My opinion
 

By Dr. Alfonso Duenas-Gonzalez
Corresponding Author Dr. Alfonso Duenas-Gonzalez
Instituto de Investigaciones Biomedicas, UNAM/Instituto Nacional de Cancerologia, - Mexico 14080
Submitting Author Dr. Alfonso Duenas-Gonzalez
PHARMACOLOGY

Biopharmaceuticals, Biogenerics, Paradigms

Duenas-Gonzalez A. Paradigms on Biogeneric Drugs - Some views. WebmedCentral PHARMACOLOGY 2010;1(10):WMC00801
doi: 10.9754/journal.wmc.2010.00801
No
Submitted on: 01 Oct 2010 10:19:32 AM GMT
Published on: 01 Oct 2010 10:26:37 AM GMT

Article


The paradigm claimed by brand-name biopharmaceutical manufacturers that “the process is the drug” hence the need for performing clinical trials for introducing biogenerics, is scientifically unsound. It comes to no surprise then, that brand-name biological manufacturers all of a sudden are tremendously concerned on the potential toxicity and potential lower efficacy of biogeneric drugs. This “concern” is traduced in supporting strong regulations including clinical trials, precluding the entrance of competitor drugs in the market despite emerging preclinical and clinical data speak on the therapeutic efficacy and comparable toxicity of biogeneric drugs. Whether all these regulatory affairs for “having effective and safe biologicals” possess a market-driven or a science-driven rationale is a provocative thought, after all, although we must bear in mind that the market of biological drugs will be overwhelmingly superior to that of small-molecule.
Key words: Biopharmaceuticals, biogenerics, paradigms.
Main: Plant-based drugs have been used around the world for thousands of years. Drugs based on chemical synthesis have been with us since the latter half of the 1800s. Now, the era of biologics—genetically engineered protein drugs made in living cells arrived to stay. Recombinant DNA is a form of artificial DNA that is created by combining two or more sequences that would not normally occur together. In terms of genetic modification, it is created through the introduction of relevant DNA into an existing organismal DNA, such as the plasmids of bacteria, to code for or alter different traits for a specific purpose, such as antibiotic resistance.   A recombinant protein therefore, is one derived from recombinant DNA technology [1]. The commercial potential of molecular biology and its kindred disciplines was first recognized in the mid-1970s. In the following years capitalist enterprises in the United States and abroad adopted the techniques of molecular biology, a scientific discipline. In the process, molecular biology has transformed an engineering discipline, bioprocess engineering, and spawned an industrial field, biotechnology. Biotechnology as a business arises out of an intersection of the scientific practices of molecular biology—formerly undertaken only in universities — and the engineering practices of biochemical engineering and other technologies necessary to produce biological commodities [2].
One breakthrough in recombinant DNA technology was the manufacture of biosynthetic "human" insulin, which was the first medicine made via recombinant DNA technology ever to be approved by the FDA. Insulin was the ideal candidate because it is a relatively simple protein and was therefore relatively easy to copy, as well as being extensively used to the extent that if researchers could prove that biosynthetic "human" insulin was safe and effective, the technology would be accepted as such, and would open opportunities for other products to be made in this fashion [3]. Thus, the first-generation biopharmaceuticals including insulin are copies of endogenous human proteins, such as erythropoietin (EPO), growth hormones and cytokines. These compounds have revolutionized the treatment of many diseases, including anemia, diabetes, cancer, hepatitis and multiple sclerosis [4]. Biologics now account for 20% of the global drug market, according to market research firm IMS Health. In 2000, only one biologic made the top ten list of worldwide drug sales (Amgen’s recombinant erythropoietin in 4th place). By 2008, five of the top 10 drugs in sales were biologics, and by 2014 biologics are expected to occupy six of the top ten positions, according to EP Vantage [5]. 
Small molecules or conventional chemical drugs eventually go off patent, as do biologics. This loss of patent protection leads to the introduction of generic drugs, which are usually priced at a small fraction of the cost of the branded drug. These conventional generics are considered to be therapeutically equivalent to a reference, once pharmaceutical equivalence (i.e. identical active substances) and bioequivalence (i.e. comparable pharmacokinetics) have been established and do not require formal clinical efficacy and safety studies. When small molecules lose their patent protection (or their patents are successfully challenged in court), their sellers can lose significant market share within days or weeks when they face a flood of competition from cheaper generic copies. Big Pharma’s solution to the generics issue has been to establish “pay for delay” agreements with generics manufacturers. They pay these companies not to challenge their patents and sell competing drugs, thereby preserving market share. The legality of this practice has come into question, since it is obviously anti-competitive and is designed to keep prices high for consumers. 
