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EMA is under pressure to exert even tighter standards on biosimilars being marketed in Europe.
The European Medicines Agency (EMA) has reached a key stage in the lengthy process of creating a regulatory framework for the development and marketing of biosimilars in Europe. In December 2014, guidelines on quality standards for biosimilars with proteins as an active substance came into effect (1), while guidance on clinical and non-clinical issues with the products was being finalized. A revised overarching guideline (2) on the basic principles governing the approval of biosimilars is due to be implemented in April 2015. It includes a provision that authorization of a biosimilar in the European Union (EU) can be based on comparisons with certain clinical and in-vivo non-clinical studies on a non-EU originator or reference product.
The first overarching guideline (3) on principles of biosimilars approval was issued in 2005, four years after the legal basis for the marketing of biosimilars was established by an EU directive (4). The laying of the legal foundations for the control of biosimilars over the past 14 years has given the EU global leadership in the regulation on the products, of which it had approved 19, including the first two monoclonal-antibody biosimilars, by late 2014.
Nonetheless, there are a number of regulatory issues with biosimilars that parts of the pharmaceutical industry believe still need to be sorted out by EMA. The biggest of these issues is the matter of labeling, on which there are differences of opinion between the original innovators and the biosimilar developers. The current position on labeling by EMA is based on a 2012 guideline (5) covering generic medicines, hybrids, and biosimilars. This guideline states that, as with generic drugs, the biosimilar’s summary of product characteristics (SmPC) has to be derived from those of the reference product.
“The general principle is that the SmPC for a biosimilar medicine has to be consistent with the reference medicinal product for the common information applicable to the biosimilar product,” explains an EMA spokesperson. “In other words, the information from the reference medicinal product’s SmPC that applies to the biosimilar should be included in the SmPC of the biosimilar.”
The SmPC also refers to detailed information being available on EMA’s website, where comprehensive and transparent information on biosimilars is presented in European Public Assessment Reports (EPAR). The agency acknowledges that the “topic has generated a lot of interest with stakeholders.” There has been speculation that because of the level of controversy on the subject, EMA will have to issue some extra guidance on the subject. Despite drawing up a series of guidelines on biosimilars, EMA has yet to draft one specifically on the labeling of the products.
Critics of EMA’s policy on the issue, led by the European Biopharmaceutical Enterprises (EBE) and the European Association of Bio-industries (EuropaBio), claim that it is too close to that on the labeling of generic medicines. They claim that it does not highlight sufficiently the inherent differences between biosimilars and their reference products because being biological, they cannot be identical as small-molecule generic drugs are with their originals. Instead, a biosimilar has to demonstrate similarity to the reference product in terms of quality characteristics, biological activity, safety, and efficacy based on a comprehensive comparability exercise.
Opponents of EMA’s position argue that biosimilars’ labeling should focus more than other medicines’ labeling on the quality characteristics-pharmacochemical and biological properties-as determined by the manufacturing process. Under the EU’s step-wise approach to biosimilars, these characteristics and any differences between them and the reference product dictate the scope of clinical and non-clinical trials necessary to establish safety and efficacy comparability. Information on quality is important because it will fulfill the whole purpose of labeling by enabling both physicians and patients to make informed decisions about the safe and effective use of biosimilars.
“The inclusion of the preclinical and clinical data [only] on the biosimilar is misleading because the assessment of biosimilarity is primarily based on extensive analytical comparisons [on quality] which may not be included in the SmPC,” says the EBE in a recent paper (6) in
Generics and Biosimilars Journal. “Since the SmPC does not usually contain analytical data, it would also be important to explain the inclusion of relevant analytical data to prescribers.”
With EuropaBio, EBE calls for a labeling approach that combines information on both the biosimilar and the reference product to achieve “full and transparent disclosure” of all data generated by the two medicines. “A lot of stakeholders at EU level have agreed that physician perception and patient acceptance impact biosimilars uptake,” says Miriam Gargesi, EuropaBio’s healthcare director. “We believe that a new and transparent labeling regime for biosimilars will contribute to facilitating physicians’ and patients’ understanding and acceptance of these products.”
