Biotech Values

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WHO guidelines presage US biosimilars legislation?

By John Hodgson Cambridge, UK. Nature biotechnology vol. 27 number 11 november 2009

As Nature Biotechnology went to press, the World Health Organization (WHO) in Geneva was finalizing a new set of guidelines for Similar Biotherapeutic Products. The WHO expects these draft guidelines, prepared by the Expert Committee on Biological Standardization, to be circulated to national regulators, manufacturers and other interested parties during 2010 and 2011. The guidelines, to which Keith Webber, deputy director of the Office of Pharmaceutical Science at the US Food and Drug Administration’s (FDA’s) Center for Drug Evaluation and Research contributed as a technical expert, come as the US prepares to draw up a long-awaited biogenerics pathway. But in the US, the debate over market exclusivity is threatening to divert the biosimilars discussion down an unproductive cul-de-sac, despite the introduction of bills for biosimilars legislation in the Senate (Senate HELP Health Care Reform bill) and the House of Representatives (HR 1548) during the summer.
When the US Congress enacted the US Drug Price Competition and Patent Term Restoration (Hatch-Waxman) Act 25 years ago, opening the way for the FDA to approve generic drugs, biologics were not included. Bill Haddad, chairman and CEO of Biogenerics in Brewster, New York, who was instrumental in initiating and negotiating the Hatch-Waxman Act takes that omission personally. “I made a big mistake 25 years ago,” he says, “and it’s time to make amends.” He is working with generics industry lobby groups such as the Generic Pharmaceutical Association in Arlington, Virginia, to accelerate the passage of US legislation on biosimilars. “The stakes are high,” says Haddad. “There are 25–30 [biologic] drugs out there with what amounts to perpetual patents.” History demonstrates, he believes, just how profound an impact biosimilars legislation could have. “Thirty-five years ago, when we were first thinking about the legislation that became Hatch-Waxman, generic compounds had only 5% [by volume] of the US pharmaceuticals market: now they have 85%.”
The impact of a biogeneric pathway, however, is unlikely to be as dramatic. In the first place, experience in the EU indicates that biosimilaroriginator competition is not comparable with the direct substitution that occurs with smallmolecule generics. The European Medicines Evaluation Agency’s (EMEA’s; London) approval pathway in 2005 has not triggered a deluge of biosimilars swamping existing markets. Some 12 products have been approved so far (Table 1) encompassing only three product classes (human growth hormone, erythropoietin (EPO) and granulocyte colony stimulating factor). Applications for follow-on insulin and interferon products have been refused or subsequently withdrawn.
According to Suzette Kox, senior director of Scientific Affairs at the European Generic Medicines Association in Brussels, the impact of biosimilars in Europe has not been profound. “There may be an overall 20–30% decrease in interchangecosts but, because the originator companies also drop their prices, market share may not shift so dramatically,” she explains. The continuing fragmentation of the healthcare market in Europe makes it difficult to assess the overall market share changes accurately. However, Islah Ahmed, the global medical director of Hospira, located in Lake Forest, Illinois, has aggregated data for Germany, the biggest single national pharmaceutical market in Europe. The data show that two years after launch, biosimilar EPOs represent ~35% of unit sales of short-acting EPOs, whereas substitution rates for small-molecule generics can exceed 90% in the first year.
The second reason to think that a biosimilars pathway in the US will have a muted impact is that industry lobbies, such as Biotechnology Industry Organization in Washington, DC, and the Pharmaceutical Research and Manufacturers of America, also in DC, have been hard at work ‘protecting their members’ interests’. Several pieces of competing legislation came before Congress this year. Bills proposed by Senator Sherrod Brown (D-Ohio) and Representative Henry Waxman (D-CA), which gave the greatest encouragement to manufacturers of follow-on biologics by proposing a period of five or seven years respectively, have faded from view. In June, the US Federal Trade Commission argued for zero years’ market exclusivity based on the premise that competition between originator compounds and biosimilars was likely to resemble brand-to-brand competition rather than a generic substitution model (Nat. Biotechnol. 27, 677, 2009). The Obama Administration’s position is that seven years of market exclusivity for novel biologic products is sufficient, in line with the interest of biosimilar producers.
