Biosimilars have a fascinating story of development and understanding it is crucial for widespread adoption

A Conversation with Rosa Giuliani: Biosimilars are crucial to maximising sustainability and accessibility of cancer care and oncologists want to know more.

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Modern cancer care relies heavily on biological medicines, which have changed the natural history of some cancer types. But the introduction of this sophisticated and expensive therapy means that throughout the world, countries are struggling to provide the best care to their patients. Biosimilars present an opportunity to lower the costs, thereby increasing access in the EU and beyond and contributing to the sustainability of healthcare. Rosa Giuliani, MD, has become a leading figure in this field and, as a medical oncologist, says the most important advantage of biosimilars is that patients currently denied access to expensive biologicals will have the chance to receive treatment. Giuliani is a consultant in medical oncology at The Christie Hospital, Manchester, UK and Chair of the ESMO Global Policy Committee.

An ESMO survey about knowledge and use of biosimilars in oncology has just been published in ESMO Open.

The survey found that three in four (75%) prescribers know what a biosimilar is. Why do you think the remainder don’t know?

The concept of biosimilarity is different from what medical oncologists are used to. We understand much better new developments such as immunotherapy, or new targeted drugs, because they have been developed according to what I like to call the “standard paradigm for drug development” – phase I, phase II, phase III – basically looking at efficacy and safety of drugs.

For biosimilars we need to change our perspective. The concept is not having a drug that is safer or more effective but is having a drug that, based on the comparability exercise and the totality of evidence, is highly similar to the originator (also called the reference product). I think that as oncologists we struggle initially to grasp the new terminology. And we struggle to leave the paradigm we have known for drug development.

The survey shows that less than half of prescribers (49%) use biosimilars in their clinical oncology practice. Did this strike you as being very low?

Yes, I was surprised by these low numbers. We also need to keep in mind that the survey was conducted in Autumn 2017. I want to be optimistic, and maybe one explanation could be that when answering the question, responders were possibly focusing more on of the new wave of biosimilars. These are the biosimilars for monoclonal antibodies and are still not available in many countries, so that’s why they’re not used. In addition, uptake of the first wave of biosimilars in oncology has been extremely low and heterogeneous in different countries and I believe this may be partly explained by the lack of clear and extensive communication about the science behind biosimilars. Therefore, it is now imperative to ensure that the oncology community learns the scientific and regulatory pathways that lead to approval of biosimilars in the EU.

The main concerns oncology prescribers have with switching from a biologic to a biosimilar are the potential for adverse events and increased risk of immune reactions. Are these valid concerns for approved biosimilars?

No, absolutely not. There is no evidence to support these concerns. No biosimilar has been withdrawn by the regulatory bodies because of safety issues, meaning adverse events in general and immunogenicity in particular. Secondly, there are no rational reasons to have immunogenicity problems if the biosimilarity has been ascertained. Because this is the concept – two products that are highly similar cannot trigger this immunogenicity problem.

So, in terms of allaying the concerns, does it come back to understanding the development of biosimilars?

This is a key point. With the introduction of biosimilars, this is the first time the medical community has learned and spoken so extensively about immunogenicity. It was already studied when every biological was developed but we did not discuss it then. So, for me the problem is insufficient knowledge and awareness of the system of development and of the body of evidence the regulators require from companies to support the approval of biosimilars.

“Insufficient knowledge and awareness”: the survey clearly revealed some educational priorities in the field. How do you envisage this teaching being delivered?

The majority of responders from every world region highlighted the need to receive further education. There is an acknowledgement of the desire for more information about the process of drug development of biosimilars. Different channels were suggested by responders including face-to-face meetings and quizzes. The main point is that this is not the end of the story, and we need to resolve some issues – for instance extrapolation (1) is the most important one requiring further explanation.

The paradigm for development of biosimilars is totally new compared to what we as medical oncologists are used to. We are aware that it’s new, but we need to understand it better. This is an evolving field. Once we understand the comparability exercise and what regulators mean by totality of evidence, we will see that we don’t need the phase III trial as a sort of cherry on the cake to show that biosimilars are really similar to the reference product.

