Biosimilar Bibliography

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Science, Manufacturing and Safety

Eckardt, Kai-Uwe; Casadevall, Nicole. "Pure Red-Cell Aplasia Due to Anti-Erythropoietin Antibodies," Nephrol Dial Transplant. 2003;18: 856-869.

Biopharmaceuticals generated by expression of DNA in cell lines have great potential for the treatment of diseases, in which the endogenous production of a specific protein is inadequately low and/or its administration has beneficial modulating effects on disease processes. Although these drugs are designed as copies of endogenous molecules, immunogenicity is a recognized risk.
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Locatelli, Francesco; Aljama, Pedro; Barany, Peter; et al. "Erythropoiesis-Stimulating Agents and Antibody-Mediated Pure Red-Cell Aplasia: Where Are We Now and Where Do We Go From Here?," Nephrol Dial Transplant. 2004;19: 288-293.

Erythropoietin molecules produced by means of gene technology (erythropoiesis-stimulating agents, ESA) have been the agents of choice to correct the anaemia of chronic kidney disease (CKD) since the first of these drugs was licensed in the late 1980s. The side effects seen in the early days may have been due to a too-rapid rise in haemoglobin concentration, along with possible direct effects on non-haematopoietic tissues, including the vascular endothelium. Recently, antibody-mediated pure red-cell aplasia (PRCA) associated with the administration of ESAs has been identified as a serious problem.
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Reed, Shelby D.; Califf, Robert M.; Schulman, Kevin A. "How Changes in Drug-Safety Regulations Affect the Way Drug and Biotech Companies Invest in Innovation," Health Affairs. 2006; 25,(5); 1309-1317

Changes in the economics of product development resulting from heightened safety regulations could have a sizable negative impact on drug and biotechnology companies' decisions about investing in innovation. We developed a model to compare the potential economic effects of pre- and postmarketing strategies to identify safety problems with new drugs. Although expanding Phase III clinical testing and postmarketing safety surveillance are not perfect substitutes, our findings suggest that even a large increase in funding for the latter will have a relatively small adverse impact on investment decisions by drug companies and venture capital firms, compared with the former.
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Schellekens H. "Biosimilar Therapeutic Agents: Issues with Bioequivalence and Immunogenicity," Eur J Clin Invest. 2004;34(12):797-799.

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Schellekens, Huub. "Bioequivalence and the Immunogenicity of Biopharmaceuticals," Nature Reviews. June 2002; 1: 457-462

The expiry of the first patents for recombinant-DNA-derived biopharmaceuticals will open the possibility of marketing generics, if they can be shown to be essentially similar to the innovator product. However, as shown by the problem of immunogenicity, the properties of biopharmaceuticals are dependent on many factors, including downstream processing and formulation. Products from different sources cannot be assumed to be bioequivalent, even if identical genes are expressed in the same host cells and similar production methods are used.
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Thorpe, Robin and Meenu, Wadhwa. "Unwanted Immunogenicity: Implications for Follow-on Biologicals," Drug Information Journal. 2007;41(01)

The unexpected and unpredictable development of unwanted immunogenicity is a significant issue affecting therapeutic proteins, including follow-on biologicals. The development of antibodies against the therapeutic biological can cause allergic or anaphylactic reactions, reduction in efficacy, and, in some cases, severe adverse effects. The risk of inducing immune responses is largely dependent on the recipient as well as a number of product-related factors (eg, production process, formulation, and number of doses administered during the course of treatment). Consideration should be given to the evaluation of unwanted immunogenicity of follow-on biologicals from preclinical development, through clinical trials, and into the postregistration period to minimize the risks associated with immunogenicity in recipients of therapeutic products.
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Webster, Christopher et al. "Biologics - Can there be abbreviated applications, 'Generics' or 'Follow-on' Products?" Biopharm International, July 2003, pp. 28-37.

In this question-and-answer discussion of "generic" biologics, the authors contend small changes in manufacturing of biologics dramatically affect the safety and efficacy of the therapeutic molecule.
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Green, James, D; Tsang, Lincoln; Cavagnaro, Joy. "'Generic' or 'Follow-on' Biologics: Scientific Considerations and Safety Issues," Expert Opin. Biol. Ther. (2003);3(7):1019-1022.

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Legal/Regulatory

FDA Questions and Answers. Omnitrope (somatropin [rDNA origin]) Questions and Answers. May 2006.

Omnitrope (somatropin [rDNA origin]), is a recombinant human growth hormone product indicated for long-term treatment of pediatric patients who have growth failure due to an inadequate secretion of endogenous growth hormone, and for long-term replacement therapy in adults with GHD of either childhood- or adult onset. Omnitrope is not rated as therapeutically equivalent to (and therefore substitutable for) any of the other approved human growth hormone products. It is is more appropriately characterized as a "follow-on protein product."
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Manheim Jr., Bruce S; Granahan, Patricia; Dow, Kenneth J. "'Follow-On Biologics': Ensuring Continued Innovation In The Biotechnology Industry," Health Affairs. 2006;25(2): 394-404.

