Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

An Overview of the Regulatory Framework of Fixed Dose Combination Medicinal Products (FDC)

Dr. Ulrich Fritsche (Abschlußjahr: 2007)

The overview on the Regulatory Framework of Fixed Dose Combination (FDC) medici-nal products opens with a brief view on the arguments for rational based fixed dose combination products used in Combination Therapy. The criteria of J.R. Crout have been a milestone of rational combination therapy and have been established the core objective of the most international regulations concerning FDC medicinal products. The justification of the rationale, the balancing of advantages and disadvantages and the risk benefit assessment are the basis for regulatory considerations of a fixed dose com-bination product discussed according to the Community Directive 2001/83/EEC as amended, the FDA guidelines related to fixed dose drug products and in demarcation to combined medical devices. Additionally to the general regulatory criteria of quality, safety and efficacy, which applies to any medicinal product FDC`s are predetermined to be effective due to the requirements of the regulations, the 21 CFR 300.50 or the Note of Guidance for Fixed combinations: Each active substance has to demonstrate its con-tribution to the composition claimed effect on the indication of that identified patient population.

FDC medicinal products are recommended as standard therapy in many therapy classes like the Parkinson treatment, the treatment of cardiovascular, cancer, pain and diabetes mellitus disorders. The WHO has changed their policy on fixed dose combina-tion to fight effectively against malaria, TB and HIV/AIDS because FDCs are effective in slowing down antimicrobial resistance. New fixed dose combination regulations have been enforced in Europe in the therapy classes discussed above. The procedures for granting a marketing authorisation of fixed combination medicinal products applies to the same principles like any other medicinal product, but the opening of Article 10b of the Community Code changed some issues related to FDCs: FDC medicinal products are not considered part of the global marketing authorisation and will beneficiate from an independent period of protection. FDC`s were recognized as a new product of con-taining new active substances protected by their own protection periods. The applica-tion for a marketing authorisation of a FDC medicinal product is applicable on any pro-cedure like it is for any other medicinal product containing a single drug substance. The optional conditions of the centralized procedure (Art. 3(2) 726/2004) may be applicable if there is concern about a significant therapeutic or a technical innovative benefit for the patients interests.

FDC therapy of first line or second line treatment, the advantages of the FDCs com-pared to monotherapy of the individual compounds or to the standard therapy, have been improved the of low dose and long term administration to control the efficacy and the adherence or the effectiveness of FDC products in hypertension, hyperlipidemia or diabetes mellitus type II in multi-factorial clinical trial designs with better or more toler-ance than monotherapy or free combinations. Fixed dose combinations have been an object of debates at international conferences. There has been a concern to regulate the access to medicines for neglected diseases, trading issues and the protection of intellectual property. The success of the WHO prequalification project and the scientific publication of the WHO network has had influenced the USA HIV guideline on fixed combination products and the EMEA product certification system (Art. 58, 726/2004). The regulation on Supplement Protection Certificate (SPC, Reg. 1768/92/ EEC) and compulsory licensing (Reg. 816/2006/EEC) are a relevant issue. The FDA regulates combination products under 21 CFR 300.50 as pharmaceutical products compared to the European Article 10b in the Community Code. As a demarcation the terms and ba-sic regulatory requirements between combined active substances and medical devices between the USA and the EU have been discussed. Special particulars of MAA data requirements of the fixed dose combination were discussed after a view on selected EPARs of FDCs approved by the EMEA. The overview compares shortly national spe-cific concerns of FDCs regulations between the EMEA, the FDA (USA) and TGA in Australia and the PHAC of Canada.

Pages: 93