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AusPAR Attachment 2

Extract from the Clinical Evaluation Report for fentanyl citrate

Date of CER: 24 July 2012

Therapeutic Goods Administration

Proprietary Product Name: Abstral

Sponsor: A. Menarini Australia Pty Ltd

Submission PM-2011-03151-3-1 Extract from the Clinical Evaluation Report for fentanyl citrate (Abstral) of 57


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About the Extract from the Clinical Evaluation Report This document provides a more detailed evaluation of the clinical findings, extracted

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Submission PM-2011-03151-3-1 Extract from the Clinical Evaluation Report for fentanyl citrate (Abstral) Page 2 of 57

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ContentsList of abbreviations__________________________________________________________4

1. Clinical rationale_________________________________________________________6

2. Contents of the clinical dossier_________________________________________7

2.1. Scope of the clinical dossier__________________________________________________7

2.2. Paediatric data________________________________________________________________7

2.3. Good clinical practice_________________________________________________________7

3. Pharmacokinetics________________________________________________________8

3.1. Summary of pharmacokinetics______________________________________________8

3.2. Evaluator’s overall conclusions on pharmacokinetics____________________21

4. Pharmacodynamics_____________________________________________________21

4.1. Studies providing pharmacodynamic data________________________________21

4.2. Summary of pharmacodynamics___________________________________________21

4.3. Secondary pharmacodynamics_____________________________________________22

4.4. Evaluator’s overall conclusions on pharmacodynamics__________________22

5. Dosage selection for the pivotal studies_____________________________22

6. Clinical efficacy__________________________________________________________23

6.1. Relief of breakthrough cancer pain________________________________________23

7. Clinical safety____________________________________________________________40

7.1. Studies providing evaluable safety data___________________________________40

7.2. Pivotal studies that assessed safety as a primary outcome______________41

7.3. Patient exposure____________________________________________________________41

7.4. Adverse events______________________________________________________________42

7.5. Laboratory tests_____________________________________________________________52

7.6. Post-marketing experience_________________________________________________53

7.7. Evaluator’s overall conclusions on clinical safety_________________________53

8. First round benefit-risk assessment_________________________________54

9. First round recommendation regarding authorisation___________54

10. Clinical questions_____________________________________________________54

11. References_____________________________________________________________55



List of abbreviationsAbbreviation Meaning

AE adverse event

ALT alanine transaminase

ANOVA analysis of variance

AUC area under the curve

AUC0-4h area under the plasma concentration-time curve from 0 to 4 hours after the dose

AUC0-6h area under the plasma concentration-time curve from 0 to 6 hours after the dose

AUC0-t area under the plasma concentration-time curve from 0 to the last quantifiable observation

AUC0-∞ area under the plasma concentration-time curve, extrapolated to infinity

AUCτ area under the plasma concentration-time curve during the dose interval

BPI Brief Pain Inventory

BTcP breakthrough cancer pain

CI confidence interval

CL clearance

CL/F clearance/fraction absorbed

Cmax maximum plasma concentration

Ctrough trough plasma concentration (at the end of the dosing interval)

CMI Consumer Medicine Information

CNS central nervous system

CYP3A4 cytochrome P-450, 3A4 isoenzyme

DAPOS Depression, Anxiety, and Positive Outlook Scale

ECG electrocardiograph

F fraction absorbed

FDA [United States] Food and Drug Administration

FEV1 forced expiratory volume over 1 second



Abbreviation Meaning

ITT intent-to-treat

IU international unit(s)

IV intravenous

LC-MS/MS liquid chromatography - tandem mass spectrometry

LOQ [lower] limit of quantification

LOCF last observation carried forward

LS mean least squares mean

MAO monoamine oxidase

NNH number-needed-to-harm

NNT number-needed-to-treat

OR odds ratio

PD pharmacodynamic(s)

PI Product Information

PID pain intensity difference

PEFR peak expiratory flow rate

PK pharmacokinetic(s)

PP per-protocol

PR pain relief

QoL quality of life

RMP Risk Management Plan

Rsq Residual sum of squares

SAE serious adverse event

SD standard deviation

SE standard error (of the mean)

SOC System Organ Class

SPID sum of pain intensity difference



Abbreviation Meaning

ss (after a PK parameter)at steady state

t1/2 terminal elimination half-life

TEAE treatment-emergent adverse event

Tmax Time (after the dose) of the maximum plasma concentration

TOTPAR total pain relief

V volume of distribution

1. Clinical rationaleAmong patients with cancer there is a high incidence of breakthrough cancer pain (BTcP), ie. transient exacerbations of otherwise controlled chronic cancer pain. Treatment guidelines for cancer pain recognise the need for an agent with appropriate potency, rapid onset and short duration of effect, which can be tailored (by dose titration) to address the individual requirements of patients suffering from BTcP.

Oral transmucosal fentanyl citrate has been identified as an agent that fulfils these criteria. One product – in the form of a lozenge on a stick with the trade name Actiq – is currently registered in Australia. The following PK information for Actiq is derived from the Australian PI (30 January 2012):

The absorption pharmacokinetics of fentanyl from Actiq are a combination of rapid oromucosal absorption (bypassing first-pass metabolism) and slower gastrointestinal absorption of swallowed fentanyl (subject to first-pass metabolism).

Approximately 25% of the total dose of Actiq is rapidly absorbed from the buccal mucosa. The remaining 75% of the dose is swallowed and slowly absorbed from the gastrointestinal tract. About 1/3 of this amount (25% of the total dose) escapes hepatic and intestinal first-pass elimination and becomes systemically available. The absolute bioavailability of Actiq is thus about 50%.

The maximum plasma concentration of fentanyl after Actiq administration occurs after about 20 to 40 minutes.

Once in the blood, fentanyl rapidly crosses the blood-brain barrier. Redistribution into tissues and hepatic metabolism provide a duration of action that is suitable for the treatment of BTcP.

One disadvantage of Actiq is that to maximise the speed and extent of absorption of fentanyl across the oral mucosa, the patient must move the lozenge around the mouth, using the attached stick, over a period about 15 minutes. Differences in the amount of movement between successive uses of the product can lead to inconsistency in the speed and extent of fentanyl absorption. In addition, moving the lozenge around the mouth would tend to encourage the swallowing of saliva (containing fentanyl), diverting fentanyl from transmucosal to gastrointestinal absorption. A rapidly-disintegrating sublingual tablet - such as Abstral - would potentially be more convenient to use and also has the potential to provide a more consistent dosage as well as improved bioavailability.

Comment: The potential advantages of Abstral are acknowledged. On the other hand, one of the advantages of Actiq – particularly during initial dose titration – is that the product



can be removed from the mouth if signs of excessive opioid effects appear. This is less feasible with a rapidly-disintegrating, mucosally-adherent, sublingual tablet such as Abstral. It is therefore particularly important that patients using Abstral should be started on the lowest available dose and that titration to a higher dose level should occur in conservative steps.

In addition, the promise of improved bioavailability compared to Actiq does not appear to have been realised (as discussed in greater detail later) and improved consistency of absorption compared to Actiq was not demonstrated in the submitted data.

2. Contents of the clinical dossier

2.1. Scope of the clinical dossierThe following clinical information was presented for evaluation:

14 pharmacokinetic studies (7 in opioid naïve healthy subjects, 1 in opioid tolerant patients with cancer pain);

1 study of the effect of acidic and basic food/beverages on oral pH;

1 placebo controlled pharmacodynamic (dose exploration) study in opioid tolerant patients with cancer pain;

1 placebo controlled efficacy/safety study in opioid tolerant patients with cancer pain;

1 uncontrolled, open label, long term safety study in opioid tolerant patients with cancer pain;

Literature references.

2.2. Paediatric dataThe submission did not include paediatric data. The sponsor provided a justification for the absence of a paediatric development program in children aged 0 to 5 years of age, based on the factors such as the limited number of patients in this age group with cancer pain, questions about “whether BTcP as an entity exists in the same way as we understand it in adults and older children” and a lack of validated and accepted tools to identify and quantify BTcP in this age group.

Comment: Sublingual administration of fentanyl without swallowing the product, be it a tablet or liquid, would also be impractical in very young children. However, no justification was provided for the lack of clinical data or a development program in children over the age of 5 years.

2.3. Good clinical practiceAll of the clinical studies in the submission were stated to have been conducted in accordance with Good Clinical Practice and in accordance with clinical trials legislation/regulations in the countries in which they were performed.



3. Pharmacokinetics

3.1. Summary of pharmacokineticsSeveral PK studies and the pivotal efficacy study used the Abstral formulation proposed for registration (Formulation A). A number of developmental formulations were also used in the clinical pharmacology studies. Of these, Formulation 1 (used in 4 PK studies and 1 PD study) was shown to be bioequivalent to Formulation A. As previously noted, Formulation 2 (used in 2 PK studies) was not directly compared to Formulation A, and cannot be regarded as bioequivalent to the market formulation.

3.1.1. Summary PK parameters

3.1.1.1. Single dose

The pharmacokinetics of fentanyl after the administration of single doses of Abstral were investigated for several formulations, for doses ranging from 50 g to 800 g, in healthy μ μsubjects and in patients with cancer pain. Summary PK parameters for the market formulation of Abstral (Formulation A) and the bioequivalent Formulation 1 are shown in Tables 1-7.

Table 1: Mean in vivo tablet dissolution time (minutes) after single doses of Abstral.

* Median; † 2 x 400 g tablets; ‡ 4μ x 200 g tablets; # 2μ x 800 g tablets; all other doses given as single tablets.μDose comp. = Type of comparison between different dose levels in that study (PG = parallel group, XO = crossover).

Table 2: Median Tfirst (minutes) after single doses of Abstral.

Dose comp. = Type of comparison between different dose levels in that study (PG = parallel group, XO = crossover).† 800 g dose given as 2 μ x 400 g tablets; all other doses given as single tablets. * Data from Site 1 only.μ



Table 3: Mean Cmax (ng/mL) after single doses of Abstral.

Dose comp. = Type of comparison between different dose levels in that study (PG = parallel group, XO = crossover).† 2 x 400 g tablets; ‡ 4μ x 200 g tablets; # 2μ x 800 g tablets; all other doses given as single tablets. § Swedish-μmanufactured tablets (data from this study for US-manufactured tablets [predating manufacturing process change] have been disregarded).* Data from Site 1 only.

Table 4: Median Tmax (minutes) after single doses of Abstral.

Dose comp. = Type of comparison between different dose levels in that study (PG = parallel group, XO = crossover).† 2 x 400 g tablets; ‡ 4μ x 200 g tablets; # 2μ x 800 g tablets; all other doses given as single tablets. § Swedish-μmanufactured tablets (data from this study for US-manufactured tablets [predating manufacturing process change] have been disregarded - see text). * Data from Site 1 only.



Table 5: Mean AUC0-t (ng.h/mL) after single doses of Abstral.

Dose comp. = Type of comparison between different dose levels in that study (PG = parallel group, XO = crossover).† 2 x 400 g tablets; ‡ 4μ x 200 g tablets; # 2μ x 800 g tablets; all other doses given as single tablets. § Swedish-μmanufactured tablets (data from this study for US-manufactured tablets [predating manufacturing process change] have been disregarded - see text).* Data from Site 1 only.

Table 6: Mean AUC0-∞ (ng.h/mL) after single doses of Abstral.

Note: The summary AUC0-∞ estimates were potentially unreliable in many studies due to inadequate characterisation of the slope of the terminal portion of the log concentration-time curve and/or extrapolation of more than 20% of AUC0-∞ in a significant proportion of subjects. See the individual study summaries for details.Dose comp. = Type of comparison between different dose levels in that study (PG = parallel group, XO = crossover).† 2 x 400 g tablets; ‡ 4μ x 200 g tablets; # 2μ x 800 g tablets; all other doses given as single tablets. § Swedish-μmanufactured tablets (data from this study for US-manufactured tablets [predating manufacturing process change] have been disregarded - see text). * Data from Site 1 only.



Table 7: Mean t1/2 (h) after single doses of Abstral.

Note: The summary t1/2 estimates were potentially unreliable in many studies due to inadequate characterisation of the slope of the terminal portion of the log concentration-time curve in a significant proportion of subjects. See the individual study summaries for details.Dose comp. = Type of comparison between different dose levels in that study (PG = parallel group, XO = crossover).† 2 x 400 g tablets; ‡ 4μ x 200 g tablets; # 2μ x 800 g tablets; all other doses given as single tablets. § Swedish-μmanufactured tablets (data from this study for US-manufactured tablets [predating manufacturing process change] have been disregarded - see text). * Data from Site 1 only.

3.1.1.2. Multiple dose

PK parameters after the administration of repeated doses of the market formulation of Abstral (Formulation A) or the bioequivalent Formulation 1 in healthy subjects are summarised in Tables 8-14, below (with single dose parameters from the same studies for comparison).

Table 8: Mean in vivo tablet dissolution time (minutes) after single and multiple doses of Abstral in healthy subjects.

Dose comp. = Type of comparison between different dose levels in that study (PG = parallel group).

Table 9: Mean Cmax (ng/mL) after single and multiple doses of Abstral in healthy subjects.


Table 10: Median Tmax (min) after single and multiple doses of Abstral in healthy subjects.




Table 11: Mean Ctrough (ng/mL) after multiple doses of Abstral in healthy subjects.


Table 12: Mean AUC0-t (ng.h/mL) after single and multiple doses of Abstral in healthy subjects.


Table 13: Mean AUCτ (ng.h/mL) after single and multiple doses of Abstral in healthy subjects.


Table 14: Mean t1/2 (h) after single and multiple doses of Abstral in healthy subjects.

Dose comp. = Type of comparison between different dose levels in that study (PG = parallel group).* Result may be unreliable due to exclusion of 5/10 subjects (see Study Summary).

No multiple dose PK studies were conducted in patients with cancer pain. There are no data for Tfirst during repeated dosing, since regular q4h and q6h dosing meant that plasma fentanyl concentrations remained detectable throughout the entire dose interval and therefore immediately after each dose at steady state. There are also no data for AUC0-∞ at steady state as this parameter was not assessed in Study 2246-EU005 and the results in Study-EU-002 were unreliable due to exclusion of 8 of the 10 subjects.

3.1.2. Pharmacokinetics in healthy subjects

3.1.2.1. Absorption

3.1.2.1.1. Sites of absorption

Abstral sublingual tablet are intended to be placed under the tongue where they adhere to the buccal mucosa then dissolve, releasing fentanyl which is systemically absorbed via three potential mechanisms:

Direct passage from the adherent tablet into the buccal mucosa.

Dissolution into saliva, followed by absorption across the buccal mucosa.

Dissolution into saliva, followed by swallowing and gastrointestinal absorption.

The sponsor asserts that oral absorption plays a minimal role and that absorption is predominantly via the transmucosal route.



Comment: The first two absorption mechanisms avoid first-pass metabolism. First-pass metabolism reduces the bioavailability of fentanyl by about two-thirds, so if oral transmucosal absorption can be made predominant then increased bioavailability would be anticipated compared to Actiq, from which only about 25% of the fentanyl is absorbed via the oral transmucosal route and 75% is swallowed.

