Assessment of Local Adverse Reactions to Subcutaneous Immunoglobulin (SCIG) in Clinical Trials

Assessment of Local Adverse Reactions to Subcutaneous Immunoglobulin (SCIG) in Clinical Trials J Clin Immunol (2017) 37:517–518 DOI 10.1007/s10875-017-0410-x LETTER TO EDITOR Assessment of Local Adverse Reactions to Subcutaneous Immunoglobulin (SCIG) in Clinical Trials 1 2 3 4 Mark Ballow & Richard L. Wasserman & Stephen Jolles & Helen Chapel & 5 4 Mel Berger & Siraj A. Misbah Received: 8 January 2017 /Accepted: 6 June 2017 /Published online: 10 July 2017 # The Author(s) 2017, corrected publication May/2018 To the editor: protocols is not scientifically possible. More importantly, it is In their recent paper on the North American pivotal trial of a inappropriate to compare preparations and practices that have new 20% immunoglobulin (Ig) for subcutaneous (SC) use, Suez not been evaluated in the same clinical trial. et al. report an incidence of local adverse events (AE) of 0.015 To illustrate the difficulties in making comparisons across events/infusion and compared this to rates reported in other stud- different trials, we reviewed several SCIG studies. Borte et al. ies of different products [1]. Comparison of different products is report that in an EU study of the same product as reported by inappropriate unless the products are studied contemporaneously Suez et al., albeit at approximately one-half the dose, the rate of within the same study using the same methodology, the same local AEs was nearly five times higher, 0.069 events/infusion [3]. investigators, and the same patient populations. Judging the rel- This is similar to another 20% SCIG preparation in an EU study ative tolerability of different products accurately and determining [4]. In comparison, a wide range of rates of local AEs has been whether manufacturing procedures, excipients, infusion supplies, reported in other studies of the latter product: 0.003/infusion to pumps, and/or infusion techniques influence local site tolerability 0.58/infusion (Table 1,ref. 4–6). It seems unlikely that these or more systemic adverse events ideally require blinded head-to- discrepant results reflect actual differences in the tolerability of head comparisons. Crossover designs, in a targeted disease pop- the products in different EU and North American studies, all of ulation of subjects with X-linked agammaglobulinemia and com- which probably involved subjects predominantly of Caucasian mon variable immunodeficiency disorders would be preferable, descent with similar diagnoses. The differences may more likely and assessments should be done by the same group of investiga- reflect differences in what the subjects were taught to expect, the tors using a standardized grading system. In addition, consider- local effect of the volume infused, and in the methods used in ation should be given to collecting and recording the long-term evaluating, recording, and reporting AEs per se. local infusion adverse events that have been described [2]. We Despite these reported differences in tolerability, none of the suggest that comparing different products using different patient studies was a single drug-related serious systemic adverse event populations, different inclusion/exclusion criteria, and different reported. In contrast to the lack of uniformity of methods and timing of describing and recording infusion site Breactions,^ all of the papers use a common well-defined efficacy endpoint, the incidence of acute serious bacterial infections, as defined in guid- * Mark Ballow ance documents published by the FDA [7]and EMA[8]. The mballow@health.usf.edu rates of drug-related AEs, other than local reactions, were all within a narrow range of 0.021 to 0.16 per infusion, confirming Department of Pediatrics, Division of Allergy & Immunology, The the low frequency of systemic adverse reactions related to SCIG Johns Hopkins All Children’s Hospital, Children’sResearch infusions. Finally, another indication of the tolerability of SCIG is Institute, University of South Florida, 140 7th Ave South, St the low percentage of subjects discontinuing treatment. Petersburg, FL 33701, USA 2 Reporting of clinical trials of new SCIG products should provide Medical City Children’s Hospital, Dallas, TX, USA more detail regarding the identification and reporting of local Department of Immunology, University Hospital of Wales, adverse events in the BMethod^ sections and should employ Cardiff, UK uniform terminology and methods for evaluating, recording, Oxford University Hospitals, University of Oxford, Oxford, UK and reporting local as well as systemic infusion-related AEs. CSL Behring, King of Prussia, PA, USA Given the current difficulties in standardizing methodologies 518 J Clin Immunol (2017) 37:517–518 Table 1 Infusion site reactions as reported in different studies of 20% SCIG preparations Author (reference) Product SCIg evaluation Infusion site reaction Non-aSBI systemic Percentage of patients time points rate/infusion AEs rate discontinuing SCIG for local AEs Suez [1] A Continuous as they occur 0.015 0.021 0 Borte [3] A Continuous as they occur 0.069 0.032 2.0 Jolles [4]B 24–72 h 0.056 0.034 6.5 Hagan [5] B 24 ± 3 h 0.58 0.044 4.0 Jolles [6] B 24 ± 3 h (US) 0.524 0.16 0 Jolles [6] B None designated (EU) 0.001 0.09 0 Recorded by the patient using an electronic diary tablet to continuously record home treatments, AEs, and