POLICY AND PRACTICE REVIEWS published: 11 September 2020 doi: 10.3389/fphar.2020.578000 The “Square Box”: Therapeutic Equivalence as a Foundation of the WHO Model List of Essential Medicines Bernadette Cappello 1*, Lorenzo Moja 1, Albert Figueras 1,2 and Nicola Magrini 3 1 Department of Health Products Policy and Standards, World Health Organization, Geneva, Switzerland, 2 Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Barcelona, Spain, 3 Italian Medicines Agency, Rome, Italy Every two years, the World Health Organization (WHO) updates its Model List of Essential Medicines, intended as a guide for countries to adopt or adapt in accordance with local priorities and treatment guidelines, for the development of national essential medicines lists. When more than one therapeutic option is available for a given indication, the WHO Edited by: Susan Leigh Craddock, Model List often includes a single medicine as representative of a group of equivalent and University of Minnesota Twin Cities, interchangeable medicines. The representative medicine of that group is listed with an United States accompanying ‘square box’ symbol. The intended purpose of the square box is to Reviewed by: highlight pharmacological classes or groups of medicines for which countries, institutions Muhammad Usman, University of Veterinary and Animal and health professionals can assume homogeneous therapeutic efficacy and safety and Sciences, Pakistan select the most appropriate single medicine based on price, local availability, and Tanja Mueller, University of Strathclyde, acceptability. Though this concept of therapeutic equivalence within a therapeutic class United Kingdom has been endorsed by most authoritative textbooks of pharmacology since Goodman & *Correspondence: Gilman’s The Pharmacological Basis of Therapeutics and evidence-based guidelines, Bernadette Cappello marketing forces have often made claims on individual drugs to distinguish them beyond cappellob@who.int relevant differences shown by reliable evidence: this has generated the concept of “me- Specialty section: too drugs” with its double meaning—i.e., market latecomers differing minimally from This article was submitted to products preceding them and whose marketing budgets have significant opportunity Pharmaceutical Medicine and Outcomes Research, costs, or medicines which may be useful to substitute for equivalent products in the event a section of the journal of shortages. The square box concept is applied in the context of a comprehensive list: Frontiers in Pharmacology therapeutic equivalence or interchangeability cannot always be easily established. Received: 30 June 2020 Accepted: 26 August 2020 Different interpretations have been applied to different groups of medicines over the 40+ Published: 11 September 2020 year history of the Model List. This paper presents the concept of the square box, provides Citation: key examples and guidance on how square box listings should be practically interpreted in Cappello B, Moja L, Figueras A and the development and implementation of national essential medicine lists, considers the Magrini N (2020) The “Square Box”: Therapeutic Equivalence as a applicability of a square box listing concept to biologic medicines and proposes that an Foundation of the WHO Model updated review of the square box concept and listings is warranted. List of Essential Medicines. Front. Pharmacol. 11:578000. Keywords: WHO model list of essential medicines, medicines selection, therapeutic equivalence, interchangeability, doi: 10.3389/fphar.2020.578000 biologic medicines Frontiers in Pharmacology | www.frontiersin.org 1 September 2020 | Volume 11 | Article 578000 Cappello et al. Therapeutic Equivalence of Essential Medicines INTRODUCTION pay worthwhile returns in terms of additional clinical benefit and deliver value for money. In low-, middle-, and high- Markets are filled with thousands of medicines: many are income countries alike, the costs of many medicines are becoming similar pharmacological analogs (so-called “me-too drugs”), prohibitive, and policies to improve the efficiency of pharmaceutical offering little, if any, additional clinical benefit in comparison. spending are increasingly important (OECD, 2010). Square box The expression “me-too” in the field of medicines was first listings build on the fundamental principal of limited selection. They introduced by Goodman in the 1950s and was popularized are intended to give countries scope to select a medicine from within during the Golden Age of pharmacotherapy, when hundreds of a pharmacological class that best suits local needs based on new chemical entities were studied and eventually approved. availability and resources (WHO, 2020a). Describing a medicine as a me-too has a double meaning, that of Against this background, countries, irrespective of income a “market latecomer which often differs trivially from earlier level, are creating or updating national essential medicines lists, products and that the billions of dollars spent marketing these guided by the work done by WHO at the