Safety and Efficacy of Intravenous Ferric Derisomaltose Compared to Iron Sucrose for Iron Deficiency Anemia in Patients with Chronic Kidney Disease With and Without Heart Failure
2021; Elsevier BV; Volume: 152; Linguagem: Inglês
10.1016/j.amjcard.2021.04.042
ISSN1879-1913
AutoresAndrew P. Ambrosy, Stephan von Haehling, Paul R. Kalra, Emma L. Court, Sunil Bhandari, Theresa A. McDonagh, John G.F. Cleland,
Tópico(s)Hemoglobinopathies and Related Disorders
ResumoFerric derisomaltose (FDI) is an intravenous (IV) high-dose iron formulation approved in the US for the treatment of iron deficiency anemia in adults who are intolerant of/have had an unsatisfactory response to oral iron, or who have non-dialysis-dependent chronic kidney disease (NDD-CKD). FERWON-NEPHRO was a randomized, open-label, multicenter clinical trial evaluating the safety and efficacy of a single infusion of FDI 1,000 mg versus up to 5 doses of iron sucrose (IS) 200 mg (recommended cumulative dose, 1,000 mg) over 8 weeks in patients with NDD-CKD and iron deficiency anemia. Of 1,525 patients included in the safety analysis, 244 (16%) had a history of heart failure (HF). Overall, the rate of serious or severe hypersensitivity reactions was low and did not differ between treatment groups. Cardiovascular adverse events (AEs) were reported for 9.4% of patients who had HF and 4.2% who did not. Time to first cardiovascular AE was longer following administration of FDI compared with IS (hazard ratio: 0.59 [95% CI: 0.37, 0.92]; p=0.0185), a difference that was similar in patients with or without HF (p=0.908 for interaction). Patients achieved a faster hematological response (assessed by changes in hemoglobin and ferritin concentrations, and increase in transferrin saturation) with FDI versus IS. In conclusion, in patients with NDD-CKD, a single infusion of FDI was safe, well tolerated, and was associated with fewer cardiovascular AEs and a faster hematological response, compared to multiple doses of IS. These effects were similar for patients with and without HF. Ferric derisomaltose (FDI) is an intravenous (IV) high-dose iron formulation approved in the US for the treatment of iron deficiency anemia in adults who are intolerant of/have had an unsatisfactory response to oral iron, or who have non-dialysis-dependent chronic kidney disease (NDD-CKD). FERWON-NEPHRO was a randomized, open-label, multicenter clinical trial evaluating the safety and efficacy of a single infusion of FDI 1,000 mg versus up to 5 doses of iron sucrose (IS) 200 mg (recommended cumulative dose, 1,000 mg) over 8 weeks in patients with NDD-CKD and iron deficiency anemia. Of 1,525 patients included in the safety analysis, 244 (16%) had a history of heart failure (HF). Overall, the rate of serious or severe hypersensitivity reactions was low and did not differ between treatment groups. Cardiovascular adverse events (AEs) were reported for 9.4% of patients who had HF and 4.2% who did not. Time to first cardiovascular AE was longer following administration of FDI compared with IS (hazard ratio: 0.59 [95% CI: 0.37, 0.92]; p=0.0185), a difference that was similar in patients with or without HF (p=0.908 for interaction). Patients achieved a faster hematological response (assessed by changes in hemoglobin and ferritin concentrations, and increase in transferrin saturation) with FDI versus IS. In conclusion, in patients with NDD-CKD, a single infusion of FDI was safe, well tolerated, and was associated with fewer cardiovascular AEs and a faster hematological response, compared to multiple doses of IS. These effects were similar for patients with and without HF. Ferric derisomaltose (FDI), previously known as iron isomaltoside, is an