What about biologics?  The barrier to entry in making biogenerics is significantly higher than with small molecules, due to much higher production costs as well as by the legal and regulatory pathways bringing biogenerics to the market. In this regard, the EMEA has forged ahead in providing guidance for national regulatory bodies in Europe. The EMEA guidelines are, however, a work in progress currently being updated (www.emea.eu.int). Some sections of the guidelines are still controversial. For instance, it is stated that comparative clinical trials can be foregone if the biogeneric can be characterized in detail by physicochemical and in vitro techniques, or alternatively that comparative pharmacokinetics (PK) and pharmacodynamics (PD) studies can replace clinical trials. The annex to the insulin concept paper echoes this: efficacy data need not be provided if equivalence can be concluded from PK and PD data. In contrast, the other three concept papers regard comparative clinical studies as a necessity.
The emphasis on adequate screening for immunogenicity events is well-warranted, given the incidence of pure red cell aplasia (PRCA). Post-marketing monitoring is an essential component in tracking rare but serious adverse events like these. The guidelines state that immunogenicity analyses should be performed especially in cases where repeated administration is proposed. A useful addition to the guidelines would be to require branding of biogenerics, to allow optimal and accurate pharmacovigilance.
Currently, no legal framework exists in the US for the approval of biogenerics, and the FDA has released no guidance documents. The EMEA has provided a valuable base for EU legislation to evolve from. However, if we wish to ensure patient safety with the arrival en masse of biogenerics to the market, it is imperative that their unique characteristics be recognized. Accrued experience will then allow regulatory authorities to optimally match guidelines to the genuine risks and benefits associated with biogenerics.
In contrast to generic versions of small molecules or conventional drugs which are introduced onto the marketplace without doing clinical trials, running clinical trials are required for biogenerics prior to approval, thus raising the bar higher to keeping out competitors. Even if biogenerics do make it onto the market, they will not be priced as cut-rate bargains like traditional small-molecule generics, because the biologics will cost more to manufacture, and develop. Partly because of their higher prices, biogenerics are predicted to capture much less market share than small molecule generics. As a result, makers of biologics will be much less concerned than makers of small molecules about a potential loss of revenue once the patents expire on their molecules.  The main question, therefore, is whether there is genuine interest based on scientific arguments or whether this is solely in the interest of just obey to economical interests of Big Pharma to keep competitors out by raising the bar higher for entrance into the market.
Paradigms:
1. The active substance of a biopharmaceutical is a collection of large protein isoforms and not a single molecular entity, which is generally the case with conventional small-molecule drugs. Thus, it is highly unlikely that the active substances are identical between two products.
2. Small changes in, or differences between, manufacturing processes may have a significant impact on the quality, purity, biological characteristics and clinical activity of the final product. Even when biogenerics are produced from the same genetic construct, using the same technique, formulation and packaging as the innovator product, there is no guarantee that they will be comparable with the reference product. Structural differences between proteins may arise for a number of reasons, including oligomerization, modification of the protein primary sequence, glycosylation patterns or the conformational state.
3. The primary safety concern for biogeneric agents is their potential immunogenicity. Although these proteins are designed to closely mimic human proteins, they have the potential to induce an immune response, especially when administered as multiple doses over prolonged periods.
Facts: The manufacturing process for biopharmaceuticals is several orders of magnitude more complex than that for small-molecule pharmaceuticals. Conventional pharmaceutical agents are small-molecule chemicals with a defined molecular weight typically between 100 and 1000 Da. In contrast, biopharmaceuticals are large, complex and heterogeneous proteins with more variable molecular weights, commonly ranging from 18 000 to 145 000 Da. Compared to the manufacture of small molecular entities, the manufacture of biopharmaceuticals requires a greater number of batch records (>250 versus <10); more product quality tests (>2000 versus <100); more critical process steps (>5000 versus <100) and more process data entries (>60 000 versus <4000). The molecular size and complexity of biopharmaceuticals and their production in living cells makes the final product very sensitive to changes in production conditions. Changes may occur to the expression systems used for production, culture conditions (e.g. temperature and nutrients), purification and processing, formulation, storage and packaging. Taken from Shellekens [24,25].
Despite it is beyond doubt that the manufacturing process are different between a conventional chemical drug and a biogeneric [24,25], there is no convincing evidence that current analytical techniques are unable to establish biopharmaceutical equivalence neither information in most recent techniques for characterization and purification of recombinant proteins has been critically analyzed by brand-name manufacturer supporters [6-16]. The following paragraphs are taken from a statement made by Theresa L. Gerrard TLG Consulting Inc.  Committee on Oversight and Government Reform Safe and Affordable Biotech Drugs — The Need for a Generic Pathway, in March 26, 2007 [17].