global level. However, me-too products could be spent in better ways” (Lee, 2004) but countries frequently face uncertainties when undertaking national also as medicines which “may be useful when equivalent drugs essential medicine selection, including how to interpret square box can replace each other in the event of shortages” (Aronson and listings on the Model List, and determine the alternatives that can Green, 2020). be considered therapeutically equivalent. Providing more explicit It is thus important to have a mechanism to facilitate the information on therapeutically equivalent medicines within the selection of a limited number of essential medicines from the square box listings on the Model List can serve to address plethora of pharmaceuticals available on the global market. these uncertainties, better informing and supporting national Controlling the number of medicines deemed essential will decision-making. deliver both healthcare and economic advantages: to facilitate The aim of this review is to provide guidance for decision- rational prescribing and use by providing more focused makers to interpret square box listings on the WHO Model List information, to enable better value procurement through in developing and implementing national essential medicine tendering and competition leading to lower costs for individuals lists. It also considers the applicability of square box listings to and health systems and to improve access (Hogerzeil, 2004). biologic and biosimilar medicines as a mechanism to stimulate The WHO Model List of Essential Medicines was first competition, reduce cost, and increase access to these therapies. published in 1977 and has since been recognized as a revolution in public health; introducing the notion that some medicines are more important than others ('t Hoen et al., 2014). WHO defines essential medicines as those that satisfy the priority health care HISTORY OF THE SQUARE BOX needs of the population, which are intended to be available in CONCEPT functioning health systems at all times in adequate amounts, in appropriate dosage forms, with assured quality, and at prices The concept of a single medicine being included on the Model List individuals and the community can afford (WHO, 2011). as a representative of a broader group of clinically or Medicines are added to or removed from the Model List on the therapeutically equivalent alternatives has been in place since the advice of the WHO Expert Committee on Selection and Use of first Model List was published in 1977. Listed medicines to which Essential Medicines, an independent, multidisciplinary group of this early concept applied were accompanied by an explanatory medical and pharmaceutical experts responsible for reviewing note stating “Listed as an example of this therapeutic category: medicines and making recommendations to the WHO Director- choose cheapest effective drug product acceptable” (WHO, 1977). General. The Expert Committee is convened every two years to The square box symbol itself (☐) was first introduced into the evaluate applications proposing additions, deletions, and changes Model List in 1983 when it was determined that therapeutically to medicines on the Model List. It is required to make its equivalent alternatives could be represented by a single medicine, recommendations having given due regard to disease prevalence so distinguished by this symbol (WHO, 1983). At that time, this and public health relevance, evidence of clinical efficacy and safety, was one of the few special symbols that could be used by and with consideration of comparative cost and cost-effectiveness typographies around the world, ensuring global understanding (WHO, 2020a). of the Model List. By 2002, with a relatively large number of The Model List is intended as a guide and reference standard medicines on the Model List with a square box listing (n = 113), for countries for the development of national and institutional the Expert Committee recommended a review of medicines listed essential medicine lists that together with other medicines’ policy with a square box, noting some confusion and inconsistency with actions, empower countries to progress towards universal health regard to the application of the concept and implications for its coverage and affordable access to safe, effective, and quality- definition (WHO, 2002). Following consideration of the review in assured essential medicines and health products. 