Biosimilars: Current regulatory perspective and challenges
Bibliographic record
Abstract
Sir, Biosimilars—the generic version of biologicals is the new buzz word in pharmaceutical industry. With annual growth rate of 7%, the sector is expected to grow to $172 billion by 2015.[1] Biosimilars are highly similar to licensed reference product notwithstanding minor differences in clinically inactive components; also there are no clinically meaningful differences between the biologicals and the reference product in terms of safety, purity, and potency. Beginning with human insulin, human growth hormone, and erythropoietin (1982, 1985, and 1989) >200 biosimilars have hit market. The market for erythropoietin was worth $13 billion in 2011, ahead of Lipitor which had market of $12.4 billion in 2008 ($12.4 billion in 2011).[2] Biologicals differ from conventional generics in size, structure, stability, in-built heterogeneity, and analytical characterization. Their unique multidimensional structure and complicated mode of action are never fully reproducible. Even with same molecular weight and production by same type of cells, they possess different properties, e.g., European Medicines Agency (EMEA) rejected the biosimilar Alpheon (interferon-oL) due to a higher number of AEs and more frequent recurrence of disease in patients treated with Alpheon than reference–Roferon-A. For immunoglobulins, small differences in core fucosylation led to big changes in receptor binding and consequently impacted immune functions like cellular cytotoxicity.[2] The classical paradigm of bioequivalence cannot be applied to protein drugs as evident from case of Retacrit. EMEA/Committee for Medicinal Products for Human Use (CHMP) burgeoned the concept of biosimilarity. Biosimilars’ approval should consider exactly same high standards and stringent requirements for quality, efficacy, or safety. First recommendation for the approval of biogenerics came in 2004 by the European Parliament. By 2011, 14 marketing authorizations were made by EMEA. EMEA lays that biosimilars be fully characterized for physicochemical and biophysical attributes.[3] Guidelines are laid for human soluble insulin, somatropin, granulocyte colony stimulating factor (G-CSF), and epoetins. With France as only exception, there are no regulations in other countries of EU. Australia adopted the EMEA guidelines, whereas Japan and Singapore issued guidelines in 2009, followed by Health Canada in 2010. WHO and some national guidance documents recommend EMEA approaches. FDA recommends two approaches: (1) biosimilar approach and (2) stand-alone approach. The guidelines are under construction and vary case to case. Sandoz's somatropin product, Omnitrope, was approved by FDA, but this pathway cannot be used for other products.[4] Till recently in India, marketing authorizations were in line with US approach. In July 2012, “Guidelines on Similar Biologics: Regulatory Requirements for Marketing Authorization in India” was introduced. It draws cues from EMEA/ICH guidelines.[5] The main points to consider about biosimilars are their safety, automatic substitution, naming, and labeling/prescription. The safety profile of biosimilars is not identical to reference as seen for biosimilar growth hormone, Valtropin, which had different precautions and warnings from reference, Humatrope. The immunogenicity of biosimilars cannot be fully predicted using preclinical/clinical studies. Robust pharmacovigilance still remains critical consideration. The story of epoetin therapy is instructive and called for subtle changes in manufacturing. Biosimilars cannot have the same international non-proprietary name as innovator. “Quality by design” approach provides assurance of quality of the reference product but requires critical understanding of variability ofevery product attribute. A manufacturer may well establish the design space for his product but cannot use this concept to ensure similarity with the reference. Every biological is different and healthcare professionals should interchange biologicals after careful analysis of supporting data.[2]
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".