II. Background

Pursuant to Section 351(i)(2) of the US Public Health Service Act (hereinafter, “PHS Act”), in order to receive authorisation for the marketing of a biosimilar product, an applicant is required to demonstrate to the FDA that: (1) the proposed product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; and (2) there are no clinically meaningful differences between the biological product and the reference product in terms of their safety, purity, and potency.

By comparison, the guidelines of the European Medicine Agency (hereinafter, EMA) on similar biological medicinal products emphasise that comparability studies are needed to generate evidence substantiating the similar nature, in terms of quality, safety and efficacy, of the similar biological medicinal product and the chosen reference medicinal product authorised in the EEA.Footnote ⁴ The EMA underlines that the guiding principle of a biosimilar development programme is to establish similarity between the biosimilar and the reference product by the best possible means, ensuring that the previously proven safety and efficacy of the reference medicinal product also applies to the biosimilar product.Footnote ⁵

A biosimilar product is additionally interchangeable with a reference productFootnote ⁶ when it has been shown to the FDA’s satisfaction that: (1) the product can be expected to produce the same clinical result as the reference product in any given patient; and (2) alternating or switching between the use of the reference product and the biosimilar product does not increase the risk to patients in terms of safety or efficacy vis-à-vis the risk without such alternation or switch.Footnote ⁷ These characteristics of interchangeable products mean they can be substituted for their respective reference product without the intervention of the prescribing doctor. Finally, related biological products are, simply put, biological products filed for approval, for which an approved product with the same drug substance name (the “core” name, see below) already exists.

Like chemically-derived drugs, biological medicines can be referred to by their proprietary (trademark) name or by their non-proprietary (proper) name, which identifies the product’s active substance. However, as a biosimilar and/or related medicine is not identical to its respective originator (ie originally approved) drug, the question arises whether, and how, non-proprietary naming should ensure differentiation between the originator, the related, and the biosimilar products.Footnote ⁸

In essence, the FDA guidance provides for complementing the non-proprietary name of each biological medicinal product with a product-specific identifier in the form of a four-letter suffix separated from the “core” name (ie the name identifying the active substance) with a hyphen. The suffix is an additional element intended to distinguish between an originator product, its related products, and its biosimilar products.Footnote ⁹ The FDA put forward four considerations that led it to adopt this particular format.Footnote ¹⁰ Firstly, this manufacturer-specific identifier would facilitate pharmacovigilance (ie measures to ensure drug safety, in particular after a product has been released onto the market) by helping to track “adverse events” (ie adverse effects of the drug) to a specific manufacturer, manufacturing site, or lot. This, in turn, would allow a more targeted remedial action. Addressing some industry groups’ scepticism about the need for a distinctive element in the non-proprietary name, the FDA notes that alternative identifiers (such as national drug codes or proprietary names) were not routinely recorded and therefore could not always be effectively used for tracking purposes. Secondly, the additional suffix contributed to a safer use of the drugs by preventing their inadvertent substitution. An originator (reference) biological medicine and its related and biosimilar medicines are not necessarily interchangeable among each other (in particular, there may be differences in indications or routes of administration), but a common non-proprietary name without an additional distinguishing identifier might create a false impression that they are, resulting in confusion and dosing errors.

Thirdly, the FDA believes that this format of an additional identifier, in particular its inclusion in a medicine’s non-proprietary name, promoted the routine use of the identifier in ordering, prescribing, dispensing, record-keeping and pharmacovigilance, thus contributing to the accomplishment of the first two objectives. Last, but not least, the application of the suffix to the originator as well as to related and biosimilar products also allowed to avoid biased perceptions as to the safety and effectiveness of related and biosimilar products.

III. Comment

While reactions to adding a distinctive suffix to a non-proprietary name were mixed, the FDA’s decision to favour suffixes, which are devoid of meaning, ie constitute, essentially, a random set of letters, appears to have attracted universal opposition from the industry since the time of FDA’s draft guidance of 2015. While the FDA now offers applicants an opportunity to propose ten variants of suffixes of their choice,Footnote ¹¹ it specifically recommends that the suffixes, among other things, not look similar to or otherwise connote the name of the licence holder.Footnote ¹²

While generally welcoming the framework proposed by the FDA, in 2015, the Alliance for Safe Biologic Medicines (hereinafter, ASBM), for example, opined that a “meaningful, intuitive suffix applied consistently to all products by a single manufacturer would be more memorable and thus easier for healthcare providers to use, limit proliferation of suffixes, and reduce the likelihood of juxtaposition or confusion”.Footnote ¹³ The Chairman of the Biosimilars Council, a division of the Association for Accessible Medicines (AAM, formerly known as the Generic Pharmaceutical Association, a US trade association of pharmaceutical industry companies), in turn, has previously questioned the entire idea of adding a distinctive identifier to non-proprietary names of biological medicines. It noted that FDA’s proposed framework conferred “no additional safety benefit, and in fact would require the healthcare professional to be armed at all times with a code-breaking reference”, while proper names without suffixes were “[…] safely and effectively utilised in EU, Canada, Australia and Japan”.Footnote ¹⁴

Indeed, in the EU, Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human useFootnote ¹⁵ does not set out any special naming conventions for biological medicinal products. It provides in Article 1(20), read in combination with Article 1(21), that the name of a medicinal product may be: (1) either an invented name not liable to confusion with the international non-proprietary name (hereinafter, INN) recommended by the World Health Organisation (hereinafter, WHO) or, if such name does not exist, with the usual common name; or (2) an INN/usual common name or scientific name accompanied by a trademark or the name of the marketing authorisation holder. Article 54(a) further provides that the outer packaging of medicinal products must contain the name of a medicinal product and, separately, its INN.