2003, the Expert Committee made a series of recommendations to Establishing a limited list of essential medicines is particularly retain or remove square boxes and modified the explanatory important in low- and middle-income countries, where total health description of the square box symbol on the Model List: expenditure is more limited and medicine expenditure constitutes a larger proportion of total health expenditure, compared to high “The square box symbol is primarily intended to income countries (Lu et al., 2011). Investments in medicines should indicate similar clinical performance within a Frontiers in Pharmacology | www.frontiersin.org 2 September 2020 | Volume 11 | Article 578000 Cappello et al. Therapeutic Equivalence of Essential Medicines pharmacological class. The listed medicine should be TABLE 1 | Square box listings on the 2019 Model List in numbers. the example of the class for which there is the best Number Examples/comments evidence for effectiveness and safety. In some cases, this may be the first medicine that is licensed for marketing; Total listings 108 − 93 unique medicines or fixed-dose combinations with a square − 89 on the core list, 19 on the complementary list in other instances, subsequently licensed compounds box may be safer or more effective. Where there is no Unrestricted 84 Examples: difference in terms of efficacy and safety data, the square box* − simvastatin (representative of statins) listed medicine should be the one that is generally − omeprazole (representative of proton pump available at the lowest price, based on international inhibitors) * some unrestricted listings have reference to drug price information sources. Therapeutic equivalence acceptable alternatives in the technical report of the is only indicated on the basis of reviews of efficacy and meeting where recommendations were made, but safety and when consistent with WHO clinical guidelines. these alternatives are not specified in the list. National lists should not use a similar symbol and should Qualified 24 Examples (specified alternatives): be specific in their final selection, which would depend on square box − enoxaparin (nadroparin, dalteparin) − erlotinib (gefitinib, afatinib) local availability and price.” Small 103 Examples (specified alternatives): molecules − bisoprolol (atenolol, metoprolol, carvedilol) This description remains unchanged to date. − morphine (hydromorphone, oxycodone) The square box is not used to indicate bioequivalence of Biological 5 Examples (specified alternatives): multisource pharmaceutical products containing the same medicines − adalimumab [certolizumab pegol, etanercept, chemical compound. Bioequivalence of pharmaceutical products golimumab, infliximab (including biosimilars)] − erythropoiesis-stimulating agents [epoetin alfa, is determined by national regulatory authorities and may differ beta and theta, darbepoetin alfa, methoxy between jurisdictions. The Model List is constructed using the polyethylene glycol epoetin-beta (including international non-proprietary names of medicines and does not biosimilars)] differentiate by proprietary names. Generic substitution between Entries without 14 e.g. cycloserine (terizidone), propofol (thiopental), a square box rituximab (quality-assured biosimilars) bioequivalent pharmaceutical products is considered acceptable but with for medicines on the Model List. named alternatives CHARACTERISTICS OF CURRENT SQUARE BOX LISTINGS pharmacological class. The ATC classification is a 5-level system There are currently 108 entries (involving 93 unique medicines that classifies medicines according to the anatomical system upon or fixed-dose combinations) on the 2019 Model List that carry a which they act, and their therapeutic, pharmacological and square box symbol (WHO, 2019). These entries appear in the chemical properties. The first level includes fourteen anatomical Model List either as “unrestricted” listings, or they are “qualified” and pharmacological groups, which are subdivided at the second by a note specifying the acceptable alternatives. In some cases, level into pharmacological or therapeutic groups, at the third and there is reference to acceptable alternatives in the technical fourth levels into chemical, pharmacological or therapeutic report of the Expert Committee meeting where specific square subgroups, with the fifth level being the individual chemical box recommendations were made, but the alternatives are not substance (WHO Collaborating Centre for Drug Statistics referenced in the list per se. An additional 14 entries do not carry Methodology, 2020). The ATC classification and the defined a square box but include annotations indicating acceptable daily dose (DDD) assignment are useful tools to identify alternatives. Square box listings apply to both small molecules medicines within pharmacological classes and inform medicine and biologic medicines (Table 1). selection decisions at country, institution, or prescriber levels. Current examples of unrestricted square box listings include Unrestricted Square Box Listings: All proton pump inhibitors (PPIs) for peptic ulcer and gastro- Medicines Are Equal esophageal reflux disease and HMG CoA reductase inhibitors The majority of square box listings on the 2019 Model List are (statins) for hyperlipidemia and prevention of cardiovascular unrestricted. That is, there is no qualifying note in the list to limit disease, represented on the Model List by omeprazole and the choice of medicine within the pharmacological class. In these simvastatin, respectively. These listings should be interpreted cases, the square box indicates that all medicines within the same to mean that PPIs and statins have