In the case of Abstral, the favouring of oral transmucosal absorption has been attempted by a combination of an optimised tablet formulation (so that the tablet adheres well to the mucosa but also does not dissolve too slowly) and careful adherence to the correct method of administration (not moving the tablet around the mouth and not swallowing the drug-containing saliva). In theory, this would lead to a higher bioavailability of fentanyl from Abstral tablets, compared Actiq lozenges. As discussed elsewhere, however, this expectation was not realised in practice.

3.1.2.1.2. In vivo tablet dissolution

The time taken for Abstral sublingual tablets to dissolve under the tongue was assessed in a number of the PK studies. Mean in vivo tablet dissolution times for the market formulation (Formulation A) ranged from 5 to 16 minutes, with the mean around 7 minutes in most studies.

Comment: No attempt was made to correlate in vivo dissolution times with Tmax, Cmax or AUC. On average, there was a delay between full dissolution of the Abstral tablets (around 5-16 minutes) and Tmax (around 30-60 minutes). This may represent a delay in the distribution of fentanyl from the buccal mucosa to the systemic circulation (ie. the formation of a transient depot of fentanyl in the buccal mucosa under the tablet application site, from which fentanyl is then released to the systemic circulation) and/or a delayed contribution to Cmax from swallowed fentanyl. In regard to the latter, the mean fentanyl plasma concentration-time curves did not display the double peak that is characteristic after Actiq administration (where the second peak represents intestinal absorption of swallowed fentanyl). However when individual plasma-concentration time curves were provided, a double peak was seen after Abstral administration in some of them, showing that swallowing of the drug and subsequent intestinal absorption do occur in some individuals.

As can be seen in the relevant tables in the EN3267-012 and-013 study summaries, Abstral tablets dissolved more rapidly than Actiq lozenges. However, this did not lead to any noticeable shortening of Tmax.

3.1.2.2. Bioavailability

3.1.2.2.1. Absolute bioavailability

The absolute bioavailability of the Abstral tablets proposed for marketing was 55% in Study EN3267-012.

Comment: The absolute bioavailability of Abstral tablets was similar to that of Actiq lozenges (50% in Study EN3267-012 and “about 50%” in the Actiq PI).

3.1.2.2.2. Bioequivalence of clinical trial and market formulations

The pivotal efficacy study EN3267-005 used the formulation that is proposed for marketing (Formulation A). Bioequivalence between Formulation A and a number of developmental formulations was assessed as follows:

Formulation 1: A number of PK studies and the single PD study used a developmental formulation (Formulation 1, also referred to as Formulation D) that was shown in a single-dose study to be bioequivalent in respect of Cmax and AUC to Formulation A and to have a similar Tmax to Formulation A (Study SuF-003).



Formulation 2: Another developmental formulation (Formulation 2) was used in two PK studies but was not compared to Formulation A (or to Formulation 1 which is bioequivalent to Formulation A). Only cross-study comparisons between Formulation 2 and Formulation A are available.

Formulations B and C: Two further developmental formulations (B and C) were compared to Formulation 1 in Study SuF-003, but were not used in any efficacy/safety studies and are not proposed for registration, so the comparison is not relevant.

Comment: Formulation 2 has not been shown, either directly or indirectly, to be bioequivalent to the market formulation (Formulation A). Accordingly, potentially formulation-dependent PK data from the studies that used Formulation 2 have been disregarded.

3.1.2.2.3. Bioequivalence of different tablet strengths

In Study EN3267-003, 2 x 400 g and 2 x 200 g Abstral sublingual tablets of the formulation μ μproposed for marketing were bioequivalent to 1 x 800 g tablet.μThe dose-adjusted bioequivalence of different tablet strengths was also assessed in Study 2246-EU-003, but that study used Formulation 2 and the results have been disregarded as discussed above.

Comment: The 800 g tablet is not proposed for registration in Australia and the μbioequivalence of 4 x 200 g to 2 x 400 g tablets was not statistically assessed. However, μ μthe comparison to the 800 g tablet provides indirect evidence that the 200 g and 400 gμ μ μ tablets are likely to be bioequivalent on a dose-adjusted basis.

3.1.2.2.4. Bioequivalence to relevant registered products

The bioavailability of Abstral Formulation A (proposed for registration) was compared to that of (US-marketed) Actiq in three studies.

In the first study, EN3267-001, Abstral appeared to have double the bioavailability of Actiq. However, the Actiq lozenges were not administered in accordance with the instructions in the Actiq PI and a post-study audit revealed that many of the Actiq lozenges were not fully consumed. Accordingly, the bioavailability comparison in Study EN3267-001 has been disregarded.

Two further studies (EN3267-012 and EN3267-013) were performed. In those studies, the Abstral formulation proposed for marketing (Formulation A) was found to be bioequivalent to US-registered Actiq lozenges, in respect of Cmax, AUC0-t and AUC0-∞, using the standard acceptance range of 80-125%. Tmax values were also similar for the two products. However, although the Actiq lozenges were fully consumed in these studies, administration was still not in strict accordance with the Actiq PI, which states that the lozenge should be manipulated in the mouth so that it is consumed over a 15 minute period. Instead, the mean time to fully consume the Actiq lozenges was 28 minutes in EN3267-012 and about 20 minutes in EN3267-013.

Comment: Consumption of the Actiq lozenges over a mean of 28 minutes instead of the PI-recommended 15 minutes in Study EN3267-012 did not appear to affect the fentanyl AUC, given that the absolute bioavailability of Actiq in that study was the same as is reported in the Actiq PI. By extension, the fentanyl AUC after Actiq administration in Study EN3267-013 - where the consumption time was closer to the PI-recommended value - would also not have been affected. However a small effect on Cmax could not be excluded.

3.1.2.2.5. Influence of food and beverages

The influence of food or beverages on Abstral bioavailability was not directly assessed.

Comment: Intake of food or beverages while the Abstral tablet is dissolving would presumably increase the swallowing of drug-containing saliva or could risk detaching the



tablet from the mucosa with subsequent swallowing of the tablet and reduced bioavailability. The draft PI appropriately states that patients should be advised not to eat or drink anything until the sublingual tablet is completely dissolved.

A different issue is whether the dissolution rate of Abstral tablets (with a potential effect on bioavailability) is altered by changes in oral pH, for example due to prior consumption of acidic or basic beverages. Oral pH did not appear to affect the dissolution of Abstral Formulation A tablets in the multi-dose study 2246-EU-005, but the capacity to assess such a relationship was very limited because there was little variability in oral pH values in the study subjects, who were fasted for at least 1 hour before each dose.

Study EN3267-PH001 investigated the effect of acidic (orange juice, coffee) and basic (milk) beverages on oral pH. When coffee and milk were held in the mouth for a period of 2 minutes, there was no meaningful effect on sublingual and buccal pH. A small effect was seen after orange juice (paradoxically, a mean rise in pH of 0.53 pH units) but this was transitory and the pH returned to baseline levels within approximately 10 minutes. The data indicate that the effect of acid and basic beverages (and by extension foods) on the absorption of Abstral is likely to be minimal, and no specific restrictions are needed in the PI regarding beverage or food consumption prior to Abstral administration.

3.1.2.2.6. Dose proportionality

Dose proportionality of bioavailability is potentially formulation dependent and was assessed for the market formulation (Formulation A) or the bioequivalent Formulation 1 in 4 studies.

In Study EN3267-001, one group of healthy subjects received a single tablet of Abstral Formulation A 100 g and another group received a single tablet of Abstral Formulation A μ800 g. The study had a number of problems and only the PK data relating to Abstral from μStudy Site 1 are considered to be reliable. Based on the data from that site, the dose-normalised ratios (low dose/high dose) and corresponding 95% CIs were 1.35 (0.93-1.97) for Cmax and 1.26 (0.81-1.95) for AUC0-t.

In Study 2246-EU-005, multiple doses of Abstral Formulation A, 100 g, 200 g, 400 g or μ μ μ800 g (as 2 x 400 g tablets) were administered to four groups of healthy subjects (one μ μdose level per group). The pair wise ratios of AUCτ, AUC0-∞, C6h and Cmax were in proximity to the ratio of the doses after single doses and at steady-state, consistent with dose proportionality of these parameters. However, no formal statistical analysis of dose-proportionality was performed.

In Study 2246-EU-001, single doses of Abstral Formulation 1, 50 g, 100 g, 150 g or 200 μ μ μg were administered to four groups of healthy subjects (one dose level per group). Mixed-μ

effect model analysis showed that none of the selected plasma PK parameters (AUC0-∞, AUC0-

t, Cmax, CLr and CL/F) met the criteria for dose proportionality, but Cmax did increase in a linear manner with dose.

In Study EN3267-013, the authors concluded that dose-proportionality had been demonstrated after single doses of Abstral 800 g and 1600 g on the grounds that “The μ μmean plasma fentanyl concentrations and the AUC and Cmax values for EN3267 [Abstral] at single doses of 1 x 800 g and 2 x 800 g, and for Actiq at single doses of 1 x 800 g and 1 x μ μ μ1600 g increased in a linear fashion (that is, at a rate and extent very close to a 2-fold μprogression between the doses). Actiq is recognized as having dose proportional pharmacokinetics and the equivalency of EN3267 and Actiq Cmax, AUC0-t, and AUC0-∞, also demonstrates that EN3267 [Abstral] has dose proportional pharmacokinetics”. However, the ratios were not actually presented in the study report and there was no statistical assessment of the dose-proportionality of fentanyl pharmacokinetics. When the ratios were calculated by the evaluator, they were found to be about 1.9 for AUC0-t and Cmax and about 1.7 for AUC0-∞, for both Abstral and Actiq. The ratios based on AUC0-∞ do not appear to be consistent with dose-proportionality, but as discussed in the study summary, the results for



AUC0-∞ may be unreliable. The ratios for AUC0-t and Cmax were consistent with dose-proportionality, although this was not confirmed by a formal statistical analysis.

Comment: The data indicate regarding dose-proportionality for Abstral Formulation A are not conclusive:

In Study EN3267-001, the 95% CIs for the dose-normalised Cmax and AUC0-t ratios for Abstral Formulation A include 1, so the data are consistent with dose-proportionality. However, the point estimates are well away from 1 and the 95% CIs are wide, so the data are also consistent with non-proportionality. It should also be remembered that the dose-proportionality assessment is based on the comparison of two different groups of subjects (rather than two different doses within the one set of subjects) and may be confounded by differences between the two groups of subjects. Assignment to the low or high dose group was randomised and this should have reduced the potential for such confounding and bias, but with only 20 subjects in each group the power of randomisation to provide comparable groups is limited.

In Study 2246-EU-005, the data for Abstral Formulation A were again consistent with dose proportionality but were not statistically analysed.

In Study 2246-EU-001, inspection of the dose-normalised mean values provided in the Study Summary shows that AUC0-t was clearly not dose proportional, which was attributed in the Clinical Summary to underestimation of exposure at the 50 g dose, μsince it was impossible to follow plasma fentanyl concentrations for long enough after that dose to depict the pharmacokinetic profile entirely. Cmax and AUC0-∞ values were closer to dose-proportional but, as noted above, were not confirmed as such in the statistical analysis.

In Study EN3267-013, the ratios for AUC0-t and Cmax were consistent with dose-proportionality, although this was not confirmed by a formal statistical analysis and dose-proportionality was not assessed within the dose range (up to 800 g) that is μproposed for Abstral.

3.1.2.2.7. Bioavailability during multiple-dosing

The bioavailability of Abstral during repeated dosing was investigated for the market formulation (Formulation A) or the bioequivalent Formulation 1 in two studies:

In Study 2246-EU-005, four groups of healthy subjects took single doses of Abstral Formulation A 100 g, 200 g, 400 g or 800 g (as 2 x 400 g tablets), followed by a 72 μ μ μ μ μhour washout period, then the same dose every 6 hours for 72 hours. Accumulation parameters are summarised in Table 15.

Table 15: 2246-EU-005: Mean accumulation ratios after repeated administration of Abstral Formulation A every 6 hours for 72 hours (13 doses).

In Study 2246-EU-002, healthy subjects took Abstral Formulation 1, 50 g every 4 hours for μ44 hours (12 doses). Accumulation parameters are summarised in Table 16.



Table 16: 2246-EU-002: Mean accumulation ratios after repeated administration of Abstral Formulation 1 every 4 hours for 44 hours (12 doses).

Comment: During repeated 6-hourly dosing with Abstral Formulation A at doses of 100 to 800 g, peak plasma fentanyl concentrations rose to about 1.5 to 2 times the peak μconcentration after a single dose, while fentanyl exposure over the dose interval rose to about 2 to 2.5 times the amount after a single dose. The mean accumulation ratios were broadly similar across the range of doses (noting the limitations of the between-dose comparison, which was based on data from different groups of patients, rather than data for different doses from a single group of patients).

During repeated 4-hourly dosing with Abstral Formulation 1 at a dose of 50 g, peak μplasma fentanyl concentrations rose to about 2.6 times the peak concentration after a single dose, while fentanyl exposure over the dose interval rose to about 3 times the amount after a single dose. The higher accumulation ratios for the 50 g dose compared μthe 100 to 800 g doses presumably reflect the shorter dose interval at which the 50 g μ μdose was administered (4 hours vs 6 hours for the other doses). Very similar accumulation ratios for Cmax and AUCτ were seen with four-hourly dosing in Study 2246-EU-004, although that study used a formulation of Abstral that has not been shown to be bioequivalent to the one proposed for registration.

The anticipated accumulation during clinical usage of Abstral would generally be lower than was seen in these studies, since the drug will be consumed at irregular intervals in response to episodes of BTcP rather than regularly every 4 or 6 hours. For example, during the Long-term Extension Phase of the pivotal efficacy study, patients took a mean of 2.9 Abstral doses per day (median 3 doses). Fentanyl accumulation might occasionally be higher in some individuals, noting that the draft PI recommends a maximum of 4 doses per day, but with only 30 minutes between doses when two doses are taken for the same episode of BTcP, and no restriction on the interval between doses taken for separate BTcP episodes. This could be avoided by specifying an appropriate minimum interval between doses taken for separate BTcP episodes.

3.1.2.3. Distribution, metabolism and elimination

The distribution, systemic clearance and excretion of fentanyl are not formulation-dependent and are well described in the published literature. As described in the PIs for registered fentanyl products:

Fentanyl is a highly lipophilic drug that is rapidly distributed to the brain, heart , lungs, kidneys and spleen, followed by a slower redistribution to muscles and fat.

The plasma protein binding of fentanyl is 80-85%. The main binding protein is alpha-1-acid glycoprotein, but both albumin and lipoproteins contribute to some extent. The free fraction of fentanyl increases with acidosis.

The mean volume of distribution at steady state (Vss) is about 4 L/kg.

Fentanyl is metabolised by CYP3A4 in the liver and intestinal mucosa where it is converted to a number of pharmacologically inactive metabolites, the major one being norfentanyl. Fentanyl has a high hepatic extraction ratio (0.8-1.0), so the hepatic clearance of fentanyl approaches hepatic blood flow.



Within 72 hours aft the intravenous administration of fentanyl, about 75% of the dose is excreted in the urine, mostly as metabolites, with less than 10% as unchanged drug. About 1% is excreted unchanged in the faeces. The metabolites are mainly excreted in the urine, while faecal excretion is less important.

