August 2015 Australian Public Assessment Report for Insulin glargine

V. Pharmacovigilance findings

Risk management plan

The sponsor submitted a Risk Management Plan EU Risk Management Plan Version 1.0 (dated 22 May 2013, Data-lock point 01 April 2013) and Australian Specific Annex Version 2 (dated 21 May 2014) which was reviewed by the TGA’s Post-Market Surveillance Branch (PMSB).

Safety specification

The sponsor provided a summary of ongoing safety concerns which are shown in Table 9.

Table 9: Ongoing safety concerns provided by the sponsor in their RMP submission.

Pharmacovigilance plan

The sponsor proposes only routine pharmacovigilance activities for all ongoing safety concerns.

Risk minimisation activities

The sponsor proposes only routine risk minimisation activities for all ongoing safety concerns.

Reconciliation of issues outlined in the RMP report

Table 10 summarises the PMSB’s first round evaluation of the RMP, the sponsor’s responses to issues raised by the PMSB and the PSMB’s evaluation of the sponsor’s responses.’

Table 10: Reconciliation of issues outlined in the RMP evaluation report (Round 1)

Recommendation in RMP evaluation report	Sponsor’s response (or summary of the response)	PSMB evaluator’s comment
Safety considerations may be raised by the nonclinical and clinical evaluators through the consolidated section 31 request and/or the Nonclinical and Clinical Evaluation Reports respectively. It is important to ensure that the information provided in response to these includes a consideration of the relevance for the Risk Management Plan, and any specific information needed to address this issue in the RMP. For any safety considerations so raised, please provide information that is relevant and necessary to address the issue in the RMP.	‘The questions received did not require an amendment to the Risk Management Plan (RMP).’
The sponsor is advised to revise the ASA document.	‘The sponsor has revised the Australian Specific Annex document according to the guidance received.’
The sponsor should add these Ongoing Safety Concerns to the risk management plan: Cardiovascular events; Lipodystrophy; and Oedema.	‘Cardiovascular (CV) events The sponsor believes that the data from the ORIGIN study precludes the need for adding CV events (The ORIGIN Trial Investigators, 2012). Cardiovascular events will be part of routine pharamacovigilance monitoring and automated signal detection would ensure any untoward increase in frequency or severity would be noted and evaluated. Lipodystrophy Lipodystrophy is a risk for Abasria; however, it does not rise to the level of important as defined in Good Pharmacovigilance Practice) Module V (Rev 1). This risk does not have an impact on the benefit-risk balance of the product or have implications for public health and thus should not be included in the RMP. Oedema Oedma based on insulin-related sodium retention is identified in the PI within the adverse event (AE) table as a recognised event; however, it does not rise to the level of an important identified risk. Oedema in conjunction with thioazolidinedione is already included as a safety concern, as it appears to be a more severe outcome for this drug-drug interaction.’	This is considered acceptable in the context of this application. However, the EU Guideline on good pharmacovigilance practices (GVP) Module V – Risk management systems also states that Important Identified Risks include conditions which can substantially affect a person’s quality of life.
Unless the sponsor can provide a compelling justification, children below 18 years of age should be added as important missing information and a relevant and appropriate PI change should be made.	‘The sponsor believes that children younger than 18 years have been adequately studied by the innovator product and are included in the approved indications in the US (age 6 and older), EU (age 2 and older) and in Australia (age 2 and older). The use of insulin glargine for the treatment of T1DM in a pediatric population was originally supported by data establishing the safety and effectiveness of subcutaneous injections of insulin glargine (Lantus®) in patients aged 6 years and older.^9 The data for children between 2 and 6 years of age (the PRESCHOOL study) was recently published and shows clinical outcomes in children similar to those of adults.^10 Assessments of plasma ‘trough’ levels of insulin glargine revealed plasma concentration patterns similar to adults. Assuming the TGA, upon review of the marketing authorisation application concludes that Abasria is biosimilar to Lantus®, that conclusion should carry over to the pediatric population as well for the purpose of labeling. The sponsor agrees that adequate data are not available for children younger than 2 years and will include this age category as important missing data in the RMP.’	This is considered acceptable in the context of this application, if the Delegate has no objections to accept the Lantus data for ABRASIA.
The sponsor should conduct a study (or assign an existing study) to investigate the potential risk of malignancies further, in particular in children.	‘The initial concern over the relationship of insulin glargine and malignancy was raised in 2009 in a published Pharmacoepidemiology survey. Sanofi-Aventis, the Lantus® sponsor, conducted 3 additional surveys, covering a total of almost 2 million patient lives, to explore this question, with conflicting results. In addition, Sanofi altered the secondary endpoints of the ORIGIN study, a 12,000-patient, prospective, 6 year longitudinal study in prediabetic and diabetic patients to explore the incidence of malignancy and also conducted a prospective study in patients with breast cancer who were newly diagnosed as diabetic and were insulin naïve. This study was planned after Committee for Medicinal Products for Human Use (CHMP) concluded that the other potential risks of a causal relationship between the use of insulin analogues and malignancy had apparently been discharged. The CHMP report from 31 May 2013 concluded ‘that overall the data did not indicate an increased risk of cancer with insulin glargine, noting that there is no known mechanism by which the insulin glargine would cause cancer and that a cancer risk has not been seen in laboratory studies.’ Neither the initial report nor any subsequent reports have reported an increased risk of malignancy in children using insulin analogues. The paediatric diabetic population is increasing in prevalence but remains small, and the number of diabetic children who either have or are likely to develop a malignancy is also quite small. To collect the number of subjects needed to reach a conclusion with any degree of reliability would require several decades of enrolment in a prospective clinical trial or an epidemiology survey to collect sufficient sample size to be able to reach reliable conclusions or the availability of many hundreds of thousands of children with exposure to insulin analogues. Accordingly, the sponsor believes that the demonstration of biosimilarity in the adult population should extend biosimilarity to the pediatric population on the basis of the innovator’s paediatric data, and furthermore, the ability to conduct any epidemiologic survey or prospective study would require a prolonged period to accumulate the population exposure required for a statistically valid analysis. In the entire 14-year period since the innovator product first became available, there has been no signal suggesting a malignancy risk in the paediatric population. On this basis, the sponsor would decline acting on the recommendation.’	This is not considered acceptable. The OPR evaluator acknowledges that the reported incidence of malignancy is low and that a paediatric diabetic population is receiving more medical monitoring. However, considering that many paediatric malignancies may be discovered late, that medical monitoring for diabetes would not necessarily increase the probability of detecting a malignancy, and that insulin glargine is a widely used medicine, the sponsor should conduct a study (or assign an existing study) to investigate the potential risk of malignancies in children further. This recommendation remains.
The sponsor recognises that this product is indicated for patients that are 2 years of age or older. This is not reflected in the proposed PI, as the PI refers to an age of 6 years and older. The sponsor is advised to remove this inconsistency. Furthermore, unless the sponsor has a compelling justification, children below the age of 18 years of age constitute important missing information which needs to be reflected in the PI.	‘The sponsor has corrected the inconsistency. This product is indicated for patients that are 2 years of age and older. Regarding the important missing information statement in the PI, the sponsor agrees that there are inadequate data on children younger than 2 years of age and will include that statement in the RMP. The rationale for this response is provided in the response to Recommendation 1.4.’	This is considered acceptable in the context of this application. This is qualified in the comment in response to recommendation 1.4.
In the ‘Precautions’ section, under the ‘Hepatic Impairment’ heading, the sponsor should include a statement that use in patients with rapidly deteriorating hepatic function is not recommended and the increased risk of hypoglycaemia in these patients (or a statement to that effect).	‘The sponsor believes that a biosimilar and the innovator product should present the same information and declines acting on the recommendation.’	The reason given by the sponsor is not sufficient to warrant non-inclusion. Each submission is assessed individually. The recommendation to the Delegate remains.
In regard to the proposed routine risk minimisation activities, it is recommended to the Delegate that the draft consumer medicine information document be revised to accommodate the changes made to the product information document.	‘The sponsor has revised the draft CMI and provided it in Module 1.3.2.’	This is considered acceptable.
In the ‘How to use Abasria’ section, the PI should contain a statement regarding the compatibility of the supplied cartridge with other insulin pens (if any) (or a statement to that effect).	‘The requested information is already provided in the ‘preparing a dose’ section and this does not need to be duplicated.’	This is considered acceptable.

