scig 20% application who eml 22nov2012...essential medicines list for children for life-long...

CSL Behring AG WHO EML Application SCIG 20% November 2012

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APPLICATION FOR INCLUSION OF

Polyvalent Human Immunoglobulins 20%

for subcutaneous administration

IN THE WHO MODEL LIST OF ESSENTIAL MEDICINES

AND

IN THE WHO MODEL LIST OF ESSENTIAL MEDICINES FOR CHILDREN


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TABLE OF CONTENTS Title Page 1. Summary statement of the proposal for inclusion of Human Normal

Immunoglobulin 20% for subcutaneous administration ............................................... 7

2. Name of the focal point in WHO submitting or supporting the application (where

relevant) ........................................................................................................................ 8

3. Name of the organization(s) consulted and/or supporting the application ................... 8

4. International Nonproprietary Name (INN, generic name) of the medicine ................. 8

5. Formulation proposed for inclusion; including adult and paediatric (if

appropriate) ................................................................................................................... 8

6. International availability - sources, if possible manufacturers and trade names .......... 9

7. Whether listing is requested as an individual medicine or as an example of a

therapeutic group ........................................................................................................ 11

8. Information supporting the public health relevance (epidemiological information

on disease burden, assessment of current use, target population) .............................. 11

8.1 Epidemiological information on disease burden ........................................................ 11

8.1.1 Prevalence ................................................................................................................... 11

8.1.2 Disease burden / PID .................................................................................................. 12

8.2 Assessment of current use .......................................................................................... 12

8.3. Target Population ....................................................................................................... 14

9. Treatment details (dosage regimen, duration; reference to existing WHO and

other clinical guidelines; need for special diagnostics, treatment or monitoring

facilities and skills) ..................................................................................................... 15

10. Summary of comparative effectiveness in a variety of clinical settings .................... 16

10.1 Identification of clinical evidence (search strategy, systematic reviews identified,

reasons for selection/exclusion of particular data) ..................................................... 16

10.2 Summary of available data (appraisal of quality, outcome measures, summary of

results) ........................................................................................................................ 16

10.3 Summary of available estimates of comparative effectiveness .................................. 16

10.3.1 European Studies (NCT00542997 and NCT00751621) ............................................. 16

10.3.2 US Studies (NCT00419341and NCT00719680) ........................................................ 18

10.3.3 Japanese studies (NCT 01199705, NCT01458171) ................................................... 19


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10.3.4 SCIG therapy in elderly PID patients ......................................................................... 19

10.3.5 SCIG therapy in paediatric PID patients .................................................................... 20

11. Summary of comparative evidence on safety ............................................................. 20

11.1 Safety information from Phase III studies ................................................................. 21

11.2 Safety information from Phase I studies .................................................................... 21

11.3 Safety information with regard to excipient L-proline ............................................... 22

11.4. Safety information in the product labeling ................................................................. 23

12. Summary of available data on comparative cost and cost-effectiveness within the

pharmacological class or therapeutic group ............................................................... 24

13. Summary of regulatory status of the medicine (in country of origin, and

preferably in other countries as well) ......................................................................... 25

14. Availability of pharmacopoeial standards (British Pharmacopoeia, International

Pharmacopoeia, United States Pharmacopoeia) ......................................................... 25

15. Proposed (new/adapted) text for the WHO Model Formulary ................................... 26

15.1 Proposed new text for the WHO Model Formulary ................................................... 26

15.2 Proposed new text for the WHO Model Formulary for Children .............................. 27

16. Literature references ................................................................................................... 29

17. Appendices ................................................................................................................. 32


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LIST OF ABBREVIATIONS

AE Adverse event

AR Adverse reaction

ASID African Society for Immunodeficiencies

AUC Area under the concentration-time curve

BPWP Blood products working party

bw Body weight

CI Confidence interval

CL Confidence limit

Cmax Maximum concentration

Ctrough Trough level

DAC Dose adjustment coefficient

EMA European Medicines Agency

EML Model List of Essential Medicines

ESID European Society for Immunodeficiencies

EU European Union

EUR Euro

FDA Food and Drug Administration

GCP Good Clinical Practice

HRQL Health-related quality of life

ICH International Conference on Harmonization

IgA Immunoglobulin A

IgG Immunoglobulin G

IgPro10 CSL Behring's internal company code for their IVIG 10% product


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now marketed under the trade name Privigen®

IgPro16 CSL Behring's internal company code for a developmental IgG 16% product

IgPro20 CSL Behring's internal company code for their SCIG 20% product marketed under the trade name Hizentra®

IPFA International Plasma Fractionation Association

IPOPI International Patient Organisation for Primary Immunodeficiencies

IUIS International Union of Immunological Societies

IV Intravenous

IVIG Human Normal Immunoglobulin for Intravenous Administration

MedDRA Medical Dictionary for Regulatory Activities

MITT Modified intention-to-treat

N Number

NCT ClinicalTrials.gov Identifier

Ph.Eur. European Pharmacopoeia

PID Primary Immunedeficiency

PK Pharmacokinetic(s)

PPTA Plasma Protein Therapeutics Association

SBI Serious bacterial infection

SC Subcutaneous

SCIG Human Normal Immunoglobulin for Subcutaneous Administration

SOC System Organ Class

SPC Summary of Product Characteristics

TLR Trough level ratio

Tmax Time of maximum concentration


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US United States

USA United States of America

USD US Dollar

USIDNET United States Immunodeficiency Network

vs. Versus (compared to)

WHO World Health Organisation


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1. Summary statement of the proposal for inclusion of Human Normal Immunoglobulin 20% for subcutaneous administration

Polyvalent human immunoglobulins are crucial in the life-long treatment of primary immune deficiencies (PIDs), as there is no other treatment for most of these disorders.

Human normal immunoglobulins for intramuscular, intravenous (IVIG), and subcutaneous (SCIG) administration are included in sections 11.2 Plasma fractions for specific use of the World Health Organisation (WHO) Model List of Essential Medicines (EML) and the WHO Essential Medicines List for Children for life-long replacement therapy in individuals with primary immune deficiencies.

In the current lists (17th edition for adults, 3rd edition for children), formulations containing 15% and 16% protein solution are listed for subcutaneous (SC) administration, reflecting the global market situation at the time the applications to WHO were made in 2006/2007. However, in recent years higher concentrated SCIG products (20%) have been developed which allow reduction of infusion volumes and infusion duration. CSL Behring has launched Hizentra®, a SCIG 20%, and plans to replace its 16% SCIG Vivaglobin® by Hizentra® globally in the next years; other companies are also developing SCIG 20% products and it can be expected that they also will replace their currently marketed ≤ 16% products.

Therefore this submission applies for the inclusion of an additional SCIG formulation, human normal immunoglobulin for subcutaneous use containing 20% immunoglobulin G (IgG), in the WHO EML and WHO EML for Children.

Human normal immunoglobulin products are prepared from pooled plasma from not fewer than 1000 donations and contain mainly IgG with a broad spectrum of antibodies against infectious agents that is representative of the immunoglobulin range of the normal population. Adequate doses of these products restore protection against infections in those with immune deficiencies.

The major advantages of SCIG in relation to IVIG relate to the ease of administration and convenience for home treatment, stable serum IgG concentration between infusions, the high safety profile with very few systemic adverse reactions, better patient compliance and shorter infusion times. SCIG was also found to be suitable for patients with poor venous access or with previous adverse reactions to IVIG and to give clinicians and patients the opportunity to use the replacement therapy without the need for premedication with corticosteroids or antihistamins. It is easy for children, adults and elderly patients to learn and handle and can reduce the costs for healthcare systems and families (EMA/CHMP/BPWP/761007/2010).

Clinical research data on the effectiveness and safety of SCIG 20% in the treatment of PIDs are outlined in this application with a focus on the SCIG 20% product manufactured by CSL Behring and approved and marketed under the trade name Hizentra®.

Previous applications for polyvalent human immunoglobulins submitted to the 15th Expert Committee meeting (http://archives.who.int/eml/expcom/expcom15/reinstatement.htm) and the 1st Meeting of the Subcommittee (http://archives.who.int/eml/expcom/children/INDEX_children_07.htm) in 2007 are available online (accessed November 2012) and therefore that data will not be provided here again.


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This application outlines the essential nature and importance of SCIG 20% as a major worldwide public health tool in the treatment and management of children and adults with primary immune deficiencies.

2. Name of the focal point in WHO submitting or supporting the application

(where relevant)

Not applicable 3. Name of the organization(s) consulted and/or supporting the application

This submission should be taken in conjunction with those supporting the applications to the 15th

EML (IVIGs) and the 1st Meeting of the Subcommittee/EML for Children in 2007

(SCIGs).

International Organisations supporting the application to include SCIG 20%:

• International Patient Organisation for Primary Immunodeficiencies (see Appendix 2)

• African Society for Immunodeficiencies (see Appendix 3)

4. International Nonproprietary Name (INN, generic name) of the medicine

Polyvalent human normal immunoglobulin, Immunoglobulinum humanum normale; solution for subcutaneous injection, containing 200 mg/ml (20 %) human normal immunoglobulin.

It is WHO's current policy not to select an INN for each of the immunoglobulins (INN Working Document 05.179).

The ATC Code J06BA01 has been assigned to the active substance, human normal immunoglobulin for extravascular administration.

5. Formulation proposed for inclusion; including adult and paediatric (if appropriate)

It is proposed to add the 20% formulation to the already listed 15% and 16% formulations of human normal immunoglobulin for subcutaneous administration (see section 7).