The total plasma clearance of fentanyl is about 0.5 L/h/kg.

The terminal elimination half-life of fentanyl after intravenous administration is about 8 hours.

Results for t1/2 from PK studies of Abstral are summarised in Table 7 (single dose studies) and in Table 14 (multiple dose studies).

Comment: In the single dose studies, t1/2 was generally consistent with published data. The half-life of fentanyl tended to increase with dose and was unusually low in Study SuF-003 and for the 100 g dose in Study 2246-EU-001, but these are probably artefacts μcaused by the limitations of the fentanyl assay and/or the collection of blood samples over too short a time period after the dose. It is probable that t1/2 was sometimes underestimated in the single dose studies, particularly after low doses when fentanyl concentrations dropped below the LOQ relatively soon after the dose. In the multiple dose studies, much higher plasma fentanyl concentrations were achieved and they remained quantifiable for a considerably longer period. The terminal half-life then appeared to be much longer (18-24 hours). The sponsor considers that the true terminal elimination phase was not captured in the single dose studies and was only seen in the multiple dose studies. It is also possible that the long terminal half-life in the multiple dose studies (measured after the final dose of Abstral) could be due to the slow redistribution of accumulated fentanyl from adipose tissue and muscle back into the systemic circulation, maintaining low plasma fentanyl levels over a prolonged period and prolonging the terminal half-life. The finding that steady-state was achieved within 2 to 3 days after starting Abstral is further evidence that the effective half-life is in the order of 8 to 10 hours, rather than 20 hours.

3.1.3. Pharmacokinetics in the target population

The pharmacokinetics of fentanyl after the administration of single doses of Abstral Formulation 1, 100, 200 and 400 g, were analysed in 8 patients with cancer pain in Study SuF-μ001.

Comment: Only a small number of patients were studied and no formal statistical analysis was conducted, but AUC0-∞ and Cmax appeared to be dose-proportional in cancer pain patients, based on the similarity of dose-normalised mean values across the three dose levels. As in healthy subjects, Tmax appeared to lengthen as the dose increased.

A comparison of PK parameters in cancer pain patients versus healthy subjects relies on cross-study comparisons and very limited PK data in patients with cancer pain, and may not be reliable. With this caveat, there did not appear to be any large PK differences between cancer pain patients and healthy subjects, although Cmax and AUC0-∞ were perhaps a little higher in the cancer patients for a given dose of Abstral.

3.1.4. Pharmacokinetics in other special populations

3.1.4.1. Pharmacokinetics in subjects with impaired hepatic function

The pharmacokinetics of fentanyl after Abstral administration were not specifically studied in patients with hepatic impairment. However, fentanyl is known to be predominantly eliminated by hepatic metabolism to norfentanyl and other inactive metabolites, with only about 10% of a dose excreted as unchanged drug in the urine. Impaired liver function would increase the bioavailability of any swallowed fentanyl and decrease the systemic clearance of fentanyl, which could lead to increased and prolonged opioid effects.



Comment: Impaired liver function can occur in patients with cancer pain for various reasons, including the effects of concomitant treatment and metastatic liver disease. It would not be clinically appropriate to completely exclude such patients from using Abstral by making hepatic impairment a contraindication, but caution should be observed when the drug is used in patients with hepatic impairment. The draft Abstral PI includes a Precaution to this effect, which is similar to the one in the Actiq PI.

3.1.4.2. Pharmacokinetics in subjects with impaired renal function

The pharmacokinetics of fentanyl after Abstral administration were not specifically studied in patients with renal impairment and limited data are available regarding the effects in general of renal impairment on fentanyl pharmacokinetics. Renal impairment would not be expected to have a direct impact on the elimination of fentanyl, which is predominantly due to hepatic metabolism. However renal impairment produces changes (eg. in plasma proteins) that would affect the volume of distribution of fentanyl and unbound fentanyl concentrations.

Comment: For various reasons, including age-related deterioration in renal function and the side effects of some antineoplastic agents, renal impairment is not uncommon in patients with cancer pain. It would not be clinically appropriate to completely exclude such patients from using Abstral by making renal impairment a contraindication, but caution should be observed when the drug is used in patients with renal impairment. The draft Abstral PI includes a Precaution to this effect, which is similar to the one in the Actiq PI.

3.1.4.3. Pharmacokinetics according to age

The effect of age on the pharmacokinetics of fentanyl was not specifically studied after Abstral administration. However, published data for other dose forms show that the elimination of fentanyl is slower and the terminal elimination half-life is longer in the elderly. In addition, the elderly are known to be more sensitive to the pharmacological effects of opioids, including fentanyl.

Comment: Abstral should be used with caution in elderly patients, especially during titration. The draft Abstral PI includes statements relating to use in the Elderly under Precautions and Dosage and Administration.

3.1.4.4. Pharmacokinetics related to genetic factors

3.1.4.4.1. Ethnicity

The pharmacokinetics of fentanyl after the administration of single 50 to 200 g doses of μAbstral Formulation 1 were comparable in healthy Japanese and Caucasian subjects (Study 2246-EU-001).

3.1.4.4.2. Gender

The pharmacokinetics of fentanyl after the administration of single and repeated doses of Abstral were compared between women and men in two studies:

In Study 2246-EU-005, four groups of healthy male and female subjects took single doses of Abstral Formulation A 100 g, 200 g, 400 g or 800 g (as 2 x 400 g tablets), followed byμ μ μ μ μ a 72 hour washout period, then the same dose every 6 hours for 72 hours. Summary PK parameters are compared in women and men in Table 17.



Table 17: 2246-EU-005. Gender comparison (females versus males) of summary PK parameters after administration of Abstral fentanyl citrate sublingual tablets (market Formulation A) as a single dose or q6h for 72 hours.

Comparisons are based on arithmetic means except for Tmax (based on medians). Negative values indicate that the mean (or median for Tmax) was lower in females than in males

In Study 2246-EU-002, healthy male and female subjects took Abstral Formulation 1, 50 g μevery 4 hours for 44 hours (12 doses). After a single dose, the mean Cmax in women was 25% higher than in men, the median Tmax was 25% shorter, and the mean AUC0-4h was 7% higher. At steady state, however, all of these parameters were comparable in women and men (<3% between-gender difference in mean values).

Comment: In Study 2246-EU-005, there were no consistent differences between males and females in respect of Cmax or Tmax after a single dose or at steady-state. Systemic exposure (AUC) was similar in males and females after a single dose and also at steady state. Half-life was consistently longer in females compared to males after a single dose and also at steady state, but this did not appear to lead to an increase in Cmax or AUC during repeated 6-hourly dosing.

The report of study 2246-EU-002 attributed the higher Cmax and slightly higher AUC0-4h in women after a single dose (compared to men) to the lower body weight of the female subjects. However, this does not explain the shorter Tmax in women after the first dose. The number of subjects of each gender was small (5 each), and the data may not be representative.

Overall, the pharmacokinetics of fentanyl after Abstral administration do not appear to differ between men and women to a clinically meaningful extent, after allowing for differences in weight. The half-life of fentanyl was longer in women than men, but this did not lead to higher plasma concentrations of fentanyl during repeated 4 or 6 hourly dosing. It is thus reasonable to recommend the same starting dose, titration steps, maximum Abstral dose and maximum number of doses per day for men and women.

3.1.5. Pharmacokinetic interactions

Pharmacokinetic interactions were not specifically examined in the submitted studies. However, fentanyl is known to be metabolised by CYP3A4 in the liver and intestinal wall. Grapefruit juice and drugs that inhibit CYP3A4 - such as macrolide antibiotics (eg. erythromycin), azole antifungal agents (for example, ketoconazole and itraconazole), certain protease inhibitors (eg. ritonavir) - would be expected to increase the bioavailability of any fentanyl that is swallowed during Abstral administration (eg. from swallowed drug-containing saliva), and would also slow the elimination of fentanyl, with resultant increased or prolonged opioid effects. Conversely, inducers of CYP3A4 would be expected to increase both the intestinal and hepatic metabolism of fentanyl, leading to reduced efficacy.

Opioid antagonists (for example, naloxone and naltrexone), and partial agonists or drugs with mixed agonist/antagonist activity (eg. pentazocine, butorphanol, buprenorphine, nalbuphine) would be expected to reduce or eliminate the efficacy of Abstral, as well as precipitating opioid



withdrawal symptoms (given that Abstral is only intended to be used in opioid-tolerant patients).

The use of opioids concurrently with monoamine oxidase (MAO) inhibitors or within 2 weeks of the cessation of MAO inhibitors is usually contraindicated, on the basis that serious and sometimes fatal reactions have been reported when the opioid analgesic pethidine has been administered to patients receiving MAO inhibitors.

Comment: The draft Abstral PI includes Precautions regarding these interactions that are similar to the ones in the Actiq PI, with the exception of the statement regarding MAO inhibitors. The Actiq PI contraindicates the use of the drug concurrently with MAO inhibitors, or within 2 weeks after the cessation of the use of MAO inhibitors. In the draft Abstral PI, this is listed only as a Precaution rather than a Contraindication.

3.2. Evaluator’s overall conclusions on pharmacokineticsThe pharmacokinetics of fentanyl after the administration of Abstral have been satisfactorily elucidated in the submitted studies or by reference to the published literature.

4. Pharmacodynamics

4.1. Studies providing pharmacodynamic dataThe submission included one pharmacodynamic study, SuF-002.

4.2. Summary of pharmacodynamics4.2.1. Primary pharmacodynamics

Study SuF-002 examined the pharmacodynamic effect of Abstral on BTcP. Twenty-three patients on background slow-release opioid therapy for cancer pain took single doses of Abstral 100 g, 200 g, 400 g and placebo, in a randomised crossover fashion, for consecutive μ μ μepisodes of BTcP (but with a washout of at least 1 day between doses).

Pain intensity was assessed using a 100 mm visual analogue scale (VAS), before each dose of study drug and 5, 10, 15, 20 and 30 minutes after each dose. Due to an error in the preparation of the patient diaries, efficacy was not assessed for the planned 60 minute post-dose period. The primary PD (efficacy) variable was the pain intensity difference (PID), ie. the change in pain intensity from the pre-dose value at each time point. A single dose of Abstral 400 g was μstatistically superior overall to placebo for the relief of BTcP. Onset of action was noted at the first post-dose assessment (5 minutes), with the difference between Abstral and placebo becoming statistically significant at 15 minutes and persisting until the final assessment at 30 minutes. The mean PID reached 20 mm, which is regarded as a clinically meaningful pain reduction, less than 15 minutes after a 400 g dose of Abstral, compared to 30 minutes after a μdose of placebo.

Lower Abstral doses (100 g and 200 g) were not significantly superior to placebo during the μ μfirst 30 minutes after the dose, but did provide satisfactory relief in some patients.

No unexpected safety concerns were raised. Most of the AEs were related to the underlying cancer and/or background opioid therapy; 2 patients had typical opioid-type TEAEs soon after the administration of Abstral 400 g.μ



4.3. Secondary pharmacodynamicsFentanyl displays typical -opioid pharmacodynamic actions other than analgesia. The most μrelevant of these in relation to the potential adverse effects of Abstral are: sedation; respiratory depression; reduced blood pressure and heart rate; decreased intestinal motility (leading to constipation); and variable effects on urinary tract smooth muscle that can lead to urinary urgency or difficulty in urination. Miosis, cough suppression and hyporeflexia are other -μopioid pharmacological effects that are listed in the Actiq PI.

4.3.1. Pharmacodynamic interactions

Pharmacodynamic interactions are expected between fentanyl and a range of other drugs. Such interactions may be beneficial or adverse. The most important beneficial interaction is the increased analgesic effect that occurs when fentanyl is used in combination with other analgesic agents, including other opioids, and which forms that basis for the use of Abstral for BTcP. The most adverse pharmacological interaction relate to the central nervous system and gastrointestinal effects of fentanyl described above. Sedation, respiratory depression and hypotension are expected to be increased when Abstral is used in combination with other CNS depressants such as opioids, general anaesthetics, skeletal muscle relaxants, sedative antidepressants, sedative antihistamines, barbiturates, benzodiazepines, hypnotics, antipsychotics, clonidine and related substances, or alcohol. Abstral would also be expected to increase the risk of gastrointestinal adverse effects such as nausea, vomiting and constipation when used in combination with other opioids.

Comment: The potential for increased gastrointestinal side effects cannot be avoided given that Abstral is intended to be used to supplement chronic opioid therapy. Careful dose titration and the use of appropriate measures to combat constipation should minimise the impact of this interaction. The complete avoidance of CNS depressant drugs is not feasible, nor is it necessary. However caution should be observed when Abstral is administered together with other CNS depressants and the draft PI includes suitable precautionary statements regarding this interactions.

4.4. Evaluator’s overall conclusions on pharmacodynamicsThe submitted PD study (SuF-002) provides evidence that Abstral Formulation 1 (and thus the bioequivalent Formulation A that is proposed for registration) should be capable of significantly relieving acute BTcP, with a sufficiently rapid onset of action, provided that an adequate dose is used for the individual patient.

SuF-002 also indicated that 100 g would be a reasonable starting dose of Abstral in μsubsequent efficacy studies (on the basis that it did not appear to be associated with excessive adverse effects and may provide adequate pain relief in some individuals), and that subsequent efficacy studies should provide for titration of the Abstral dose up to at least 400 g.μSuF-002 only measured pain severity for 30 minutes after the dose, and did not by itself show that the duration of action of Abstral is sufficient to treat BTcP. Being a single dose study, the PD study also did not examine whether the therapeutic and adverse effects of Abstral remained consistent across successive episodes of BTcP.

5. Dosage selection for the pivotal studiesThe report of the pivotal study (EN3267-005) stated: “The study medication, EN3267 [Abstral], was examined in doses of 100, 200, 300, 400, 600 (two 300 g tablets), and 800 g (two 400 gμ μ μ tablets) during this study. These doses were provided to allow the flexibility for each patient to achieve a personally effective dose that avoided intolerable adverse effects. The dose range chosen for this study was based on pharmacokinetic studies, which examined doses up to 800



g and on studies in opioid-tolerant cancer population using doses up to 400 g, which μ μdemonstrated that the study medication was well tolerated.”

Comment: What is not made explicit in the report of EN3267-005, but is evident from the data package as a whole, is that the maximum dose of Abstral in the pivotal study was limited to 800 g on the basis that this is half the maximum approved dose of Actiq, μcombined with a belief that the bioavailability of Abstral is double that of Actiq. As is discussed elsewhere, this belief was subsequently shown to be mistaken.

6. Clinical efficacy

6.1. Relief of breakthrough cancer pain6.1.1. Pivotal efficacy study: EN3267-005

The submission contained one adequate, well-controlled efficacy study, EN3267-005, which used a randomised, double-blind, multiple crossover design to compare Abstral and placebo.

The relevant TGA-adopted guideline, CPMP/EWP/612/00 Note for Guidance on Clinical Investigation of Medicinal Products for Treatment of Nociceptive Pain, states that crossover designs are useful as exploratory studies of treatments for nociceptive pain, but parallel group designs are recommended for confirmatory studies. One reason for this, as stated in the Guideline, is the risk of carryover effects between the two study treatments. However, issues of practicality and ethical considerations mean that it would be difficult, if not impossible, to conduct a successfully blinded parallel-group study involving a placebo arm when confirmation of efficacy requires the treatment of multiple pain episodes and where the dose of the active agent needs to be titrated over a period of several days. Under these circumstances, reliance on a crossover design is reasonable.

