By Sean Skulski
Based on a biologic drug (reference product) whose patent has expired, biosimilars are “copycat drugs” that demonstrate proven bioequivalence to the reference product. Unlike generic drugs (chemical products), which are identical to a branded drug, biosimilars are only similar to a reference product; due to the complex nature of biologic drugs, it is impossible to produce an exact replica of a biologic, hence the adoption of the nomenclature “biosimilar.” What encouraged the growth of the biosimilar market in the European Union and the US has been the discounts incited by biosimilars. As seen in the EU, biosimilars are cheaper, and once biosimilars are made readily available to patients, the price of the reference product tends to drop, too.
The European Union has been keen on approving biosimilars; in fact, the EU has approved over 40 biosimilar products to date, spearheading the crusade for cheaper, more affordable drugs. In second place, the US just approved its eleventh biosimilar product, and although the US lags behind the EU, the Food and Drug Administration (FDA) has recently announced its intent to increase generic competition through newer and better guidance.
Emerging nations with burgeoning national health systems such as China and India have enacted legislation and drafted guidance to commence domestic production of biosimilars. For example, in 2014, inspired by EU guidelines and terminology, China’s Center for Drug Evaluation (CDE) released its much-anticipated guidelines for biosimilars in 2014.
LATAM: An overview
In LATAM, despite idiosyncratic disparities among countries, multiple biosimilars to 11 active substances including etanercept, filgrastim, infliximab, and rituximab, among others, have found approval. Argentina, Brazil, and Mexico are steadily rising to the forefront of biosimilar adoption and production, and experts have forecasted the value of the LATAM biosimilar market to reach $4 billion in 2020. But overall, biosimilar uptake started off slowly in these countries because of unclear and laxed regulation, but Argentina, Brazil, and Mexico, all of which have markets known to favor generic drugs, are working to enact legislation to ensure accessibility and availability of cheaper, yet highly-effective drugs.
In these countries, oncology, immunosuppressant, and autoimmune biosimilars have been the most popular. The active substance filgrastim, which is used to help the body replenish white blood cells after receiving cancer medication, has seen the highest uptake in Brazil, with etanercept, which aids in fighting off autoimmune diseases, coming in second.
Although Argentina looks to the horizon with welcoming arms, a lack of transparency and regulatory framework has made it difficult for the country to attain stride when it comes to adopting biosimilars.
In Argentina, a biosimilar is referred to as a “biologic product,” whereas the reference drug is called the “comparator.” Initial guidance on biosimilars appeared in 2008, introduced by Provision No. 7075 and 7729. In 2011, Argentina published Provision No. 7729/11, which outlines requirements and guidelines of medicinal specialties of biologic origin whose qualitative composition, therapeutic indication, and route of administration have been approved, and which have antecedents in other medicinal specialties of biologic origin authorized and registered before, of which there is evidence of effective commercialization and sufficient characterization of risk-benefit. In the following year, Argentina published Provision No. 3397/12, which detailed specific requirements for the presentation of applications for authorization and registration of biological drugs and/or monoclonal antibodies obtained by recombinant DNA methods.
To gain approval for a biosimilar, Argentina’s HTA body, the National Administration of Drugs, Food, and Medical Technology (ANMAT), akin to Europe and the US, requests studies that demonstrate homogeneity as well as clinical trials demonstrating safety and efficacy. Though idiosyncrasies regarding size, shape, and inactive ingredients are permitted, there is still a lack of detailed technical guidance.
As of now, Argentina has approved the following biosimilars:
- Biosidus’ Neutromax (filgrastim) in November 2015
- Biosidus’ Bioferon (Inteferon Alfa-2b) in January 2018
- Eli Lilly’s Abasaglar (insulin glargine) in March 2018
- Sandoz’s Omnitrope (somatropin) in April 2018
- Gobbi’s Remsima (infliximab) in April 2018
- Elea’s Novex (rituximab) in May 2018
- Duncan’s Filgrastim (filgrastim) in May 2018
Argentina looks to the future, too. The approval of the rituximab biosimilar saw ANMAT’s insistence on furthered, more prevalent pharmacovigilance, and Argentinean doctors have since been required to monitor patient reaction, exemplifying that, all in all, despite a lack of transparency on behalf of ANMAT, there are biosimilars in development pipeline.