Every biological product is subjected to rigorous analytical testing. The same  would hold true for biogenerics. Analytical testing consists of multiple tests that are used to assess the physical, chemical and biological characteristics of the product. Many more tests are used to assess a biologic than are typically used to assess a drug. This battery of tests is conducted for every batch of biopharmaceutical product manufactured and is also used to monitor the product during the manufacturing process. In the field of  biopharmaceuticals both the Food and Drug Administration (FDA) and industry rely on  analytical testing to ensure consistency so that every batch of the biopharmaceutical will  be deemed safe and effective for its intended use.
Many biologics, including almost all of the biotech products, can be now defined by chemical and physical attributes. This fact can be attributed to two scientific advances. The first is the increasing purity of biological products, especially recombinant  biotech products. The production of human proteins through recombinant technology  continuously improves, providing ever more highly purified human proteins. The second  advance is the increasing sophistication of the analytical technology that allows a very  detailed characterization of these products. Although the cells that are used to produce biopharmaceuticals are complex living organisms, all finished biopharmaceutical  products used to treat patients are highly purified human proteins that are produced  consistently using advanced manufacturing technologies. The large array of  sophisticated analytical tools that exist today now allow for the characterization of  biopharmaceuticals to ensure safety and efficacy.
The advances in analytical characterization and the ability to assess the specified  or well-characterized biologicals by analytical tests allowed FDA to develop scientific  policies on comparability in the early 1990s. These policies gave brand manufacturers  the ability to change the manufacturing process without the need for clinical trials if the  new product was shown to be comparable to the previous product. Prior to this time, every change in a manufacturing process necessitated the need for new clinical data. It was the innovator biotech manufacturers who pressed FDA for this change, because they rightly claimed that their biopharmaceuticals were so well characterized. They proved  this through their ability to identify potential product changes with analytical testing  technology.
The brand companies fought for these policies because the need to make manufacturing changes for biotech products was common and manufacturers wanted to make changes to the manufacturing process without the need to repeat clinical trials.  FDA agreed that the nature of the products allowed manufacturing changes to be assessed  predominantly by analytical testing for characterization. In fact, and this is a critically important point, FDA recognized that analytical testing was far more sensitive in the ability to detect product changes than a typical clinical trial. For the past 15 years, manufacturers of well-characterized biopharmaceuticals have been able to make manufacturing changes without repeating clinical trials if they demonstrate that the  product made after the manufacturing change is comparable to the product made before  the change.
It is therefore at least surprising that now, brand-name  companies of biotechnological medicinal products point on the need of performing clinical trials for biogenerics to demonstrate efficacy and safety. If it is assumed to be true (that small differences in the process require clinical trials to demonstrate equivalent therapeutic efficacy), then the same would apply for “innovator” products as small changes in the process of manufacturing are likely to occur, as well as potential  changes on subsequent steps (storage, transport, etc) occurring from the process of manufacturing until the product is administered to the patient. Nevertheless, the regulatory processes favor the “reference” product. In fact, the commonly cited example of the impact of variability between biological products on safety is the large increase in the incidence of Antibody-mediated PRCA (Pure Red Cell Aplasia) that occurred between 1998 and 2003 in chronic renal failure patients using the reference epoetin alfa Eprex® marketed by Johnson & Johnson  [17-20].
There is no reason for giving by granted that the “reference” product is free of immunogenicity or any other potential serious side-effect therefore identical regulatory issues and quality testing should be applied to reference and biogeneric products particularly when the reference biological has been evaluated in distinct populations. Although any two humans are 99.9% identical at the nucleotide sequence level many phenotypic differences are apparent in individuals within the same and from distinct human populations. Genetic diversity underlying the remaining 0.1% nucleotide differences has been postulated to contribute to phenotypic diversity among humans, and to population-specific susceptibility to disease and variability in the response to pharmacological treatments [21-23].
So far, there are several biogenerics approved or in clinical trials. These include a number of epoetins and granulocyte-colony stimulating factors, interferons, activated factor VII, and ready-to-use liquid formulations of human growth hormone. Against all concerns, all these products have demonstrated safety and efficacy with no unexpected adverse events, comparable to the reference biological product [26-44].

