Similar and mimics: Latin America biosimilar regulations

1 INTRODUCTION

The current therapeutic approach to rheumatic diseases includes early and intensive treatment, aiming to reach persistent low disease activity and remission. Recently, new drugs increased the therapeutic options for patients, including both novel targeted therapies (biological disease modifying drugs) and biosimilars.

A biosimilar is a biotherapeutic product which is similar in terms of quality, safety and efficacy to an already licensed reference biotherapeutic product.1

In recent years, with the aim to improve access to expensive biological agents and with the patent expiration of reference products, biosimilars have come to market.

Due to the complicated factors involved in manufacturing copies of biological therapeutic products, potential concerns on safety, efficacy and quality have been raised. In this context, the distinction between biosimilars and biomimics, that is versions of monoclonal antibodies or fusion proteins available in countries where regulation is less strict, is of great importance.2 Unlike a biosimilar, these products don't have enough evidence to demonstrate biosimilarity and may therefore present clinically significant differences from the reference drug.3

With the introduction of biosimilars and biomimics in Latin America in the past years, regulatory authorities have been discussing and establishing the pathways to allow these drugs to receive market registration, whilst securing safety, quality and efficacy.

The regulatory scenario on biological medications in Latin America is undergoing a full consolidation process as the region proceeds towards a stronger strictness on biosimilar registration.4 Even though there are important disparities between countries in terms of regulatory pathways and quality of evidence required to achieve market authorization. Most Latin American countries follows the WHO guidelines on biotherapeutic products4 or follow regulatory approval practices similar to those of the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA). Similar situations are seen in the Asian markets as reported in this issue of the journal.5 The developing world is facing the conundrum of access vs quality in their populations with different diseases.

This paper summarizes the status of biosimilars in Latin America, focusing on the regulations, extrapolation of indication and the products available in the countries of the region with the aim to provide key information about the use of biosimilars in the treatment of rheumatic diseases.

2 REGULATORY PATHWAYS FOR BIOSIMILARS

The use of biological therapies in many Latin America countries consumes a substantial portion of the health care budget. Economic pressure to introduce biosimilar agents into market has forced regulatory agents to create different pathways to accelerate the process of licensing biosimilars.

Brazil regulations differ from other countries of Latin America. In 2010, ANVISA, the Brazilian Health Surveillance Agency introduced two pathways for approving comparable biological products, differing in the amount of data required for market approval: the comparative pathway and the individual development pathway.6

The comparative pathway is more rigorous, requires pharmacokinetic and pharmacodynamic studies and phase 3 trials, and allows extrapolations into other indications. This pathway is for licensing monoclonal antibodies and other complex molecules.6-8 Through this pathway, in 2015,9 Remsima, a biosimilar of Infliximab and in 201710 Brenzys (SB4), a biosimilar of Etanercept where approved. In the individual development pathway, the requirements on data quality and clinical trials is less stringent. Depending on the amount of knowledge of pharmacological properties, safety and efficacy of the originator product, clinical requirements can be reduced.7 Extrapolation of indications is not permitted here. Less complex biotherapeutics such as pegylated interferon, for example, are approved via this pathway.

In Mexico, in 2009, the Mexican Congress passed Article 222 into the general Health Law, which defined a biosimilar drug, allowing comparison with an originator biologic.7 Although there is requisite for clinical studies to compare the innovator with the biosimilar in terms of quality, safety and efficacy, this is made on a case by case basis. That regulation allows for an abbreviated clinical proof as the biochemical characterization closely resembles the biosimilar to the original. Mexico is also dealing with intended copies or biomimics. According to new criteria approved in 2011, previously licensed drugs must be renewed every five years, and therefore these intended copy biological drugs will have to demonstrate true biosimilarity with preclinical and clinical studies as well as pharmacovigilance including detection of inmunogenicity.11 There are no specific rules for the extrapolation of indications in the Mexican regulation. Currently two biosimilars are approved for clinical used in Mexico: Infinitam a biosimilar of Etanercept and Remsima, a biosimilar of Infliximab. Infinitam has no clinical trials published in peer reviewed journals comparing to the originator so far. A previous biosimilar of Rituximab (Kikuzubam) was withdrawn from the market after it was shown to increase the risk of adverse events.

Argentina has well established pathways for licensing biosimilars products since 2011 and is a major producer of biosimilars in the Latin America region. Well defined non-clinical (pharmacological) and clinical data is required for products to be approved.12 The legislation establish is that is not necessary for biosimilars to undergo the same clinical rigor as an innovative drug. Biosimilars for approval in Argentina have similar requirements as described by the WHO. Two biosimilars has been approved to date in Argentina. Novex (Rituximab) has done a study for lymphoma which has still not been published in a peer review journal, and no study has been done on rheumatoid arthritis. ANMAT (the National Administration of Drugs, Foods and Medical Devices) authorized the commercialization of Novex prior to completion of required clinical trials, which was in violation of their own regulation.13 Bevax (Bevacizumab), does not have any study comparing to the reference product so far. Extrapolation of indications is not allowed.

Chile began drafting guidelines for the evaluation of biosimilars in 2011 and employed EMA and WHO guidelines as valuable starting points.8 New approvals require pre-clinical and clinical studies to demonstrate safety, efficacy and immunogenicity of the biosimilar comparable with the reference product. Extrapolation of indications is permitted. Remsima (CT-P13) and Reditux (Rituximab) have been approved. Reditux was approved before the new legislation and has no clinical trial published in a peer review journal.

Colombia has three routes for licensing biological products. For the first two, a full application pathway (for original biotherapeutics products) and the comparable pathway are consistent with the regulations of other countries and follows the WHO guidelines. The third route is an abbreviated pathway that requires only laboratory studies of bioequivalence of the drug (biosimilar) without clinical trials confirming its efficacy or safety. This is for pharmaceutical products that have been approved in another country.8 Concerns about quality, safety and efficacy of the approved drugs via this third pathway have been raised and it is not consistent with the WHO guidelines requirements. Etanar, a biosimilar of Etanercept, is available in Colombia and was approved by the regulatory agency of this country based on preclinical and clinical studies carried out mainly in China. There is an observational cohort study carried out in Colombia, of 105 patients with active rheumatoid arthritis in spite of treatment with sDMARS, in whom Etanar was added.14 The results showed a surprising high percentage of patients reaching ACR 20, 50 and 70 responses, compared to what is available in the literature. An adequate, safety profile is document.

Recently Peru and Paraguay, in the year 2016, established the regulations to license biosimilars products. Both countries follow the WHO guidelines and required pre-clinical and clinical studies to determine biosimilarity.

Other countries like Bolivia and Ecuador are working on a regulatory draft.

3 CONCLUSIONS

A substantial pipeline of biosimilars is in development with over 700 products reported to be in preclinical and clinical trials.15 Even though, there is still a lot of challenges remaining in clinical practice and unanswered question regardless biosimilars in terms of switching, substitution, naming, extrapolations of indications and pharmacovigilance. In this context Latin American countries must deal also with the inequities in accesses to therapy based on economic differences across countries, the respect of the norms that they have written, the deficiency on the pharmacovigilance for any drug, the poor infrastructure of some of the health care systems and the absence of harmonization of regulatory guidance and recommendations.

Biosimilarity should be granted through pre- clinical and clinical head to head studies comparing with the innovator product. Also the biosimilars agents already on the market before the regulations where done should be reevaluated in order to be relicensed, securing safety, quality and efficacy for patients as recommended by the WHO.16

Clinicians in Latin America should be well informed on this topic and educational efforts should be done.