similar clinical performance pharmacological class can be considered therapeutically equivalent within their pharmacological classes and represent a group and interchangeable. The representative listed medicine is usually of medicines from which countries can select the most the one for which there is the best or more evidence for appropriate for their national lists. The ATC classification effectiveness and safety. structures for PPIs and statins are illustrated in Table 2. The The Model List relies on the Anatomical Therapeutic Chemical individual medicines at the fifth ATC level represent options for (ATC) classification to define medicines within the same country-level selection. Frontiers in Pharmacology | www.frontiersin.org 3 September 2020 | Volume 11 | Article 578000 Cappello et al. Therapeutic Equivalence of Essential Medicines However, there are some instances where unrestricted square as well as for treatment of acute coronary syndromes and venous box listings have reference to acceptable alternatives in the thromboembolism, the indications for which they are included in technical report of the meeting where recommendations were the EML. The absence of sufficient evidence on the relative made, without this recommendation being reflected in the list efficacy of other agents in this pharmacological class in per se. This has the disadvantage for users of the Model List of conditions other than prevention or treatment of venous requiring reference to the historical meeting reports. For thrombosis drove this decision by the Expert Committee. example, in 2009, intravenous ibuprofen was included in the Similarly, in 2017, the Expert Committee recommended the Model List with a square box for the management of patent ductus addition of erythropoiesis-stimulating agents to the Model List for arteriosus in preterm infants. In making this recommendation, the treatment of anemia in patients with chronic kidney disease Expert Committee recommended that indomethacin was an requiring dialysis, with a qualified square box listing, limiting appropriate alternative, yet this is not explicit in the list (WHO, alternatives to epoetin alfa, beta and theta, darbepoetin alfa, 2009). Instances such as this give rise to uncertainty for country- and methoxy polyethylene glycol-epoetin beta (WHO, 2017). level decision makers and warrant revision as qualified square box The Expert Committee further recommended that their listings to increase clarity and eliminate inconsistency. respective biosimilars were also acceptable alternatives based on evidence of therapeutic equivalence and safety of switching to biosimilars from the reference products. Peginesatide, a Qualified Square Box Listings: When Some synthetic erythropoiesis-stimulating agent was not included as Medicines Are Better Than Others an accepted alternative due to serious post-marketing safety Over 20% of square box listings on the 2019 Model Lists are concerns that led to its withdrawal from the market in several qualified by a note to indicate that acceptable alternatives countries (Hermanson et al., 2016). are limited to specific medicines. These qualifying notes are In some cases, the square box is used to indicate recommended by the Expert Committee for a variety of reasons: interchangeability, based on therapeutic indication, of medicines when there is evidence to suggest within-class differences between with different pharmacological properties but considered to be medicines (e.g., opioid analgesics) or when there is more limited therapeutically equivalent alternatives. This use of the square box clinical evidence for some medicines in the class. Qualified square is only seen in circumstances where comprehensive reviews of box listings more clearly inform and support rational, evidence- efficacy and safety support a conclusion of therapeutic equivalence based medicine selection decisions at institution or country level, and when use of the medicines is consistent with recognized assist with tendering and procurement processes, and tacitly clinical guidelines. In such circumstances, the listing is always discourage use of unspecified agents, which would be based on qualified. However, determining therapeutic equivalence in untested assumptions about equivalence in terms of efficacy such circumstances is complex. These cases require detailed and safety. and comprehensive review of clinical data on comparative For example, the 2015 addition to the Model List of enoxaparin effectiveness and safety and are uncommon. For example, with a qualified square box listing limits alternatives for low- methadone for use in opioid substitution therapy, was added to molecular-weight heparins (LMWHs) to nadroparin and the Model List in 2005 (WHO, 2005). A square box is included dalteparin, based on the supporting evidence (WHO, 2015). with this listing, along with a qualifying note to identify Different LMWHs have been directly compared in a limited buprenorphine as an alternative. While methadone and number of studies, mostly exploring benefits for venous buprenorphine