The SCIG 20% product manufactured by CSL Behring (Hizentra®) has high purity (≥98% IgG and only trace amounts of IgA) and is formulated without preservatives (Jolles and Sleasman 2011). In contrast to other SC IgG preparations, it is stabilized with L-proline (250 mmol/L) (Table 1).


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Table 1: Hizentra® characteristics (Jolles and Sleasman 2011)

Characteristic Parameter Protein concentration 200 g/L IgG content ≥98% IgA content ≤50 μg/mL L-proline 210-290 mmol/L Polysorbate 80 10-30 mg/L Sodium Trace Carbohydrate None Preservatives None Stability

Stable at room temperature (up to 25°C) for up to 24 months

Number of recommended simultaneous sites/infusion

Maximum of 4

Recommended maximal volume/site

15 mL for the first four infusions; maximum 25 mL for following infusions

Recommended maximal infusion rate

15 mL/hour/site for the first infusion; maximum 25 mL/hour/ site for following infusions

IgA=immunoglobulin A; IgG=immunoglobulin G

Human normal immunoglobulin 20% solution for subcutaneous injection is indicated for children and adults (EMA Core SPC; Hizentra SPC; Hizentra US prescribing information).

6. International availability - sources, if possible manufacturers and trade names

To our knowledge the companies listed below manufacture and/or distribute human normal immunoglobulins for subcutaneous administration (tradenames in brackets). Other companies and organisations may also manufacture human normal immunoglobulin products, including SCIGs, for national markets. Baxter (SUBCUVIA, GAMMAGARD Liquid) One Baxter Parkway Deerfield, IL 60015-4625 USA Tel.: +1 847 948 2000 Bio Products Laboratory (SUBGAM) Dagger Lane Elstree Herts WD6 3BX United Kingdom Tel.: +44 20 8957 2342


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CSL Behring (HIZENTRA) P.O. Box 61501 1020 First Avenue King of Prussia, PA 19406 USA Tel.: +1 610 878 4000 Fax: +1 610 878 4009 Grifols (GAMUNEX-C) Avinguda de la Generalitat, 152 Parque empresarial Can Sant Joan 08174 Sant Cugat del Vallès, Barcelona Spain Tel.: +34 93 5712200 Fax: +34 93 5710267 Kedrion S.p.A. (GAMMAKED) Loc. Ai Conti 55051 Castelvecchio Pascoli Barga (Lucca) Italy Tel.: +39 0583 19691 Fax: +39 0583 1969 878 Octapharma (GAMMANORM) Seidenstrasse 2 8853 Lachen Tel.: +41 55 4512121 Fax: +41 55 4512110 Sanquin (GAMMAQUIN) Postbox 9892 1006 AN Amsterdam The Netherlands Tel.: +31 20 512 3000 Fax: + 31 20 512 3303 Currently, a SCIG 20% product is only manufactured and marketed by CSL Behring under the trade name Hizentra®. However, other companies are developing SCIG 20% products and it is expected that they will be approved by regulatory authorities and marketed in the near future. As the SCIG 20% products have advantages compared to the SCIG ≤16% formulations (see section 1), it can be anticipated that they will replace their SCIG 16% and 15% products on the global markets during the next years as well. CSL Behring's Hizentra® was approved for marketing in the USA in March 2010, in the European Union in April 2011 (centralised procedure EMEA/H/C/002127), in Switzerland in June 2011, in Canada in July 2011 and in Argentina in November 2012. Marketing authorisation applications have also been submitted outside Europa and North America, for example in Mexico, Peru and Brazil where regulatory procedures are ongoing,


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and submissions in additional countries, including developing countries, are planned for the near future. CSL Behring plans to replace its SCIG 16% product Vivaglobin® by Hizentra® on a global level when marketing authorisations have been granted.

7. Whether listing is requested as an individual medicine or as an example of a

therapeutic group

Listing is requested on the WHO Model List of Essential Medicines and the WHO Model List of Essential Medicines for Children as an addition to the therapeutic group under:

• section 11.2 Plasma Fractions for specific use

Complementary list

To be added to existing SCIG products 11.2 Plasma fractions for specific use

All plasma fractions should comply with the WHO Requirements for the Collection, Processing and Quality Control of Blood, Blood Components and Plasma Derivatives (Revised 1992). (WHO Technical Report Series, No. 840, 1994, Annex 2).

Complementary List

human normal immunoglobulin

Subcutaneous administration 15%, 16%, 20% protein solution Intravenous administration: 5%, 10% protein solution. Intramuscular administration: 16% protein solution.

8. Information supporting the public health relevance (epidemiological

information on disease burden, assessment of current use, target population)

8.1 Epidemiological information on disease burden

8.1.1 Prevalence

True incidence and prevalence of PIDs are unknown as no population screening takes place for these disorders, prevalence of various PIDs varies in different countries and classification of PIDs is updated regularly (Boyle and Buckley 2007; Al-Herz et al. 2011).

Centres from Europe, Turkey, Egypt, Belarus, Ukraine and Russia that specialise in PID are collaborating to document their patients in the European Society for Immunodeficiencies (ESID) database which as of 27 April 2012 comprises over 15'700 patients documented by 91 centers (ESID 2012). For example, the ESID minimum estimate of prevalence rates calculated from the number of documented cases in the ESID database is 5.6 patients per 100'000 inhabitants for France, 4.23 for Spain, and 2.23 for Turkey. 55.9% of patients are diagnosed with predominantly antibody disorders with 46.99% of alive patients being on Ig replacement and 13.6% on SCIG treatment (ESID 2012). Distribution between age groups shows that two thirds of patients are younger than 20 years (ESID 2012).


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In other countries, national registries exist that are run independently from ESID, for example the Iranian Primary Immunodeficiency Registry established in 1999.

Also in the USA, an online registry has been initiated, the United States Immunodeficiency Network (USIDNET), currently being expanded from eight diseases to include over 30 different genetic disorders (USIDNET 2012). A total of 3025 cases were registered to date in 2012, with the majority being common variable immunodeficiency (853 cases), chronic granulomatous diesease (429 cases), DiGeorge Anomaly (364 cases) and X-linked agammaglobulinaemia (356 cases). A US national probability sample survey contacted 10'000 households by random digit dialing in 2005 to screen nearly 27'000 household members to assess how many had been diagnosed with a PID. The findings suggested a polulation prevalence of diagnosed PID at approximately 1 in 1200 persons (Boyle and Buckley 2007), equating to a population estimate of between 150'000 and 360'000 persons in the USA with diagnosis of PID. This suggests that the diagnosis of PID may be more common than reported in the literature and calculated from registry entries.

As registration of patients with PID is ongoing, the databases will provide emerging insight into the prevalence of PID in each country.

8.1.2 Disease burden / PID

PIDs include a variety of disorders in which there is an intrinsic defect in the immune system that renders patients more susceptible to infections. These infections may be fatal if left untreated. The PID disorders constitute a spectrum of more than 100 defects in the body’s immune system (Notarangelo et al. 2004; Al-Herz 2011). Common PIDs include disorders of humoral immunity (affecting B-cell differentiation or antibody production), T-cell defects and combined B- and T-cell defects, phagocytic disorders, and complement deficiencies. Major clinical manifestations of these disorders include multiple infections despite aggressive treatment, infections with unusual or opportunistic organisms, and failure to thrive or poor growth (Cooper et al. 2003). Immunoglobulin replacement therapy is the standard treatment for patients with immunodeficiency. Providing passive immunity by administering exogenous IgG controls most recurrent infections and results in a significantly improved quality of life for these patients. SCIG products are an effective alternative to IVIG products for patients who prefer self-administration at home, who have poor venous access, or who cannot tolerate systemic adverse events (AEs) associated with IV infusions of IgG.

Please also refer to the submission by IPOPI and IUIS to the 15th Expert Committee meeting – March 2007 (http://archives.who.int/eml/expcom/expcom15/reinstatement.htm).

8.2 Assessment of current use

The recognition of the safe and efficacious treatment of PID patients with immunoglobulins for SC, as well as IV use, is confirmed by recognized regulatory authorities worldwide. For example, the European Medicines Agency has published a Note for Guidance on the clinical development of SCIGs (EMEA/CPMP/BPWP/283/00) and a Core Summary of Product Characteristics for SCIGs (EMEA/CPMP/BPWP/282/00) which emphasize their established use in replacement therapy of PID patients. According to these documents, therapeutic indications are:


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Replacement therapy in adults <and children> in primary immunodeficiency syndromes, such as:

- congenital agammaglobulinaemia and hypogammaglobulinaemia

- common variable immunodeficiency

- severe combined immunodeficiency

- IgG subclass deficiencies with recurrent infections

More recently a Concept Paper for updating both documents (EMEA/CHMP/BPWP/761007/2010) was published which again strengthens the place that SCIGs have in PID therapy. In the US, the FDA Guidance for Industry entitled "Safety, Efficacy, and Pharmacokinetic Studies to Support Marketing of Immune Globulin Intravenous (Human) as Replacement Therapy for Primary Humoral Immunodeficiency" (FDA 2008) also points out the established use of human normal immunoglobulins in therapy of PID.

Clinical data have clearly demonstrated that SC treatment, as well as IV treatment, with polyvalent human immunoglobulins for patients affected by these conditions can be life saving (reduced mortality and morbidity) as well as greatly improve their quality of life. Treatment of PIDs with IVIG/SCIG is well established and recommmended by the Immune Deficiency Foundation (Buckley et al. 2009), other patient organisations and clinical societies (Bonilla et al. 2005; Consensus Statement 2006).

