Biosimilars: Reading FDA’s Tea Leaves

When biosimilars hit FDA, what will be the review criteria? Everyone cares, since so much is at stake. The market for generic versions of eligible biologics might soon reach $20 bil. Recent FDA actions might hint at the new era. In a Citizen Petition for Lovenox (Aventis), FDA shared its review guidelines for approving a generic. In a petition for Copaxone (Teva), FDA asserted broad discretion in scientific decisions. Both petitions are filled with clues, and other clues are sure to follow. Biosimilars: are we there yet, are we there yet? First, some background. In the US, most new drugs become subject to generic competition sooner or later, under 1984 Hatch-Waxman laws. “Biologics” don’t qualify, though, if they’re approved under laws where Hatch-Waxman doesn’t apply. For years, the pharmaceutical world has wondered when FDA might approve copies of a biologic product. In the past, FDA said it had no legal authority to approve copies on just a “paper” application without clinical trials. The issue then moved to Congress to create that authority. The term “biosimilars” came into favor along the way. Congress eventually acted – as part of healthcare reform – and FDA now has a mandate to approve biosimilars. Pioneer biologics (vaccines, blood-based products, pricey rDNA insulins, certain biotech products) will now enjoy 12 years of market exclusivity in most cases. The process seems similar to the European approvals that began in 2006. If we’re on our way, then what’s our destination? The imminent arrival of biosimilars is making the pharma industry a different place. Everyone needs to know who’ll be winning and losing. Anyone with a good picture of FDA’s upcoming guidance will have a leg up on that future market. And of course, predicting the future is always trickier than it looks. […MORE jump goes here] FDA has considered standards for biosimilars for many years, and many outside groups have weighed in. FDA has given public testimony on its thinking and built internal multi-disciplinary workgroups to settle complex issues. It’s still not clear, though, how long it will take to see FDA regulations or guidance that could allow industry to understand the rulebook and which products to pursue. The stakes are high. The global market is huge. By one estimate, $25 bil. in biologics will go off-patent by 2016, and potential biosimilars sales in 2014 could reach $19.4 bil., with EPO products the largest slice at $6.1 bil. The push to market biosimilars is well on its way. The future of biosimilars has now revived an age-old tradition – trying to read the tea leaves at FDA. [Long-time FDA-watchers may remember that until 1996, FDA hosted a Tea Board of Experts with actual jurisdictions over tea leaves. Some things never change.] 1. The Tea Leaves of the Lovenox Petition One such tea leaf just became visible. On July 23rd, in an announcement that seemed unrelated to the biosimilars regulations, FDA issued a response to an obscure Citizen Petition that had been languishing in the Agency since 2003. The subject was Lovenox, a blood-thinner in the class of low molecular weight heparin products (LMWH). While Lovenox starts out as a biologic (blood-based) product, the final drug is considered a new “drug” and not a “biologic.” This means the Lovenox petition is not really a biosimilars petition at all, but simply another generic drug review under Hatch-Waxman. Even then, FDA had a difficult time building review criteria for such a large and ill-defined molecule as Lovenox (enoxaparin). Sanofi-Aventis was hoping that its pioneer Lovenox product was so complex a molecule with such a unique means of action that approving a generic version would be difficult at best. During seven years of review, FDA apparently struggled with a definition of what would be an “identical” product for generic drug standards when the pioneer product can’t be 100% “identical.” The source material for LMWH products begins in pig gut, so there is some inevitable biologic variability. The Hatch-Waxman rules anticipate a generic version showing an identical molecule with identical bioavailability. FDA had a delicate balance to achieve. FDA’s response, seven years later, caught much of the pharma world by surprise. In a detailed, scientific thesis, FDA set out five specific criteria to support a generic approval, and then announced approval for one of the generic applications on file (Novartis’ Sandoz). [Other ANDAs for Lovenox are pending, including Teva’s.] The news is not just that FDA approved a generic Lovenox without knowing the molecule’s exact structure. The bigger news is that even though this petition is based on the laws of generic drugs, the standards may foretell the standards that might evolve for biosimilars, as well. For tea leaf readers, it’s required reading. 2. The Tea Leaves of Teva’s Copaxone Petition In another development, Teva had a pending Citizen Petition on its only blockbuster drug, Copaxone (glatiramer). Teva argued that Copaxone, which treats multiple sclerosis, was a large molecule so unique and complex that FDA might never find a route to approve a generic. On May 11^th, FDA issued a blistering denial, specifically leaving an open door for generic approvals even for molecules that can’t be proven as fully identical. FDA said it would review each application on its own merits, and would not tie its own hands with general pronouncements on bioequivalence. Both the Copaxone and Lovenox petitions involved drugs and not biologics, so the cases don’t speak directly to the future of biosimilars in the US. Even so, the timing of these letters might help interpret the tea leaves at FDA, certainly enough to know what classes of products might have an easier time through the biosimilars approval route. One lesson in the tea leaves relates to how much clinical testing FDA will require for biosimilars. We know the standard for a new, full, pioneer application is typically two well-controlled clinical trials, and the simpler biosimilars route will need to involve less than that. The Lovenox and Copaxone petitions imply that even in for drugs (much less biosimilars), some in vivo (clinical) evidence of “sameness” is needed. So if FDA will require fewer than two trials, but more than zero, the number of trials needed for biosimilars approval seems to be something along the lines of… one. 3. The Tea Leaves of FDA’s own Regulation Drafters and Publications Another tea leaf is that FDA has built its regulations team from both the drugs and the biologics review centers. This suggests that the Agency is dedicated to a goal of Agency-wide parity for scientific reviews, so standards announced in the Lovenox petition may serve as harbinger of the final guidance on biosimilars. In still another tea leaf, FDA released on August 4^th its long-awaited Issues Assessments for medical devices. One theme of the review was how so-called 510(k) devices might enjoy a new model for Risk Evaluation and Mitigation Strategy (REMS). This Assessment, fallout of the 2007 medical device amendments, recognizes that different degrees of risk require different strategies from FDA. Applying REMS theory to biosimilars, we’d have support for the belief that products with greater risk will have different risk management strategies than slam-dunks. That has not always been the case for new drugs or biologics, whether pioneer or generic. 4. Still More Tea Leaves, If You Know Where to Look Looking around the Agency, there are other tea leaves that might give hint to the final review standards for biosimilars. Piecing together these stray bits of evidence, it’s possible to build an educated guess – but still just a guess – as to how the world of FDA reviews will look in an era of biosimilars. Given the size of the pipeline for biosimilars over the next decade, it seems worthwhile to read all the tea leaves we can find. Eventually, FDA will offer final guidance that will define the US biosimilars market, and until then we may have plenty of tea leaves for guessing where things are heading. But no, we’re not there yet.