ALDARA - ALDARA - CT 7369 - English version

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Introduction ALDARA 5%, cream Box of 12 250 mg single-use sachets (CIP: 349 204-4) Posted on May 30 2011 Active substance (DCI) imiquimod ATC Code D06BB10 Laboratory / Manufacturer MEDA PHARMA ALDARA 5%, cream Box of 12 250 mg single-use sachets (CIP: 349 204-4) Posted on May 30 2011

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The legally binding text is the original French version

TRANSPARENCY COMMITTEE

OPINION

10 March 2010



Review of the dossier of the proprietary drug included on the list of reimbursable products for
a period of 5 years as from 4 May 2005 (JO of 9 August 2005)

ALDARA 5%, cream
Box of 12 250 mg single-use sachets (CIP: 349 204-4)


Applicant: MEDA PHARMA

Imiquimod

ATC code: D06BB10

List I

Date of Marketing Authorisation: 18/09/1998 (indication for external genital warts)
Amendment dated 13/07/2004: extension of indication to basal cell carcinomas
Amendment dated 24/04/2007: extension of indication to actinic keratoses



Reason for the request: Renewal of inclusion on the list of medicines reimbursed by National
Health Insurance.















Medical, Economic and Public Health Assessment Division
1 1 CHARACTERISTICS OF THE MEDICINAL PRODUCT

1.1. Active ingredient
Imiquimod

1.2. Indications
“Imiquimod is indicated for the topical treatment of:
- external genital and perianal warts (condylomata acuminata) in adults.
- small superficial basal cell carcinomas (sBCCs) in adults.
- clinically typical, non-hypertrophic, non-hyperkeratotic actinic keratoses (AKs) on the
face or scalp in immunocompetent adult patients when size or number of lesions limit the
efficacy and/or acceptability of cryotherapy and other topical treatment options are
contraindicated or less appropriate.”

1.3. Dosage
The application frequency and duration of treatment with imiquimod cream are different for
each indication.

“External genital warts in adults: imiquimod cream should be applied 3 times per week
(example: Monday, Wednesday and Friday; or Tuesday, Thursday and Saturday) prior to
normal sleeping hours and should remain on the skin for 6 to 10 hours. Imiquimod cream
treatment should continue until the clearance of visible genital or perianal warts or for a
maximum of 16 weeks per episode of warts.

Superficial basal cell carcinoma in adults: apply imiquimod cream for 6 weeks, 5 times per
week (example: Monday to Friday) prior to normal sleeping hours, and leave on the skin for
approximately 8 hours.

Actinic keratosis in adults: treatment should be initiated and monitored by a physician.
Imiquimod cream should be applied 3 times per week (example: Monday, Wednesday and
Friday) for four weeks prior to normal sleeping hours, and left on the skin for approximately 8
hours. Sufficient cream should be applied to cover the treatment area. After a 4-week
treatment-free period, clearance of AKs should be assessed. The maximum recommended
dose is one sachet. The maximum recommended treatment duration is 8 weeks. An
interruption of dosing should be considered if intense local inflammatory reactions occur or if
infection is observed at the treatment site. In this latter case, appropriate other measures
should be taken. Each treatment period should not be extended beyond 4 weeks due to
missed doses or rest periods. If the treated lesion(s) show an incomplete response at the
follow-up examination at 4-8 weeks after the second treatment period, a different therapy
should be used.”

2
2 REMINDER OF THE COMMITTEE"S OPINIONS AND CONDITIONS OF
INCLUSION


Opinion of the Committee of 3 November 1999

External perianal and genital warts (condylomata acuminata) in adults:
Analysis of clinical trials on the drug and comparative data
The efficacy of ALDARA versus placebo has been clearly demonstrated. The product is well
tolerated apart from localised skin reactions.
A meta-analysis of published studies into various forms of therapeutic management has
been added to the dossier. The methodology is imperfect and does not allow the proprietary
drug ALDARA cream to be clearly positioned in respect of the alternative treatments.
The following points should be underlined:
- experience with the use of ALDARA cream to treat foreskin warts in uncircumcised men is
limited. Data from patients in this category using ALDARA three times a week and
cleaning their foreskin daily related to fewer than 100 patients.
- repeat-treatment following the recurrence of warts has not been investigated; therefore,
repeat-treatment is not recommended.
- ALDARA is less effective in removing condylomata among HIV-positive patients, although
limited data has shown a statistically significant difference versus placebo in one of the
secondary efficacy endpoints (rate of partial reduction in condylomata size).

