EU PSUR Work Sharing

Final Assessment Report

Roferon-A (Interferon alfa-2a)

NL/H/PSUR/0044/002

P-RMS NL

Invented name of the medicinal product(s)

Roferon-A easy Ject,

pre-filled syringes3 | 4.5 | 6 | 9 MIU/0.5ml

Roferon-A, cartridges 18 MIU/0.6ml

INN (or common name) of the active

substance(s) Interferon alfa-2a

MAHs whose PSURs were included in this

work-sharing Roche/NL

Pharmaco-therapeutic group (ATC Code) Interferon alfa-2a (L03AB04)

Indications authorised in the P-RMS for the

product

Interferon alfa-2a is approved for use in several

oncology indications (hairy cell leukemia, AIDS-

related Kaposi’s sarcoma, chronic myelogenous

leukemia, cutaneous T-Cell lymphoma, follicular

non-Hodgkin lymphoma, advanced renal cell

carcinoma, and surgically resected malignant

melanoma),

as well as for the treatment of chronic hepatitis B

and chronic hepatitis C. The optimal way to use

interferon alfa-2a in patients with chronic hepatitis

C is in combination with ribavirin.

Pharmaceutical form(s) and strength(s) pre-filled syringes 3 | 4.5 | 6 | 9 MIU/0.5ml

cartridges 18 MIU/0.6ml

PSUR Period The period covered by this work sharing assessment was 01 January 2010 to 31 December

2012 (inclusive).

Final Conclusion In the light of the information provided in the reviewed PSUR, the P-RMS considers there

were no new major findings affecting the overall safety profile of Interferon alfa-2a and the

benefit-risk profile of the medicinal product(s) remains favourable.

Recommendations: During this PSUR period, and since the renewal of 2008, no new safety concerns or change in

benefits have been identified. Therefore, the benefit/risk ratio of the product remains

unchanged and favourable.

No changes to the SmPC are needed based on the PBRER data.

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Administrative information P-RMS contact person:

Name: Marianne Kuijpers Tel: + 31 (0)88 224 8156 Email: m.kuijpers@cbg-meb.nl

Names of assessors (internal and external):

Name(s)Hanneke Brandt-Dominicus/Ruben Duijnhoven/Liana Gross-Martirosyan/Kartini Gadroen (response)

GENERAl- Steps taken for the assessment

This is the assessment of PSUR(s) received for interferon alfa-2a with a DLP 31 Dec 2012

submitted under the work sharing scheme as indicated on the cover page:

Procedure Start Date 20 January 2014

Date of preliminary AR 31 January 2014

Deadline for comments to P-RMS 20

Clockstop/ RFI / LoQ 5 May 2014

Procedure Restart Date 28 August 2014 (Day 106)

Date of Draft Final AR 28 August 2014 (Day 106)

Deadline for comments to P-RMS 12 September 2014 (Day 120)

Date of Final AR 27 September 2014 (Day 135)

Discussion at PRAC N/A

DLP of the next PSUR submission

and period of PSUR

3 June 2017

1. PSUR Data

1.1. Introduction

Interferon alfa-2a is an antiviral and anti-neoplastic agent. Interferon alfa-2a is the product of a

cloned human leukocyte interferon gene inserted into and expressed in Escherichia coli and is

produced biosynthetically using recombinant deoxyribonucleic acid (DNA) technology. It exerts its

antiviral effects by inducing a state of resistance to viral infections in cells and by modulating the

effector arm of the immune system to neutralise viruses or eliminate virus-infected cells.

Interferon alfa-2a is approved for use in several oncology indications (hairy cell leukemia, AIDS-

related Kaposi’s sarcoma, chronic myelogenous leukemia, cutaneous T-Cell lymphoma, follicular

non-Hodgkin lymphoma, advanced renal cell carcinoma, and surgically resected malignant

melanoma), as well as for the treatment of chronic hepatitis B and chronic hepatitis C. The optimal

way to use interferon alfa-2a in patients with chronic hepatitis C is in combination with ribavirin.

The product was first registered in the US on 04 June 1986. The product is registered in the EU by

a mutual recognition procedure. It has been registered in the Netherlands since 1999.

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The MAH submitted a periodic nenefit/risk evaluation report (PBRER) for the period 01 January

2010 to 31 December 2012 (inclusive) on 26 March 2013.

On 09 August 2013, the MAH submitted a corrigendum to the PSUR: “The MAH has identified some

inconsistencies in adverse event (AE) data, and is submitting this corrigendum to acknowledge and

correct these inconsistencies. The MAH has conducted a comprehensive analysis of the revised

data, and concludes that the benefit-risk profile of interferon alfa-2a in the approved indications

remains favourable.”

Together with this corrigendum the MAH submitted a memo of the QPPV describing the issues,

root cause analysis, and the associated CAPAs (dated 29 July 2013).

The MAH concluded that the benefit-risk profile remains favourable and that no changes to the

SmPC are needed based on the PBRER data.

RMS comment:

Currently a ‘Follow-up to pharmacovigilance inspection conducted by MHRA (UK) – Handling of

safety data arising from non-Interventional programmes and expedited & periodic reporting

failures – Outcome of CAPA Impact assessments’, is ongoing and under discussion in the CHMP

(see also 1.3.1 in this report). In the section on Data in Summary Tabulations, the MAH in the

original PBRER refers to this procedure claims that ‘…all affected cases were corrected in the

Company Global Safety Database and thus any cumulative data shown in this PBRER should now

be correct’.

The MAH should explain why at first they claim the data to be correct and afterwards a

corrigendum had to be sent. It should be clear whether the inconsistencies found in the first

PBRER were new findings – based on other root causes - or already included in the inspection

procedure.

1.2. Worldwide Marketing Authorisation Status

Interferon-alfa-2a was first authorised in the US on 04 June 1986 and in the EU in the UK on 14

July 1999. In the EU, it has been marketed in 26 countries. It is approved in a total of more than

100 countries worldwide.