Compared to IVIG treatment, with SC treatment regimens, smaller doses of IgG are given more frequently, resulting in more stable serum IgG concentrations, as indicated by lower peak concentrations and higher trough levels (Ctrough) (i.e., serum concentrations before the next dose) of IgG (see section 10). In contrast, the large IV bolus doses result in rapidly attained and high peak concentrations of serum IgG, followed by an initially rapid decline and a period of more gradual decline to baseline concentrations (Berger 2004; Bonilla 2008). Therefore, SC IgG administration is increasingly widely used (see Fig.1), with use increasing from about 7.5% of patients in 2006 to 13.6% of patients in the first 4 months of 2012, according to the ESID database (ESID 2012).

SCIG replacement therapy is particularly suitable for children as it does not require venous access and smaller needles are used compared to IV infusions; moreover, compared to adults, children require lower volumes for the infusion of prescribed doses which make them well suited for SCIG therapy (Borte et al. 2011). In addition, the possibility to be treated at home is very important for children (see also section 10.3.6). Also in elderly (aged ≥ 65 years) and very elderly (aged ≥ 75 years) patients, home-based therapy of PID with SCIG 16% and 20% was effective and safe and 83% of them self-infused (Stein et al. 2011) (see also section 10.3.5).

The high concentration in a SCIG 20% product allows for infusion of lower volumens compared to currently listed 16% SCIG products administered at equivalent doses, which may reduce the number of infusion sites needed (Jolles et al. 2011b).

The estimated market usage of IVIG versus SCIG products in selected countries for the treatment of PIDs is shown in Figure 1 (Jolles and Sleasman 2011).


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Fig. 1: Estimated market usage of IVIG versus SCIG products in selected countries for the treatment of PIDs

The poor HRQL of untreated patients with PID was markedly improved by IVIG therapy, and further improved by home therapy with SCIG. Studies indicate that patients and caregivers alike perceived SCIG more favourably than IVIG. In investigations where the impact on HRQL of switching from hospital-based IVIG to home-based SCIG was measured, SCIG was highly appreciated by adults and paediatric patients (Gardulf et al. 2004; Gardulf 2007; Hoffmann et al. 2010). Compared with IVIG, several aspects of HRQL improved following SCIG treatment of adults and children with PID, including fewer restrictions and interruptions of family activities, less disruption of daily activities, school and work, and improvements in vitality, mental health and social functioning (Gardulf et al. 2004). Other studies have demonstrated that, when patients already receiving IVIG at home are switched to SCIG, the majority of patients preferred the SC administration route (Gardulf et al. 2008; Nicolay et al. 2006). The impact of Hizentra® on HRQL of PID patients was investigated in the European phase III clinical trial (see section 10.3.1).

8.3. Target Population

People with primary immunodeficiencies have an impaired protection against common pathogenic organisms and as a result suffer life-long life-threatening infections and increasing, permanent, damage to various body organs, especially the lungs and guts. This increasing damage with each infection renders the person more susceptible to more severe and frequent infections. Many of the conditions are genetic and there are no known reliable cures, resulting in a need for life long replacement immunoglobulin therapy. Regular replacement therapy with immunoglobulin is the only way to provide protection and enable those affected to enjoy the benefits of antibodies to fight infection. The provision of immunoglobulin is


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essential to prevent morbidity and mortality in this group of patients, in whom there was, prior to treatment, a considerably shorter lifespan and significant mortality due to life threatening infections.

Please also refer to the submission by IPOPI and IUIS to the 15th Expert Committee meeting – March 2007 (http://archives.who.int/eml/expcom/expcom15/reinstatement.htm)

9. Treatment details (dosage regimen, duration; reference to existing WHO and other clinical guidelines; need for special diagnostics, treatment or monitoring facilities and skills)

Treatment schedules and doses of SCIG 20% are the same as with the SCIG 15-16% products already listed in the WHO EML and EML for children, only infusion volumes are smaller due to the higher content of IgG.

As with IVIG and SCIG 15-16%, the doses of SCIG 20% may need to be individualised for each patient dependent on the pharmacokinetic and clinical response and serum IgG trough levels. This is supported by a recent analysis of seven studies of four different SGIC preparations (including Hizentra®) from three different manufacturers, including data from 322 PID patients on SCIG treatment. Results showed that there is no threshold level above which all patients may be presumed to be in satisfactory health. The author therefore concluded that treatment regimens, doses, and target serum IgG levels should be individualized to optimize treatment effects and costs for individual patients (Berger 2011c).

The dose regimen should achieve a sustained level of IgG. A loading dose of at least 0.2 to 0.5 g/kg (1.0 to 2.5 mL/kg) body weight may be required. This may need to be divided over several days. After steady state IgG levels have been attained, maintenance doses are administered at repeated intervals to reach a cumulative monthly dose of the order of 0.4 to 0.8 g/kg (2.0 to 4.0 mL/kg) body weight.

Trough levels should be measured and assessed in conjunction with the patient’s clinical response. Depending on the clinical response (e.g. infection rate), adjustment of the dose and/or the dose interval may be considered in order to aim for higher trough levels (European Core SPC for SCIGs (EMEA/CPMP/BPWP/282/00); SPC for Hizentra®).

As the posology is given by body weight and adjusted to the clinical outcome (i.e. infection rate), the posology in the paediatric population is not considered to be different to that of adults.

Subcutaneous infusion for home treatment should be commenced and initially monitored by a healthcare professional experienced in the guidance of patients for home treatment. The patient or a caregiver will be instructed in infusion techniques, the keeping of a treatment diary and measures to be taken in case of severe adverse reactions. Infusion pumps appropriate for subcutaneous administration of immunoglobulins can be used (Jolles and Sleasman 2011).


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10. Summary of comparative effectiveness in a variety of clinical settings

10.1 Identification of clinical evidence (search strategy, systematic reviews identified, reasons for selection/exclusion of particular data)

Clinical evidence for the effectiveness of SCIGs in general in the treatment of PIDs has been demonstrated in the application to the 1st Meeting of the Subcommittee/EML for Children in 2007 (http://archives.who.int/eml/expcom/children/INDEX_children_07.htm). As mentioned above (see section 6), SCIG 20% products, for which the present application is made, are currently marketed only by one company, CSL Behring. Therefore, a literature search was not considered relevant and this submission is based on clinical studies performed by the applicant. These studies are summarised in sections 10.2 and 10.3. The clinical evidence for the effectiveness of this SCIG 20% product in PID has been extensively reviewed by Health Authorities in the European Union, the US and other countries before granting marketing authorisations (see section 13). 10.2 Summary of available data (appraisal of quality, outcome measures, summary

of results)

A tabular overview of clinical studies with CSL Behring's SCIG 20% product is provided in Appendix 1. All clinical studies with IgPro20 were conducted in compliance with Good Clinical Practice (GCP), as required by the International Conference on Harmonisation E6 Guideline for GCP. The studies were also in accordance with the principles laid down in the Declaration of Helsinki (version of 1996, as the version of 2000 was never completely accepted by the scientific community and regulatory authorities) and met the requirements for the sponsor’s standard operating procedures for clinical investigations and documentation, applicable national laws and regulations, and the ethical principles of Clinical Trials Directive 2001/20/EC of the European Parliament. CSL Behring's Phase III studies with their SCIG 20% product are summarised in section 10.3, Phase I studies in section 11. 10.3 Summary of available estimates of comparative effectiveness

Pivotal Phase III studies with CSL Behring's SCIG 20% product have been conducted in Europe, USA and Japan; these studies are summarized below. 10.3.1 European Studies (NCT00542997 and NCT00751621)

A prospective, open-label, multicenter, single-arm, Phase III study evaluated the efficacy and safety of Hizentra® in 51 PID patients (including 25 subjects < 18 years of age) over 40 weeks. Patients previously on intravenous or subcutaneous IgG were switched to weekly subcutaneous infusions of Hizentra® at doses equivalent to their previous treatment during a 12-week wash-in/wash-out period, followed by a 28-week efficacy assessment period during which the efficacy and safety of Hizentra® were evaluated (NCT00542997; Borte et al. 2011; Jolles et al. 2011a).

The efficacy analysis was conducted in 46 subjects, including 17 children from 2 to


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< 12 years of age and 5 adolescents from 12 to < 16 years of age, and the PK analysis was conducted in 23 subjects, including 9 children from 2 to < 12 years of age and 3 adolescents from 12 to < 16 years of age.

IgG levels achieved with Hizentra® were similar to pre-study levels with subcutaneous, and higher by 17.7% than pre-study levels with intravenous IgG. Weekly administration of Hizentra® treatment resulted in stable IgG levels in children and adults.

A pharmacokinetic substudy in 23 subjects (including 9 children and 3 adolescents) was conducted in Week 28±1. As expected for steady-state concentrations, changes in serum IgG concentrations during one dosing interval (Week 28±1) were small: mean values measured throughout Week 28 ranged between 7.44 and 7.98 g/L. The mean maximum serum IgG concentration (Cmax) of 8.26 g/L was achieved after 2.06 days (mean Tmax). The mean AUClast was 53.70 g·day/L (Jolles et al. 2011a).

No serious bacterial infections were reported in the efficacy period. The rate of all infections was 5.18/year/patient (95% CI: 4.305; 6.171), the rates of days missed from work/school, and days spent in hospital were 8.00/year/patient and 3.48/year/patient, respectively. Local reactions (rate 0.060/infusion) were mostly mild (87.3%). No serious, Hizentra®-related adverse events were reported (Jolles et al. 2011a). Individual median infusion durations ranged between 1.14 and 1.27 h.

