Guidelines for Registration of Fixed-dose Combination Medicinal Products. WHO Technical Report Series, No. 929, 2005, Annex 5 (Chinese translation) 固定剂量复方制剂注册指导原则
(2005; 27 pages) [English]


The development of fixed-dose combinations (FDCs) is becoming increasingly important from a public health perspective. They are being used in the treatment of a wide range of conditions and are particularly useful in the management of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), malaria and tuberculosis, which are considered to be the foremost infectious disease threats in the world today.

FDCs have advantages when there is an identifiable patient population for whom treatment with a particular combination of actives in a fixed ratio of doses has been shown to be safe and effective, and when all of the actives contribute to the overall therapeutic effect. In addition there can be real clinical benefits in the form of increased efficacy and/or a reduced incidence of adverse effects, but such claims should be supported by evidence.

Additionally, in a situation of limited resources, the cost of an FDC finished pharmaceutical product (FDC-FPP) may be less than that of separate products given concurrently, and there are simpler logistics of distribution. Improved patient adherence and reduced development of resistance in the case of antimicrobials can be difficult to prove, but may be additional benefits.

Notwithstanding these potential benefits, FDCs must be shown to be safe and effective for the claimed indications. It should not be assumed that benefits outweigh risks. As for any new medicine, the risks and benefits should be defined and compared.

The World Health Organization has published a series of guidelines relating to marketing authorization of finished pharmaceutical products (FPPs) (see Table 1). Currently there are no specific international guidelines for FDCs. Some national authorities have developed their own guidelines, some for specific classes of medicines (see Table 2). These guidelines are intended to provide advice to those countries that do not, as yet, have guidelines for this type of product. They will also provide guidance to industry when developing new products and when considering the regulatory requirements that will need to be met.

In drafting these guidelines, existing international publications have been taken into account and in some cases text has been copied directly. The various scenarios considered below are essentially the same as those in the draft Scientific and technical principles for fixed dose combination drug products that followed a meeting of interested parties held in Botswana in April 2004.

1.1 The scope of these guidelines is restricted to medicines that in most jurisdictions would be available only on prescription. Although similar principles would apply to the registration of non-prescription products, the risk–benefit considerations (and consequently data requirements) may be different.

1.2 The principles in these guidelines would also apply to chemical combinations and complexes that comprise more than one active.

1.3 Registration of co-packaged medicines is not the primary purpose of these guidelines. However, many of the same considerations apply in balancing the advantages and disadvantages of co-packaged medicines, although the quality issues are different (see Appendix 1).

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