Australian public assessment for Albumin (human)

III. Nonclinical findings

It was agreed, pre-submission, that a nonclinical evaluation was not required, as long as the nonclinical aspects of the proposed Australian PI for the Swiss manufactured Albunate were the same as those for the already-registered Australian-manufactured Albumex.

Albumin is unlikely to have toxicological effects on humans because it is of human origin.

IV. Clinical findings

A summary of the clinical findings is presented in this section. Further details of these clinical findings can be found in Attachment 2.

Introduction

Clinical rationale

Albumin is responsible for maintaining the colloid osmotic pressure in plasma and thereby sustains the circulating plasma volume. The clinical efficacy of albumin is mainly due these osmotic properties. In dehydrated patients, patients with hypovolemia or with circulatory shock, HAS 5% was shown to support the total plasma volume while in trauma patients or in severely burned patients, the concentrated HAS 20% and 25% solutions are known to augment the plasma volume by drawing extra vascular water into the circulation.

Albumin also reversibly binds to cations and anions and thus acts as a transport protein for many endogenous and exogenous substances.

Albumin, derived from a variety of blood extraction, separation and purification processes has been in clinical practice for decades. Albunate is one such albumin that has been registered for clinical use in the US since 1976 (with a different trade name). Because of the long development and clinical use history the sponsor of Albunate in the US was not required to provide evidence of efficacy, comparative efficacy or safety. The submission to register Albunate in Australia is due to a request from the Blood Products Working Party (BPWP) to have a backup for the supply of blood products should there be issues with the current registered albumin product.

Guidance

There are multiple Guidelines nationally and internationally for the use of crystalloids versus colloid products for this indication, and for different types of colloid products, in addition. The type of recommended product depends on institution preference and patient situation (disease, clinical state, underlying comorbidity). This is evidenced in a review of the literature provided in the literature part of the hybrid submission.

There is no European CPMP for human albumin use.

It is noted that there has been updated literature based submission (LBS) guidance released on 27 May 2014. However the sponsor completed the compilation of the dossier in March 2014 for pre submission.

Contents of the clinical dossier

The submission is based on a three pronged hybrid LBS. The literature review part of this submission focuses on randomised controlled trial and meta analyses around the safety and efficacy of albumin generally (some data which does or is likely to have included Albunate) and based on the proposed indication, which is based on the European Union (EU) Core Summary of Product Characteristics (SmPC) for albumin. This approach was approved by the TGA.

The second part of the hybrid literature based submission consist of company pharmacovigilance data collected from periodic safety activities from 1996 to the present and the third part is a small post-marketing safety study of Albunate (marketed as Albumin SRK in Austria), the product seeking registration.

The sponsor was given approval to not submit nonclinical data based on advice from the nonclinical evaluation stream leader; essentially that statements in the proposed PI relating to nonclinical matters must be consistent with ones contained in the existing approved PI for Albumex.

The literature review consisted of an appropriate search strategy. It located 1,256 publications in the Embase search and 278 from the Cochrane search. The results were tabulated and 84 of the Embase search papers were included in the review, as well as the 278 from the Cochrane and 11 others based on updated editorials and reviews of the original Cochrane data and other publications picked up during preparation of the Risk Management Plan (RMP) and this submission; these were selected for Review based on research around the efficacy and safety of any of the albumins. Details of the reasons for selection for each of the 1,256 were provided. This summary has been checked and is appropriate for the discussion around efficacy and safety of albumins in clinical practice.

The primary clinical data to support the use of Albunate is collected from periodic safety activities from 1996 to the present and was summarised, with supporting literature provided. The following were presented;

Post-marketing experience

Efficacy of Albumin in hypovolaemia following shock due to trauma or sepsis

Efficacy of Albumin in hypovolaemia following surgery

Efficacy of Albumin in burn patients

Efficacy of Albumin in the management of patients with liver cirrhosis and ascites

Meta-analyses

Safety profile of albumin (data from published literature)

The quality module contained the following:

The quality dossier is based on the current EU Mutual Recognition Procedure dossier and consists of a separate Drug Substance and Drug Product section for each of the three concentrations. It includes data around drug substance control of materials, process validation and evaluation, impurities and container closure system, drug product process validation and or evaluation, control of excipients and control of drug product analytical procedures.