intravenous (IV) high-dose iron formulation. Since its approval by the European Medicines Agency in 2009, FDI has been commercially available for the treatment of iron deficiency in several European countries. In 2020, the US Food and Drug Administration (FDA) approved FDI for the treatment of iron deficiency anemia in adults who are either intolerant of or have had an unsatisfactory response to oral iron, or who have non-dialysis-dependent chronic kidney disease (NDD-CKD). FDA approval was based on two randomized, open-label, multicenter trials, FERWON-IDA1Auerbach M Henry D Derman RJ Achebe MM Thomsen LL Glaspy J. A prospective, multi-center, randomized comparison of iron isomaltoside 1000 versus iron sucrose in patients with iron deficiency anemia; the FERWON-IDA trial.Am J Hematol. 2019; 94: 1007-1014Crossref PubMed Scopus (34) Google Scholar and FERWON-NEPHRO.2Bhandari S Kalra PA Berkowitz M Belo D Thomsen LL Wolf M. Safety and efficacy of iron isomaltoside 1000/ferric derisomaltose versus iron sucrose in patients with chronic kidney disease: the FERWON-NEPHRO randomized, open-label, comparative trial.Nephrol Dial Transplant. 2021; 36: 111-120Crossref PubMed Google Scholar FERWON-IDA included younger patients (mean age 44 years) with iron deficiency anemia, mainly women (89%),1Auerbach M Henry D Derman RJ Achebe MM Thomsen LL Glaspy J. A prospective, multi-center, randomized comparison of iron isomaltoside 1000 versus iron sucrose in patients with iron deficiency anemia; the FERWON-IDA trial.Am J Hematol. 2019; 94: 1007-1014Crossref PubMed Scopus (34) Google Scholar and only 16 had heart failure (HF) (unpublished data). FERWON-NEPHRO reported that, in patients with NDD-CKD, a single dose of FDI resulted in a rapid hematological response (improvements in iron indices and hemoglobin), was well-tolerated, and was associated with fewer cardiovascular adverse events (AEs) compared with multiple doses of iron sucrose (IS).2Bhandari S Kalra PA Berkowitz M Belo D Thomsen LL Wolf M. Safety and efficacy of iron isomaltoside 1000/ferric derisomaltose versus iron sucrose in patients with chronic kidney disease: the FERWON-NEPHRO randomized, open-label, comparative trial.Nephrol Dial Transplant. 2021; 36: 111-120Crossref PubMed Google Scholar For patients with HF, iron deficiency and anemia are common and associated with more severe symptoms, poorer quality of life, reduced exercise capacity, impaired renal function and a worse prognosis.3Ambrosy AP Gurwitz JH Tabada GH Artz A Schrier S Rao SV Barnhart HX Reynolds K Smith DH Peterson PN Sung SH Cohen HJ Go AS; RBC Heart Investigators. Incident anaemia in older adults with heart failure: rate, aetiology, and association with outcomes.Eur Heart J Qual Care Clin Outcomes. 2019; 5: 361-369Crossref PubMed Scopus (6) Google Scholar, 4Ambrosy AP Fitzpatrick JK Tabada GH Gurwitz GH Artz A Schrier SL Rao SV Reynolds K Smith DH Peterson PN Fortmann SP Sung SH Cohen HJ Go AS; RBC Heart Investigators/PACTTE Consortium. A reduced transferrin saturation is independently associated with excess morbidity and mortality in older adults with heart failure and incident anemia.Int J Cardiol. 2020; 309: 95-99Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 5Cleland JGF Zhang J Pellicori P Dicken B Dierckx R Shoaib A Wong K Rigby A Goode K Clark AL. Prevalence and outcomes of anemia and hematinic deficiencies in patients with chronic heart failure.JAMA Cardiol. 2016; 1: 539-547Crossref PubMed Scopus (64) Google Scholar, 6von Haehling S Gremmler U Krumm M Mibach F Schön N Taggeselle J Dahm JB Angermann CE. Prevalence and clinical impact of iron deficiency and anaemia among outpatients with chronic heart failure: The PrEP registry.Clin Res Cardiol. 