Systematic review

In response to increasing advocacy for the use of FDCs in the control of both communicable and non-communicable disease, we recently conducted a systematic review of the research literature to attempt to quantify any adherence or treatment benefit of FDCs. This review is reported in detail separately¹⁰.

The review was limited to randomised (or quasi-randomised) controlled trials that compared medications combined in a single pill, or medications combined within unit-of-use packaging, with the same medications in their usual presentation. “Unit-of-use packaging” included blister packaging of several medications in fixed combination to be taken together (with or without calendar labelling) and the use of devices into which customised combinations of medications are loaded at regular intervals, to be self-administered according to calendar labelling. Studies of adult patients taking more than one oral self-administered medication, and including at least one outcome measure relating to adherence, the pharmacological goal of medication (e.g. blood pressure control) or cost of therapy were included.

Fourteen trials were identified which met the review criteria, but a FDC was only used in three. Most of the remaining studies used blister packaging or medication boxes to improve the adherence to individualised medication regimens, particularly in the elderly or for the reduction of blood pressure.

Five of the 14 studies involved treatments for the control of communicable diseases (tuberculosis¹¹¹², HIV¹³, leprosy¹⁴, malaria¹⁵) and are described below, including the three FDC trials.

Two trials compared FDCs of anti-tuberculosis drugs with the same drugs given separately over a 6-month course. A US study conducted in 1984-6¹² with 701 subjects found a significant difference in the proportion of patients with sputum conversion at 8 weeks in favour of the FDC group, but no difference in “compliance” with medication at 8 weeks or at 6 months (see Table 2). Compliance in this study was assessed using a combination of self-report, pill counting and urine testing. The other tuberculosis trial was conducted in Taiwan in 1997-8¹¹ and was much smaller, with only 57 and 48 patients in the intervention and control groups respectively. Differences in sputum conversion at 8 weeks, in compliance, and in radiological improvement at 2 years all favoured the FDC group, but none reached statistical significance. Loss to follow-up was so high in this trial (50%) that slight improvements in adherence amongst those remaining were not considered clinically important.

The third FDC trial was in HIV patients in the US¹³, randomising 223 subjects to having two of their three medications combined in a single tablet. Self-reported adherence and questionnaire scores reflecting adherence behaviours were significantly improved in the intervention group, while clinical outcomes showed a non-significant trend towards improvement. Unfortunately this trial was powered only to show non-inferiority of the combined pill, which it did, but was too short to adequately assess relevant clinical outcomes.

The other two communicable disease trials were conducted in developing countries using cluster randomisation of health centres to investigate the effect of pre-packaging medications^{14 15}. Clinical outcome data were not collected in either of these studies and the clusters were not accounted for in the analyses. The Indian trial of calendar-blister packs (CBP) containing 3 medications for leprosy¹⁴ followed subjects for 6 months and found no differences in adherence between groups by pill counting or urine testing. They did find significant advantages in storage, handling and preservation of medication and that CBPs were preferred by staff and users. Pre-packaging of three-day courses of medication for malaria was trialed in Ghana¹⁵ with significant improvement in adherence in the intervention group (82% vs 60.5%), measured by self-report and medication checks. There was also a 50% reduction in the total cost of treatment, and a 50% reduction in time patients spent waiting at the clinic.

The remaining 9 trials were conducted within the health-care systems of developed countries; 4 assessed improvements in compliance with long-term therapy for chronic conditions (hypertension and diabetes) and measured clinically relevant outcomes^16-19; 5 others aimed to reduce the complexity of self-administered medication amongst geriatric patients on multiple medications, and measured only adherence^620-23. Details are given in the accompanying paper ¹⁰.