Conclusion


Brand-name biological manufacturers that essentially are the same that develop “small-molecule” drugs all of a sudden are tremendously concerned on the potential toxicity and potential lower efficacy of biogeneric drugs. This “concern” is translated into supporting strong regulations that preclude the entrance of competitor drugs into the market despite that emerging preclinical and clinical data speak of the therapeutic efficacy and comparable toxicity of biogeneric drugs. Whether all these regulatory affairs for “having effective and safe biologicals” derive from a market-driven or science-driven rationale is a provocative thought; after all, one should be reminded that the biologicals market is going to be overwhelming superior to that of the small-molecule. The following paragraphs taken from “The Scientist” journal is an straigthforth evidence for thinking on the issues raised before.
Manufacturers say they need the longer protection to earn a profit on biotech drugs, which can take over $1 billion and a decade to bring to market. Generic companies say waiting that long would discourage them from developing competing products and would keep drug prices high. The lobbying battle has so far been one-sided. That dominance is partly due to a huge disparity in money, according to the nonpartisan Center for Responsive Politics and the Senate Office of Public Records. Representing biotech companies, the Biotechnology Industry Organization has spent $3.7 million lobbying so far this year. Their ally, Tauzin's association of drug makers, has spent $13.1 million — the second most of any group that lobbies in Washington. The main group opposing them, the Generic Pharmaceutical Association, has spent $1.1 million lobbying this year. Another group, a coalition of generic drug companies, insurers and large employers, has spent another $180,000. Individual biotech companies like Amgen are also easily outspending their generic rivals such as Teva Pharmaceuticals USA, Inc. The one-sidedness extends to campaign contributions, too. The biotech organization contributed $192,000 to federal candidates in the two-year 2008 election cycle, the pharmaceutical association $155,000. The generic association: $51,000 [49].
What appears to be clear is that Big Pharma has the advantage in this game, not to mention that in addition to tight regulations, this leaves little room for competition by domestic pharmaceutical industries, particularly within developing countries. This kind of legislations discourages local research and development, increases drug importation, and decreases local self-reliance in dealing with disease.