2017; 106: 436-443Crossref PubMed Scopus (49) Google Scholar, 7Ebner N Jankowska EA Ponikowski P Lainscak M Elsner S Sliziuk V Steinbeck L Kube J Bekfani T Scherbakov N Velentova M Sandek A Doehner W Springer J Anker SD von Haehling S. 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Anemia and mortality in heart failure patients: A systematic review and meta-analysis.J Am Coll Cardiol. 2008; 52: 818-827Crossref PubMed Scopus (485) Google Scholar Randomized controlled trials conducted in patients with HF and a reduced ejection fraction (HFrEF) have shown that IV iron improves symptoms and exercise capacity, and may reduce hospitalizations for worsening HF; the effects on mortality are less certain.10Anker SD Comin Colet J Filippatos G Willenheimer R Dickstein K Drexler H Lüscher TF Bart B Banasiak W Niegowska J Kirwan B-A Mori C von Eisenhart Rothe B Pocock SJ Poole-Wilson PA Ponikowski P FAIR-HF Trial InvestigatorsFerric carboxymaltose in patients with heart failure and iron deficiency.N Engl J Med. 2009; 361: 2436-2448Crossref PubMed Scopus (1207) Google Scholar, 11Ponikowski P van Veldhuisen DJ Comin-Colet J Ertl G Komajda M Mareev V McDonagh T Parkhomenko A Tavazzi L Levesque V Mori C Roubert B Filippatos G Ruschitzka F Anker SD CONFIRM-HF InvestigatorsBeneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency.Eur Heart J. 2015; 36: 657-668Crossref PubMed Scopus (583) Google Scholar, 12van Veldhuisen DJ Ponikowski P van der Meer P Metra M Böhm M Doletsky A Voors AA Macdougall IC Anker SD Roubert B Zakin L Coehn-Solal A EFFECT-HF InvestigatorsEffect of ferric carboxymaltose on exercise capacity in patients with chronic heart failure and iron deficiency.Circulation. 2017; 136: 1374-1383Crossref PubMed Scopus (163) Google Scholar, 13Ponikowski P Kirwan B-A Anker SD McDonagh T Dorobantu M Drozdz J Fabien V Filippatos G Göhring UM Keren A Khintibidze I Kragten H Martinez FA Metra M Milicic D Nicolau JC Ohlsson M Parkhomenko A Pascual-Figal DA Ruschitzka F Sim D Skouri H van der Meer P Lewis BS Comin-Colet J von Haehling S Cohen-Solal A Danchin N Doehner W Dargie HJ Motro M Butler J Friede T Jensen KH Pocock S Jankowska EA AFFIRM-AHF investigatorsFerric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial.Lancet. 2020; 396: 1895-1904Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar In response, many clinical practice guidelines14Yancy CW Jessup M Bozkurt B Butler J Casey Jr, DE Colvin MM Drazner MH Filippatos GS Fonarow GC Givertz MM Hollenberg SM Lindenfeld J Masoudi FA McBride PE Peterson PN Stevenson LW Westlake C 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America.J Am Coll Cardiol. 2017; 70: 776-803Crossref PubMed Scopus (970) Google Scholar, 15Ponikowski P Voors AA Anker SD Bueno H Cleland JGF Coats AJS Falk V Gonzàlez-Juanatey JR Harjola V-P Jankowska EA Jessup M Linde C Nihoyannopoulos P Parissis JT Pieske B Riley JP Rosano GMC Ruilope LM Ruschitzka F Rutten FH van der Meer P ESC Scientific Document Group2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) developed with the special contribution of the Heart Failure Association (HFA) of the ESC.Eur Heart J. 2016; 37: 2129-2200Crossref PubMed Scopus (7425) Google Scholar, 16Ezekowitz JA O'Meara E McDonald MA Abrams H Chan M Ducharme A Giannetti N Grzeslo A Hamilton PG Heckman GA Howlett JG Koshman SL Lepage S McKelvie RS Moe GW Rajda M Swiggum E Virani SA Zieroth S Al-Hesayen A Cohen-Solal A D'Astous M De S Estrella-Holder E Fremes S Green L Haddad H Harkness K Hernandez AF Kouz S LeBlanc MH Masoudi FA Ross HJ Roussin A Sussex B 2017 comprehensive update of the Canadian Cardiovascular Society Guidelines for the management of heart failure.Can J Cardiol. 