By Nick Taylor, contributing editor
The imminent loss of patent protection on blockbuster biologics is creating an interesting market opportunity — biosimilars. It is a highly lucrative opportunity too, with BCC Research predicting the global biosimilars market will swell to $3.6 billion by 2016. That figure has attracted virtual biotechs, generics giants, and the biggest of Big Pharma. Each is united in pursuit of a piece of the $3.6 billion and by a common challenge — regulations.
Diem Nguyen grapples with the challenge every day. “From a biosimilars regulatory perspective, there’s still a lot of uncertainty,” says Nguyen, general manager of Pfizer Biosimilars. Because biosimilars are never exact copies of the innovator medicine, establishing appropriate standards for biosimilarity remains an important area for scientific, legislative, and regulatory debate. While all regulators in established markets have created guidelines, they are still ironing out the details. The sector is too young for anyone in industry or regulation to know how things will play out. Everyone is navigating untrodden paths.
Differences in regulations across the major markets further complicate biosimilar development. Some regulators, such as the FDA, allow developers to run similarity tests against innovator drugs sourced from overseas. (The U.S. still requires an FDA-licensed reference product.) The European Medicines Agency (EMA) and other regulators want developers to source comparators, called reference products, locally. Europe plans to become more flexible, like the FDA, but global alignment is a distant dream. The variance means that even in the preclinical stage, a ”one-size-fits-all” approach is impossible.
Invest Early In Robust Preclinical Data
Common regulatory goals and values lie behind the different biosimilar development guidelines though. Regulators are united on the value of data showing similarity between a biosimilar and reference product. They all want to see similarity shown through structural and functional characterization of a biosimilar and reference product. The biosimilar concept is based on robust evidence of similarity being demonstrated in preclinical, quality, and functional comparisons, which then allows a tailored preclinical/ clinical program to be followed which does not require repetition of the entire development program of the innovator.
Money spent on generating data showing similarity can therefore save time and resources later by reducing clinical testing requirements. Still, Pfizer is committing significant resources in time, money, and intellectual expertise into clearly showing similarity and ensuring the safest and most effective biosimilars are developed. Analytical tools and cell-line development knowhow from the innovative biologics division support the effort. Backed by these resources, Nguyen thinks Pfizer has an advantage in technically demanding areas of biosimilar production.
The FDA showed just how hard it is to replicate biomanufacturing processes when it rejected a Genzyme drug in 2008. Genzyme had already won FDA approval for the Pompe disease drug, Myozyme, but a manufacturing change caused problems. The FDA said scaling up from 160L to 2,000L reactors altered the drug enough to make it a different product. Regulators accept that biosimilars will differ from innovators — small differences without clinically meaningful effects are allowed — but showing similarity is still tough. It is also just the first of many obstacles on the path to approval.
How To Design A Global Biosimilars Trial
The goal when designing a global biosimilar trial is to meet the needs of as many regulators as possible. This way, a company can run one trial, instead of several smaller studies, to access multiple markets. The challenge is finding a trial design that satisfies the needs of all the major regulators.
Nguyen shares a hypothetical example to show potential global trial design pitfalls. Say Pfizer designs a trial and takes it to the European Committee for Medicinal Products for Human Use (CHMP). The CHMP likes the trial design and clears it without any alterations. But when Pfizer takes it to the FDA, the U.S. regulator asks for tweaks to the trial design. Pfizer then has to modify the trial to meet the needs of both regulators or run separate trials for the U.S. and Europe.
Matters become even more complicated when emerging markets are thrown into the mix. India, for example, largely follows the European biosimilar pathway, but requires local trials. And its guidance is short on detail about Phase 3. “So, even though India broadly follows European standards, a product could win approval in one market, but not the other,” Nguyen explains.
A flexible, creative approach is needed to navigate through the regulatory maze. For Pfizer, this means applying experience with innovator biologics, which was boosted in 2009 by its merger with Wyeth. Newcomers to biologics are partnering to gain expertise, a trend illustrated by the joint venture between Samsung, Quintiles, and Biogen. Knowing what worked in the past will only get a firm so far though. “If there’s one thing about biosimilars development I’m comfortable with, it’s that it will evolve,” Nguyen says.
