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The World Health Organization last week (4 May) announced plans to explore options for prequalifying insulin, a process that already assesses the quality, safety and efficacy of medicinal products, such as tuberculosis and malaria drugs.

It’s a step towards making a lifesaving – but often expensive – medicine more widely available in low- and middle-income countries, it said.

The WHO is considering whether to extend the prequalification process to manufacturers creating me-too versions of insulins, more commonly known as biosimilars. If a manufacturer of biosimilar insulin could, in theory, get its products prequalified, this stamp of approval could enable international agencies to buy it for patients in low and middle-income countries at lower prices than originator products. The agency has already given the go-ahead for pilots of some biosimilar cancer products (IPW, Public Health, 4 May 2017).

Today there is a shortage of affordable insulin, around 50 million people worldwide are unlikely to reliably access this life-saving medication because it is unavailable, unaffordable or both.

That’s despite expiring patents on the most popular insulins and a great deal of interest in creating biosimilars by manufacturers from India to Brazil.

But getting a new affordable insulin onto the market is fraught with complexity. Not least because the regulatory pathways to get such drugs approved vary so much across different countries.

The “Addressing the challenge and constraints of insulin sources and supply” (ACCISS) study, a three-year collaboration between NGO Health Action International (HAI), Geneva hospitals, the University of Geneva, and Boston University School of Public Health, has looked in detail at the regulatory routes that biosimilars must take to reach the market in countries from China to Cuba, the US to Iran.

So complex are the processes, (particularly in highly-regulated markets) that often regulatory authorities have taken many years to licence their first biosimilar insulins. In fact, the first biosimilar insulin – a copy of Eli Lilly’s blockbuster insulin glargine – which has received marketing authority in Europe, Japan and Australia, did so only in in 2014 and 2015. There is no biosimilar version of glargine in the US.

Marg Ewen, coordinator of global projects (pricing) at HAI, said as well as research, discussions with several biosimilar insulin manufacturers revealed that harmonisation might make medicines more affordable.

“It was clear there is a need to align regulatory requirements for biosimilar insulin across countries,” she said. “Harmonised regulatory requirements will help reduce barriers to market entry, while ensuring insulins are quality-assured.”

She reckons the WHO, in collaboration with regulatory authorities such as the European Medicines Agency, are best placed to develop global regulatory guidelines and to help countries strengthen their regulatory capacity (WHO said on 4 May it would update its own 2009 biosimilar guidelines).

The approvals process for a biosimilar is far more onerous than for normal generic medicines. That’s because they are more complex and large biological compounds – usually recombinant proteins – and making direct copies without intimate knowledge of the (originator’s) manufacturing processes is pretty much impossible. In contrast, generics are usually carbon copies of small molecules that can be continually created by chemical synthesis.

Therefore, more evidence is needed to prove the biosimilar is similar enough to the originator – or reference product. In other words, companies must produce more data to show there are no clinically meaningful differences in terms of safety and effectiveness from the original. Only minor differences in clinical active inactive components are allowable in biosimilar products.

In a rapidly-evolving and new field, what makes things even more complicated, is that most regulators have differing criteria for what precisely constitutes a biosimilar, the kinds of data that must be collected and human trials that must be carried out. Indeed, guidelines on these criteria are relatively new in some jurisdictions (2015 in China, 2010 in Brazil), or may not exist at all. Whereas in others, such as the EMA, they are advanced and have been around for well over a decade.

There are significant differences between the US and other regulatory systems – including the EU, Australian and Japanese regulatory authorities. The EMA classes insulin as a biologic, but so far the US has not. In fact, they’ve been approved but aren’t classed as biologics, or biosimilars, since they have not been subject to a specific pathway created for such biologic, called Biologics Price Competition and Innovation Act (BPCI Act), which forms part of the Affordable Care Act signed in by President Obama in 2010. Insulin and some other older proteins, such some heparins – have instead been approved through an entirely different approval pathway – so called 505(b)(2). That pathway falls under a different law, the Federal Food, Drug, and Cosmetic Act. That means, technically, these biosimilars are not biosimilars under US law. Instead they are called “follow-on biological products”.

By 2020, however, it’s expected that all insulins will be regulated by the BPCI Act.

There are also insulin-specific guidelines in the EU and Saudi Arabia, but no other countries.

The US system also distinguishes between different kinds of biosimilar; a bog-standard biosimilar and a sort of gold star biosimilar, with a higher degree of similarity that means it’s interchangeable with the reference product. Essentially, interchangeability means it’s so similar to the original drug that a pharmacy could automatically substitute the biosimilar for the originator product depending on state laws or insurance company policies.

The downside of not being legally defined as interchangeable, is that a biosimilar is less likely to be prescribed compared with the originator (although it will probably be cheaper too).

In contrast, the EMA won’t take a decision on which biosimilars are interchangeable, leaving it up to individual EU regulators.

Getting a biosimilar to the market is further complicated by the possibility of patent litigation.

Last week, the US Supreme Court started hearing oral arguments on a part of US biosimilar regulatory process designed to minimise patent disputes between originator and both similar manufacturers.

The BPCI Act has a process for resolving patent disputes that has so many choreographed steps, with precise timings, that it has become known as the “patent dance.”

Under the patent dance, the originator gets to review the biosimilar manufacturer’s application for marketing approval – for a predetermined length of time – to work out which active patents it believes could be infringed. Then the two parties tango; they exchange patent lists, explanations of infringement and negotiate to resolve their differences (albeit through litigation on a smaller number of infringements) all with carefully crafted timescales.

The US Supreme Court is now involved because one biosimilar manufacturer, Sandoz, unilaterally chose to not enter the patent dance – refusing to supply originator Amgen with a copy of its biosimilar application.

Many believe it did so because it did not want to share its licence application or manufacturing process with a future competitor, say observers. It seems a biosimilar manufacturer like Sandoz may prefer to go straight to litigation rather than put its cards on the table beforehand for negotiations with originators, says Prof Dmitry Karshtedt, now at George Washington University, who has been following the arguments for some years. Amgen wants the court to decide that the patent dance is mandatory (which it had assumed was the case).

A decision is expected by July. But, there’s a chance the court may decide the patent dance is optional. If that happens, the entire patent dance will be rendered obsolete, says Claire Laporte, a patent litigation specialist at Boston law firm Foley Hoag.

“If you sidestep the patent dance it may mean that biosimilars come to the market with unresolved legal challenges. This increases the risk that a biosimilar could be launched and then be forced to withdraw from the market,” she said.

So, its biosimilars might get to the market more quickly, before being bogged down in litigation, say observers.

Elsewhere, there might be other options for bringing insulin to the market more quickly. The ACCISS study reckons Article 58, a process introduced by the European Commission to help speed up the time low and middle-income countries take to approve new drugs[link], might also be a good route for getting insulins to developing-country jurisdictions. It’s never been done before, say the researchers and could be particularly fruitful, but only if the applicant has no interest in marketing their biosimilar in the EU – one condition of Article 58.