The development and introduction of biosimilar anticoagulants – focus on enoxaparin
Bibliographic record
Abstract
Jeffrey S GinsbergDepartment of Medicine, McMaster University, Hamilton, Ontario, CanadaAbstract: The aims of this paper are to discuss the: (1) pharmacology of low-molecular-weight heparins (LMWHs) emphasizing their synthesis, mechanism of action, and comparison with the parent compound, unfractionated heparin (UFH); and (2) recent controversial approval by the Food and Drug Administration (FDA) of a generic enoxaparin. Enoxaparin is one of several LMWHs that are currently available worldwide for clinical use. LMWHs are derived by chemical or enzymatic depolymerization of the “parent” molecule, UFH. Both UFH and LMWHs exert their primary antithrombotic effect by binding to and catalyzing the naturally-occurring anticoagulant, antithrombin. LMWHs are more effective at inhibiting factor Xa than factor IIa (thrombin). They also produce less heparin-induced thrombocytopenia and osteoporosis than UFH and are at least as effective and safe as UFH for each approved indication. They are safe and effective when given subcutaneously once or twice daily, without the need for anticoagulant monitoring, and are suitable for out-of-hospital treatment. The FDA first approved enoxaparin (Lovenox®) in March 1993. Despite its cost effectiveness, individual patients without drug insurance are often left paying for the cost of the drug. Uninsured pregnant subjects are particularly disadvantaged because they often require several months of therapy, costing several thousand dollars. To evaluate a less expensive, generic enoxaparin, the FDA chose to use the “abbreviated new drug application” because it considered enoxaparin to be a drug rather than a biologic medicine. This requires that the generic enoxaparin meets the following five criteria for “sameness”: equivalence of (1) UFH source material and method of depolymerization; (2) physicochemical properties; (3) disaccharide building blocks, fragment mapping, and sequence of oligosaccharide species; (4) biological and biochemical assays; and (5) in vivo pharmacokinetic profile. Based upon meeting these criteria, and despite protests from several outside expert groups, the generic enoxaparin was approved by the FDA in July 2010.Keywords: antithrombotic therapy, enoxaparin, unfractionated heparin, low molecular weight heparin
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".