Clinical and Regulatory Challenges and Opportunities for Monoclonal Antibodies in Low- and Middle-Income Countries: Lessons from COVID-19 and Beyond

Monoclonal antibodies are an effective and growing class of pharmaceuticals for the treatment and prevention of a broad range of non-communicable and infectious diseases; however, most low- and middle-income countries have limited access to these innovative products. Many factors contribute to the global inequity of access to these products; however, in this report, we focus on clinical and regulatory complexities as further highlighted by the coronavirus disease 2019 pandemic. Despite a higher prevalence of many diseases in low- and middle-income countries, only 12% of clinical trials for monoclonal antibodies are conducted in these countries. Additionally, only a fraction of the available monoclonal antibodies in the USA and European Union are authorized for use in low- and middle-income countries. Through learnings from desk research and global symposia with international partners, we present recommendations to harmonize processes and facilitate regional and international collaborations for more rapid approval of fit-for-purpose innovative monoclonal antibodies and biosimilars in low- and middle-income countries.


Introduction
The 21st century has witnessed the greatest boom in medical technologies along with a significant disparity in access to life-saving medicines around the world. The path to approval for innovative medicines is often paved with complex regulatory and clinical trial hurdles, and this is clearly seen with the class of pharmaceuticals known as monoclonal antibodies (mAbs). Monoclonal antibodies are based on natural antibodies, which are proteins that the body produces to defend itself against disease. Monoclonal antibodies are expressed in the laboratory using clonal cell lines and can be developed and commercialized to treat and prevent diseases. The first mAb product was licensed more than 30 years ago [1]. Since then, millions of people have benefitted from mAb-based treatments and preventative treatments for diseases with high rates of morbidity and mortality. While monoclonal antibody products have been increasingly and consistently approved in high-income countries (HICs), low-and middle-income countries (LMICs) have licensed far fewer mAbs and have not fully reaped the benefits of these innovative products ( Table 1).
The global response to coronavirus disease 2019 (COVID-19) has raised awareness to the inequity in access to mAbs in LMICs. Despite unprecedented innovation, speed, and collaboration in the research and development of therapeutics, there has been limited access to mAbs for treating COVID-19. As of late 2022, there were six severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific mAb products licensed for the treatment of COVID-19 in the USA and Europe; however, only a handful of them are currently licensed in LMICs (Table 2). With the continuous evolution of new variants of concern of the SARS-CoV-2 virus and their rapid spread and global prevalence, first-generation mAbs that may be accessible in LMICs several months/years after their licensure in HICs may not be effective against current circulating strains [9]. Moreover, traditional manufacturing strategies and business models based on low-volume high-cost products for HICs were likely used to supply mAbs for SARS-CoV-2 during the peak of the pandemic, as suggested by the high price of these mAbs. Specifically, Regeneron's Ronapreve was priced at $2100 per dose in the USA, $2000 per dose in Germany, and $820 per dose in India [10]. These approaches have not resulted in broad access, which highlights the need to apply alternative technological and business solutions to address global needs without significant delays [11,12]. The time it takes for global access to innovative mAbs, particularly in LMICs, poses a threat to global health for COVID-19 and many emerging infectious diseases.
Equitable access to mAbs is a complex issue, impacted by many inter-related factors including regulatory challenges, clinical study requirements, manufacturing capability and capacity, acceptability of the product in local populations, medical care infrastructure, intellectual property, and cost. In the context of these challenges, we compare the state of clinical development and regulatory hurdles in high-, middle-, and low-income countries to offer insights and recommendations to enable access to mAbs in LMICs, with some focus on Africa.