I have the impression that now, the phase III trial that is run to confirm the biosimilarity concept is just something we need because everything is novel. But actually, we need to understand that all data that are collected and provided with respect to pharmacokinetics, immunogenicity – the data that are more globally referred to as the comparability exercise and the totality of evidence – are definitely more important compared to the last bit of information which is the phase III trial. I have the impression that without the phase III trial, very few people in the clinical community would have ever accepted biosimilars. So, I think this is something that we need for now. But once everybody is more aware of this new drug development platform, I think that we should also move away from the concept of a phase III clinical trial.

So that should really speed up adoption and development?

Absolutely. Biologics have had an unimaginable impact on the course of cancer and I understand that nobody on earth wants to risk losing this outcome. We really want our patients to be treated in the best way. But I’m sure that if we seriously consider and learn how these drugs are developed, and there is proper education about these drugs, then we will understand this new paradigm for drug development is as good as what we are used to. And that will be a means to save money, because if we do not need expensive phase III clinical trials to show the biosimilarity those are other resources that can be used in the smartest way.

But nearly one in four (24%) prescribers said they do not use biosimilars because they are not approved or reimbursed in their country…

In order to have proper uptake of any therapeutic intervention, and even more in the case of biosimilars, collaboration between different bodies is required. First of all, it needs to be regulated at European level and this is done, from a scientific point of view, by the European Medicines Agency (EMA). Political awareness needs to be raised, in conjunction with political bodies (European Commission), the World Health Organization (WHO), and more importantly scientific societies (ESMO for oncology as well as other organisations). This work that is done centrally should be translated and continued at a national level, in every country, mainly by the national competent authorities and the national oncology societies. And then from the national level it should be translated at the level of the local practice. This is up to us, medical oncologists, playing an active role, not just as prescribers, but understanding the whole system for drug development and being informed and knowledgeable. So, it’s an effort that requires collaboration between central and local authorities. And in this context clinicians have a key role in their respective fields.

It seems surprising, given that biologicals are less expensive, that they wouldn’t be reimbursed. Maybe people are not satisfied with the evidence for them?

No, I don’t think so. I think it’s a matter of bureaucracy, which can be different from country to country. When I myself answered this question in the survey I also stated that I was not using some biosimilars, because I was thinking of the monoclonal antibodies that are not reimbursed. So responders possibly focused on the new wave of biosimilars. At the time of the survey in 2017 some were centrally authorised, but even when the EMA approves a drug there is a delay in the uptake of that drug in different countries. That’s why it is very important how active the national competent authorities in each member state are.

Less than half (45.2%) of prescribers could define “sensitive indication”. What does the term mean and why is it important?

This is almost common sense. If you want to prove biosimilarity you should choose the indication and patient population where the evidence can be collected in an unbiased way. The sensitive indication is the population and line of treatment considered sensitive enough to detect any potential difference between a proposed biosimilar and the reference product. A sensitive population is considered the most representative of the patients for whom the biosimilars, and the biological before, is prescribed. If I want to study a monoclonal antibody biosimilar for breast cancer I wouldn’t study a population that is very heavily pre-treated because there are many confounding factors. I will go either for the first line setting or, where it’s possible, the neoadjuvant setting. This is a sensitive indication and population. I will also choose sensitive endpoints, which are the measures that will allow me to understand any meaningful difference between the originator and the biosimilar.

What happens if a patient refuses to switch?

In my experience, when patients receive a rational explanation they are reasonable and they understand. It would be interesting to capture this data in clinical practice because I think that some of these problems are more theoretical than practical. In other words, I believe we are anticipating problems that don’t exist.

Were there notable differences in responses between prescribers from Europe and the Asia Pacific region?

What I found very interesting is that with respect to the education required, responders from the European region were more interested in knowing about clinical safety and clinical efficacy while responders from the Asia Pacific region were more interested in having specific activities tailored for low income countries. Our Asian colleagues are more comfortable with the concept of extrapolation, meaning we need to raise more awareness within Europe. Responders in both regions were equally concerned about toxicity, but in Europe the concern was more about the immune reaction and in Asia it was about adverse events in general but always in relation with switching.

There are slightly different definitions, regulations, and requirements in different areas of the world. It would be good to have some sort of alignment and harmonisation because drug development is a global process and cancer patients should be offered the same level of care wherever they live.

Note

(1) Extrapolation is the approval, by a regulatory agency, of a biosimilar in one or more indications of the reference biologic without the requirement to carry out clinical trials of the biosimilar in all those indications.