August 2015 Australian Public Assessment Report for Insulin glargine
VI. Overall conclusion and risk/benefit assessment
Yüklə 1,57 Mb.
|
- Bu səhifədəki naviqasiya:
- Pharmacokinetic and pharmacodynamic studies
- Efficacy from Phase III studies
- Delegate’s considerations
- Conditions of registration
- Proposed action The Delegate had no reason to say, at this time, that the application for Abasria should not be approved for registration. Request for ACPM advice
- Advisory Committee Considerations
- Specific conditions of registration applying to these goods
VI. Overall conclusion and risk/benefit assessmentThe submission was summarised in the following Delegate’s overview and recommendations: QualityAbasria has the same pharmaceutical form and strength as the reference product, Lantus. The primary amino acid sequence of the active ingredient for Abasria is the same as that for Lantus. Each mL of Abasria contains: 100 units of insulin glargine, zinc oxide, metacresol, glycerol and water for injections; as well as hydrochloric acid and sodium hydroxide for pH adjustment. There are some differences in excipients: zinc oxide replaces zinc chloride, 100% glycerol replaces 85% glycerol. The biosimilar comparability testing included structural characterisation, physicochemical characterisation, biological potency, impurity characterisation and stability assessment. Impurities were low and adequately controlled. The biological chemistry evaluator concluded that comparability between Abasria and EU approved Lantus has been satisfactorily established. The biological chemistry evaluator accepted the sponsor’s justification for use of the EU sourced Lantus for Australian registration.
NonclinicalThe nonclinical evaluator had no objections to registration. The scope of the nonclinical program complied with the relevant EU guideline. Comparability was shown between Abasria and EU sourced Lantus (and depending on the study, US sourced Lantus) on: pharmacological activity (receptor binding affinity and functional activity in cell-based assays; glucodynamic profile in vivo in rats); toxicity profile (assessed in 4 week, GLP compliant studies in rats). ClinicalPharmacokinetic and pharmacodynamic studiesFor a biosimilar insulin, the draft Committee for Medicinal Products for Human Use (CHMP) guidance11, states that PK/PD insulin clamp studies represent the mainstay of the proof of similar efficacy of the biosimilar insulin and the reference product. The guidance further states that Phase III efficacy studies cannot be used to establish efficacy because the endpoints HbA1c are not sufficiently sensitive for the purposes of showing biosimilarity. In other words, Phase III studies (endpoint: HbA1c) only provide supportive evidence of efficacy; the pivotal evidence for claims of equivalent efficacy must come from the PK/PD studies. (The main role of the Phase III studies is to establish safety [and exclude any reduction in efficacy]; by measuring immunogenicity endpoints.) The CHMP agreed with the sponsor that studies in healthy volunteers provide a more homogeneous and sensitive PK comparability model than studies in patients with diabetes. Consequently, all PK/PD studies were done in healthy volunteers; except of ABEE, which was done in patients with T1DM. PK studies used C-peptide-corrected insulin concentration-time data. Given the flat time-concentration profile, AUC is the most sensitive measure; Cmax is less sensitive. For the PD measurements, the draft CHMP guideline12 states that the euglycaemic clamp technique is the best available method for measurement of insulin action. In these clamp studies, the plasma insulin concentration is raised (by subcutaneous injection of insulin) and the blood-glucose level maintained (‘clamped’) at a pre-defined level by means of variable infusion of glucose. The main variable of interest is the time profile for the glucose infusion rate: AUC and Cmax; denoted Gtot and Rmax, below. Table 12: PK/PD studies
Table 13: Results for pivotal ABEA study, healthy volunteers, ratio of least squares geometric means, dose=0.5 U/kg, completers