2017; 33: 1342-1433Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar, 17Atherton JJ Sindone A De Pasquale CG Driscoll A MacDonald PS Hopper I Kistler PM Briffa T Wong J Abhayaratna W Thomas L Audehm R Newton P O'Loughlin J Branagan M Connell C NHFA CSANZ Heart Failure Guidelines Working GroupNational Heart Foundation of Australia and Cardiac Society of Australia and New Zealand: guidelines for the prevention, detection, and management of heart failure in Australia 2018.Heart Lung Circ. 2018; 27: 1123-1208Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar recommend that IV iron should (or may) be considered in order to improve health-related quality of life and functional status in patients with symptomatic HFrEF and iron deficiency, whether or not accompanied by anemia. The objective of this post hoc analysis of the FERWON-NEPHRO trial was to investigate the safety and hematological efficacy of FDI versus IS in patients with NDD-CKD and iron deficiency anemia, with or without a history of HF. FERWON-NEPHRO (NCT02940860) was a randomized, open-label, multicenter trial to evaluate the safety and efficacy of FDI (Monofer®/Monoferric®, Pharmacosmos A/S, Holbæk, Denmark) versus IS (Venofer®, American Regent, Shirley, NY, USA) in 1,538 patients with NDD-CKD and iron deficiency anemia.2Bhandari S Kalra PA Berkowitz M Belo D Thomsen LL Wolf M. Safety and efficacy of iron isomaltoside 1000/ferric derisomaltose versus iron sucrose in patients with chronic kidney disease: the FERWON-NEPHRO randomized, open-label, comparative trial.Nephrol Dial Transplant. 2021; 36: 111-120Crossref PubMed Google Scholar CKD was defined by either: (i) estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 at screening (as calculated by the Modification of Diet in Renal Disease formula), or (ii) eGFR <90 mL/min/1.73 m2 at screening, a medical record of abnormal urine composition, and/or increased risk of cardiovascular disease based on the Framingham model.2Bhandari S Kalra PA Berkowitz M Belo D Thomsen LL Wolf M. Safety and efficacy of iron isomaltoside 1000/ferric derisomaltose versus iron sucrose in patients with chronic kidney disease: the FERWON-NEPHRO randomized, open-label, comparative trial.Nephrol Dial Transplant. 2021; 36: 111-120Crossref PubMed Google Scholar Iron deficiency anemia was defined as hemoglobin ≤11 g/dL and a serum ferritin ≤100 ng/mL (or ≤300 ng/mL if the transferrin saturation [TSAT] was ≤30%).2Bhandari S Kalra PA Berkowitz M Belo D Thomsen LL Wolf M. Safety and efficacy of iron isomaltoside 1000/ferric derisomaltose versus iron sucrose in patients with chronic kidney disease: the FERWON-NEPHRO randomized, open-label, comparative trial.Nephrol Dial Transplant. 2021; 36: 111-120Crossref PubMed Google Scholar When used, the dose of erythropoiesis-stimulating agents had to be stable for 4 weeks prior to randomization.2Bhandari S Kalra PA Berkowitz M Belo D Thomsen LL Wolf M. Safety and efficacy of iron isomaltoside 1000/ferric derisomaltose versus iron sucrose in patients with chronic kidney disease: the FERWON-NEPHRO randomized, open-label, comparative trial.Nephrol Dial Transplant. 2021; 36: 111-120Crossref PubMed Google Scholar Patients were randomized 2:1 to receive treatment with FDI (single dose of 1,000 mg) or IS (200 mg administered up to 5 times within the first 2 weeks, according to the product label, with a recommended cumulative dose of 1,000 mg) and were followed up for 8 weeks to assess the incidence of serious or severe hypersensitivity reactions and the change in hemoglobin, as co-primary endpoints.2Bhandari S Kalra PA Berkowitz M Belo D Thomsen LL Wolf M. Safety and efficacy of iron isomaltoside 1000/ferric derisomaltose versus iron sucrose in patients with chronic kidney disease: the FERWON-NEPHRO randomized, open-label, comparative trial.Nephrol Dial Transplant. 