Comment assessor:

In the executive summary the IBD is 04 June and in this section 14 July. The MAH should amend

this.

1.3. Overview of exposure and safety data

1.3.1. Actions Taken in the Reporting Interval for Safety Reasons

In January and February 2012, the United Kingdom (UK) Medicine and Healthcare products

Regulatory Agency (MHRA) conducted a statutory pharmacovigilance inspection at Roche. Findings

from this inspection revealed deficiencies in safety data collection from non-interventional

programs, failures in expedited and periodic reporting of individual case safety reports (ICSRs)

from the US Access Solutions program and inappropriate data management and inclusion of data

in aggregate reports. Following a comprehensive review of all cases impacted by the above issues,

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an assessment on the benefit-risk for interferon alfa-2a, in relation to the MHRA inspection

findings, was performed.

As per the last assessment of the interferon alfa-2a Periodic Safety Update Report (PSUR) in the

EU, the MAH was asked to add neutropenia to the EU SmPC as an undesirable effect.

Comment assessor:

The discussion on the inspection results is still ongoing. The variation to include neutropenia has

been finalised.

1.3.2. Changes to Reference Safety Information

The MAH used the CDS version 5.0 (01 July 2010) as reference safety information.

During the reporting interval the CDS was updated to include new safety information on graft

rejection with alpha interferons regarding autoimmune disease, psoriasis and graft rejection.

Comment assessor:

This information is included in the current SmPC.

1.3.3. Estimated Exposure and Use Patterns

Patient exposure was calculated based on total sales divided by defined daily dose (DDD) per indication. The use in oncology patients is almost ten times as high as the use in virology patients.

In confidential annex: Patient exposure innovator PSUR.

Comment assessor:

The DDD of the WHO is 2 MU in the indication chronic hepatitis B. Other DDDs are not given for

interferon alpha 2a. As the provided doses by the MAH do reflect those in the SmPC sufficiently,

the calculation method is accepted.

1.3.4. Data in Summary Tabulations

The MAH did refer to the pharmacovigilance inspection of January and February 2012 by the UK

(MHRA). Findings from this inspection revealed deficiencies in safety data collection from non-

interventional programs, failures in expedited and periodic reporting of individual case safety

reports (ICSRs) from the US Access Solutions program and inappropriate data management and

inclusion of data in aggregate reports. Following a comprehensive review, all affected cases were

corrected in the Company Global Safety Database and thus any cumulative data shown in this

PBRER should now be correct.

RMS comment:

The issue of non-compliance with the pharmacovigilance guidelines is currently under assessment

of the CHMP and involves a number of products, including Roferon for which Roche is the MAH:

‘Follow-up to pharmacovigilance inspection conducted by MHRA (UK) – Handling of safety data

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arising from non-Interventional programmes and expedited & periodic reporting failures –

Outcome of CAPA Impact assessments’.

The PRAC already noted that Roche should carefully consider the cumulative data for these

products within the next PSURs. New documents were discovered by the MAH which are related to

Access Solutions programme and other NIPs.

Reference is made to the corrigendum to this PSUR sent by the MAH because deficiencies of the

safety database outputs were found, see comment section 1.1 of this assessment report:

The MAH should explain why at first they claim the data to be correct and afterwards a

corrigendum had to be sent. It should be clear whether the inconsistencies found in the first

PBRER were new findings – based on other root causes/deficiencies - or already included in the

inspection procedure.

In the memo of the MAH’s QPPV, it is explained that until November 2005 adverse events could be

considered as ‘signs and symptoms’ or ‘co-manifestations’ and were coded as such. They were

included in the total count of AEs, but did not have seriousness coded. As they were presented in

the first PSUR report of this current period included in the total cumulative number, but were NOT

in the overall table because that table only listed events with coded seriousness the number of

(serious and non-serious) events did not sum up to the grand total in the table.

RMS comment:

The explanation of the MAH is understood. However, the MAH should clearly explain what ‘co-

manifestations’ are, provide examples, and confirm that all reported adverse events are coded

with seriousness since November 2005.

The MAH provided cumulative summary tabulations of adverse events from clinical trials, sorted by

SOC and PTs. These can be found in appendix 1.

A summary is provided below:

Table 1 Cumulative tabulation of serious adverse events from clinical studies

SOC (abbr) Number of adverse events

Infections 481

Neoplasms 329

Blood disorders 528

Immune disorders 25

Endocrine disorders 50

Metabolic disorders 202

Psychiatric disorders 335

Nervous system disorders 446

Eye disorders 45

Ear disorders 28

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Cardiac disorders 275

Vascular disorders 156

Respiratory disorders 274

Gastrointestinal 575

Hepatic disorders 87

Skin disorders 64

Musculoskeletal disorders 136

Renal disorders 114

Pregnancy 2

Reproductive disorders 23

Congenital disorders 2

General disorders 967

Investigations 111

Injury & procedural 118

Surgery 35

Social circumstances 3

Total 5414

RMS comment:

The number of ‘Unique AEs’ in the first column of the tabulation of the MAH does not always match

which the sum of the numbers in the other columns. The MAH should explain this and discuss

whether this is related to the issue discussed in the corrigendum.

Post-marketing sources

The MAH cumulative and interval summary tabulations from post-marketing data sources sorted

by SOC and PTs are provided in appendix 2. A summary is given below. These data are from the

corrigendum PBRER.