6.1.1.1. Study design, location and dates

EN3267-005 was a double-blind, randomised, placebo-controlled, multiple crossover, multicentre study to evaluate the efficacy and safety of Abstral (Formulation A) for the treatment of BTcP in opioid tolerant cancer patients. The study was conducted in the USA from January 2006 to December 2008.

EN3267-005 enrolled patients aged ≥17 with cancer-related pain. The most important entry criteria were:

Receiving a stable, fixed-schedule oral opioid regimen equivalent to 60 to 1000 mg of oral morphine per day or transdermal fentanyl equivalent to 50 to 300 g/h. The fixed-dose μopioid regimen must have been taken for at least 14 days before screening, and must have been expected to remain unchanged for the duration of the Open-label Titration and Double-blind Treatment Phases of the study (ie. up to approximately 4 weeks);

On a stable dose of opioid for relief of BTcP. This drug/dose combination was to be used, if required, as rescue medication during the course of the study.

Experiencing 1 to 4 episodes of BTcP per day.

Patients with moderate to severe ulcerative mucositis (≥grade 2 according to WHO criteria) were excluded from the study.

The study initially consisted of Screening, followed by an Open-label Titration Phase, then a Double-blind Treatment Phase, then an Open-label Long-term Extension Phase. The protocol was amended 3 times during the course of the study:



Protocol Amendment 1 added an observed test dose of Abstral 100 g to the screening μphase and added Quality of Life (QoL) assessments.

Protocol Amendment 2 added an interim analysis and associated stopping rules.

Protocol Amendment 3 (made after the interim analysis demonstrated positive efficacy according to the criteria set in Protocol Amendment 2) removed the Double-blind Treatment Phase, so that patients who completed the Open-label Titration Phase then proceeded directly to the Open-label, Long-term Extension Phase. In October 2008, it was determined that the study had collected a suitable quantity of safety and efficacy data and the study was terminated early on 31 December 2008. Any patients that were still enrolled (eg. still in the Long-term Extension Phase) were to undergo an end-of-study visit by this date.

The study phases are described in further detail below.

Screening

– Patients were screened to determine if they satisfied the entry criteria.

– Each patient identified a particular type or location of BTcP as their “target pain,” which was the only pain treated with study medication throughout the study

– Prior to Protocol amendment 1, patients who satisfied the entry criteria proceeded directly to the Open-label Titration Phase.

– After Protocol Amendment 1, patients who satisfied the entry criteria were given an open-label test dose of Abstral 100 g while under observation. Patients who could not μtolerate the test dose were withdrawn from the study and excluded from the efficacy analyses. Patients who tolerated the test dose were eligible to proceed to the Open-label Titration Phase.

Open-label Titration Phase. During the Open-label Titration Phase, patients had up to 2 weeks to self-determine a single appropriate dose of Abstral for adequate treatment of BTcP.

– Patients took a single dose of Abstral 100 g for the first BTcP episode.μ– For each subsequent BTcP episode, patients titrated the dose up (if pain relief had been

inadequate at the previous dose) or down (if adverse effects were intolerable at the previous dose), within the range of 100 to 800 g, until they found a dose that provided μadequate pain relief without intolerable adverse effects and that remained stable for 2 consecutive days. The doses available to each patient were 100 g, 200 g, 300 g, 400 μ μ μ

g (each as single tablets), 600 g (2 x 300 g) and 800 g (2 x 400 g).μ μ μ μ μ– For each dose of study drug, patients recorded efficacy data (described below) in a

patient diary.

– If pain relief was unsatisfactory 30 minutes after taking a dose of Abstral, patients were to take rescue medication (ie. their previously prescribed drug/dose of BTcP medication).

– Patients were instructed to wait at least 2 hours after the treatment of one BTcP episode before treating the next episode.

– Patients who were unable to titrate to a satisfactory and stable dose (eg. because of lack of efficacy, adverse effects or unstable dose requirements), or who did not continue to



have 1-4 episodes of BTcP per day,1 were withdrawn from the study and excluded from the efficacy analyses.

– Patients who achieved a satisfactory, stable dose of Abstral and continued to have 1-4 episodes of BTcP per day were eligible to proceed to the Double-blind Treatment Phase (or, after the interim analysis and protocol amendment, directly to the Open-label Long-term Extension Phase).

Double-blind Treatment Phase. Patients who entered the Double-blind Treatment Phase were issued with a blister card of 10 sequentially numbered doses of study medication that contained 7 doses of Abstral (at the dose level determined for that patient by the Open-label Titration Phase) and 3 doses of matching placebo, organised in a randomised fashion.

– Patients were instructed to take one tablet, in the order presented in the blister card, for consecutive episodes of BTcP over a period of up to 2 weeks.

– For each dose of study drug, patients recorded efficacy data (described below) in a patient diary.

– If pain relief was unsatisfactory 30 minutes after taking a dose of study medication, patients were to take rescue medication (ie. their previously prescribed drug/dose of BTcP medication).

– Patients were instructed to wait at least 2 hours after the treatment of one BTcP episode before treating the next episode.

– Patients who completed the Double-blind Treatment Phase were eligible to enter the Open-label Long-term Extension Period.

Open-label Long-term Extension Phase. During the Open-label Long-term Extension Phase, patients used Abstral to treat BTcP episodes over a period of up to 12 months.

– Investigators could adjust the dose of Abstral as required (eg. due to lack of efficacy or AEs) within the range of 100 to 800 g.μ

– Patients returned to the study site monthly (± 2 weeks) and site personnel contacted patients via telephone monthly (ie. approximately 2 weeks after the monthly visits).

The Abstral tablets used in this study were Formulation A, which is proposed for registration in Australia. Patients were instructed to place the study medication under the tongue into the deepest part of the oral cavity and allow it to dissolve. Patients were told not to move or touch the medication once it had fastened to the mucous membrane, not to eat or drink until the tablet had completely dissolved, not to swallow the medication, and to allow it to dissolve completely in the mouth without chewing or sucking. Patients were told that the medication should have dissolved completely in approximately one minute. The proper method for using the study medication was described to the patient and reviewed regularly throughout the course of the study.

Although it was expected that episodes of BTcP would be treated with study medication, patients could choose, for the purpose of convenience, not to treat an episode of BTcP with study medication if it occurred during sleeping hours (which would mean having to remain awake to perform the required efficacy assessments). In these instances, patients could use their previously prescribed drug/dose of BTcP medication to treat the episode.

Comment: Since study patients were suffering up to 4 BTcP episodes per day, the time between successive doses of study medication would have been short enough to allow carryover of effect between some of the doses. For those placebo doses that followed a dose

1 Patients could have a day without an episode of BTcP during the 2-week Open-Label Titration Phase, as long as at least one episode was recorded either on the previous day or on the subsequent day (ie. patients could not have 2 consecutive days without at least one episode of BTcP).



of Abstral, this carryover would tend to increase the apparent efficacy of placebo, thereby reducing the difference between Abstral and placebo. On the other hand, when two or more Abstral doses were taken in succession, any carryover would tend to increase the apparent efficacy (and also the apparent adverse effects) of the second and subsequent Abstral doses, thereby increasing the apparent difference between Abstral and placebo. Depending on the randomisation sequence, 3 or 4 out of the 7 Abstral doses received by each patient directly followed a preceding Abstral dose. Either 2 or 3 of the placebo doses received by each patient directly followed an Abstral dose (patients never received 2 placebo doses in succession, but some received placebo as the first dose of the Double-blind Treatment Phase). Finally, most of the efficacy endpoints were based on the change from the predose pain value, rather than absolute pain measurements. Considering these factors, one would expect the potential carryover effects favouring Abstral and placebo to approximately balance out.

6.1.1.2. Efficacy assessments

During the Open-label Titration and Double-blind Treatment Phases, the following efficacy data were recorded using electronic patient diaries:

Dose of study treatment. During the Open-label Titration Phase, patients recorded the strength, date and time of each dose of study treatment. During the Double-blind Treatment Phase, patients recorded the identification number, date and time of each dose of study treatment.

Pain intensity. Pain intensity was rated on an 11-point scale, where 0 indicated “no pain” and 10 indicated “pain as bad as you can imagine”, in response to the question: “Please rate your pain by indicating the one number that tells how much pain you have right now.” Pain intensity was rated immediately before treating a BTcP episode with study medication (ie. at 0 minutes), at 10, 15, 30, and 60 minutes after treating the episode, and at the time of treatment with rescue medication, if applicable.

Pain relief. Pain relief (PR) was rated on a 5-point scale in response to the question: “How much pain relief do you have now compared to immediately prior to taking the study medication?”. The rating scale was 0 = None, 1 = Slight, 2 = Moderate, 3 = A lot, 4 = Complete. Pain relief was rated at 10, 15, 30, and 60 minutes after treatment of a BTcP episode with study medication and at the time of treatment with rescue medication, if applicable.

Rescue Medication Use. Patients recorded the date and time at which any rescue medication was used.

Patient Global Evaluation of Medication. Patients recorded a global evaluation of study medication 60 minutes after each dose of study drug or upon the use of rescue medication, in response to the following prompt: “Please rate your overall satisfaction with the pain medication you took for this episode of breakthrough pain. The rating scale is: 1 = excellent, 2 = very good, 3 = good, 4 = fair, 5 = poor”. Patients were also asked at each study visit regarding their overall degree of satisfaction with their usual BTcP medication (at the screening visit) or with the study medication (at subsequent visits), categorised as “very satisfied”, “satisfied”, “no preference”, “dissatisfied” or “very dissatisfied”.

During the Open-label Long-term Extension Phase, patients were asked to complete a daily paper diary to record the following efficacy data:

Occurrence or non-occurrence of BTcP.

The dose of study medication used to treat BTcP episodes (with provision for up to 6 episodes per day).

The number of BTcP episodes treated with other (ie. non-study) medication.



Patient satisfaction with study medication was recorded as described above at each monthly visit.

Quality of life. After Protocol amendment 1, Quality of Life (QoL) was assessed at screening, at the end of the Double-blind treatment phase, and at each monthly visit during the Open-label, Long-term Extension Phase. QoL was assessed using the Brief Pain Inventory (BPI) and Depression, Anxiety, and Positive Outlook Scale (DAPOS) questionnaires.

6.1.1.3. Efficacy endpoints

6.1.1.3.1. Primary endpoint

The primary efficacy endpoint was the sum of pain intensity difference (SPID) from baseline to 30 minutes after dosing. Baseline for each episode was defined as the pain score recorded before taking study medication for that episode. The PID at each time point was the score at Baseline minus the score at that time point, so pain relief resulted in positive PID values. The SPID for an episode was the area under the PID versus time curve up to the cutoff time point (30 minutes for the primary efficacy endpoint), calculated using the trapezoidal rule.2 The mean SPID across episodes for each treatment for each patient then was calculated and used in the statistical analysis. Thus, for each patient the 7 episodes treated with Abstral were averaged into one value and the 3 episodes treated with placebo were averaged into one value and then used in the analysis.

Comment: The SPID is analogous to the AUC of a drug in plasma, but based on a measure of drug effect rather than drug concentration. It is a common efficacy endpoint in analgesic trials. A higher SPID corresponds to greater “total” pain relief over the assessment period. Other clinically relevant aspects related to the SPID include:

The duration over which the SPID is determined. In the case of BTcP, an assessment period of 30 minutes is arguably too short to assess whether the analgesic effect is adequately maintained throughout an episode of BTcP. The SPID over 60 minutes would provide a more clinically relevant assessment, but is affected by differential use of rescue medication after 30 minutes in a manner that would tend to exaggerate the difference between Abstral and placebo (because of the combination of the LOCF analysis and the natural resolution over time of BTcP episodes).3

The shape of the PID curve. This shows whether pain relief is concentrated around a particular time after the dose or is adequate throughout the assessment period.

6.1.1.3.2. Secondary endpoints

Secondary efficacy endpoints were:

Pain intensity difference (PID) at each post-baseline time point (ie. 10, 15, 30, and 60 minutes).

Pain relief (PR) scores at each post-baseline time point (ie. 10, 15, 30, and 60 minutes). PR was scored as: 0 = None, 1 = Slight, 2 = Moderate, 3 = A lot, 4 = Complete.

2 The EN3267-005 study report stated that when calculating the SPID and TOTPAR, the base of the trapezoid (ie. the time between successive PID or PR values) would be expressed in hours (ie. 5 minutes would be expressed as 1/12, 30 minutes as 1/2). Examination of the reported SPID values (for which no units were given) revealed that this was not actually done and the time in minutes rather than hours was used in calculating the SPID and TOTPAR. This increased the magnitude of the SPID and TOTPAR for both treatments (and the between-treatment difference in SPID and TOTPAR) by a factor of 60 compared to the planned analysis. However it does not affect the between-treatment statistical comparison of these endpoints.3 The LOCF analysis appropriately disregarded PID values after the use of rescue medication (not to do so would have led to an underestimation of the true difference between Abstral and placebo). However, given the higher use of rescue medication in the placebo group, the LOCF analysis meant that a higher proportion of placebo SPIDs at 60 minutes were based on data where the PID had been locked at the value observed when rescue medication was taken, thereby disregarding the subsequent contribution to the SPID that would otherwise have flowed from natural resolution of the BTcP episode after that time point.



Total pain relief (TOTPAR) at 30 and 60 minutes. The TOTPAR score for a pain episode was calculated as the area under the patient’s PR score vs time (in hours after the dose) curve for that episode, using the trapezoidal rule.

SPID at 60 minutes (as per the primary efficacy endpoint but incorporating data to 60 minutes after the dose).

Percentage of treated BTcP episodes that required use of rescue medication.

Percentage of responders (defined as patients who have at least a 30% decrease in pain intensity from Baseline to 30 minutes).

Percentage of the 30% and 50% responder rates at 10 and 15 minutes.

Patient global evaluation of study medication.

Comment: As will be discussed later, some of these secondary efficacy endpoints are potentially informative as to whether Abstral provides analgesia for BTcP that is clinically meaningful and not merely statistically significant.

6.1.1.4. Statistical methods

6.1.1.4.1. Determination of sample size

Data from SuF-002 were re-analysed to determine the SPID up to 30 minutes in that study. The mean ± SD treatment difference between Abstral 400 g and placebo in that study was found to μbe 3.61 ± 7.1. Based on this, a sample size of 83 was required to provide 90% power using a 2-sided test at the 5% significance level. Assuming a 40% dropout rate, a total of 140 patients were to be enrolled into the Open-label Titration Phase of the study. In addition, at least 10 patients were required to be randomly assigned to each of the Abstral low dose (100 to 400 g) μand high dose (600 to 800 g) subgroups. Therefore, enrolment was planned to continue until μthere were 10 patients randomly assigned to each dose subgroup and there were at least 83 patients randomly assigned to treatment in the Double-blind Treatment Phase of the study.

Comment: The sample size was not based on the ability to detect a predefined clinically meaningful analgesic effect, but rather to detect an effect of the magnitude that was statistically significant (but not necessarily clinically meaningful) in an earlier study. As a consequence, statistically significant differences between Abstral and placebo in Study EN3267-005 need to be interpreted carefully with regard to their magnitude and clinical relevance.