The results of patient evaluation of treatment satisfaction with Hizentra® showed a significant improvement from baseline to study end in the domain ‘Convenience’ in patients switching from IVIG and sustained treatment satisfaction in patients switching from SCIG, suggesting favorable effects on patients' quality of life:

At baseline, the HRQL, as assessed by the Life Quality Index and Treatment Satisfactory Questionnaire for Medication, was better in patients previously on SCIG than in those previously on IVIG. After switching to Hizentra®, the HRQL remained stable for the former and improved for the latter, with a statistically significant change in median Treatment Satisfactory Questionnaire for Medication domain score for “convenience” (from 55.6 at baseline to 83.3 at study end; 95% CI: 22.2, 38.9) (Jolles and Sleasman 2011).

Hizentra® maintained or improved serum IgG levels without dose increases and effectively protected patients against infections (Jolles et al. 2011). The overall efficacy was similar in paediatric patients and adults, no paediatric-specific dose requirement was necessary (Borte et al. 2011).

Patients from the pivotal study continued with the same weekly Hizentra® dose in a prospective, multicenter, open-label, single-arm Phase III extension study (Borte et al. 2012). Efficacy endpoints included maintenance of IgG trough levels, rate of overall and serious bacterial infections, days missed off school/work, rate of hospitalization, and antibiotic use.

Forty patients aged 4-52 years received 5405 infusions at a median IgG dose of 116 mg/kg (range 58-136) for 148 weeks (range 9-166). The median serum trough IgG level achieved was 8.12 g/L (interquartile range: 7.15-8.74). The annualized rate of any infections was 3.33 events/patient, and that of SBIs, 0.048 events/patient (upper 99% confidence interval, 0.125). Other clinical outcomes were also favorable: 6.8 days of work/school missed, 1.1 days of hospitalization due to infection, and 72.1 days on antibiotics were reported per patient/year. Fourteen patients experienced 18 serious adverse events (AEs) that were unrelated to study drug; 0.09 AEs per infusion were reported. Local tolerability was very good, with 0.0013 AEs per infusion. In conclusion, long-term Hizentra® treatment at stable doses resulted in sustained IgG levels and effective protection from infections (Borte et al. 2012).


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10.3.2 US Studies (NCT00419341and NCT00719680)

A multicentre, single-arm, prospective, open-label, Phase III study was conducted in the US that evaluated the PK, efficacy, safety, and tolerability of IgPro20 in subjects with PID over 15 months (NCT00419341; Hagan et al. 2010; Wasserman et al. 2011).

Forty-nine patients (including 10 paediatric subjects < 16 years of age and 6 elderly subjects ≥ 65 years of age) previously treated with IVIG received weekly SC infusions of IgPro20 during a 12-week wash-in/wash-out period, followed by a 12-month efficacy period. Following the FDA Guidance for Industry for developing IVIG products (FDA 2008) doses in the efficacy period were adjusted to provide non-inferior serum IgG concentrations (based on AUC values) compared to the concentrations obtained during the subjects’ previous IVIG therapy (see details of PK substudy below). The primary objective was to evaluate whether the annual rate of SBIs per subject during the efficacy period was < 1.

Because the doses of IgPro20 administered in this study were higher than in the pivotal Phase III study conducted in Europe, the safety data are relevant to the safety of IgPro20 when administered at the lower doses recommended in Europe.

The primary efficacy endpoint was the annual rate of SBIs. Since none of the subjects in this study had an SBI, i.e., the annual rate per subject was 0 (upper 99% confidence limit: 0.132 for the modified intention-to-treat (MITT) population in the efficacy period starting with Week 13), the rate was < 1 and the primary objective of the study for demonstrating the efficacy of IgPro20 was clearly met.

Of the subjects treated during the efficacy period, 31 subjects (81.6%) had an infection (annual rate: 2.76 infections/subject/year; 95% CI: 2.235-3.370). The most frequent infection was sinusitis (0.40 infections/subject/year), followed by nasopharyngitis and bronchitis (both 0.20 infections/subject/year). Twelve subjects (31.6%) missed work/school/kindergarten/day care or were unable to perform normal activities due to infections on a total of 71 days (annual rate: 2.06 days/subject/year), 1 subject was hospitalized due to infection (annual rate: 0.20 days/subject/year), and 27 subjects (71.1%) used antibiotics on 1688 days (annual rate: 48.5 days/subject/year) for AEs, prophylaxis, or medical/surgical/current condicitons.

A two-part PK substudy was conducted in a subset of 18 subjects (Wasserman et al. 2011). Part I determined the appropriate dose adjustment to achieve equivalent serum IgG exposure with SC IgPro20 treatment for use during the subsequent 12-month efficacy period, as compared to the previous IVIG treatment. Part II evaluated the primary objective of the PK substudy, i.e., whether the selected individual SC dose regimens for IgPro20 resulted in steady-state AUC values for serum IgG that were non-inferior to those obtained with the previous IVIG dose regimen. In addition, steady-state serum PK parameters for total IgG, IgG subclasses, specific IgGs, and L-proline were assessed at Week 28 ± 1 during the efficacy period.

Overall, mean serum IgG trough levels in the efficacy period were maintained between 12.1 and 12.9 g/L, and no IgG Ctrough values < 5 g/L were observed. Thus, at the start of SCIG therapy, doses can be selected by means of published mean dose adjustment coefficient (DAC) or mean trough level ratio (TLR), with subsequent dose adjustment for long-term maintenance therapy guided by the clinical response of each patient.

In an extension study (NCT00719680; Nelson RP et al. 2012) of the 52-week study, longer-term (11−104 weeks, median 87 weeks) outcomes, including efficacy, tolerability, and HRQL in 21 subjects treated at home were assessed. Maximum infusion rates were 35 mL/h (1 pump)


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or 70 mL/h (2 pumps; maximum volume=40 mL/site; ≤4 sites/infusion). The SBI rate was 0.06/subject-year (2 pneumonia cases), and total infection rate was 2.4/subject-year. Subjects were hospitalized a mean of 0.55 days/subject-year and missed work/school or were unable to perform normal activities a mean of 4.3 days/subject-year. Antibiotics were used a mean of 84 days/subject-year. Mean IgG levels were 11.7−12.8 g/L. HRQL scores were consistent with US norms; treatment satisfaction remained high and stable. The local adverse reaction rate was 0.5/infusion; 99.1% were mild. Adverse event and local reaction rates were similar among subjects infused at low (<35 mL/h), medium (35−50 mL/h), and high (>50−70 mL/h) rates.

Hizentra® was well-tolerated and effective over an extended period in subjects with PID. Adverse event rates were similar among low, medium, and high infusion rate patients.

10.3.3 Japanese studies (NCT 01199705, NCT01458171)

A prospective multicenter, open-label, single-arm Phase III study performed in Japan consisted of an IVIG treatment period with 3 infusions, followed by a 12-week wash-in/wash-out period and a 12-week efficacy period during which SCIG 20% (Hizentra®) was given weekly at doses (median 77.82 mg/kg/week, range 26.7-172.7) equivalent to those in the IVIG period (NCT 01199705; Miyawaki et al. 2012). The primary endpoint was serum IgG level with SCIG therapy; secondary endpoints included rate of infection, hospitalization, and antibiotic use.

Twenty-five patients (11 of them ≤16 years old) were enrolled; 24 completed the study. The primary objective was met: mean (±SD) serum IgG levels increased from 6.51±1.32 g/L in the IVIG period to 7.28±1.47 g/L in the SCIG efficacy period (geometric mean SCIG/IVIG ratio: 1.09; 90% CI: 1.06-1.13). There were no serious bacterial infections. The rate of non-serious infections/patient/year was 2.98. Twenty-four patients experienced 267 AEs (173 possibly related), the most common being local reactions of mild intensity. The mean life quality index total score increased from 53.7±19.5 at Week 1 (IVIG) to 71.5±15.1 at Week 24 (SCIG).

This study confirmed the results obtained in European and US trials: Hizentra® treatment maintained high serum IgG levels, provided effective passive immunity in adults and children with PID to control most recurrent infections, and improved life quality. A follow-up extension study has been completed, data analysis is still ongoing and therefore results are not yet available.