Inclusivity in Clinical Trials
Global authorization of innovative products including mAbs depends in part on the success of regional clinical trials and licensures. For any product to achieve a full global impact, it is important to include subjects in different geographic regions, demographic groups, and socioeconomic levels during a clinical evaluation. In addition, regional infrastructure, comorbidities, and cultural traditions vary widely and must be considered as factors that impact the execution of clinical studies. Low-to middle-income countries are often severely impacted by both infectious diseases and genetic disorders, which are not as prevalent in many high-income regions [15]. For instance, in many African countries, HIV and tuberculosis are highly endemic, while these diseases are less prevalent in most HICs. However, there is a well-recognized discrepancy between clinical research priorities and disease burden. Most clinical trial research focuses on diseases that have higher rates of morbidity and mortality in HICs [16]. Overall, about one-third of all interventional clinical trials occur outside the USA and European Union (EU); however, for mAbs, only 12% of clinical trials are ex-USA and ex-EU 1 . Because of the higher incidence of certain conditions in LMICs, clinical sites are sometimes included to facilitate expedient demonstration of efficacy with a lower sample size than would be required in a low-burden setting. However, once these products are licensed, they are not systematically made available in these settings.
For example, sickle cell disease (SCD) is an inherited red blood cell disorder that affects over 12 million people, mostly with origins in sub-Saharan Africa, India, Saudi Arabia, and Mediterranean countries. In Africa, an estimated 50-80% of infants born with the disorder die before the age of 5 years [17]. In the USA where SCD is rare, Novartis' mAb product Adakveo® (crizanlizumab) was first licensed for the disease in 2019 [18]. In countries in West, Central, and East Africa, the prevalence of the sickle cell gene is between 10% and 30%, and up to 45% in Uganda [19]. Crizanlizumab is also being evaluated in a phase II safety and dose-finding clinical study in pediatric patients under the age of 16 years in the USA [20]. While efficacy studies are ongoing in several African countries, including Ghana, Kenya, and South Africa, 3 years after approval in the USA, crizanlizumab is not yet licensed in African LMICs with a high prevalence of SCD [21]. Some targeted diagnosis and treatment program initiatives are being sponsored by Novartis in African countries with the SCD prevalence up to 1-2%; however, broader licensure and availability in the region are still lacking [22].
Another important example is clinical trial inclusion for respiratory syncytial virus (RSV). Respiratory syncytial virus is a leading cause of deaths in children during the first year of life, with 97% of deaths from RSV occurring in LMICs [23]. Currently, the only licensed mAb in LMICs to prevent infections from RSV, palivizumab (Synagis®), for high-risk infants and high-risk children under 2 years of age, has limited access and requires 5-monthly doses administered intramuscularly, which is challenging to administer in resource-limited contexts. There are currently four mAbs for RSV in clinical trials: one biosimilar of palivizumab and three innovative next-generation long-acting mAbs (nirsevimab, clesrovimab, and RSM01) with greatly improved half-lives, requiring a single dose and lower product and delivery costs [24]. While some of the late-stage trials are being conducted in lower-and upper-middle income countries (China, South Africa, Argentina, Colombia, Malaysia, Mexico, Peru, Philippines, Thailand, Türkiye), there are no trials listed in Nigeria, a country with the highest RSV incidence and where palivizumab is unavailable [24,25]. Nirsevimab was approved by the European Medicines Agency (EMA) in November 2022 for all infants and children under 2 years of age, but no pricing or access plans for LMICs have been disclosed [26]. The palivizumab biosimilar mAb has the potential to be a lower cost product to enable broader access in LMICs; however, its development is significantly behind long-acting RSV mAbs that better align with preferred product profiles for LMIC use.
Another current example is the limited involvement of LMICs in clinical trials for mAbs for COVID-19. Of the more than 4500 trials currently exploring drug treatments (including mAbs) for COVID-19, only about 274 are registered to take place in Africa [27]. Four of the six currently licensed SARS-CoV-2-targeted mAbs are in clinical trials in Africa. However, only sotrovimab (GlaxoSmithKline and Vir) is undergoing testing in Africa solely sponsored by private industry, with all the other trials supported by international global health collaborations [28]. In March 2020, the World Health Organization (WHO) launched its flagship Solidarity trial, a global study of four potential COVID-19 treatments including mAbs. Only two African countries participated in the first phase of the study [29] and, in late 2022, the trial expanded to include eight more African nations [30]. Collaborative efforts such as the ANTICOV, a program coordinated by the non-profit Drugs for Neglected Diseases initiative, are focused on COVID-19 treatment using repurposed drugs that would be accessible in low-income nations. This is a multi-center, open-label, randomized, adaptive platform trial that, as of November 2022, has randomized 1753 participants across 23 sites in the Democratic Republic of the Congo, Burkina Faso, Guinea, Mali, Ghana, Kenya, Mozambique, Brazil, Sudan, Tanzania, Côte d'Ivoire, and Ethiopia [31]. It aims to eventually recruit 3000 participants across 13 countries. However, their testing is limited to repurposed small molecules, and currently, no new mAbs responsive or cross-reactive to circulating/emerging strains of COVID-19 are being tested in this study.