6.1.1.4.2. Analysis of the primary efficacy endpoint

The primary efficacy endpoint was analysed using an analysis of variance (ANOVA) model with fixed effects for treatment, centre, and sequence, and random effect for patient. The observed margins option was used in estimating the least squares (LS) means for treatment groups to weight each centre according to the number of patients treated in that centre. Least squares means, p-values, and 95% CIs of the between-treatment difference were calculated. Missing data were imputed as follows:

If the baseline value was missing for the first episode in the Double-blind Treatment Phase, the baseline value from the last episode in the Open-label Titration Phase was used.

For all other episodes in the Double-blind Treatment Phase where the baseline value was missing, the baseline value from the previous episode was used.

Missing post-baseline values for an episode were imputed using the last observation carried forward (LOCF) method.



6.1.1.4.3. Analysis of secondary efficacy endpoints

PID and PR scores at each post-baseline time point, SPID at 60 minutes after dosing, and TOTPAR at 30 and 60 minutes after dosing were analysed in the same manner as the primary endpoint.

The patient global evaluation after each dose of study medication was analysed in the same manner as the primary endpoint. Results for the patient global evaluation of medication at the clinic visits were summarised by visit.

The percentage of treated BTcP episodes that required the use of rescue medication was summarised for each of the 2 treatments and analysed using mixed effects logistic regression with repeated measures using generalised estimating equations with logit link and the following covariates: treatment, episode, and centre. Odds ratios and 95% CIs were also calculated.

The percentage of responders was summarised for each of the 2 treatments and analysed in the same manner as the use of rescue medication.

6.1.1.4.4. Interim and end-of-study analyses

An Interim analysis was added at approximately 75% of the planned enrolment. In order to preserve the overall type I error of 0.05, Pocock’s group sequential procedure was applied to the analysis of the primary efficacy endpoint. The resulting critical p-values were 0.0414 for the interim analysis performed at 75% of data, and 0.0239 for the End-of-Study analysis performed at 100% of the data. The decision rule for the interim analysis based on the primary efficacy endpoint was:

If the p-value was <0.0414, the efficacy portion of the study would be considered positive, the efficacy portion of the study would be stopped (ie. the protocol would be amended to remove the Double-blind Treatment Phase), but patients would continue to be enrolled for the safety portion of the study (Open-label Titration followed directly by Open-label Long-term Extension).

If the p-value was ≥0.0414 and the effect size was 0.356 or greater, then the study would continue to its full enrolment of 83 randomised patients. (Note: an effect size of 0.356 corresponded to the study, if it were continued, retaining 50% power to demonstrate a statistically significant result at the End-of-Study analysis using the adjusted critical p-value of 0.0239.)

If the p-value was 0.0414 or greater and the effect size was less than 0.356, then the study would be stopped due to futility.

As it turned out, the first element of the decision rule was satisfied and the Double-blind Treatment Phase was stopped due to positive efficacy (according to the definition in the stopping rules). The interim analysis therefore became the primary efficacy analysis. The End-of-Study analysis, which is regarded as secondary in respect of efficacy, included 3 additional patients who completed the Double-blind Treatment Phase between closure of the database for the interim analysis and the discontinuation of the Double-blind Treatment Phase. The End-of-Study analysis also included 12 patients who went directly from the Open-label Titration Phase to the Long-term Extension Phase.

The statistical analyses of secondary endpoints were not adjusted for the interim analysis or for multiplicity.

6.1.1.4.5. Analysis populations

The following populations were used in the efficacy and/or safety analyses:



6.1.1.4.5.1. Interim analysis

All Treated Patients (Open-label Titration Phase): Included all patients who received at least one dose of the open-label titration medication, including the test dose.

All Treated Patients (Double-blind Treatment Phase): Included all patients who received at least one dose of double-blind medication.

Intent-to-Treat (ITT) Population: This was the primary efficacy analysis population. It included all randomly assigned patients who received at least one dose of double-blind study medication and provided baseline and at least one post-baseline pain intensity score during the Double-blind Treatment Phase.

Per-Protocol (PP) Population: Included all ITT patients with evaluable episodes who were also compliant with the protocol. A patient must have had at least one evaluable episode to be included in the PP population. All unevaluable episodes were excluded from the analyses. Unevaluable episodes were excluded for reasons such as: the pain treated was not target BTcP, changed the fixed dose of pain medication, incomplete episodes, etc. An incomplete episode was defined as an episode without baseline and at least one post-baseline pain intensity assessment before 60 minutes. Evaluable episodes were defined by the following criteria:

– Use of no more than one dose of study medication for each BTcP episode.

– Use of rescue medication no sooner than 30 minutes after study medication use.

– Allowance of at least 2 hours between BTcP episodes treated with study medication.

– Use of study medication to treat only target BTcP.

6.1.1.4.5.2. End-of-study analysis

All Treated Patients (Open-label Titration Phase): Defined as per the Interim analysis. Demographic data for the study and safety data for the Open-label Titration Phase were summarised using this population.

All Treated Patients (Double-blind Treatment Phase): Defined as per the Interim analysis. Safety data for the Double-blind Treatment Phase were summarised using this population.

All Treated Patients (Long-term Extension Phase): Included all patients who received at least one dose of the open-label medication in the Long-term Extension Phase. Safety data for the Long-term Extension Phase were summarised using this population.

All Treated Patients (Overall): Included all patients who received at least one dose of Abstral during the entire study. Safety data during the entire study were summarised using this population.

Intent-to-Treat Population: Defined as per the Interim analysis.

Per-Protocol Population: Defined as per the Interim analysis.

6.1.1.4.6. Study patients

Patient disposition proceeded as follows:

136 patients underwent initial eligibility assessment; 5 were excluded from further participation.

131 patients entered the Open-label Titration Phase; 53 patients discontinued during the Open-label Titration Phase and 78 completed the Open-label Titration Phase.

Of the 78 patients who completed the Open-label Titration Phase, 66 entered the Double-blind Treatment Phase, and 12 proceeded directly to the Long-term Extension Phase (after Protocol amendment 3).



Of the 66 patients who entered the Double-blind Treatment Phase, 3 were still engaged in the Double-blind Treatment Phase at the time the Interim (primary) analysis; 63 patients were therefore included in the Interim (primary) analysis, but 2 of these did not have any data for the Double-blind Treatment Phase, so the ITT population for the Interim analysis included 61 patients. The End-of-Study (secondary) analysis of efficacy included all 66 patients. 6 patients discontinued during the Double-blind Treatment Phase and 60 patients completed the Double-blind Treatment Phase.

72 patients entered the Long-term Extension Phase (60 after completing the Double-blind Treatment Phase and 12 directly from the Open-label Titration Phase; 47 patients discontinued during the Long-term Extension Phase and 25 completed the Long-term Extension Phase (either after 12 months or when the study was discontinued early as previously described).

A flow chart summarising patient disposition, together with the reasons for discontinuation at each stage of the study, is presented below in Figure 1.

Figure 1: EN3267-005: Patient flow diagram.

Comment: Of the 131 patients who commenced titration with Abstral:

11 (8.3%) withdrew during titration due to lack of efficacy (this potentially includes patients who were unable to titrate to a stable Abstral dose)

11 patients (8.3%) withdrew during titration due to treatment-related AEs.

It is also feasible that at least some of the 10 patients who withdrew consent during the titration period did so because they were unsatisfied with Abstral.



None of these patients - who in clinical practice would be regarded as treatment failures - were included in the efficacy analyses. This means that the so-called ITT population was not really a true ITT population but one that had been enriched with Abstral responders. This has implications for the interpretation of the results as will be discussed later.

Long term safety data were available from this study, but only for a very small number of patients compared to the expected clinical usage if Abstral is marketed.

Briefly, baseline demographic characteristics of the study participants are:

The overall mean age was 55 years, with an age range of 21 to 80 years.

Most of the patients (81%) were in the 18-64 years age group. Only 5 patients aged ≥75 years were enrolled, of whom 2 discontinued during titration and only 1 received double-blind medication and was included in the efficacy analysis.

46% of the participants were male and 54% were female.

81% were Caucasian, with the remainder being mainly Hispanic or African American.

Data regarding the medications that patients were currently taking for their background cancer pain and for BTcP at the time of screening were not provided, although what medications had been used during the 6 months prior to screening were noted.

The median time to reach a stable Abstral dose (amongst those who were able reach a stable dose) was 7 days. Data regarding the open-label stabilisation dose in the additional 12 patients who proceeded directly from the Open-label Titration Phase to the Long-term Extension Phase were not provided, but the distribution of Abstral doses and time to stabilisation would presumably have been similar.

Comment: Information was not provided regarding the type/location of cancer or the type/location of the “target” BTcP. This information is relevant to assessing the generalisability of the study results.

Information was also not provided regarding the baseline severity of pain episodes, either overall or according to study treatment. This meant that the mean PID and the between-treatment difference in mean PID at the various observation times could not be assessed in terms of their magnitudes relative to the baseline pain intensity.

Patients who entered the study had been using opioids (most commonly fentanyl, morphine or oxycodone) for the treatment of background cancer pain and an opioid or combination analgesic for BTcP (most commonly hydrocodone/paracetamol, oxycodone/paracetamol, morphine or oxycodone).

About half of the patients who were successfully titrated required an Abstral dose above 400 g. Thus, one would expect that in Australian clinical practice about half of the μpatients using Abstral would be taking 2 tablets for each episode of BTcP, given the Sponsor's proposal to not register in Australia the 600 and 800 g tablet strengths that μare available overseas. The proportion of patients requiring 2 tablets per dose would be expected to increase over time due to increasing opioid tolerance. Data regarding the percentage of patients taking each Abstral dose level during the Long-term Extension Phase were not presented, but the median dose of Abstral during that phase was 600 g, μcompared to 400 g in the Double-blind Treatment Phase. μ

6.1.1.5. Efficacy results

6.1.1.5.1. Evaluable BTcP episodes

During the Open-label Titration Phase only 16 of 1001 episodes (1.6%) were considered unevaluable. During the Double-blind Treatment Phase, 14 of 393 episodes (3.6%) treated with Abstral were unevaluable and 12 of 168 episodes (7.1%) treated with placebo were



unevaluable. In both phases, the main reason episodes were considered not evaluable was the use of rescue medication sooner than 30 minutes after the dose of study medication. The remaining unevaluable episodes were due to patients waiting less than 2 hours between doses of study medication.

As previously noted, 61 patients provided efficacy data for the Interim (primary) analysis. However, the related study tables all show “N=57” for placebo.

Comment: The reason for the lower N for placebo is not given in the study report. However, it can be deduced - from other information in the report - that 4 of the subjects in the ITT population at the Interim analysis must have provided data for at least one double-blind dose of Abstral, but not for any doses of placebo (either because they discontinued before taking any placebo doses or because all of their placebo doses were not evaluable as described above).

6.1.1.5.2. Primary endpoint - double-blind treatment phase

6.1.1.5.2.1. Interim (primary) analysis

Figure 2 shows the LS Mean PID-time curves for Abstral and placebo in the ITT population during the Double-blind Treatment Phase (Interim analysis).

Figure 2: EN3267-005: LS Mean PID vs time after dose during the Double-blind Treatment Phase. ITT population, Interim (primary) analysis.

In the ITT population, SPID at 30 minutes after treatment of BTcP with Abstral was significantly higher (better) than with placebo treatment (p=0.0004; LS mean difference 14.1; 95% CI for LS mean difference 6.52-21.64 [Table 18]). Note that the adjusted critical p-value for this comparison was 0.0414 rather than the usual 0.05, due to the added interim analysis.

Table 18: EN3267-005: SPID (units*min) at 30 minutes during the Double-blind Treatment Phase. ITT population, Interim (primary) analysis.



The difference between Abstral and placebo remained statistically significant in the per-protocol (PP) population (p=0.0077; LS mean difference 13.76; 95% CI for LS mean difference 3.85-23.67).

6.1.1.5.2.2. End-of-study (secondary) analysis

In the ITT population, SPID at 30 minutes after treatment of BTcP with Abstral was significantly higher (better) than with placebo treatment (p=0.0004; LS mean difference 15.0; 95%CI for LS mean difference 7.00-22.96). Note that the adjusted critical p-value for this comparison was 0.0239 rather than the usual 0.05, due to the added interim analysis.

6.1.1.5.2.3. Subgroup analyses of SPID

The SPID at 30 and 60 minutes in the ITT and PP populations were examined in several subgroups, but without statistical testing of differences between Abstral and placebo within or between the subgroups. The results for the Interim (primary) analysis were as follows:

Gender

– The mean SPIDs at 30 and 60 minutes favoured Abstral in both males and females but the between-treatment difference was somewhat higher in women than in men. In the ITT population, the mean SPID in women was 50.8 at 30 minutes and 153.9 at 60 minutes for Abstral and 36.6 and 109.0, respectively, for placebo. In men, the mean SPID was 48.1 at 30 minutes and 131.7 at 60 minutes for Abstral and 36.6 and 99.5, respectively, for placebo. These correspond to (unadjusted) between-treatment differences of 14.2 in women compared to 11.5 in men for SPID at 30 minutes and 44.9 in women compared to 32.2 in men for SPID at 60 minutes. The same pattern of results and gender difference was seen in the PP population.

Age group (18-64, 65-74, >74 years)

– The majority of patients were in the 18 to 64 years age group. In the ITT population, patients in this age group reported higher (better) mean SPIDs after Abstral than after placebo at both 30 minutes (51.2 vs 36.6, difference = 14.6) and 60 minutes (145.7 vs 100.6, difference = 45.1). The same pattern was seen in the PP population: 57.4 vs 43.6 (difference = 13.8) at 30 minutes and 160.8 vs 118.5 (difference = 42.3) at 60 minutes.

– The 65-74 years age group of the ITT population included only 8 patients for Abstral and 7 patients for placebo. In this age group, the difference between Abstral and placebo was not consistently favourable: The mean SPIDs after Abstral and placebo were 37.3 vs 35.2 at 30 minutes (difference = 2.3), and 121.3 vs 125.0 at 60 minutes (difference = -3.7). In the PP population (N=6 for Abstral, 5 for placebo) the mean SPIDs were higher (better) for Abstral than placebo at both time points: 27.7 vs 17.3 (difference = 10.4) at 30 minutes; 98.5 vs 73.1 (difference = 25.4) at 60 minutes.

– The >74 years age group had only 1 patient in the ITT population, in whom SPID at 30 and 60 minutes was higher (better) after Abstral than after placebo. The PP population had no patients in this age group.

Route of background opioid medication (oral, transdermal, other)

– The route of administration of background fixed-schedule opioid medication was categorised as oral, transdermal or “other”. Some patients were using medication by both the oral and transdermal routes. In both the ITT and PP populations, for SPID at 30 and 60 minutes, the route of administration of background opioid medication did not appear to affect the difference between Abstral and placebo.

– In the ITT population, the mean SPIDs at 30 and 60 minutes were higher (better) after Abstral than after placebo amongst the 60 patients who were using oral background opioid medication: 48.6 vs 35.1 (difference = 13.5) at 30 minutes; 140.5 vs 99.8 (difference = 40.7) at 60 minutes.



