FIXED‐DOSE COMBINATIONS FOR HIV/AIDS,
TUBERCULOSIS, AND MALARIA
Report of a meeting held 16‐18 December 2003
Geneva
World Health Organization Geneva
Please go to the Table of Contents page to access the entire publication.
Contents
Summary: Observations and some ways forward... 1
A. Overall observations ... 1
B. Experiences with fixed‐dose combinations ... 2
C. Public health priorities ... 4
D. IP and legal options ... 5
E. Pharmaceutical development, quality assurance, and regulatory requirements ... 7
Welcome... 9
Objectives of the meeting ... 10
Expected outcomes... 10
Presentations on TB FDC issues ... 11
Presentations and discussions on malaria FDC issues... 12
Presentations and discussions concerning ARV FDCs ... 14
Presentation and discussion of cross‐cutting issues related to logistics, adherence and resistance with FDCs ... 17
Procurement experiences ... 19
Intellectual property and industry issues ... 20
Regulatory issues ... 22
Concluding session ... 24
Fixed‐dose combinations for tuberculosis: lessons learned from a clinical, formulation and regulatory perspective ... 29
Abstract... 30
Tuberculosis in the world of today... 30
Combination therapy and fixed‐dose combination (FDC) formulations in the management of TB ... 35
Continuation Phase... 40
Registration requirements for rifampicin‐containing FDC formulations... 45
Conclusions... 46
Acknowledgments ... 47
Annex: Bioavailability of rifampicin, the Biopharmaceutic Classification System and the 4D approach to disease management... 48
Results/c results/comments... 53
References... 63
Product costs of fixed‐dose combination tablets in comparison with separate dispensing and or co‐blistering of antituberculosis drugs... 67
Introduction ... 67
Method... 68
Results... 69
Discussion ... 70
References:... 75
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Fixed‐dose combinations: artemisinin‐based combination therapies for malaria
treatment ... 77
Introduction ... 77
Background ... 78
Implementation issues... 82
Process leading to the development of guidelines on the use of artemisinin‐based combination therapies (ACTs)... 85
Support to countries in the implementation of ACTs ... 87
Challenges/way forward ... 88
Recommendations for further research... 89
Conclusion... 89
References... 90
Developing combinations of drugs for malaria examination of critical issues and lessons learnt... 91
Background ... 91
Parasite resistance to antimalarial drugs: a major impediment to effective control ... 92
Strategies to overcome resistance... 92
Evidence – the key to sensible recommendations... 93
Further work on the artemisinins ... 95
Recommendations & outstanding challenges ... 96
References... 97
Safety and long‐term effectiveness of generic fixed‐dose formulations of nevirapine‐ based HAART amongst antiretroviral‐naïve HIV‐infected patients in India ... 99
Abstract... 99
Introduction ... 100
Methods ... 104
Results... 106
Discussion ... 109
Immunological improvement... 110
Viral load ... 110
Clinical findings ... 110
Conclusions... 111
References... 112
Effect of introduction of fixed‐dose combinations on the drug supply chain: experiences from the field ... 113
Abstract... 113
Intoduction... 113
Procurement... 114
Distribution ... 115
Prescribing... 116
Dispensing to patients ... 116
Cost to patient... 116
Patient use ... 117
Consumption data... 117
Conclusion... 118
References... 118
Effect of fixed‐dose combination (FDC) medications on adherence and treatment
outcomes ... 119
Introduction ... 119
Evidence of effect of FDCs or unit‐of‐use packaging on adherence and treatment outcomes... 121
Research needs... 124
Conclusion... 126
Acknowledgements ... 131
References:... 132
Effect of fixed‐dose combination (FDC) drugs on development of clinical antimicrobial resistance: a review paper... 135
Executive summary... 135
Introduction ... 137
Biological basis for drug resistance to anti‐TB, HIV/AIDS and malaria drugs... 138
Combination drugs in the context of AMR... 140
Overcoming clinical resistance using combinations: what is the evidence?... 143
Future research needs... 145
Conclusion... 146
Selected studies comparing combinations, FDCs, blister packs and monotherapy with regard to development of antimicrobial resistance ... 147
References... 151
Fixed‐dose combination (FDC) drugs availability and use as a global public health necessity : intellectual property and other legal issues... 155
Executive summary... 155
Introduction ... 156
IPRs and Fixed‐dose Combinations: Introduction to the “Anticommons Problem” ... 157
IPRs and Fixed‐dose Combinations: The “Anticommons Problem” (II) ... 158
Overcoming IP/Legal barriers ... 160
Back to the Future: TRIPS, Public Health, Access to Medicines ... 163
Recommendations... 165
Conclusions... 166
References... 167
Pharmaceutical development and quality assurance of FDCs... 169
Abstract... 169
Introduction ... 170
Preformulation studies ... 171
Some examples of the relevance of the properties of the API to product formulation! ... 174
Good Manufacturing Practice (GMP)... 176
Issues that may arise in the formulation of FDCs that do not arise for single entity products include:... 176
Changes to registered products (variations) ... 177
Quality control of FDCs... 178
Recommendations... 180
References... 180
Annotated agenda ... 183
List of participants ... 189
