Unravelling the complex world of biologics and biosimilars

Tuesday, 14 Jun 2016

In the next five years we are likely to have up to 36 biosimilars to treat rheumatologic diseases – that’s in addition to the biologics we already have. But do we have enough evidence to confidently switch patients between innovator products and their biosimilars? Is there anything to learn from the less complex molecules that have been around for a while? In this feature leading experts from the US and Canada take us through the complex world of what we know, and what we don’t know.


Biologics are changing the landscape

Speaking at a satellite symposium called Unravelling the mystery between structure and sustained clinical outcomes at this year’s EULAR congress Professor Edward Keystone from Mount Sinai Hospital in Toronto told delegates biologics had changed the landscape of therapy in rheumatic diseases.

They had substantially reduced the signs and symptoms of rheumatoid arthritis, inhibited radiographic progression and joint damage, and improved quality of life for patients.

However, rising healthcare costs across the globe had created a need for less costly biologics, leading to the development of biosimilars.

But with this change in the market place had come the issue of ‘non-medical switching’ – whereby patients whose disease was adequately controlled on a biologic were switched within one class, or from a reference product to a biosimilar or vice versa.

This was usually motivated by the potential for cost savings or patient preference if their health care system required high co-payments, Professor Keystone said.

However, there was currently insufficient robust evidence to provide a definitive answer on non-medical switching, he said.

“As the biologic treatment landscape evolves and becomes more complex one of the main challenges will be how to clinically inform and follow-up on non-medical switching,” he said.

 Complex terms for a complex situation

Taking to the podium Thomas Dörner from the Charite University Hospital in Berlin said the terms interchangeability, switching and substitution were often referred to when talking about switching a patient from a biologic reference product to one within the same class or a biosimilar.

According to the US FDA an interchangeable biologic product, in addition to meeting the biosimilarity standard, is one that is expected to produce the same clinical result as the reference product in any given patient.

Whereas the EMA says an interchangeable biologic product is: ‘the medical practice of changing one medicine for another that is expected to achieve the same clinical effect in a given clinical setting and in any patient.’

“One needs to bear in mind that the FDA requires additional switch studies compared to EMA which is not so insistent and rather puts this in the post-marketing domain,” Dörner told the audience.

Transitioning/switching was a physician-controlled action of a single transaction of patients from a reference product to a biosimilar.

And substitution was the action of the pharmacist dispensing one medicine for another equivalent and interchangeable medicine at the pharmacy level without consulting the prescribing physician.

“I think we need to be insistent as the prescribing doctors that we need to know what our patients are receiving,” he said.

“When we do not know what our patients are receiving we are not able to really act in terms of pharmacovigilance.”

Medical switching is evidence based

Professor Dörner said medically relevant switching – that is, switching patients treated with biologic therapy who have an inadequate response or an intolerable adverse event to a different biologic for clinical reasons – was backed up by evidence.

“This practice is evidence based, you find it in the literature, updated in the 2015 ACR guidelines for the treatment of RA, and EULAR recommendations are considering this”.

“When patients are not responding adequately to a certain drug or they experience an adverse event we are basing it on clinical experience, clinical data, retrospective data, post-marketing surveillance.

We are quite sure about switching our patients to another biologic or to another mechanism of action,” he said.

Can we learn anything from the less complex biosimilars?

The less complex molecules: epoetins, growth hormone and G-CSFs have been in the market for some time. Because of this there is some data on the effects of switching between these products and their biosimilars, Professor Dörmer explained.

For instance, a review involving 58 clinical trials and 12,039 patients looked at switching patients for non-medical reasons across reference products and between reference products and biosimilars.

The authors came to the conclusion that there were limited clinical data investigating the effects of switching/transitioning from biologics. Most of the trials were not designed to identify switching-related adverse events.

Furthermore, they said adequate substantive data and post-marketing surveillance were required.

However, they concluded that for these less complex biosimilars there was currently no indication that switching/transitioning impacted on safety and efficacy.

