Therapeutic Goods Administration
July 2016Australian Public Assessment Report for Adalimumab (rch)
Proprietary Product Name: Humira
Sponsor: AbbVie Pty Ltd
About the Therapeutic Goods Administration (TGA)
· The Therapeutic Goods Administration (TGA) is part of the Australian Government Department of Health and is responsible for regulating medicines and medical devices.
· The TGA administers the Therapeutic Goods Act 1989 (the Act), applying a risk management approach designed to ensure therapeutic goods supplied in Australia meet acceptable standards of quality, safety and efficacy (performance) when necessary.
· The work of the TGA is based on applying scientific and clinical expertise to decision–making, to ensure that the benefits to consumers outweigh any risks associated with the use of medicines and medical devices.
· The TGA relies on the public, healthcare professionals and industry to report problems with medicines or medical devices. TGA investigates reports received by it to determine any necessary regulatory action.
· To report a problem with a medicine or medical device, please see the information on the TGA website <https://www.tga.gov.au>.
About AusPARs
· An Australian Public Assessment Report (AusPAR) provides information about the evaluation of a prescription medicine and the considerations that led the TGA to approve or not approve a prescription medicine submission.
· AusPARs are prepared and published by the TGA.
· An AusPAR is prepared for submissions that relate to new chemical entities, generic medicines, major variations and extensions of indications.
· An AusPAR is a static document; it provides information that relates to a submission at a particular point in time.
· A new AusPAR will be developed to reflect changes to indications and/or major variations to a prescription medicine subject to evaluation by the TGA.
Copyright
© Commonwealth of Australia 2016
This work is copyright. You may reproduce the whole or part of this work in unaltered form for your own personal use or, if you are part of an organisation, for internal use within your organisation, but only if you or your organisation do not use the reproduction for any commercial purpose and retain this copyright notice and all disclaimer notices as part of that reproduction. Apart from rights to use as permitted by the Copyright Act 1968 or allowed by this copyright notice, all other rights are reserved and you are not allowed to reproduce the whole or any part of this work in any way (electronic or otherwise) without first being given specific written permission from the Commonwealth to do so. Requests and inquiries concerning reproduction and rights are to be sent to the TGA Copyright Officer, Therapeutic Goods Administration, PO Box 100, Woden ACT 2606 or emailed to <>.
PM–2014-04326-1-4 Final 12 July 2016 / Page 4 of 39
Therapeutic Goods Administration
Contents
Common abbreviations 4
I. Introduction to product submission 7
Submission details 7
Product background 7
Regulatory status 9
Product Information 10
II. Quality findings 10
III. Nonclinical findings 10
IV. Clinical findings 10
Clinical rationale 10
Pharmacokinetics (PK) 12
Pharmacodynamics 13
Dosage selection for the pivotal studies 13
Efficacy 14
Safety 15
First round benefit–risk assessment 17
First round recommendation regarding authorisation 18
Clinical questions 18
Second round evaluation of clinical data submitted in response to questions 18
Second round benefit–risk assessment 20
V. Pharmacovigilance findings 21
Risk management plan 21
VI. Overall conclusion and risk/benefit assessment 27
Introduction 27
Quality 27
Nonclinical 27
Clinical 27
Risk management plan 31
Risk-benefit analysis 32
Outcome 38
Attachment 1. Product Information 38
Attachment 2. Extract from the Clinical Evaluation Report 38
ADR
Common abbreviations
Abbreviation / Meaning /AAA / Anti-adalimumab antibody
ACPM / Advisory Committee on Prescription Medicines
AE / Adverse event
AESI / Adverse event of special interest
ALT/SGPT / Alanine aminotransferase/serum glutamic pyruvic transaminase
ASA / Australian specific annex
AN / Abscess and inflammatory nodule
AN25 / At least 25% reduction in abscess and inflammatory nodule count relative to Baseline
AN50 / At least 50% reduction in abscess and inflammatory nodule count relative to Baseline
AN75 / At least 75% reduction in abscess and inflammatory nodule count relative to Baseline
AN100 / 100% reduction in abscess and inflammatory nodule count relative to Baseline
AS / Ankylosing spondylitis
BMI / Body mass index
CD / Crohn’s disease
CMH / Cochran Mantel Haenszel
CMI / Consumer Medicine Information
DLQI / Dermatology Life Quality Index
EU / European Union
HiSCR / Hidradenitis Suppurativa Clinical Response
HIV / Human immunodeficiency virus
HS / Hidradenitis suppurativa
HS–PGA / Hydradenitis suppurative Physician`s Global Assessment
HSTCL / Hepatosplenic T–cell lymphoma
IBD / International birth date
ITT / Intent to treat
JIA / Juvenile idiopathic arthritis
LOCF / Last observation carried forward
LOR / Loss of response
NMSC / Non–melanoma skin cancer
NR / Non–responder
NRI / Non–responder imputation
Nr–ax SpA / Non–radiographic axial spondylarthritis
PBO / Placebo
PedERA / Paediatric enthesitis related arthritis
PGA / Physician's Global Assessment
PI / Product Information
PK / Pharmacokinetic
Ps / Psoriasis
PsA / Psoriatic arthritis
PY / Patient year
qw / Weekly
Q2w / Every other week
RA / Rheumatoid arthritis
SAE / Serious adverse event
SmPC / Summary of product characteristics
SpA / Spondylarthritis
TEAE / Treatment emergent adverse event
TESAE / Treatment emergent serious adverse event
TNF / Tumor necrosis factor
UC / Ulcerative colitis
US / United States
Wk / Week
I. Introduction to product submission
Submission details
Type of submission: / Major variation; extension of indicationsDecision: / Approved
Date of decision: / 06 April 2016
Date of entry onto ARTG / 08 April 2016
Active ingredient: / Adalimumab (rch)
Product name: / Humira
Sponsor’s name and address: / AbbVie Pty Ltd
Locked Bag 5029
Botany NSW 1455
Dose form: / Solution for injection
Strengths: / 10, 20 and 40 mg
Containers: / Pre–filled syringe (10, 20 and 40 mg), vial (40 mg) and pen (40 mg).