2021; 36: 111-120Crossref PubMed Google Scholar Symptoms of fatigue were evaluated as a secondary efficacy endpoint.2Bhandari S Kalra PA Berkowitz M Belo D Thomsen LL Wolf M. Safety and efficacy of iron isomaltoside 1000/ferric derisomaltose versus iron sucrose in patients with chronic kidney disease: the FERWON-NEPHRO randomized, open-label, comparative trial.Nephrol Dial Transplant. 2021; 36: 111-120Crossref PubMed Google Scholar Secondary safety endpoints included the incidence of a composite of cardiovascular AEs, and the incidence of hypophosphatemia (defined as serum phosphate 100% (an indication that the IV iron infusion had occurred before the baseline blood sample was taken), the screening value was used as baseline in the data analysis Definitions of CKD stage (based on estimated GFR): Stage 1, normal or high GFR (GFR >90 mL/min/1.73 m2); Stage 2, mild CKD (GFR=60–89 mL/min/1.73 m2); Stage 3A, moderate CKD (GFR=45–59 mL/min/1.73 m2); Stage 3B, moderate CKD (GFR=30–44 mL/min/1.73 m2); Stage 4, severe CKD (GFR=15–29 mL/min/1.73 m2); Stage 5, end-stage CKD (GFR <15 mL/min/1.73 m2) FACIT Fatigue Scale score range: 0–52; higher scores denote a better quality of life; a score 100% (an indication that the IV iron infusion had occurred before the baseline blood sample was taken), the screening value was used as baseline in the data analysis Definitions of CKD stage (based on estimated GFR): Stage 1, normal or high GFR (GFR >90 mL/min/1.73 m2); Stage 2, mild CKD (GFR=60–89 mL/min/1.73 m2); Stage 3A, moderate CKD (GFR=45–59 mL/min/1.73 m2); Stage 3B, moderate CKD (GFR=30–44 mL/min/1.73 m2); Stage 4, severe CKD (GFR=15–29 mL/min/1.73 m2); Stage 5, end-stage CKD (GFR <15 mL/min/1.73 m2) FACIT Fatigue Scale score range: 0–52; higher scores denote a better quality of life; a score <30 indicates severe fatigue ACE=angiotensin-converting enzyme; ARB=angiotensin receptor blocker; BMI=body mass index; CKD=chronic kidney disease; FACIT=Functional Assessment of Chronic Illness Therapy; FDI=ferric derisomaltose; GFR=glomerular filtration rate; HF=heart failure; IQR=interquartile range; IS=iron sucrose; IV=intravenous; MedDRA=Medical Dictionary for Regulatory Activities; SGLT2=sodium–glucose co-transporter-2; TSAT=transferrin saturationACE inhibitor/ARB85 (54%)41 (48%)510 (59%)256 (61%)Beta-blocker118 (75%)68 (79%)430 (50%)217 (52%)Digoxin5 (3%)4 (5%)9 (1%)2 (<1%)Loop diuretics123 (78%)68 (79%)334 (39%)147 (35%)Mineralocorticoid receptor antagonist18 (11%)10 (12%)32 (4%)17 (4%)Sacubitril-valsartan3 (2%)3 (3%)3 (<1%)2 (1%)SGLT2 inhibitors––6 (1%)1 ( 100% (an indication that the IV iron infusion had occurred before the baseline blood sample was taken), the screening value was used as baseline in the data analysisDefinitions of CKD stage (based on estimated GFR): Stage 1, normal or high GFR (GFR >90 mL/min/1.73 m2); Stage 2, mild CKD (GFR=60–89 mL/min/1.73 m2); Stage 3A, moderate CKD (GFR=45–59 mL/min/1.73 m2); Stage 3B, moderate CKD (GFR=30–44 mL/min/1.73 m2); Stage 4, severe CKD (GFR=15–29 mL/min/1.73 m2); Stage 5, end-stage CKD (GFR <15 mL/min/1.73 m2)FACIT Fatigue Scale score range: 0–52; higher scores denote a better quality of life; a score <30 indicates severe fatigueACE=angiotensin-converting enzyme; ARB=angiotensin receptor blocker; BMI=body mass index; CKD=chronic kidney disease; FACIT=Functional Assessment of Chronic Illness Therapy; FDI=ferric derisomaltose; GFR=glomerular filtration rate; HF=heart failure; IQR=interquartile range; IS=iron sucrose; IV=intravenous; MedDRA=Medical Dictionary for Regulatory