Barriers towards effective pharmacovigilance systems of biosimilars in rheumatology: A Latin American survey

Abstract Purpose This review summarises the current status of regulatory guidelines for the approval of biosimilars in Latin America and highlights the main barriers to effective pharmacovigilance in this region. We also report results from a survey of Latin American rheumatologists assessing their understanding of prescribing biosimilars and the pharmacovigilance of these drugs. Methods We reviewed the current guidelines for the regulatory approval of biosimilars and barriers to effective pharmacovigilance in Latin American countries. Rheumatologists attending the II Pan‐American League of Rheumatology Associations PANLAR Review Course (Biosimilars update) in Lima, Peru were asked to complete a short survey to determine their knowledge of biosimilars. Results Many Latin American countries continue to lag behind Europe and the United States in establishing regulatory guidance and effective pharmacovigilance systems for biosimilars. Results from our survey also highlight a lack of awareness regarding the availability of biosimilars, their nomenclature, automatic substitution, and reporting adverse drug reactions because of these drugs. Conclusions The main barriers to effective pharmacovigilance in Latin America are the lack of consensus on the interchangeability of reference biologics and biosimilars, and the need for more suitably trained personnel to carry out effective postmarketing pharmacovigilance of biosimilars. Inconsistencies in biosimilar nomenclature make it difficult to adequately trace drugs and record adverse drug reactions associated with their use, creating a barrier to the global pharmacovigilance of biologics.


| INTRODUCTION
As patent portfolios for reference biologics near end of term, pharmaceutical companies are developing safe and effective biosimilars for these drugs. [1][2][3][4] A biosimilar is highly similar to an approved reference product, with no clinically meaningful differences in purity, potency, and safety (Table 1). [5][6][7][8][9][10] Biosimilars can potentially increase patient access to more affordable biologic treatments and have an important role in the treatment of chronic conditions, including rheumatic and musculoskeletal diseases. 11,12 Several biosimilars are approved for treating patients with rheumatic and musculoskeletal diseases such as rheumatoid arthritis, ankylosing spondylitis, idiopathic juvenile arthritis, psoriatic arthritis, and other immune-mediated inflammatory conditions. 2,13 In addition, several potential biosimilars are in development.
As with reference biologics, biosimilars can cause an immunogenic response in treated individuals. The immune system can induce the development of antidrug antibodies in response to a biologic, which can impact the medicine's clinical efficacy and increase the risk of adverse drug reactions (ADRs). 14 Adverse events (AEs) such as cardiotoxicity, cytokine-release syndrome, and reactivation of latent tuberculosis can also be encountered with biologic treatments. 15 To ensure patient safety, it is important to monitor immunogenicity and ADRs during drug development and through postmarketing surveillance to gain real-world clinical experience. 16,17 Effective pharmacovigilance systems are essential for detecting, reporting, understanding, and preventing ADRs.
Unfortunately, only a few Latin American countries have the necessary systems in place to collect, manage, and analyse reported safety data. 18

KEY POINTS
• Many Latin American countries lag behind Europe and the United States in establishing regulatory guidelines and effective pharmacovigilance systems for biosimilars.
• Inconsistencies in the nomenclature of biosimilars make it difficult to adequately trace drugs and record adverse drug reactions, creating a barrier to global pharmacovigilance.
• For effective pharmacovigilance input from academic bodies and regulatory agencies, it is vital to agree a common definition and legislation on the interchangeability of reference products and biosimilars.
• More suitably trained personnel are needed to carry out effective pharmacovigilance of biosimilars in Latin American countries.

Term
Definition Reference Biosimilar A biopharmaceutical that is highly similar to an already licensed biologic product (the reference product), notwithstanding minor differences in clinically inactive components, and for which there are no clinically meaningful differences in purity, potency, and safety between the two products FDA 5 A biological medicinal product that contains a version of the active substance of an already authorised original biological medicinal product (reference medicinal product). Similarity to the reference medicinal product in terms of quality characteristics, biological activity, safety, and efficacy, based on a comprehensive comparability exercise, needs to be established EMA 6 Noncomparable biotherapeutic Biotherapeutic medicinal products that are intended to "copy" another biotherapeutic product; have not been directly compared and analysed against an already licensed reference biotherapeutic product; and have not been approved via a regulatory pathway that is in alignment with World Health Organization Similar Biotherapeutic Product guidelines that ensure quality, safety, and efficacy IFPMA 7

Interchangeability
One medicine is exchanged for another medicine that is expected to have the same clinical effect. For example, a reference product could be replaced with a biosimilar (or vice versa), or one biosimilar could be replaced with another EMA 8 A biosimilar is designated as interchangeable if it is "expected to produce the same clinical result as the reference product in any given patient" and if a biological product "is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between the biological product and reference product is not greater than the risk of using the reference product without such alternation or switch" FDA 9