Small-scale clinical trials for innovative mAbs have been successfully initiated in LMICs for the treatment or prevention of HIV, COVID-19, RSV, malaria, and SCD [32]. However, some doubts still linger in the scientific community regarding the ability of LMICs to conduct large-scale, more complex clinical trials for innovative biological products [33]. Recently, a large and complex study, referred to as the Antibody Mediated Prevention study (NCT02568215), evaluating an innovative mAb for HIV prevention, was successfully conducted in seven countries in East and Southern Africa (South Africa, Malawi, Botswana, Kenya, Zimbabwe, Tanzania, and Mozambique). The Antibody Mediated Prevention study was a phase IIb trial enrolling almost 2000 sub-Saharan African women to test the VRC01 mAb for HIV prevention. During the study, 38,490 clinic visits were completed with a retention rate of 96%, and 16,807 drug infusions were administered with an adherence rate of 98% [34]. Although this mAb did not meet its primary endpoint, this proof-of-concept, large-scale mAb study demonstrated the feasibility of conducting complex trials involving intravenous infusions of mAbs in high-incidence populations in sub-Saharan Africa [34].

Regulatory Ambiguity
In addition to the discrepancy in where trials are conducted, each country has its own drug regulatory authority with its own regulations for approving clinical trial protocols, overseeing the conduct of clinical trials, and approving new medicines. Drug regulatory authorities have important quality assurance responsibilities in the development of new drugs, as well as in the production, distribution, labeling, and pharmacovigilance for medicines.
Ethical review and approval in some countries may involve a series of bodies, including institutional and national review boards prior to final approval by a national drug regulatory authority. These sequential processes can lead to substantial delays. Multiple research ethics committees reviewing the same protocol for the same site, with both in-country and international committees engaged, can lead to conflicting findings without a clear definition of decision-making authority [35]. There are many complex and sometimes undefined or absent local regulations for the development and testing of new mAbs, which may be further confounded by multiple layers of approvals for clinical trials. All these factors can make it difficult to obtain approval in a timely manner. Differing standards for the conduct of trials across countries also make it difficult to conduct multi-center and multi-country trials (Table 3).
An additional compounding factor is the limited availability of biorepository facilities, which means specimens obtained from clinical trials in LMICs may need to be exported to another country for further research. Clear regulatory guidance is required for timely exportation and to prevent exploitation of any future use of human biological specimens. Differences in the approach to the storage, use, and export of clinical samples is seen across the globe, which range from the requirement for prior ethics approval for each new evaluation to the requirement for mandatory in-country collaborators. Material transfer agreements are required in many settings governing the storage of samples, ethics requirements, identification of specific samples, and participant's rights to withdraw samples from the storage facility [35]. Monoclonal antibody studies require complex assays for pharmacokinetic, anti-drug antibody,  [37]. An unspecified age of minors can lead to further ambiguity around informed consent and can complicate trials involving adolescents and young adults. These challenges can collectively lead to significant delays in clinical trial initiation, review processes, and increased costs. The COVID-19 pandemic has served as a stress test for drug regulators across the world, exposing weak spots in many regulatory authorities. In partnership with the Bill & Melinda Gates Foundation, Eli Lily offered to provide doses of bamlanivimab free of charge to Rwanda and Morocco [38]. However, prior to the pandemic, Rwanda had no formal guidance for emergency use of medicines. The Rwanda Food and Drug Administration introduced bamlanivimab for emergency use in February 2021 and only afterwards in May 2021 issued a draft for the Authorization for Emergency Use Products [39,40].