additional information as they occurred. In addition, the patient was contacted by the investigator within 3–5 days after each infusion, either at the study site or at their home for follow-up to ensure appropriate documentation of AEs. The investigators reviewed patients’ eDiary entries at every site visit All patients received a diary to record home treatments, AEs, and additional information continuously as they occurred. In addition, the patient was contacted by the investigator, within 3–5 days after each infusion, either at the study site or at their home for follow-up to ensure appropriate documentation of AEs. The investigators reviewed patients’ diary entries at every site visit Local tolerability was assessed by the patients within 24 to 72 h after infusion and reviewed by the investigators during visits Local reactions were assessed by both patients and investigators. Patients assessed the overall perception of local reactions at 24 ± 3 h after the end of infusion via diaries, using a 5-point scale. Appropriate completion of the diary was monitored at every visit to the study site. Investigators evaluated local reactions (erythema, edema/induration and itching, local pain, and local heat) independently at 15–45-min post-infusion for the first four infusions at the study site and at every visit to the study site, thereafter In addition, local reactions could be reported via standard AE reporting methods at any time during the study No specific time point for assessment of local reactions was designated in the EU extension study; however, local reactions were identified manually from AE diary listings during each study visit across sites and studies, comparisons of Btolerability^ of different References products in reported clinical trials should be avoided. 1. Suez D, Stein M, Gupta S, Hussain I, Melamed I, Paris K, et al. Efficacy, safety, and pharmacokinetics of a novel human immune globulin subcutaneous, 20% in patients with primary immunodefi- Compliance with Ethical Standards ciency diseases in North America. J Clin Immunol. 2016;36:700–12. 2. Datta R, Kuruvilla M, Gill M, de la Morena MT. Association of skin necrosis with subcutaneous immunoglobulin therapy. Ann Allergy Conflict of Interest Mark Ballow received research grant from CSL Behring Immunol. 2014;113:232–3. (61198060) and an investigator for Grifols, speaker honorarium from American 3. Borte M, Kriván G, Derfalvi B, Maródi L, Harrer T, et al. Efficacy, College of Allergy, Asthma and Immunology, Baxalta, Shire, advisory boards and safety, tolerability and pharmacokinetics of a novel human immune consultant for CSL Behring, Shire, and Grifols, Data Safety Monitoring Boards – globulin subcutaneous, 20%: a phase 2/3 study in Europe in patients Prometic, Green Cross, CSL Behring. with primary immunodeficiencies. Clin Exp Immunol 2016. doi: 10. Richard L. Wasserman received a speaker honorarium from American 1111/cei.12866. [Epub ahead of print]. College of Allergy, Asthma and Immunology, Shire, Oklahoma Allergy 4. Jolles S, Bernatowska E, de Gracia J, Borte M, Cristea V, Peter HH, Society, Florida Allergy Society and Intermountain Allergy Society, et al. Efficacy and safety of Hizentra(®) in patients with primary im- Consultant for Gerson Lehman Group, Guidepoint Global, Grifols, munodeficiency after a dose-equivalent switch from intravenous or CSL Behring, Therapure, Prometic, Bioplasma Laboratories and Shire. subcutaneous replacement therapy. Clin Immunol. 2011;141:90–102. Stephen Jolles received support for consulting, conferences, and/or 5. Hagan JB, Fasano MB, Spector S, Wasserman RL, Melamed I, research from CSL Behring, Baxalta, Bio Products Laboratory, Biotest Rojavin MA, et al. Efficacy and safety of a new 20% immunoglobulin AG, Octapharma, Shire, Grifols, LFB Biotechnologies, UCB Pharma and preparation for subcutaneous administration, IgPro20, in patients with Swedish Orphan Biovitrum AB. primary immunodeficiency. J Clin Immunol. 2010;30:734–45. Helen Chapel declares that he has no conflict of interest. 6. Jolles S, Borte M, Nelson RP Jr, Rojavin M, Bexon M, Lawo JP, et al. Mel Berger is a salaried employee of CSL Behring with stock holdings. Long-term efficacy, safety, and tolerability of Hizentra® for treatment of Siraj A. Misbah_s institution has received honoraria for advisory board primary immunodeficiency disease. Clin Immunol. 2013;150:161–9. membership/lectures/research from BPL, Baxalta, Biotest, CSL Behring 7. U.S. Food and Drug Administration, Center for Biologics Evaluation and Grifols. and Research. Guidance for industry: safety, efficacy, and pharma- cokinetic studies to support marketing of immune globulin intrave- nous (human) as replacement therapy for primary humoral immuno- Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http:// deficiency. 2008. creativecommons.org/licenses/by/4.0/), which permits unrestricted use, 8. European Agency for the Evaluation of Medicinal Products, Note for distribution, and reproduction in any medium, provided you give appro- Guidance on the Clinical Investigation of Human Normal priate credit to the original author(s) and the source, provide a link to the Immunoglobulin for Subcutaneous and Intramuscular Use Creative Commons license, and indicate if changes were made. (CPMP/BPWG/283/00), 2002. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Clinical Immunology Springer Journals