Table 2 Interval and cumulative adverse drug reactions form post-marketing sources

SOC (abbr) Number of adverse events

Interval Cumulative

Infections 63 333

Neoplasms 47 199

Blood disorders 134 772

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Immune disorders 19 148

Endocrine disorders 28 285

Metabolic disorders 71 402

Psychiatric disorders 139 1116

Nervous system disorders 128 1369

Eye disorders 25 352

Ear disorders 8 92

Cardiac disorders 34 367

Vascular disorders 34 271

Respiratory disorders 45 495

Gastrointestinal 153 933

Hepatic disorders 31 191

Skin disorders 94 1105

Musculoskeletal disorders 76 601

Renal disorders 23 237

Pregnancy 11 106

Reproductive disorders 2 78

Congenital disorders 5 25

General disorders 433 2297

Investigations 119 993

Injury & procedural 35 136

Surgery 1 27

Social circumstances 4 17

Total 1762 12,947

The MAH discussed that during the reporting period, the most frequently reported AEs from post-

marketing sources were from the following SOCs: General Disorders and Administration Site

Conditions (433 AEs), Gastrointestinal Disorders (153 AEs) and Psychiatric Disorders (139 AEs).

Cumulatively, the most frequently reported AEs from post-marketing sources were from the

following SOCs: General Disorders and Administration Site Conditions (2297 AEs), Nervous System

Disorders (1369 AEs) and Psychiatric Disorders (1116 AEs).

During the interval period and cumulatively, the most frequently reported AEs post-marketing

were in patients with the indication hepatitis C.

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RMS comment:

The data on post-marketing events did not give rise to new safety information.

1.3.5. Summaries of Significant Findings from Clinical Trials in the Reporting Interval

The most frequently reported SAEs from clinical trials were from the following SOCs: General

Disorders and Administration Site Conditions, Gastrointestinal Disorders and Blood and Lymphatic

System Disorders.

The most frequently reported SAEs from clinical trials were in patients receiving interferon alfa-2a

for indication of solid neoplasms (2151 SAEs), hepatitis C (1060 SAEs) and other indications (978

SAEs).

RMS comment:

The data provided on the clinical trials did not identify new safety information.

1.3.6. Non-clinical Data

Not applicable.

1.3.7. Literature

In this period, the MAH retrieved with their ongoing literature search, 19 articles that contained

important safety findings.

Amir et al. 2008 studied cutaneous manifestations in patients with hepatitis C. Most

adverse events were listed in the SmPC. For the unlisted cutaneous adverse reactions, the

MAH concluded that detailed information regarding the individual patients (including their

medical history, clinical course and concomitant medications) is required for an

assessment.

RMS comment:

There were 5 cases of the unlisted event of lichen planus and 1 case of aggravated lichen planus.

Cumulatively, 13 post marketing cases including 1 new case. There are some cases of other lichen

manifestations. The MAH should discuss:

- Why these 6 literature cases were apparently not included

- Provide a cumulative overview of all lichen cases, including the numbers per indication (as

lichen planus seems to be associated with hepatitis C).

Strayer et al. 2012 discussed the Incidence And Clinical Impact of Neutralizing Antibodies with the

use of recombinant and natural human interferons. The authors concluded that patients receiving

r- interferons should be monitored for NAB formation and consideration should be given to

switching these patients to n- interferons. The MAH commented that this was a retrospective

review of published literature and did not evaluate the influence of NAB titers because of the

problem of controlling for assay variability and specific activity of the different interferons among

the various studies. Anti-interferon titers were underestimated when patients were still receiving

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interferon treatment and the timing of blood collection in relationship to interferon treatment was

an important factor.

RMS comment:

At the moment no action is necessary.

One in vitro study gave an explanation for the inhibitory effects of interferon alfa on human

astrocytes (Wang et al. 2012). Another – in vitro and animal – study discussed the mechanism of

induction of depression (Huberner et al. 2012).

RMS comment:

The other discussed studies did not give rise to any action at the moment.

1.3.8. Other Periodic Reports

Not applicable.

1.3.9. Lack of Efficacy in Controlled Clinical Trials

No lack of efficacy data from CCTs concerning interferon alfa-2a became available during this

reporting interval.

1.3.10. Late-Breaking Information

In January 2013, during the late breaking period, a request from the Medicines Evaluation Board

was received in which the MAH was asked to update the EU SmPC of its ribavirin product,

Copegus, with a boxed warning that patients with a history of substance abuse who receive alfa

interferon have an increased risk of psychiatric complications. The MAH has committed to perform

a review of its data for interferon alfa- 2a, peginterferon alfa-2a and ribavirin (in combination with

interferon alfa-2a or peginterferon alfa-2a) and to propose appropriate wording for the SmPC of all

three products. This assessment has not yet been completed.

RMS comment: This issue is ongoing.

1.4. Discussion and conclusions on PSUR data

RMS comment:

Currently a ‘Follow-up to pharmacovigilance inspection conducted by MHRA (UK) – Handling of

safety data arising from non-Interventional programmes and expedited & periodic reporting

failures – Outcome of CAPA Impact assessments’, is ongoing and under assessment in the CHMP.

This current PSUR should contain the correct data. However, the MAH sent a corrigendum and an

explanation that some cases (before 2005) were never given a seriousness criterion. These were

‘co-manifestation’. The MAH should explain this (See comment boxes above).

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Data on post-marketing events and clinical trial events did not give rise to new safety concerns.

In literature, lichen planus cases were found. Lichen planus is not included in the SmPC

. The MAH should elaborate on this issue (see comment boxes above) within this procedure.

At the moment, the presented data does not have an impact on SmPC or package leaflet.

2. Signal and Risk Evaluation

Tabular overview of signals: new, ongoing or closed during the reporting interval

01.01.2010 to 31.12.2012.

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Summary of Safety Concerns

No RMP is in place for interferon alfa-2a. The MAH presented the following safety concerns in the PSUR: Table 3 Summary of ongoing safety concerns

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Signal Evaluation

The signal of ‘Black particle contamination’ led to a root cause analysis which pointed to a food-grade lubricant residue which was subjected to high temperature as part of the glass syringe manufacturing process. There has been no analytical data generated by the date of this report to indicate there is a dislodgement of particles, dissolution or interaction of the black residue with the drug product. The pharmacovigilance safety database was reviewed and no (increase in) AEs were found that might be due to this issue. Reverse Phase-High Pressure Liquid Chromatography (RP-HPLC) testing has shown that the drug product has and continues to meet its established release specifications. The MAH refuted and closed the signal. A second signal was refuted: ‘Cracked syringe’. The Roche Drug Safety database, ARISg, was extensively searched for any and all adverse events reported on the relevant batches. No related events were found and the data through 13 June 2012 (submission date of this medical assessment report-1050805) provided no evidence that the container closure system and sterility of interferon alfa-2a had been compromised by the present technical issue, nor had Roche received any product complaints or AE reports involving the affected batches.