Albunate complies with the Ph. Eur. monograph (Human Albumin Solution). Although Australian approved terminology has been used for all of the application forms in the product descriptions and labelling documents, as Module 3 is the EU dossier, sodium caprylate and caprylic acid have been used in place of the excipient Australian approved names AANs sodium octanoate and octanoic acid.

Albunate contains a new non-proprietary ingredient sodium tryptophanate. The excipient N-acetyltryptophan is added to stabilise human albumin in accordance with the Ph. Eur monograph² and United States Pharmacopeia (USP) monograph.³ The excipient complies with the Ph. Eur monograph for N-Acetyltryptophan.⁴ Albunate has been stabilised with sodium tryptophanate since its registration in the US and EU and has over 35 years of clinical use and a safety profile with this excipient.

The active ingredient, human albumin, is manufactured from human source or recovered plasma as described in the TGA approved CSL Behring (Type I) Plasma Master File (PMF).

In summary the clinical module includes:

Clinical study reports

Post marketing experience (AE by system organ class (SOC))

Austrian post marketing survey with Albumin 5% and 20% (Albunate)

Periodic Safety Update Report (PSUR) 1 October 1997 to 31 March 2002

PSUR 1 April 2002 to 20 October 2006

PSUR 21 October 2006 to 20 October 2009

PSUR 21 October 2009 to 20 October 2012

Rep-efficacy-safety studies

Blood volume deficiency

rep-analysis-data-more-one-stud (22 studies)

stud-rep-uncontrolled (2 studies)

stud-rep-controlled (63 studies)

The primary clinical data specific to Albunate is the pharmacovigilance and post-marketing data collected from periodic safety activities from 1996 to the present. This consists of:

An observational study performed in Austria with Albunate (Albumin SRK 5% and Albumin SRK 20%)

Periodic Safety Update Reports from October 1997 to October 2012

Adverse Event Line Listings from 1996 to 2013.

This primary data, specific to Albunate, is supported by the publications provided in the clinical module. These use a variety of different HAS products (although some studies are likely to have included patients on Albunate, not specified). Specifically, the module includes meta-analyses and several series of Cochrane reviews – presented in the tabular summaries in the clinical module and also summarised and discussed in the clinical summary as supporting studies. Also included in the clinical module is supporting literature for the efficacy and safety of albumin generally.

This literature is thus helpful to understand the well-established place of practice of albumins in clinical practice, gives some data on efficacy in specific population groups and some safety data (where reported). The Austrian study data must be used to examine Albunate specifically, although this primary data is observational only, as is the PSUR.

Paediatric data

The submission included no paediatric pharmacokinetic / pharmacodynamic / efficacy / safety data.

The application notes that data has been submitted neither to the EU nor the US. There is no paediatric investigation plan (EMEA) nor US Paediatric Assessment (US). As there has been registration in those jurisdictions for many decades, it is stated that the provisions for a Paediatric Investigational Plan (EU) or a Paediatric Plan (US) do not apply.

There is no paediatric development plan for Albunate. However CSL has requested listing in a paediatric population in Australia (from newborns through to adults). There is no specific Albunate paediatric data in this application although there is data from use of albumins generally in children since registration; covered in the literature review and post-marketing reviews. This suggests there is efficacy in this population, and further that the spectrum of AEs is similar (although the frequency is unable to be ascertained with observational reported data).

In the proposed PI no specific dosing requirements or pharmacokinetic statements are included for the paediatric population.

Good clinical practice

No new clinical trials were undertaken for the purposes of registering in this indication. Good Manufacturing Practice (GMP) certification has been provided.