– The mean SPIDs at 30 and 60 minutes were also higher (better) after Abstral than after placebo amongst the 20 patients who were using transdermal background opioid: 40.1 vs 27.2 (difference = 12.9) at 30 minutes; 127.5 vs 85.2 (difference = 42.3) at 60 minutes.

– The ITT population only had 1 patient in the “other” route category, in whom SPIDs at 30 and 60 minutes were better after Abstral than after placebo.

Dose group (low and high)

– Abstral dosage was characterised as low (100 to 400 g) or high (600-800 g). About μ μhalf of the patients end up in each dose group after titration. In both the low and high dose groups of the ITT population, the mean SPIDs at 30 and 60 minutes were higher (better) after Abstral than placebo: 53.1 vs 40.6 at 30 minutes and 152.2 vs 114.0 in the low dose group; 45.2 vs 31.9 at 30 minutes and 132.1 vs 93.1 at 60 minutes.

Comment: The placebo-subtracted effect of Abstral on SPID was only 11% greater in women than in men at 30 minutes but about 40% greater in women than in men at 60 minutes. The corollary of this is that the effect of Abstral on SPID at 60 minutes in men was not only lower than in women but also lower than in the overall study population. It is unclear whether the effect of gender was statistically significant, since gender was not included as a term in the ANOVA models used to analyse the SPID data. It is also unclear whether the lower effect of Abstral on SPID at 60 minutes in men would remain statistically significant, since there was no statistical analysis of the efficacy of Abstral within the subgroup of males. As previously noted, although SPID to 30 minutes was the primary efficacy endpoint in this study, SPID to 60 minutes is arguably more clinically relevant, given the typical duration of an episode of BTcP. As discussed later, the SPID at 60 minutes has also been shown to bear a relationship to a clinically meaningful treatment effect. Accordingly, the apparent gender difference in the placebo-subtracted effect of Abstral on SPID at 60 minutes is a matter that requires explanation.

The number of elderly patients in the Study EN3267-005 was too small to make any meaningful conclusions about whether the efficacy of Abstral differed according to age. The between-treatment differences in mean SPID were noticeably lower in the 65-74 years age group than in the 18-64 age group in the ITT population, but less so in the PP population. This suggests that the apparently lower efficacy of Abstral amongst elderly patients in the study might be due to reduced medication adherence (eg. due to AEs and other factors) rather than inherently lower efficacy. Whatever the explanation, however, it is reasonable to conclude that efficacy has not been convincingly demonstrated in the elderly and this should be reflected in the PI.

The efficacy of Abstral did not appear to be affected by the route of administration (oral or transdermal) of background opioid medication.

The effect of Abstral was greater than that of placebo in both the high and low dose groups. The finding in the high dose group provides some reassurance that Abstral doses can be satisfactorily administered as two tablets, since both dose levels in that group (600 and 800 g) were administered as two tablets.μ

6.1.1.5.3. Secondary endpoints - double-blind treatment phase

As previously noted, the statistical analyses of secondary endpoints were not adjusted for multiplicity or for the addition of the interim analysis.

6.1.1.5.3.1. Interim (primary) analysis

In the ITT population:

SPID at 60 minutes was significantly higher (better) after Abstral doses than after placebo doses (p=0.0002; LS mean difference 41.6; 95%CI for LS mean difference 20.44-62.79).



PID was significantly higher (better) after Abstral doses than after placebo doses at all time points. The LS mean difference between treatments was 0.28, 0.55, 0.87 and 0.98 at 10, 15, 30 and 60 minutes, respectively, after the dose).

PR was significantly higher (better) after Abstral doses than after placebo doses at all time points. The LS mean difference between treatments was 0.15, 0.36, 0.54 and 0.53 at 10, 15, 30 and 60 minutes, respectively, after the dose).

TOTPAR at 30 minutes and TOTPAR at 60 minutes were significantly higher (better) after Abstral doses than after placebo doses.

BTcP intensity reduction of ≥30% from baseline was seen after a significantly higher proportion of Abstral doses compared to placebo doses (63.5% vs 41.8%; p<0.0001; Odds ratio [OR] 2.79; 95% CI for OR 1.74-4.49).

Rescue medication was used after 11.2% of Abstral doses compared to 27.4% of placebo doses (p-value and OR “not evaluable due to sparse data” using the planned statistical test).

Patient Global Evaluation of Medication was not assessed in the Interim (primary) analysis.

Results in the PP population were consistent with those seen in the ITT population, with statistically significant differences between Abstral and placebo for: SPID at 60 minutes; PID at all time points; PR at 15, 30 and 60 minutes (not at 10 minutes); TOTPAR at 30 and 60 minutes; and the percentage of doses that were followed by a ≥30% reduction in BTcP intensity. Rescue medication use was numerically less common after Abstral than placebo in the PP population, but not statistically tested.

6.1.1.5.3.2. End-of-study (secondary) analysis - double-blind treatment phase

The End-of-Study efficacy analysis of the Double-blind Treatment Phase included the 3 additional patients who were engaged in the Double-blind Treatment Phase at the time of the Interim analysis and gave similar results to the Interim analysis for all of the secondary efficacy endpoints that had been examined in the Interim analysis. In relation to other endpoints that were examined only in the End-of-Study analysis:

Patient Global Evaluation of Medication. The LS mean score was significantly lower (better) after Abstral compared to placebo (LS mean 3.06 vs 3.64; LS mean difference -0.58; p=0.0006).

QoL. The timing of the QoL assessments in relation to the Double-blind Treatment Phase - at Visit 1 (Screening) and Visit 5 (end of the Double-blind Treatment Phase) - combined with the crossover design, meant that the study could not distinguish between QoL effects related to Abstral and QoL effects related to placebo.

6.1.1.5.4. Efficacy analysis - open-label long-term extension phase

The Open-label Long-term Extension Phase of the study did not include a placebo comparison.

Data on the Patient Global Evaluation of Medication over the course of the study were provided for the 64 ITT patients who completed the Double-blind Treatment Phase. Amongst these 64 patients:

Only 50% had been satisfied or very satisfied with their prestudy (non-Abstral) BTcP medication; 88% were satisfied or very satisfied with open-label Abstral at the end of titration.

80% remained satisfied or very satisfied with study treatment (a mix of Abstral and placebo) at the end of the Double-blind Treatment Period.

The number of patients remaining in the study at each visit during the Long-term Extension decreased over time, but amongst those who remained in the study, the proportion who were satisfied or very satisfied with Abstral remained high at around 90%.



Data were not provided regarding the percentage of patients who were satisfied or very satisfied with Abstral at their last available assessment.

Comment: The data regarding satisfaction with pre-study BTcP medication compared to Abstral are very likely to be biased, since patients who were satisfied with their existing BTcP medication would be unlikely to volunteer for the study. However, the findings do indicate that Abstral can be a useful alternative in patients who are unsatisfied with their current BTcP medication.

The information regarding satisfaction during the Long-term Extension is clearly biased in favour of Abstral since it excludes any patients who discontinued early because they were unsatisfied with the product.

6.1.1.5.5. Evaluator’s comments on efficacy in the pivotal study

Statistically significant differences between Abstral and placebo were demonstrated for the primary efficacy endpoint and most secondary efficacy endpoints.

In clinical practice, treatment with Abstral would be regarded as having failed in patients who cannot obtain adequate relief of BTcP despite titrating to the maximum dose, who cannot settle on a stable dose of Abstral for their BTcP, or who are unable to continue taking Abstral because of treatment-related AEs. In Study EN3267-005, however, these patients were counted as “screen failures”, removed from the study and excluded entirely from the efficacy analyses. The population contributing to the efficacy analyses was thus enriched with responders to Abstral, does not represent a true ITT population, and the resulting comparisons between Abstral and placebo were biased in favour of Abstral.

The study demonstrates that amongst patients who have been selected because they respond to and can tolerate Abstral, the short-term effect of Abstral in those patients is greater than that of placebo. This provides no information about how much better than placebo Abstral would be in an unselected population or after a prolonged period of use.

The study report, Clinical Overview and Summary of Efficacy asserted that the statistically significant differences between Abstral and placebo represented a clinically meaningful treatment effect, but did not provide any evidence to support that assertion. As previously noted, the sample size was not determined with reference to the demonstration of a predefined clinically meaningful difference, so statistical superiority over Abstral over placebo cannot be assumed to represent a clinically meaningful treatment effect.

The sponsor did provide two published papers4 which presented the reasonable argument that if a patient in a clinical trial of a treatment for BTcP does not require rescue medication in addition to the study medication for an episode of BTcP, then this of itself represents a clinically meaningful treatment effect of the study medication in that patient for that episode. Based on the analysis of published data from placebo- and active-controlled studies of Actiq, the published papers then showed that this clinically meaningful effect corresponded to:

A maximum %PID of ≥33% during the 60 minutes after a dose, where the %PID is calculated as the percentage change in PI from the baseline value. This was not analysed in Study EN3267-003, but a near-equivalent (10% lower) effect is represented by the secondary endpoint in Study EN3267-005 of a ≥30% decrease in pain intensity from baseline. A ≥30% reduction in pain intensity is also commonly accepted as a clinically worthwhile treatment effect in studies supporting the registration of analgesic medications. A substantially higher clinical effect is represented by the secondary endpoint in Study EN3267-005 of a ≥50% decrease in pain intensity from baseline.

4 Farrar JT, et al. (2000) Defining the clinically important difference in pain outcome measures. Pain 88: 287-294; Farrar JT, et al. (2003) Clinically important changes in acute pain outcome measures: a validation study. J Pain Symptom Manage. 25: 406-11.



A ≥33% increase in “%Max TOTPAR” over the 60 minutes after a dose. The definition of “%Max TOTPAR” was not clearly expressed, but the endpoint does not appear to be the same as TOTPAR in Study EN3267-005.

A PR score of ≥2 (moderate), on a 0-4 scale, during the 60 minutes after a dose. The PR score at any given time point was determined using the same method as Study EN3267-005, but it was not clear whether a clinically meaningful effect was represented by a PR score of ≥2 at any single time point during the 60 minutes after treatment, or a mean PR score of ≥2 over all time points during the 60 minutes, or an “overall” PR assigned by the patient at the end of the 60 minutes on the basis of pain relief over the entire period. In any case, information regarding the frequency with which Abstral and placebo use led to a PR ≥2 was not presented for Study EN3267-005.

A Global Medication Performance score of ≥2 (good) on a 0-4 scale where 0 = poor and 4 = excellent. This corresponds to a Patient Global Evaluation of ≤3 (good) on the scale used in Study EN3267-005 (which ran in the reverse direction from 1 = excellent to 5 = poor).

A SPID of ≥2 over 60 minutes. The SPID was stated to be “the sum of 4 PID measurements over 60 minutes, divided by 4” (that is, a simple average of the 4 PID measurements). Examination of the studies on which the analysis was based5 shows that the SPID was actually calculated as an AUC in a comparable manner to Study EN3267-005, but with the time component expressed in hours instead of minutes. A SPID ≥2 (units*h) over 60 minutes using that definition thus corresponds to a SPID ≥120 (units*min) at 60 minutes in EN3267-005.

The inherently meaningful efficacy endpoint to which all of the above refer, namely the avoidance of rescue medication, is also available as a secondary endpoint in EN3267-005.

Having defined a clinically meaningful analgesic effect for an individual dosing episode, one can then examine whether an effect of that size was significantly more common with Abstral than with placebo, and if it was, then it follows that the difference between Abstral and placebo must be clinically meaningful (albeit within the inherently biased population that made it through to the Double-blind Treatment Phase).

Considering in turn the endpoints from the above list that are available in Study EN3267-005:

SPID at 60 minutes:

– The presentation of the SPID data in Study EN3267-005 did not include the frequency with which Abstral and placebo use led to a SPID ≥120 at 60 minutes.

30% or 50% decrease in pain intensity

– A 30% decrease in pain intensity from baseline was seen after 63.5% of Abstral doses compared to 41.8% of placebo doses in the Interim (primary) analysis. The odds ratio for Abstral compared to placebo was 2.79, with a lower 95%CI boundary of 1.73 and p-value <0.0001.

– Data regarding a 50% reduction in pain intensity were not assessed in the Interim analysis but at the End-of-Study analysis this level of response was achieved after 24.7% of Abstral doses compared to 19.9% of placebo doses. The result favoured Abstral but could not be assessed for statistical significance using the planned method and was not tested using an alternative method.

Pain relief:

5 Farrar JT, et al. (1998) Oral transmucosal fentanyl citrate: randomized, double-blinded, placebo- controlled trial for treatment of breakthrough pain in cancer patients. J Natl Cancer Inst. 90: 611-616; Coluzzi PH, et al. (2001) Breakthrough cancer pain: a randomized trial comparing oral transmucosal fentanyl citrate (OTFC) and morphine sulfate immediate release (MSIR). Pain 91: 123-130



– The mean difference in PR between Abstral and placebo at each time point was always less than 2, but this does not necessary mean that Abstral did not produce a clinically meaningful effect (PR ≥2) at a significantly higher frequency than placebo. However, as noted above, data regarding the frequency with which Abstral and placebo use led to a PR ≥2 were not presented.

Patient Global Evaluation of Medication:

– Data for the Patient Global Evaluation of Medication were only presented for the End-of-study analysis. As with PR, the presentation of the data for the Patient Global Evaluation of Medication did not include the frequency with which Abstral and placebo use led to a clinically meaningful vale (Patient Global Evaluation ≤3).

Rescue medication was required less frequently after Abstral than placebo, but the difference could not be assessed for statistical significance using the planned method and was not tested using an alternative method.

In summary, the data relating to a 30% reduction in pain intensity indicate that the statistically significant difference between Abstral and placebo was indeed clinically meaningful within the biased population that was studied. However, the data relating to other endpoints which could have confirmed this (most importantly SPID at 60 minutes, the use of rescue medication and the Patient Global Evaluation of Medication) were presented and analysed in a manner that prevented an assessment of whether Abstral had a clinically meaningful effect on those endpoints.

It should also be remembered that an unbiased comparison between a candidate medication and placebo is required if the true population benefit of the drug is to be assessed. As noted above, the double-blind assessment in EN3267-005 was enriched with proven Abstral responders and does not provide an unbiased comparison. This means that the true (placebo-subtracted) population benefit of Abstral could not be satisfactorily quantified, e.g. in terms of the “number-needed-to-treat” or NNT (that is, the number of patients who need to be treated with the drug to produce a clinically worthwhile treatment effect in one additional patient compared to placebo). In turn, this means that the benefits of Abstral could not be quantitatively compared with its risks (for example in terms of the “number-needed-to-harm” or NNH).

Finally, the effect of Abstral on the clinically important endpoint of SPID at 60 minutes appeared to be reduced in men compared to women and this finding has not been adequately explored or explained.

6.1.2. Other efficacy studies

SuF-002 was listed as an efficacy study in the submission Table of Contents, but patients only received a single dose of Actiq at each dose level and a single dose of placebo. It is more appropriately regarded as a PD/dose-finding study and has therefore been covered elsewhere in this report.

The open-label study EN3267-007 included baseline and post-baseline assessments of the Patient Global Evaluation of Medication and QoL, but the lack of a control group means that these assessments do not provide meaningful evidence of efficacy.

