Table 3

Evaluation of published trials against four selected WHO general principles for approval of FDCs sorted by FDC components

Year of publication; country of study; sponsorMinimum number of subjects (≥300)*Minimum duration
(≥6 months)†
Designed to show advantage over individual components given concomitantly as SDFs or monotherapy‡Effects of the FDC§
Significant decrease in HbA1c for FDC vs comparator(s)
(P value vs comparator)
Percentage of patients reporting adverse events with FDC(s)
(P value vs comparator)
Percentage of patients reporting hypoglycaemia with FDC(s)
(P value vs comparator)
2001; France; Hoechst Marion Roussel30 3725x(1) Metformin SDF
(2) Glimepiride SDF
(3) FDC (glimepiride/metformin)
Yes
(metformin and glimepiride)
(P<0.001)
31% vs 29% (metformin) and 25% (glimepiride)
(P value NR)
22% vs 11% (metformin) and 13% (glimepiride)
(P=0.039)
2009; Mexico; Laboratorios Silanes34152x12(1) FDC (glimepiride/metformin)
(2) FDC (glibenclamide/metformin)
xYes
(P=0.025)
69.7% vs 68.4% (glibenclamide)
(P=0.851)
17.1% vs 28.9% (glibenclamide)
(P=0.047)
2009; India; not listed2328x3x(1) FDC (glimepiride/metformin)
(2) FDC (glibenclamide/metformin)
xYes
(P value NR)
0% vs 0% (glibenclamide)
(P value NR)
17.64% vs 27.27% (glibenclamide)
(P value NR)
2011; India; not listed24 101x3x(1) metformin+insulin
(2)FDC (glimepiride/pioglitazone/metformin)
xNo0% vs 0%
(metformin+insulin)
(P value NR)
0% vs 0% (metformin+insulin)
(P value NR)
2005; India; Unichem Laboratories25 101x2x(1) FDC (glimepiride/pioglitazone/metformin)
(2) No comparator
xNo7.9%
(P value NR)
NR
2003; USA; Bristol-Myers Squibb35 246x4.5x(1) Metformin SDF
(2) Glipizide SDF
(3) FDC (glipizide/metformin)
Yes
(metformin and glipizide)
(P<0.001)
63.2% vs 73.3% (metformin) and 67.9% (glipizide)
(P value NR)
12.6% vs 1.3% (metformin) and 0% (glipizide)
(P value NR)
2002; USA; Bristol-Myers Squibb36 6394x(1) Metformin SDF
(2) Glibenclamide SDF
(3) FDC (dose 1) (glibenclamide/metformin)
(4) FDC (dose 2) (glibenclamide/metformin)
Yes
(metformin and glibenclamide)
(P<0.001)
NR
(67% of total participants)
6.8% vs <1% (metformin) and 1.8% (glibenclamide)
(P value NR)
2004; USA; Bristol-Myers Squibb27 31012(1) FDC (dose 1) (glibenclamide/metformin)
(2) FDC (dose 2) (glibenclamide/metformin)
xNoNR
(79% of total participants)
NR
(1 patient total)
2006; USA; Bristol-Myers Squibb37 50x5x(1) Metformin SDF
(2) Glibenclamide SDF
(3) FDC (glibenclamide/metformin)
No44% vs 87% (metformin) and 65% (glibenclamide)
(P value NR)
11% vs 29% (glibenclamide)
(P value NR)
2006; Italy; not listed38 198x6(1) FDC (dose 1) (glibenclamide/metformin)
(2) FDC (dose 2) (glibenclamide/metformin)
xNo3.6%
(P value NR)
11.2%
(P value NS)
2007; Taiwan; Orient Europharma39 100x4x(1) Metformin SDF
(2) Glibenclamide SDF
(3) FDC (dose 1) (glibenclamide/metformin)
(4) FDC (dose 2) (glibenclamide/metformin)
Yes
(dose 1:
P=0.002 vs metformin, P<0.001 vs glibenclamide dose 2:
P=0.005 vs metformin, P<0.001 vs glibenclamide)
NR
(98 episodes total)
7.7% vs 8.3% (metformin)
(P value NR)
2007 and 2008; Italy; Takeda Italy40 41250x6(1) FDC (glibenclamide/metformin)
(2) FDC (pioglitazone+metformin or sulfonylurea)
xNo21.3% vs 20.6% (pioglitazone)
(P>0.05)
1.3% vs 0% (pioglitazone)
(P value NR)
2004; USA; Bristol-Myers Squibb28 3656(1) FDC (glibenclamide/metformin)
(2) FDC (glibenclamide/metformin+rosiglitazone)
xNoNR25% vs 53% (glibenclamide+rosiglitazone)
(P value NR)
2004; USA; Bristol-Myers Squibb22††40x0.5x(1) Glibenclamide+metformin
(2) FDC (glibenclamide/metformin)
NRNRNR
1999; Italy; Laboratori Guidotti SpA, Pisa42 40x6(1) Glyburide SDF
(2) FDC (glibenclamide/metformin)
xYes
(P<0.01)
NRNR
2003; Mexico; not listed43 19x0.5x(1) FDC (brand 1) (glibenclamide/metformin)
(2) FDC (brand 2) (glibenclamide/metformin)
xNRNRNR
2002; USA; Bristol-Myers Squibb44 8064x(1) Placebo
(2) Metformin SDF
(3) Glibenclamide SDF
(4) FDC (dose 1) (glibenclamide/metformin)
(5) FDC (dose 2) (glibenclamide/metformin)
Yes
(dose 1:
P=0.006 vs metformin dose 2:
P<0.001 vs metformin
P=0.037 vs glibenclamide)
NR
(69 episodes total)
24.7% vs 21.3% (glibenclamide)
(P value NR)
2003; USA; Bristol-Myers Squibb45 4864x(1) Metformin SDF
(2) Glibenclamide SDF
(3) FDC (glibenclamide/metformin)
Yes
(metformin and glibenclamide)
(P=0.0003)
78.8% vs 73.2% (metformin)
and 75.5% (glibenclamide)
(P value NR)
57.6% vs 17.7% (metformin)
and 39.1% (glibenclamide)
(P value NR)
2006; USA; Bristol-Myers Squibb29 3186(1) FDC (glibenclamide/metformin)
(2) Metformin+rosiglitazone
xYes
(P<0.001)
68% vs 63% (metformin+rosiglitazone)
(P value NR)
74% vs 26% (metformin+rosiglitazone)
(P value NR)
2009; Mexico; Laboratorios Silanes31**152x12(1) FDC (glibenclamide/metformin)
(2) FDC (glimepiride/metformin)
xNo68.4% vs 69.7% (glimepiride)
(P=0.851)
28.9% vs 17.1% (glimepiride)
(P=0.047)
2002; Europe; Merck Lipha46 4114x(1) Metformin SDF
(2) Glibenclamide SDF
(3) FDC (dose 1) (glibenclamide/metformin)
(4) FDC (dose 2) (glibenclamide/metformin)
Yes
(metformin and glibenclamide)
(P<0.05)
45.1% vs 40% (metformin)
and 43% (glibenclamide)
(P value NR)
12.3% vs 1% (metformin)
and 8% (glibenclamide)
(P value NR)
2002; Mexico; not listed47 122x1x(1) FDC (dose 1) (glibenclamide/metformin)
(2) FDC (dose 2) (glibenclamide/metformin)
(3) FDC (dose 3) (glibenclamide/metformin)
xNRNR3.3%
(P value NR)
1996; Greece; not listed48 30x6(1) FDC (glibenclamide/metformin)
(2) FDC (phenformin/metformin)
xYes
(P<0.02)
NRNR
2009; India; not listed23**28x3x(1) FDC (glibenclamide/metformin)
(2) FDC (glimepiride/metformin)
xNo0% vs 0% (glimepiride)
(P value NR)
27.27% vs 17.65% (glimepiride)
(P value NR)
2002; Italy; Laboratori Guidotti SpA, Pisa49 80x12(1) Metformin SDF
(2) Glibenclamide SDF
(3) FDC (glibenclamide/metformin)
Yes
(metformin and glibenclamide)
(P<0.0001)
NRNR
(11.3% of total participants)
Total meeting criteria81010
  • *‘Studies investigate the efficacy of the biomedical or behavioural intervention in large groups of human subjects (from several hundred to several thousand)…’.26 For these purposes, trials involving at least 300 subjects have been regarded as being within the numbers range.