References


1. Steinberg FM, Raso J. Biotech pharmaceuticals and biotherapy: an overview. J Pharm Pharm Sci 1998;1(2):48-59.
2.http://hcd.ucdavis.edu/faculty/webpages/kenney/articles_files/Biotechnology%20and%20the%20Creati on%20of%20a%20New%20Economic%20Space.pdf
3. The MJ. Human insulin: DNA technology's first drug. Am J Hosp Pharm 1989;46(11 Suppl 2):S9-11.
4. Black WJ. Drug products of recombinant DNA technology. Am J Hosp Pharm 1989;46(9):1834-44.
5. http://www.icis.com/Articles/2010/02/15/9333235/follow-on-biologics-present-opportunity-to-big-pharm a.html
6. Grzeskowiak JK, Tscheliessnig A, Wu MW, et al.Two-dimensional difference fluorescence gel electrophoresis to verify the scale-up of a non-affinity-based downstream process for isolation of a therapeutic recombinant antibody. Electrophoresis 2010;31(11):1862-72.
7. Zaia J. Mass spectrometry and glycomics. OMICS 2010;14(4):401-18.
8. Salehpour M, Ekblom J, Sabetsky V, Håkansson K, Possnert G. Accelerator mass spectrometry offers new opportunities for microdosing of peptide and protein pharmaceuticals. Rapid Commun Mass Spectrom 2010;24(10):1481-9.
9. Yang Y, Strahan A, Li C, Shen A, et al. Detecting low level sequence variants in recombinant monoclonal antibodies. MAbs 2010;2(3):285-98.
10. Demeler B. Methods for the design and analysis of sedimentation velocity and sedimentation equilibrium experiments with proteins. Curr Protoc Protein Sci 2010;Chapter 7:Unit 7.13.
11. Toledo-Rubio V, Vazquez E, Platas G, et al. aggregation and soluble aggregate formation screened by a fast microdialysis assay. J Biomol Screen 2010;15(4):453-7.
12. Yamaguchi H, Miyazaki M, Briones-Nagata MP, Maeda H. Refolding of difficult-to-fold proteins by a gradual decrease of denaturant using microfluidic chips. J Biochem 2010;147(6):895-903.
13. Rege K, Heng M. Miniaturized parallel screens to identify chromatographic steps required for recombinant protein purification. Nat Protoc 2010;5(3):408-17.
14. Ye H, Hill J, Kauffman J, Han X. Qualitative and quantitative comparison of brand name and generic protein pharmaceuticals using isotope tags for relative and absolute quantification and matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry. Anal Biochem 2010;400(1):46-55
15. Ye H, Hill J, Kauffman J, Gryniewicz C, Han X. Detection of protein modifications and counterfeit protein pharmaceuticals using isotope tags for relative and absolute quantification and matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry: studies of insulins. J Pharm Biomed Anal 2010 Aug 6 [Epub ahead of print].
16. Liu C, Dong S, Xu XJ, et al.  Assessment of the quality and structural integrity of a complex glycoprotein mixture following extraction from the formulated biopharmaceutical drug product. J Pharm Biomed Anal 2010 Aug 6 [Epub ahead of print].
17. Statement of Theresa L. Gerrard TLG Consulting Inc. Committee on Oversight and Government Reform Safe and Affordable Biotech Drugs — The Need for a Generic Pathway.
18. Bennett CL, Luminari S, Nissenson AR, et al. Pure red-cell aplasia and epoetin therapy. N Engl J Med 2004;351(14):1403–1408.
19. Casadevall N, Eckardt KU, Rossert J. Epoetin-induced autoimmune pure red cell aplasia. J Am Soc Nephrol 2005;16(Suppl 1):S67–S69.
20. Gershon SK, Luksenburg H, Coté TR, Braun MM. Pure red-cell aplasia and recombinant erythropoietin. N Engl J Med  2002;346(20):1584–5.
21. Daar AS, Singer PA. Pharmacogenetics and geographical ancestry: implications for drug development and global health. Nat Rev Genet 2005;6(3):241–6.
22. Burchard EG, Ziv E, Coyle N, et al. Importance of race and ethnic background in biomedical research and clinical practice. N Engl J Med 2003;348(12):1170–5.
23. Armengol L, Villatoro S, González JR, et al. Identification of copy number variants defining genomic differences among major human groups. PLoS One 2009;4(9):e7230.
24. Schellekens H. Biosimilar therapeutics-what do we need to consider? NDT Plus 2009;2(Suppl_1):i27-i36.
25. http://www.economiadelasalud.com/ediciones/66/08_pdf/manufacture.pdf
26. Sörgel F, Thyroff-Friesinger U, Vetter A, et al. Bioequivalence of HX575 (recombinant human epoetin alfa) and a comparator epoetin alfa after multiple intravenous administrations: an open-label randomised controlled trial. BMC Clin Pharmacol 2009;9:10.
27. Sörgel F, Thyroff-Friesinger U, Vetter A, Vens-Cappell B, Kinzig M. Bioequivalence of HX575 (recombinant human epoetin alfa) and a comparator epoetin alfa after multiple subcutaneous administrations. Pharmacology 2009;83(2):122-30.