RMS comment:

The table of the MAH is accepted. The closing of the two signals are endorsed.

There are 2 signals ongoing which may be subject to closing:

‘Pulmonary fibrosis’: this signal has been ongoing since 2000. Cumulative 12 cases have been

reported, of which 9 serious. In this PSUR period there were no new cases. Previous literature

review and case analysis did not indicate a safety issue. The MAH provided a discussion on this

issue and concluded that no new information was received. Therefore, the MAH can close the

signal and make the event subject to routine monitoring.

‘Hearing impairment’: Cumulatively, 24 cases have been reported, including 2 new cases in this

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period. This signal has been ongoing since 2000. The MAH should provide a cumulative review and

discussion of this issue.

Evaluation of Risks and New Information

In this PSUR period, there were no signals recognized that are identified of potential risks not

categorised as important. Two signals were refuted (black particles and cracked syringes. The MAH

presented overviews of AEs reported on all the risks and concluded that no new significant information

was received.

RMS comment:

It is agreed that in this PSUR period no new information has been received and no actions are

necessary at the moment.

Characterisation of Risks

The important identified risks of the product are to be found in several SOCs in general:

Psychiatric disorders, Nervous system disorders (CNS), Blood and lymphatic system disorders,

Autoimmune disorders, Hepatic disorders, Infections, Ocular disorders, hyperglycaemia, Renal

disorders, Anorexia and Nausea, Us in neonates, preterm infants and children op to 3 years

(because of the benzylalcohol component), and Graft rejection.

Treatment with Interferon-alfa-2a should under supervision of an experienced HCP. During

treatment, the most specific important problems may be: hypersensitivity, immune activation

(transplant rejection), serious infections, depression, impaired vision, bone marrow depression.

Some of these events may lead to discontinuation of the product.

Discussion and conclusion on signal and risk evaluation

Discuss whether updates of the product information are necessary as well as risk minimisation

activity to address specific safety concern(s).

All risks are well-known and clearly laid down in the SmPC section 4.3, 4.4 and 4.8. During this

reporting period, no important new safety information has been identified. No new risks have been

identified, no new insights on already included risks have been identified. There are no risk

minimization activities (beyond routine activities) currently ongoing for this product. The SmPC is

supposed to adequately provide information and guidance on the treatment with interferon alfa-

2a.

3. Benefit Evaluation

Important Baseline Efficacy and Effectiveness Information

Interferon alfa-2a has 13 approved indications which can be grouped into 3 categories:

1. Treatments of neoplasms of the lymphatic or hematopoietic system; including:

• hairy cell leukemia (HCL);

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Interferon alfa in combination with other treatments has been shown to improve blood counts and

so alleviates symptoms for the patient. It is an agent which contributes to a durable clinical

response and remission in patients with HCL. The benefit is clearly demonstrated in the improved

median five - 10 year survival for HCL from 50% to 90% using current treatment regimens. No

new benefits over and above those established at baseline have been identified as part of this

review.

• Multiple myeloma;

Multiple myeloma is an incurable disease. Prolongation of life and quality of survival become

important goals for treatment. Quality of survival is in part determined by the patient experiencing

few symptoms and few treatment side effects. Interferon alfa used as an adjuvant therapeutic

measure in the treatment of multiple myeloma boosts overall survival rates as shown in one

recently reported long-term study. Interferon alfa forms one of the agents which have contributed

to the improvement in median survival of multiple myeloma patients from three years to six years.

Overall, these data are consistent with the benefits established at baseline.

• Cutaneous T-cell Lymphoma (CTCL);

Interferon alfa can be used in all stages of CTCL as either monotherapy or in combination

treatment. The treatment strategy depends on the stage of disease. The greatest response is seen

in those patients who begin treatment early in the disease. One recent study reported remarkable

response and remission rates when interferon alfa was combined with arsenic trioxide and

zidovudine. The response rate of 70 % (includes complete, minor and partial responses) is

indicative of the benefit of treatment.

• Philadelphia chromosome-positive chronic myelogenous leukemia (CML);

Philadelphia chromosome-positive chronic myelogenous leukemia is a disease which, without

treatment, is rapidly progressive. The survival time is a matter of months. The aim of treatment is

to control progression of the disease by reducing leukemic cells. Interferon alfa is typically used in

combination treatment. In those patients who have a cytogenic response to treatment, remission

may be maintained for up to nine years. Interferon alfa has been recently shown to facilitate the

discontinuation of more toxic drugs following combination therapy. In particular, one study

reported increased numbers of patients remaining in remission following cessation of treatment

with combination therapy with imatinib, followed by interferon alfa maintenance therapy. Overall,

these new data are considered to be consistent with previously reported data at baseline.

• Thrombocytosis associated with myoproliferative diseases.

When used in patients with CML and thrombocytosis the aim of treatment is to induce a

hematological response whilst eliminating thromboembolic events. Interferon alfa is known to

reduce platelets in a period of days and reduce the frequency of thromboembolic and hemorrhagic

complications. It does not have leukemogenic potential. It is used in select patient groups

(younger patients or those with cytotoxic failures) and is balanced with the need for parenteral

administration and toxicities. No new studies with interferon alfa were completed in the period

January 2008 until December 2012, therefore the benefits of interferon alfa are deemed to be

consistent with those established at baseline.

• Interferon alfa-2a is also indicated as an adjunctive treatment to chemotherapy (with or without

radiotherapy) in patients with low-grade non-Hodgkin’s lymphoma (NHL).