Gtot (total amount of glucose infused during the euglycaemic clamp procedure). Rmax (maximum glucose infusion rate) Summary of other PK/PD studies ABEI (n=16); this pilot assessed the relative bioavailability and PD response of Abasria versus EU approved Lantus. This was a single-dose (0.5 U/kg), open label study in normal-weight healthy volunteers; insulin levels were corrected for baseline C-peptide level; results were supportive; point estimates for insulin (AUC, Cmax) and glucose infusion (Gtot, Rmax) were indicative of biosimilarity. Some of the 90% confidence limits did not meet the 80%-125% acceptance limits but this is not surprising, given the small sample size. ABEM (n=24) assessed the relative bioavailability and PD response of Abasria versus EU approved Lantus at two single doses: 0.3 U/kg and 0.6 U/kg. At both doses, results were supportive. ABEE (n=20) assessed the duration of action of Abasria versus EU approved Lantus (0.3 U/kg) in patients with T1D (mean age=42 years) (all the other studies were in healthy volunteers). These were stable T1D patients who were receiving baseline insulin treatment. The study was primarily PD in nature and its main objective was to compare the duration of action of Abasria and EU sourced Lantus. The median duration of action was estimated to be 37.1 and 40.0 hours for Abasria and Lantus, respectively. A survival analysis was carried out with a Cox PH model; Hazard ratio (HR)=1.063, p=0.8777; supporting the conclusion that there does not seem to be a significant difference in duration of action between Abasria and Lantus. ABEN (n=40; 34 completers) showed similarity of EU sourced and US-sourced Lantus. Table 14: PK results from Study ABEN
ABEO (n=91) was requested by the FDA (Abasria versus US sourced Lantus). Results were not available at the time the dossier was submitted. Phase III studiesThe primary focus of the two Phase III studies (ABEB, ABEC) was the evaluation of immunogenicity and implications this might have for safety (or any reduction in efficacy). The EMA advised the sponsor that formal demonstration of non-inferiority in terms of antibody response was not required. The EMA considered that HbA1c is not a sensitive enough endpoint on which to establish similar efficacy. For the purposes of establishing efficacy, the results for HbA1c were considered supportive to the PK/PD studies. Both studies were multinational (ABEB: 59 centres in 9 countries; ABEC: 88 centres in 13 countries). Patients in the comparison group either received EU-approved Lantus or US approved Lantus depending on the site (EU approved Lantus: EU, Mexico, Japan, South Korea, Taiwan; US approved Lantus: US, Puerto Rico). The sponsor argued that given the scientific bridge demonstrated in the PK/PD studies, it was not necessary to stratify the results by EU-Lantus versus US-Lantus.
Table 16: Baseline characteristics
Insulin antibodiesThe proportions of patients with detectable antibodies and treatment-emergent antibody response (TEAR) were reported. Definition of TEAR: 1+% increase (absolute) in insulin antibody levels (measured in percent binding) and a 30+% relative increase from baseline for patients who were insulin antibody-positive at baseline, or changed from insulin antibody-negative status at baseline to antibody-positive during the course of the study. The proportions of patients with detectable antibodies were similar for Abasria and Lantus in both ABEB and ABEC.
a) overall (anytime) during treatment period, not including baseline For ABEB, at 52 weeks, the proportion of patients with detectable antibodies was similar. For example, for overall (anytime) the proportions were: Abasria (38%) versus Lantus (39%). Stratified analyses by TEAR did not show any differences for Abasria versus Lantus by HbA1c, basal insulin dose, or hypoglycaemia.
HypoglycaemiaNot surprisingly, the rate of hypoglycaemic attacks was greater in Study ABEB (T1D, all patients were insulin dependent at study entry) than study ABEC (T2D, approximately 60% of patients insulin-naïve at study entry). There were no clinically meaningful differences in total, severe or nocturnal hypoglycaemia for Abasria versus Lantus (or relative or symptomatic or other categories hypoglycaemia, not included in the above summary table). Table 19: Incidence of hypoglycaemia to 24 weeks
A hypoglycaemic event was defined as: any time a patient felt that he/she was experiencing a symptom or sign associated with hypoglycaemia or blood glucose ≤3.9 mmol/L (≤70 mg/dL). Severe hypoglycemia was defined as a hypoglycemic event that required assistance of another person to actively administer carbohydrate, glucagons, or other resuscitative actions. These episodes may have been associated with sufficient neuroglycopenia to induce seizure or coma. Blood glucose measurements may not have been available during such an event, but neurological recovery attributable to the restoration of BG to normal was considered sufficient evidence that the event was induced by low plasma glucose. Nocturnal hypoglycemia was defined as any hypoglycemic event that occurred between bedtime and waking. The 52 week report for ABEB also did not show any clinically meaningful differences in hypoglycaemia.