28. Sörgel F, Thyroff-Friesinger U, Vetter A, Vens-Cappell B, Kinzig M.  Biosimilarity of HX575 (human recombinant epoetin alfa) and epoetin beta after multiple subcutaneous administration. Int J Clin Pharmacol Ther 2009;47(6):391-401.
29. Togawa A, Tanaka T, Nagashima S, et al. A comparison of the bioequivalence of two formulations of epoetin alfa after subcutaneous injection. Br J Clin Pharmacol 2004;58(3):269-76.
30. Cho SH, Lim HS, Ghim JL, et al. Pharmacokinetic, tolerability, and bioequivalence comparison of three different intravenous formulations of recombinant human erythropoietin in healthy Korean adult male volunteers: an open-label, randomized-sequence, three-treatment, three-way crossover study. Clin Ther 2009;31(5):1046-53.
31. Milutinović S, Plavljanić E, Trkulja V. Comparison of two epoetin brands in anemic hemodialysis patients: results of two efficacy trials and a single-dose pharmacokinetic study. Fundam Clin Pharmacol 2006;20(5):493-502.
32. Pérez-Oliva JF, Casanova-González M, García-García I, et al. Comparison of two recombinant erythropoietin formulations in patients with anemia due to end-stage renal disease on hemodialysis: a parallel, randomized, double blind study. BMC Nephrol 2005;6(1):5.
33. Lubenau H, Sveikata A, Gumbrevicius G, et al. Bioequivalence of two recombinant granulocyte colony-stimulating factor products after subcutaneous injection in healthy volunteers. Int J Clin Pharmacol Ther 2009;47(4):275-82.
34. Lubenau H, Bias P, Siegler KE, Mehltretter K. Pharmacokinetic and pharmacodynamic profile of new biosimilar filgrastim XM02 equivalent to marketed filgrastim Neupogen: single-blind, randomized, crossover trial. BioDrugs 2009;23(1):43-51.
35. Hernández-Bernal F, García-García I, González-Delgado CA, et al. Bioequivalence of two recombinant granulocyte colony-stimulating factor formulations in healthy male volunteers. Biopharm Drug Dispos 2005;26(4):151-9.
36. Waller CF, Bronchud M, Mair S, Challand R. Pharmacokinetic profiles of a biosimilar filgrastim and Amgen filgrastim: results from a randomized, phase I trial. Ann Hematol 2010;89(9):927-33.
37. Di Girolamo G, Kauffman MA, González E, et al. Bioequivalence of two subcutaneous pharmaceutical products of interferon beta la. Arzneimittelforschung 2008;58(4):193-8.
38. Gatzemeier U, Ciuleanu T, Dediu M, et al. XM02, the first biosimilar G-CSF, is safe and effective in reducing the duration of severe neutropenia and incidence of febrile neutropenia in patients with small cell or non-small cell lung cancer receiving platinum-based chemotherapy. J Thorac Oncol 2009;4(6):736-40.
39. Engert A, Griskevicius L, Zyuzgin Y, Lubenau H, del Giglio A. XM02, the first granulocyte colony-stimulating factor biosimilar, is safe and effective in reducing the duration of severe neutropenia and incidence of febrile neutropenia in patients with non-Hodgkin lymphoma receiving chemotherapy. Leuk Lymphoma 2009;50(3):374-9.
40. Bysted BV, Scharling B, Hansen BL. A randomized, double-blind trial demonstrating bioequivalence of the current recombinant activated factor VII formulation and a new robust 25 degrees C stable formulation. Haemophilia 2007;13(5):527-32.
41. Ducongé J, Rodríguez-Vera L, Valenzuela C, et al. XM02 is superior to placebo and equivalent to Neupogen in reducing the duration of severe neutropenia and the incidence of febrile neutropenia in cycle 1 in breast cancer patients receiving docetaxel/doxorubicin chemotherapy. BMC Cancer 2008;8:332.
42. Carlsson G, Ahlin A, Dahllöf G, et al. Efficacy and safety of two different rG-CSF preparations in the treatment of patients with severe congenital neutropenia. Br J Haematol 2004;126(1):127-32.
43. Fuhr U, Tuculanu D, Berghout A, et al. Bioequivalence between novel ready-to-use liquid formulations of the recombinant human GH Omnitrope and the original lyophilized formulations for reconstitution of Omnitrope and Genotropin. Eur J Endocrinol 2010;162(6):1051-8.
44. Stanhope R, Sörgel F, Gravel P, et al. Bioequivalence Studies of Omnitrope, the First Biosimilar/rhGH Follow-on Protein: Two Comparative Phase 1 Randomized Studies and Population Pharmacokinetic Analysis. J Clin Pharmacol 2010 Feb 19 [Epub ahead of print]
45. Wu TY, Jen MH, Bottle A, et al. Ten-year trends in hospital admissions for adverse drug reactions in England 1999-2009. J R Soc Med 2010;103(6):239-50.
46. Saul S, Berenson A. Maker of Lipitor digs in to fight generic rival. New York Times. 2007 Nov 3;:A1.
47. Beck M. Inexact copies: how generics differ from brand names. Wall Street Journal. 2008 Apr 22;:D1.
48. Rockoff J. Cost of medicine could increase. Baltimore Sun. 2008 Jun 17;:1A.
49.  http://www.the-scientist.com/community/posts/list/578.page#ixzz0zEqIloBH

