Christine Clark PhD FRPharmS
One of the most effective safety interventions in healthcare is prophylaxis against venous thromboembolism (VTE), and yet, in spite of advances in this field, fatal pulmonary embolism (PE) remains a major killer, according to Lord Kakkar (Director, Thrombosis Research Institute, London United Kingdom). Speaking at a satellite symposium sponsored by Sanofi-Aventis he said that in the United Kingdom there are an estimated 32,000 deaths per annum associated with recent hospital treatment, 80% of which could be avoided if prophylactic treatment were given. Low dose unfractionated heparin (UFH) given perioperatively saved seven lives per 1000pts in moderate- to high-risk surgical patients and even bigger effects were seen with low-molecular-weight heparins (LMWHs). Extended prophylaxis in total hip replacement (THR) operations and total knee replacement (TKR) operations has had a big impact in reducing venous thromboembolism (VTE). Similarly successful results have been reported in other surgery and general medical patients – with relative risk reductions of 40–60%.
Many thousands of patients have now been evaluated and the LMWHs that are currently available are both safe and effective, Professor the Lord Kakkar concluded.
Biosimilars and generics
Biosimilars are clearly different from generic drugs and more stringent clinical risk management measures must be applied at the point of adoption, in monitoring when in use and when reporting problems to regulators, Ian Bourns (Director of Medicines Management and Pharmacy, East Sussex Hospitals NHS Trust, UK) told the audience. Conventional medicines are normally small, relatively simple molecules whose action is related to their chemical structures. Production of conventional medicines is based on relatively simple chemical reactions with easily controlled variables and licensing is based on clinical effects, dosing and safety studies. Importantly, variation in clinical effects and side effects is minimal. In contrast, biologics are large, complex molecules whose action is related both to molecular composition and the way in which the molecule is folded and its resulting shape. Production techniques for biologics are complex but licensing is based on clinical effect, dosing and safety studies. It is likely that the production systems for biosimilars will have some variations from the original reference product and as a result the structure and folding of the biosimilar may be different. Current analytical techniques cannot fully characterise such complex molecules. It is therefore not possible to prove that a biosimilar is the same as the original. Furthermore, contaminants can vary in biosimilars, depending on the production process. Most importantly, variations in clinical effects and side effects can only be determined in trials.
Turning to the regulation of biosimilars, Mr Bourns said that the European Medicines Agency (EMA) takes the view that biosimilars are not the same but similar. Comparative clinical trials with the original reference biologic are required and separate trials are required for each condition for which approval is sought. The Medicines and Healthcare Products Regulatory Agency (MHRA) in the UK follows the EMA position and brand name prescribing is recommended. Care is needed in the reporting of adverse reactions to ensure that the correct product is identified, he emphasised.
Mr Bourns concluded that clear differences exist between generics and biosimilars and that there are additional potential hazards associated with biosimilars, although the nature of these is not yet entirely clear. Because of the risks, more stringent licensing requirements are applied than for generics. These differences will mean that a different approach is needed for the adoption of biosimilars.
For pharmacists, the implications are that more stringent clinical-risk-management thinking must be applied to the adoption of biosimilars and that past planning assumptions about generics coming to market may not apply to biosimilars. Horizon-scanning timeframes and may differ and financial planning and savings assumptions may need to be adjusted.
Immunogenicity is a major concern when considering the use of biosimilars and this can have serious clinical consequences, according to Huub Schellekens (Professor of Pharmaceutics and Innovation Science, Utrecht University, the Netherlands).
For small-molecule drugs, the generic paradigm applies: If a product is pharmaceutically and bio-equivalent then it is considered to be the same as the originator product. However, biologics are always mixtures of products that are made in living cells. “The moment that a cell makes a protein, the breakdown system is also activated and so there is always a mixture,” he explained.