Other safety dataThere were no imbalances in serious adverse events or deaths. There were no differences in treatment-emergent allergic events (for example, arthralgia, pruritus, rash, asthma and injection-site reactions). The majority of these events were mild and none led to discontinuation. Efficacy from Phase III studiesTable 20: Results for HbA1c, 24 weeks
These results meet the non-inferiority margin of 0.3% at 24 weeks for the endpoint of ‘change in HbA1c’; although the point estimates show that Abasria was slightly worse than Lantus, in terms of HbA1c. The updated analysis at 52 weeks for ABEB (T1D) also met the non-inferiority margin of 0.3%. For example, for the full analysis set, last observation carried forward (LOCF), Abasria -0.256%, Lantus -0.276%, least squares (LS) mean difference: 0.020%, (95% confidence interval (CI): 0.099%, 0.140%). Results for secondary efficacy endpoints (such as fasting blood glucose and insulin dose) were consistent with those for HbA1c.
Risk management planNo new risks were identified for Abasria and the risk management plan is based on that for Lantus. Important identified risks for Abasria/Lantus include hypoglycaemia, hypersensitivity reactions, injection site reactions, medication errors. Important potential risks include malignancies and immunogenicity. The plan is to mitigate these risks through routine risk minimisation measures (for example, education for prescribers through the PI and spontaneous reporting of adverse events). Risk-benefit analysisDelegate’s considerationsThe sponsor’s clinical development program was conducted according to EMA guidelines and after discussion with EMA. The PK/PD profiles of Abasria and Lantus are similar. Two Phase III studies have shown that the immunogenicity profiles of Abasria and Lantus are similar. Establishment of non-inferior (similar) efficacy was not the primary aim of the Phase III studies (that is, the primary aim was to show that the immunogenicity profiles were similar). Point estimates for change in HbA1c were similar but slightly in favour of Lantus. (The 95% CI did not include the non-inferiority margin of 0.3%). These results are broadly supportive of the PK/PD data, which are the primary data that establish similar efficacy. If the TGA’s Advisory Committee on Prescription Medicines (ACPM) is satisfied that the submitted data show that Abasria is similar to Lantus, then the efficacy and safety of Abasria can be inferred from the evidence base for Lantus. Conditions of registrationImplement EU Risk Management Plan Version 1.0 (dated 22 May 2013, Data Lock Point (DLP) 01 April 2013) and Australian Specific Annex Version 2 (dated 21 May 2014), and any future updates (where TGA approved) as a condition of registration. The Australian Biological Name of the reference product may be used as the non-proprietary name of Abasria, however it is a condition of registration that when the International Nonproprietary Names (INN) Biological Qualifier proposal is adopted by the World Health Organization, that the biosimilar identifier is used in all references to the product in the labelling, PI and CMI. When this change is made, the TGA should be informed and the labels, PI and CMI submitted for assessment and updating of the website. Proposed actionThe Delegate had no reason to say, at this time, that the application for Abasria should not be approved for registration. Request for ACPM adviceDoes the ACPM consider that the PK/PD studies provide sufficient evidence to establish that Abasria has a PK/PD profile similar to that of Lantus? Does the ACPM consider that the Phase III studies provide sufficient evidence to establish that immunogenicity is similar to Lantus? Studies of similarity between Abasria and Lantus have been conducted in adults. Does the ACPM consider that these allow extrapolation of the similarity to children, 2 years and older? Biosimilars are not regarded as interchangeable on a same-dose basis with the reference product. That is, any switch from Lantus to Abasria should only be done under medical supervision and may require different dosing and particular caution regarding hypogylcaemia. Does the ACPM consider that the information provided in the PI is appropriate? Response from sponsorThe sponsor’s response will focus on the key areas of:
The sponsor of the reference product Lantus® has conducted studies in children aged 2 years and older. The Australian package insert (PI) for Lantus contains the following statement regarding use in paediatric patients: In general the safety profile for patients ≤18 years of age is similar to the safety profile for patients >18 years. Based upon the accepted similar safety of insulin glargine in adults and paediatric patients, the extensive postmarketing experience of the reference product in both populations, and the demonstrated comparability of Abasria to Lantus®, the sponsor concludes that Abasria is appropriate for use in the paediatric setting. The Abasria PI proposes the following information for paediatric use consistent with the reference PI:
The practice of adopting the reference product label following demonstration of comparability is consistent with the approach agreed to by the EMA and the FDA. According to EU regulations, paediatric investigation has been waived for Abasria because the safety and efficacy of the reference product (Lantus) has been investigated in the paediatric population. Data on Lantus in paediatric populations have been published.12 The EMA approved Abasria on 9 September 2014, including the Abasria Summary of Product Characteristics (SmPC) text based on the Lantus® SmPC shown below. Lantus® SmPC Section 5.1 states: Safety and efficacy of Lantus® (insulin glargine, Sanofi-Aventis) have been established in adolescents and children aged 2 years and older. Safety and efficacy of Lantus® have not been established in children below the age of 2 years. Lantus® SmPC Section 4.8 (Undesirable Effects) includes the following safety summary: In general, the safety profile for children and adolescents (≤18 years of age) is similar to the safety profile for adults. The adverse reaction reports received from postmarketing surveillance included relatively more frequent injection site reactions (injection site pain, injection site reaction) and skin reactions (rash, urticaria) in children and adolescents (≤18 years of age) than in adults. Clinical study safety data are not available for children under 2 years. Additionally, the USPI will contain similar statements for paediatrics based on the findings of the reference product. The following is tentatively approved in the US PI (Note: The tradename for Abasria in the US is proposed as BASAGLAR): The safety and effectiveness of BASAGLAR have been established in pediatric patients (age 6 to 15 years) with Type 1 diabetes based on an adequate and well-controlled trial of another insulin glargine product in pediatric patients (age 6 to 15 years) with Type 1 diabetes and additional data in adults with type 1 diabetes. [see Clinical Studies (14.2)]. The safety and effectiveness of BASAGLAR in pediatric patients younger than 6 years of age with Type 1 diabetes and pediatric patients with Type 2 diabetes has not been established. The dosage recommendation when changing to BASAGLAR in pediatric patients (age 6 to 15 years) with Type 1 diabetes is the same as that described for adults [see Dosage and Administration (2.2, 2.3) and Clinical Studies (14)]. As in adults, the dosage of BASAGLAR must be individualized in pediatric patients (age 6 to 15 years) with Type 1 diabetes based on metabolic needs and frequent monitoring of blood glucose. In the pediatric clinical trial, pediatric patients (age 6 to 15 years) with Type 1 diabetes had a higher incidence of severe symptomatic hypoglycemia compared to the adults in trials with Type 1 diabetes [see Adverse Reactions (6.1)]. Interchangeability The sponsor agrees that Abasria and Lantus® are not interchangeable (). As stated in the Precautions section of the proposed Abasria PI: The level of comparability that has been shown is not sufficient to designate this product as a generic version of Lantus. Replacement of Lantus with Abasria, or vice versa, should take place only under the supervision of a health care professional. What is being referenced in the topic for discussion is switching and the sponsor agrees that any change of insulin should be done under medical supervision as per the Precautions section of the proposed Abasria PI: Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type (regular, NPH, lente, long-acting, etc.), origin (animal, human, human insulin analogue), or method of manufacture may result in the need for a change in dose. Importantly, both Phase III studies provided data on patients switching from Lantus to Abasria at the same dose regimen; no difference in dose changes after titration to tighten glucose blood control was reported between the 2 treatment arms. Subgroup analyses based on prestudy insulin indicated no clinically relevant effect on selected safety and efficacy outcomes. Clarifications The sponsor notes 2 corrections that should be made to the Request for ACPM’s Advice document: • In Section Insulin Antibodies, it is incorrectly stated that there was a difference in the proportion of patients with detectable antibodies for insulin-naïve patients (e.g., overall [anytime] at 24 weeks: Abasria 19% versus Lantus 8%) in Study I4L-MC-ABEC (ABEC). This difference was observed in the subgroup of prior Lantus® patients in Study ABEC. The difference in the prior Lantus® subgroup is difficult to interpret given the small number of patients in this subgroup who had detectable antibodies at any point during the study (n=40). It is noteworthy to mention that this difference was not observed in the entire Full Analysis Set population or in the subgroup of insulin-naïve patients in Study ABEC. Also, no difference was found in Study I4L-MC-ABEB, which was the study with the most sensitive population for detecting immunogenicity (Type 1 diabetes mellitus). • In Discussion; regarding the topic of non-inferiority, it is correctly stated that the 95% confidence interval did not include the non-inferiority margin of 0.3%; however, it is not entirely accurate to state that these were not corrected for multiplicity. It was not necessary to adjust for multiplicity due to the gatekeeping procedure for non-inferiority for the 24-week endpoint of both studies. Advisory Committee ConsiderationsThe ACPM, having considered the evaluations and the Delegate’s overview, as well as the sponsor’s response to these documents, advised the following: The submission seeks to register a new biosimilar medicine. The ACPM, taking into account the submitted evidence of efficacy, safety and quality, agreed with the Delegate and considered Abasria, Abasria KwikPen, solution for injection as pre-filled syringe or pre-filled pen, containing 100 IU/mL of insulin glargine to have an overall positive benefit–risk profile for the indication:
The ACPM agreed with the Delegate on the proposed conditions of registration and specifically advised on the inclusion of the following: Subject to satisfactory implementation of the Risk Management Plan most recently negotiated by the TGA, Negotiation of Product Information and Consumer Medicines Information to the satisfaction of the TGA. Proposed Product Information (PI)/Consumer Medicine Information (CMI) amendments The ACPM agreed with the Delegate to the proposed amendments to the Product Information (PI) and Consumer Medicine Information (CMI) and specifically advised on the inclusion of the following: Change the wording in the CMI under How Much to Use, which states; ‘…do not change your insulin unless your doctor tells you. Be very careful if you do change insulin’ to the wording in the Lantus CMI: ‘It is very important that you manage your diabetes carefully. Too much or too little insulin can cause serious effects’. The ACPM considered that the current wording is unclear whether the change is referring to the dose or the brand of insulin. It is clear in the Lantus CMI that change is referring to dose, which is appropriate as it is under ‘How Much to Use’. However, consumers should also be made aware that they should not switch brands of insulin glargine unless under proper supervision as products are not equivalent.
Specific adviceThe ACPM advised the following in response to the Delegate’s specific questions on this submission: Does the ACPM consider that the PK/PD studies provide sufficient evidence to establish that Abasria has a PK/PD profile similar to that of Lantus? The ACPM advised that acceptable similarity between Abasria and Lantus has been demonstrated by the PK and PD studies. Does the ACPM consider that the Phase III studies provide sufficient evidence to establish that immunogenicity is similar to Lantus? The ACPM advised that the results from the two Phase III clinical trials (ABEC and ABEB) demonstrated similarity of the two products, including for immunogenicity. Studies of similarity between Abasria and Lantus have been conducted in adults. Does the ACPM consider that these allow extrapolation of the similarity to children, 2 years and older? The ACPM noted that Lantus is registered for use in children from the age of 2 years but has not been studied in children less than 2 years of age. Therefore, as Abasria has been accepted as similar to Lantus, the ACPM advised that extrapolation can be allowed for use in children 2 years and older. Biosimilars are not regarded as interchangeable on a same-dose basis with the reference product. That is, any switch from Lantus to Abasria should only be done under medical supervision and may require different dosing and particular caution regarding hypoglycaemia. Does the ACPM consider that the information provided in the PI is appropriate? The ACPM advised that the statement regarding switching between the two products is appropriate. The ACPM also considered that an educational program for health professionals may be needed to highlight that any product switching must be supervised and dose equivalence should not be assumed for any individual patient. The ACPM advised that the implementation by the sponsor of the recommendations outlined above to the satisfaction of the TGA, in addition to the evidence of efficacy and safety provided would support the safe and effective use of these products. OutcomeBased on a review of quality, safety and efficacy, TGA approved the registration of to approve the registration of Abasria insulin glargine (the) 100 IU/mL solution for Injection cartridge Abasria KwikPen insulin glargine (the) 100 IU/mL solution for injection cartridge for subcutaneous injection, indicated for: Insulin glargine an insulin analogue indicated for once-daily subcutaneous administration in the treatment of Type 1 diabetes mellitus, in adults and children and Type 2 diabetes mellitus in adults who require insulin for the control of hyperglycaemia. Specific conditions of registration applying to these goods
As a minimum, the first five independent batches of Abasria (insulin glargine (rbe)) solution for injection in cartridge and prefilled pen 100 IU/mL imported into Australia are not released for sale until samples and/or the manufacturer’s release data have been assessed and endorsed for release by the TGA Office of Laboratories and Scientific Services (OLSS). Yüklə 1,57 Mb. Dostları ilə paylaş:
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||