10.3.4 SCIG therapy in elderly PID patients

A retrospective chart review of 47 elderly patients (age 65 to 89 years) with PID in a single clinical practice in the United States evaluated the practicality, safety, and efficacy of home-based SCIG infusions in elderly patients with PID over a 13-month period (Stein et al. 2011). All 47 patients who had elected to receive SC treatment received SCIG 16% or 20% infusions at home; 39 (83.0%) self-infused the medication. Most patients (n = 46; 98%) received weekly infusions, requiring a mean duration of 65.3 minutes. The mean SCIG dose of 103 mg/kg/week resulted in a mean steady-state serum IgG concentration of 1074 mg/dL. Two patients experienced serious infections on SCIG: an exacerbation of chronic obstructive pulmonary disease/bronchitis, and an abscess. There were no serious systemic AEs. Local injection site reactions, including swelling, redness, burning, or itching, were considered mild or moderate by the patients and resolved within 24 hours. No bruising, bleeding, or skin


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breakdown occurred, despite concomitant anticoagulant or platelet inhibitor treatment in 45% of patients. Two patients discontinued home-based SCIG, but did not continue any IgG treatment. No patient switched from SCIG to another route of IgG treatment. In summary, home-based SCIG was safe and effective in elderly and very elderly (≥ 75 years) patients who may have comorbid condiditons and receive concomitant therapies. Most of them could self-infuse. Infection rates were low, and no AEs or difficulties in administering SCIG occurred that resulted in treatment discontinuation. 10.3.5 SCIG therapy in paediatric PID patients

As discussed in section 8.2, SC administration has several advantages compared to IV treatment. Subcutaneous IgG treatment for PID is particularly well suited for children because it does not require venous access and systemic adverse events rates are lower. In addition, for children in particular, the possibility to be treated at home is important. On account of its higher IgG concentration, the use of a 20% SCIG formulation reduces the infusion volume and duration of infusion compared to the currently listed 15% and 16% SCIG products. As described in section 10.3.1, in the prospective, open-label, multicenter, single-arm, Phase III study conducted in Europe (NCT00542997; Borte et al. 2011; Jolles et al. 2011a) 18 children and five adolescents with PID were switched from previous intravenous (IVIG) or subcutaneous (SCIG) IgG treatment to receive dose-equivalent, weekly subcutaneous infusions of Hizentra® for 40 weeks. The efficacy analysis was conducted in 46 subjects, including 17 children from 2 to < 12 years of age and 5 adolescents from 12 to < 16 years of age, and the PK analysis was conducted in 23 subjects, including 9 children from 2 to < 12 years of age and 3 adolescents from 12 to < 16 years of age. Mean IgG trough levels were maintained in patients previously on SCIG, or increased in those previously on IVIG, regardless of age. No serious bacterial infections were reported during the efficacy period of the study. The rates of non-serious infections were 4.77 (children) and 5.18 (adolescents) infections per patient per year. Related AEs were observed in seven children (38.9%) and two adolescents (40%). Three serious AEs and

two AEs leading to discontinuation (all unrelated) were reported in children. In conclucion, Hizentra® showed to be an effective and well tolerated treatment for paediatric patients (Borte et al. 2011). No paediatric-specific dose requirements were necessary to achieve the desired serum IgG levels. This data support the application for including SCIG 20% to the WHO EML for Children.

11. Summary of comparative evidence on safety

As Hizentra® has only recently been approved for marketing it is still in the launch phase in most countries and therefore reliable patient exposure data are not yet available. In the USA the product is currently used in about 10'000 patients.

The risks of parenteral treatment with immunoglobulins has been discussed in previous applications for polyvalent human immunoglobulins submitted to the 15th Expert Committee meeting (http://archives.who.int/eml/expcom/expcom15/reinstatement.htm) and to the 1st Meeting of the Subcommittee/EML for Children in 2007 (http://archives.who.int/eml/expcom/children/INDEX_children_07.htm).


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Evidence for the safety of SCIG products in general in the treatment of PIDs has been provided in the application to the 1st Meeting of the Subcommittee/EML for Children in 2007 (http://archives.who.int/eml/expcom/children/INDEX_children_07.htm). The safety information for the SCIG 20% product developed by CSL Behring (IgPro20, Hizentra®) was reported in clinical studies as summarised in section 10 above (Hagan et al. 2010, Jolles et al. 2011a, Jolles et al 2011b, Borte et al. 2011). Additional supportive data on the safety of IgPro20 was provided by a Phase I safety study that was conducted in healthy male subjects during development of Hizentra® and is summarised below for completeness. As part of the marketing authorisation of Hizentra®, a pharmacovigilance plan was implemented (EMA/CHMP/110226/2011). Suspected adverse drug reactions for medicinal products authorised in the EU through the centralised procedure are published by EMA in the "European database of suspected adverse drug reaction reports" available at www.adrreports.eu; this database is updated regularly and also includes information on Hizentra®. Safety data are regularly evaluated by CSL Behring, and updated and summarised information is provided in the respective sections of the product labeling (Hizentra US prescribing information; Hizentra EU SPC). Based on the findings in clinical studies and post-marketing experience, it can be concluded that SC treatment with CSL Behring's SCIG 20% product Hizentra®/IgPro20 is safe and well tolerated. 11.1 Safety information from Phase III studies

In the European and the US Phase III trials (Jolles et al. 2011a; Hagan et al. 2010), Hizentra® was well tolerated by PI patients (Jolles and Sleasman 2011). As expected with SC infusions, the most common AEs were local injection site reactions, with rates of 0.580 events/infusion and 0.060 events/infusion in the US and European trials, respectively. Patients’ tolerability to local reactions improved over time. Systemic AEs, such as headache, fatigue, and nausea were relatively rare. For example, the rate of headache was 0.018 events/infusion in the US trial and 0.029 events/infusion in the European trial. No serious AEs were considered related to Hizentra® treatment.

Safety data from the clinical studies are also summarised in section 10 above.

11.2 Safety information from Phase I studies

Additional supportive safety information is available from a Phase I study conducted during development of IgPro20 in male heathy volunteers to assess tolerability and safety of IgPro20 in comparison to marketed IgG products (see overview in Appendix 1).

A single-center, randomized, four-way crossover, assessment-blinded study was performed in 28 healthy, male, white subjects aged 18 to 45 years to compare the local tolerability of IgPro16 and IgPro20 with the marketed 16% SCIG Vivaglobin® (Hagan et al. 2010).


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Each patient received a single subcutaneous dose of IgPro16/Vivaglobin® 15 mL, IgPro20 15 mL, IgPro20 12 mL, or Vivaglobin® 15 mL at a single abdominal site on day 1 at 25 mL/h. The next test samples were administered at weekly intervals at different abdominal sites.

The primary end point was assessment of local tolerability. Evaluation of local tolerability was based on the subjects’ assessment of pain and assessment of various other symptoms (erythema, oedema/induration, local heat, and itching) by the blinded investigator.

Maximum and mean pain associated with infusion were assessed as very low and were lower with IgPro20 than with Vivaglobin®. Intensity of eythema was less severe with IgPro20 than with Vivaglobin® and no substantial differenecs beween products were seen with regard to edema/induration, itching and local heat. Thus, in this Phase I trial, IgPro20 was not inferior in its safety and tolerability when compared with Vivaglobin®.

In another Phase I study conducted during development of Hizentra®, its safety and tolerability after IV administration was compared with the IVIG product Privigen®. As IV administration does not provide relevant information for and is outside the scope of this application, this study is only mentioned for completeness, but details are not discussed here.

11.3 Safety information with regard to excipient L-proline

CSL Behring's SCIG 20% product Hizentra® contains the excipient L-proline (250 mmol/L). L-proline stabilizes Hizentra® at room temperature throughout the shelf-life (Berger 2011b) and it decreases the viscosity of the highly concentrated IgG solution to a level comparable to a 16% solution stabilized with glycine which has commonly been used in IgG products (Maeder et al. 2011, Hagan et al. 2012). L-proline is known to be well tolerated in humans, and there is a long history of its safe administration as a medicinal product in high doses for parenteral nutrition, which is also indicated for premature and/or newborn babies. During the development of CSL Behring's IVIG 10% product Privigen®, the safety of L-proline was specifically investigated in nonclinical and clinical studies, which consistently revealed no safety signals of concern (Hagan et al. 2012). Due to the higher IgG concentration of Hizentra® compared to Privigen®, and the equal concentration of L-proline, lower amounts of L-proline are administered with IgPro20 than with Privigen® (i.e., 144 mg/kg bw vs. 288 mg/kg bw at 1 g IgG/kg). Furthermore, the doses administered per infusion are lower with Hizentra® compared to Privigen® due to the different dosing schedules. There were no safety concerns associated with the administration of L-proline in the clinical studies with IgPro20. The pre-infusion serum concentrations of L-proline were within the normal range (120 to 450 μmol/L) in almost all subjects in both Phase III studies, and generally concurred with the expected physiological range. One day after infusion of IgPro20 at steady-state, the serum L-proline concentration had returned to approximately the same level as before the infusion, indicating rapid elimination of L-proline and a lack of accumulation. The amount of L-proline given did not exceed 58 mg/kg bw in the US Phase III study, in which higher doses compared to the European pivotal Phase III study were administered. There is no evidence to suggest that patients with defects of proline metabolism would be affected by transient elevations in plasma proline following Hizentra® treatment. Nevertheless, L-proline-stabilized IgG products should be contraindicated in patients with hyperprolinaemia.