The role of interferon alfa in the treatment of low-grade NHL has been considered to be an

important component of combination therapy and underpins its current use within clinical practice.

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It is used as a maintenance therapy to prolong chemo-therapy induced remission and reduce the

rate of relapse. Interferon alfa has been shown to significantly increase remission duration and

survival, over five to10 years when compared to chemotherapy alone. The combination of

interferon alfa with cyclophosphamide, adriamycin, etoposide, prednisolone and rituximab provides

superior disease control in the long-term in patients with follicular lymphoma. Furthermore, its

ability to perform against NHLs in almost any organ of the body has been highlighted. The

treatment of conjunctival mucosa-associated lymphoid tissue lymphoma in one study led to a

complete a response in 75% of the eyes treated and no local occurrence in 85% of eyes after over

five years after various cycles of treatment.

2. Solid neoplasms; including:

• AIDS-related Kaposi’s Sarcoma (KS) in patients without history of opportunistic infection;

Interferon alfa when used as a single agent has been shown to produce a response in 20-40% of cases. In some cases it leads to notable tumor regression. The time for a response ranges from

three to 20 months. No new studies with interferon alfa were completed in the period January

2008 until December 2012, therefore the benefits of interferon alfa are deemed to be consistent with those established at baseline.

• Advanced renal cell carcinoma;

Advanced renal cell carcinoma caries a poor prognosis with 10% of patients surviving five years after diagnosis. Treatment is aimed at slowing disease progression and managing the signs and symptoms of the disease. Interferon alfa has a major role in the treatment of RCC. In general, its beneficial effects are maximized when in combination with other chemotherapeutic agents such as bevacizumab, temsirolimus, dendritic-cell vaccine with interleukin 2, meloxicam, interleukin-2 and fluorouracil, and celecoxib. Its efficacy as a monotherapy in direct comparison to sunitinib for

example, may not mirror the impressive results obtained from combination therapy, however its ability to still match up to some of its contemporaries such as sorafenib highlights its enduring value, importance and relevance in the treatment of RCC.

• Metastatic malignant melanoma;

And

• Surgically resected malignant melanoma without nodal or distant metastases.

Metastatic melanoma is an aggressive and incurable disease. The median survival time is between eight and 18 months. The role of interferon alfa in the treatment of metastatic malignant melanoma is varied. On the one hand, it is still used in combination with agents such as thymosin alfa 1 and bevacizumab to prolong overall and progression free survival; however its effectiveness

is not marked when used as maintenance agent following radiation or enucleation in patients with uveal melanoma. On balance, these data are considered to be consistent with the efficacy data established at baseline. There is no real trend or pattern for treatment benefits of interferon alfa in subgroups.

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3. Viral diseases; including:

• Patients with proven CHB (e.g. by liver biopsy) who have elevated serum ALT and markers for

viral replication, i.e. those who are positive for HBV-DNA, DNA polymerase or HBeAg without liver

decompensation (Child’s class A);

Interferon alfa has long been used in the treatment of HCB due to its anti-viral and immunomodulatory properties resulting in remission of liver disease. The use of interferon alfa is associated with a significantly higher proportion of patients showing virologic response. Limited

study data concerning lamivudine combination treatment does not alter the benefits established at baseline. Interferon alfa-based therapy provides the opportunity for control of CHB with a finite treatment duration of 48 weeks. Although unpegylated interferons retain a useful beneficial role in

the treatment of CHB, pegylated interferons tend to be the preferred formulation utilized in this indication.

Patients with proven chronic hepatitis C (e.g. by liver biopsy) who are positive for

HCV antibodies and have elevated serum ALT without liver decompensation (Child’s class A);

Interferon alfa is used in combination with other agents and remains beneficial in those with PEG immunogenicity. As with hepatitis B, the use of interferon alfa is associated with virologic response. No studies with interferon alfa were completed in the period January 2008 until December 2012, therefore the benefits of interferon alfa are deemed to be consistent with those established at baseline. Although unpegylated interferons retain a useful beneficial role in the treatment of CHC, a finite treatment course of 24 to 48 weeks of pegylated interferon combined with ribavirin and more recently with telaprevir or boceprevir remains the preferred interferon

regimen utilized in this indication.

• Condylomata acuminata.

Interferon alfa use in patients with HPV provides symptomatic benefits. It has been shown to result in a decrease in the wart affected area, and an increase in the percentage of patients showing clearance of the disease compared to placebo. None of the other treatment options used currently clear HPV therefore genital warts are usually recurrent. No studies with interferon alfa were completed in the period January 2008 until December 2012, therefore the benefits of

interferon alfa are deemed to be consistent with those established at baseline.

Newly Identified information on Efficacy and Effectiveness

The MAH provided an overview of new literature 7 articles on the efficacy of interferon alfa-2a in

the treatment of neoplasms of the lymphatic or hematopoietic system (except for thrombocytosis

no publications were found). All these articles confirmed the efficacy and did not provide any

information with effect on the benefit assessment. On renal carcinoma the MAH retrieved 11

publications. None of them effected the benefit assessment.

RMS comment: Sorafenib-treated patients experienced greater rates of tumour size reduction in one study. Sunitinib demonstrates longer overall survival compared with interferon alfa plus improvement in response and progression free survival in the first line treatment of patients with metastatic renal

cell carcinoma.

For malignant melanoma three new publications did not have effect on the benefit assessment. In

one it was concluded that interferon alfa has no nfluence on survival in patients with choroidal

melanoma.

There was no important new information on interferon alfa use in viral diseases.

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Characterisation of Benefits

RMS comment:

The benefit of the product has not substantially changed since the last Renewal in 2008. Some

new information on benefits did not impact the benefit assessment. See the paragraph on the

baseline efficacy information. Interferon alfa mostly has its benefits in the treatment of neoplasms

of the lymphatic or hematopoietic system. The solid neoplasms have poor prognoses and the effect

of interferon alfa is less evident.

