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Biopharm Development & Manufacturing How Pfizer Navigates Changing Biosimilar Regulations T By Nick Taylor, contributing editor he 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. 36 LifeScienceLeader.com 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 April 2013 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