New biosimilar guidance from EMA allows non-EU comparator
This article was originally published in SRA
The revised version of the European Medicines Agency's general guideline on biosimilar medicines has now been published, complete with a number of changes from the original, including the possibility of using a non-EU comparator drug in order to avoid unnecessary clinical testing, and of extrapolating indications in certain cases without clinical data1,2.
One of three "overarching" guidances originally dating from September 2005, the "guideline on similar biological medicinal products" describes the key principles involved in developing and submitting a biosimilar product application.
The updated version clarifies a number of aspects in light of experience, including the principles of biosimilarity and the requirements regarding dosage and route of administration. It officially comes into effect on 30 April 2015, although companies can apply some or all of its provisions immediately.
According to Cecil Nick, vice-president at consultancy and services firm Parexel, the new version suggests that the CHMP, the EMA's main scientific committee, wants to introduce more flexibility when it comes to demonstrating biosimilarity, to allow more room for a case-by-case approach3.
A key feature of biosimilar development, the guideline says, is to show that the product is similar to the reference biological product in terms of quality characteristics, biological activity, and safety and efficacy, based on a comprehensive comparability exercise. The biosimilar must, for example, have the same amino acid sequence and the same posology and route of administration, while differences in terms of strength, pharmaceutical firm and excipients must be justified.
To establish biosimilarity, it says that a stepwise approach is normally best, starting with a comprehensive physicochemical and biological characterization. The kind of non-clinical in vivo and clinical studies required will depend on how much evidence was obtained in the previous step.
If clinical studies are required, it will be to address slight differences shown in previous steps, and to confirm the comparable clinical performance of the biosimilar and reference products. A confirmatory clinical trial may not be necessary in cases where similar efficacy and safety can be clearly shown by the similarity of physicochemical characteristics, biological activity/potency, and the PK/PD profiles of the two products.
Non-EEA reference product
A key feature of the revised guideline is that biosimilar companies are now able to reference a drug that is not itself authorized in the European Economic Area (the EU plus Norway, Iceland and Liechtenstein).
Generally speaking, the reference product must be one that is authorized for marketing in the EEA, and the same product must be used as the comparator throughout the biosimilar comparability program.
However, in a major change that was keenly sought by the generics industry, the guideline now introduces the possibility of comparing the biosimilar, in certain clinical and/or in vivo non-clinical studies, with a non-EEA authorized version of the reference product. The reference drug will need to be authorized by a regulatory authority "with similar scientific and regulatory standards" to those of the EMA – the International Conference on Harmonisation member countries, for example.
The company will have to show that the non-EEA comparator is "representative" of the EEA-authorized drug. If certain clinical and in vivo non-clinical studies are conducted with the non-EEA drug, the company will have to supply adequate information to justify the relevance of these data and establish a bridge to the EEA-authorized product. The bridging data would have to include information from analytical studies comparing all three products, and could also include clinical pharmacokinetic and/or pharmacodynamic bridging studies.
For Mr Nick, the move to allow non-EEA reference products is in line with views that the CHMP has been giving for some, and also chimes with the committee's wish for more flexibility in evaluating biosimilarity.
In the same vein, he pointed out that some sections of the original guideline have been removed, notably those explaining why blood- and plasma-derived products are not suitable for development as biosimilars.
The revised version says only that the biosimilar approach is more likely to be successful for well characterized products, but more difficult for other medicines, "which by their nature are more difficult to characterize, such as biological substances arising from extraction from biological sources and/or those for which little clinical and regulatory experience has been gained".
Extrapolation
The guideline also addresses the thorny issue of extrapolation. It says: "If biosimilarity has been demonstrated in one indication, extrapolation to other indications of the reference product could be acceptable with appropriate scientific justification."
Mr Nick noted that extrapolation "is generally not a big issue", and that the CHMP is reluctant to approve a biosimilar for fewer indications than the reference drug, on the basis that if there are issues with approving all the indications, "do you have a biosimilar at all?" The EMA is keen on extrapolation, but it has not gone as far as to say it should be automatic, he observed.
Extrapolation is an issue that continues to generate great controversy within the originator industry, though, with some claiming that physicians may be reluctant to prescribe a biosimilar for an extrapolated indication, without clinical data to back it up. Just last month, for example, the European biotech industry body EuropaBio said that the labeling of biosimilars should make clear whether the data used for their approval were generated for the biosimilar or for its reference product, and should include information on the reasons for any extrapolation.
The idea, however, received a cool reception from the EMA, which said the biosimilar and reference drugs should be "closely aligned. The European Generic medicines Association (EGA) said such an approach would suggest that there are differences between the biosimilar and the originator, which is "not the case"4.
Also briefly addressed in the guideline is the question of naming of biosimilars. This has generated a huge debate, with the World Health Organization finally proposing a four-consonant "biological qualifier" for all biologic drugs to address perceived traceability problems with biosimilars5. But the CHMP says simply that "all appropriate measures should be taken to clearly identify any biological medicinal product which is the subject of a suspected adverse reaction report, with due regard to its brand name and batch number". There is no mention of the need for any other identifying marks.
The other two overarching biosimilar guidelines cover quality issues and the clinical and non-clinical aspects of biosimilar development. A revised version of the quality guideline was published in June this year and comes into effect in December, while a new version of the clinical/non-clinical guidance should be published by the end of the year.
References
- EMA press release, 29 October 2014, www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2014/10/news_detail_002201.jsp&mid=WC0b01ac058004d5c1
- EMA, Guideline on similar biological medicinal products, 23 October 2014, www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/10/WC500176768.pdf
- Personal communication, Parexel, 30 October 2014
- Biosimilar labeling row breaks out in Europe, Scrip Regulatory Affairs, 25 September 2014
- The WHO's biological qualifier: voluntary or compulsory?, Scrip Regulatory Affairs, 2 October 2014