Pharmacokinetics

Studies providing pharmacokinetic data

There were no studies providing pharmacokinetic data however pharmacokinetic knowledge of albumin in disease and healthy states and the effect of infusing intravenous (IV) exogenous albumin are well documented. Pharmacokinetically, albumin products are comparable to normal human plasma albumin, with a biological half-life of 18 to 19 days, and the equilibration between an intravascular (40%) and extra vascular body pools (60%) and resulting complex shifts of fluid. The pharmacokinetics of Albunate are expected to be those of other human albumins given intravenously.

Evaluator’s conclusions on pharmacokinetics

There is no pharmacokinetic data presented in this application. Bioequivalence studies between different albumin products have also not been undertaken. Both are feasible but probably of limited clinical relevance in this situation, especially as the clinical rationale for these products is in volume expansion, clinical response is variable and measured/monitored by clinical signs. Further because studies to examine clinical differences between Albunate and other albumins have not been undertaken nor seen as a clinical need, there is arguably little clinical need for detailed pharmacokinetic studies to be undertaken.

Pharmacodynamics

Studies providing pharmacodynamic data

There were no studies providing pharmacodynamic data, although there was summary pharmacodynamic data provided in studies in the literature review.

Human albumin accounts quantitatively for more than half of the total protein in the plasma. The most important physiological functions of albumin are its role in plasma oncotic pressure, its transport function and its role as an extracellular antioxidant in human plasma. Albumin is the major determinant of colloid osmotic or oncotic pressure (COP) in normal patients; one of the main reasons to use human albumin in states of reduced volume.

Iso-oncotic albumin as with Albunate 5 restores and maintains the circulating blood volume where volume deficiency has been demonstrated. The hyperoncotic Albunate 20 and 25 contribute to maintaining the plasma colloid osmotic (oncotic) pressure of plasma and therefore plasma volume by balancing the hydrostatic pressure within the tissue capillaries. Older work has suggested that 1 g of 20 to 25% human serum albumin retains 18 mL of fluid in the circulation in patients with a normally hydrated interstitium; in dehydrated patients the 5% solution has greater volume effects.

There were a number of publications cited in the LBS provided that showed the efficacy of albumin in increasing COP in critically ill surgical patients, in patients with hypovolemia and septic shock.

However the relationship between volume and clinical outcomes has not been demonstrated; nor has the method of measurement of changing volumes and clinical outcomes been discussed (including crystalloid versus colloid) and within the group of colloids the difference between different types of colloid and between the product under submission has not been discussed.

Evaluator’s conclusions on pharmacodynamics

There were no pharmacodynamic studies submitted with Albunate. Although there was literature provided on albumins and change in COP or other pharmacodynamic endpoints, there were a number of factors making this data non evaluable for this application. The type of volume expander, the type of colloid and the type of albumin are not always clear, studies that are clearly of Albunate and pharmacodynamic endpoints were unable to be located; and the rationale in the application for Albunate specifically and pharmacodynamic outcomes was not well discussed.

Dosage selection for the pivotal studies

There were no pivotal studies. Dosage selection is difficult with HAS as dose and concentration is titrated to an individual clinical state. Further, the relationship with outcomes is more related to volume expansion than a set albumin dose or concentration.

Efficacy

Restoration and maintenance of volume status

Data for evaluation of Albunate was provided by a literature review of predominantly randomised controlled trials (RCTs) and meta-analyses of albumin usage for the requested indication:

“Restoration and maintenance of circulating blood volume where volume deficiency has been demonstrated, and the use of a colloid is appropriate”.

Although these manuscripts were reviewed, they were not evaluated due to:

multiple types and concentrations of albumin used, and

Albunate use not specified (presumed use in the US data but numbers/percentages in the trials not specified)

no specific Albunate data

multiple indications, multiple settings

lack of comparative efficacy with other HAS registered in Australia

lack of comparison to crystalloids

In terms of the volume restoration indication as proposed in this application, there are no clinical studies specifically with Albunate; although it is likely that Albunate was used for at least some the patients in some of the studies. The sponsor however states that data showing efficacy of albumin in hypovolaemia using formulations from other manufacturers can be used as supportive evidence and results can be extrapolated to the human albumin CSL formulations.

