The European Regulatory Scene
Some observers of the European regulatory scene expected that the EMEA might have begun to approve FOBs last month. As this went to press, we have not seen any evidence of that.
The EMEA is co-sponsoring a workshop on biosimilars, organized by the Drug Information Association (DIA) scheduled for December 89 in Paris. Speakers at the workshop may provide insights about the potential timing of approvals and the unresolved issues and questions.
Linda Horton, a partner in the Brussels office of global law firm Hogan & Hartson, spoke on the proposed EMEA Guidelines and draft annexes for the approval of biosimilars, issued in May 2005. The comment period closed October 31.
The proposed guideline is accompanied by four annexes providing specific guidance on approval requirements for erythropoietin (EPO), granulocyte-colony stimulating factor, insulin, and somatropin (hGH). Horton pointed out that the requirements are hefty, especially in relation to those for generics of small molecule drugs. The requirements include: full quality dossier, extensive nonclinical and clinical studies, immunogenicity studies, extensive comparability, and comparative pharmacokinetics.
The application should include a "risk specification" describing possible safety issues due to the manufacturing process being different from that of the innovator and a pharmacovigilance plan in accord with EU legislation/guidelines. The EMEA will strictly monitor compliance and is preparing a penalties regulation in case of non-compliance.
Each application will be handled on a case-by-case basis; early discussions with the EMEA are encouraged. The same reference product should be used for all aspects of the application. Clinical studies of the biosimilar should be performed using product made by the final manufacturing process, which Horton says is a difficult requirement.
The guidelines were prompted by political pressure for access to cheaper biologics as well as scientific pressure. Several applications are pending from BioPartners and Sandoz. The EMEA issued a favorable opinion of Omnitrope in mid-2003, but has not approved the product.
Horton thinks the guidelines likely represent an amalgamation or compromise of the content of the pending applications. She believes the guidelines mean that the EMEA is serious about getting biosimilars approved and wants to do so in the short-term.
Despite all the thought that has gone into the proposed guidelines, Horton identified some unanswered questions and issues: Can regulators refer to innovator data files and do they intend to? Is the safety barrier sufficiently high, particularly if a conditional approval requires that safety be shown post-marketing?
Looking at EPO, for example, dose-to-dose variability may be critical. Will product substitution be allowed? This has been decided at the member state level so far, but she expects the EMEA to take a stance. Will individual patient consent be needed where premarket trials were small and there may be some unresolved risks?
Horton also expressed concern about some inconsistencies. For example, the EPO annex calls for substantial clinical studies, including at least 12 months immunogenicity data plus post-market reporting. Depending on the size of the studies, relatively infrequent adverse effects may not be observed.
The EMEA is also proposing to excuse EPO biosimilars from many safety studies carried out by the innovator companies. Horton says it is more worrying that the guideline requires testing on just one indication to get approval of all authorized indications. Despite the shortcomings, Horton believes these guidelines, or something like them, will be approved.
The potential approval of biosimilars may not automatically lead to widespread switching to biosimilars. Perceptions of safety may play out against price, especially as biologics become more complex. For a range of economic reasons, the price of biosimilars is not likely to be much lower than the innovator's original drug.
Reimbursement of biosimilars and switching from the innovator product will be decided by each country. Doctors and patients may perceive biosimilars to be less safe. Innovators can be expected to leverage their reputation, brand, and safety data to discourage switching.
Horton asked rhetorically about the utility of the regulatory pathway offered by the guidelines. Given the stringent data requirements, risks, and uncertainties around post-approval marketing, will potential competitors be better off developing improved biologics, distinguishable from the original in dosage convenience?