6.1.3. Analyses performed across trials (pooled & meta analyses)

Not applicable.

6.1.4. Evaluator’s conclusions on clinical efficacy for BTcP

The design and analysis of Study EN3267-005 mean that it will have exaggerated the population benefit of Abstral compared to placebo, and did not permit an unbiased assessment of the NNT. Nevertheless, the study demonstrates that there is a large subpopulation of BTcP sufferers who



can be identified - via a process of dose titration - as responders to Abstral, and that the response to Abstral in those individuals is greater than the “placebo effect”.

Study SuF-002 provided only limited supporting efficacy data that involved the treatment of only a single BTcP episode with placebo and each dose level of Abstral, and did not cover the full dose range of Abstral as proposed in the PI.

Study EN3267-007 did not provide meaningful efficacy data due to the lack of a control group.

The Abstral dose range that was examined in the submitted studies, and that is now proposed for approval in Australia, appears to reflect a mistaken belief that the bioavailability of Abstral is double that of Actiq and therefore that the starting dose, titration steps, and maximum doses of Abstral should be half those that are approved for Actiq. The recommended Abstral starting does, titration steps and maximum dose may therefore be unduly conservative. However, it would be unwise to change the Abstral starting dose, titration steps and maximum dose to higher ones that have not been studied in any clinical trial. The more conservative titration steps are also advisable for another reason: unlike an Actiq lozenge which can be easily removed from the mouth, it is less feasible to terminate absorption from a rapidly-disintegrating and mucosally adherent Abstral sublingual tablet should excessive opioid side effects start to develop.

7. Clinical safety

7.1. Studies providing evaluable safety data7.1.1. Pivotal efficacy study

In Study EN3267-005, the following safety data were collected:

Adverse events (AEs) were elicited by open-ended questioning and by observation of patients at each study visit. An AE was any unfavourable or unintended change in signs, symptoms, laboratory test (if performed), or worsening of a pre-existing condition associated temporally with the use of the study medication, whether or not it was considered related to the study medication. All AEs, including observed and volunteered problems, complaints, signs, or symptoms, were recorded on the electronic case report form, regardless of whether the AE was associated with the use of study medication. This included AEs resulting from concurrent illness, reactions to concurrent medication use, or progression of disease states. Recurrent symptoms of a chronic pre-existing condition were not considered AEs unless they occurred in a worse or unexpected pattern during study medication. A treatment-emergent AE (TEAE) was any condition that was not present before treatment with the study medication but appeared after treatment, was present at treatment initiation but worsened during treatment, or was present at treatment initiation but resolved and then reappeared while the individual was on treatment

The oral mucosa was examined at each clinic visit for the duration of the study, preferably by the same examiner for each patient. Oral erythema and ulcers were recorded as AEs. The presence, severity, and location (site of sublingual study medication application or other oral site) of mucositis were recorded. After Protocol Amendment 1, erythematous mucositis was rated as: 0 = none; 1 = mild (areas of tissue just noticeably red); 2 = moderate (red); 3 = severe (deep beefy red colour).

Laboratory tests were specified only at Screening. Additional laboratory tests were performed during the study in some patients as part of their clinical management, but the results were generally not reported except in some cases where laboratory abnormalities were reported as AEs.



Vital signs were assessed at Screening and during the first hour after the test dose of Abstral. Physical examination and 12-lead ECG were assessed at Screening.

Comment: Throughout Study EN3267-005, patients received background opioid therapy for their cancer pain as well as a range of concomitant medications. The reported TEAEs therefore represent a combination of the effects of Abstral, of background and concomitant medications, and of the patients underlying cancer and other medical conditions. However a causal relationship to Abstral could reasonably be deduced for some TEAEs, particularly those that occurred during the titration period and that represented the new onset of a typical opioid-type side effect or hypersensitivity reaction.

The multiple crossover design of the Double-blind Treatment Phase meant that TEAEs during that phase could not be reliably assigned to one or the other of Abstral and placebo. This means that the pivotal study does not provide placebo-controlled safety data, does not allow a determination of the placebo-subtracted TEAE rate for Abstral and does not permit calculation of the NNH.

7.1.2. Other studies

7.1.2.1. EN3267-007

Study EN3267-007 was a long-term, open-label, uncontrolled study that enrolled opioid-tolerant cancer pain patients. After screening, eligible patients entered a Titration Period during which participants had up to 2 weeks to determine a single effective and tolerable dose of Abstral in the range 100 to 800 g. The titration scheme was essentially the same as in the μpivotal Study EN3267-005. Successfully-titrated patients then entered an open-label Maintenance Period of up to 12 months during which they used Abstral (maximum dose 800

g) to treat episodes of BTcP. Data were collected regarding AEs (including specific assessmentsμ of oral mucosal effects), clinical chemistry, haematology, urinalysis, ECG, vital signs and physical examination.

7.1.2.2. Clinical pharmacology studies

Data relating to AEs, laboratory tests, physical examination, vital signs and ECG were collected during the clinical pharmacology studies. Data from the clinical pharmacology studies in the original submission were aggregated by the sponsor in the Summary of Clinical Safety. Corresponding safety information from the clinical pharmacology studies submitted as supplementary data were not included in the Summary of Clinical Safety but were later provided separately for each study in the evaluation.

7.2. Pivotal studies that assessed safety as a primary outcomeNot applicable. Study EN3267-007 primarily examined the safety of Abstral, but was uncontrolled and therefore not regarded as pivotal.

7.3. Patient exposure7.3.1. Pivotal study

In Study EN3267-005:

131 cancer pain patients received at least one dose of Abstral.

52 patients were exposed to Abstral for ≥3 months.

The mean exposure duration was 123.7 days (giving a cumulative exposure during the study of 131×123.7 or 16,205 patient-days). The median exposure duration was 51 days.



Patients took a cumulative total of 41,596 doses of Abstral during the study (3,167 during the Open-label Titration Phase, 414 during the Double-blind Treatment Phase and 38,015 during the Long-Term Extension Phase).

About half of the patients who were successfully stabilised on Abstral were taking a dose of 100-400 g and half were on 600-800 g.μ μ

Amongst the 72 patients who entered the Long-term Extension Phase, the mean dose of Abstral per BTcP episode over the course of the Long-term Extension Phase was 551 g, μwith a median dose of 600 g and a range of 100-800 g.μ μ

7.3.2. Other studies

7.3.2.1. EN3267-007

In the long-term open-label safety study EN3267-007:

139 cancer pain patients received at least one dose of Abstral.

62 patients were exposed to Abstral for ≥3 months.

The mean exposure duration was 138.8 days (giving a cumulative exposure during the study of 139 ×138.8 or 19,293 patient-days). The median exposure duration was 79 days.

About half of the 96 patients who were successfully stabilised on Abstral were taking a dose of 100-400 g and half were on 600-800 g.μ μ

7.3.2.2. Clinical pharmacology studies

In the clinical pharmacology studies in the original submission (including Suf-002), a total of 221 healthy subjects and 41 cancer pain patients received at least one dose of Abstral. Healthy subjects received from 1 to 20 doses of Abstral, at dose levels of 50 to 800 g. Cancer pain μpatients received from 1 to 3 doses of Abstral at dose levels of 100 to 400 g.μIn the supplementary clinical pharmacology studies, a total of 162 healthy subjects received at least one dose of Abstral, at dose levels of 400 or 800 g.μ

7.4. Adverse events7.4.1. All adverse events (irrespective of relationship to study treatment)

7.4.1.1. Pivotal study

7.4.1.1.1. Adverse events in general

In Study EN3267-005, 96 patients (73.3%) reported at least 1 TEAE. TEAEs reported in ≥5% of patients overall are summarised in Table 19. In descending order of incidence, they were nausea (22.1% of patients); vomiting (11.5%); fatigue (8.4%); anaemia, diarrhoea, stomatitis (6.9% each); dizziness, headache, somnolence, weight decreased, urinary tract infection (6.1% each), asthenia, pain in extremity, pneumonia, upper respiratory tract infection (5.3% each).



Table 19: EN3267-005: Summary of TEAEs reported in ≥5% of patients overall, according to SOC, Preferred Term and study phase. Final analysis, All-treated population.

Comment: The most common TEAEs were a combination of typical opioid side effects and AEs that are expected given the patients’ underlying cancers and the treatment of those cancers. Constipation does not feature in the above list, but patients would have been using preventative treatment for constipation due to their background opioid therapy. A wide range of TEAEs were reported at frequencies below 5%, which is again not surprising given the patient’s background medication and underlying medical conditions.

7.4.1.1.2. Adverse events related to the application site

Two patients had evidence of oral mucositis at screening. During the Open-label Titration Phase (Visit 2 and Visit 3), 6/131 patients (4.9%) had evidence of oral mucositis. During the Double-blind Treatment Phase (Visit 4 and Visit 5), 3/131 patients (2.3%) had evidence of oral



mucositis. The number of patients with evidence of oral mucositis did not increase during the Long-term Extension Phase. Throughout the study, there were fewer patients reported to have both ulcers and erythema than patients with erythema alone. In all cases, the erythema was reported as mild or moderate.

One patient experienced oral mucosal blistering that was reported as a TEAE. The oral mucosal blistering in this patient was present during the Open-label Titration Phase and the Double-blind Treatment Phase, and resolved after the patient had entered the Long-term Extension Phase despite continuing to take Abstral.

TEAEs that could potentially represent local adverse effects of Abstral at or near the application site included: stomatitis (9 patients [7%]); pharyngolaryngeal pain (4 patients [3.1%]); lip ulceration, dry mouth (3 patients [2.3%] each); dry mouth (3 aphthous stomatitis, oral pain, tongue ulceration, gingival swelling, gingival ulcer, gingivitis, dysgeusia, throat tightness (1 patient [0.8%] each). Of these, 2 cases of dry mouth, and 1 case each of stomatitis, aphthous stomatitis, gingival ulceration, lip ulceration, pharyngolaryngeal pain, dysgeusia and throat tightness were classified as treatment-related.

7.4.1.2. Other studies

7.4.1.2.1. EN3267-007

In the long-term open-label safety study EN3267-007, 116 patients (83.5%) reported at least one TEAE. TEAEs reported in ≥5% of patients overall are summarised in Table 20. In descending order of incidence, they were nausea (23.0% of patients); fatigue (15.1%); vomiting (12.9%); dehydration (11.5%); peripheral oedema (10.8%); arthralgia (10.1%); back pain, insomnia (9.4% each); asthenia, constipation (8.6% each), anorexia, cancer pain, diarrhoea, somnolence, stomatitis (7.9% each); anaemia, dizziness (7.2% each); headache (6.5%); abdominal pain, anxiety, depression, dry mouth, hypotension, weight decreased (5.8% each); rash, thrombocytopenia (5.0% each). Overall, a similar percentage of men and women experienced TEAEs (82.5% and 84.2%, respectively. The most commonly reported TEAEs in women were nausea (28.9%), arthralgia, back pain, and vomiting (13.2% each), whereas the most commonly reported TEAEs in men were dehydration (19.0%), fatigue (15.9%), and nausea (15.9%).



Table 20: EN3267-007: Summary of TEAEs reported in ≥5% of patients overall, according to SOC, Preferred Term and study phase. All-treated population (N=139).



Table 20 (continued): EN3267-007: Summary of TEAEs reported in ≥5% of patients overall, according to SOC, Preferred Term and study phase. All-treated population (N=139).

A total of 18/139 patients (12.9%) showed evidence of oral mucositis during the course of the study. The number of patients with evidence of oral mucositis did not increase during the Maintenance Period with only one patient reporting oral mucositis at End-of-Study. TEAEs that might represent local adverse effects of Abstral but which did not necessarily meet the criteria for oral mucositis included stomatitis (11 patients); dry mouth (8 patients); mouth ulceration (4 patients); gingival bleeding, gingivitis, oral hypaesthesia, oral discomfort, oral soft tissue disorder, tongue disorder, tongue dry, tongue ulceration, application site irritation, application site reaction, and mucosal inflammation, (1 patient each).

7.4.1.2.2. Clinical pharmacology studies

TEAEs reported in ≥1% of healthy volunteers or cancer patients in the clinical pharmacology studies in the original submission are summarised in Table 21. In the originally-submitted clinical pharmacology studies, TEAEs were reported in 71% of the healthy subjects after Abstral administration and 49% of the cancer patients. In the supplementary clinical pharmacology studies, TEAEs were reported in approximately one-third of the Abstral recipients, all of whom were healthy volunteers. The lower incidence of TEAEs in the supplementary clinical pharmacology studies reflects the fact that naltrexone was used in all of those studies to reduce the risk of opioid-related AEs. TEAEs in the supplementary clinical pharmacology studies were broadly similar in nature to those summarised in Table 21.



Table 21: Number (%) of participants reporting TEAEs in the clinical pharmacology studies in the original submission (AEs reported in ≥1% of healthy subjects or cancer patients).

† All 3 cases of tremor were reported in healthy subjects in StudyEN3267-001, where they were correctly included in the ‘Nervous system disorders’ SOC. These events were incorrectly included in the ‘Eye disorders’ SOC. They were also incorrectly included in the totals for the ‘Eye disorders’ SOC in Clinical Summary. The evaluator has moved them to the correct SOC and adjusted the number of healthy subjects and the total number of participants with AEs in the ‘Eye disorders’ SOC. The number of healthy subjects and the total number of participants with AEs in the ‘Nervous system disorders’ SOC has not been adjusted because:(a) The evaluator was unable to determine whether or not the patients who experienced tremor are already included in the total for the ‘Nervous system disorders’ SOC (due to also having some other nervous system AE). The listing that would have clarified this was not included in the submission (Study EN3267-001).



(b) The maximum possible number of additional healthy volunteers with AEs in the ‘Nervous system disorders’ SOC is 3, which is very small compared to the number already appearing in that SOC (133). * Examination of the original terms used by the investigators show that the dermatitis/irritation occurred at ECG recording tab sites, pCO2 probe sites and BP cuff sites, not at the drug application site.

7.4.2. Treatment-related adverse events (adverse drug reactions)


In Study EN3267-005, TEAEs judged to be at least possibly related to study treatment were reported in 41/131 (31.3%) of the patients. Treatment-related TEAEs reported in more than 2% of patients were nausea (12.2% of patients), vomiting (5.3%), somnolence (4.6%) and headache (3.8%). Treatment-related rash, allergic pruritus and drug hypersensitivity were reported in 1 patient each. As previously noted, treatment-related TEAEs of dry mouth (2 cases), stomatitis, aphthous stomatitis, gingival ulceration, lip ulceration, pharyngolaryngeal pain, dysgeusia and throat tightness (1 case each) may represent adverse effects of Abstral at or near the application site.


7.4.2.2.1. EN3267-007

In the long-term open-label safety study EN3267-007, treatment-related TEAEs were reported in 49/139 (35.3%) of the patients. Treatment-related TEAEs reported in more than 2% of patients were nausea (8.6% of patients); constipation, somnolence (5.8% each); fatigue (4.3%); dry mouth, headache (3.6%); dizziness (2.9%) and vomiting (2.2%).