In CHB and -B, interferon is associated with a virologic response. In the treatment of condylomata

acuminata interferon alfa leads to a decrease in the wart affected area.

In the period of this PSUR, no important new benefit information became available.

4. Benefit-Risk Balance

RMS comment:

During this PSUR period, and since the renewal of 2008, no new safety concerns or change in

benefits have been identified. Therefore, the benefit/risk ratio of the product remains unchanged

and favourable.

5. Request for supplementary information

Regarding the corrigendum sent by the MAH including new summary tabulations:

o The MAH should explain why at first they claim the data to be correct and afterwards a corrigendum had to be sent. It should be clear whether the inconsistencies found in the first PBRER were new findings – based on other root causes - or already included in the inspection procedure.

o Furthermore, the MAH should clearly explain what ‘co-manifestations’ are, provide

examples, and confirm that all reported adverse events aare coded with

seriousness since November 2005.

o The number of ‘Unique AEs’ in the first column of the tabulation of the MAH do not always match which the sum of the numbers in the other columns. The MAH should explain this and discuss whether this is related to the issue discussed in the corrigendum.

There were 5 cases of the unlisted event of lichen planus and 1 case of aggravated lichen

planus. Cumulatively, 13 post marketing cases including 1 new case. There are some

cases of other lichen manifestations. The MAH should:

o Discuss why these 6 literature cases were apparently not included.

o Provide a cumulative overview of all lichen cases, including the numbers per indication (as lichen planus seems to be associated with hepatitis C).

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6. Assessment of MAH responses

Q1: Regarding the corrigendum sent by the MAH including new summary tabulations:

o The MAH should explain why at first they claim the data to be correct and afterwards

a corrigendum had to be sent. It should be clear whether the inconsistencies found in the first PBRER were new findings – based on other root causes - or already included in the inspection procedure.

o Furthermore, the MAH should clearly explain what ‘co-manifestations’ are, provide

examples, and confirm that all reported adverse events are coded with seriousness

since November 2005.

o The number of ‘Unique AEs’ in the first column of the tabulation of the MAH do not always match which the sum of the numbers in the other columns. The MAH should explain this and discuss whether this is related to the issue discussed in the corrigendum.

MAH Response:

Reason for preparing the corrigendum to PBRER 1053707

The identified inconsistencies in adverse event (AE) data in the submitted Roferon-A (interferon

alfa-2a) Periodic Benefit Risk Evaluation Report (PBRER) 1053707 (Data Lock Point [DLP]: 31

December 2012) were independent of any inspection procedure. The Marketing Authorization

Holder (MAH) noted that the ‘Total’ column in the summary tables of adverse events from post-

marketing experience did not always reflect the sum of the other columns. Upon further analysis,

it was determined that events for which no seriousness assessment had been made were included

in the ‘Total’ column, but were excluded from the various ‘Serious’ and ‘Non-serious’ columns, as

they could not be properly allocated.

The MAH identified 1758 events for Roferon-A with missing seriousness criteria on the Roche

global safety database, ARISg, in April 2013. Virtually all of these events were reported before

November 2005, when the MAH changed its coding convention for AEs. Prior to that time,

seriousness criteria were not assigned to AEs that were considered signs and symptoms (also

called co-manifestations) of a primary adverse event. (Please see below for a further discussion of

co-manifestations).

To ensure transparency and accuracy of the data presentation, the MAH decided to introduce an

additional column to the summary tabulations and to present such events with no seriousness

criteria as ‘not assessed’. These updated tabulations were provided as a corrigendum to the

current PBRER, and henceforth, all future PBRERs will include a ‘not assessed’ column in the

summary tabulations.

Irrespective of whether a seriousness assessment was captured on the global safety database for a

particular AE, the AE was included in the appropriate ‘Total’ column of the summary tabulation.

Thus, the ‘total’ columns presented in the initially submitted PBRER as well as the corrigendum

were consistent and correct, and all impacted events were used for product evaluation and

conclusions for this PBRER. Once identified, the MAH has conducted a comprehensive analysis of

this issue, and concludes that, the benefit-risk profile of interferon alfa-2a in the approved

indications is considered to remain favorable.

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Separate presentation of Access Solutions events in the summary tabulations of the

PBRER corrigendum

The discrepancies in the summary tabulations described above, which led to the issuance of the

corrigendum, had no relationship to the MHRA pharmacovigilance inspection. However, in addition

to adding the new columns of ‘not accessed’, the tabulations in the corrigendum also provided a

summary of AEs identified during the CAPA activities following the MHRA inspection. This may

have given the impression that the corrigendum was somehow related to the CAPA activities –

which was not the case.

Between the issuance of the original PBRER and of the corrigendum, the MAH changed its standard

tabulation programs to present the number of new events resulting from the CAPA-related

activities in parentheses. For some products, the number of CAPA-related AEs was fairly

significant, and this new presentation allowed assessors to distinguish the CAPA-related events

from other AEs occurring during the reporting interval. The MAH regrets any confusion this may

have caused during the assessment of the Roferon-A PBRER.

Explanation of co-manifestations

Prior to November 2005, if an AE report included several events, some of which were considered signs and/or symptoms of a ‘primary’ AE, the signs and/or symptoms were coded as ‘co-manifestations’ of the primary AE and no seriousness assessment was made. The MAH only assessed seriousness for the primary AE. Two case report examples below illustrate the concept of co-manifestations:

AER 81875: The reported AEs of ‘Lymphangitis’, ‘Localised infection’, ‘Necrosis’ and ‘Skin ulcer’ were marked as co-manifestations (signs and/or symptoms) of the event of

‘Raynaud's phenomenon’.

AER 52747: The AEs of ‘Decreased activity’, ‘Dysphoria’, ‘Alcoholism’, and ‘Irritability’ were marked as co-manifestations (signs and/or symptoms) of the event ‘Depression’.