differ in their pharmacological properties, they thromboembolism (White and Ginsberg, 2003). Enoxaparin, were considered appropriate therapeutic alternatives for use as nadroparin, and dalteparin are the only LMWHs with substitution therapy for opioid dependence based on the evidence in the prevention of venous thrombosis after surgery, available evidence. TABLE 2 | ATC classification structures for proton pump inhibitors and statins. ATC level PPIs ATC code Statins ATC code 1: Anatomical main group Alimentary tract and metabolism A Cardiovascular system C 2: Therapeutic subgroup Drugs for acid related disorders A02 Lipid modifying agents C10 3: Pharmacological subgroup Drugs for peptic ulcer and gastro- A02B Lipid modifying agents, plain C10A oesophageal reflux disease (GORD) 4: Chemical subgroup Proton pump inhibitors A02BC HMG CoA reductase inhibitors C10AA 5: Individual chemical substance omeprazole A02BC01 simvastatin C10AA01 pantoprazole A02BC02 lovastatin C10AA02 lansoprazole A02BC03 pravastatin C10AA03 rabeprazole A02BC04 fluvastatin C10AA04 esomeprazole A02BC05 atorvastatin C10AA05 dexlansoprazole A02BC06 cerivastatin C10AA06 dexrabeprazole A02BC07 rosuvastatin C10AA07 lansoprazole, combinations A02BC53 pitavastatin C10AA08 rabeprazole, combinations A02BC54 Frontiers in Pharmacology | www.frontiersin.org 4 September 2020 | Volume 11 | Article 578000 Cappello et al. Therapeutic Equivalence of Essential Medicines APPLICATION OF THE SQUARE BOX Switching from a reference biologic product to its biosimilar or CONCEPT TO BIOLOGIC OR between biosimilar medicines remains a matter of debate in clinical practice (Faccin et al., 2016). The issue of interchangeability and BIOTHERAPEUTIC MEDICINES switching between therapeutically equivalent biologic and biosimilar There is increasing availability of biologic medicines on medicines is important for wider access and to foster market pharmaceutical markets, many of which are associated with a competition. The stringent regulatory criteria and the need for significant budget impact to health systems. Biosimilar medicines providing a comprehensive data package have often been claimed as are versions of originator products approved by regulatory putting unnecessary burden and cost on the development and agencies that can be manufactured after the originator product licensing of biosimilars, thus leading to delay in the availability of patent expires. By virtue of their complex, biological production alternatives. On the other hand, these criteria are meant to provide methods, biosimilar medicines cannot be considered identical to a sufficient level of evidence to reduce patients’ and health care their reference counterparts in the same way that generics of professionals’ concerns about the use of biosimilars. Pre-marketing small molecule medicines are considered identical to their trials and post-marketing drug-utilization data help to consolidate reference counterparts (Weise et al., 2014). It has also been not only the therapeutic equivalence of two products, but also the noted that each batch of a reference biological is not ‘identical’ to safety of switching from reference to biosimilar medicines (Ebbers previous or subsequent batches—”as ‘non-identicality’ is a et al., 2012; D’Amore et al., 2016; CADTH, 2017). normal feature of biotechnology that has to be controlled by Most biosimilars have been approved after switching patients tight specifications of critical product attributes, within current that have been previously treated with either an originator or a technical and scientific limitations (inherent variability)” biosimilar medicine. Finally, it should be emphasized that many (Schneider, 2013). Indeed, the promotion and use of originators have become biosimilars of themselves due to biosimilars have given rise to concerns and been the subject of modifications and improvements in their manufacturing intense debates. However, biosimilars are approved following the processes after their approval and along the product life cycle same standards of pharmaceutical quality, safety, and efficacy (Schneider, 2013). A 2011 study analyzed the quality profiles of that apply to all biologic medicines, and they can reach the same market-sourced darbepoetin alfa, rituximab, and etanercept clinical effect in given clinical settings. between 2007 and 2010, identifying changes in relevant molecular Since 2015, the number of biologics on the Model List has attributes over time. The tested products remained on the market increased, raising the question of how the square box concept with unaltered labels, indicating that the changes were not expected should apply to biologic and biosimilar medicines. The 2019 to be associated with an altered clinical profile and were thus Model List includes erythropoiesis-stimulating agents, considered acceptable by health authorities (Schiestl et al., 2011). enoxaparin, human insulin, filgrastim, leuprorelin, pegaspargase and monoclonal antibodies adalimumab, nivolumab, rituximab and trastuzumab (WHO, 2019). Several of these medicines are