Since the passage of the Health Care Reform Act, the Food and Drug Administration has been working to develop consistent regulations for the approval of biosimilar drugs. However, there has been little public discussion of the scientific challenges associated with approval of follow-on versions of non-biologic complex drugs (NBCDs), which more closely resemble biologics than small-molecule drugs. Abbreviated new drug applications (ANDAs) are appropriate for low-molecular-weight, well-characterized drugs. In contrast, some complex drugs, including synthetic proteins and polypeptides, are not characterizable or amenable to therapeutic equivalence testing. Essential to new regulations for biosimilars are guidelines for the necessary degree of similarity to the innovator drug, and the extent of testing needed to demonstrate safety and efficacy of the follow-on product. These issues also apply to follow-on NBCDs, as exemplified by experience with members of the glatiramoid class. As the FDA and Congress develop legislation for biosimilars, regulatory guidelines for follow-on versions of NBCDs should be addressed.
WoodcockJGriffinJBehrmanRThe FDA's assessment of follow-on protein products: a historical perspective. Nat Rev Drug Discov. 2007;6:437–442.
5.
European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP). Guideline on similar biological medicinal products. CHMP/437/04 October 30, 2005.
6.
DudzinskiDMKesselheimAS. Scientific and legal viability of follow-on protein drugs. N Engl J Med. 2008;358:843–849.
7.
Federal Register. Approval Pathway for Biosimilar and Interchangeable Biological Products; Public Hearing; Request for Comments (75 FR 61497). http://federalregister.gov/a/2010-24853. Accessed March 3, 2011.
NilssonBLSoellnerMBRainesRT. Chemical synthesis of proteins. Annu Rev Biophys Biomol Struct. 2005;34:91–118.
10.
VarkonyHWeinsteinVKlingerEThe glatiramoid class of immunomodulator drugs. Expert Opin Pharmacother. 2009;10:657–668.
11.
YeungNLinYWGaoYGRational design of a structural and functional nitric oxide reductase. Nature. 2009;462:1079–1082.
12.
SohmaYKentSB. Biomimetic synthesis of lispro insulin via a chemically synthesized "mini-proinsulin" prepared by oxime-forming ligation. J Am Chem Soc. 2009;131:16313–16318.
13.
RamageRGreenJMuirTWOgunjobiOMLoveSShawK. Synthetic, structural and biological studies of the ubiquitin system: the total chemical synthesis of ubiquitin. Biochem J. 1994;299(pt 1):151–158.
14.
KochendoerferGGChenSYMaoFDesign and chemical synthesis of a homogeneous polymer-modified erythropoiesis protein. Science. 2003;299:884–887.
De StefanoNFilippiMConfavreuxCThe results of two multicenter, open-label studies assessing efficacy, tolerability and safety of protiramer, a high molecular weight synthetic copolymeric mixture, in patients with relapsing-remitting multiple sclerosis. Mult Scler. 2009;15:238–243.
PrimeNewswireI. Momenta Pharmaceuticals announces filing of abbreviated new drug application with a Paragraph IV certification for generic version of Copaxone [press release]. Cambridge, MA. http://ir.momentapharma.com/releasedetail.cfm?ReleaseID=320978. Accessed February 11, 2011.
Data on File. Teva Pharmaceutical Industries, Ltd. 2011.
25.
SchellekensHMoorsE. Clinical comparability and European biosimilar regulations. Nat Biotechnol. 2010;28:28–31.
26.
JohnsonKP. Glatiramer acetate and the glatiramoid class of immunomodulator drugs in multiple sclerosis: an update. Expert Opin Drug Metab Toxicol. 2010;6:643–660.
27.
TeitelbaumDAharoniRSelaMArnonR. Cross-reactions and specificities of monoclonal antibodies against myelin basic protein and against the synthetic copolymer 1. Proc Natl Acad Sci U S A. 1991;88:9528–9532.
28.
WebbCTeitelbaumDArnonRSelaM. In vivo and in vitro immunological cross-reactions between basic encephalitogen and synthetic basic polypeptides capable of suppressing experimental allergic encephalomyelitis. Eur J Immunol. 1973;3:279–286.
29.
SchellekensHKlingerEMuhlebachSBrinJFStormGCrommelinDJ. The therapeutic equivalence of complex drugs. Regul Toxicol Pharmacol. 2011;59:176–183.
30.
WeberMSProd'hommeTYoussefSType II monocytes modulate T cell-mediated central nervous system autoimmune disease. Nat Med. 2007;13:935–943.
31.
WeberMSStarckMWagenpfeilSMeinlEHohlfeldRFarinaC. Multiple sclerosis: glatiramer acetate inhibits monocyte reactivity in vitro and in vivo. Brain. 2004;127:1370–1378.
32.
KalaMRhodesSNPiaoWHShiFDCampagnoloDIVollmerTL. B cells from glatiramer acetate-treated mice suppress experimental autoimmune encephalomyelitis. Exp Neurol. 2010;221:136–145.
33.
AharoniRKayhanBEilamRSelaMArnonR. Glatiramer acetate-specific T cells in the brain express T helper 2/3 cytokines and brain-derived neurotrophic factor in situ. Proc Natl Acad Sci U S A. 2003;100:14157–14162.
34.
TeitelbaumDBrennerTAbramskyOAharoniRSelaMArnonR. Antibodies to glatiramer acetate do not interfere with its biological functions and therapeutic efficacy. Mult Scler. 2003;9:592–599.
35.
BrennerTArnonRSelaMHumoral and cellular immune responses to Copolymer 1 in multiple sclerosis patients treated with Copaxone. J Neuroimmunol. 2001;115:152–160.
36.
European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP). Guideline on immunogenicity assessment of biotechnology-derived proteins. http://www.tga.gov.au/pdf/euguide/bmwp1432706en.pdf. 2006.
37.
BielekovaBGoodwinBRichertNEncephalitogenic potential of the myelin basic protein peptide (amino acids 83-99) in multiple sclerosis: results of a phase II clinical trial with an altered peptide ligand. Nat Med. 2000;6:1167–1175.
38.
DiCucciR. Is Europe ahead of the USA in biosimilars?J Generic Med. 2006;3:201–208.
