2 3 The practical value of biologics registries in Africa and Middle East: challenges and opportunities

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2 3 The practical value of biologics registries in Africa and Middle East: challenges and opportunities
           1 3 Clinical Rheumatology Journal of the International League of Associations for Rheumatology ISSN 0770-3198 Clin RheumatolDOI 10.1007/s10067-011-1918-8 The practical value of biologics registriesin Africa and Middle East: challenges and opportunities Najia Hajjaj-Hassouni, Marzooq Al-Badi, Ala’ Al-Heresh, Samar Al-Emadi,Ahmed El Bawendi, Ayman El Garf,Khaled El Hadidi, Hussein Halabi, et al.           1 3 Your article is protected by copyright andall rights are held exclusively by ClinicalRheumatology. This e-offprint is for personaluse only and shall not be self-archived inelectronic repositories. If you wish to self-archive your work, please use the acceptedauthor’s version for posting to your ownwebsite or your institution’s repository. Youmay further deposit the accepted author’sversion on a funder’s repository at a funder’srequest, provided it is not made publiclyavailable until 12 months after publication.  REVIEWARTICLE The practical value of biologics registries in Africaand Middle East: challenges and opportunities Najia Hajjaj-Hassouni  &  Marzooq Al-Badi  & Ala ’  Al-Heresh  &  Samar Al-Emadi  & Ahmed El Bawendi  &  Ayman El Garf   & Khaled El Hadidi  &  Hussein Halabi  & Mohammed Hammoudeh  &  Selma El Hassani  & Mustafa Al Maaini  &  Ibrahim Nahar  & Aïcha Ladjouze Rezig  &  Slaheddine Sellami  & Wafaa Sweiri  &  Ramiz Alswailem  &  Beverly Traub  & Imad Uthman  &  Elsa van Duuren  &  Leith Zakraoui  & Bassel El Zorkany  &  Loreto Carmona  & Maxime Dougados Received: 8 November 2011 /Accepted: 15 December 2011 # Clinical Rheumatology 2012 Abstract  Biologics, including tumor necrosis factor (TNF)inhibitors, are increasingly used for the treatment of inflam-matory conditions such as rheumatoid arthritis (RA), psori-atic arthritis, and ankylosing spondylitis. The efficacy of these drugs has been demonstrated in randomized controlledtrials (RCTs). However, these studies are conducted in con-trolled environments, and the results may not necessarilyreflect clinical outcomes in daily clinical practice. In Europe  N. Hajjaj-Hassouni ( * )University Mohammed Vth Souissi,Rabat, Moroccoe-mail: nhajjajhassouni@gmail.com N. Hajjaj-HassouniEl Ayachi Hospital,Salé, MoroccoM. Al-BadiSecurity Force Hospital,Riyadh, Saudi Arabia A. Al-HereshKing Hussein Medical Center, Royal Medical Services,Amman, JordanS. Al-EmadiWeill Cornell Medical School,Doha, Qatar R. AlswailemRiyadh Military Hospital,Riyadh, Saudi Arabia M. Al MaainiMafraq Hospital,PO Box 2951, Abu Dhabi, United Arab EmiratesA. El BawendiTripoli Medical Center,PO Box 83338, Tripoli, Libya E. van DuurenJakaranda Hospital,Pretoria, South Africa A. El Garf Cairo University Hospitals,Cairo, Egypt K. El HadidiCairo University,Giza, Egypt H. HalabiKing Faisal Specialist Hospital and Research Center   —  Jeddah,Riyadh, Kingdom of Saudi Arabia M. HammoudehHamad Medical Corporation,Doha, Qatar S. El HassaniFaculté de Médecine et de Pharmacie de Marrakech, UniversitéCadi Ayyad,Sidi Abbad 40000, MoroccoClin RheumatolDOI 10.1007/s10067-011-1918-8  and other western countries, numerous biologics registriesthat enroll and monitor patients receiving biologics have been established. These registries follow patients irrespec-tive of whether they continue with the initial biologic drug.Thus, real-life efficacy data from these registries can be usedto assess the long-term safety of biologics through longitu-dinal studies. In Africa and Middle East (AFME), suchregistries currently exist only in Morocco and South Africa.In light of the increasing availability of biologics and scar-city of long-term safety data of these agents in the AFME population, there is a need to establish biologics registries inother countries across the region. This review discusses thevalue of biologics registries versus RCTs as well as safetyand efficacy data from observational studies presented aslessons from well-established biologics registries. In addi-tion, the rationale for establishing such registries in theAFME region is also presented. Keywords  Africa andMiddleEast .Biologics.Registries.Rheumatoidarthritis.Safety.Tumornecrosisfactor inhibitors Introduction AFME is a large region that encompasses countries inWestern Asia as well as North and South Africa. The MiddleEast, traditionally including the countries of Bahrain, SaudiArabia, Kuwait, Qatar, Oman, Yemen, Iraq, Iran, Egypt,Jordan, Lebanon, Palestinian territories, Turkey, United ArabEmirates (UAE), Syria, Yemen and western parts of Pakistan,is a region with challenging political, social, and economicconditions and an unmet need of sustainable healthcare deliv-ery systems in several countries [1, 2]. Many countries lack  regular,updatedpopulation-baseddataonthe commoncausesof mortality and morbidity, such as cardiovascular diseases(CVD), cancer, and injuries. This hinders identification of health priorities and the development of effective healthcaresystems [3]. North African countries including Morocco,Algeria, Tunisia, Libya, and Mauritania have limited water resources and agricultural land, and many have recently wit-nessed political unrest [1]. African countries, particularly thesub-Saharan countries, face grave health issues such as ma-ternal and child mortality, high burden of communicable dis-eases,andrisingratesofnon-communicablehealthconditionssuch as violence and injuries due to political and socioeco-nomic instability [4].The burden of RA in AFME has not been accuratelyestimated due to the lack of updated registers on the diag-nosis and treatment of the condition [5]. Given that RA is a chronic inflammatory disease that may cause significant disability and decreased quality of life if untreated, the goalsof treatment are to induce remission or at least low diseaseactivity [6]. Biologics represent a significant milestone inthe RA therapeutic armamentarium. Although the efficacyand safety of biologics were established in clinical trials,there was uncertainty regarding the long-term safety, partic-ularly with regards to serious infections and malignancy,with these agents. Thus, biologics registries were estab-lished in several countries to monitor patients receivingthese drugs. However, there are scant published data onthe use of biologics in AFME. In this review, we discussthe value and rationale for establishing biologics registries I. Nahar Department of Medicine, Mubarak Al-Kabir Hospital,Kuwait City, Kuwait A. Ladjouze RezigService Rhumatologie, Hôpital Ben Aknoun,EHS Appareil Locomoteur,Route des 2 Bassins,Alger, Algéria S. SellamiEPS La Rabta,Tunis, Tunisia W. SweiriKing Abdul Aziz Medical City,King Fahad National Guard Hospital,Riyadh 11426, PO Box 22490/MC 1510, Saudi Arabia B. TraubBergstrasse 15,Eppstein, Germany 65817I. UthmanAmerican University of Beirut Medical Center,PO Box 11-0236, Beirut 1107 2020, LebanonL. ZakraouiHôpital Mongi Slim, University of Tunis El Manar,2046 La Marsa, Tunisia B. El ZorkanyRheumatology Department, Kasr El-Aini Hospitals, Cairo University,Manial Cairo, Egypt 11451L. Carmona Health Sciences School, Universidad Camilo José Cela,Calle Castillo de Alarcón, 49-Urb, Villafranca del Castillo,28692 Madrid, SpainM. DougadosUPRES-EA 4058, APHP, Cochin Hospital,Paris-Descartes University,Rheumatology B Dpt,Paris 14, FranceClin Rheumatol  in this region as well as the opportunities and challengesinvolved. The value of registries versus RCTs  Numerous RCTs demonstrate that early intensive treatment of active RA with a combination of disease modifying anti-rheumatic drugs (DMARDs) and steroids slows disease progression and erosive joint damage [7]. However, thesetrials do not answer practical questions such as how early tocommence treatment, how to define the lower end of activeRA, and how long to continue intensive treatment [7].ItiswidelyacknowledgedthatRCTs may have limitations.These trials run for short periods (2  –  3 years) and do not  provide long-term efficacy and safety data-essential informa-tion in RA management as patients require treatment for severalyears[8].Surrogateendpointsareusedtodemonstratedrugefficacy,while clinicians lookatabsolute targets(suchasremission, low inflammatory activity, no pain, and high func-tional ability) in real life [9]. Drug efficacy may be superior inclinical trials as compared with that in clinical practice due towashout periods prior to inclusion, dose differences, co-medications, and treatment adherence [10]. Furthermore, patients