listed with a square box. The square box introduces the IMPLICATIONS FOR THE MODEL LIST opportunity at country level for biosimilar versions of these FOR THE 2021 UPDATE medicines to be procured along with the reference products, or as alternatives. It has been applied when a biosimilar has been Square box listings on the Model List were last reviewed in 2003. An shown not to have clinically meaningful differences from the updated review is therefore warranted. In 2021, the Expert reference product in terms of quality, safety, and efficacy and Committee will be asked to consider a proposal to revise the should be considered to be therapeutically equivalent for national definition of the square box concept and the related jargon. or institutional selection and procurement purposes. The “Square box” is a term that lacks both clarity and consistency in availability of alternative biosimilar medicines also creates its use—a critical flaw for any technical term if it is to be globally increased choice for patients and clinicians. understood. The Committee will also be asked to review the existing It is expected that with increasing availability of biosimilar square box listings and determine the specific alternatives for medicines, prices will fall, as has been the experience with the country-level selection. How best to present square box listings to prices of small-molecule medicines with the introduction of provide the greatest clarity for countries regarding therapeutically generics. Cost-efficiencies can potentially be achieved through equivalent medicines is important to support informed decision- increased market competition, which facilitates the treatment of a making about pharmacological class effects. greater number of patients and adds further sources of supply, To clearly indicate appropriate alternatives for therapeutic potentially reducing the likelihood of shortages (NHS England, equivalence, applications for new medicines will need to provide 2019). However, in 2019, the Expert Committee expressed concern evidence for the medicines deemed to provide equivalent clinical that to date, availability and access to biosimilars of some essential benefits. Applications will also be required to consistently and medicines (e.g. rituximab) have been limited. To address this, the preferentially use the “qualified” square box listing option. Expert Committee recommended WHO to consider expanding its Following this approach, the Model List will continue to medicines’ prequalification program to include biosimilars of recommend a representative medicine for classes of medicines medicines listed on the Model List, such that they are routinely where the Expert Committee accepts therapeutic equivalence. evaluated along with the reference counterparts (WHO, 2019). Recognized therapeutically equivalent medicines will be included Frontiers in Pharmacology | www.frontiersin.org 5 September 2020 | Volume 11 | Article 578000 Cappello et al. Therapeutic Equivalence of Essential Medicines in the listing in a dedicated field, providing more clear information better inform decision-making for national essential medicine to support countries in their national selection, tendering, and lists. The Model List continues to evolve with time, with new procurement processes. medicines regularly considered for inclusion to meet changing The release of an electronic version of the Model List in 2020 public health needs. In 1983, quality information about (the “eEML”) has introduced the ability to easily and clearly indicate medicines was scarce and its access very limited; four decades the specific therapeutic alternatives recommended for all medicines later, prescribers face an overflow of information which mixes listed with a square box, effectively allowing all square box listings to biased and low-quality studies with relevant evidence. be qualified (WHO, 2020b). This will overcome inconsistency in Additionally, a plethora of me-too medicines have entered the recommendations and address the uncertainty experienced by market, many of them without showing clear differences in country-level decision makers in interpreting some listings with a efficacy or safety over the competitors, yet often at higher square box symbol in the traditional print version of the list. costs. Finally, the appearance of biologic products and their Recently, the Model List has adopted inclusion criteria for biosimilars has changed some paradigms of the chemical quality-assured biosimilars of listed biologic medicines in order to medicines and worsened the affordability of essential medicines support both their therapeutic equivalence and potential at country level. Therefore, it is timely to perform an updated interchangeability. Efforts to identify and address the issues and review of the square box concept, definition and listings at the barriers to interchangeability of biologic medicines to improve next update of the Model List in 2021. access and affordability are also warranted. This includes tackling Within this panorama, guidance provided by WHO