Karen Carey

Biosimilars encircle Rituxan, US debates innovator exclusivity

Sandoz, the generic drugs unit of Basel’s Novartis, announced in January that it has begun a phase 2 rheumatoid arthritis trial with its own version of blockbuster monoclonal antibody (mAb) Rituxan (MabThera, rituximab). It joins Teva Pharmaceuticals, of Petach Tikva, Israel, and Spectrum Pharmaceuticals, of Irvine, California, both of whom are also working on versions of the antiCD20 chimeric mAb approved for chronic lymphocytic leukemia, non-Hodgkin’s lymphoma and r h e u m a t o i d arthritis. The progress of these biosimilar versions of Rituxan will be closely monitored by biotech innovators, particularly the rapidity with which they proceed through the review process. At

BIO marches to Congress with growth package in hand

6.6 billion in 2010 sales, Rituxan is the largest revenue-producing biologic yet to come into the crosshairs of biosimilar developers. Besides the allure of its billion-dollar market, Rituxan has been prioritized by biosimilar manufacturers for two simple reasons. The first is intellectual property. The drug, marketed in Europe by Roche of Basel, and in the US by Biogen Idec, of Cambridge, Massachusetts, and Genentech, of South San Francisco, was first approved in 1997, and is due to lose European patent protection in 2014, and US coverage in 2015. The second has to do with new guidelines for biosimilar mAbs released by European regulators last November (Nat. Biotechnol. 29, 10, 2011). To gain approval, the demands placed on biosimilar manufacturers are less onerous than anticipated. The requirements for approval outlined by the European Medicines agency include pharmacodynamic and pharmacokinetic studies, an equivalency margin of 80% to 125%, a full comparative clinical trial or an interim endpoint for approval followed by a traditional endpoint for postapproval as well as safety data gained through sufficient patient exposure. In essence, biosimilars makers need to show only similarity and conduct clinical trials with only a small number of patients. That has lowered the bar further than some biosimilars developers had dared hope. The decisiveness in Europe has made the US’s inability to agree on its own pathway more conspicuous. (Europe already has cleared for marketing several recombinant small proteins as biosimilars, such as growth hormones and insulin.) US Congress gave the Food and Drug Administration (FDA) authority to approve biosimilars for the US market as part of the Obama administration’s Patient Protection and Affordable Care Act passed a year ago. But it’s unclear what the FDA will do. Some observers predict the agency could take a few years to draft its plan. The possibilities run the gamut from replicating the EU model to adopting more stringent guidelines that require larger, separate trials with efficacy objectives. With several biosimilars already approved in Europe (Table 1), there will be “pressure” on the agency, says Rajesh Shrotriya, Spectrum’s chairman, CEO and president “to provide guidance to individual companies while still developing guidance documents on biosimilars.” Some of that pressure is already here, as major stakeholders are voicing their varied concerns with the FDA. Robert K. Coughlin, the Massachusetts Biotechnology Council’s president and CEO, stresses that a follow-on biologic pathway in the US “must rely strongly on robust clinical testing to ensure patient safety and efficacy.” The Washington, DC–based Biotechnology Industry Organization’s 34-page commentary issued late in December urges the FDA to take a class-by-class approach to determine the scope of clinical trials. It supports a biosimilarity objective, allowing lower patient enrollments, but says that safety requirements may ultimately dictate a trial’s size. On the flip side, the Generic Pharmaceuticals Association, also of Washington, DC, has argued that it is appropriate to rely on a reference product’s safety and efficacy profile if a biosimilar meets similarity standards. Perhaps the most contentious issue is exclusivity. The Patient Protection and Affordable Care Act not only gives the FDA authority to