All biologics induce antibodies in patients but because current analytical techniques are less sensitive than the human immune system they cannot fully predict which antibodies will be formed. A number of factors are known to influence immunogenicity including structural factors such as sequence variation and glycosylation. Other critical factors include contaminants, formulation, route of administration and patient factors. The most serious consequence of immunogenicity and antibody formation is loss of efficacy. In Europe, hundreds of patients now receive products that are no longer effective for them because of antibody formation, said Professor Schellekens. One example was an erythropoietin (EPO) product that induced formation of an antibody that not only neutralised the drug but also the patient’s own erythropoietin. The result was pure red cell aplasia (PRCA), a serious, life-threatening condition.
LMWHs are considered to be biosimilars in Europe. However, despite considerable progress with the biochemistry of complex sugars, enoxaparin is not yet fully characterised and this is noted in the European Pharmacopaeia. Much is known about the active site – the antithrombin III (ATIII) binding sequence – but current analyses do not accurately reflect either the number of ATIII-binding sequences and their structural diversity or the wide range of ATIII-affinity (caused by the particular monosaccharides flanking the classical ATIII-binding sequences).
Heparin-induced thrombocytopaenia (HIT) is the most serious side effect of heparins, said Professor Schellekens. LMWH chains form complexes with platelet factor 4 (PF4) that activate B-cells which then produce antibodies. The result of this is immune HIT. The type of heparin used influences the extent of the immunogenic response. There is a higher incidence of HIT antibodies and clinical HIT with UFH than with LMWH. Moreover, the incidence of HIT antibodies varies amongst LMWHs and even amongst biosimilar versions of enoxaparin. The reasons for these differences are poorly understood.
In the European Union, biosimilars are covered by Article 10 of the Human Code, which stipulates that where differences exist between the biosimilar and the originator, for example in the manufacturing process, the results of appropriate pre-clinical tests or clinical trials relating to these conditions must be provided when approval is sought. There are then three tiers of guidelines that specify the safety and efficacy data required.
The EU is the only region with a comprehensive regulatory framework for biosimilars. So far, two biosimilar growth hormone (GH) products, two EPOs and two granulocyte-stimulating factors (GSFs) have been approved. At present, the most important issue is substitution and interchangeability of biosimilars, explained Professor Schellekens. Ideally there should be no substitution of biosimilars, he added. EMA policy is to allow each country to decide on its own provisions.
In clinical practice, every product is different and only the treating healthcare professional can ensure the safe use of biologics. This requires careful monitoring and meticulous documentation, concluded Professor Schellekens.
There is discordance between the United States Food and Drug Administration (FDA) and the EMA concerning the status of LMWHs. In the USA, they are considered to be generic drugs whereas in the EU they are considered to be biosimilars, said Jawed Fareed (Professor, Departments of Pathology and Pharmacology, Thrombosis Research Unit, Loyola University Medical Center, Illinois, USA).
In the EU, clinical studies are required to demonstrate ‘sameness’ whereas the FDA does not require a clinical trial but relies on five criteria to determine the sameness of generic enoxaparin. They are:
- Equivalence of physicochemical properties
- Equivalence of heparin source material and mode of depolymerisation
- Equivalence of disaccharide building blocks, fragment mapping and sequence of oligosaccharide species
- Equivalence in biological and biochemical assays
- Equivalence of in vivo pharmacodynamic profile.
The FDA claims that its approach (that is, the five criteria) is more sensitive to differences between two enoxaparin products than the clinical studies recommended in the EMA guideline.
However, studies have shown that there are differences between the originator product and generic versions. Despite comparable molecular profiles and potency equivalence, the generic versions of enoxaparin show variations in other coagulation tests. Obvious pharmacodynamic differences in tests such as global clotting assays and tissue factor pathway inhibitor (TFPI) release have also been reported. In addition, different immunogenic responses have also been reported among various generic versions of LMWHs, said Professor Fareed. He concluded that the current approval pathways for generic drugs might not be adequate for complex multifunctional drugs such as LMWHs. A globally harmonised approach to develop international guidelines, with the inclusion of pharmacodynamic validation is needed, he suggested. Moreover, since the safety margin of these drugs is comparatively narrow and the LMWHs can be used in critical indications, it is important to require clinical validation data on the generic products to avoid compromises on safety or efficacy.