Speaker Interviews

Comparability from both US and European perspectives will be presented. Enclosed are interviews with two speakers at the event. Chris Holloway, Group Director, Regulatory Affairs, ERA Consulting Group. Chris will be speaking on Comparability for Innovator Products from a European Perspective. Keith Chidwick, Senior Pharmaceutical Assessor, Biologicals Unit, MHRA. Keith will be speaking on the European Regulatory Approach towards Comparability for a Biosimilar.

Chris Holloway, Ph.D., Dr.rer.hum.biol.habil., Group Director, Regulatory Affairs, ERA Consulting Group

Q: How important is comparability? 
A: Comparability is possibly the greatest single CMC challenge for the biologics industry. From the European Public Assessment Reports, one can deduce that more than half of failed biologics marketing authorization applications in Europe cite comparability issues. Results in the US are unpublished but the issue is equally problematic.

Q: Where is the industry going wrong?
A: Resources are often poured into clinical trials, which are of course incredibly important, but an equal amount should be devoted to analytical development for comparability studies, and that is often not the case. In other words, I believe that CMC is often under-resourced compared with clinical investment.

Q: How much is enough and how much is too much?
A: Regulatory assessment is risk based, and it is a widely held impression that regulators both in the US and Europe are highly risk averse. Sponsors would obviously prefer a minimalistic approach, while the regulator may opt for "more rather than less". When in doubt, do more towards comparability assessment to avoid this becoming a pitfall. Most importantly, interactions between the sponsor and regulator are required at appropriate times, certainly before initiating major process changes, so that the basis for the comparability exercise can be agreed.

Q: What are the expectations regarding impurities
A: The impurity profile is an integral part of the definition of the product, and this is particularly applicable to a biologic. A process change may not alter the characteristics of the product itself, but may affect the impurity profile and therefore impact on safety.

Q: Can clinical comparability be avoided?
A: Definitely, yes. In fact, most process changes, historically, have been approved without bridging clinical data. In most cases, therefore, this can be avoided but to do this you need an adequate CMC database with a good number of batches, and of course the impact of any differences in the product arising from the change need to be assessable in terms of "no expected effect" on safety and efficacy of the product.

Q: Should major process changes be avoided during development of a biologic
A: Not necessarily. It is not the change to the process that matters, but rather the impact of that change. A major process change may not, in fact, have a great impact on the product, whereas an apparently minor process change could alter the product characteristics. The emphasis, therefore, is on impact and the consequences for efficacy and safety of the product.

Q: Are there differences in expectations between the EU and the US and also Japan?
A: The science, as one would hope and expect, is basically the same around the globe, so regulatory expectations do not differ greatly. However, sponsors need to understand the emphasis of the various agencies, and the way that interactions with regulators, during development, are conducted. The global future of the product is dependent on simultaneous interaction with several key authorities, not just one, and a company's regulatory strategy should take that into account, even if development, including clinical trials, are currently only underway in one jurisdication.

Keith Chidwick, Ph.D., Senior Pharmaceutical Assessor, Biologicals Unit, MHRA (Medicines and Healthcare products Regulatory Agency in the UK)

Q: What is new regarding guidelines for Biosimilars in the EU?  
A: In Europe we now have an overarching guideline and product specific guidelines for biosimilar products such as human growth hormone, erythropoietin, recombinant insulin and monoclonal antibodies. All applications are reviewed on a case-by-case basis, where applicants have areas of doubt, due to the complexities of their specific product, formal scientific advice procedures can assist applicants in their development programs.

Q:  What in your opinion is required for comparability for a biosimilar compared with a post-approval change for an innovator?
A: A biosimilar producer can only demonstrate similarity with the final innovator product whereas for comparability studies a comparison can be made at every stage of production.   Investigators may want to opt for making a new innovator stand-alone product rather than going for the biosimilar option.

Q: What is the standard for demonstrating equivalence and gaining regulatory approval?
A: A thorough analysis with state-of-the-art analytical technologies such as sequencing and peptide mapping is required. Moreover the pre-clinical and clinical study must come together with a compelling argument. As stated before, each application is reviewed on a case-by-case basis.

Q: Can you comment on successes and failures?
A: There have been a number of successes for human growth hormone, erythropoietin, and recombinant insulin, although it has not always been an easy ride. There are failures too and these are in the public domain.


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