Pack sizes: / Prefilled syringe 10 mg and 20 mg as a pack of 2 syringes; and 40 mg as a pack containing either 1, 2, 3, 4 or 6 syringes.
Humira 40 mg solution prefilled pen: a pack containing either 1, 2 , 3, 4 or 6 syringes
Humira 40 mg solution (vial): Pack containing 1 vial
Approved therapeutic use: / Humira is indicated for the treatment of moderate to severe hidradenitis suppurativa (acne inversa) in adult patients with an inadequate response to conventional systemic hidradenitis suppurativa therapy.
Route of administration: / Subcutaneous (SC)
Dosage: / 160 mg at Day 1 (given as 4 40 mg injections in one day or as two 40 mg injections per day for two consecutive days) followed by 80mg two weeks later at Day 15 (given as two 40mg injections in one day). Two weeks later (day 29) continued with a dose of 40 mg every week.
ARTG numbers: / 238700, 216038, 199412, 199411, 199410, 95779
Product background
This AusPAR describes the application by Abbvie Pty Ltd (the sponsor) to register Humira (adalimumab (rch)) for the indication:
Humira is indicated for the treatment of active moderate to severe hidradenitis suppurativa (acne inversa) in adult patients, including treatment of inflammatory lesions and prevention of worsening of abscesses and draining fistulas.
Humira (adalimumab (rch)) is a fully human immunoglobulin G1(IgG1) type recombinant monoclonal antibody against tumor necrosis factor (TNF)–a. It binds to TNF and neutralises the biologic function of TNF by blocking its interaction with the p55 and p75 cell surface receptors. Adalimumab also modulates biological responses that are induced or regulated by TNF. Humira is produced in a Chinese hamster ovary (CHO) cell expression system.
The currently approved indications in Australia are rheumatoid arthritis (RA), polyarticular juvenile idiopathic arthritis (JIA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn’s disease (CD), ulcerative colitis (UC) and psoriasis (Ps).
Hidradenitis suppurativa (HS) is a chronic follicular occlusive disease involving the follicular portion of folliculo–pilo–sebaceous units[1]. Primary sites are intertriginous skin areas of the axillary, groin, perianal, perineal and inframammary regions. Clinical manifestations range from recurrent inflamed nodules and abscesses through to draining sinus tracts and bands of severe scarring. Pain, malodour, drainage and disfigurement contribute to a profound psychosocial impact. Onset is usually between puberty and 40 years. Incidence is higher in women. There is a strong correlation with smoking, and a weaker correlation with obesity.
The Hurley staging system refers to three stages of severity based on the presence and extent of sinus tracts and scarring (Table 1). The Hidradenitis Suppurativa Physicians Global Assessment scale (HS–PGA) refers to five stages (from no skin disease to very severe symptoms) based on the presence or absence of abscesses, draining fistulas, inflammatory and non–inflammatory nodules (Table 2).
Table 1: Hurley stages
Stage / Description /I / Abscess formation (single or multiple) without sinus tracts and cicatrisation.
II / Recurrent abscesses with tract formation and cicatrisation; single or multiple, widely separated lesions.
III / Diffuse or near–diffuse involvement or multiple interconnected tracts and abscesses across entire areas.
Annals of Internal Medicine, Vol. 157, No12, 18 Dec 2012.