Activities; SGLT2=sodium–glucose co-transporter-2; TSAT=transferrin saturation Open table in a new tab Data are median (IQR), unless otherwise stated; safety analysis set The incidence of serious or severe hypersensitivity reactions was low after administration of FDI in patients with HF (n=2) and without HF (n=1); no events were reported following administration of IS. The incidence of all-cause treatment-emergent AEs and serious AEs was higher in patients with HF compared to those without HF, but was similar for each iron formulation (Supplementary tables 1 and 2). Time to first cardiovascular AE was longer following administration of FDI compared with IS (hazard ratio: 0.59 [95% confidence intervals {CI}: 0.37, 0.92]; p=0.0185) (Figure 1). The effect was similar in patients with HF or without HF (hazard ratio: 0.57 [95% CI: 0.25, 1.29] and 0.60 [95% CI: 0.35, 1.03], respectively; test for interaction of treatment effect and presence or absence of HF [p=0.908]) and driven by fewer hospitalizations for HF (Table 2). Overall, the incidence of adverse drug reactions was low regardless of treatment administered (Table 3), although numerically higher in patients with HF (odds ratio=1.98 [95% CI: 0.54, 7.20]; p=0.300). The most common adverse drug reactions were nausea and pruritus in patients with HF, and hypertension and pruritus in patients without HF (Table 3). Hypophosphatemia was rare after administration of either FDI or IS (Supplementary table 3).Table 2Incidence of adjudicated and confirmed treatment-emergent composite cardiovascular AEs, by type of CV eventn (%)Patients with HFPatients without HFFDI (n=158)IS (n=86)p-valueFDI (n=861)IS (n=420)p-valueAny event12 (7.6)11 (12.8)0.25130 (3.5)24 (5.7)0.075Hospitalization for HF4 (2.5)6 (7.0)0.1728 (0.9)7 (1.7)0.273Arrhythmia4 (2.5)3 (3.5)0.7003 (0.3)5 (1.2)0.123Hypertension2 (1.3)1 (1.2)1.00015 (1.7)9 (2.1)0.662Hypotension1 (0.6)1 (1.2)1.0001 (0.1)1 (0.2)0.548Acute coronary syndrome1 (0.6)0 (0.0)1.0003 (0.3)1 (0.2)1.000Fatal event not otherwise classifiedaCellulitis was experienced by 1 patient, which progressed to septic shock and the patient died – both events were classified as a 'Fatal event not otherwise classified' and captured in the table. However, the classification of cellulitis event as a fatal CV event in the adjudicated data was made in error; therefore, septic shock was the only fatal CV event to have occurred among patients HF defined as patients with medical history terms coded as MedDRA preferred term, 'cardiac failure congestive' AE=adverse event; CV=cardiovascular; FDI=ferric derisomaltose; HF=heart failure; IS=iron sucrose; MedDRA=Medical Dictionary for Regulatory Activities2 (1.3)0 (0.0)0.5420 (0.0)3 (0.7)0.035Cannot be classified0 (0.0)1 (1.2)0.3520 (0.0)0 (0.0)–Stroke1 (0.6)0 (0.0)1.0002 (0.2)1 (0.2)1.000Sudden death0 (0.0)0 (0.0)–1 (0.1)0 (0.0)1.000Transient ischemic attack0 (0.0)0 (0.0)–1 (0.1)0 (0.0)1.000p-values were obtained using Fisher's exact test; safety analysis seta Cellulitis was experienced by 1 patient, which progressed to septic shock and the patient died – both events were classified as a 'Fatal event not otherwise classified' and captured in the table. However, the classification of cellulitis event as a fatal CV event in the adjudicated data was made in error; therefore, septic shock was the only fatal CV event to have occurred among patientsHF defined as patients with medical history terms coded as MedDRA preferred term, 'cardiac failure congestive'AE=adverse event; CV=cardiovascular; FDI=ferric derisomaltose; HF=heart failure; IS=iron sucrose; MedDRA=Medical Dictionary for Regulatory Activities Open table in a new tab
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