Determinants of Use of Biotherapeutics in sub-Saharan Africa

Biotherapeutics have become an essential component of the modern clinical armamentarium due in part to their high specificity and potency, but access biotherapeutics is currently uneven across global settings.Compared with small molecule drugs, unique features that affect way they are manufactured, supplied, administered patients.The disease burden sub-Saharan Africa includes many communicable noncommunicable indications for which already approved or development.Technical, regulatory, health system, economic factors all impact safe reliable Africa. Biologic drugs reshaping practice various disciplines, even while them imbalanced settings. In Africa, potential roles play treatment a range conditions include infectious diseases (NCDs). However, literature scarce on guidance addressing local challenges, including technical, affordability, other healthcare delivery aspects. This article aims assess fundamental determinants use biologic medicines The purpose inform strategic actions scientists, physicians, policymakers, stakeholders working improve innovative therapies low resource parts world. Advances therapeutic science increasingly translating biologically active selective disease-influencing genes proteins well-defined signaling pathways, leading development potent, highly effective favorable toxicity profiles. More than 130 injectable biotherapeutic been since first recombinant protein (human insulin management diabetes) monoclonal antibody (muromonab-CD3 prevention kidney transplant rejection) were licensed 1980s [1.Leader B. et al.Protein therapeutics: summary pharmacological classification.Nat. Rev. Drug Discov. 2008; 7: 21-39Crossref PubMed Scopus (1248) Google Scholar]. Currently, medicinal products containing biotechnology-derived (also referred this as ‘biotherapeutics’ ‘biologics’) fastest growing segment predicted constitute nearly third drug market by 2024, reflecting pivotal changing [2.Kesselheim A.S. Avorn J. most transformative past 25 years: survey physicians.Nat. 2013; 12: 425-431Crossref (29) Given pertinence biologics medicine, it important assure benefits these innovations reach populations need. It has clear now standard care high-income countries, certain types cancer autoimmune disorders, also prevalent problems low- middle-income countries [3.Hay S.I. al.Global, regional, national disability-adjusted life-years (DALYs) 333 injuries healthy life expectancy (HALE) 195 territories, 1990–2016: systematic analysis Global Burden Disease Study 2016.Lancet. 2017; 390: 1260-1344Abstract Full Text PDF (1065) Yet there increasing underdeveloped still greatly limited. Here we focus specific case (Figure 1), suffers world’s disproportionate relative population sizei. epidemiology complex dynamic While continue be among main causes death disability, rates dropped decade concurrent rising NCDsii. light medical needs given epidemiologic trends increased demand future, sought describe successful region. Specifically, examined selected relating needs, manufacturing, supply storage, delivery, comorbidities, regulatory aspects, economics. envisioned patients, clinicians, regulators, seeking settings globally. For exercise focused antibodies well hormones, excluding vaccines (for chains established regionally), blood (that collection, testing, storage needs), cell gene require sophisticated ancillary capabilities). Several decidedly relevant A profile example Ebola virus (EVD), United States FDA recently disease-specific therapy, mixture three antibodiesiii. Biologics being studied such malaria could particular long-acting prophylaxis) AIDS (the CD4 receptor agonist, ibalizumab, was 2018, more HIV development) [4.Macintyre F. al.Injectable anti-malarials revisited: discovery new agents protect against malaria.Malar. 2018; 17: 402Crossref (13) Scholar,5.Emu al.Phase 3 ibalizumab multidrug-resistant HIV-1.N. Engl. Med. 379: 645-654Crossref (85) addition, 50 antibody-based treatments address COVID-19, documented every African country 30 000 deaths reported 8-month period beginning March 2020iv–vi. Examples programs phases research bearing neglected include: (i) antibody-drug conjugate human trypanosomiasis known ‘sleeping sickness’); (ii) prophylactic dengue; (iii) antivenoms snakebite; (iv) humanized designed prevent complications associated sickle [6.MacGregor P. al.A single dose cures stage 1 model trypanosomiasis.PLoS Negl. Trop. Dis. 2019; 13e0007373Crossref (6) Scholar, 7.Laustsen A.H. al.In vivo neutralization dendrotoxin-mediated neurotoxicity black mamba venom oligoclonal IgG antibodies.Nat. Commun. 