Regulatory Perspectives on Biopharmaceuticals for Chronic Inflammatory Diseases in North Africa: A Narrative Review

2.1. Background/Definitions

Biologic agents are large molecules derived from living cells, usually manufactured using recombinant DNA or other biotechnologies. These agents (i.e., reference, originator, or innovator products) have greater complexity than chemically synthesized drugs because of their structural heterogeneity and specific activity within biologic systems, and their cost is usually higher [5, 14, 15]. Biologic Disease-Modifying AntiRheumatic Drugs (bDMARDs) such as anti-TNFα agents are very effective in the treatment of chronic immunoinflammatory diseases [4, 16, 17], but access is limited in many regions, including North Africa, partly because of cost constraints [18, 19].

Pharmaceutical companies are developing biosimilar versions for regulatory approval and introduction into global markets. Because of the natural inconsistencies in biologic sources and the unique, intricate (and usually proprietary) processes involved in engineering biologics, biosimilar manufacturers are unable to precisely replicate reference products [20]. Rigorous evaluation of biosimilars is thus required to establish their similarity to reference products in chemical structure, biologic activity, and clinical profile.

Although currently available in some countries, intended copies (i.e., non-comparable biologics or biomimics) are not supported by adequate evidence of comparability with reference products and fail to satisfy the requirements for biosimilarity established by regulatory authorities [13]. Certain intended copies have received regulatory approval based on generic drug standards [13].

2.2. Regulatory Pathways

Generic drugs are typically small, easily characterized molecules manufactured by chemical synthesis to produce exactly the same molecules as their respective reference products. Therefore, the demonstration of bioequivalence between generic and reference products in bioavailability studies is sufficient to assume therapeutic equivalence [10]. However, this approach is inappropriate for biosimilars as reference biologics are larger, more complex molecules that are more difficult to characterize and have clinical profiles that may be influenced by the manufacturing process. Consequently, biosimilar agents are not considered generics of biologics and are required to undergo more extensive investigation than generic drugs to obtain regulatory approval. To demonstrate biosimilarity, differences between biosimilar and reference products can be no greater than those expected between different batches of the same reference product and cannot affect the biosimilar’s safety or efficacy.

In 2009, the WHO Expert Committee on Biological Standardization established global guidelines for evaluation and regulation of biosimilars [10, 21], which are reflected in a broad range of regional/national regulatory standards (Table 1). The WHO authorization process for biosimilars requires data from stepwise comparability exercises, including quality, non-clinical, and clinical studies. Similarly, for the EMA, comprehensive comparability studies must be conducted to demonstrate high similarity between the biosimilar and reference product in structure, biologic activity, safety, immunogenicity, and efficacy (Fig. 1) [11, 20]. In the US, licensure by the FDA requires a robust characterization of the biosimilar based on a “totality of evidence” [22, 23], with sufficient clinical data to support the biosimilar’s “safety, purity, and potency” when administered for one or more of the indications of the reference product.

2.3. Currently Approved Biosimilars for Chronic Inflammatory Diseases (EU/US)

Several biosimilars of the reference products adalimumab, etanercept, infliximab, and rituximab have been approved by the EMA or FDA, and many others are currently under review or in development (Table 2). In addition, biosimilars or intended copies of these reference agents are marketed globally or are in a pre-market development phase outside the EU and US (Table 3).

3.1. Algeria

Biosimilar legislation is expected to be introduced soon in Algeria, based largely on the work of the country’s expert committee in rheumatology. Launched in 2017 to oversee new product registration and approval, the National Agency of Pharmaceutical Products (ANPP) includes several expert committees of different specialties assembled to examine biosimilar registration applications. Relying in part on the recommendations of the WHO, EMA, and FDA, the ANPP will confirm that registered products satisfy biosimilarity, quality, efficacy, and safety standards; scrutinize manufacturing/marketing sites; and review post-marketing pharmacovigilance plans.

The Algerian Ministry of Health, Population, and Hospital Reform (MSPRH) routinely schedules meetings to allow review and discussion of product dossiers (including information on manufacturing, clinical/non-clinical study findings, and pharmacovigilance monitoring) by expert committee members. Meetings on biopharmaceuticals for rheumatic diseases include rheumatologists and other specialists involved in managing approved biologic/biosimilar products in their fields. The committee sends decisions regarding product approval/rejection to the Directorate of Pharmacy of the MSPRH, which makes the final decision and subsequently notifies applicants.