The use of mAbs for infectious diseases requires continual monitoring for the emergence of resistant strains, and delays in access can render mAbs inefficacious against circulating strains. For example, currently, Evusheld® (combination of tixagevimab and cilgavimab, AstraZeneca) is the only mAb that is responsive to the widely circulating Omicron BA.5 strain in the USA [41]. In India, there are currently two SARS-CoV-2-specific mAb treatments available from Regeneron (casirivimab and imdevimab) and Eli Lilly (bamlanivimab and etesevimab); however, these mAbs are not responsive to the currently circulating and predominant Omicron viral strains. In addition to mAbs specific to SARS-CoV-2, a mAb that is used to treat arthritis (tocilizumab) was added by the WHO to its list of treatments for COVID-19, and another mAb for psoriasis (itolizumab) has received Emergency Use Authorization (EUA) for patients with severe COVID-19 in India. However, the Indian regulatory agency, the Central Drugs Standard Control Organization, has received criticism for its handling of the mAb itolizumab (Alzumab™) for treating patients with COVID-19. Itolizumab is an anti-CD6 monoclonal antibody that was originally developed by Biocon, one of India's largest pharmaceutical companies, to treat psoriasis. The company was hopeful that the drug could be repurposed to manage the cytokine storm that frequently occurs in severe cases of COVID-19. The drug was tested on a small cohort of 30 patients, and from those results the Central Drugs Standard Control Organization granted an EUA to manage the cytokine release syndrome in patients with moderate-to-severe COVID-19. Criticism about the Central Drugs Standard Control Organization's actions in properly vetting itolizumab arose over concerns for its trial design, lack of transparency regarding the selection of the subject expert committee, and confusion about the laws granting EUA for a drug [42]. After the initial EUA approval, an Indian government taskforce established for the COVID-19 pandemic response rejected itolizumab from the national treatment protocol, demonstrating a lack of alignment and trust amongst governmental offices [43]. Interestingly, a phase III study to evaluate the safety and efficacy of itolizumab in patients hospitalized with COVID-19 was withdrawn prior to initiation in Columbia by the study sponsor Equilium Inc. [44]. The mAb did receive EUA in Cuba, but there are no ongoing or new trials in the public domain to evaluate this mAb for COVID-19 [45].
Despite these challenges, the expansion in access to some mAbs in LMICs is driven by the introduction of biosimilars, a biologic product that is approved based on demonstrating that it is highly similar to the original mAb and often available at a lower price compared with the original. Biosimilars are often produced by multiple manufacturers and commercialized as different brands [46]. Biosimilar antibodies have been essential in increasing access to rituximab, trastuzumab, infliximab, adalimumab, and bevacizumab for the treatment of non-communicable diseases. However, owing to their similar but not identical composition compared to innovative mAb products, biosimilars require significant investments in clinical development and specific regulatory approval guidelines. However, inconsistencies in these guidelines hamper access to these mAbs.
Today, most countries have approved specific regulations for registering biosimilars. For example, Indian regulatory authorities introduced specific guidelines for biosimilars in 2012. This led to a significant increase in mAb biosimilar approvals in India [47]. However, some LMICs lack clear and precise guidelines resulting in access delays (Table 4). Moreover, there is variation and ambiguity in the biosimilar guidelines, which may contribute to developer hesitation towards LMIC market entry. The non-acceptance of global clinical data and mandatory requirements for repetition of clinical studies in local populations by regional regulatory agencies can significantly increase development costs. In addition, a recent study found that the cost of biosimilar development is driven by clinical studies that require the inclusion of costly originator mAbs for comparison [48]. Acceptability of products by policy makers, healthcare providers, and patients in local populations is of critical importance; however, duplication of studies is likely to impact the overall biosimilar development process and approval timelines in these countries [49]. In April 2022, the WHO issued guidelines on the evaluation of biosimilars, including specific data requirements and considerations for licensing such products. It is expected that these WHO guidelines on the scientific principles for evaluating biosimilars will contribute to harmonizing global regulatory requirements, and, where possible, reach regulatory convergence. This would lead to streamlined and more rapid approval and assurance of the quality, safety, and efficacy of these products at more affordable prices [50].