Actual benefit
This proprietary drug is intended to provide curative treatment.
It should have a prominent position in the treatment strategy for this condition. This position
needs to be confirmed by studies comparing the product to other drugs treatments and
surgery. Furthermore, the efficacy and tolerance of ALDARA cream have not been
sufficiently evaluated in HIV-positive patients or in uncircumcised male patients undergoing
repeat-treatment after the recurrence of warts.
The actual benefit of this proprietary drug is high.

Improvement in actual benefit
Though no comparative studies versus other drug treatments have been carried out, the
Committee is of the opinion that ALDARA represents a minor improvement in actual benefit
(level IV) in terms of ease of use (one application per day rather than two applications per
day) compared to the proprietary product CONDYLINE solution for local application.

Recommended therapeutic strategy
Doctors use a variety of therapeutic strategies: drug treatments (including podophyllin
preparations made up in the pharmacy) or ablative procedures (removal by surgery,
cryotherapy, laser or electrocauterisation). No consensus position has been established as to
the best strategy for this condition.

Opinion of the Committee of 13 April 2005
Renewal of inclusion:
Actual benefit
External perianal and genital warts (condylomata acuminata) in adults are caused by a
sexually transmissible viral infection.
Their recurrence is a major problem in this infection.
The efficacy/adverse effect ratio of ALDARA 5% cream is high.
It is intended for curative treatment.
3 The actual benefit of ALDARA 5% cream is substantial.

Treatment strategy
1 2New guidelines have been published in Europe and the USA since the Transparency
Committee"s last opinion. These guidelines place treatments in two categories: those
administered by a doctor (surgery, laser treatment, cryotherapy, trichloroacetic acid) and
those which can be applied by the patient (imiquimod, podophyllotoxin).
Most condylomata acuminata are suitable for treatment with any of these options, which can
be used in the case of the initial infection or in the event of relapse. In view of the fact that no
therapeutic strategy results in a complete cure of the condylomata acuminata, and that the
various treatments offered have identical levels of proof of efficacy, there is no consensus as
to which of the various options available (drug treatments and ablative procedures) should be
preferred in terms of treatment strategy. The choice of treatment, particularly in the case of
imiquimod, therefore depends on the nature of the lesions, the practitioner"s experience and
the patient"s preference.

Improvement in actual benefit
ALDARA 5% cream is still a useful additional therapeutic option the overall management
strategy for condylomata acuminata in adults.


Opinion of the Committee of 16 March 2005
Small basal cell carcinomas in adults:
Actual benefit
Basal cell carcinomas are tumours whose malignancy is essentially local, are slow to
develop, and are very rarely life-threatening.
Among the forms which have been frequently described on the basis of clinical and
histological criteria, small superficial basal cell carcinomas which are not located near
the facial orifices are regarded as having a good prognosis in respect of the risk of
relapse.
The efficacy and tolerance of ALDARA 5% cream have been demonstrated in placebo-
controlled studies on small superficial tumours. No data is currently available to assess
the long-term efficacy of imiquimod. No data is available to describe the mode of
superficial or deep relapse.
There is no alternative drug treatment, as ALDARA 5% cream is the only proprietary
drug indicated for small superficial basal cell carcinoma. The only possible alternative is
a non-drug treatment: surgery is the treatment of choice that should be offered as first-
line treatment. If surgery is contraindicated, other techniques such as cryosurgery,
radiotherapy and electrocoagulation can be suggested.
Public health benefit:
In terms of public health, the burden represented by small superficial basal cell
carcinomas in adults is low as this cancer has a good prognosis (relapse is rare and it
is never fatal) and the target population (patients for whom surgery is contraindicated)
is small (fewer than 7,000 patients).
The only alternatives available for patients for whom surgery is contraindicated are
non-drug treatments. The option to use an effective drug can be an interesting
therapeutic alternative. However, there is no public health need.
Furthermore, in view of:
- the absence of any studies versus alternative therapies,
- the long-term uncertainties as to the risks of relapse and treatment compliance,

1
von Krogh, G. et al., European guideline for the management of anogenital warts. INT J STD AIDS, 2001. 12 Suppl 3:p.40-7.
2
CDC, Sexually transmitted diseases treatment guidelines 2002. Centers for Disease Control and Prevention, in MMWR
Recomm Rep., 2002, Centers for Disease control. P.1-78.
4 - the fact that it may not be possible to transpose the results of studies into practice,
since the populations taking part in the studies were generally different from those
likely to have treatment,
no impact on morbidity is expected.
Consequently, in the light of the data available and the existence of non-drug
alternatives, ALDARA 5% cream is not expected to benefit public health.
In view of the aforementioned criteria, the Committee is of the opinion that the actual benefit
of ALDARA 5% cream is substantial only where surgery is contraindicated.
It considers that the actual benefit of ALDARA 5% cream is inadequate in all other situations.