new approaches to develop, license, and monitor biosimilars to through the Model List on therapeutic equivalence within a improve efficiency, accelerate access, and reduce uncertainties about pharmacological class and interchangeability of medicines will their use. It is also relevant to explore different types of switching— support countries to make evidence-based informed choices and from an originator product to a biosimilar (or vice versa) or between avoid listing redundant me-too products with the same efficacy biosimilars—and if there are implications in terms of efficacy, safety and safety profile. In the case of biological products, the inclusion or immunogenicity issues. Recommendations issued by the Expert of biosimilars on the Model List as therapeutic alternatives to Committee might target which medicines can be identified as reference biologics can serve to improve affordability of alternatives, how the switch can be implemented (e.g. prior to the otherwise expensive treatments being considered for inclusion start of a biological treatment or during prolonged treatment) and on national essential medicines lists by stimulating market policies related to interchangeability. For instance, there are multiple competition and introducing opportunities for better value levels at which switching can be enacted: by the physician, by the procurement. Utilization studies of access and use policies of pharmacist, or by the healthcare system (Barbier et al., 2020). medicine classes would enable a better understanding of the Recommendations could clarify cases in which the switch should impact of the therapeutic equivalence and interchangeability, be under the responsibility of the treating physician, cases in which helping countries to better respond to the strategic opportunities the patient can safely switch among biologic and biosimilar and challenges being faced. medicines (e.g. insulins), and cases in which the switch is automatic (i.e. without consulting the prescriber). Automatic switching might allow for optimal allocation of resources, given the potential or actual associated cost-reductions (Jensen AUTHOR CONTRIBUTIONS et al., 2020). BC, LM, and NM contributed to the conceptualization of the review. BC, LM, and AF researched and wrote the manuscript. NM was the Secretary of the WHO Expert Committee on Selection and Use of CONCLUSIONS Essential Medicines between 2015 and 2020 and an employee of the World Health Organization, Geneva, Switzerland, at the time of This review aims to clarify the interpretation and practical writing of this paper. All authors contributed to the article and application of square box listings of essential medicines to approved the submitted version. REFERENCES Technologies in Health). 18 January 2017. Available at: https://www.ncbi.nlm. nih.gov/books/NBK442045/ (Accessed March 27, 2020). Aronson, J. K., and Green, A. R. (2020). Me-too pharmaceutical products: History, D’Amore, C., Da Cas, R., Rossi, M., and Traversa, G. (2016). Switching Between definitions, examples, and relevance to drug shortages and essential medicines Epoetins: A Practice in Support of Biosimilar Use. BioDrugs 30 (1), 27–32. lists. Br. J. Clin. Pharmacol. doi: 10.1111/bcp.14327 [Epub ahead of print] doi: 10.1007/s40259-015-0155-0 Barbier, L., Ebbers, H., Declerck, P., Simoens, S., Vulto, A. G., and Huys, I. (2020). Ebbers, H. C., Muenzberg, M., and Schellekens, H. (2012). The safety of switching The efficacy, safety and immunogenicity of switching between reference between therapeutic proteins. Expert Opin. Biol. Ther. 12 (11), 1473–1485. biopharmaceuticals and biosimilars: a systematic review. Clin. Pharmacol. doi: 10.1517/14712598.2012.711308 Ther. doi: 10.1002/cpt.1836 [Epub ahead of print] Faccin, F., Tebbey, P., Alexander, E., Wang, X., Cui, L., and Albuquerque, T. CADTH (2017). Switching from Innovator to Biosimilar (Subsequent Entry) (2016). The design of clinical trials to support the switching and alternation of Infliximab: An Updated Review of the Clinical Effectiveness, Cost- biosimilars. Expert Opin. Biol. Ther. 16 (12), 1445–1453. doi: 10.1080/ Effectiveness, and Guidelines (Ottawa ON: Canadian Agency for Drugs and 14712598.2017.1238454 Frontiers in Pharmacology | www.frontiersin.org 6 September 2020 | Volume 11 | Article 578000 Cappello et al. Therapeutic Equivalence of Essential Medicines Hermanson, T., Bennett, C. L., and Macdougall, I. C. (2016). Peginesatide for the WHO (2005). “The selection and use of essential medicines. Report of the WHO treatment of anemia due to chronic kidney disease - an unfulfilled promise. Expert Expert Committee, 2005 (including the 14th Model List of Essential Opin. Drug Saf. 15 (10), 1421–1426. doi: 10.1080/14740338.2016.1218467 Medicines),” in (WHO Technical Report Series, No. 933) (Geneva: World Hogerzeil, H. V. (2004). The concept of essential medicines: lessons for rich Health Organization). countries. BMJ 329 (7475), 1169–1172. doi: 10.1136/bmj.329.7475.1169 WHO (2009). “The selection and use of essential medicines. Report of the WHO