Assessment of Local Adverse Reactions to Subcutaneous Immunoglobulin (SCIG) in Clinical Trials

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Biomedicine; Immunology; Infectious Diseases; Internal Medicine; Medical Microbiology
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10.1007/s10875-017-0410-x
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Abstract

J Clin Immunol (2017) 37:517–518 DOI 10.1007/s10875-017-0410-x LETTER TO EDITOR Assessment of Local Adverse Reactions to Subcutaneous Immunoglobulin (SCIG) in Clinical Trials 1 2 3 4 Mark Ballow & Richard L. Wasserman & Stephen Jolles & Helen Chapel & 5 4 Mel Berger & Siraj A. Misbah Received: 8 January 2017 /Accepted: 6 June 2017 /Published online: 10 July 2017 # The Author(s) 2017, corrected publication May/2018 To the editor: protocols is not scientifically possible. More importantly, it is In their recent paper on the North American pivotal trial of a inappropriate to compare preparations and practices that have new 20% immunoglobulin (Ig) for subcutaneous (SC) use, Suez not been evaluated in the same clinical trial. et al. report an incidence of local adverse events (AE) of 0.015 To illustrate the difficulties in making comparisons across events/infusion and compared this to rates reported in other stud- different trials, we reviewed several SCIG studies. Borte et al. ies of different products [1]. Comparison of different products is report that in an EU study of the same product as reported by inappropriate unless the products are studied contemporaneously Suez et al., albeit at approximately one-half the dose, the rate of within the same study using the same methodology, the same local AEs was nearly five times higher, 0.069 events/infusion [3]. investigators, and the same patient populations. Judging the rel- This is similar to another 20% SCIG preparation in an EU study ative tolerability of different products accurately and determining [4]. In comparison, a wide range of rates of local AEs has been whether manufacturing procedures, excipients, infusion supplies, reported in other studies of the latter product: 0.003/infusion to pumps, and/or infusion techniques influence local site tolerability 0.58/infusion (Table 1,ref. 4–6). It seems unlikely that these or more systemic adverse events ideally require blinded head-to- discrepant results reflect actual differences in the tolerability of head comparisons. Crossover designs, in a targeted disease pop- the products in different EU and North American studies, all of ulation of subjects with X-linked agammaglobulinemia and com- which probably involved subjects predominantly of Caucasian mon variable immunodeficiency disorders would be preferable, descent with similar diagnoses. The differences may more likely and assessments should be done by the same group of investiga- reflect differences in what the subjects were taught to expect, the tors using a standardized grading system. In addition, consider- local effect of the volume infused, and in the methods used in ation should be given to collecting and recording the long-term evaluating, recording, and reporting AEs per se. local infusion adverse events that have been described [2]. We Despite these reported differences in tolerability, none of the suggest that comparing different products using different patient studies was a single drug-related serious systemic adverse event populations, different inclusion/exclusion criteria, and different reported. In contrast to the lack of uniformity of methods and timing of describing and recording infusion site Breactions,^ all of the papers use a common well-defined efficacy endpoint, the incidence of acute serious