Swiss food giant enters diagnostics

volume 29 number 9 SePTember 2011 nature biotechnology government, that are making these value tradeoffs,” Conko says. Both BIO and NVCA want to redraw the rules that prevent experts from sitting on advisory committees. They propose that committee members handle conflicts of interests through disclosures rather than being excluded. “You need the best people at the table, period,” says Peter Pitts, president and cofounder of the Center for Medicine in the Public Interest in New York. A former FDA associate commissioner, Pitts recalls how his staff at the FDA “jumped down [his] throat” to sign a waiver for an overly conflicted expert because “there would be no meeting without him.” BIO is also calling for the creation of a new post of chief medical policy officer to oversee the FDA advisory committee process. The FDA’s mission needs redefining to incorporate innovation. To this end, BIO suggests the creation of an experimental space led by a new chief innovation officer charged with the authority to pilot new initiatives and incorporate them into the regulatory process. To relieve FDA commissioners from political pressure, BIO proposes a fixed six-year term for commissioners, and the agency, BIO says, should be independent and respond directly to the US president and Congress, rather than be part of Department of Health and Human Services, as it is at present. Many contacted by Nature Biotechnology felt that a regulatory shake-up is warranted. Mark Kessel of Symphony Capital, for example, says the regulatory proposals are BIO’s strongest suit. “The ideas for changes in regulations have [a] better chance...as no legislation and no [political action committee] PAC money or lobbying would be involved.” Not everyone is as impressed, however; a “rehash of old ideas,” is how Henry Miller, the Robert Wesson Fellow in Scientific Philosophy and Public Policy at the Hoover Institution, Stanford University, California, characterizes BIO’s proposals. Another thrust of BIO’s proposals aims to rekindle investors’ interest in the industry. This is an urgent need as, according to Pricewaterhouse Coopers, the first quarter of 2011 marked the fewest biotech venture deals of any quarter since 2003. BIO wants Congress to enact financial legislation to make it attractive to invest in startups and to strengthen small businesses. To make these more appealing, the proposals are not aimed at the biotech industry exclusively, but would be applicable across many industries. Several of these proposals are aimed specifically at tax law. First, BIO is proposing a federal angel investor tax credit modeled after similar credits enacted by many US states as an incentive for investors to fund small innovator businesses. To qualify, investments have to be made into a Planning for this innovation package began last summer when BIO commissioned Elias Zerhouni, the former director of the US National Institutes of Health (subsequently appointed president of global R&D at Paris-based Sanofi in January), to gather comments from key opinion-makers in academia, medical institutions and biotech firms. The merits of the resulting proposals were debated internally and shaped into an eight-page summary document, which was presented to the Health Subcommittee last month by Paul Hastings, BIO’s vice-chairman of emerging companies and the president and CEO of Redwood City, California–based OncoMed Pharmaceuticals. Also invited to the meeting was Jonathan Leff, managing director of New York– based Warburg Pincus, who testified on behalf of the Arlington, Virginia–based National Venture Capital Association (NVCA). The NVCA’s proposals, developed by its Medical Innovation and Competitiveness Coalition, which includes life science venture capitalists, were mostly aligned with those drawn up by BIO. Patient advocacy groups were also present, represented by Marc Boutin, executive vice president and CEO of the National Health Council in Washington, DC. The shining part of BIO’s document, according to Greg Conko, senior fellow at Washington’s Competitive Enterprise Institute, is the proposal to create a progressive or conditional approval pathway. This approach allows all data and information associated with a product to be taken into account during regulatory review, whatever its value. This would allow the US Food and Drug Administration (FDA) to gradually introduce new drugs to the market for defined patient populations after phase 2 studies, while phase 3 testing is still ongoing. Although this possibility has been discussed before, this new version of progressive approval would apply only to innovative products for unmet needs, those that offer significant improvements in standard of care, targeted therapies or those that have been approved by other regulators, such as the London-based European Medicines Agency. BIO is also calling for the FDA to use a weight-of-evidence approach to assess a drug’s effectiveness. This would allow applications for new drugs to focus on the overall benefitto-risk balance, not just endpoints. “It has to be the patients, not the On July 7, members of the Biotechnology Industry Organization (BIO)’s board of directors were invited to Capitol Hill to testify at a hearing on Prescription Drug User Fee Authorization (PDUFA) V. BIO attended the hearing, summoned by the House Energy and Commerce Subcommittee on Health, to help lay the groundwork for revising PDUFA IV (due to expire September 2012) and also to present ideas on what should be done to jump-start the drug innovation engine. BIO hopes its policy proposals (http://www.bio.org/sites/default/files/ PromiseofBiotech.pdf) will be incorporated into new legislation, as Congress redraws PDUFA. But beyond regulatory reform, the industry association also highlighted strategies aimed at making more money available for early-stage innovator companies and to introduce rewards to US-based companies to keep innovation on American soil. A few of the proposed changes “might make a critical difference,” says Washington attorney John Cohrssen, an Organisation for Economic Co-operation and Development (OECD; Paris) advisor who once worked on Capitol Hill. BIO marches to Congress with growth package in hand