Table 2: Hidradenitis suppurativa physicians global assessment scale
Rating / Description /Clear / 0 abscesses, 0 draining fistulas, 0 inflammatory nodules and 0 noninflammatory nodules
Minimal / 0 abscesses, 0 draining fistulas, 0 inflammatory nodules, and presence of non–inflammatory nodules
Mild / 0 abscesses, 0 draining fistulas, and 1 to4 inflammatory nodules or
1 abscess or draining fistula and 0 inflammatory nodule
Moderate / 0 abscesses, 0 draining fistulas, and ≥ 5 inflammatory nodules or
1 abscess or draining fistula ≥ 1 inflammatory nodule or
2 to 5 abscesses or draining fistulas and ≤ 10 inflammatory nodules
Severe / 2 to 5 abscesses or draining fistulas and ≥ 10 inflammatory nodules
Very severe / ≥ 5 abscesses or draining fistulas
Annals of Internal Medicine, Vol. 157, No12, 18 Dec 2012.
Goals of treatment include:
· To prevent the formation of new lesions and thus reduce the extent and progression of the disease.
· To treat new lesions quickly and effectively to prevent development of chronic sinuses.
· To eliminate existing nodules and sinus tracts to limit or prevent scar formation.
Current treatments can involve topical and systemic medication, surgery (for example for nodules, sinus tracts and scarring) and behavioural/lifestyle approaches (for example smoking cessation and weight management). Medicines include antibiotics and hormonal therapies; in those who do not respond to these approaches, biological therapies and oral retinoids can be considered.
Regulatory status
The product received initial registration on the Australian Register of Therapeutic Goods (ARTG) on 10 December 2003.
At the time the TGA considered this application, a similar application had been approved in the European Union (EU) in June, 2015 for:
adults with active moderate to severe hidradenitis suppurativa (acne inversa), who have failed to respond to conventional systemic treatments.
Submission dates for the HS dossier in EU, US and Canada are included in Table 3.
Table 3: Submission and approval dates for HS dossier in the EU, US and Canada.
Country or Region / Submission date / Status / Approved indications /EU / 11 November 2014 / Approved on 29 July 2015 / Humira is indicated for the treatment of active moderate to severe hidradenitis suppurativa (acne inversa) in adult patients with inadequate response to conventional systemic HS therapy.
US / 10 November 2014 / Approved on 09 September 2015 / Humira is indicated for the treatment of moderate to severe hidradenitis suppurativa.
Canada / 14 January 2015 / Approved on 31 December 2015 / Humira is indicated for the treatment of active moderate to severe hidradenitis suppurativa in adult patients, who have not responded to conventional therapy (including systemic antibiotics).
Product Information
The Product Information (PI) approved with the submission which is described in this AusPAR can be found as Attachment 1. For the most recent PI, please refer to the TGA website at <https://www.tga.gov.au/product-information-pi.
II. Quality findings
There was no requirement for a quality evaluation in a submission of this type.
III. Nonclinical findings
There was no requirement for a nonclinical evaluation in a submission of this type.
IV. Clinical findings
A summary of the clinical findings is presented in this section. Further details of these clinical findings can be found in Attachment 2.
Clinical rationale
Hidradenitis suppurativa (HS) is a debilitating, chronic inflammatory follicular disease characterised by the formation of recurrent abscesses, inflammatory nodules, and fistulas. It mainly involves skin regions with apocrine glands such as axillae, groins, perineal and perianal areas, and submammary areas. Lesions are often painful and result in malodorous discharge. Complications include excessive scarring and fibrosis potentially leading to contractures and limitations in mobility, as well as anal, urethral, and rectal strictures. Other comorbidities associated with HS include anaemia, secondary infection, malignancy (such as non–melanoma skin cancer [NMSC]), depression, and anxiety. These disease sequelae result in significant reduction of health related quality of life in affected individuals.
The estimated prevalence of HS is approximately 1%. The disease onset is typically in the second and third decade of life and is rare in prepubertal children. Women are affected more commonly than men (female/male ratio approximately 2:1). Predisposing factors include obesity and cigarette smoking. The diagnosis is usually established based on the clinical presentation. Several disease severity scores have been developed, with the most commonly used being the three–stage Hurley score (Table 1).
Regarding management, the general lack of large randomised controlled studies limits therapeutic options for HS, which include both medical and surgical treatments. Medical treatment options include topical and systemic antibiotics (clindamycin and rifampicin alone or in combination, tetracyclines), oral anti androgen agents in women, dapsone and/or isotretinoin. More recently, the use of systemic anti TNF therapy (infliximab, etanercept, adalimumab) has shown promising results. Surgical options include radical excisions and deroofing as well as laser ablation (CO2 and Nd:YAG lasers). Most of the described treatments are based on small case series, and no widely accepted therapeutic guidelines are available for HS.