bacterial infections, as defined in guid- * Mark Ballow ance documents published by the FDA [7]and EMA[8]. The mballow@health.usf.edu rates of drug-related AEs, other than local reactions, were all within a narrow range of 0.021 to 0.16 per infusion, confirming Department of Pediatrics, Division of Allergy & Immunology, The the low frequency of systemic adverse reactions related to SCIG Johns Hopkins All Children’s Hospital, Children’sResearch infusions. Finally, another indication of the tolerability of SCIG is Institute, University of South Florida, 140 7th Ave South, St the low percentage of subjects discontinuing treatment. Petersburg, FL 33701, USA 2 Reporting of clinical trials of new SCIG products should provide Medical City Children’s Hospital, Dallas, TX, USA more detail regarding the identification and reporting of local Department of Immunology, University Hospital of Wales, adverse events in the BMethod^ sections and should employ Cardiff, UK uniform terminology and methods for evaluating, recording, Oxford University Hospitals, University of Oxford, Oxford, UK and reporting local as well as systemic infusion-related AEs. CSL Behring, King of Prussia, PA, USA Given the current difficulties in standardizing methodologies 518 J Clin Immunol (2017) 37:517–518 Table 1 Infusion site reactions as reported in different studies of 20% SCIG preparations Author (reference) Product SCIg evaluation Infusion site reaction Non-aSBI systemic Percentage of patients time points rate/infusion AEs rate discontinuing SCIG for local AEs Suez [1] A Continuous as they occur 0.015 0.021 0 Borte [3] A Continuous as they occur 0.069 0.032 2.0 Jolles [4]B 24–72 h 0.056 0.034 6.5 Hagan [5] B 24 ± 3 h 0.58 0.044 4.0 Jolles [6] B 24 ± 3 h (US) 0.524 0.16 0 Jolles [6] B None designated (EU) 0.001 0.09 0 Recorded by the patient using an electronic diary tablet to continuously record home treatments, AEs, and additional information as they occurred. In addition, the patient was contacted by the investigator within 3–5 days after each infusion, either at the study site or at their home for follow-up to ensure appropriate documentation of AEs. The investigators reviewed patients’ eDiary entries at every site visit All patients received a diary to record home treatments, AEs, and additional information continuously as they occurred. In addition, the patient was contacted by the investigator, within 3–5 days after each infusion, either at the study site or at their home for follow-up to ensure appropriate documentation of AEs. The investigators reviewed patients’ diary entries at every site visit Local tolerability was assessed by the patients within 24 to 72 h after infusion and reviewed by the investigators during visits Local reactions were assessed by both patients and investigators. Patients assessed the overall perception of local reactions at 24 ± 3 h after the end of infusion via diaries, using a 5-point scale. Appropriate completion of the diary was monitored at every visit to the study site. Investigators evaluated local reactions (erythema, edema/induration and itching, local pain, and local heat) independently at 15–45-min post-infusion for the first four infusions at the study site and at every visit to the study site, thereafter In addition, local reactions could be reported via standard AE reporting methods at any time during the study No specific time point for assessment of local reactions was designated in the EU extension study; however, local reactions were identified manually from AE diary listings during each study visit across sites and studies, comparisons of Btolerability^ of different References products in reported clinical trials should be avoided. 