Congress adopted legislation in 1984 to encourage pharmaceutical companies to develop new drugs, while simultaneously allowing competitors to bring cheaper generic versions to market. More than twenty years later, Congress may be faced with a similar balancing act for biologics. When Congress takes up this issue, it must focus on the substantial differences that exist between biologics and drugs. It should also evaluate the patent law, which is yielding increasingly narrow patents. If additional measures are not adopted in light of the intersection of these factors, then any legislation allowing for "follow-on" biologics could stifle development of new medicines from biotechnology.
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Raines, JD, Lisa J. "Bad medicine: Why the Generic Drug Regulatory Paradigm Is Inapplicable to Biotechnology Products," Journal of BioLaw and Business. 2001:5, (1)

Biotechnology products are different from traditional drug products in several important respects. These differences relate not only to their vastly greater size and complexity, but also to the inextricable relationship between such products and the biological processes that are used to make them. Biotechnology manufacturing involves hundreds of variables that can affect product identity, quality, purity, and potency. For this reason, a manufacturing process that has produced a biotechnology product that has been demonstrated clinically safe and effective may be modified only by changes that have been validated to ensure that product safety and effectiveness will not be compromised.
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Market

Calfee, John E. and Elizabeth DuPre. "The Emerging Market Dynamic of Targeted Therapeutics," Health Affairs. 2006; 25(5): 1302-1308.

Targeted biotech drugs that attack specific biological molecules that cause disease are bringing new benefits even as they foment pricing dynamics that are very different from those of traditional drugs. Targeted drugs tend not to compete with each other even when treating closely related diseases, which makes them resistant to price controls. We can expect the supply of expensive new so-called biotech drugs to continue. But the same properties that generate premium prices also facilitate inventing around successful drugs, eventually leading to vigorous competition despite the lack of generic alternatives.
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Grabowski, Henry; Cockburn, Iain; Long, Genia. "The Market for Follow-On Biologics: How Will It Evolve?," Health Affairs. 2006;25(5):1291-1301.

With spending on biologics rising and patent expiry approaching for several blockbuster biologics, Congress and the Food and Drug Administration are considering creating a clear pathway for so-called follow-on biologics. Differences between drugs and biologics will affect market outcomes in various ways. Conservative budget impacts are appropriate in the short run because fewer competitors will enter, and average prices will drop less than was the case following the Hatch-Waxman Act. Over the long term, intellectual property provisions will be important considerations for policymakers designing a pathway for follow-on biologics that balances price competition and innovation incentives.
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Saha, Atanu; Grabowski, Henry; Birnbaum, Howard; Greenberg, Paul; Bizan, Oded. "Generic Competition in the U.S. Pharmaceutical Industry," International Journal of the Economics of Business. 2006;13(1): 15-38(24)

We develop a simultaneous equations estimation framework to understand the interactions among generic entry, prices, and market shares. We base our estimates on a panel data sample of 40 brand-name drugs that first experienced generic competition during the period July 1992--January 1998. We find that generic share and price are simultaneously determined, while the number of generic entrants is a key determinant of generic market share and the generic-to-brand price ratio. In addition, we find generic competition to be particularly intense for blockbuster drugs, which experience significantly more generic entrants, price erosion, and generic penetration than other drugs.
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European

Guideline of Similar Biological Medicinal Products, CHMP/43/04. October 2005.

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Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Quality Issues, EMEA/CHMP/BWP/49348/2005. February 2006.

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Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Non-Clinical and Clinical Issues, EMEA/CHMP/BMWP/42832/2005. February 2006.

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Annex: Guidance on Similar Medicinal Products Containing Recombinant Human Soluble Insulin, EMEA/CHMP/BMWP/32775/2005. February 2006.

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Annex: Guidance on Similar Medicinal Products Containing Comatropin, EMEA/CHMP/BMWP/94528/2005. February 2006.

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Annex: Guidance on Similar Medicinal Products Containing Recombinant Erythropoietins, EMEA/CHMP/BMWP/94526/2005. March 2006.

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Annex: Guidance on Similar Medicinal Products Containing Recombinant Granulocyte-Colony Stimulating Factor, EMEA/CHMP/BMWP/31329/2005. February 2006.

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Commission Directive 2003/63/EC of 25 June 2003, amending 2001/83/EC on the Community code related to medicinal products for human use.

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Commission Directive 2004/27/EC of 31 March 2004, amending 2001/83/EC on the Community code related to medicinal products for human use.

Article 10.4 (182 KB PDF)

Regulation (EC) No 726/2004 of 31 March 2004 laying down Community procedures for the authorization and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency

"Centralised Procedure" (254 KB PDF)

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