Biosimilars used in hematology, oncology, diabetology, and endocrinology have already been introduced in Algeria. In rheumatology, although several dossiers have been submitted, only a biosimilar of infliximab (Remsima^®) has received marketing authorization (in 2017).

3.2. Morocco

In the absence of laws or regulations on the use of biosimilars or intended copies, the Moroccan Drug and Pharmacy Directorate approves registered agents for chronic rheumatic diseases based on the opinion of an expert committee, including rheumatology/internal medicine professors and pharmacists. These experts examine evidence related to the product’s manufacturing, structure and biological activity, safety/efficacy demonstrated in clinical studies, and plans for post-marketing pharmacovigilance. The Directorate’s assessment is sent to the Moroccan Ministry of Health, the body responsible for final decisions regarding approval and pricing. In 2015, the Ministry of Health indicated that biosimilars are a better alternative for patients from a financial standpoint without providing more specific guidance. Remsima^® is currently the only biosimilar authorized in Morocco.

The national safety institution and public/private insurance companies in Morocco currently provide reimbursement for biologic therapies according to treatment guidelines published for rheumatoid arthritis and ankylosing spondylitis, and as established by vthe Moroccan Society of Rheumatology [25, 26]. In these guidelines, biosimilars are mentioned as TNF-inhibitor options, with the same indications as the reference products, but no switching recommendations are offered.

3.3. Tunisia

The Tunisian Directorate of Pharmacy and Medicine is ultimately responsible for regulatory submissions and authorization of new products in Tunisia. The assessment process is multi-layered, involving the National Medicine Control Laboratory, specialized scientific commissions, and the Technical Committee for Proprietary Medicinal Products. With national regulations on biosimilars lacking, the Tunisian authorities apply procedures recommended by the WHO, EMA, and FDA. Several biosimilars for other diseases have been approved in Tunisia (e.g., erythropoietin, filgrastim, and somatropin biosimilars). Remsima^® was the first biosimilar for rheumatic disease to be introduced in Tunisia, generating discussion about its possible exclusive use given the country’s current socioeconomic situation. Tunisian authorities recently revealed plans to approve the least expensive product, i.e., Remsima^® or Remicade^®.

The Tunisian League Against Rheumatism (LITAR) and the Tunisian Gastroenterology Society have recommended that safe and effective treatments be made available to Tunisian patients at the lowest cost possible. However, all new medications must be introduced with caution to ensure patient safety. These societies are developing a biosimilar position paper based on clinical study findings, relevant policies of other rheumatology/gastroenterology societies, and the country’s current economic circumstances. Biosimilar approval and use should be based on multiple factors, including safety, efficacy, and traceability/interchangeability. While the value of introducing biosimilars in Tunisia is recognized, a strict legal and regulatory framework must be in place and prescription of biologic/biosimilar products must remain a clinical decision, made in consultation with patients and in consideration of possible health consequences, safety concerns, and economic impact. LITAR does not approve switching a patient who is stable on a biotherapy to a biosimilar to reduce costs without prior consent of the prescriber and patient. Biologic-to-biosimilar switching requires careful consideration on a case-by-case basis, not automatic implementation. Interchangeability studies have demonstrated safety and efficacy when switching from reference product to biosimilar, but not the inverse. Moreover, the societies have reservations about the importation of products that have not undergone rigorous quality control, e.g., intended copies.

4.1. Adherence to Established Regulatory Biosimilarity Standards

Regulatory pathways for biosimilar approval by the EMA and FDA require the submission of data from head-to-head clinical studies carefully designed to rule out the possibility of clinically relevant differences between biosimilar and reference products [11, 23]. Ideally, the pathways established by these large regulatory authorities will be universally adopted at regional and national levels around the world, including North Africa. Biosimilar approval based on international criteria has been shown to instill confidence among clinicians [27]. However, achievement of such harmonization will be challenging given the profound cultural/political/social/economic disparities among continents, countries, and regions.

In North Africa, as elsewhere, adoption of legislation defining the pathway for biosimilars should ideally precede establishment of the regulatory framework for the biosimilar approval process. Acceptance of a statutory basis for this process will help ensure that stakeholders have the opportunity to offer their input and expertise in developing and evaluating fundamental principles. Moreover, subsequent changes to regulation or guidance would need to be consistent with the statute, providing stakeholders with a stable, predictable regulatory environment.