The European Biosimilars Group (hereinafter, EBG), a sector group of “Medicines for Europe”, an association representing the generic and biosimilars industry in Europe (formerly, European Generic Medicines Association), believes that this approach was “highly reliable and the model for the world”.Footnote ¹⁶ The EBG is convinced that the European model allowed reliable identification and traceability of medicines using already-existing identifiers (eg the brand name, company name, or lot number) and that there was no need in the EU for biosimilar products, whose comparability to a reference product in terms of quality, safety and efficacy were guaranteed, to be distinguished with additional signs.Footnote ¹⁷

This opinion is shared by the EU’s EMA, which believes that, in particular, a “biological qualifier scheme” recently developed by the WHO would not add value to the EU’s existing identification system because “biologicals have a well-established identification system in Europe”.Footnote ¹⁸ The WHO’s proposal seeks “to provide a uniform global means of identification to avoid the proliferation of differing national schemes”.Footnote ¹⁹ The proposal was released in January 2016 and lays down a framework similar to that put forward by the FDA. In particular, it provides for the introduction of a “Biological Qualifier” (hereinafter, BQ), which is a unique identification code distinct from the respective medicine’s INN and consisting of four consonant letters and, optionally, a two-digit checksum to be located immediately after the letters or between two groups of two letters each.Footnote ²⁰ Like the FDA’s suffix, the BQ will ensure traceability back to the manufacturer. In contrast to the FDA’s scheme, however, the BQ is not attached to the INN, the letters in the BQ are assigned automatically by an online system, and it is up to the individual regulatory authority to decide whether it wants to adopt the BQ system with or without the two-digit checksum.Footnote ²¹

While the FDA’s guidance remains silent on why the authority did not heed to the industry’s calls to use meaningful suffixes, the WHO explained that it eventually decided not to link BQs to applicants’ names because: (1) this would effectively make the BQ code a proprietary item; (2) over the years, mergers and acquisitions would result in a BQ code which represents one marketing authorisation holder being used by another; and (3) national regulatory authorities, when consulted, preferred a meaningless random code.Footnote ²²

Inconsistency in the naming conventions for biological and biosimilar medicinal products may prove a significant barrier to international trade. The dispositive issue, if a challenge were to be brought before the Dispute Settlement Body of the World Trade Organisation (hereinafter, WTO) would be whether or not biological and biosimilar medicinal products are “like products” under WTO rules. According to Article 2.1 of the Agreement on Technical Barriers to Trade (hereinafter, TBT Agreement), WTO Members must “ensure that in respect of technical regulations, products imported from the territory of any [WTO] Member shall be accorded treatment no less favourable than that accorded to like products of national origin and to like products originating in any other country” (emphasis added). Similar language is found in Article III:4 of the General Agreement on Tariffs and Trade 1994 (hereinafter, GATT), and has effectively been interpreted to mean products that are in a “competitive relationship”. In one WTO dispute, US – Clove Cigarettes, the Panel stated that, when dealing with a technical regulation, it did not believe that the interpretation of Article 2.1 of the TBT Agreement “should be approached primarily from a competition perspective” (instead, favouring a focus on the health objective of the measure).Footnote ²³ However, more recently, in US – Tuna II (Mexico), the Panel recognised the potential differences in interpretation between Article III:4 of the GATT and Article 2.1 of the TBT Agreement, but chose to nonetheless favour an analysis based on the competitive relationship between the products in question.Footnote ²⁴ Such analyses of whether products in question are “like products” under WTO rules are done on a case-by-case basis, but there is a possibility that the naming conventions put forward by the FDA may be inconsistent with relevant international trade rules.

Regardless, it appears at the very least that it imposes a significant burden on globally acting pharmaceutical companies and will likely cause higher costs, albeit a potentially minute benefit for health care providers and patients. As the WHO itself recognises, its efforts to establish uniform rules “will only be as useful as the breadth with which [they are] taken up globally”.Footnote ²⁵ A level playing field with compatible rules across the major markets, however, would be the best solution in view of the public health objectives of those measures.

IV. Conclusion

While the FDA’s rules appear generally compatible with the WHO’s proposal, some important jurisdictions, such as the EU, may be unwilling – perhaps, for a lack of objective need – to follow this approach and to adopt a similar system for their market and their producers. It is, therefore, for relevant authorities to ensure that the requirements they set in this area are proportionate to the objectives pursued and do not create unnecessary impediments for globally acting pharmaceutical companies, and do not negatively affect patients’ access to advanced medicines.