The clinical efficacy is therefore discussed in the context of Albunate being one of the HAS and examining efficacy for albumins in this indication.

A review of literature provided does suggest the HAS is effective in this setting and this fact was relied upon in the design of the Australian and New Zealand study SAFE study (Saline versus Albumin Fluid Evaluation)⁵. SAFE can be used to examine the comparative efficacy of albumins versus crystalloid as it is a local study reflecting local use, was appropriately designed (including enrolment of 6,997 patients) and provides evidence around the indication the sponsor is seeking registration. The albumin in this study was Albumex 4 % which is a HAS already available in Australia but manufactured using a different chromatographic process. SAFE showed that both Albumex 4% and saline were equally effective resuscitation fluids using death as the primary endpoint.

As further discussion point the Cochrane analysis provided in the submission and which included the SAFE study (which notably did add 91% of the weight) showed that for patients with hypovolaemia there was no evidence that albumin reduced mortality when compared with cheaper alternatives such as saline. There is no evidence that albumin reduces mortality in critically ill patients with burns and hypoalbuminaemia and there is a suggestion that albumin may increase the risk of death.⁶ In the more recent Cochrane review of November 2011 (Roberts I et al. 2011)⁷ results of the SAFE trial contributed 75.2 % of the weight. This review concluded that there is still no conclusive evidence that HAS reduces mortality in patients with hypovolaemia, burns and hypoalbuminaemia. Given the limitations of the data in the meta-analyses, the SAFE study still remains the backbone of the evidence that HAS does not decrease mortality compared to crystalloid.

However the reality of clinical practice in Australia is that there are pockets of clinical care that use HAS and subsets of the population that appear to benefit, for example paracentesis in patients with fluid overload and low serum albumin such as gastroenterology. For this reason, although reviewed the literature will not be discussed manuscript by manuscript as to the efficacy of HAS, but rather whether there is sufficient evidence to support a listing for a new albumin on efficacy and safety grounds.

Studies providing efficacy data

There were no pivotal efficacy studies undertaken.

Evaluator’s conclusions on efficacy

Evaluator’s conclusions on clinical efficacy for volume restoration and maintenance.

Clinical data published and presented here since a publication date of 1990 has shown that HAS generally has the following effects:

it raises a lowered plasma COP

in a normally hydrated or mildly dehydrated patient, 1 g of human serum albumin retains 16 to 18 mL of fluid within the circulation

in a hypovolaemic patient, the intravascular volume effects of HAS correspond to the volume infused rather than the albumin dose or concentration

Crystalloid is as effective as HAS as volume restoration in overall mortality in intensive care unit (ICU) patients.

There is published randomised controlled trial (RCT) and Cochrane Library evidence that HAS is effective in replacing fluid volume in patients with hypovolaemia following shock due to trauma or sepsis, hypovolaemia following surgery and in burn patients, and for the treatment of ascites in liver cirrhosis.

The major study on which the claim of efficacy for treatment of hypovolaemia following trauma, shock, or acute respiratory disorder syndrome is based is the SAFE study which was a robust, double blind, randomised, prospective, multi-centre study carried out by a clinical trials group across Australia and New Zealand. It included 6,997 patients based on its primary end point, allcause mortality at 28 days. It was designed to reflect clinical practice and the objective measures of haemodynamic efficacy but showed HAS to be equivalent to saline. The albumin used was Albumex 4%.

The literature provided in this submission is thus supportive data only for evaluating efficacy and safety of HAS as a class, not for a new albumin. The evidence in the literature review discussed several aspects: are colloids effective at improving COP; does increasing COP with colloids translate into a clinically meaningful endpoint (morbidity or mortality); are there differences in efficacy between the colloids; are there differences between the albumins; is there evidence to support a concentration of 5% versus 20% or 25% or is volume the key variable for efficacy. If so does it matter how volume is restored?