Opportunities and Recommendations
In many LMICs, guidelines and approval processes for mAb products are protracted and often poorly defined. There is a need for effective regulatory processes to ensure product developers receive appropriate guidance in a timely manner to avoid delays in approvals and launches. Despite many barriers to clinical and regulatory development of mAbs in LMICs, COVID-19 has helped raise the level of global discourse. A series of meetings/symposia were convened by IAVI and international partners (Unitaid, Wellcome, Department of Biotechnology, India) to define and discuss potential solutions for regulatory and global access pathways to mAbs [54][55][56][57]. Here, we discuss learnings and recommendations to improve pathways for clinical studies, regulatory approvals, and access in LMICs emerging from those meetings (Fig. 1).

Centralization Across Regional Regulatory Agencies in Africa: Lessons from the EMA
In Africa, divergent regulatory frameworks across the continent at times necessitate the conduct of repetitive trials and increase the cost of developing biologics, including mAbs, which leads to delays in approval and a lack of widespread access. Formation of regional regulatory bodies can help address many of these hurdles including the lack of adequate human resource capacity in individual countries. To facilitate the development of mAbs in Africa, standardized development criteria and regulatory convergence by regions with well-defined and transparent guidelines and an efficient and predictable review process could accelerate product development, licensure, and access. To further streamline processes, regional regulatory reviews of non-clinical and clinical data can be simplified by either increased reliance on a single reference agency or multiple agencies in a single forum. Finally, a process that allows for open communication channels between product developers and regulatory authorities is needed to ensure adequate scientific advice can be given in a timely manner to inform the course of the development program.
In Africa, several regional harmonization efforts were introduced through the African Medicines Regulatory Harmonization initiative, to expedite market authorization of medical products and to facilitate the alignment of national legislative frameworks. Enabled by the African Union Model Law of domestication and implementation, this effort led to the formation of the Africa Medicines Agency (AMA) to mandate and coordinate a regional harmonization system [58]. One of the key goals of the AMA is to coordinate joint reviews of clinical trial applications for vaccines and complex pharmaceutical products such as mAbs. In parallel, bolstering local pharmaceutical production is a key pillar of the Pharmaceutical Manufacturing Plan for Africa [59]. Regional initiatives including the Partnership for African Vaccine Manufacturing, the mRNA Technology Transfer hub, and the newly inaugurated Africa Pharmaceutical Technology Foundation will also help to strengthen regional manufacturing capacity, which can help ensure supply security for the region [59]. While the AMA has yet to function at its full potential, there is an opportunity to form a central committee for a review of biologics through the AMA mechanism. However, legislation will need to be in place to allow for agreements to be applicable across the region to ultimately reduce the time to approval of mAbs in individual countries. A similar model has been successful across the EU, with centralized and mutual recognition procedures allowing for efficient approval of medicinal products. The centralized procedure requires pharmaceutical companies to submit a single authorization application to the EMA and allows the marketing of a medicine on the basis of a single EU-wide assessment and marketing authorization valid throughout the EU [60].
A centralized approach in Africa like the EMA could define regional priorities and enable a clear path for approval of relevant products. For example, clear and centralized Fig. 1 Recommendations to improve pathways for clinical development, regulatory approvals and access to mAbs in LMICs regulatory guidance on products for endemic diseases, local epidemics, and pandemics is needed. Pooling of resources from across the region could allow for teams to specialize in specific types of products, thus allowing individuals involved in this review to gain in-depth knowledge in their area of expertise as opposed to working across a wide breadth of pharmaceutical products. For example, standards for quality, manufacturing, reference biological products, and product safety and efficacy that have been set effectively in some regions could be adopted more broadly to simplify and enable the approval of biologics in other regions. Centralized regulatory approaches have been successful in the EU and are gaining momentum in Africa; however, they should also be considered in other regions of the world including Asia and South America where several reliance mechanisms between countries are already in place.

