Provisional observations

1. Combination treatment can be delivered in any of four presentations: (a) individual medicines in bulk; (b) individual medicines in blister packs; (c) co-blistering of the 2, 3 or 4 needed medicines in a single pack (CBCs); (d) fixed-dose combination of the 2, 3 or 4 active ingredients into one tablet or capsule (FDCs).

2. The possible benefits of FDCs and/or CBCs are that they can:

a. Increase patient adherence to treatment (especially FDCs)

b. Delay the development of resistance (especially FDCs)

c. Lower the total cost, including production, storage, transport, dispensing and other health system costs

d. Reduce the risk of medication errors by prescribers, dispensers or patients themselves

e. Simplify and increase security of supply systems (especially FDCs)

f. Facilitate patient counselling and education, reduce waiting time

g. Help in scaling-up access to ARVs, as their use has been associated with a significant increase in enrollment in some pilot ARV programmes.

3. The strength of experiential and scientific evidence presented in support of these benefits varied. Specifically, clinical trial evidence on the effect of FDC use on clinical outcomes, patient adherence and resistance is limited; but what does exist supports a benefit from FDC use.

4. For FDCs, even where measured benefits are not seen, patients and providers appear to prefer them to loose combinations. No significant negative evidence is available against the use of quality assured FDCs.

5. Operational arguments for FDCs and the need for “common sense” approaches concerning cost, supply logistics and patient counselling may be stronger in resource-limited settings.

6. In practice, pharmaceutical companies have routinely developed and marketed FDCs when combination therapy has proven advantages, companies have access to all components of the combination (through ownership or licensing), and an FDC is technically feasible.

7. It was noted, however, that it is, “not simple to make things simple.” FDCs/CBCs can create significant challenges for:

a. Toxicity management

b. Paediatric and weight-based dosing

c. Drug interactions (e.g., with rifampicin, nevirapine, other medicines)

d. Adjustment of regimens in response to resistance

e. Lead-in dosing

f. Dose and frequency adjustment for renal and hepatic impairment (this is not only true for FDCs but for all products)

g. Management of ARV therapies in child-bearing women

h. Management of co-infections of HIV with TB and HBV.

8. Adherence depends on a combination of approaches, including counselling; packaging and labelling to promote understanding.

9. In addition, there are a variety of dispensing options including “co-ziplocking”, “MEMS caps”, pill boxes and unit dose packaging. These should be implemented in the context of Good Dispensing Practices.

Some ways forward

1. For HIV/AIDS, TB and malaria, FDCs and CBCs should be developed according to standard treatment guidelines.

2. Each national programme needs to establish the role of FDCs, CBCs and individual medicines within the context of its health-care providers and health-care system. WHO’s guidance may be crucial to support this needed development. National programmes should build-in ways of overcoming or slowing antimicrobial resistance. FDCs are one of the important tools for achieving this objective.

3. There remains a place for combination dispensing packs according to individual patient needs.

4. Clinical and operational research is needed to expand the evidence base and, using natural experiments in combination with monitoring and resistance surveillance systems, including post-marketing surveillance of FDCs when they are first introduced.

5. Pharmacoviligance needs to be considerably strengthened, since these systems are not well-developed in many of the countries that are or will be using modern medicines for HIV/AIDS, malaria and TB.

6. Monitoring outcomes of the programmes in health-care systems is necessary as a feedback to update and possibly modify treatment plans using FDCs and/or CBCs. This should include documentation of the role of FDCs in increasing enrollment in ARV treatment programmes.

7. The role of dispensing and co-packaging systems as complementary approaches to FDCs and CBCs should be further developed.