by a short PR interval and a slurredin 5 out of 2779 subjects (0.2% prevalence). However, a

raised thyroid stimulating hormone alone was found in initiation of the QRS complex—the delta wave [20]. Itis also a recognized feature of the pre-excitationan additional 7.5% of females and an additional 2.8% of

males. In our study such individuals would have been syndrome that it may be intermittent [21] and Mungeret al. reported that 22% of patients with Wolf Parkinsondiagnosed as having subclinical hypothyroidism [15] and

excluded from the panel. Previously undiagnosed hyper- White syndrome had no features of pre-excitation ontheir initial ECG [22]. This suggests that cardiacthyroidism occurred in 0.2% of the Whickham popu-

lation. Therefore, our finding that at medical screening screening of volunteers should certainly include serial12-lead ECGs to detect this syndrome which isthe prevalence of previously undiagnosed hypothyroidism

is more common than previously undiagnosed hyper- associated with paroxysmal tachycardias and suddencardiac death [23] and can be exacerbated by drugs [24].thyroidism is similar to that found in the Whickham

study overall. The incidence of hypothyroidism in our Guidelines for the use of 24 h ambulatory ECGmonitoring in health screening and clinical studies havevolunteer panel was 0.05% per year. In a follow up study

of the Whickham population the incidence of hypothy- previously been reported [6].Vasovagal reactions are caused by an autonomicroidism was reported at 0.35%/year for females and

0.06%/year for males [16]. The prevalence and incidence imbalance due to vagal overstimulation [22]. This resultsin symptoms such as light headedness, weakness, nauseaof previously undiagnosed thyroid disorders was higher

in the Whickham survey which may be because they and vomiting. Hypotension, bradycardia and loss ofconsciousness may be observed [25, 26]. Over the 4-yearstudied a more elderly population than our volunteer

panel which was restricted to those aged between 18 and period of the study 0.13% of volunteers per yearexperienced vasovagal episodes during phlebotomy62 years. Our results indicate that thyroid function testing

should be an important component in the health screening which were severe enough for them to be excludedfrom further participation in the panel. Less severeof volunteers before participation in clinical research and

that repeat testing is of value to protect volunteers’ safety vasovagal episodes were experienced by other volunteerswhich did not require exclusion from the panel but thedespite this procedure not being recommended for the

general population [15]. incidence of these was not quantified in our study. Theprevalence of all vasovagal reactions in blood donors hasThe incidence of medical conditions occurring in panel

members was 0.8% per year. The most common previously been reported as 2.1% including 0.1%regarded as severe [27]. Cardiac arrest followingconditions found were anaemia, cardiovascular abnormali-

ties, vasovagal syncope, hypothyroidism, liver function venepuncture in a healthy subject has also been described[28]. It is important to identify individuals who suffertest abnormalities and haematuria. Anaemia occurred in

volunteers who had all donated blood for research with vasovagal episodes during medical procedures asearly studies of experimental drugs with unknownpurposes which occurred despite this unit following the

Blood Transfusion Service guidelines [17] for blood cardiac effects in humans could be potentially hazardousfor such volunteers, e.g. if the drug supressed sinus nodedonation quantities. The majority of cases occurred in

female blood donors who are more at risk of iron or conducting pathway activity or acted as a vasodilator[29].deficiency anaemia than male donors [18]. Blood ferritin

levels are now measured annually in volunteers on our In summary, this study demonstrated the importanceof performing medical screening before volunteers arevolunteer panel in order to predict those who are at risk

of anaemia through repeated blood donation. allowed to participate in clinical research. In our unitpreviously undiagnosed medical conditions were theHypertension was the commonest cardiovascular

abnormality found. The pre-excitation syndrome was most common reason for exclusion from the healthyvolunteer panel. Additionally, repeating the screening ofnoted in two volunteers (incidence 0.05% per year) with

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