Since July, however, the impetus has shifted to two ‘pro-innovation’ bills that have progressed through Congress rapidly because they are tied into the heath reform package (HR 3200). The Senate Health, Education, Labor and Pensions Committee introduced the ‘Hatch Amendment’ and the House Energy and Commerce Committee added the ‘Eshoo Amendment’. Both propose to provide developers of pioneer products with 12 years’ market exclusivity, regardless of the patent status of the product, based on an economic model outlined by Henry Grabowski of the Fuqua School of Business at Duke University (Nat. Rev. Drug Discov. 7, 479–488, 2008).
Buoyed by such high-level support for biosimilar- friendly legislation, the public relations campaign is likely take a new and more aggressive twist. Colleagues of Bill Haddad recently undertook an ad hoc survey of drug bills at municipal, volunteer and not-for-profits hospitals— those hospitals which act as the safety net for the majority of American sick and unininsured. Haddad claims that the high prices for biologics affects those hospitals severely. “The 5% of patients treated with biologics account for 45% of the drug bills in those hospitals,” he says. “Every Congressional district has hospitals that are struggling because of the high cost of biologics and that makes for a lot of local media coverage.” The next phase in the campaign will involve a detailed cost-and-profit breakdown for current ‘innovator’ products.
Although the short-term political fireworks will establish the magnitude of the contribution that biosimilars can make in the US, the deliberations at WHO will likely shape the nature of the regulatory process that FDA ultimately implements. The WHO draft guidelines on similar biotherapeutic products (http://www.who.int/biologicals/publications/trs/areas/biological_therapeutics/BS2110Dft_guidelines_Final_HK_IK_29July_09.pdf) were closed for comments on October 9, 2009, and the document was being deliberated by the WHO Expert Committee on Biological Standards as Nature Biotechnology went to press.
The WHO document is a guideline and has no legal force on WHO member states. But the document has political significance because it is unlikely that it would contain proposals unacceptable to regulators in such countries as the United States and China. “Personally, we do not expect the USA to have a scientifically different approach to the EU or Japan,” says Kox. “There are some significant principles in the [WHO] Guidelines.” Jacques Mascaro, senior vice president, global regulatory affairs, pharmacovigilance and quality from Dublin-based Elan, was involved in establishing the EMEA biosimilar guidelines in the EU and has reviewed the WHO guidance documents as an innovator industry representative. He agrees that the WHO guidelines are “an important step” that provides “an agenda to move things along.”
Mascaro was keen not to appear to be telling the FDA what to do. He nevertheless raised three key issues of interest. “Firstly, will the FDA take a case-by-case approach? Secondly, will it integrate the data and experience that already exists from assessments in the EU and elsewhere? And, thirdly, what will be the position with respect to the interchangeability of products?”
The WHO draft guidance provides clear direction to the first and third questions. It states that the basis for licensing a biosimilar—similar biotherapeutic product (SBP), in WHO parlance— depends on “its demonstrated similarity to a suitable reference biotherapeutic product in quality, nonclinical and clinical parameters.” So, yes, there should be a case-by-case approach. Furthermore, the WHO guidance indicates that “automatic substitution of SBP is not recommended” and that decisions on interchangecosts ability of reference and similar biotherapeutics “should be made by physicians.” Therefore, no assumed substitutability of similar products.
As to the second question, the WHO guidance says very little about whether the data gathered and examined for the approval of a similar biotherapeutic in one territory could or should be used in another. The EGA is pushing national regulators to accept data globally. “If you have a highly similar compound and the same reference compound, then we think the information should be transferable,” says Kox. “Same reference product—same data package.” Jacques Mascaro, too, thinks that the FDA is keen to learn from the European regulators, perhaps by keeping a watching brief rather than by welcoming European data submissions wholesale. “The EU is relatively advanced with biosimilars, but the FDA may want to see how the products perform post-approval before implementing its own system.”
Bill Haddad, however, hopes that the FDA will move soon. “We could have regulations in place in 2010 and the first biosimilar approvals in the USA in 2011,” he says. He believes that putting the system in place earlier rather than later would make a significant difference to President Barack Obama’s healthcare plans by saving an estimated $100–200 billion in drug costs. “The savings over the 10 years of the plan would be enough so that he [Obama] doesn’t have to spend one penny over budget on Universal Healthcare.”