Collaborations and Reliance Across International Regulatory Agencies, Product Developers/Manufacturers, and the WHO
Leveraging collaborative processes for approval across mature regulatory agencies, policy bodies, and national regulatory agencies can break down regulatory barriers for LMICs. There are already some formal pathways in place to facilitate broader registrations of both innovative and biosimilar products in LMICs. These programs include the WHO's prequalification and collaborative registration programs, the EMA EU-Medicines4all pathway, Swissmedic (Switzerland), and the US President's Emergency Plan for AIDS Relief tentative approval. Swissmedic has an authorization procedure involving African national regulatory authorities and the WHO in the assessment process. This process incorporates regional considerations while accelerating marketing authorizations in Switzerland for Africa and elsewhere [61]. The Food and Drug Administration's expedited review of the President's Emergency Plan for AIDS Relief innovative HIV products is as short as 6 months. This program allows for tentative approval of generics and the sale of HIV products, still under US market exclusivity, in non-US markets [62]. The WHO's collaborative registration process enables expedited regulatory review and licensure of products that have been WHO prequalified or licensed by a regulatory authority of maturity level 3 in a network of 80 countries [63,64]. However, so far these programs have not been utilized to accelerate regulatory approvals and facilitate access to mAbs. To build capacity and collaborate at an international level, the EMA developed the EU-Medicine-s4all procedure to issue scientific opinions in collaboration with the WHO and non-EU national regulatory authorities. Its scope includes all medicinal products that are new or improved therapies for unmet needs, and diseases of major public health interest, to facilitate patient access in LMICs [65]. While this mechanism has been successfully applied for vaccines and small molecules, no applications for mAbs have been filed using these procedures. Such collaborative approaches should be considered for broader and more rapid regulatory approvals of mAbs [66,67]. The WHO prequalification was born of the need to ensure a supply of quality-assured health products in LMICs by assessing the quality, safety, and efficacy of a wide range of health products to prevent, diagnose, and treat priority diseases. Prequalification serves as a seal of regulatory approval for medicines to enable procurement agencies and regulators with limited capacity to license the prequalified medicines. The WHO prequalification has been a powerful enabler for financing, distribution, and access to other medicine types. For example, prequalification of drugs for malaria and firstline tuberculosis alone has enabled ~90% of market access in terms of total value [68]. For HIV, 51% of the market access to antiretroviral agents are WHO prequalified with 21% of those medicines relying solely on the WHO's recommendation for approval at the national level [69]. The recent and growing inclusion of prequalified mAbs expands the possibility of increased access to these products. The first mAb prequalified was Samsung Bioepis' biosimilar medicine, Ontruzant (trastuzumab) in December 2019, which is reported to be 65% cheaper than the originator product [70]. Although nine mAbs are included on the Essential Medicines List, only three distinct mAbs (trastuzumab and rituximab for cancer, tocilizumab for arthritis) from six manufacturers have been prequalified, and only one of these manufacturers (India's Biocon) is located in a LMIC [71]. The specific requirements for prequalification of biosimilar mAbs were outlined in a pilot procedure for prequalification of biotherapeutic products and similar biotherapeutic products, but the final guidance on prequalification of preventive mAbs has not yet been issued [72].
The WHO also supports good global reliance practices with the objective of improving the effectiveness and efficiency of regulation of medical products in LMICs. For example, the WHO is providing secretariat support to the South-East Asian Regulatory Network made up of 11 member states and several LMICs including India, Bangladesh, Bhutan, Nepal, Sri Lanka, Thailand, Maldives, Myanmar, Timor-Leste, and Indonesia [66]. The South-East Asian Regulatory Network is focused on developing regulatory collaboration, convergence, and reliance over shared regulatory issues and challenges. Similarly, in Latin America, the Pan American Health Organization has encouraged member states to rely on national and international regulatory agencies to minimize duplication, improve efficiencies, and strengthen regulatory capabilities to enable market authorizations. To navigate through legal hurdles, Latin American countries have signed memoranda of understanding and cooperation agreements with inter-regional countries and countries from other continents including with mature regulatory agencies (e.g., Swissmedic, Food and Drug Administration, EMA). These types of reliance mechanisms have been set up to facilitate an exchange of regulatory and scientific information of therapeutic products and encourage collaborative activities. As publicized on the websites of these agencies, 11 memoranda of understanding and eight cooperation agreements have been signed across regulatory authorities in the past 10 years. While a formal and transparent process for promoting such reliance agreements is not yet in place, the WHO has provided guidelines to navigate through hurdles to promote reliance within the context of national and regional laws [67].