Many North African rheumatologists are aware of the potential cost/access benefits of biosimilars but may not favor biosimilar authorization unless manufacturers have received authorization from other globally respected regulatory agencies. Intended copies with limited or non-comparable data are not expected to receive market authorization in this region because they do not satisfy stringent regulatory approval criteria and may pose a threat to patient safety.

4.2. Biosimilar Data Availability and Comparability

A substantial number of biosimilar products, including biosimilars of adalimumab, infliximab, etanercept, and rituximab, do not have published the evidence of structural and functional comparability from non-clinical studies [28]. Additionally, much of the evidence from registration studies has only been published in conference abstracts. Release of findings from biosimilar trials in the public domain as full-text publications is essential to ensure that HCPs and patients are well informed.

Clinicians may have safety concerns related to biosimilar immunogenicity, as small or indiscernible differences arising during production may result in antidrug antibody formation [28]. Differences in immunogenicity between biosimilars of monoclonal antibodies or fusion proteins and their reference products may be especially likely because of the large size and complexity of the reference biomolecules and post-translational modifications. Considerable differences in immunogenicity rates among biotherapies used to treat chronic inflammatory diseases have been reported in some clinical trials, with the highest rates seen with adalimumab, infliximab, and the infliximab biosimilar CT-P13 [29].

In a recent randomized controlled trial, Emery et al. observed a significant difference in the incidence of antidrug antibodies in patients treated with reference product versus biosimilar (SB4) etanercept, although this difference was not considered clinically relevant [30]. By contrast, in another study, the incidence of antidrug antibody development was consistent among patients receiving reference product and biosimilar (SB2) infliximab [31]. Immunogenicity can result in reduced therapeutic levels and loss of efficacy after months or years of treatment, requiring dose increases and/or shortening of dosing intervals in some patients. However, despite the frequency and clinical consequences of biologic immunogenicity, relatively limited data have been published on immunogenicity in biosimilar clinical trials.

The comparability of efficacy between biosimilars and anti-TNFα agents has also raised questions. In phase III comparative studies, biosimilars of reference TNF inhibitors satisfied pre-specified criteria for equivalence in efficacy in patients with rheumatoid arthritis [30] and plaque psoriasis [32]. However, higher treatment response rates were observed with both biosimilars and their reference biologics in recent comparative clinical trials than with the reference biologics in pivotal registration trials [33]. Although these differences in efficacy may have resulted from differences in study design and/or patient characteristics, the findings warrant additional research. Because definitive conclusions cannot be drawn from a comparison of findings from clinical trials with different designs and methodology, a strong argument can be made in favor of standardization of future biosimilar studies [34]. Greater uniformity across biosimilar clinical studies may also increase HCP confidence in these biopharmaceuticals.

4.3. Interchangeability, Switching, and Substitution

Future regulations for biosimilar approval in North Africa may include guidelines on interchangeability, switching, and substitution among biologic and biosimilar products. According to the EMA, interchangeability is defined as the possibility of replacing a reference product with a biosimilar (or the inverse) or replacing one biosimilar product with another [20]. The clinician may decide to exchange one product for another, with the same therapeutic intent, a practice known as “switching.” Alternatively, one interchangeable product may be dispensed instead of another at the pharmacy level without consultation with, or the consent of, the prescriber, which is known as “substitution.”

Because established regulatory authorities such as the WHO and EMA do not require switching studies for biosimilar approval and do not provide guidance on this practice (Table 1), the effects of switching are often not evaluated in biosimilar registration studies [35]. However, the FDA does require the submission of data on alternating (one transition) and switching (three transitions) to support these practices [36].