With a population of over 200 million, Brazil has a nascent need for access to affordable biologic products to serve the public; most notably, Brazil’s national policy prefers generics over branded drugs. Brazil’s regulatory agency ANVISA issued its first biosimilar guidance in 2010, and as in Argentina, a biosimilar is referred to as a “biologic product,” whereas the reference drug is called the “comparator.” Prior to this, in 2008, ANVISA adopted prioritization policies to accelerate the analysis of products considered to be strategic, such as generic drugs and public-private partnership products. ANVISA’s efforts to improve regulatory processes are paying off; nowadays, Brazil is a recognized member of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH).
To seek biosimilar approval in Brazil, a manufacturer must follow the regulatory-enacted “comparative pathway,” which requires the drug under scrutiny to identify a previously-authorized biologic product to be used as a reference product. Once this initial step has been accomplished, the new copycat biologic drug will then be developed to demonstrate comparable and observable quality, safety, and efficacy.
Thus far, Brazil has approved the following biosimilars:
- Celltrion’s Remsima (infliximab) in April 2015
- UCB’s Wosulin R (human insulin) in May 2015 (extended presentation in July 2015)
- Eurofarma Lab’s Fiprima (filgrastim) in October 2015
- Reddy’s Granomax (filgrastim) in April 2016
- Industria Quimica’s Hemoprex (filgrastim) in April 2017
- Biocon/Mylan’s Zedora (trastuzumab) in December 2017
- Eli Lilly’s Basaglar (insulin glargine) in April 2018 (extended indication in May 2018)
- Blau Pharma’s Eritromax (epoetin alfa) in April 2018
- Blau Pharma’s Filgrastim (filgrastim) in April 2018
- Biosintetica’s Filgrastim (filgrastim) in April 2018
- Sandoz’s Omnitrope (somatropin) in April 2018
- Teva’s Tevagrastim (filgrastim) in April 2018
- Bergamo’s Myograf (filgrastim) in April 2018
- Merck’s Brenzys (etanercept) in May 2018
Due to gubernatorial investment, along with public need and disparities between public and private health insurance coverage, more blockbuster biosimilars are expected to be greenlighted.
Though biosimilar guidelines were initially established in 2009, in 2012, Mexico took initiative and released full-fledged guidelines and regulatory principles, via Article 222 bis in the Mexican Health Law, and has since become known as one of the leading countries among domestic markets for biosimilar adoption and regulation. Presently, Mexico introduced a proposal—currently pending approval—to prevent automatic switching (i.e. interchangeability) from the reference product to a biosimilar due to unforeseen and potential health issues. Mexico’s Subcommittee of the Evaluation of Biotechnology Products, part of the New Molecules Committee, is responsible for determining the approval process of new, innovative drugs. To gain approval, biosimilars, known as innovator drugs, must demonstrate clinical safety and efficacy and bioequivalence to the reference drug, dubbed “biocomparable biotech drugs” in Mexico. While such trials are necessary, the specifics and requirements are wholly underdefined by Mexico’s HTA authority, the Federal Commission for the Protection Against Sanitary Risk (COFEPRIS).
In turn, since 2014, Mexico has seen the approval of two biosimilars:
- Shanghai CP Guojian’s Etenar (etanercept)
- Probiomed’s Infinitam (etanercept)
Originally, Probiomed’s Kikuzimad (rituximab) had found approval, but the drug was withdrawn from Mexico in March 2014 due to adverse anaphylactic events associated with its use.
Although only two biosimilars have been approved in Mexico, the country has seen a growing generics market due to the extreme costliness of drugs in the country. Recent studies have found that Mexico wastes over 2 billion pesos. To resolve the problem of expenditure, Mexico believes that improved competition will insinuate price cuts, and the country therefore expects discounts on biologic originators of 10 to 30%, thus diminishing the burden. While the Mexican Industry of Industrial Property (IMPI) protects patents in the country, as of 2017, there were 22 drugs with expired patents in Mexico that had yet to experience generic competition. Moreover, the Mexican government has targeted life sciences and biotechnology as key areas of development, thus nourishing the terrain for future biological product growth. It’s evident that there’s money to be made in Mexico; however, as with Argentina and Brazil, legal framework and public policy must be changed, including incentivization, to fuel a more rapid uptake of biosimilars.
Looking towards the future
While Argentina, Brazil, and Mexico have all taken steps in the right direction to commercialize biosimilars, in the end, the three LATAM countries need to further concretize regulation and framework to ensure pharma can easily find approval for biosimilar products. Each country has a health system craving generic drugs; biosimilars are simply the next step to enhance the healthcare palate of Argentina, Brazil, and Mexico.
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