Improvement in actual benefit
ALDARA 5% cream offers no improvement in actual benefit (level V) compared to the
existing treatment alternatives.

Transparency Committee recommendations
Since the population likely to derive particular benefit from treatment with ALDARA 5%
cream is made up of patients for whom surgery is contraindicated or in whom surgery would
be difficult because of the presence of multiple basal cell carcinomas,
- favourable opinion for inclusion on the list of medicines reimbursed by National Insurance
and on the list of medicines approved for use by hospitals and various public services, in
the indication “small superficial basal cell carcinoma”, only in the circumstances described
in the preceding paragraph,
- provided that the product is prescribed by a dermatologist, a plastic medicine specialist or
cancer specialist, in view of the need to clearly define the characteristics of the tumour to
be treated.

Post-inclusion study:
The Transparency Committee would like a study to be set up to monitor patients treated with
ALDARA 5% cream in order to ensure that this proprietary drug is being used correctly and
to assess its tolerance. For this study following aspects should be described:
- the population treated with ALDARA 5% cream (compliance with the MA indication,
clinical picture, tumour size, single-site or multiple-site, relapse, etc.)
- how ALDARA 5% cream is used (dosages, duration of treatment, concomitant treatments,
role in management strategy, etc.)
- compliance to treatment
- the adverse effects of this treatment.
The study will last 1 year.


Opinion of the Committee of 26 November 2008

Extension of indication to non-hypertrophic, non-hyperkeratotic actinic keratoses on
the face or scalp in adults:

Actual benefit
Actinic keratoses are lesions which develop on areas exposed to the sun, most
frequently among elderly people. Patients often have multiple lesions which, if effective
treatment is not administered, can develop into skin cancers (spinocellular carcinoma).
This proprietary drug is intended to provide curative treatment.

Public health benefit:
The public health burden caused by actinic keratoses is low, even though the
condition is quite common, because the prognosis is often good.
Improving the management of actinic keratosis is not a public health need: both drug
and non-drug treatment alternatives are available.
5 In view of clinical trial data, this proprietary drug is not expected to have any impact
in terms of morbidity for patients with actinic keratosis.
Consequently, in the light of the data available and existing treatments, ALDARA is
not expected to benefit public health in this indication.

The efficacy/adverse effects ratio is high.

Cryotherapy is the standard treatment for cases of superficial, localised actinic keratosis.
This proprietary drug is a second-line treatment for clinically typical forms of non-
hypertrophic, non-hyperkeratotic actinic keratosis of the face or scalp in
immunocompetent adults where the size or number of lesions limits the efficacy and/or
tolerance of cryotherapy and if other topical treatments are contraindicated or less
appropriate.

The actual benefit of ALDARA 5% cream in this indication is substantial.

Improvement in actual benefit
ALDARA 5% cream offers no improvement in actual benefit (IAB V) in the treatment of
superficial actinic keratosis of the face or scalp in adults, but is a useful additional therapeutic
option treatment.


3 SIMILAR MEDICINAL PRODUCTS

3.1. ATC Classification (2009)
D: Dermatologicals
D06: Antibiotics and chemotherapeutics for dermatological use
D06B: Chemotherapeutics for topical use
D06BB: Antivirals
D06BB10: Imiquimod

3.2. Medicines in the same therapeutic category
ALDARA is the only drug in its therapeutic category that is indicated in adults for the local
treatment of external genital and perianal warts, small superficial basal cell carcinomas and
some forms of actinic keratosis.

3.3. Medicines with a similar therapeutic aim
EFUDIX (5-fluorouracil): indicated for genital condylomata and pre-epitheliomatous keratosis.
METVIXIA (dynamic phototherapy): indicated in cases of fine or non-hyperkeratotic and non-
pigmented actinic keratosis of the face and scalp, to treat non-relapsing superficial basal cell
carcinoma of the trunk, limbs and neck, and the treatment of unpigmented intra-epidermal
carcinomas (Bowen"s disease) in immunocompetent patients where surgery is impossible.
CONDYLINE (podophyllotoxin): indicated in cases of genital condylomata.
SOLARAZE (diclofenac): not reimbursed (insufficient AB) indicated in cases of actinic
keratosis.