The WHO further encourages access to innovative mAbs in LMICs by providing guidance documents on product profiles to product developers and through the WHO prequalification process [73,74]. The WHOpublished preferred product characteristics reports describe preferences for product attributes that would help optimize value and use to address global public health needs, with a particular focus in LMICs. The WHO recently published preferred product characteristics for mAbs to prevent severe RSV disease in infants [72] and HIV prevention [74]. The documents outline the preferred product characteristics for long-acting RSV mAbs and HIV preventive mAbs defining the key parameters for each mAb including indication, target population, schedule delivery strategies, safety, efficacy, strain specificity, formulation, co-administration, route of administration, registration, prequalification and programmatic suitability, and access and affordability. These documents serve as guides to product developers to influence all stages of product development including candidate selection and early-and late-stage clinical development. Early engagement between regulatory agencies, the WHO, and mAb developers is essential in ensuring regional suitability of the target product profile during product development. This can avoid delays in licensure and access after pivotal trials have been completed. Early engagement and communication can also ensure that authorities have the capacity, and that adequate scientific advice can be given in a timely manner to inform the course of the development program. These consultations will benefit from clear guidance on what constitutes binding scientific advice, and areas where there may be room for the modification of approaches. Ensuring products are fit for purpose in LMICs, together with prequalification by the WHO, could facilitate speedy approval and the ability to purchase affordable mAb products in LMICs.
The WHO has additional mechanisms in place that can be utilized or adapted to aid LMICs to establish more rapid approval for, and better access to, mAbs. For example, the WHO advises and provides support to regulatory authorities to develop their infrastructure and capacity to meet the complex evaluation requirements for a mAb. In addition, the introduction of mAbs in many countries has been encouraged by the guidelines and recommendations of the WHO as seen with tocilizumab in the COVID-19 pandemic. To promote access to treatments, the WHO added the mAb tocilizumab to its list of treatments for COVID-19 and issued an Expression of Interest for additional suppliers to manufacture the product [75]. Tocilizumab had already been authorized for the treatment of arthritis in about 120 countries worldwide; however, priced at US$500-600 a dose in lower-income markets, the drug is unaffordable to most. Additionally, the sudden surge in demand for the drug has resulted in a global shortage. The primary patent for tocilizumab has expired in many countries, and Roche, the originator, has suspended its patent rights on the medication in LMICs, clearing the legal path for biosimilar sales [76]. However, global availability of quality-assured biosimilars has not yet been achieved. The WHO, Unitaid, and partners encouraged Roche to facilitate technology transfer, knowledge, and data sharing to broaden access to this important mAb treatment. Roche has acknowledged limited access to this mAb in low-income countries and is selling their product at cost in resource-limited countries as a stop-gap measure pending the entry of a lower-cost prequalified biosimilar manufacturer [77]. At the height of the pandemic, Roche contracted facilities from two other bio-pharmaceutical companies to produce tocilizumab and quadrupled the amount of the drug delivered to LMICs prior to the pandemic [78]. Collaborations such as this are essential to address the inequities in access to mAbs in LMICs and can set a precedent for the future.

Conclusions
Without clear processes and guidelines for conducting clinical trials and for regulatory approval of innovative and biosimilar mAbs in LMICs, current inequities in access to mAb products are likely to persist and increase in the years to come. The challenges and lessons learned from the COVID-19 experience have raised awareness of the gaps and opportunities for mAb access in LMICs, and the international community has started to engage in dialog and initiatives to drive change. In Africa, simplification of mAb approvals could be achieved through regionally driven regulatory review processes with central oversight. More generally, collaborations and early engagement between product developers, manufacturers, regulatory agencies, and the WHO could enable accelerated and streamlined approvals and access to mAb products aligned with regional needs. Finally, an increase in WHO-prequalified mAbs could also enable faster access to such products in resource-limited settings. This will require advocacy, political will, publicprivate partnerships, and a strong commitment to global health.