Treatment-related TEAEs in the clinical pharmacology studies in the original submission are summarised in Table 22. In the supplementary clinical pharmacology studies, 37/162 (22.8%) of the Abstral-treated subjects experienced treatment-related TEAEs. These are summarised in the individual study summaries and were broadly similar in nature to those summarised in Table 22 (but generally occurred at lower frequencies than in the originally-submitted clinical pharmacology studies due to the concomitant administration of naltrexone).



Table 22: Number (%) of participants reporting TEAEs that were categorised as being at least possibly related to study treatment in the clinical pharmacology studies in the original submission (AEs reported in ≥1% of healthy subjects or cancer patients).

*Data for application site dermatitis and application site irritation were transposed in the source table in the Clinical Summary (corrected in the above table). In addition, examination of the original terms used by the investigators show that the dermatitis/irritation occurred at ECG recording tab sites, pCO2 probe sites and BP cuff sites, not at the drug application site.The total number and percentage of study participants with treatment-related AEs was not reported, nor were the number and percentage of patients with treatment-related AEs in each SOC.

7.4.3. Deaths and other serious adverse events


A total of 10 (7.6%) patients died in Study EN3267-005: 2 during the Open-label Titration Phase and 8 during the Long-term Extension (Table 23). Six deaths (6/131 patients [4.6%]) were considered to be a result of progression of the underlying disease (metastatic cancer). Other causes of death included pneumonia, septic shock, myocardial infarction, and completed suicide (one of each).



Table 23: EN3267-005: Number (%) of patients who died, with the fatal TEAEs listed according to SOC, Preferred Term and study phase. End-of-study analysis, All-treated population.

None of the deaths were considered to be related to study medication. The event of completed suicide did not involve overdosing with study medication.

A total of 24 patients (18.3%) experienced at least one treatment-emergent SAE: 6 (4.6%) patients in the Open-label Titration Phase and 18 (25%) patients in the Long-term Extension Phase). Most SAEs were considered to be related to the patients’ underlying medical conditions rather than study treatment. SAEs that were classified as at least possibly related to Abstral were:

1 case of mild affect lability during Abstral titration. Abstral was discontinued and the event resolved.

1 case of non-fatal accidental overdose with opioids and lorazepam during the Long-Term Extension in a woman who was taking multiple medications, including 3 different opioids (oxycodone 180 mg daily; morphine 30 mg as needed, total daily amount not confirmed; and Abstral 100 g per dose, total daily amount not confirmed).μ


7.4.3.2.1. EN3267-007

A total of 19 (13.7%) patients died in the long-term open-label safety study EN3267-007. None of the deaths were considered to be related to Abstral. A total of 46 patients (33.1%) experienced at least one treatment-emergent SAE: 7 (5.0%) patients in the Titration Period and 40 (41.7%) patients in the Long-term Maintenance Period. All of the SAEs were considered to be related to the patients’ underlying medical conditions or concomitant therapy, and none were considered to be related to Abstral.




There were no deaths in the originally-submitted or supplementary clinical pharmacology studies. SAEs occurred only in the originally submitted clinical pharmacology studies, with no SAEs in the supplementary clinical pharmacology studies.

One SAE in the clinical pharmacology studies was considered to be related to Abstral. A healthy male subject who had not received pre-emptive naltrexone experienced severe vomiting after the fourth dose of Abstral 200 g q4h. This was considered an SAE due to the need for μintervention (IV fluids, naloxone and metoclopramide) and the severity of the event. The SAE, classified as probably related to study treatment, resolved the next day. Further investigation revealed the presence of non-typhoid salmonella in the subject’s stool sample taken at the time of discharge from the study. Nonetheless, the SAE was kept as ‘probably’ related to study drug.

7.4.4. Discontinuation due to adverse events


A total of 30 of 131 patients (22.9%) experienced at least one TEAE that led to discontinuation: 15 patients in the Open-label Titration Phase, 2 patients in the Double-blind Treatment Phase, and 13 patients in the Long-term Extension Phase). The most common SOCs for TEAEs that led to discontinuation during the Open-label Titration Phase were gastrointestinal disorders (4/131 patients [3.1%]) and psychiatric disorders (3/131 patients [2.3%]). The most common SOC for TEAEs that led to discontinuation during the Long-term Extension Phase was neoplasms benign, malignant, and unspecified (4/72 patients [5.6%]).

A total of 15/131 (11.5%) patients discontinued due to a total of 17 treatment-related TEAEs. The events were: dyspnoea, nausea (2 each); abdominal pain, affect lability, allergic pruritus, anxiety, diarrhoea, disorientation, drug hypersensitivity, headache, mental status changes, paranoia, rash, throat tightness, and vomiting (1 each).

Comment: The data show the expected pattern of early discontinuations due to treatment-related TEAEs (particularly during titration), with later discontinuations that were mostly related to progression of the underlying cancer. However some patients did discontinue during the Long-term Extension Phase due to treatment-related TEAEs (abdominal pain, allergic pruritus and dyspnoea).


7.4.4.2.1. EN3267-007

Overall, 37 patients (26.6%) experienced TEAEs leading to discontinuation during EN3267-007: 14/139 (10.1%) in the Titration Period and 23/96 (24.0%) in the Maintenance Period. Overall, metastatic prostate cancer and nausea (each in 5 patients) were the most frequently cited TEAEs leading to discontinuation. The most common TEAEs resulting in discontinuation during the Titration Period were nausea (3 patients), somnolence (3 patients), metastatic prostate cancer (2 patients), and fatigue (2 patients). In the Maintenance Period, the most frequently reported events causing discontinuation were metastatic prostate cancer (3 patients), metastatic lung cancer (2 patients), and nausea (2 patients). A total of 11/139 (7.9%) patients discontinued due to a total of 12 treatment-related TEAEs. The events were: nausea (3 patients); nausea and depression (1 patient); somnolence (3 patients); fatigue, lethargy, headache , pruritus (1 patient each). Of the treatment-related withdrawals, 10 occurred during the Titration Period and the remaining one was during the first month of the Maintenance Period.


A total of 14 volunteers discontinued due to AEs (4 from Study 2246-EU-004, 1 from Study 2246-EU-005, 5 from EN3267-001, 3 from EN3267-003 and 1 from EN3267-013). The AE leading to the discontinuation of the largest number of volunteers was respiratory



depression, in 4 volunteers (all opioid naïve, from a study where pre-emptive opioid antagonist was not administered).

No cancer patients in the clinical pharmacology studies discontinued treatment due to TEAEs.

7.5. Laboratory tests7.5.1. Pivotal study

Post-baseline laboratory data were not routinely collected in Study EN3267-005. Post-baseline laboratory tests were performed in some patients as part of their clinical management, but the results were not presented in the study report. Clinically significant abnormalities of these tests could be reported as TEAEs.

Clinical chemistry abnormalities reported in this manner were: hypokalaemia (3 patients [2.3%]); abnormal liver function test (2 patients [1.5%]); increased alkaline phosphatase, increased creatinine, increased carcinoembryonic antigen, increased testosterone hypoglycaemia, hyponatraemia (1 patient [0.8%] each). Hepatitis and jaundice were each reported in 1 patient, as were proteinuria and renal failure.

Haematological abnormalities reported in this manner were anaemia (9 patients [6.9%]), neutropenia (5 patients [3.8%]), pancytopenia (3 patients [2.3%]), thrombocytopenia (2 patients [1.5%] and leukopenia (1 patient [0.8%]).

None of these abnormalities were classified as treatment-related.


7.5.1.1.1. EN3267-007

Laboratory parameters were examined at intervals during the long-term open-label safety study EN3267-007. Screening and subsequent laboratory parameters reflected a population in a diseased state, and many patients had abnormal baseline and post-baseline values. The lack of a control group also meant that any effects of Abstral could not be separated from changes due to the underlying cancer, other concomitant illnesses, or concomitant medications.


Laboratory parameters were examined before and after Abstral administration in the clinical pharmacology studies.

One subject developed a clinically-significantly raised alanine transaminase (ALT) level of 80 IU/L (normal range: 8-45 IU/L), one day after his fourth dose of Abstral (200 g, after μprevious doses of 50, 100 and 150 g). ALT was still raised (70 IU/L) one day later and had μreturned to normal (16 IU/L) 12 days later. The abnormality was classified as possibly treatment-related.

No other clinically significant treatment-related clinical chemistry or haematology changes were observed in the clinical pharmacology studies.

7.5.2. Other clinical trial safety assessments

7.5.2.1. ECG

In the pivotal Study EN3267-005, ECGs were routinely performed only at screening.

In the long-term open-label safety study EN3267-007, ECGs were recorded at baseline and at intervals during the study. There were no clinically significant ECG changes during the study.



In the clinical pharmacology studies in the original submission, ECGs were performed before and after Abstral administration. No clinically relevant abnormalities were seen. ECGs were routinely performed only at screening in the supplementary clinical pharmacology studies.

7.5.2.2. Vital signs

In the pivotal Study EN3267-005, vital signs were routinely recorded only at screening.

In the long-term open-label safety study EN3267-007, vital signs were recorded at baseline and at interval during the study. There were some individual abnormalities, as expected given the study population, but mean values were similar at screening and End-of-Study.

In the clinical pharmacology studies, vital signs were recorded before and after Abstral administration. The administration of higher doses of Abstral to opioid-naïve subjects was sometimes followed by decreases in respiratory rate, oxygen saturation and blood pressure. No other clinically relevant abnormalities were seen.

7.6. Post-marketing experienceFrom first international launch to 30 April 2010, the sponsor received a total of 30 case reports with 52 suspected adverse reactions. The majority (71%) of the adverse reactions were considered non-serious by the reporters.

One fatal case was received. This case was a poorly documented regulatory authority report of a patient who had died (cause of death not reported) in whom “high levels” (not quantified) of fentanyl were found at post-mortem. Other relevant information was not available, for example: the specific fentanyl product(s) involved; route of administration; indication for the patient’s use of fentanyl; whether the patient was opioid-tolerant or opioid-naïve and whether the “high levels” occurred as a result of usage at the recommended dose, or deliberate or accidental overdose).

A number of the spontaneously-reported post-market AEs represent possible local effects of Abstral at or near the application site.

Comment: The suspected post-market adverse reactions comprise a mixture of systemic opioid effects and administration site adverse effects. The data are now 2 years out of date and an updated summary of post-marketing adverse event reports should be sought from the Sponsor.

7.7. Evaluator’s overall conclusions on clinical safetyIn the submitted studies, Abstral was associated with typical opioid-type adverse effects, the most common being gastrointestinal effects such as nausea and vomiting, and effects reflecting the CNS depressant action of fentanyl, such as somnolence, fatigue and asthenia. A small percentage of patients had AEs that could represent local effects of Abstral at or near the application site. Hypersensitivity/allergic reactions and rashes were also seen in a small percentage of patients. Overall, the types of AEs are what one would expect for a sublingually administered fentanyl product.

Long term safety data were relatively limited, being available from only 170 patients 72 in EN3267-005 and 98 in EN3267-007). However, no unexpected safety issues were identified and the systemic safety profile of Abstral is expected to be broadly similar to that of Actiq (based on the similarity of fentanyl plasma concentrations during use of the two products).

The Abstral studies did not reveal any major problems in relation to AEs at or near the application site, but the database is limited. Given the underlying frequency with which oral AEs occur in the general population and in patients with cancer, it is unlikely that preregistration studies will be able to either detect or exclude, with a satisfactory degree of confidence, an



increased risk of such events in users of Abstral. Rather, if Abstral use is associated with oral adverse effects, then this would only become apparent after marketing and consequent usage in a much larger number of patients (as was the case, for example, with Actiq).

The Sponsor’s proposal to not register the 300 g, 600 g and 800 g tablet strengths in μ μ μAustralia means that some patients will be titrated to doses that can only be achieved by using two different strength tablets, with a consequent risk of administration error that could be avoided if these tablet strengths were available. In addition, the need to take two tablets instead of one (for titration and also to achieve doses above 400 g) may have an adverse impact on μcompliance, that could be avoided if the sponsor were to market in Australia all of the strengths that are available overseas.

As expected, the incidence of opioid-type AEs, including respiratory depression, was relatively high amongst non-opioid-tolerant healthy subjects in the clinical pharmacology studies. This serves to underline the recommendation that Abstral should only be used in patients who are opioid-tolerant.

8. First round benefit-risk assessmentThe design and analysis of Study EN3267-005 mean that it will have exaggerated the population benefit of Abstral compared to placebo, and did not permit an unbiased assessment of the NNT. Nevertheless, the study demonstrates that there is a large subpopulation of BTcP sufferers who can be identified - via a process of dose titration - as responders to Abstral, and that the response to Abstral in those individuals is greater than the “placebo effect”. The dose-titration process by which responders are identified is associated with AEs, so that some individuals who start Abstral will therefore experience AEs without eventually gaining any benefit from the drug. However, treatment-related AEs during the titration period were generally minor and transient, and overall the benefit-risk balance is considered to be favourable.

9. First round recommendation regarding authorisationAuthorisation of Abstral is recommended, provided that:

The PI and Consumer Medicine Information (CMI) are revised to more accurately reflect the available information.

The sponsor provides satisfactory responses to the clinical questions.

10. Clinical questionsThe Periodic Safety Update Reports (PSURs) included in the submission are now 2 years old. The sponsor should provide up to date PSURs for review before authorisation.

The sponsor should be asked to comment on the gender difference in Sum of Pain Intensity Differences (SPID), particularly at 60 minutes after the dose, in the pivotal Study EN3267-005.

As noted in the Clinical Pharmacology Study Summaries, a few minor issues could be addressed if the Sponsor were to make available certain appendices to the study reports that were omitted from the material provided to the TGA. However, these minor issues would not affect the registration decision, so it is not necessary to obtain or evaluate the data.



11. References1. Center For Drug Evaluation and Research. Application number 022510Orig1s000.

Summary Review

<http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022510Orig1s000SumR.pdf>

Accessed 2 March 2012.

2. Center For Drug Evaluation and Research. Application number 022510Orig1s000. Clinical Pharmacology and Biopharmaceutics Review(s).

<http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022510Orig1s000ClinPharmR.pdf>

Accessed 2 March 2012.

3. Australian Product Information for Actiq (30 Jan 2012).

4. Stengel B. (2010) Chronic kidney disease and cancer: a troubling connection. J Nephrol. 23: 253-262.

5. Farrar JT, et al. (2000) Defining the clinically important difference in pain outcome measures. Pain 88: 287-294.

6. Farrar JT, et al. (2003) Clinically important changes in acute pain outcome measures: a validation study. J Pain Symptom Manage. 25: 406-411.

7. Farrar JT, et al. (1998) Oral transmucosal fentanyl citrate: randomized, double-blinded, placebo- controlled trial for treatment of breakthrough pain in cancer patients J Natl Cancer Inst. 90: 611-616.

8. Coluzzi PH, et al. (2001) Breakthrough cancer pain: a randomized trial comparing oral transmucosal fentanyl citrate (OTFC) and morphine sulfate immediate release (MSIR). Pain 91: 123-130.


Therapeutic Goods AdministrationPO Box 100 Woden ACT 2606 Australia

Email: [email protected] Phone: 1800 020 653 Fax: 02 6232 8605http://www.tga.gov.au

http://www.tga.gov.au/

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