On February 6, 2009, the U.S. Food and Drug Administration (FDA) approved the first human biologic produced from transgenic animals,1 after a favorable review by the Blood Products Advisory Committee a month earlier. Recombinant human antithrombin (rhAT) is used for treatment of hereditary antithrombin deficiency, an orphan disease. It is produced in the milk of goats containing the gene-coding sequences for human AT. The unusual scheme for the regulation of such sources can present interesting life cycle management opportunities for other such innovative products.
A number of bills were introduced in Congress during 2008 addressing the statutory scheme for the marketing of versions of brand name biologics, or so-called follow-ons. The subject has engendered fierce debate on a number of scientific, policy, patent, and economic matters. A key scientific issue has been the extent to which clinical trial testing is necessary for all follow-on products, in part because changes in production methods can give rise not only to alterations in impurities but also to differences in three-dimensional conformation and in chemical structure, perhaps due to post translational modifications. These concerns typically arise when different methods of production utilize eukaryotic and prokaryotic organisms such as CHO cells or E. coli. The use of multicellular organisms such as goats and other animals (or plants) can make this scientific calculus even more challenging. Another potential complication of using such sources are the associated regulatory approval mechanisms for them, which are separate and distinct from the approval requirements for the human biologics they produce. Such mechanisms can present further significant challenges to the marketing of follow-on versions.
Regulation of Transgenic Sources of Human Biologics
At least one other federal regulatory agency has substantive jurisdiction over transgenic drug production platforms. The Animal Plant Health Inspection Service (APHIS) of the U.S. Department of Agriculture regulates experimental and commercial releases into the environment of transgenic plants, including those producing pharmaceuticals or plant-made pharmaceuticals (PMPs).2 An APHIS guidance exists on the permitting procedures for pharmaceutical crops.3 The permit process often involves an assessment under the National Environmental Protection Act (NEPA), in the form of claiming a categorical exclusion from the requirement of conducting a NEPA assessment, or, more typically, the performance of an environmental assessment (EA) and related finding of no significant impact (FONSI) that is published for comment in the Federal Register.4 This regulatory process for genetically engineered plants in general and PMPs in particular is now undergoing reevaluation as part of an overhaul by APHIS of its Part 340 regulations.5 How PMPs will fare as part of the anticipated revisions is unclear.
With respect to transgenic animal sources, the FDA published an early 1995 guidance on the manufacturing and testing of therapeutic products for human use from transgenic animals.6 More recently, the Center for Veterinary Medicine (CVM) announced in September 2008 that nucleic acid sequences coding for human biologics or other such drugs are subject to investigational new animal drug application (INADA) and new animal drug application (NADA) requirements. The CVM’s view is that the DNA is intended to affect the structure or function of the animal as a production source and therefore is a drug. It recently finalized Guidance 187 on the subject in conjunction with the pending approval of rhAT.7 The latest guidance notes that, to demonstrate effectiveness, the inserted genetic information used for production of a human biologic must have appropriate expression in the source animal; that the CVM will hold a public advisory committee prior to approving any transgenic animal; and that NEPA applies to both INADAs and NADAs, among other requirements.
It remains unclear whether the timing of approval of an NADA for a specific product source must coincide, or otherwise occur roughly in conjunction, with the approval of the associated human biologic. Approval of the NADA for the production source would clearly be essential to market a product. In the case of the approval of rhAT, the corresponding NADA approval occurred simultaneously, along with publication of an EA and a FONSI.8
Another complicating factor pertaining to the use of transgenic animals as sources for the production of follow-on biologics is the role of APHIS instead of CVM in the possible licensure of such DNA sequences as animal biologics under the Virus Serum and Toxin Act (VSTA). Further, APHIS has published a notice seeking comment on its options for the regulation of genetically engineered animals under the Animal Health Protection Act.9 This type of multi-tiered regulation of animal and plant production sources of human biologics can suggest that even with the legislative adoption of a pathway for the approval of follow-on biologics similar to that for traditional generic drugs, the barriers to commercialization could still be different, greater, and more costly for followons, resulting in a different market paradigm.10