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11.4. Safety information in the product labeling

As an example for safety information in product information texts, section 4.8 of the EU SPC is provided here (the current version of the complete EU SPC and the US prescribing information are provided with the References to this application); please note that the first paragraph entitled "summary of safety profile" originates from section 4.8 of the EU Core SPC and is therefore not specific for Hizentra® but is a class-labelling for all SCIGs in the EU: Summary of safety profile Adverse reactions such as chills, headache, fever, vomiting, allergic reactions, nausea, arthralgia, low blood pressure and moderate low back pain may occur occasionally. Rarely human normal immunoglobulins may cause a sudden fall in blood pressure and in isolated cases, anaphylactic shock, even when the patient has shown no hypersensitivity to previous administration. Local reactions at infusion sites: swelling, soreness, redness, induration, local heat, itching, bruising and rash. For safety with respect to transmissible agents, see section 4.4. Tabulated summary of adverse reactions Adverse Reactions (ARs) have been collected from one phase I study with healthy subjects (n = 28) and two phase III studies in patients with primary immunodeficiency (n = 100) with Hizentra. The ARs reported in these three clinical studies are summarised and categorised according to the MedDRA System Organ Class and frequency below. Frequency per infusion has been evaluated using the following criteria: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), and rare (≥1/10,000 to <1/1,000). Frequency of Adverse Reactions (ARs) in clinical studies with Hizentra System Organ Class (SOC, MedDRA)

Frequency of ARs (MedDRA Preferred Term, PT) Very

common (≥1/10)

Common (≥1/100 to

<1/10)

Uncommon (≥1/1,000 to

<1/100)

Rare (≥1/10,000 to <1/1,000)

Infections and Infestations

Nasopharyngitis

Immune system disorders

Hypersensitivity

Nervous system disorders

Headache Dizziness, migraine, psychomotor hyperactivity, somnolence

Cardiac disorders Tachycardia Vascular disorders Haematoma, hot flush Respiratory, thoracic and mediastinal disorders

Cough

Gastrointestinal disorders

Vomiting Abdominal discomfort, abdominal distension, abdominal pain, abdominal pain lower, abdominal pain upper, diarrhoea, nausea

Skin and subcutaneous tissue disorders

Pruritus Dermatitis contact, erythema, rash, urticaria


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System Organ Class (SOC, MedDRA)

Frequency of ARs (MedDRA Preferred Term, PT) Very

common (≥1/10)

Common (≥1/100 to

<1/10)

Uncommon (≥1/1,000 to

<1/100)

Rare (≥1/10,000 to <1/1,000)

Musculoskeletal and connective tissue disorders

Arthralgia, back pain, muscle spasms, muscular weakness, musculoskeletal pain, myalgia, neck pain, pain in extremity

Renal and urinary disorders

Haematuria

General disorders and administration site conditions

Injection/ infusion site reactions

Fatigue, pain Chest pain, chills, feeling cold, hypothermia, influenza like illness, malaise, pyrexia

Investigations Aldolase increased, blood creatine phosphokinase increased, blood lactate dehydrogenase increased, blood pressure increased, body temperature increased, weight decreased

Injury, poisoning and procedural complications

Contusion

12. Summary of available data on comparative cost and cost-effectiveness

within the pharmacological class or therapeutic group

Reference is made to the application submitted to the 15th Expert Committee meeting (http://archives.who.int/eml/expcom/expcom15/reinstatement.htm) which provided cost-effectiveness information for immunoglobulin replacement therapy in PIDs. Data demonstrating the cost-effectiveness of SCIG in PIDs has been submitted with the application to the 1st Meeting of the Subcommittee (http://archives.who.int/eml/expcom/children/INDEX_children_07.htm) in 2007 (publications by Hogy et al. 2005 and Gardulf et al.1995) and were summarized by Jolles and coworkers (Jolles et al. 2011b).

More recently, a review of pharmacokinetic studies and applications of SCIG therapy also discussed pharmacoeconomics of SCIG versus IVIG treatment in the US (Berger 2011a), including costs for the IgG products, pumps and other supplies for therapy. The author concluded that costs to payers should be about the same for both routes, but that there may be significant savings in travel costs and time lost from work for patients who self-infuse at home, which in turn is facilitated by SCIG.

A Canadian government assessment concluded that i.v. infusions at home would be the least expensive form of replacement therapy, with SCIG at home only slightly more expensive, but with office or hospital-based IV infusions most expensive (Ho et al. 2008). A recent comparison of the actual costs accrued during patients’ last year on IVIG vs. the following year on SCIG showed that costs of pumps and supplies for SCIG were almost exactly offset by facility and administration costs for IVIG. However, when travel and time lost from work were included, SCIG was less expensive than IVIG by USD 2830 per year/patient (P<0.01) (Ducruet et al. 2011).


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A study presented in October 2012 by Zbrozek and coworkers (Zbrozek et al. 2012) provides a comprehensive evaluation of pharmacoeconomic factors in switching from IVIG to SCIG therapy. A pharmacoeconomic modeling from payer perspective over one year of SCIG vs. IVIG was conducted: a 65 kg patient on IVIG dosed 0.48 g/kg every 4 weeks was modeled for the switch to SCIG at 0.120 g/kg/week (1:1). Current price differences were USD 3-10/g (USA) and EUR 3-10 (EU). At-home IgG infusions avoid 13 annual in-center infusion days, saving USD 1'698/EUR 1'290 per patient in costs. A switch from IVIG dosed 0.568 g/kg every 4 weeks to SCIG 0.213 g/kg/week (1.5:1) was also modeled. The 1.5:1 dosing resulted in additional annualized benefits per patient of 2.42 fewer infections (mean USD 8'684 per episode), 3.28 fewer hospital days, and 24 fewer days of antibiotics. Value of SCIG dosing 1:1 ranged from annual net savings of EUR 73.20 to net additional cost of EUR 2'766 per patient. Additional cost translated to EUR 212.77 spent per day avoided in the infusion center. SCIG dosing 1.5:1 led to net direct medical cost savings of USD 663-4'023 per patient which depended on the cost of infections avoided. The authors concluded that SCIG vs. IVIG at 1:1 dosing either saves costs or is cost-effective over a wide range of IVIG prices. 1.5:1 dosing of SCIG is cost-saving by avoiding additional infections. These results support dosing being individualized based on the patient's clinical condition.

13. Summary of regulatory status of the medicine (in country of origin, and preferably in other countries as well)

Currently, a SCIG 20% product is only manufactured and marketed by CSL Behring under the trade name Hizentra®. Hizentra® was approved for marketing in the USA in March 2010, in the European Union in April 2011 (centralised procedure EMEA/H/C/002127), in Switzerland in June 2011, in Canada in July 2011 and in Argentina in November 2012. Marketing authorisation applications have also been submitted outside Europe and North America, for example Mexico, Peru and Brazil where regulatory procedures are ongoing, and submissions in additional countries are planned for the near future. 14. Availability of pharmacopoeial standards (British Pharmacopoeia,

International Pharmacopoeia, United States Pharmacopoeia)

The European Pharmacopoeia (Ph.Eur.) contains a monograph for human normal immunoglobulin (Ph. Eur. monograph 0338) and in addition a monograph for human normal immunoglobulin for intravenous administration (Ph. Eur. monograph 0918). The specification for CSL Behring's SCIG 20% product is fully compliant with the current European Pharmacopoeia (Ph. Eur.) Monograph 338 for human normal immunoglobulin, except with respect to protein content and pH. Ph. Eur. Monograph 338 specifies a total protein content of 100 to 180 g/L and a pH of 5.0 to 7.2 whereas IgPro20/Hizentra, as an SCIG product that has been specifically designed to have a higher IgG content than currently marketed SCIG products, has a total protein content of 180 to 220 g/L together with a pH of 4.6 to 5.2. Ph. Eur. Commission Group 6B concluded that the clinical data available for


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IgPro20/Hizentra confirmes that the higher protein content and the lower pH had no negative impact on the clinical safety and tolerability of the product. The group therefore agreed that the data were satisfactory subject to a licence for marketing approval of IgPro20/Hizentra being granted by a competent authority, and that the Ph. Eur. Monograph 338 should then be revised with respect to SCIG products. On this basis, IgPro20/Hizentra® was considered as being effectively compliant with the Ph. Eur. Monograph 338 for human normal immunoglobulin. In the meantime Ph. Eur. Commission Group 6B has decided to generate a new monograph for human normal immunoglobulin for subcutaneous administration (planned Ph. Eur. monograph 2788) in addition to monographs 0338 and 0918. Implementation of this new monograph 2788 has delayed publication of the agreed revisions regarding protein content and pH. 15. Proposed (new/adapted) text for the WHO Model Formulary

The applicant proposes to add human normal immunoglobulin for subcutaneous administration 20% protein solution to the WHO Model Formulary and WHO Model Formulary for Children. The proposed changes are limited to the addition of 20% protein solution as highlighted in blue colour in sections 15.1 and 15.2. 15.1 Proposed new text for the WHO Model Formulary

Human normal immunoglobulin Intramuscular administration: 16% protein solution* Intravenous administration: 5%; 10% protein solution** Subcutaneous administration: 15%; 16%; 20% protein solution* *Indicated for primary immune deficiency. **Indicated for primary immune deficiency and Kawasaki disease Normal immunoglobulin Normal immunoglobulin solution is administered by intravenous infusion for primary immunodeficiencies and immunomodulation in autoimmune disease including Guillain-Barré syndrome and Kawasaki disease. Solutions for intramuscular and subcutaneous injection are used for primary immune deficiency. Normal immunoglobulin should be used in hospital settings where specialist supervision is available. Normal immunoglobulin (human, polyvalent) Plasma fractions should comply with the Requirements for the Collection, Processing and Quality Control of Blood, Blood Components and Plasma Derivatives (Revised 1992). WHO Technical Report Series No. 840, 1994, Annex 2. NOTE. Formulations from different manufacturers vary and should not be regarded as equivalent; consult individual manufacturer’s product literature. Uses: replacement therapy in primary immunodeficiency, Kawasaki disease. Precautions: monitor vital signs; interactions: Appendix 1. Dose: NOTE. National recommendations may vary. Consult individual manufacturer’s product literature for dose and administration recommendations for specific diseases; recommended doses may vary from those listed below.


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Replacement therapy in primary immunodeficiencies: Initial loading intravenously in divided doses until serum IgG level is > 6 g/l. Maintenance doses by intravenous, subcutaneous or intramuscular routes: normally 0.4 –0.8 g/kg/month for children and adults. Dose to be titrated depending on inter-current infections or trough serum IgG level. Intravenous doses may be given at one, two, 3 or 4 week intervals. Subcutaneous doses may be given at 1, 2, 3, 4 or 7 day intervals.