Teva hits bull's eye with Cephalon

volume 29 number 8 august 2011 nature biotechnology Inequitable conduct stems from a principle referred to as ‘unclean hands’ established in the 1930s and 1940s, during three US Supreme Court cases. The Court held that perjury and the manufacture of false evidence to mislead the USPTO constituted inequitable conduct. Over the years, the elements proliferated and expanded to include nondisclosure of information to the USPTO. This includes failing to submit items such as references, papers or abstracts from conferences as prior art (that is, information in the public domain that could be relevant to determining if the invention described in the patent is novel). To prove a patentee is guilty of inequitable conduct, two criteria must be met: intent to deceive the USPTO and a determination of whether the information that was withheld was material (that is, important to the issuing of the patent). The stringency for meeting these criteria has relaxed in recent years; so much so that inequitable conduct has been gaining popularity as a litigation defense tactic. In the Therasense case (http://www.cafc. uscourts.gov/images/stories/opinionsorders/08-1511.pdf), the CAFC realized lowered standards had led to increasing misuse of the inequitable conduct charge during litigation, so it revisited its definition of nondisclosure of information. According to CAFC’s new definition, the charge of omitting prior art references can only be leveled against a patentee if it can be determined that, had the USPTO Us court bolsters biotech patent protection

Anti-nerve growth factor drugs exonerated

Amgen has set its sights on the lucrative Brazilian pharma market in two recent moves: a

Chinese vaccine developers gain WHO imprimatur.

215 million takeover of star-performer Bergamo of São Paulo, and a separate agreement to buy back rights to several of its own drugs licensed previously to Mantecorp, now a subsidiary of São Paulo–based Hypermarcas. Bergamo, which supplies Brazil’s hospital sector with oncology treatments, has seen 19% growth over the past four years and earned

Avastin loses breast cancer indication

80 million in 2010 alone. The acquisition provides the Thousand Oaks, California, biotech with a large portfolio of marketed products, an experienced workforce and sales channels for its own products. In parallel, by buying back rights to its products from Hypermarcas, Amgen regains Mimpara (cinacalcet) for hyperparathyroidism and Vectibix (panitumumab) for colorectal carcinoma, which are already marketed in Brazil, along with Nplate (romiplostim), a platelet growth factor for immune thrombocytopenic purpura approved by the US Food and Drug Administration and under regulatory consideration in Brazil. According to Rolf Hoffman, senior vice president of Amgen’s international commercial operations, the company sees potential for “strong future growth” in Brazil for biopharmaceuticals and biologics, and its recent deals allow immediate access to the market, incountry capability and a firm foundation on which to further build its business. The activity should complement Amgen’s 2009 establishment of a clinical development hub in São Paulo to conduct clinical trials in Latin America. But the firm’s international expansion coincides with shrinkage closer to home: the laying off of 134 employees in two Colorado plants. Jennifer Rohn Teva hits bull’s eye with Cephalon