It is reasonable to conclude that the meta-analyses and RCTs presented in this submission suggest that albumins are effective at expanding intravascular volume; however the effect on clinically relevant endpoints (such as death and morbidity) is unlikely to be any more than that achieved with crystalloid. It could also be argued that the in comparison of albumins with different colloids, although may show safety differences in specific groups, are all reasonably similarly effective at restoring blood volume. The issue for this application is about the entry into the market of a new to Australia (but old to the rest of the world) HAS and the safety and efficacy of this product.

This submission does not have any clinical trial evidence presented for Albunate.

However because the manufacturing of the already registered Albumex 4% is relatively similar, and because it is possible that it is the volume effect rather than the albumin type is more important, and because it has been available across the globe for over 40 years and clinicians use it clinically, it would be reasonable to assume this albumin product has efficacy at volume expansion. However it cannot be assumed that this product is even as effective as Albumex without comparative clinical and pharmacokinetic/ pharmacodynamic data.

These conclusions hold true for the effectiveness of HAS for the maintenance and/or the restoration of haemodynamics in surgical patients, burns (where one meta-analysis suggested the outcome was worse if albumin was used) and decompensated cirrhosis with associated complications such as spontaneous bacterial peritonitis.

In terms of the efficacy for the meta-analyses and systematic reviews, the conclusions are similar. There have been many have been published since 1998 that look at the outcome of volume resuscitation with different fluids; undertaken with the purpose of trying to address the perennial crystalloids versus colloid debate as well as to look at the use of the more expensive colloid resuscitation fluids. These reviews are difficult to summarise due to many heterogeneous factors including heterogeneity of clinical patient groups, the age and quality of the publications used, varied dosages of the fluids, differing types and concentrations of albumin used as well as different treatment protocols. Their direct relevance to the question of this application; is there enough efficacy data to support registration of Albunate is also unanswered by these meta-analyses; unless it is assumed that Albunate and the other available HAS are all similar enough to be interchangeable. However there is no evidence presented to support that.

Safety

Studies providing safety data

There were no studies providing comparable and evaluable safety data and there was no clinical trial data for the drug in this application. For this section, the observational Austrian study “Observation Study with Albumin SRK 5% and Albumin SRK 20%” was evaluated.

Pharmacovigilance data was also reviewed. ‘Results’ sections in the supporting literature documents were also viewed for safety information; this data was poorly reported in all but a few recent studies and meta-analyses. It should be noted that safety data in the literature was for HAS generally, not for Albunate.

It is noted that there have not been any regulatory actions taken on Human Albumin CSL Behring 5%, 20%, and 25% for safety reasons for 17 years; since the beginning of the reporting period of the first PSUR (1997). Further, one of the meta-analyses on safety of albumin versus other colloids showed albumin was safer.⁸ Overall it also showed that on the basis of large-scale pharmacovigilance study results, albumin infusion resulted in a low rate of both total adverse events (3.1 to 8.6 per 105 infusions) and serious adverse events (1.29 per 106 infusions) overall.

Evidence of significant safety concerns associated with albumin administration, as compared to colloids overall is small and the known risks of hypotension and immunological reactions with HAS occur infrequently.⁹ Specifically, the most relevant systematic review of the relative safety of colloids showed that starch infusions caused more anaphylactoid reactions (4.51 relative ratio), pruritus (1.78 relative ratio), and coagulopathy (relative ratio not reported) compared with HAS administration. In addition, multivariate analysis of larger, blinded randomised controlled trials showed a reduction in mortality associated with HAS administration (OR 0.78; 95 % confidence interval (CI): 0.76 to 0.81).⁴

Patient exposure

Over 40 years in many countries around the globe.

Safety issues with the potential for major regulatory impact

Haematological toxicity

Incompatibility reactions have been previously reported when HAS are mixed with other medicines/coagulation products or diluted with water.