Come Prepared To Meetings With Regulators
To glimpse into the future, companies must pay attention to the utterances of regulators. Ask the right questions, and a regulator can make the path forward a little clearer. Comment periods on draft guidance documents are an agency’s opportunity to listen. But meetings to discuss an individual biosimilar or indication are the best chance to talk over the fine details.
At Pfizer, the process of preparing for regulatory meetings begins by looking backwards. “We draw on our knowledge of regulatory precedents, past programs, and known issues with similar products,” Nguyen explains. With few biosimilar precedents, the regulatory fate of the innovator biologic being copied is a useful guide. If side effects were a regulatory hurdle for the innovator biologic, a biosimilar will face scrutiny, too.
Pfizer feeds knowledge of what happened in the past into its models of biosimilar development pathways. Before meeting with regulators, Nguyen and her team investigate the feasibility of all credible biosimilar development options. The impact of different development choices, such as enrollment targets, is predicted. One pathway might offer the cheapest, fastest route to market but increase the likelihood of regulatory restrictions.
Regulatory meetings are particularly useful in markets that are still finalizing the details of their approval pathways. But even in Europe — which was a pioneer in biosimilars — guidance is still evolving. The EMA expects to publish a revised draft of its 2005 guidelines on biosimilars later this year. And, with several emerging markets taking their lead from Europe, the changes could have far-reaching consequences. As with much in biosimilars though, it is too early to say with total conviction. “We’ve not progressed far enough to know if a change in European biosimilars’ guidance could trigger a shift in Brazil or India, too,” Nguyen states.
All this uncertainty is a problem for developers of biosimilars. Even at this early stage in the history of biosimilars, some firms have hit development difficulties as regulatory expectations change around them. In October 2012, both Teva, which is developing biosimilars with CMO Lonza, and Samsung independently halted trials of rituximab. Media reports linked the decisions to halt tests to doubts about regulatory situations in the U.S. and Europe.
If these companies reach the stage of submitting data to regulators, they will face a whole new set of uncertainties. The FDA is yet to accept an application under the biosimilars approval pathway, so nobody knows what will happen.
Physicians Need To Be Educated
In small molecule generics, being the first to bring a copycat to market almost guarantees a big slice of the sector. But biosimilars, as in so many other areas, are more complicated. The path from approval to taking market share is less certain. For starters, though the U.S. law includes a definition of “interchangeability” that speaks to substitution without the intervention of the prescriber, it is a question of individual state laws whether pharmacists are permitted to switch patients from innovator drugs to biosimilars. Pfizer is of the opinion that the physician should own the decision to treat an individual patient with a biosimilar in view of the complexity of biologics in general, and, therefore, automatic substitution of biosimilars for innovator drugs without the intervention of the physician is inappropriate.
Whatever the FDA decision, biosimilars manufacturers will need to work to win market share. The price difference between biosimilars and innovator products will be less pronounced than for generics. And the complexity of the products further shifts the risk-reward balance away from the biosimilar. The challenge will be similar in scale to marketing innovator biologics. Pfizer, with its background in innovative biologics, believes this gives it an advantage. “Our relationships with physicians across multiple therapeutic areas allow us to understand what they want from data,” Nguyen says.
Physicians are, along with regulators, pharmacists, and payors, one of the key stakeholders dictating how patients will access biosimilars. It is important they understand the issues. “Physicians need to be educated about differentiation, quality, and data perspectives in biosimilars,” Nguyen states. With this understanding in place, physicians can make informed decisions about prescribing and help increase trusted acceptance of biosimilars.
If biosimilars take market share, patients will benefit from more affordable versions of lifesaving biologics, and payors will gain a new tool to drive down healthcare costs. There is still a long way to go until this is achieved, though, and getting there will require creative thinking. “A cookie-cutter approach to biosimilars development simply isn’t going to work,” Nguyen concludes.