Despite the importance of improving adherence, we found surprisingly few large, reliable trials of the effect of combining medications on adherence with treatment. In all but two of fourteen trials identified there were trends to improved clinical and/or adherence outcomes. Seven of 12 studies (58%) reported a statistically significant improvement in medication adherence, although the outcome measures used were heterogeneous. Four of seven studies reporting clinical outcomes found a significant improvement in a clinically relevant endpoint; one in sputum conversion rate in tuberculosis patients, two in blood pressure, and one study in diabetics showed a reduction in both diastolic blood pressure and HbA1c. However interpretation of these findings is limited by the methodological quality of the studies. Almost all the studies were too small or had inadequate follow-up time, and were therefore likely to miss small to moderate-sized effects. Also Haynes²⁴ has suggested that for long-term treatments studies with initially positive findings need to continue for at least 6 months because of waning adherence over time. Substantial loss to follow up was common and intention-to-treat analysis was only performed in two trials^{13 16}. These two trials, which were the most methodologically rigorous, showed statistically significant improvements in adherence¹³ and in clinically relevant endpoints¹⁶. In the other trials bias may have resulted from assessing adherence in only those patients sufficiently compliant to remain in this study, and may have reduced the differences between the groups. Subjects were not blind to the interventions and assessors rarely were.

Self-reported and pill-counting adherence measures may have resulted in significant misclassification. As this is usually in the direction of overestimating adherence it may have also contributed to underestimating of the effect of interventions²⁴.

Other evidence in TB, malaria and HIV/AIDS

In searching the literature several studies were identified that investigated the adherence and treatment benefits of FDCs in TB, malaria and HIV/AIDS that did not meet the criteria of the systematic review. These are described in the remainder of this section and are included in Table 2, which summarises the evidence specific to these three diseases.

No trials were identified that directly compared FDC medications with co-blister packaging of component medications. A number of studies were identified where the safety and efficacy of FDC medications were compared with separately dispensed alternative drugs. These studies do not address the effect of physically combining the same drugs in a single “unit-of-use” separately from the effect of the different medication, and so have not been included in this summary

Tuberculosis

Studies from Singapore²⁵²⁶, Hong Kong²⁷ 28 and China²⁹ have investigated the effect of using FDCs in place of some or all of the medications used in directly observed therapy (DOT) for tuberculosis. As medication was taken under the supervision of health care workers there was no adherence effect with the FDC apart from rates of attending the appointments. In all three studies attendance at the clinic was very high for both FDC and free combination groups.

In all three studies the FDCs were at least as effective as free combinations of drugs in terms of culture negativity rates, and had similar experience of adverse reactions. In the Singapore study²⁵ there was a slightly higher relapse rate in the FDC groups at 2 years (6% vs 1%; p=0.04) and at 5 years (7.9% vs 2.2%; p=0.03) but there was no difference in the other two studies. Two of the three studies²⁸²⁹ reported a positive effect of FDCs on acceptability to the patient, and one on acceptability to physicians, pharmacists and administrators. The third study showed no difference in acceptability.

Malaria

A randomized study conducted in 1994 in China³⁰ showed that the use of blister packs for an 8day -course of antimalarial drugs significantly increased patients compliance (97% vs 83% and 97% vs 81% in two phases of the study; p<000.1) compared to usual methods of dispensing. This study included written instructions with the blister packs in addition to the oral instructions received by both groups. Much of the non-compliance in the control group was due to the deterioration or loss of the tablets dispensed in a paper envelope. No difference in efficacy was demonstrated.

A series of studies were conducted in Myanmar to compare the efficacy of artesunate and mefloquine with artesunate alone³¹. The research reported an adherence rate of >99% in both arms of their randomized study using blister packaging and written instructions for the 5 day treatment, and the authors drew the comparison with an adherence rate of 28% to usual treatment without intervention in a previous patient sample. They also reported high levels of prescribing of incorrect dosages in usual practice that was avoided with the blister packs.

HIV/AIDS

Numerous descriptive studies have shown that a simpler dosage regimen and lower pill burden is associated with better average compliance to HIV/AIDS treatments, and this was demonstrated reliably in the single HIV trial described above¹³. A recent retrospective study from Spain³² illustrated a benefit to adherence associated with a change from a free combination to FDC in HIV-infected adult outpatients. In a group of 76 patients there was an overall improvement in adherence from 93.7 to 96.1% (p=0.0024). In the patients who previously had not previously achieved >95% doses, 16 of 31 patients changed from non-adherent to adherent with the simplification of dosage regimen.