Human Albumin Solution (HAS) does not appear to affect the blood coagulation profile, in contrast to some starches or gelatin. However, it has been shown to be associated with prolongation of activated partial thromboplastin time (APTT)¹⁰, as have the infusion of larger fluid volumes of other agents.¹¹ However, in a meta-analysis of colloids, artificial colloid administration was consistently associated with coagulopathy and clinical bleeding, most frequently in cardiac surgery patients receiving Hydroxyethyl starch (HES).⁴

Serious skin reactions

Nil reports. Pruritus occurrence was significantly increased by HES exposure (OR 1.78; 95 % CI: 1.23 to 2.58).

Cardiovascular safety

Hypotensive reactions have been reported in many clinical trials. In some cases where there is a ‘batch’ effect, it has been related to elevated activity of prekallikrein activator (PKA) which can occur in storage.

Following a systematic review of the comparative safety of colloids,⁴ it was reported that with HAS as the reference colloid, the incidence rate ratio for anaphylactoid reactions was:

4.51 (95 % CI: 2.06-9.89) after HES administration

2.32 (95 % CI: 1.21-4.45) after dextran

12.4 (95 % CI: 6.40-24.0) after gelatin

Unwanted immunological events

Hypersensitivity and anti-erythrocyte antibodies occur infrequently with HAS.

Safety in special populations

Paediatrics

Human Albumin Solution (HAS) has been used for many years in special populations including geriatrics and paediatrics. Although there have been no studies in children with Albunate, there are clinical trials in children with other albumins and also other colloids (for example HES). It appears that children receiving colloids improve intravascular volume. HAS is widely used and there were a few submitted publications in the literature review showing it had been used in children and appeared safe, or at least as safe as other colloids, for example.¹² Sadly data on the effect on overall outcome (morbidity or mortality) was not collected.

From 18 September 1996 to 1 September 2013, a total of five reports involving the use of Albunate in children (< 12 years) were retrieved from the CSL safety database. Primary preferred terms (PTs) include blood pressure systolic decreased, hypersensitivity, medication error, anti-erythrocyte antibody and anaphylactic shock. All patients recovered.

Additionally, two reports involving the use of Albunate in adolescents (≥ 12 to < 18 years of age) were reported. Primary preferred terms (PTs) include type I hypersensitivity and flushing. The patients received human albumin 20% and AlbuRx 25%, respectively. Both patients recovered.

There were no variations in benefit and no indication of a new safety concern from these 7 reports.

Elderly use

There is no specific Albunate data in the elderly but as albumin is infused as a solution and the elderly are less able to tolerate fluid overload, care should be taken if albumin products are being used in conditions where hypervolaemia could represent a special risk for the patient; these pathophysiological situations are well known for practitioners using volume expansion, are already documented in the PI and would not be specific to Albunate.

Cumulatively, from 18 September 1996 to 1 September 2013, there were 60 case reports for Albunate in the elderly patient population (≥ 65 years old). Age span ranged from 65 to 87 years of age. There were no reports suggesting a different safety profile in the elderly compared to the known effects. There has been no indication of any new safety concerns from the post-marketed use of Albunate in the elderly.

Pregnant or breast feeding women

Human albumin is a normal constituent of human blood. Apart from risk of infection or volume alterations there is theoretically unlikely to be teratogenic concerns from infusion of albumin. No animal reproduction studies have been conducted with Albunate. Clinical experience with HAS generally has not reported harmful effects on the course of pregnancy, the fetus or the neonate. The use of Albunate in human pregnancy has not been examined in clinical trials (controlled/uncontrolled).

Two non-serious reports (same patient) with preferred term (PT) of exposure during pregnancy have been received for Albunate, reported from the literature.¹³ A woman requiring surgery while pregnant received albumin. A post-op ultrasound scan confirmed a viable pregnancy although there was no follow-up data after 5 days.