For immunomodulation in autoimmune conditions: Maximum recommended dose is 2g/kg over at least 48 hours. Depending on specific autoimmune disease: 0.4 g/kg/day for 5 days or 0.8-1 g/kg the first day and repeated once if indicated.

ADMINISTRATION. Infusion rates of less than 8 g per hour are recommended. Immunoglobulin should be administered under the supervision of an immunologist or other experienced physician. In general, this should be in a hospital with adequate facilities for monitoring the infusion as well as the condition for which it is being administered, until the patient is stable, at which point treatment at home can be considered after formal training in an expert centre. Adverse effects: nausea, vomiting, headache (may develop 24 hours after infusion); dizziness, dry mouth, chills, sweating, hypothermia, fever, eczema, rash, urticaria, hypotension, wheezing; anaphylactoid reactions also reported; with immunomodulatory doses also immune haemolysis, aseptic meningism, increased plasma viscosity, hypercoagulopathy, and renal impairment. Interactions acc. to Appendix 1 of Formulary: Immunoglobulin, Human normal * Vaccine, Live Avoid use of live vaccine during 3 weeks before or during 3 months after injection of human normal immunoglobulin (impairment of immune response) 15.2 Proposed new text for the WHO Model Formulary for Children

Human normal immunoglobulin ATC code: J06BA02 Intramuscular administration: 16% protein solution* Intravenous administration: 5%; 10% protein solution** Subcutaneous administration: 15%; 16%; 20% protein solution*

Intravenous human normal immunoglobulin may very rarely induce thromboembolic events and should be used with caution in those with risk factors for arterial or venous thrombotic events and in obese individuals. Normal immunoglobulin may interfere with the immune response to live virus vaccines which should therefore only be given at least 3 weeks before or 3 months after an injection of normal immunoglobulin (this does not apply to yellow fever vaccine since normal immunoglobulin does not contain antibody to this virus).

Special Notes: *Indicated for primary immune deficiency. **Indicated for primary immune deficiency and Kawasaki disease. NOTE Formulations from different manufacturers vary and should not be regarded as equivalent; consult individual manufacturer’s product literature.


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Indications: Replacement therapy in primary immunodeficiency; Kawasaki disease. Contraindications: Hypersensitivity to immunoglobulin or blood products. Precautions: IM PREPARATION Use with caution in patients with thrombocytopenia or coagulation disorders.

Dose: Consult individual manufacturer’s product literature for dose and administration recommendations for specific diseases; recommended doses may vary to those listed below. Replacement therapy in primary immune deficiencies. IV infusion: Child all ages initial loading dose, administer until serum IgG level is > 6 g/l. IV, IM or SC (depending on formulation): Child all ages maintenance dose, normally 400–800 mg/kg/month, titrated according to intercurrent infections or trough serum IgG level. IV doses may be given at 1, 2, 3 or 4 week intervals. SC doses may be given at 1, 2, 3, 4 or 7 day intervals. Kawasaki disease. IV infusion: Infant or Child 2 g/kg as a single dose, given over 10–12 hours; if signs and symptoms persist, re-treatment with a second 2 g/kg infusion should be considered. Must be used in combination with acetylsalicylic acid.

Renal impairment: Dose reduction not required. Hepatic impairment: Dose reduction not required. Adverse effects: Common Nausea, vomiting, headache (may develop 24 hours after infusion), dizziness,

dry mouth, chills, sweating, hypothermia, fever, eczema, rash, urticaria, hypotension, wheezing, anaphylactoid reactions.

Rare Immune haemolysis, aseptic meningism, increased plasma viscosity, hypercoagulopathy, renal impairment.

Interactions with other medicines (* indicates severe): Live virus vaccines (measles, mumps, rubella): see Warnings. Notes: IV compatibility: general advice is not to administer with any other drugs or IV fluids. IV infusion over 2–12 hours. ADMINISTRATION Infusion rates of < 8 g per hour are recommended. Immunoglobulin should be administered under the supervision of an immunologist or other experienced physician. In general, this should be in a hospital with adequate facilities for monitoring the infusion as well as the condition for which it is being administered, until the patient is stable, when treatment at home can be considered after formal training in an expert centre. References: Hill SR, Kouimtzi M, Stuart MC, eds. WHO model formulary. Geneva, World Health Organization, 2008. Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook. 16th ed. Hudson, Lexi-Comp, 2009. Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group RBS Publishing, 2009.


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16. Literature references

Al-Herz W, Bousfiha A, Casanova JL et al. Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency. Frontiers in Immunology 2011; 2: 1-26 published online 08 Nov 2011: doi: 10.3389/fimmu.2011.00054 Berger M. Subcutaneous immunoglobulin replacement in primary immunodeficiencies. Clinical Immunology 2004; 112: 1-7 Berger M. Choices in IgG replacement therapy for primary immune deficiency diseases: subcutaneous IgG vs. intravenous IgG and selecting an optimal dose. Current Opinion in Allergy and Clinical Immunology 2011a; 11: 532–538 Berger M. L-proline-stabilized human IgG: Privigen 10% for inravenous use and Hizentra 20% for subcutaneous use. Immunotherapy 2011b; 3 (2): 163-176 Berger M. Incidence of Infection is Inversely Related to Steady-State (Trough) Serum IgG Level in Studies of Subcutaneous IgG in PIDD. J Clin Immunol 2011c; 31:924–926 published online 04 June 2011: DOI 10.1007/s10875-011-9546-2 Berger M, Rojavin M, Kiessling P et al. Pharmacokinetics of subcutaneous immunoglobulin and their use in dosing of replacement therapy in patients with primary immunodeficiencies. Clinical Immunology 2011d; 139: 133–141 Bonilla FA, Berstein IL, Khan DA et al. Practice parameter for the diagnosis and management of primary immunodeficiency. Annals of Allergy, Asthma & Immunology 2005; 94: S1-S63 Bonilla FA. Pharmacokinetics of immunoglobulin administered via intravenous or subcutaneous routes. Immunology and Allergy Clinics of North America 2008; 28: 803-819 Borte M, Pac M, Serban M et al. Efficacy and Safety of Hizentra®, a New 20% Immunoglobulin Preparation for Subcutaneous Administration, in Pediatric Patients with Primary Immunodeficiency. J Clin Immunol 2011; 31:752–761 Borte M, Fassbauer M, Bernatowska E et al. Long-term efficacy and safety of Hizentra® after a dose-equivalent switch from subcutaneous or interavenous replacement therapy. J Clin Immunol. 2012; 32 (Suppl 1):S142-43 15th Biennial Meeting of the European Society for Immunodeficiencies, Florence 2012; Abstract: A-451-0006-00417 (draft abstract, accepted) Boyle JW, Buckley RH. Population Prevalence of Diagnosed Primary Immunodeficiency Diseases in the United States. J Clin Immunol 2007; 27:497–502 Buckley RH, Ballow M, Berger M et al. The Immune Deficiency Foundation Diagnostic and Clinical Care Guidelines for Primary Immunodeficiency Diseases, 2009


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Consensus Statement: European Primary Immunodeficiencies Consensus Conference, Langen, Germany 2006 Cooper MA, Pommering TL, Korànyi K. Primary immunodeficiencies. American Family Physician 2003; 68: 2001-2008 Ducruet T, Levasseur MC, Des Roches A et al. Treatment costs associated with hospital/-based IVIG therapy compared to home-based SCIG therapy in a cohort of patients with primary immunodeficiency. J Clin Immunol 2011 EMA Core SPC for human normal immunoglobulin for subcutaneous and intramuscular use (CPMP/BPWP/282/00) European Medicines Agency (July 2002) - Core SPC for human normal immunoglobulin for subcutaneous and intramuscular use. EMEA/CPMP/BPWG/282/00. EMA (July 2002) - Note for guidance on the clinical investigation of human normal immunoglobulin for subcutaneous and intramuscular use. EMEA/CPMP/BPWG/283/00 EMA/CHMP/BPWP/761007/2010: Concept paper on revision of: Note for Guidance on the Clinical investigation of human normal immunoglobulin for subcutaneous and intramuscular use (CPMP/BPWP/283/00), Core SPC for human normal immunoglobulin for subcutaneous and intramuscular use (CPMP/BPWP/282/00) EMA/CHMP/110226/2011: EMA Summary of opinion (initial authorisation) Hizentra

ESID 1-3: European Society for Immunodeficiencies Registry: http://www.esid.org/registry-number-of-patients, accessed 18 June 2012

Food and Drug Administration (June 2008). Guidance for Industry. Safety, efficacy, and pharmacokinetic studies to support marketing of immune globulin intravenous (human) as replacement therapy for primary humoral immunodeficiency. Food and Drug Administration, Center for Biologics Evaluation and Research. (http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/ucm078526.pdf, accessed June 2012)

Gardulf A, Nicolay U, Math D et al. Children and adults with primary antibody deficiencies gain quality of life by subcutaneous IgG self-infusions at home. J Allergy Clin Immunol 2004; 114: 936-942

Gardulf A. Immunoglobulin treatment for primary antibody deficiencies: advantages of the subcutaneous route. Biodrugs 2007; 21: 105-116 Gardulf A, Borte M, Ochs HD et al. Prognostic factors for health-related quality of life in adults and children with primary antibody deficiencies receiving SCIG home therapy. Clin Immunol 2008; 126 (1): 81-88


