A big change is on the way for big pharma. By 2020, 20 biologics with global sales of $67 billion will see their patents expire, meaning they will be open to competition from less costly imitations; namely, biosimilars, an approximate copy of a biologic product manufactured by a different company.

Biologics are protein-based therapies that come from living cells cultured in laboratories, and according to a report by the UK Office of Health Economics, they now take up one third of R&D funds in the pharmaceutical industry globally.

By 2016, ten of the 20 best-selling drugs on Earth will belong to this category.

"This whole concept of biosimilars wouldn’t have been allowed or been made available while the patents were still in place," says Richard Markus, vice-president, global development, Biosimilars at Amgen, which is developing six such products and is launching its portfolio in 2017, a task he’s been working on for roughly four years.

He believes that the intellectual property changes represent the biggest opportunity for pharmaceutical products in a generation − and he believes the timing is lucky. If this had happened 20 years ago, he argues, the technology might not have been available to take full advantage of the situation.

"If these were hypothetically coming off patents, then we would be in a very different, and awkward, place," he says. "I don’t think technology was necessarily available as it is today to understand the molecules to the same level, to ensure there are appropriate standards, and that the risks and the changes are going to be seen on the molecules.

"We have to be able to understand those differences and characterise them, but more than that we have to be able to understand the molecules themselves."

Copy approval

“Biosimilars are not identical to the drugs they imitate and are better understood as approximate copies – not clones.” 

Biosimilars, for one thing, are not identical to the drugs they imitate and are better understood as approximate copies – not clones. They are also complex, because they are derived from living organisms (the biologic Enbrel, for example, contains more than 20,000 atoms), which makes exact replicas impossible.

The cells from which these products are derived are simply too sensitive to a range of external factors, and manufacturers must develop unique and tailor-made processes to get the cells to behave in the correct way. And while a patent might be lifted, manufacturers can still keep production techniques as closely guarded secrets. Each manufacturer of biosimilars, therefore, has to develop its own cell line.

"That’s a fundamental basis of why these are different from a small molecule generic, a chemical entity like an aspirin," says Markus. "Those are made through basic chemistry − mixing things together, and voila you have your active ingredient and at an atomic level the atoms are identical.

"But when we get to the biologics they clearly are not identical and it’s quite easy to show they’re not, but that doesn’t mean they’re bad. They’re good copies and equivalent functionally, but they’re made up of fundamentally different molecules."

The clinical trials are different, too, compared with those undertaken with original biologic medicines.

The fundamental difference is that the goal of a biosimilar study is to confirm similarity to the originator biologic product, and not just prove safety and efficacy. If the growth of biosimilars is going to be as significant as pundits predict, then this represents a new paradigm in clinical studies and how they are managed.

"They’re very different in concept, so when you have a new drug, you want it to show that it’s superior, better than a current therapy, and if not that then at least that it’s better than a placebo," says Markus. "But for biosimilars the design of these studies is to show that they are equivalent in activity, efficacy, and safety and immunogenicity. Our goal is to show that we are equivalent in risk and benefit as the innovator."

To do this, manufacturers have to do one of two things. First, they have to show biological equivalence with a study, where they examine absorption and elimination, and how long the proteins are circulating in the blood.

"We still have to do a clinical study to confirm the activity of the molecule while it’s circulating," says Markus. "So it’s a different scientific question being answered with studies that have to be designed to answer these different problems."

Regulation and efficacy

Another key challenge for the biosimilars market is the issue of regulation of the intellectual property of the biologics they are emulating and of the trials process itself. Each new biosimilar cannot simply imitate the biogenic to pass; it must prove that its outcomes match the drug it is mimicking.

For the industry, it was a matter of anticipating when these drugs would come off patent, and having the appropriate legal and scientific framework to deal with multiple companies trying to make copies at the same time, reveals Markus.

"So the timing for the pathways was right to allow developers to make biosimilars at the time that they are coming off patent," he says. "People saw that coming, so they then had to create the pathway understanding, which has legal and scientific merits as to what would be appropriate and capable."

And the main risk associated with biosimilars is, of course, that they might not work as well as the biologics they imitate. Markus says their success is dependent on their ability to mirror the effects of the drugs they are mimicking and that the industry has a while to go before achieving total substitutability.

"It’s a bit challenging, I think some technology needs to be evolved further and certainly needs to get some more experience," he says. "I think it’s conceivable in the future."

Decreasing efficacy is also a concern. There are two main reasons for this: the first could be from the body developing antibodies that make the drug less effective, which can be common with biologics as living matter is introduced to the body.

"The question is whether this happens faster or not over time, so that the treatments are as effective as possible for as long as possible," says Markus. "We just don’t know what’s going to happen when you have highly related proteins that are immunogenic being switched around, how the body’s immune system is going to respond − it’s a true unknown right now. People could theorise on a whiteboard but it’s something we don’t have data for.

“Biosimilars are already making significant headway in Europe. According to a report last year by Allied Market Research, the market could be valued at $35 billion by 2020.” 

"That’s the burden of the sponsor − to prove that it’s safe to do − not the patient receiving that to determine whether or not they should or shouldn’t have had these switches taking place. That’s why it should be a physician’s or a patient’s choice whether or not they want to be switched around."

The future of biosimilars

Biosimilars are already making significant headway in Europe. According to a report last year by Allied Market Research, the market could be valued at $35 billion by 2020. And having seen massive growth in the EU in recent years, they are heading to the US – in May the Food and Drug Administration gave the all-clear to the first biosimilar product in the country. And the more the technology improves, the more popular, and effective, biosimilars will be, says Markus, as long as the molecules that are used and approved are of high quality.

"And I mean that they are close matches: that they look and feel and work like the innovator, and so that there’s no sense that these are second-class molecules," he says.

"If standards or experiences are not equivalent and the substitutability is in question, no one really wants to choose a molecule that is potentially inferior."

Biosimilars also hold a number of benefits for the consumer. In a May op-ed for Forbes entitled ‘Unleashing the Potential of Biosimilars’, George Mason University economist Wayne Winegarden argued that they have an "impeccable" safety track record in countries where they are in regular competition with biologics. Markus argues that a key benefit is that they also offer a wider choice for patients.

"I think which specific treatment a patient receives is really a conversation and decision by the physician and patient," he says.

"But even with that though, the biosimilars will provide more options of therapeutic choices."

"I think it’s a matter of providing more therapeutic choices and hopefully with that is increased access to these important medicines."

The Forbes report also argued that they can play a major role in bringing down high drug prices, estimating that they frequently sell at 30% the price of the branded medicines they are imitating.

There’s also the effect biosimilars can have on the drugs they originally mimicked – in what are known as "biobetters" or "biosuperiors", these products can in many ways improve on the original biologic.

"Thus a robust market for biosimilars would increase the quality of pharmaceutical drugs in addition to exerting downward pressure on pharmaceutical prices," argued Winegarden.