Source(s) of Funding


None.

Competing Interests


None declared.

Disclaimer


This article has been downloaded from WebmedCentral. With our unique author driven post publication peer review, contents posted on this web portal do not undergo any prepublication peer or editorial review. It is completely the responsibility of the authors to ensure not only scientific and ethical standards of the manuscript but also its grammatical accuracy. Authors must ensure that they obtain all the necessary permissions before submitting any information that requires obtaining a consent or approval from a third party. Authors should also ensure not to submit any information which they do not have the copyright of or of which they have transferred the copyrights to a third party.
Contents on WebmedCentral are purely for biomedical researchers and scientists. They are not meant to cater to the needs of an individual patient. The web portal or any content(s) therein is neither designed to support, nor replace, the relationship that exists between a patient/site visitor and his/her physician. Your use of the WebmedCentral site and its contents is entirely at your own risk. We do not take any responsibility for any harm that you may suffer or inflict on a third person by following the contents of this website.

Reviews
0 reviews posted so far

Comments
0 comments posted so far

Please use this functionality to flag objectionable, inappropriate, inaccurate, and offensive content to WebmedCentral Team and the authors.

 

Author Comments
0 comments posted so far

 

What is article Popularity?

Article popularity is calculated by considering the scores: age of the article
Popularity = (P - 1) / (T + 2)^1.5
Where
P : points is the sum of individual scores, which includes article Views, Downloads, Reviews, Comments and their weightage

Scores   Weightage
Views Points X 1
Download Points X 2
Comment Points X 5
Review Points X 10
Points= sum(Views Points + Download Points + Comment Points + Review Points)
T : time since submission in hours.
P is subtracted by 1 to negate submitter's vote.
Age factor is (time since submission in hours plus two) to the power of 1.5.factor.

How Article Quality Works?

For each article Authors/Readers, Reviewers and WMC Editors can review/rate the articles. These ratings are used to determine Feedback Scores.

In most cases, article receive ratings in the range of 0 to 10. We calculate average of all the ratings and consider it as article quality.

Quality=Average(Authors/Readers Ratings + Reviewers Ratings + WMC Editor Ratings)