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Laurence A Goldberg FRPharmS
Editorial Consultant
This workshop, held in New Orleans in November 2010 and sponsored by the American Academy of Pharmacy Scientists (AAPS) in collaboration with the European Federation for Pharmaceutical Sciences (EUFEPS) and the International Pharmaceutical Federation (FIP), brought together pharmaceutical scientists from industry, academia and regulatory agencies from different countries to review scientific and regulatory issues in demonstrating therapeutic equivalence and interchangeability of multisource (generic) drugs including complex molecules. The key message from this meeting was the importance of developing for the future a process for the global harmonisation of therapeutic equivalence requirements.
Drug products are considered to be therapeutically equivalent if they are pharmaceutically equivalent and if they can be expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the label, according to captain Edward Bashaw (Director, Division of Clinical Pharmacology-3, Centre for Drug Evaluation and Research, FDA). The most efficient way of assuring therapeutic equivalence is to ensure that the formulation performs in an equivalent manner by demonstrating pharmaceutical equivalence and bioequivalence. Captain Bashaw went on to say that demonstration of pharmaceutical equivalence relies on sameness of active ingredient, dose form, route of administration, strength/concentration and meeting the applicable standards for identity, strength, quality and purity. Demonstration of bioequivalence of systemic products involves comparison of plasma concentrations of the test and reference product in healthy subjects. The area under the curve (AUC) and peak plasma concentration (Cmax) must lie between 80–125% of the values for the reference product to be acceptable; this usually ensures a mean difference of less than 10%.
Bioequivalence (BE) based on the comparison of bioavailability (BA) under strict conditions and criteria has long been the gold standard as a clinical surrogate for the approval of new drugs applications as well as generic medicinal products and variations to the formulation and manufacture of approved medicinal products. There has been over forty years’ experience without major incidents, explained José A. Guimarães Morais (Professor of Pharmacy, University of Lisbon and European Medicines Agency). Several issues have been the subject of appeals within the European medicines evaluation system due to differing interpretations of previous guidelines, on subjects such as food effects, use of metabolite concentrations, conditions for extrapolating results from one BE study to other strengths and, especially, biowaivers based on biopharmaceutics classification systems (BCS). Clear guidance covering more specific cases is now given in sections addressing these issues. Steady-state design is now restricted and other designs such parallel group, replicate and two-stage design are now incorporated in a more explicit form. Professor Guimarães Morais went on to say that new practical guidance on highly variable drug products and narrow therapeutic index drugs has now been introduced. The possibility of a biowaiver based on the BCS is now more explicit for class I drugs (high solubility, high permeability) and can be extended to class III drugs (high solubility, low permeability) under stricter conditions. The initial goal of providing very specific and clear guidance on these issues has not been entirely achieved mainly because it is almost impossible to predict every possible scenario. Demonstration of bioequivalence will still be required in many instances, he concluded.
WHO’s mandate is to act as the directing and coordinating authority on international health work, to encourage technical cooperation for health with member states and to develop, establish and promote international standards on biological, pharmaceutical and similar product, explained Sabine Kopp (Programme Manager, Quality Assurance and Safety: Medicines, WHO, Geneva).
The WHO secretariat works in close collaboration with the expert panel on the international pharmacopoeia and pharmaceutical preparations, national and regional authorities, non-governmental organisations, international professional associations and specialists in order to harmonise and limit the number of guidelines worldwide, including the FIP Board of Pharmaceutical Sciences special interest group on bioavailability/bioequivalence.
WHO has issued guidelines for product interchangeability and identified four types of studies considered to demonstrate it – comparative pharmacokinetic and comparative pharmacodynamic studies in humans, comparative studies using clinical endpoints and comparative in-vitro tests. Multisourced products considered to be equivalent to the comparator without additional documentation include parenteral products if they are aqueous solutions, containing the same active pharmaceutical ingredient (API), of the same molar concentration and with the same or similar excipients. Similar definitions exist for certain other pharmaceutical forms such as powders for reconstitution, gases and nebuliser inhalations. However, in-vivo equivalence studies are required for a number of products including modified release products designed to act systemically, oral products with narrow therapeutic indices, critical use medicines and fixed-combination products with systemic action where at least one of the APIs requires and in-vivo study. WHO defines a comparator product as a drug with which the generic product is expected to be interchangeable in clinical practice, or a product whose safety and efficacy data have been the basis for marketing approval and will be the basis for approval of all its pharmaceutical equivalents, or a product that generally has the largest market share (usually the originator product). Selecting a comparator product presents a number of challenges, said Dr Kopp. There is no global agreement on the selection of comparator products, national market leaders may be more relevant for patient safety, market leaders may not be the originator products, market leaders and originator products may differ between countries.