9: 3928Crossref (43) 8.Ataga K.I. al.Crizanlizumab pain crises disease.N. 376: 429-439Crossref (287) 9.Budigi Y. al.Neutralization antibody-enhanced dengue infection VIS513, pan serotype reactive targeting domain III E protein.PLoS 12e0006209Crossref (7) Globally, common NCDs, evidence NCDs follows needed optimal [10.Gouda H.N. al.Burden non-communicable 1990–2017: results from 2017. Lancet Glob.Heal. e1375-e1387Scopus (171) incorporated into World Health Organization’s (WHO) Essential Medicines List (EML) published 1977, latest edition (2019) specifies biological diabetes, hematology, oncology, ophthalmology, rheumatologyvii. Taking cues WHO EML, therapies, antibodies, guidelinesviii–x. Furthermore, some experts believe current policies do not go far enough recommending [11.Foster H.E. Scott C. Update EML paediatric rheumatology.Nat. Rheumatol. 2020; 16: 123Crossref (8) Table lists commonly distributed several 2017 closely mirrors utilization top [12.Urquhart L. Top companies sales 2018.Nat. 18: 245Google Scholar].Table 1Top Ten Therapeutics Number Units Distributed South Namibia, Kenya 2017–2018aCountries based available data (source: calculations authors derived IQVIA database). ‘Units’ represents actual number packs, tablets, syringes sold private sector; public centers.TherapeuticRegistered indicationsSouth AfricaNamibiaKenyaTotalInsulin (assorted forms)Diabetes mellitus3 576 439174 1421 160 7054 911 286InfliximabCertain forms arthritis; inflammatory bowel disease; ankylosing spondylitis37 61748133838 436FilgrastimNeutropenia; acute myeloid leukemia36 845––36 845RituximabRheumatoid non-Hodgkin’s lymphoma; chronic lymphocytic leukemia33 2791422118635 887EtanerceptCertain arthritis psoriasis; spondylitis32 60675099534 351AdalimumabCertain spondylitis; uveitis32 1128703133 013CetuximabCertain head, neck, colorectal cancers29 235155686631 657Interferon betaMultiple sclerosis22 300––22 300BevacizumabCertain ovarian, cervical, renal cell, lung, cancer; recurrent glioblastoma16 4172652117920 248TrastuzumabCertain breast cancer17 674119033319 197a Countries centers. Open table tab Recombinant DNA-derived therapeutics produced large reactors using engineered living cells made express antibodies. Refrigerated at 2–8oC then required maintain molecular conformation. Protein denaturation aggregation, can induce unwanted immunogenicity, occurs when temperature, pH, humidity, environmental controlled [13.Johnson M. Antibody shelf life.Mater. Methods. 2012; 2: 120Google 14.Ratanji K.D. al.Immunogenicity proteins: influence aggregation.J. Immunotoxicol. 2014; 11: 99-109Crossref (332) 15.Rogawski E.T. al.Use quantitative diagnostic methods investigate effect enteropathogen infections linear growth children low-resource settings: longitudinal MAL-ED cohort study.Lancet Glob. Health. 6: e1319-e1328Abstract (108) 16.Ignjatovic al.Aggregation its role immunogenicity.Curr. Pharm. Biotechnol. 19: 343-356Crossref (3) Accordingly, thermodynamic physiochemical liabilities must considered where precise handling challenging reliably monitor maintain. Weaknesses cold chain described lack consistent refrigeration result interrupted power supplies [17.Ashok A. al.Improving systems: challenges solutions.Vaccine. 35: 2217-2223Crossref (74) limited capacity biopharmaceutical production, combined technical efficiency advantages producing centralized specialized manufacturing facilities, often transported long distances site production bedside. As such, safeguarding paramount concern. Temperature indicators, used heat exposure vaccine settings, may means help preserve bioactivity safety biotherapies. These devices chemical-based ‘cards’ packaged vials change color according cumulative exposurexi. recently, engineering possible generate significantly improved thermostabilities [18.McConnell A.D. general approach thermostabilization.MAbs. 1274Crossref (28) Novel formats variable fragments constructed withstand elevated temperatures without losing thereby potentially diminishing risks faulty management. Another overcoming constraints related physical patients remote locations novel mechanisms distribution clinics communities. Thus, drones revolutionized transport Rwanda, expanded Ghana, Tanzania, [19.(2017) Look! Up sky! It’s bird. plane. drone! Haematol. 4, e56Google Zipline, California-based company, over drone deliveries 2016, reducing time multi-hour journey car less minutes products, vaccines, antivenoms, medicinesxii. remains seen how leveraged distribute routine any setting. theoretically immediate supporting efficient timely research, enabling quantities delivered same-day utilization, therefore waste. Adoption biotherapies impeded fragmented poorly-resourced systems generally oriented used. example, country-level decision support through standardized criteria algorithms diseases; recent report jointly WHO, Bank, Organisation Economic Co-operation Development (OECD) found seven diagnosed correctly only one-third three-quarters timexiii. Laboratory radiology services diagnosis locally incur prohibitive costs patients. Adequate requires skilled practitioners, yet dearth specialists crisis level. By reports fewer ten trained rheumatology physicians Eastern (population million) Western 320 million; Figure 1) [20.Genga E.K. al.Building team East Africa: call action.Rheumatology. 