Authors of the open-label SWITCH trial that involved the non-medical switching of patients with Crohn’s disease from Remicade to Humira concluded that adherence to the first anti-TNF was recommended if the patient was stable.

Another IBD retrospective study presented at ECCO 2015 involved the non- medical switching of 158 patients with IBD patients across anti-TNFs.

Non-medically switched patients had more clinic visits during follow-up and they experienced more side effects and lack of efficacy.

The authors concluded that: “cost related switching in medically stable patients may have unintended consequences.”

“These studies are based on very heterogeneous IBD populations on very different anti-TNFs… we still lack this data in an inflammatory joint population,” Professor Dörmer cautioned.

Evidence is increasing but there is still uncertainty

There is increasing ongoing evidence on switching among reference products and biosimilars for several indications including rheumatic diseases, Professor Dörmer told the audience.

However the results of these studies should be interpreted with caution since the study designs varied widely and included randomized active controlled trials, single-switch studies, open-label studies without a control arm and retrospective studies, and small cohorts.

The data also mostly came from abstracts, posters, and oral presentations presented at medical and scientific congresses.

“Altogether there is still a need to generate more robust data on switches and also to serve the idea that all of these compounds are interchangeable”.

“This is still an area of uncertainty…and we definitely await more final data from these cohorts in the future.”

Multiple switches a particular challenge

According to Professor Dörmer one of the biggest challenges for clinicians and regulatory bodies will be multiple switching – where patients are switched between the reference product and different biosimilar versions based only on price considerations.

“So far we have do not any knowledge on how this will turn out, particularly in terms of safety and maintenance of efficacy,” he said.

“We don’t have sufficient data, we might in two or three years, but right now we have a lack of data in this specific situation” he told the audience.

According to Professor Dörmer we need a large randomised controlled trial with an appropriate control group of at least two switches between one biosimilar and one reference product.

“If there is an additional biosimilar in play we would need to have much larger trials,” he said.

However, he noted that these scenarios are usually not of clinical relevance and do not reflect clinical practice.

“In order to address all these remaining aspects rigorous clinical trials cannot be expected,” he added.

The importance of post-marketing surveillance

Professor Dörmer said one of the most important points to get right was setting up rigorous post-marketing surveillance.

“It is of utmost importance that we have sufficient pharmacovigilance in place for the biologics, much more than for the classical generics,” he says.

Pharmacovigilance, Professor Dörmer explained, was the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other possible drug-related problems.

It was a continuous assessment of the risk-benefit profile of every drug and minimised the risks associated with the use of drugs.

However, one challenge facing the pharmacovigilance of biologics was the lack of a uniform naming system for biosimilars.

For example the European Medical Agency use the brand name and the US FDA use the generic name with the four letters of the producer.

“In terms of the biologics it is important we have a tracking system and a distinguished naming for specific products that we are then able to trace and record, report on a spontaneous and periodic basis” says Professor Dörmer.

Traceability is important because it enhances adverse event reporting, promotes effective pharmacovigilance and increases accurate prescribing, he says.

“That’s important for the transparency of the dispensed product to the patient it also assures that the physician has sufficient control of what they are prescribing and minimises the risk of unintentional prescribing and inappropriate automatic substitution.”

Clinical challenges ahead

The number of biologics in the treatment of inflammatory rheumatic diseases will increase substantially in the future. There are likely to be more than 36 biosimilars available in the next five years, Professor Dörmer told the audience.

“Remember this will be in addition to the currently available reference products and we expect a few more new mechanisms of action drugs also coming into clinical practice”.

“The market will be complex, but the clinical challenges will be very complex for us to identify the right treatment algorithms and to find the right patients for the right drugs,” he said.


This article was commissioned and sponsored by AbbVie PTy Ltd. Mascot. The content is based on published studies and the speakers’ opinions presented at Abbvie’s Satellite Symposium during EULAR 2016. The views expressed are not necessarily those of AbbVie PTy Ltd. Please consult the full Product Information for any medications mentioned in this article at before prescribing. Treatment decisions based on these data are the full responsibility of the prescribing physician. AU-HUMS-2016-44

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