The coding of such events as co-manifestations ceased in November 2005. Due to the setup of the current safety database events cannot be captured without seriousness criterion. The MAH therefore confirms that all reported AEs in the Roche global safety database since November 2005

have been coded with seriousness. Such historic events (co-manifestations) with no seriousness criteria will henceforth be presented as ‘not assessed’ events in all upcoming PBRERs. The MAH believes that no further action is required.

Definition of unique AEs The tables “Cumulative Tabulations of Serious Adverse Events from Clinical Studies”, sorted by SOC and PTs, wich was provided in Appendix 2a of Roferon-A PBRER 2013 (RDR No. 1053707) provide cumulative counts of all serious adverse events (SAE) from clinical trials. Each occurrence of an SAE is counted once; thus, if a patient had two occurrences of ‘Acute respiratory failure’ these will be counted as two unique events in the tabulation.

Column ‘Unique AE count’

The first column ‘Unique AE count’ presents a count of all SAEs meeting the inclusion criteria for the tabulation, e.g. period end date. Each occurrence of SAEs is counted exactly once.

Columns ‘AE count per drug category’ The following columns (2 through 5) count SAEs per associated drug information.

A patient may have received the drug of interest multiple times, e.g. as blinded and unblinded; thus, an SAE may qualify for inclusion in more than one drug specific column. For interferon alfa 2a this may cause an over-count of SAEs when summarizing over the drug specific columns.

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RMS comments:

The MAH submitted satisfactory response and provided details regarding the corrigendum to the PSUR. The corrigendum was provided in order to accommodate the events classified as co-manifested before 2005. The MAH’s explanation on which adverse events were classified as co-manifested prior to 2005 is accepted. It is acknowledged that the corrigendum was not related to the MHRA pharmacovigilance inspection nor is it related to the definition of unique AEs. The differences in the number of ‘Unique AEs’ in the first column of the tabulation of the MAH and the

number in the other cells are due to different inclusion criteria for tabulation, i.e., per patient and per AE respectively. Issue solved.

Q 2: There were 5 cases of the unlisted event of lichen planus and 1 case of aggravated lichen

planus. Cumulatively, 13 post marketing cases including 1 new case. There are some cases of

other lichen manifestations. The MAH should:

o Discuss why these 6 literature cases were apparently not included.

o Provide a cumulative overview of all lichen cases, including the numbers per indication (as lichen planus seems to be associated with hepatitis C).

MAH Response: Discuss why these 6 literature cases were apparently not included.

The guidelines, on GVP Module VI - Management and reporting of adverse reactions to medicinal products and GVP Module VII – Periodic safety update report, have come into effect as of 02 July 2012 as a result of the new legislation. Prior to the new legislation coming into effect, the company policy regarding literature study cases was not to process any non-serious events for any noninterventional/interventional studies referred to in literature articles.

The MAH received the article

1 in the global safety literature line-listing for identification of ICSRs

via Embase on 07 June 2010. The abstract was assessed as invalid, as there were no serious adverse events reported and the source was literature non-interventional study (NIS). These 6 literature non-serious cases reported from the NIS therefore were not processed in the safety database and were apparently not included in the PBRER.

However, the MAH confirms that the company policy was updated in relation to the new legislation and all serious and non-serious ADRs reported in literature articles referring to non-interventional studies are processed onto the safety database since November 2012. Provide a cumulative overview of all lichen cases, including the numbers per indication Introduction:

Lichen planus is not listed in the EU SmPC, USPI or in the current core data sheet (CDS, version 6) of Roferon-A. Section 2.6.1 (Undesirable Effects, Clinical Trials) of the Roferon-A CDS states “Skin, mucous membranes and adnexa. Common: Mild to moderate alopecia occurred in up to one fifth of patients, but this was reversible on discontinuation of treatment. Rare: Re-exacerbation of

herpes labialis, rash, pruritus, dry skin and mucous membranes, rhinorrhea and epistaxis.” Lichen planus is not listed in the labels of various classes of interferon alfa, such as Pegasys (peginterferon alfa-2a), Pegintron (peginterferon alfa-2b), or Intron A (interferon alfa-2b).

Background:

1 Aamir S, Ullah Z, Iqbal Z, Khan AA, Yaqub F, Malik K. Cutaneous Manifestations Of Interferon Alfa And Ribavirin For

Hepatitis C. Journal of Pakistan Association of Dermatologists. 2008; 18(1); 14-20.

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Lichen planus (LP) is a T-cell-mediated autoimmune disease. T-cell activation is central to the

pathogenesis of lichen planus. Inflammatory cells involved in this process consist of T helper and T cytotoxic lymphocytes, natural killer (NK) cells, and dendritic cells. There are a number of factors that contribute to lichen planus, including clinical conditions, target antigens, and drugs. Among

these factors, a focus was on the possible role of viruses, particularly hepatitis C virus (HCV). HCV has been reported to be associated with extra-hepatic manifestations and immune abnormalities, such as rheumatoid arthritis, cryoglobulinemia, autoimmune thyroiditis, Sjogren’s syndrome and lichen planus. Safety Database review: A cumulative review of cases for PTs under HLT papulosquamous conditions with interferon alfa-2a

(cut-off date of 13 May 2014) in the Roche global drug safety database along with review of all available literature data was performed. A total of 39 cases were retrieved from the database. All the cases were medically confirmed and analyzed. Of these 39 cases, 7 were serious.

There are 11 cases with PT of rash popular / papulosquamous that the PT is unspecificand considered listed under ‘rash’ for Roferon-A labels. Another one case of pityriasis rosea is

considered most likely by viral infection with other pathology. These cases are excluded from the further evaluation. The remaining 27 cases had PT of lichen planus or other lichenoid disorders. Three cases of lichen planus reported in patients treated for leukaemia have insufficient information for proper medical assessment. Five lichenoid disorders cases reported in patients treated for non-hepatitis indications (4 cases have neoplasm diseases and another case of thrombocytopenia has an unusual long latency time [near 10 years]).