Jensen, T. B., Kim, S. C., Jimenez-Solem, E., Bartels, D., Christensen, H. R., and Andersen, Expert Committee, 2009 (including the 16th WHO Model List of Essential J. T. (2020). Shift From Adalimumab Originator to Biosimilars in Denmark. JAMA Medicines and the 2nd WHO Model List of Essential Medicines for Children),” Intern. Med. 180 (6), 902–903. doi: 10.1001/jamainternmed.2020.0338 [Epub ahead of in (WHO Technical Report Series, No. 958) (Geneva: World Health print] Organization). Lee, T. H. (2004). “Me-too” products–friend or foe? N. Engl. J. Med. 350 (3), 211– WHO (2011).WHO Medicines Strategy. Revised procedure for updating WHO’s 212. doi: 10.1056/NEJMp038215 Model List of Essential Drugs. Report by the Secretariat, EB109/8. In: (Geneva: Lu, Y., Hernandez, P., Abegunde, D., and Edejer, T. (2011). The World Medicines World Health Organization). Available at: https://apps.who.int/gb/archive/e/ Situation 2011 - Medicine Expenditures (Geneva: World Health Organization). e_eb109.html (Accessed March 27, 2020). NHS England (2019). What is a biosimilar medicine? (NHS England, United WHO (2015). “The selection and use of essential medicines. Report of the WHO Kingdom). Available at: https://www.england.nhs.uk/publication/what-is-a- Expert Committee, 2015 (including the 19th WHO Model List of Essential biosimilar-medicine/ (Accessed March 27, 2020). Medicines and the 5th WHO Model List of Essential Medicines for Children),” OECD (2010). Value for Money in Health Spending. OECD Health Policy Studies in (WHO Technical Report Series, No. 994) (Geneva: World Health (Paris: OECD Publishing). doi: 10.1787/9789264088818-en Organization). Schiestl, M., Stangler, T., Torella, C., Cepeljnik, T., Toll, H., and Grau, R. (2011). WHO (2017). “The selection and use of essential medicines. Report of the WHO Acceptable changes in quality attributes of glycosylated biopharmaceuticals. Expert Committee, 2017 (including the 20th WHO Model List of Essential Nat. Biotechnol. 29 (4), 310–312. doi: 10.1038/nbt.1839 Medicines and the 6th WHO Model List of Essential Medicines for Children),” Schneider, C. K. (2013). Biosimilars in rheumatology: the wind of change. Ann. in (WHO Technical Report Series, No. 1006) (Geneva: World Health Rheumatol. Dis. 72 (3), 315–318. doi: 10.1136/annrheumdis-2012-202941 Organization). 't Hoen, E. F., Hogerzeil, H. V., Quick, J. D., and Sillo, H. B. (2014). A quiet WHO (2019). “The selection and use of essential medicines. Report of the WHO revolution in global public health: The World Health Organization’s Expert Committee, 2019 (including the 21st WHO Model List of Essential Prequalification of Medicines Programme. J. Public Health Policy 35 (2), Medicines and the 7th WHO Model List of Essential Medicines for Children),” 137–161. doi: 10.1057/jphp.2013.53 in (WHO Technical Report Series, No. 1021) (Geneva: World Health Weise, M., Kurki, P., Wolff-Holz, E., Bielsky, M. C., and Schneider, C. K. (2014). Organization). Biosimilars: the science of extrapolation. Blood 124 (22), 3191–3196. WHO (2020a). Selection of essential medicines at country level: using the WHO doi: 10.1182/blood-2014-06-583617 model list of essential medicines to update a national essential medicines list. White, R. H., and Ginsberg, J. S. (2003). Low-molecular-weight heparins: are they (Geneva: World Health Organization). all the same? Br. J. Haematol. 121 (1), 12–20. doi: 10.1046/j.1365-2141.2003. WHO (2020b). WHO electronic Essential Medicines List (eEML) (beta version 1.0). 04196.x (Geneva: World Health Organization). Available at: https://list.essentialmeds. WHO Collaborating Centre for Drug Statistics Methodology (2020). ATC/DDD Index. org/. Available at: http://www.whocc.no/atc_ddd_index/ (Accessed March 27, 2020). WHO (1977). “The selection of essential drugs. Report of a WHO Expert Conflict of Interest: The authors declare that the research was conducted in the Committee, 1977,” in (WHO Technical Report Series No. 615) (Geneva: absence of any commercial or financial relationships that could be construed as a World Health Organization). potential conflict of interest. WHO (1983). “The use of essential drugs. Report of a WHO Expert Committee, 1983,” in (WHO Technical Report Series No. 685) (Geneva: World Health Copyright © 2020 Cappello, Moja, Figueras and Magrini. This is an open-access Organization). article distributed under the terms of the Creative Commons Attribution License WHO (2002). “The selection and use of essential medicines. Report of the WHO (CC BY). The use, distribution or reproduction in other forums is permitted, provided Expert Committee, 2002 (including the 12th Model List of Essential the original author(s) and the copyright owner(s) are credited and that the original Medicines),” in (WHO Technical Report Series No. 914) (Geneva: World publication in this journal is cited, in accordance with accepted academic practice. No Health Organization). use, distribution or reproduction is permitted which does not comply with these terms. Frontiers in Pharmacology | www.frontiersin.org 7 September 2020 | Volume 11 | Article 578000