  • †‘If the combination is intended for long-term use, data on safety in patients will normally be required for 6 months or longer’ (paragraph 6.6.1.8).20

  • ‡‘Clinical studies should be designed to determine whether the combination has an advantage over the component actives given alone in a substantial patient population’ (paragraph 6.6.1.4).20 Comparator(s) in clinical trial are listed.

  • §‘If there is an increase in the number or severity of adverse reactions to the FDC as compared with those in response to the individual actives given alone, evidence and argument should be presented showing that the advantages outweigh the disadvantages’ (paragraph 6.6.1.16).20 A trial met this guideline if the trial design compared the FDC with monotherapies of the individual components and demonstrated the FDC had better outcome measurements denoted by a statistically significant decrease in HbA1c, the proportion of patients on the FDC who experienced adverse events or symptoms of hypoglycaemia was significantly better than with the comparator treatment, and an explanation of how the FDC is able to balance the advantages and disadvantages over an alternative treatment is provided in the manuscript. P values from each study, if available, are reported for the FDC versus the comparator treatment. Significant P values are in bold.

  • ¶Two publications were evaluated as one because they reported different findings of the same study.47 48

  • **These two trials are listed twice, under both glimepiride and glibenclamide, as they compare the two treatments.23 33

  • ††This US study published in 2004 was the only trial that compared an FDC with the component SDFs given concomitantly.22

  • FDCs, fixed-dose combinations; HbA1c, haemoglobin A1c; NR, not reported; SDFs, single-drug formulations.