Switching
The prescriber decides to exchange one medicine for another medicine with the same therapeutic intent EMA 8

Substitution (automatic)
The practice of dispensing one medicine instead of another equivalent and interchangeable medicine at pharmacy level without consulting the prescriber EMA 8

Extrapolation
The approval of a biosimilar for use in an indication held by the reference product but not directly studied in a comparative clinical trial with a biosimilar We also conducted a survey to gain an insight into the heterogeneous position on biosimilars between Latin American countries regarding topics such as the pharmacovigilance and regulation of these drugs.
We report results from this survey assessing current awareness of these key issues among Latin American rheumatologists.

| European Union
The European Medicines Agency (EMA) guidelines for approval of biosimilars are well established; the first biosimilar was approved in the European Union (EU) in 2006. 8,25 However, guidance regarding interchangeability, switching, and substitution of a reference product with a biosimilar is determined by individual EU member states. 8 To date, no EU-approved biosimilars have been withdrawn or suspended because of safety concerns. 26

| United States
The United States Food and Drug Administration (FDA) has published guidelines for the approval of biosimilars and first approved a biosimilar in 2015. 5,27 In contrast to EMA guidelines, the FDA can designate a biosimilar as "interchangeable", although individual states also regulate interchangeability. 28 When interchangeability status is granted, a biosimilar can be substituted for its reference product at the pharmacy level without further input from the prescriber. However, interchangeability is not automatically granted upon approval of a biosimilar; additional evidence is required to demonstrate that the clinical result achieved with the biosimilar is expected to be the same as the reference product. In addition, switching treatment between the reference product and biosimilar should demonstrate no increased risk to the patient. 9,29

| Rest of the world and the World Health Organization
In 2009, World Health Organization (WHO) published guidance documents, based on those from the EMA, with the aim of providing "globally acceptable principles for licensing products … claimed to be similar to licensed biotherapeutic products of assured quality, safety, and efficacy that have been licensed based on a full licensing dossier". 30 Many other countries have established or are developing guidelines for the approval of biosimilars, based on EMA and WHO guidance. 28

| Latin America
Some Latin American countries have published guidelines for biosimilar approval, based on EMA and WHO guidance, while others have issued only draft documents or none at all (Table 2). 17,18,31 Brazil has two regulatory pathways for biosimilars-a "comparative pathway" and an "individual development pathway". 18,32 The former requires preclinical and clinical data to demonstrate similarity to the reference product; only products approved via this pathway are considered to be biosimilars. In contrast, the individual development pathway does not compare the potential biosimilar with the reference product; rather, summaries of preclinical and clinical studies are required. 32,33 Colombia has three regulatory pathways for biosimilars; the "complete dossier" approach, the "comparability approach", and an "abbreviated comparability approach". 34 These pathways share common elements, and the pathway followed will depend on the biologic submitted for approval. For example, the "abbreviated comparability approach" is followed when the reference product is sufficiently characterised, with well-defined safety and efficacy, and adequate data are available in terms of clinical experience and pharmacovigilance evidence. 34 In Mexico, biologics (including biosimilars) have been available for a number of years. 35

| Use of noncomparable biotherapeutics, counterfeit, and stolen medicines in Latin America
The use of noncomparable biotherapeutics in Latin America presents a challenge for pharmacovigilance. These drugs are copies of reference biologics introduced before the release of regulatory guidance. As a result, they have not met the requirements for establishing

| Pharmacovigilance and interchangeability: A traceability approach
The terms "interchangeability" and "substitution" should be differentiated from each other (Table 1). Interchangeability permits a prescriber to replace a reference product with a biosimilar, whereas substitution allows a biosimilar to be dispensed in place of a reference product without further input from the prescriber. 23 Guidance on the interchangeability and substitution of biosimilars, either with reference products or another biosimilar, also differs between regulatory agencies. 18,55 This poses a challenge for postmarketing pharmacovigilance if automatic substitution is permitted without the original prescriber's input. 17 Extrapolation of data across indications is not permitted in Brazil for products approved under the individual development pathway (see above). 32,33 The Brazilian National Health Surveillance Agency, ANVISA, considers interchangeability to be "more directly related to clinical practice than to regulatory status". As such, the decision to switch treatment between biosimilars and their reference products should be made by the physician and patient. In addition, ANVISA does not recommend multiple switching between biosimilars and reference products, due to challenges relating to traceability. 56, 57 The Mexican College of Rheumatology recommends that substitution of interchangeable biosimilars includes intervention from a healthcare professional. 58