Hepatic impairment

Human Albumin Solution has been studied extensively in patients with decompensated liver cirrhosis and is widely used in this indication globally. It has been shown to reduce the prevalence of circulatory dysfunction after paracentesis and to improve outcomes in patients with spontaneous bacterial peritonitis.¹⁴

Cumulatively, from 18 September1996 to 1 September 2013, a total of 25 reports involving patients with hepatic impairment were retrieved from CSL safety database. A total of 95 events were reported in the 25 cases. Review of these events indicated an AE pattern similar to that of the overall patient population.

Renal impairment

Cumulatively, from 18 September 1996 to 1 September 2013, a total of 20 reports involving patients with a history of renal impairment were retrieved from CSL safety database. A total of 64 events were reported in these 20 cases. Review of these events indicated a pattern similar to that of the overall patient population.

There have been literature and prospective observational studies regarding HAS use in renal patients; some showing bias in terms of HAS being used for the sickest patients. A recent systematic review examined comparative safety of colloids based on clinical studies reported from 2002 to 2010 included sixty-nine publications (42 RCTs with 10,382 patients, 8 cohort studies, 7 non-randomised controlled studies, 7 meta-analyses, 4 systematic reviews, and 1 pharmaco-surveillance study).¹⁵ Except for an observational study where HAS was reserved for sicker patients, there was no other reported deleterious renal effects attributable to hyperoncotic albumin. One study actually suggested albumin-mediated renal protection.

Post-marketing data

These are covered in

1. 
   The Austrian post-marketing survey “The observational Austrian study “Observation Study with Albumin SRK 5% and Albumin SRK 20%” and
   
2. 
   The PSUR
   

The Austrian study was a very small study (211 subjects observed over 1999 to 2000) who had an Albumin SRK 5% ((250 mL and 500 mL) or 20% (50 mL and 100 mL) infusion, this product is the Albunate product in this application. Inclusion criteria included traumatised patients suffering volume loss, shock, burns, patients for whom the administration of HAS is indicated in connection with an accident or an operation (Austrian Codex Technical Information 1998/1999). Patients were excluded if the product would be contraindicated or who would be considered included in any of the warnings listed in the current technical information (Austrian Codex Technical Information 1998/1999). Overall five patients died due to the severity of their injuries (not otherwise specified); non-serious adverse drug reactions (ADRs) were reported by 20 patients (9.5%); in most cases these were classified as mild (“light”) to moderate (“medium”) and all patients recovered from these ADRs.

The study evaluated safety and clinical effectiveness, based on a 4 point scale: “very good”, “good”, “poor “and “unclear”. For patients whose efficacy was not evaluated (due to multiple events) the effectiveness was recorded as “not evaluated”. The clinical evaluation of Albunate was given as “very good” or “good” for 81.6% of patients (n = 172) and for 1.9% as “not good” (“poor”, n = 4). The remaining patients (16.6%, n = 35) could not be evaluated because of multiple events.

Eleven patients (5.2%) had a drop in BP which was classified as mild for 8 and moderate for 3 patients. Nine patients (4.3%) had erythema (mild in 7 and moderate in 2 patients). No other ADRs were reported. No patient experienced an anaphylactic shock, nor was Quincke’s oedema observed for any patient.

The data provided was pretty low quality although it is noted that individual patient data is available on request. For example, it is unknown who the efficacy data is evaluated by - presumably by the doctor and hence the efficacy bias is likely to be large. Also there is no reference nor comparison group. Further the efficacy scale is not robust. The safety data displays ADEs widely known to occur with albumin. It is reassuring that no new events were detected (although there were small numbers).

This study is helpful in terms of efficacy and safety data with the HAS specified in this application.

The PSUR has identified no new reports since 1997.

Evaluator’s conclusions on safety

Overall the safety profile of HAS, a group of products that has been in clinical use for many decades is well documented. Mortality outcomes have been investigated in several studies, with the most relevant in the SAFE study (due to the recency of the study, it being undertaken in an Australasian population and using it in the indication requested in the application) showing similar mortality to saline. Several meta–analyses including one of colloid products have suggested similarly.