1. Suez D, Stein M, Gupta S, Hussain I, Melamed I, Paris K, et al. Efficacy, safety, and pharmacokinetics of a novel human immune globulin subcutaneous, 20% in patients with primary immunodefi- Compliance with Ethical Standards ciency diseases in North America. J Clin Immunol. 2016;36:700–12. 2. Datta R, Kuruvilla M, Gill M, de la Morena MT. Association of skin necrosis with subcutaneous immunoglobulin therapy. Ann Allergy Conflict of Interest Mark Ballow received research grant from CSL Behring Immunol. 2014;113:232–3. (61198060) and an investigator for Grifols, speaker honorarium from American 3. Borte M, Kriván G, Derfalvi B, Maródi L, Harrer T, et al. Efficacy, College of Allergy, Asthma and Immunology, Baxalta, Shire, advisory boards and safety, tolerability and pharmacokinetics of a novel human immune consultant for CSL Behring, Shire, and Grifols, Data Safety Monitoring Boards – globulin subcutaneous, 20%: a phase 2/3 study in Europe in patients Prometic, Green Cross, CSL Behring. with primary immunodeficiencies. Clin Exp Immunol 2016. doi: 10. Richard L. Wasserman received a speaker honorarium from American 1111/cei.12866. [Epub ahead of print]. College of Allergy, Asthma and Immunology, Shire, Oklahoma Allergy 4. Jolles S, Bernatowska E, de Gracia J, Borte M, Cristea V, Peter HH, Society, Florida Allergy Society and Intermountain Allergy Society, et al. Efficacy and safety of Hizentra(®) in patients with primary im- Consultant for Gerson Lehman Group, Guidepoint Global, Grifols, munodeficiency after a dose-equivalent switch from intravenous or CSL Behring, Therapure, Prometic, Bioplasma Laboratories and Shire. subcutaneous replacement therapy. Clin Immunol. 2011;141:90–102. Stephen Jolles received support for consulting, conferences, and/or 5. Hagan JB, Fasano MB, Spector S, Wasserman RL, Melamed I, research from CSL Behring, Baxalta, Bio Products Laboratory, Biotest Rojavin MA, et al. Efficacy and safety of a new 20% immunoglobulin AG, Octapharma, Shire, Grifols, LFB Biotechnologies, UCB Pharma and preparation for subcutaneous administration, IgPro20, in patients with Swedish Orphan Biovitrum AB. primary immunodeficiency. J Clin Immunol. 2010;30:734–45. Helen Chapel declares that he has no conflict of interest. 6. Jolles S, Borte M, Nelson RP Jr, Rojavin M, Bexon M, Lawo JP, et al. Mel Berger is a salaried employee of CSL Behring with stock holdings. Long-term efficacy, safety, and tolerability of Hizentra® for treatment of Siraj A. Misbah_s institution has received honoraria for advisory board primary immunodeficiency disease. Clin Immunol. 2013;150:161–9. membership/lectures/research from BPL, Baxalta, Biotest, CSL Behring 7. U.S. Food and Drug Administration, Center for Biologics Evaluation and Grifols. and Research. Guidance for industry: safety, efficacy, and pharma- cokinetic studies to support marketing of immune globulin intrave- nous (human) as replacement therapy for primary humoral immuno- Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http:// deficiency. 2008. creativecommons.org/licenses/by/4.0/), which permits unrestricted use, 8. European Agency for the Evaluation of Medicinal Products, Note for distribution, and reproduction in any medium, provided you give appro- Guidance on the Clinical Investigation of Human Normal priate credit to the original author(s) and the source, provide a link to the Immunoglobulin for Subcutaneous and Intramuscular Use Creative Commons license, and indicate if changes were made. (CPMP/BPWG/283/00), 2002.

Journal

Journal of Clinical ImmunologySpringer Journals

Published: Jul 10, 2017

References

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