56: 1441-1442PubMed Scholar,21.Etomi O. enhancing non-specialists.Rheumatology. 57: e48-e49Crossref consequence imbalance select practitioners cities will likely training confidently prescribe biologics. Moreover, dispensing medicines, facilities whole accreditation order adequate presence subspecialists might manage complications. distinct service consideration act administering Unlike degraded gastrointestinal tract easily cross membranes; intravenous subcutaneous injection target (Box [22.Irvine D. al.Routes products.in: Wang W. Manmohan S. Biological products: strategies. 1st edn. Wiley Online, 2013: 677-724Crossref biologics, those treat cancers rheumatologic conditions, via infusion pump specified rate duration, in-line filters. considerations add complexity perspective requisite steps introduce (e.g., if lyophilizates improperly reconstituted promote aggregates, incompatible diluents inadvertently used, and/or sterility compromised). Though technological pre-filled autoinjectors administration errors bedside, ploys greater expense compared vials. Innovations horizon techniques extending half-lives so injections would formulations intramuscularly subcutaneously, instead intravenously) [23.Hooft van Huijsduijnen R. al.Reassessing tropical diseases.PLoS 14e0007860Crossref Scholar].Box 1Differences between Small Molecule DrugsBiotherapeutics differ ways discovery, development, activity, (Table I). mammalian, bacterial, yeast cells) DNA technology processes, contrast molecules chemical synthesis [39.Zelikin A.N. al.Materials drugs.Nat. Chem. 2016; 8: 997-1007Crossref (168) exponentially mass; typical 20 atoms 100 Indeed, derive structure allows and, multiple action, potency minimizing side effects off-target activity [40.Redman al.Mechanisms action cancer.Mol. Immunol. 2015; 67: 28-45Crossref different modes (with injection) dosage frequency frequently) [41.Tabrizi M.A. al.Elimination antibodies.Drug Today. 2006; 81-88Crossref (381) usually refrigerated configuration, typically expensive manufacture higher cost goods [42.Birch J.R. Racher A.J. production.Adv. Deliv. 58: 671-685Crossref (379) IKey Differences Monoclonal Antibodies Medicines–Monoclonal antibodiesSmall moleculesTypical size150 kilodaltons0.3–0.5 kilodaltonsMechanism actionInhibition activationPrimarily inhibitionDrug substanceBiological processChemical synthesisSelectivityHigh selectivityGenerally selectiveToxicityLargely ‘on target’ mediatedOften ‘off mediatedClearance/dosingSlow clearance/long half-life (i.e., days)Rapid clearance/short hours)DosingInfrequent dosing weekly monthly)/ parenteral subcutaneous)Frequent daily)/often oral administrationImmunogenicitySometimes observedRarely observed Numerous additionally delivery. An illustration Accra, our experience irregularly stocked Pharmacy wholesalers contract pharmaceutical own facilities. When patient prescribed biologic, wholesaler alerted parties (patient, staff, representative) coordinate meet arranged clinic’s center. Delays arising procedures risk interfering care. Registries receiving commonplace practical longitudinal, ‘real-world’ complements obtained trials pharmacovigilance systems. [24.Nikiphorou E. al.Biologics registers RA: methodological future applications.Nat. 13: 503-510Crossref (37) registries hold promise deficiencies incidence prevalence data, provide vital efficacy monitoring influences, genetic groups [25.Hajjaj-Hassouni N. al.The value Middle East: opportunities.Clin. 31: 407-416Crossref mechanism regularly assessing efficacy, detection counterfeit widely Association Rheumatism Arthritis developed online registry rheumatic which, 2008, assembled observational 5000 [26.Pettipher Benitha Tuberculosis users diseases: Registry (SABIO).Ann. Rheum. 79: 292-299Crossref Use tool requirement funded insurance. 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Some perceptions pervasive actually unexpected enablers instance, preferences populations, view potent pills [30.Alhassan R.K. al.Correlates patients’ preference major regional referral hospital Ghana: implications policy practice.SAGE Open. 1-8Crossref (1) intermittent regimens compliance negating need take daily. increase opportunistic community-acquired [31.Tarr G. al.Superheroes warfare: practice.South 104: 787-791Crossref (9) concern reactivation latent tuberculosis (LTBI) tumor necrosis factor (TNF) inhibitors [32.Zhang Z. al.Risk tu