inclinicaltrials are treatedincontrolledenvironmentsand differ from real-life patients in terms of disease severity,treatment history, and comorbidity [10].Since RA is associated with an increased risk of infec-tions, lymphoproliferative malignancies, and CVD, there areconcerns that long-term use of DMARDS and biologics mayimpair immunity and increase adverse events such as seriousinfections, autoimmune disorders, and malignancies [11].Thus, pharmacovigilance systems were created for sponta-neous notification of adverse events. However, in reality,there is significant underreporting leading to difficulties inmaking realistic estimates of adverse events [11]. In addi-tion, RCTs are often underpowered to estimate the true risk of lymphomas with anti-TNF therapy [12].Thus, long observational studies in RA are needed toobtain long-term safety and efficacy data and help cliniciansto use biologics more effectively. To that end, biologicsregistries were established in several European countriesand the US. These registries examine various endpointsincluding efficacy [9], quality of life [13], safety [14], drug survival [15], and cost-effectiveness [16] of biologics by conducting longitudinal observational studies in largecohorts undergoing anti-TNF treatment.These studies have several advantages over RCTs. Asthese run for long periods ( ≥ 5 years), a large sample sizeis examined which helps in investigating rare adverseevents. All patients receiving biologics are enrolled, andinclusion criteria are not limited by disease activity,treatment guidelines, or economical aspects. As there is nowashout period, results reflect the true efficacy of the bio-logics [17]. The studies also provide information about thechanging patterns of drug treatment and drug survival. Thissheds light on the reasons for switching treatments in reallife [8, 17]. Unlike RCT data, registry data also allow clinicians to make head-to-head comparisons between dif-ferent biologics [18].Registriesinvolvethesystematiccollectionofadverseevent data and could therefore also serve as pharmacovigilancesystems. Regulatory agencies such as the Food and DrugAdministration (FDA) and European Medicine Agency(EMEA) are increasingly demanding long-term safety data as partoftheapprovalprocess.Asinglepharmaceuticalcompanyis unable toprovidethese data as patients receiveseveral drugssimultaneously in clinical practice [13].It is also important to acknowledge the limitations of registries. Unlike RCTS, patients included in these longobservational studies are not matched for baseline character-istics, and not all registries have well-defined controlgroups. As a result, true causal association can be obscuredin these studies. It has been recommended to examine care-fully the systematic differences between treated and controlgroups that may arise due to patient characteristics such asdisease severity, comorbidity, drug use, etc., as well as lossto follow-up and the methods of outcome assessment andverification. Selection bias and confounding, including re-sidual and unmeasured confounding, should be taken intoconsideration during statistical analyses [19]. Lessons from well-established registries Biologics registries have now been established in severalEuropean countries including the UK, France, Sweden,Germany, Spain, Norway, Denmark, The Netherlands, andSwitzerland. Although these differ in terms of size, methodsof follow-up, and control groups, most were initiated incollaboration with national rheumatology societies and aremanaged by medical professionals [11]. These are not drugspecific. Rather, they include all licensed biologics as patients are treated with more than one biologic in real life.The registers are designed as epidemiological cohort studiesfor which patients are recruited from clinics or the general population and all enrolled patients are followed irrespectiveof continuation with the initial drug. Pharmaceutical com- panies whose products are being monitored have pledgedlong-term commitment to these registries. Furthermore,there is close collaboration between international registrieswhich allows evaluation of data across registries, if required,to obtain robust knowledge on rare events such as lympho-ma or pregnancy. Data from these registries have been Clin Rheumatol
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