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The final guidance explains some principles for developing biosimilars and establishes some rules about extrapolation across indications for various medical conditions.
EMA released final guidance on extrapolation of biosimilars on Oct. 23, 2014. The updated guidance revises information from 2005 and suggests that extrapolation, which involves extending data from clinical studies for a primary indication to other indications, may be possible if clinical similarity can be shown in the key indication during comparability studies.
The guidance says, "If biosimilarity has been demonstrated in one indication, extrapolation to other indications of the reference product could be acceptable with appropriate scientific justification." It also provides clarification on manufacturing changes, saying that manufacturers do not need to demonstrate biosimilarity again if there is a change in the manufacturing steps, provided that marketing authorization has already been granted. In addition, it says that an active substance of a biosimilar must be similar molecularly and biologically to its reference product, and deviations from the reference product related to “strength, pharmaceutical form, formulation, exicipents, or presentation require justification.” The route of administration of a biosimilar is also expected to mirror that of the innovator product.
FDA is still undecided as to how the agency will handle extrapolations of indications for biosimilars and if it will require clinical studies for approval for each indication in which the innovator product is licensed. The ease with which a manufacturer will be able to extrapolate across indications could influence how the drug maker will file a product with the FDA.
If FDA allows for extrapolation, the move may greatly increase interest in filing a product through the 351(k) pathway. If the 351(k) pathway requires too high a level of clinical study requirements for extrapolated indications, drug makers may file with the 351(a) pathway to get the product on the market more quickly. This method, however, may not be ideal for manufacturers seeking to get approval for many indications at once. For example, Teva's neutropenia drug Granix (tbo-filgrastim), which was filed in the United States through a 351(a) pathway, was approved for only one indication, which was not the indication considered to be the "most definitive" for that particular product. If it had been filed through the 351(k) pathway, the drug would have potentially been eligible to gain indication extrapolation for all five of filgrastim’s (the reference product’s) indications.
Various medical societies, such as the American College of Rheumatology and the Association of the British Pharmaceutical Industry, among others, have spoken out against the use of biosimilars for extrapolated indications, according to GaBI. Many players in the medical community assert that acceptance of biosimilars in Europe has been poor, and as a result, market uptake of the medications has suffered. “This is especially true in therapeutic indications for which no specific clinical trials with the biosimilar have been performed and which have been licensed based on extrapolation of efficacy and safety data from other indications,” members of the Working Party on Similar Biological (Biosimilar) Medicinal Products said an editorial in the journal Blood earlier this month.
The authors of the Blood article argue that since clinicians tend to look at clinical trial data to help them judge drug efficacy and safety, it may be difficult to make sound medical decisions without data on biosimilar extrapolations. Extrapolation is fine, say the authors, if the relevant mechanism of action of the active substance and the target receptor(s) involved in the tested and in the extrapolated indication(s) are the same. “On the other hand, if different active sites of the biotherapeutic or different receptors of the target cells are involved in different therapeutic indications, or if the historical safety profile of the reference product differs qualitatively between the different therapeutic indications, additional data may have to be generated to justify the extrapolation of safety and efficacy data.” Despite this assertion, the authors concede that biosimilars have been on the European market for several years and have “performed as expected in all licensed indications, including extrapolated indications.”
Weise, M. et al., Blood online, DOI: 10.1182/blood-2014-06-583617, Oct. 8, 2014.