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The FDA currently has no mechanism or authority to license generic equivalents of brand name large-molecule, protein-based medications such as vaccines, insulin, clotting factors, and human growth hormone (HGH). This situation is unlikely to change soon, because qualifying a medication as a generic requires demonstrating that both products' active pharmaceutical ingredients have identical molecular structures and are equally safe and effective. The science now available does not permit a determination of the first criterion. Consequently, every biologic licensed in the United States must undergo extensive clinical testing.
If Congress passes legislation that was introduced in mid-February, however, unbranded versions of biologics that (using the bill's language) are "comparable" with brands would be spared the requirement for multiple, lengthy, costly human tests in many instances.1
Several biopharmaceutical products already on the US and world markets fall into the "comparable" category. To cite just 2 American examples, the Drugs@FDA Web site lists 5 licensed standardrelease versions of recombinant human insulin and 10 versions of the most widely used recombinant HGH somatropin.2 In China, where the government took a very broad view of what international patent laws allowed until recently, >400 companies are producing 30 recombinant drugs, 41 vaccines, and 18 blood products currently under patent in other countries.3
The drug-patent situation and what it means for generics will be the subject of an article in next month's issue. Suffice it to note here that not requiring a full-blown license and approval process for each biologic saved money in China and would likely do the same here. The pharmacy benefit manager Express Scripts estimates that allowing copies of patented biotech products onto the US market would produce savings of $71 billion over 10 years.4
The Legal Status of Biogenerics
Legally speaking, biogenerics do not exist. Rather, there are "biosimilars" in Europe and "follow-on biologics" in the United States. In 2005, Sandoz did claim to have received the firstever FDA license for a biogeneric, when the agency issued a positive decision on Omnitrope (serotropin [rDNA origin]). According to the drug-maker, its product was the equivalent of Pfizer's Genotropin. The agency explained that, because neither the structural nor the effectual equivalence of the 2 products could be adequately assessed, Omnitrope was best characterized as a follow-on product with the same indication as Genotropin.5
Reaching such a decision, as illustrated above, was not unique for the agency. The recently introduced Access to Life-Saving Medicine Act (HR 1038) aims to make it more common.
Following the model for licensing similar biologic medicinal products articulated by the European Agency for the Evaluation of Medicinal Products (EMEA), the US bill would establish a framework for companies to submit Abbreviated Applications for Biologic Products (AABP).6,7
AABPs seeking "comparable" status with a brand product would have to meet the criteria outlined in the sidebar. An applicant also could seek "interchangeable" status, but it would have to clearly demonstrate that its product was exactly the same in molecular structure, safety, and efficacy as the reference product. The legislation acknowledges that meeting these criteria would be difficult. A key provision of HR 1038 is that it would allow the FDA to demand clinical tests by AABP applicants if the comparability or interchangeability claimed was not initially apparent.
Are Comparable Biologics Really Any Different?
The most accurate answer is, "No one knows yet." Even a summary of HR 1038 states, "There is currently no equivalent of a simple ?bioequivalence' study for biologics as there is for traditional drugs."1
Additionally, as the Biotechnology Industry Organization, which represents biopharmaceutical manufacturers, explains, "Due to ...differences in how the product is manufactured, different versions of the same biotechnology product produced by companies other than the innovator will inevitably differ in certain respects from the innovator product."7 What that means for practical purposes, according to the EMEA, is that product "parameters such as the 3-dimensional structure, the amount of acidobasic variants, or posttranslational modifications such as the glycosylation profile can be significantly altered by changes, which may initially be considered to be ?minor'in the manufacturing process."7
Determining whether any follow-on biologics are true biogenerics will require completely characterizing both products'molecular composition. Then an assessment of whether nonidentical manufacturing processes produce any significant differences in product characteristics will be needed. Last, it will be necessary to determine whether any dissimilarities between products are related to clinically meaningful differences in how the products affect patients.
Mr. Lamb is a freelance pharmacy writer living in Virginia Beach,Va, and is president of Thorough Cursor Inc.
1. Detailed Outline: The Access to Life-Saving Medicine Act. February 14, 2007. Representative Henry Waxman Web site. Available at: www.henrywaxman.house.gov/pdfs/biologicsbillsummary_2.14.07.pdf. Accessed February 20, 2007.
2. Drugs@FDA. Available at: www.accessdata.fda.gov/scripts/cder/drugsatfda. Accessed February 20, 2007.
3. Zhou EY, Langer E. China today: defining the Chinese biopharmaceutical market. BioPharm Intl. 2007;January. Available at: www.biopharminternational.com/biopharm/article/articleDetail.jsp?id=395607. Accessed February 20, 2007.
4. Express Scripts. Generic biotech medicines could save plan sponsors and patients $71 billion. Press release. February 15, 2007. Available at: http://phx.corporate-ir.net/phoenix.zhtml?c=69641&p=irol-newsArticle&ID=963453&highlight=Generic%20biotech. Accessed February 20, 2007.
5. US Food and Drug Administration. 2005. Omnitrope (somatropin [rDNA origin) Questions and Answers. Available at: www.fda.gov/cder/drug/infopage/somatropin/qa.htm. Accessed February 21, 2007.
6. Biotechnology Industry Organization. Follow-on Biotechnology Products. Available at: www.bio.org/healthcare/followon. Accessed February 21, 2007.
7. European Agency for the Evaluation of Medicinal Products. 2005. Guideline on Similar Biological Medicinal Products. Available at: www.emea.eu.int/pdfs/human/biosimilar/043704en.pdf. Accessed February 21, 2007.