In terms of specific concerns around potential safety with Albunate; HAS do not appear to affect the blood coagulation profile (although it has been shown to be associated with prolongation of APTT); HAS does not appear to affect the electrolyte/acid base balance; anaphylactoid reactions do occur but this is likely to be more common in Hydroxyethyl starch (HES) infusions; the review of relevant literature has not clearly shown a signal on renal outcomes with HAS, although it is becoming clear that the plasma expansion effects need to be separated from the albumin effects. Specifically the meta-analyses suggest volume overload with HAS could be dangerous, particularly in the elderly. The concentration, volume and the infusion rate should be adjusted to the patient's status and individual requirements using measures of circulating volume, not plasma albumin levels. This fact is important and could be made clearer in the proposed PI and CMI.

The relevance of the product under review, Albunate, to the literature on is that Albunate is an HAS the SAFE study used Albumex 4%. There is no other safety data on Albunate apart from the post-marketing Australian observation study which showed an AE profile similar to other HAS. The PSUR for is unremarkable and no new AEs have been reported.

Safety concerns:

1. 
   Information around fluid and oncotic overload and importance of appropriate assessment prior to using Albunate clearly in the PI, CMI and sponsor advertising.
   
2. 
   Post-marketing database to be collected on efficacy, safety especially in special groups for a period of one year.
   

First round benefit-risk assessment

First round assessment of benefits

The benefits of HAS in the proposed usage are:

[Information redacted]

Albunate has nearly 40 years of use in US, Canada and Europe with no new safety concerns

Clinical place of HAS and the clinical risk-benefit analysis/place of use is becoming more defined in practice compared to at the time of initial registration in the US.

First round assessment of risks

The risks of Albunate in the proposed usage are:

Clear need for both 20% and 25% not ascertained

Lack of trial efficacy and safety data to be aware of true efficacy

Comparison with current HAS in Australia not made.

First round assessment of benefit-risk balance

Overall, the application did not contain any data to enable a comparison between Albunate and Albumex or any of the other formulations of HAS used in the literature. If both are used in Europe and the US and the formulations all comply with the European and US Pharmacopoeia for Human Albumin then that could be considered. However it would be a stronger case if pharmacology, bioequivalence and clinical data could be provided considering there is no stand-alone data and clinical evidence in those areas for Albunate.

Notwithstanding, it is clear that there is global clinical practice usage data to suggest that as a HAS, Albunate is effective and safe for intravenous infusions for the indication of restoring and maintaining volume. In terms of overall survival, there was no data available to examine this. The clinical evaluator recommended the 5% concentration be registered in keeping in line with the SAFE study and one of the hyperoncotic concentrations; for consistency with Albumex the clinical evaluator suggested the 20% concentration.

First round recommendation regarding authorisation

Advise that the TGA obtain expert clinical advice.

Clinical questions

1. 
   What was the evidential basis for registration in European countries in 1997? Can the European Medicines Agency (EMA)/ European Medicines Evaluations Agency (EMEA) evaluation reports from 1997 be provided?
   
2. 
   Why are both the 20% and 25% concentrations being proposed for registration in Australia? That is, what is the clinical need for both 20% and 25%; in addition to 5%?
   
3. 
   What are the current volumes of use of Albumex 4% and 20% in Australia?
   
4. 
   What is the current place of albumin in clinical practice in Australia?
   
5. 
   [information redacted]
   
6. 
   Please justify differences between the PI for Albumex and the proposed PI for Albunate?
   
7. 
   Why are three separate PIs proposed for the three different concentrations? Could different concentrations be included in the one PI?
   

Second round evaluation of clinical data submitted in response to questions

A second round evaluation was not prepared. The Delegate reviewed the information provided by the sponsor in response to the questions raised above (please see the Delegate’s review in the overall conclusion and risk benefit analysis section below).