title: How safe are bioequivalence studies in healthy volunteers?
abstract: Between 1981 and 1994, 58 bioequivalence studies (b.s.) were performed in 885 healthy volunteers. 93.1 per cent were single-dose, mainly of two way cross-over design. According to ATC groups, 13 were of cardiovascular drugs(C), 11 musculoskeletal (M), nine alimentary (A), seven urogenital (G), seven antimicrobial (J), six haematological (B), three nervous (N) and two respiratory (R). 97.2 per cent of volunteers finished the studies. Out of 25 withdrawals, 14 did it by their own will, seven were excluded because of lack of compliance with the protocol, one because of an adverse drug reaction (ADR) (preputial oedema), one because of intercurrent illness, and two for other objective reasons. In 35 studies the probants have been males, in 23 both sexes. Subjects were between 18 and 40 years. 209 adverse events were reported in 18 studies (31 per cent). From 885 volunteers that came to first session at the time, 115 (13 per cent) had ADRs. The association of the drug and ADRs was defined as probable in 91 ADRs (45.9 per cent), definite in 66 (33.4 per cent) and possible in 41 (20.7 per cent). 73 (63.5 per cent) volunteers had one ADR, 22 (19.1 per cent) had two and 20 (17.4 per cent) more than two ADRs. The majority -117 (56 per cent)-of ADRs were mild, 78 (37.3 per cent) moderate and 14 (6.7 per cent) severe. The most frequent ADR was headache (22.9 per cent), followed by nasal congestion (12.9 per cent), sweating (12.4 per cent), nausea (6.7 per cent), restlessness (6.7 per cent), deafness and tinnitus (6.2 per cent), change of biochemical or haematological parameters (5.3 per cent) and other. An unusual and rare ADR was impotence and preputial oedema (two volunteers on frusemide). All studies of G group (7-100 per cent) had ADRs, followed by C group (5-38 per cent) and A (3-33 per cent). Glipizide (5 mg) had highest number of ADRs (64-30.6 per cent), bromocriptine (10 mg) had 31 (14.8 per cent) and frusemide (500 mg) 22 (10.6 per cent). The largest number of subjects with ADRs were on frusemide (13-72 per cent), glipizide (17-68 per cent) and bromocriptine (15-52 per cent). At a time when generic drugs are of increasing importance, the safety of b.s. is of considerable interest. Our data confirm their safety and indicate that the majority of ADRs are mild.
authors.affiliation: Department of Medicine, University Hospital Rebro, Zagreb, Croatia.
authors.forename: M
authors.initials: M
authors.lastname: Huic
authors.forename: B
authors.initials: B
authors.lastname: Vrhovac
authors.forename: V
authors.initials: V
authors.lastname: Macolic-Sarinic
authors.forename: I
authors.initials: I
authors.lastname: Francetic
authors.forename: I
authors.initials: I
authors.lastname: Bakran
authors.forename: S
authors.initials: S
authors.lastname: Giljanovic
mesh_terms: D000293:Adolescent; D000328:Adult; D017523:Croatia / Q000453:epidemiology; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D015989:Healthy Worker Effect; D006801:Humans; D008297:Male; D012189:Retrospective Studies; D012306:Risk; D013810:Therapeutic Equivalency; D014838:Volunteers