There were 19 cases reported lichen planus in patients treated for hepatitis below:

Five cases have insufficient information to make any solid medical assessment.

Six cases are considered to have underlying hepatitis C or unspecified hepatitis without other confounding factor.

Eight cases are reported to have underlying hepatitis C with other confounding factors that make the event-drug causal relationship unlikely:

o 6 cases have pre-existing lichen planus before the initiation of Roferon-A treatment.

o Short latency (same day) reported in one case and event improved while Roferon-

A ongoing in the another case.

The estimated cumulative market exposure of interferon alfa-2a until 30 April 2014 (from IBD: June 1986) is approximately 758,000 patients. The crude reporting rate for lichen planus thus far to Roche global drug safety, with interferon alfa-2a use is 0.0036% (27 cases reported in 758’000 patients) which is lower than the observed epidemiologic values (the estimated prevalence of LP is in the range of 0.22% to 5% worldwide). Literature Review: Dalekos, G N et al. conducted a prospective case-control study in Greece to investigate the incidence of the development of immune-mediated dermatological diseases during alpha-interferon therapy in patients with chronic viral hepatitis. 120 consecutive patients with chronic viral hepatitis (67 with hepatitis B, 45 with hepatitis C, 6 with both hepatitis viruses, and two with delta hepatitis) were evaluated during a course of alpha-interferon therapy. In addition, 120 consecutive patients with chronic liver diseases (disease control group), who had never received alpha-interferon therapy, were evaluated during the period of the study. Three to six months after the initiation of alpha-interferon three patients with chronic viral hepatitis (two with hepatitis C and one with hepatitis B) developed

23

lichen planus. None of the patients from the disease control group had such a manifestation during the follow-up. Lichen planus resolved after the end of therapy in all of them. The author concluded that patients with chronic B or C hepatitis treated with alphainterferon are at risk of developing immune-mediated dermatological diseases, particularly lichen planus. This risk was significantly higher among patients with a positive ANA test before the initiation of therapy, indicating the possible emergence of a pre-existing subclinical or covert autoimmune background in these patients, which is mediated by alpha-interferon. Thorough examination for skin rash or mucosal lesions is necessary in every patient who receives alpha-interferon, especially when a positive ANA test is present. However, this side-effect was mild, quite rare (3.33%), and did not require the discontinuation of therapy. MAH comments: Underlying hepatitis is considered as the confounding factor of the 3 LP cases. Just as the author mentioned, the risk is significantly higher among patients with positive ANA test before initiation of alpha-interferon therapy. This suggests that the immune disorders have already existed before treatment. Thereafter, this makes the likelihood of causal relationship between alpha-interferon and LP very low. Nagao Y et al. presented a study report on the development and exacerbation of oral lichen planus (OLP) before, during and after interferon therapy for hepatitis C. Oral surgeons examined 24 hepatitis C patients for oral lesions before, during and after interferon treatment. OLP was observed in 16.7% (4/24). Two patients had OLP before treatment, one during and one after treatment. Those who developed OLP during or after treatment had neither improvement nor disappearance of OLP even when serum HCV RNA became negative. The author discussed that OLP onset mechanism is unclear; many reports indicate that host immune reaction may play a role in the pathogenesis of OLP. The present study suggested that cytokines induced in vivo at the time of HCV infection play an important role in OLP occurrence and exacerbation after interferon administration. As OLP neither disappeared nor improved but developed when HCV RNA became negative, it is unlikely that HCV participates directly in pathogenesis at the OLP site, but rather acts as a main triggering factor. Caution should be taken to limit OLP occurrence or exacerbation by interferon treatment in hepatitis C patients, but interferon therapy is not necessarily contraindicated in these patients. MAH comment: The results of this study are consistent with the epidemiology data that LP/OLP prevalence among patients with hepatitis C is much higher than average population. This suggests that the underlying hepatitis C could be considered as confounding factor in LP cases. Furthermore, the finding in this study of 3/4 cases of OLP presented before and after interferon treatment strongly indicates that the causal relationship between LP/OLP and interferon is unlikely. MAH Conclusion: Taking into account the strong evidence of association between hepatitis C and lichen planus, and based on the currently available scientific and safety data, a possible causal relationship between interferon alfa-2a and lichen planus could not be established at this point of time. The MAH concludes that an update of the current Roferon-A CDS with regard to lichen planus is not warranted.

RMS comments:

The review of the literature indicates that patients with hepatitis C or B infection receiving

interferon might be at higher risk of developing lichen planus, however, these patients have a higher risk for lichen planus as compared to the general population. The viral hepatitis is a know trigger for lichen planus and the cumulative analysis of cases reporting lichen planus showed that in vast majority of cases, the patients had underlying viral hepatitis B or C. Therefore, the MAH’s conclusion is endorsed. No further action is necessary at this moment.

Issue solved.

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7. Recommendations

During this PSUR period, and since the renewal of 2008, no new safety concerns or change in benefits have been identified. Therefore, the benefit/risk ratio of the product remains unchanged and favourable.

25

1. List of annexes

I. Recommended changes to the product information

II. Any other recommended changes or risk minimisation measures (optional)

III. Patient Exposure

26

ANNEX I

RECOMMENDED CHANGES TO THE PRODUCT INFORMATION

The benefit-risk profile remains favourable and that no changes to the SmPC are needed based on

the PBRER data.

Summary of product characteristics

None

Package leaflet

None

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ANNEX II

ANY OTHER RECOMMENDED CHANGES OR

RISK MINIMISATION MEASURES

None

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Annex III

PATIENT EXPOSURE (one annex for each PSUR of products authorised in

the P-RMS)

Patient exposure in this PSUR :

Methodology used for the exposure number calculation :

X Defined Daily Dose

patients/day

number of prescriptions

number of doses

Other (please specify)

Comparison with previous PSUR, if information is available

Change in methodology used for calculation:

Yes No X

Overall change in patient exposure:

Yes No X

Increase Decrease