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Hagan JB, Fasano MB, Spector S et al. Efficacy and Safety of a New 20% Immunoglobulin Preparation for Subcutaneous Administration, IgPro20, in Patients With Primary Immunodeficiency. J Clin Immunol 2010; 30 (5): 734-745 published online 08 May 2010: DOI 10.1007/s10875-010-9423-4 Hagan JB, Wasserman RL, Baggish JS et al. Safety of l-proline as a stabilizer for immunoglobulin products. Expert Rev. Clin. Immunol. 2012; 8(2): 169–178 Hizentra Summary of Product Characteristics (Annex I to EPAR- EMA/166555/2011) rev May 2012 Hizentra US prescribing information, rev Sept. 2011 Ho C, Membe S, Cimon K et al. An overview of subcutaneous vs. intravenous immunoglobulin for primary immunodeficiencies: systematic review and economic analysis [Technology overview #36] Canadian Agency for Drugs and Technologies in Health, 2008. Hoffmann F, Grimbacher B, Thiel J et al. Vivaglobin Study Group. Home-based subcutaneous immunoglobulin G replacement therapy under real-life conditions in children and adults with antibody deficiency. Eur J Med Res 2010; 15: 1-8 INN Working Document 05.179: International Nonproprietary Names (INN) for biological and biotechnological substances (a review); World Health Organization 2009 Jolles S, Bernatowska E, de Garcia J et al. Efficacy and safety of Hizentra® in patients with primary immunodeficiency after a dose-equivalent switch from intravenous or subcutaneous replacement therapy. Clinical Immunology 2011a; 141: 90–102 Jolles S, Stein MR, Longhurst HJ, et al. New Frontiers in Subcutaneous Immunoglobulin Treatment. Biol Ther 2011b; 1(1):003 published online 14 Dec 2011: DOI 10.1007/s13554-011-0009-3 Jolles S, Sleasman W. Subcutaneous Immunoglobulin Replacement Therapy with Hizentra®, the First 20% SCIG Preparation: a Practical Approach. Adv. Ther. 2011; 28 (7): 521-533 published online 14 June 2011: DOI 10.1007/s12325-011-0036y Maeder W, Lieby P, Sebald A et al. Local tolerance and stability up to 24 months of a new 20% proline-stabilized polyclonal immunoglobulin for subcutaneous administration. Biologicals 2011; 39: 43-49 Miyawaki T, KaneganeH, Imai K et al. Efficacy and safety of Hizentra®, a subcutaneous immune globulin, in Japanese patients with primary immunodeficiency diseases. J Clin Immunol. 2012; 32 (Suppl 1):S145-46 Nelson RP, Melamed I, Stein MR, et al. Safety, tolerability, and efficacy of Hizentra over an extended period for the treatment of primary immunodeficiency disease. JACI 2012; 129 (2): AB83 Nicolay U, Kiessling P, Berger M et al. Health-Related Quality of Life and Treatment


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Satisfaction in North American Patients with Primary Immunedeficiency Diseases Receiving Subcutaneous IgG Self-Infusions at Home. J Clin Immunol 2006; 26 (1): 65-72 Notarangelo L, Casanova JL, Fischer A et al. (2004) Primary immunodeficiency diseases: an update. Journal of Allergy and Clinical Immunology 2004; 114: 677-687 Stein MR, Koterba A, Rodden L et al. Safety and efficacy of home-based subcutaneous immunoglobulin G in elderly patients with primary immunodeficiency diseases. Postgraduate Medicine 2011; 123 (5) 186-193

USIDNET: US Immunodeficiency Network, http://www.usidnet.org/index.cfm , accessed 19 November 2012

Wasserman RL, Melamed I, Nelson RP et al. Pharmacokinetics of Subcutaneous IgPro20 in Patients with Primary Immunodeficiency. Clin Pharmacokinet 2011; 50 (6): 405-414 Zbrozek A, Hubsch A, Baggish J et al. Subcutaneous immunoglobulin therapy for patients with primary immunodeficiency povides economic value across a wide range of dosing. J Clin Immunol 2012; 32 (1):S139 17. Appendices

17.1. Tabular Listing of Clinical Studies 17.2. Letter from IPOPI supporting this application 17.3. Letter from ASID supporting this application

CSL Behring AG WHO EML Application SCIG 20% Appendix 1 Tabular Listing of Clinical Studies

November 2012 Page 1 of 5

APPENDIX 1

TABULAR LISTING

OF CLINICAL STUDIES SUPPORTING THE EFFICACY AND SAFETY OF SCIG 20%



Reference Study type Objective(s) of the study

Study design and type of control

Test product(s); Dosage regimen; Route of administration

N Duration of Treatment

Main findings

Hagan et al. 2010

Phase I; Safety and tolerability

Assess local tolerability and safety of IgPro16 and IgPro20 in comparison to Vivaglobin

Single-centre, randomised, assessment blinded, 4-way crossover

Active control

IgPro16 (16% liquid formulation of human IgG); single dose, 15 mL; SC

IgPro20 (20% liquid formulation of human IgG); single dose, 15 mL; SC

IgPro20; single dose, 12 mL; SC

Vivaglobin (16% liquid formulation of human IgG); single dose, 15 mL; SC

28

Healthy male subjects

4 single SC doses, separated by washout period of 7 days each

Safety and tolerability (pain, erythema, edema/induration, itching, local heat) of IgPro20 was not inferior to the marketed SCIG 16% Vivaglobin

n.a. Phase I; Safety and tolerability

Compare tolerability and safety of IV administration of IgPro20 with Privigen

Single-centre, randomised, single-blind, 2-way crossover

Active control

IgPro20; single dose, 50 mL; IV

Privigen (IgPro10, 10% liquid formulation of human IgG); single dose, 100 mL; IV

20

Healthy male subjects

2 single IV doses, separated by washout period of 14 to 21 days

n.a.

(IV administration not relevant for further development of Hizentra® and for application to include SCIG 20% to WHO EML).







Main findings

NCT 00419341 Hagan et al. 2010 Wasserman et al. 2011

Phase III; Efficacy, safety, and tolerability

(US)

Assess efficacy, safety, tolerability, and PK of IgPro20 in subjects with PID

Multicentre, single-arm, prospective, open-label

Uncontrolled/ Historical control (PK)

IgPro20; 1.30 times previous weekly equivalent IV dose of IVIG (Privigen®) during wash-in/wash-out; adjusted dose (determined from PK at end of wash-in/wash-out) during efficacy period; weekly infusion; SC

49

PID patients

12-week wash-in/wash-out period, followed by 12-month efficacy period

mean serum IgG level= 12.5 g/L.

No SBIs were reported. 96 nonserious infections (rate 2.76/patient per year).

Rate of days missed from work/school: 2.06/patient per year, Rate of hospitalization: 0.2/patient per year.

99% of AEs were mild or moderate. No serious, IgPro20-related AEs were reported.

NCT 00719680 Nelson et al. 2012

Phase III extension study (US)

Assess long-term efficacy, safety, HRQL; show that IgG levels can be maintained up to 2 years

Multicenter, single-arm, prospective, open-label

Weekly SC infusions at max. infusion rates of 35 mL/h or 70 mL/h

21

PID patients

11-104 weeks mean serum IgG levels 11.7 to 12.8 g/L.

SBI rate: 0.06 subject-year Total infection rate: 2.4/subject-year







Main findings

NCT 00542997 Borte et al. 2011 Jolles et al. 2011

Phase III; Efficacy, safety, and tolerability

(Europe)

Assess efficacy, safety, tolerability, PK, and HRQL of IgPro20 in subjects with PID

Multicentre, single-arm, prospective, open-label

Uncontrolled

IgPro20; dose generally equal to previous weekly equivalent IVIG or SCIG dose; weekly infusion; SC

51

PID patients

12-week wash-in/wash-out period, followed by 28-week efficacy period

IgG levels achieved with IgPro20 were similar to pre-study levels with SC higher by 17.7% than pre-study levels with IVIG

Rate of all infections: 5.18/year/patient (95% CI: 4.305; 6.171)

No SBIs reported

NCT 00751621 Borte et al. 2012

Phase III extension study

(Europe)

Assess long-term efficacy and safety; show that IgG levels can be maintained up to 42 months

Multicenter, single-arm, prospective, open-label

Patients from the pivotal study continued with the same weekly Hizentra® dose.

40

PID patients

Up to 42 months

The annualized rates of

any infections: 3.33 events/patient, SBIs: 0.048 events/patient

NCT 01199705 Miyawaki et al. 2012

Phase III;

Efficacy, safety, and tolerability

(Japan)

Assess efficacy and safety of IgPro20 in Japanese patients with PID

multicenter, single-arm, prospective, open-label

IgPro20; during efficacy period: weekly doses equivalent to previous IVIG doses; weekly infusion; SC

25

PID patients

12-week wash-in/wash-out period, followed by 12-month efficacy period

mean (±SD) serum IgG levels increased from 6.51±1.32 g/L in the IVIG period to 7.28±1.47 g/L in the SCIG efficacy period. No SBIs.

Rate of non-serious infections/patient/year: 2.98







Main findings

NCT 01458171

Phase III follow-up study

(Japan)

Assess long-term safety, tolerability, efficacy

Multi-cernter,

open-label

IgPro20; patients who had participated in NCT01199705

23

24 weeks Study analysis/report is ongoing

HRQL = Health-related quality of life; IgG = Immunoglobulin G; IV = Intravenous; IVIG = Human Normal Immunoglobulin for Intravenous Administration; N= Number; PID = Primary immunodeficiency; PK = Pharmacokinetic(s); SC = Subcutaneous; SCIG = Human Normal Immunoglobulin for Subcutaneous Administration; US = United States.

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