According to Mei-Ling Chen (Associate Director, Office of Pharmaceutical Science, Center for Drug Evaluation and Research, FDA) pharmaceutical equivalents do not necessarily contain the same inactive ingredient or have the same release mechanisms as the originator products. Determination of pharmaceutical equivalence has traditionally been made by a qualitative and quantitative comparison between formulations. Whilst this approach is appropriate for simple dose forms, it is insufficient for complex drug products, she said. Further scrutiny of pharmaceutical characteristics and use of state-of-the-art methodology may be necessary in assessing identity or similarity of complex active ingredients and novel dose forms. Difficulties in establishing the identity of the active ingredient can arise if the active ingredient is too complex and cannot be fully characterised. Examples are oligosaccharides (e.g. low molecular weight heparins), peptide mixtures (e.g. glatiramoids) and iron-sugar drugs (e.g. iron sucrose).
Parenteral iron is widely used in the treatment of iron deficiency and iron deficiency anaemia in chronic kidney disease, said George Bailie (Professor, Department of Pharmacy Practice, Albany College of Pharmacy and Health Sciences, New York State). Iron sucrose is the most common representative of the iron-oxyhydroxide carbohydrate drugs. Iron sucrose and iron sucrose similars (ISS) have the same general structure – a core of ferric oxyhydroxide surrounded by a shell of carbohydrate that allows slow release of iron from the core. Iron sucrose has a long clinical track record and a good safety profile. In recent years the use of iron sucrose has increased considerably whereas usage of iron gluconate and iron dextran has remained more or less static.
The iron sucrose complex is taken into storage sites (in the reticulo-endothelial system) in a controlled way without the release of large amounts of labile iron directly into the circulation. This prevents the over-saturation of the iron transport system (transferrin) and reduces the potential for oxidative stress.
Small differences in the structure of the ISS complexes affect product stability and the physicochemical properties of these complexes are highly dependent on the manufacturing process. Possible differences can be found in the structure of the iron core, molecular weight distribution of the iron core and molecular weight distribution of the iron sucrose complex. Only rigorous standardization can lead to high reproducibility, minimal batch-to-batch variation and a product with consistent quality, said Professor Bailie.
Several ISSs have now been approved in a number of countries but they are not identical to the original iron sucrose complex (Venofer®). Physicochemical analyses of three different ISS injections showed that they did not conform to the USP specification on at least one parameter. Polarograms for the three ISSs and Venofer showed that the peaks were shifted to the left, indicating that they were more likely to trigger oxidative stress at physiological pH than Venofer, the originator product.
Studies in rats comparing Venofer and ISSs showed differences in iron deposition, inflammatory markers and oxidative stress parameters. When ISSs were administered, there were increased iron deposits in the liver and kidneys but ferritin stores in the liver were reduced when compared with Venofer. The appearance of free iron deposits in the liver and kidneys suggests that the iron was released more rapidly from ISSs causing over-saturation of the iron transport system and consequent inefficient use of iron. Levels of the pro-inflammatory cytokines, interleukin six (IL-6) and tumour necrosis factor alpha (TNF-α) were raised, suggesting inflammation and/or oxidative stress. Levels of protective antioxidant enzymes including glutathione peroxidase and copper-zinc-superoxide dismutase were significantly increased with ISS and not with Venofer. In addition, serum liver enzymes (alanine transaminase, alkaline phosphatase and aspartate aminotransferase) were raised and blood pressure was reduced. There was also a small reduction in creatinine clearance and a significant increase in proteinuria compared with the originator product. Professor Bailie commented that for every parameter there were significant differences between the ISSs and the originator product.
An observational study examined the impact of a switch from the originator iron sucrose (Venofer) to an ISS (Fer Mylan®) on 75 stable, chronic dialysis patients.
Data were gathered for two 27-week periods before (December 2008–June 2009) and after (June 2009–January 2010) the introduction of Fer Mylan.
The results of the study suggested that iron sucrose (Venofer) and the ISS (Fer Mylan) might not be therapeutically equivalent. The switch to the ISS led to a loss of control of the patients who were destabilised causing a significant decrease in haemoglobin levels and iron indices. A direct consequence of the switch was an increase in drug consumption in order to maintain target haemoglobin levels. There was a 35% increase in the IV iron dose and a 13% increase in the ESA dose. The anticipated savings on IV iron were not achieved and the overall cost of drug treatment was increased by 11.9%. The switch resulted in patients being exposed to higher doses of ESA and IV iron. The differences seen in the iron indices following the switch raised questions about the stability of the ISS complex and its impact on iron distribution and oxidative stress, commented Professor Bailie.
Professor Bailie concluded that the generic paradigm does not guarantee that ISSs are as safe as the originator product and or that they are therapeutically equivalent. ISSs are similar but not identical to Venofer and should therefore be referred to as ‘similar’ and not ‘generic’. Non-clinical studies have demonstrated significant differences in safety markers of ISSs and clinical experience suggests that ISSs may not be as effective as the originator.
Treatment with ISSs should be monitored over time to document differences in adverse effects in patients. The data suggest that clinicians need to be cautious when substituting an ISS for the originator Venofer in CKD patients, he emphasised. A new standard on which to base equivalence of ISSs is required. In addition Professor Bailie recommended that pre-clinical studies for safety markers should be undertaken along with ferrokinetic studies of iron incorporation into red blood cells.
Furthermore, clinical safety and efficacy data to show equivalence and substitutability should be presented and a patient registry study should be performed to confirm the safety of ISS.