Summary of recommendations

It is considered that the sponsor’s response to the TGA request for further information has adequately addressed most of the issues identified in the RMP evaluation report (other than PI recommendations).

Outstanding issues

It is considered that the sponsor’s response to the TGA request for further information has adequately addressed most the issues identified in the RMP evaluation report (other than PI recommendations).

Summary of outstanding issues (including additional recommendations)

The sponsor should conduct a study (or assign an existing study) to investigate the potential risk of malignancies further, in particular in children.

In regard to the proposed routine risk minimisation activities, it is recommended to the Delegate that the draft product information document be revised.

Advice from Advisory Committee on the Safety of Medicines (ACSOM) has been sought at the request of the Delegate.

Key changes to the updated RMP

EU Risk Management Plan Version 1.0 (dated 22 May 2013, Data Lock Point (DLP) 01 April 2013) and Australian Specific Annex Version (no version given, undated)

has been superseded by:

EU Risk Management Plan Version 1.0 (dated 22 May 2013, Data Lock Point (DLP) 01 April2013) and Australian Specific Annex Version 2 (dated 21 May 2014).

It is noted that in the Australian Specific Annex Version 2 (dated 21 May 2014), the sponsor seems to refer to an EU Risk Management Plan Version 2.0. However, after consulting with the sponsor, it was found that the updated ASA also refers to EU Risk Management Plan Version 1.0.

Table 11: Key changes to the ASA

Summary of key changes between Australian Specific Annex (no version given, undated) and Australian Specific Annex Version 2 (dated 21 May 2014)
Safety specification	Part II:SI, SII, SIII, SVII added
Pharmacovigilance activities	Part III: III.1 added Updated Table V.1 Use in children to reflect changes in the reference label; from less than 6 years to less than 2 years

Suggested wording for conditions of registration

Any changes to the RMP that were agreed to by the sponsor become part of the RMP, whether they are included in the currently available version of the RMP document, or not included, inadvertently or otherwise. The suggested wording is:

Implement EU Risk Management Plan Version 1.0 (dated 22/05/2013, DLP 01/04/2013) and Australian Specific Annex Version 2 (dated 21/05/2014), and any future updates (where TGA approved) as a condition of registration.