“It is important for physicians and other healthcare professionals, as well as patients, to understand how the biosimilarity exercise was built up and which additional data were generated to show that previously proven safety and efficacy of the reference product also apply to the biosimilar,” Gargesi continues. “For this reason, and since the development of each distinct biosimilar requires generating specific preclinical and clinical data, we believe that a specific label should better reflect the outcomes of these data. The label must provide the information needed for prescribers to understand the technical and scientific context under which the product was approved to ensure its safe and effective use.”
The scientific principles underlying the comparability exercise required for changes in the manufacturing process of a biological medicinal product and for development of a biosimilar medicinal product are much the same. However, the data requirements for the biosimilar are higher, because of the potential impact of quality differences on safety and efficacy, Gargesi points out.
On the other hand, the European Generic Medicines Association (EGA) argues that any deviations in the labeling between information on a biosimilar and its reference product would be highly confusing to physicians and patients. “[The deviations] would increase the ongoing misunderstanding and misinterpretation of the biosimilarity concept,” says Adrian van den Hoven, EGA director general. “They would not reflect the totality of evidence of the biosimilar being comparable to a reference product with regard to quality, safety, and efficacy. They would mislead the healthcare professionals and the patients on the data requirements for approvals of biosimilar medicines,” he adds. “They may lead to potential medication errors. Physicians may withhold biosimilar medicines from patients in need.”
Non-comparable biotherapeutic products
The disagreements over labeling in the EU reflect controversies over the regulation of the global biosimilars sector, which has prompted arguments over the quality, safety, and efficacy controls of the products. The International Federation of Pharmaceutical Manufacturers & Association (IFPMA), the Geneva-based organization representing the research-based drugs industry, has claimed that in addition to biosimilars, there are “non-comparable biotherapeutic products” on the world market, which have not undergone complete comparability exercises on quality, safety, and efficacy.
With biosimilars, most national regulatory authorities (NRAs) are approving them in a way consistent with the guidance of the World Health Organization (WHO) on similar biotherapeutic products (SBPs), which is consistent with the EMA guidelines. But some are still not conducting comparability studies in line with the WHO guidance. With non-comparables, the scope of their quality as well as safety data is unknown, while their data may also not include any side-by-side assessments showing similarity to the reference products, says IFPMA.
“Some NRAs are still in the process of adapting their regulatory frameworks for biotherapeutic products,” the organization continues in a policy statement (7). “As a result there are some countries where intended ‘copy’ (or non-comparable) biotechnology products have been licensed under regulatory pathways that are not appropriate for biotherapeutic medicines.”
With so many doubts about the quality, safety, and efficacy of biosimilars and what are now being called “biosimilar-type” products on the world market, EMA is under pressure to exert even tighter standards on biosimilars being marketed in Europe. One way of doing this is seen to be, at least by the R&D sector, the introduction of a fully transparent labeling system.
1. EMA, Guidance on similar biological medicinal products containing biotechnology-derived proteins as active substance:quality issues (revision 1) EMA/CHMP/BWP/247713/2012 (London, June 2014).
2. EMA, Guidance on similar biological medicinal products (revision 1) CHMP/437/04 (London, October 2014).
3. EMA, Guideline on similar biological medicinal products, CHMP/437/04 (London, October 2005).
4. EU Directive 2001/83/EC, Community code relating to medicinal products for human use (Brussels, November 2001).
5. EMA, QRD general principles regarding the SmPC information for a generic/hybrid/biosimilar product, EMA/627621/2011 (London, May 2012).
6. K. Watson et al., Generics and Biosimilars Journal 3 (4) (2014), accessed Jan. 15, 2015.
7. International Federation of Pharmaceutical Manufacturers & Associations (IFPMA), Policy Statement: Non-comparable Biotherapeutic Products (Geneva, July 2014).
About the Author
Sean Milmo is a freelance writer based in Essex, UK, email@example.com.
Article DetailsPharmaceutical Technology
Vol. 39, No. 2
Citation: When referring to this article, please cite it as S. Milmo, “Labeling of Biosimilars,” Pharmaceutical Technology39 (2) 2015.