General
Written by Dr. Paolo Biffignandi, Advisory Board member of the pan-European pharmaceutical regulatory affairs organisation ELC Group and former President of TOPRA (The Organisation for Professionals in Regulatory Affairs).
Biosimilar medicines, one of the fastest growing sectors of the industry, constitute a major share of pharmaceutical expenditure in the EU, the US and globally. From a regulatory perspective, they are a new paradigm in drug development, similarly to the early days of the acceptability of generic medicines. In the same way, the stakeholders of biosimilars are not only the patients but also the pharmaceutical industry, the regulator and the physician.
The fact that biosimilars are biological substances mostly endogenous to the human body, or analogues of the same, is perceived positively by the patient (as they are considered to be ‘natural’) and yet cautiously by the regulator and the prescriber; the regulator is driven by concern for unexpected risk (e.g., adverse drug reactions due to immunogenicity) and the prescriber by the best therapeutic outcome of an expensive treatment.
The EU Commission and the EMA have established a regulatory framework proving guidance that has permitted 13 European approvals (interestingly, all German, except for one Austrian) for these new medicines. These marketing authorisations were for somatotropin (developed as biosimilars before guidelines), epoetin alfa, epoetin zeta and filgrastrim (for recombinant human interferon alfa-2a, a negative opinion was adopted).
On January this year, the EMA launched a six-month public consultation on the revised guideline on non-clinical and clinical development of similar biological medicinal products containing low-molecular-weight heparins (LMWHs).This guideline describes the non-clinical and clinical requirements for a LMWH-containing medicinal product claiming to be similar to another one already on the market. The non-clinical section addresses the pharmacotoxicological requirements and the clinical section describes the requirements for pharmacokinetic, pharmacodynamic, efficacy and safety studies as well as pharmacovigilance aspects. This new guideline may have a definitive impact on the development of LMWHs and related products, approaching a more relaxed model.
In the US, alternatives to huge EU development pathways are possible, such as that exemplified by enoxaparin sodium, a LMWH approved by the FDA through an abbreviated NDA (ANDA) pathway, remarkably, with an AB interchangeable rating (the US term for substitution) with a minimum of pharmacokinetic data to extrapolate to efficacy and safety. Immunogenicity was also resolved based on the decision on ‘sameness’ established by quality data. The overall concept of fingerprinting, using the FDA’s five criteria, is uniquely adopted by the FDA in its pragmatic approach to approval of biosimilars.
To better understand the differences and similarities between these two scenarios, one should consider that the FDA divisions can be viewed almost in the same way as Competent Authorities are in Europe, each with its own history, philosophy, review and approval practice. Decisions, therefore, would be on a case-by case basis by product and division but these guidances (e.g., the FDA draft guidance for industry: Quality considerations in demonstrating biosimilarity to a reference protein product, 2012) would provide an overarching perspective as for the European biosimilar framework defined by overarching CHMP/EMA guidelines.
Finally, immunogenicity should be recognised but not over-stressed. This is a major concern for the regulator of biologics and is addressed in several EU and FDA guidelines. The EU has a general guideline, covering quality, nonclinical and clinical (plus a class-specific guidance for monoclonal antibodies). The FDA, in its 2012 guidance, emphasises analytical validation methodology, which needs to be robust.
The cooperation of the EMA and FDA has been exceptional and covers MAA/NDA/biologics licensee applications reviews, clinical safety, scientific advice, joint GMP inspections and all facets of drug development and approval. Harmonisation will progress and impact global development of biosimilars.
Dr. Paolo Biffignandi, paolo@elc-group.com.