| Establishing risk-management plans for biosimilars
Risk-management plans (RMPs) can assist with early pharmacovigilance planning for new drugs by assessing the potential risks of certain medicines and detailing how these issues will be addressed in postmarketing follow-up. 17 RMPs cover a medicine's entire life cycle and must be regularly updated as new safety information becomes available. The EMA requires an RMP to be submitted when applying for market authorisation of a biosimilar. 59 The aim of these plans is to ensure that the benefits of using a particular medicine outweigh its risks. 9,59,60 To improve pharmacovigilance in Latin America, RMPs should be essential for all biologics, including biosimilars. 17 Mexico recently updated their official standard on pharmacovigilance, and RMPs are now mandatory. 61

| Reporting ADRs in Latin American countries: Key challenges
Healthcare professionals play a key part in improving pharmacovigilance through accurate reporting and recording of ADRs. 17,22,50 In developing countries, healthcare is often fragmented, with limited financial resources for pharmacovigilance systems. 62 There is also a lack of awareness among physicians about accurate reporting, which contributes to under-reporting of ADRs. 63,64 To evaluate awareness of biosimilars and prescribing practices in

| Design and methodology
Rheumatologists attending the II PANLAR Review Course ("Biosimilars update") in Lima, Peru (6-8 September 2017), were asked to voluntarily complete a short survey, comprising six questions (in Spanish) with multiple-choice responses (Figure 1). The survey was designed to determine experts' awareness of biosimilars, including prescribing practices, nomenclature, automatic substitutions, and ADR reporting.
The survey was conducted by administrative staff from PANLAR on behalf of G.C-H., H.S., and C.P.

| Results
In total, 104/155 (67%) rheumatologists completed the survey. Seven surveys were excluded from the analysis as they were incomplete.

| Current awareness of biosimilars and prescribing practices
Most respondents indicated that biosimilars were available in the country where they practised (Figure 2A). However, some rheuma-

| Nomenclature and automatic substitutions
The majority of respondents (58 rheumatologists) indicated that a naming system was not used to differentiate between reference products and biosimilars in the country where they practised, or they were not aware of such a system (29 rheumatologists) ( Figure 2C). Approximately one third reported that automatic substitution between reference products and biosimilars was permitted in the country where they practised, while a further third reported that automatic substitution was not permitted ( Figure 2D).

| ADRs/pharmacovigilance notifications
Over half of the respondents (51 rheumatologists) were not aware of any ADRs because of automatic substitution of a reference biologic with a biosimilar ( Figure 2E). In this survey, the most frequently reported ADRs resulting from substitution were anaphylactic reaction, joint pain, allergy, hypersensitivity, urticaria, and tachycardia. Most of the rheumatologists (59 respondents) had not reported possible ADRs due to biologics or biosimilars during the past 3 years ( Figure 2F), while 18 respondents had reported more than three ADRs in the same period.

| CONCLUSIONS
In To address some of these barriers, rheumatology societies and biosimilar experts in Latin America have proposed several recommendations. One suggestion is to use a unique identifier throughout the region for noncomparable biotherapeutics and approved biosimilars.
Another suggestion is to raise awareness about the importance of reporting ADRs resulting from treatment with biologics, including biosimilars, and to establish effective tracking systems to capture and analyse data. 50 Physicians and regulatory agencies should work collaboratively to ensure the appropriate use of biologics, including biosimilars. 58,72 The importance of pharmacovigilance should also be highlighted in medical schools, with the support of national rheumatology societies. 17 PANLAR is currently drafting a consensus on biosimilars to guide rheumatologists and regulatory authorities when making decisions on biosimilar use and approval. 73 Our survey of rheumatologists in Latin America aimed to determine the current awareness when prescribing biosimilars and some of the perceived barriers, including nomenclature, automatic substitution, and reporting of possible ADRs because of the use of biosimilars. Results from our survey highlight several issues, including a lack of awareness regarding the availability of biosimilars and automatic substitution. Additionally, nomenclature for biosimilars remains unclear to many rheumatologists, which affects the traceability of biosimilars and, subsequently, the accurate reporting of ADRs associated with their use. Improving the knowledge of rheumatologists on these key issues could facilitate improvements in the pharmacovigilance of biosimilars in Latin America.
The overall goal of pharmacovigilance is to accurately and promptly trace ADRs to a particular product and manufacturer; therefore, agreement on a common definition of, and legislation for, interchangeability of biosimilars is essential for well-functioning pharmacovigilance systems and has important implications for rheumatologists prescribing these drugs. Clear guidelines on the interchangeability of biologics and biosimilars are needed to ensure patient safety and effective postmarketing pharmacovigilance. Further input from academic bodies and regulatory agencies is vital to establish a common position on these issues.

ETHICS STATEMENT
The authors state that no ethical approval was needed.