In a 2012 review, Ebbers et al. found no evidence of safety concerns related to switching from biologic to biosimilar agents in clinical studies or post-marketing surveillance [37]. Similarly, in a 2017 review, Moots et al. found no differences in safety/efficacy outcomes with or without switching between the reference biologics adalimumab, infliximab, etanercept, and rituximab and their biosimilars [35]. The authors nonetheless concluded that the available evidence is qualitatively and quantitatively insufficient to confirm the safety /efficacy of switching. In systematic literature reviews of randomized controlled trials and real-world studies, Numan et al. [38] and McKinnon et al. [39] reached similar conclusions with regard to non-medical switching, which occurs as a result of non-medical concerns such as treatment costs. The studies conducted in patients with chronic inflammatory diseases were not adequately designed to assess efficacy and safety after non-medical switching, and evidence from these studies was often inconsistent and inconclusive. Even when assessing only the 17 randomized controlled trials found in their literature searches (January 2012 to February 2018; (Table 4), Numan et al. found that none satisfied all of the study design elements considered important for robust switching studies [38].

Given that the goals of switching from a stable biologic to a biosimilar are cost savings and broader access, because biosimilars have not demonstrated better safety or efficacy, regulatory agencies will need to determine whether they may be substituted for reference biologics for non-clinical reasons. To date, in the EU, no country has explicitly authorized the automatic substitution of products from different manufacturers without clinician/patient involvement. In many regions, including North Africa, pharmacy-level substitution is generally not considered appropriate unless stringent legal and regulatory criteria are satisfied in addition to biosimilarity requirements. Prescribing clinicians are also supported as primary decision-makers, with the right to prescribe the most appropriate product based on their clinical judgment, scientific evidence, and individual patient profiles, and to override automatic substitution not deemed in a patient’s best interest.

4.4. Pharmacovigilance

Plans for post-marketing monitoring and risk-management activities, at least as rigorous as those for reference biologics, are essential for biosimilar approval [10, 11, 20, 23], and are expected to be mandatory in the legal/regulatory framework for biosimilar authorization in North Africa. As with all medications, adverse events related to biosimilar use in daily practice can only be detected through continuous post-approval surveillance at the clinical level [40]. The importance of post-marketing surveillance in identifying safety concerns related to intended copies was demonstrated with the rituximab intended copy Kikuzubam^®, as reports of anaphylactic reactions in rheumatology patients switched to this biosimilar in the Mexican pharmacovigilance program resulted in its removal from the market [41, 42].

Over the past few decades, awareness of the importance of pharmacovigilance to the healthcare system in Africa has increased [43]. Morocco and Tunisia were among the first African member countries of the WHO International Drug Monitoring Programme (1992–1993), and Algeria subsequently became an associate member. In North Africa, post-marketing monitoring of drug safety is hindered by several common obstacles, including HCPs’ lack of awareness of surveillance requirements and reporting forms, unfamiliarity with product labeling, inability to identify adverse events, and hesitation to report events because of guilt or fear of legal action. Improved HCP education/training and greater financial/logistical support for pharmacovigilance systems are needed to overcome these challenges.

4.5. Biopharmaceutical Nomenclature

Biosimilars require names that can be easily distinguished from those of reference biologics to ensure accurate identification and effective pharmacosurveillance, and to reduce the risk of unintended substitution of non-interchangeable products. Guidance on biologic and biosimilar names has been provided by the WHO, EMA, and FDA [20, 44, 45], as summarized in Table 1. To date, recommended approaches are inconsistent, which may lead to confusion, but further refinement is expected.

4.6. Accessibility and Cost Issues

Since the first biosimilar (Omnitrope^®) was approved in the EU in 2006, the biosimilar pipeline has seen remarkable growth. Introduction of biosimilar products is anticipated to reduce costs and expand patient access in public and private healthcare systems [46, 47]. Although the difference in price between reference and biosimilar products may be <30%, such a cost saving is sufficient to generate considerable interest, particularly in countries with negative economic forecasts. In addition to wider access for patients of all socioeconomic levels, competition in biosimilars may lead to lower prices of the reference biologics. In countries facing a difficult economic situation, such as Tunisia, competitive pricing of reference biologics is particularly important.

Accessibility to healthcare and treatment is problematic across North Africa, but each country has specific challenges. In Algeria, the state provides free treatment for the entire population, regardless of socioeconomic status, but costs must remain below a specified threshold. In Morocco and Tunisia, patients covered by the social security system are entitled to receive free treatment. However, the number of patients requiring specialist care and biopharmaceuticals affects access, so that a cost reduction of only 20-30% for biosimilars is expected to improve access. Nonetheless, rheumatologists are cautious that lower cost for, and increased patient access to, biosimilars is not achieved at the expense of patient safety.