Other non-drug treatments: cryotherapy (standard treatment for actinic keratosis),
radiotherapy, laser CO , le curettage-electrocoagulation. 2

6
4 UPDATING OF AVAILABLE DATA SINCE THE PREVIOUS OPINION

The pharmaceutical company has submitted new data:
condylomata acuminata:
- an efficacy study into the use of imiquimod as pre-treatment prior to ablation of
lesions (study 1526-IMIQ)
- an efficacy study on HIV-positive patients being treated with powerful antivirals
(study 1456-IMIQ); this study will not be described below as it was a non-
comparative study on 50 patients, only 36 of whom completed the study.
superficial basal cell carcinomas:
- the five-year results of the extension phase of phase III studies (1393-IMIQ and
1408-IMIQ), the aim of which was to assess the long-term maintenance of efficacy;

No new clinical data is available in the indication of non-hypertrophic, non-hyperkeratotic
actinic keratosis of the face or scalp.

4.1. Efficacy
4.1.1. External condylomata acuminata

Efficacy as pre-treatment prior to ablation of lesions (study 1526-IMIQ)
Randomised, double-blind, placebo-controlled study assessing the efficacy of imiquimod
administered as pre-treatment (3 applications per week for 4 weeks) prior to ablation of
condylomata using laser CO or electrocoagulation techniques. 2

The primary efficacy endpoint was the percentage of relapse of condylomata 24 weeks after
ablation. Relapse was defined as the presence of a lesion in the area which was originally
treated or the need for a second intervention two weeks after the first in order to completely
eliminate the lesions.

Results
A total of 128 patients took part: 67 in the imiquimod group and 61 in the placebo group. In
about 80% of cases the condylomata were located exclusively in the genital region, while
they were also or only present in the perianal region in the other cases. The total average
2 2area was 3.61 cm (0.59 – 20) in the imiquimod group and 3.06 cm (0.38 – 13) in the
placebo group, and the number of lesions in each group was 4.97 (1 – 27) and 4.18 (1 – 23).

After the 4 weeks of pre-treatment, 51.6% of the patients being treated with imiquimod had
no more lesions and did not undergo ablative treatment. The corresponding figure for the
placebo group was 17.5%.
About 80% of the patients in each group who underwent ablative treatment had an
electrocoagulation procedure. Two patients (one in each group) needed a second operation.

The relapse rates 24 weeks after ablation (30 patients on imiquimod and 47 patients on the
placebo) were 24.2% in the imiquimod group and 17.5% in the placebo. There was no
statistically significant difference between the groups.

This study did not show imiquimod pre-treatment to be beneficial prior to lesion ablation.




7 4.1.2. Small basal cell carcinomas

Assessment of long-term relapse of small basal cell carcinomas following treatment
with imiquimod (study 1412-IMIQ)
This was a non-comparative extension of phase III studies (1391-IMIQ and 1408-IMIQ)
aimed at assessing long-term relapse rates (5 years after treatment) of tumours classified by
the investigator as “clinically cured” at the end of treatment (6 weeks of treatment at 5
applications a week).

Reminder of the initial studies (1393-IMIQ and 1408-IMIQ)
The inclusion and exclusion criteria for the phase III studies were:
- Inclusion: patients aged over 18 with a single histologically confirmed superficial basal cell
carcinoma located on the lower limbs, trunk, neck or head, suitable for surgery, at least
20.5 cm in area and no more than 2 cm in diameter;
- Exclusion: patients with a superficial basal cell carcinoma located less than 1 cm from the
eyelids, nose, lips or hairline, and patients with relapsing tumours and tumours that had
previously been treated.
The lesions had undergone biopsy prior to treatment to obtain diagnostic confirmation that
they were superficial basal cell carcinomas.
Efficacy had been assessed purely on the basis of clinical appearance 12 weeks after the
cessation of treatment. No biopsy check-up or exeresis had been performed.

Results
A total of 724 patients took part in these studies. 364 of them had five applications per week
following the administration regimen set out in the MA.
Only the results obtained from these 364 patients (ITT population) were taken into
consideration.
Imiquimod caused the clinical and histological disappearance of the lesions (primary efficacy
endpoint) in 70% (66/94) of patients in study 1393-IMIQ and 80% (73/91) of patients in study
1408-IMIQ (see table 1). When lesion assessment was based purely on clinical cure, the
percentage of patients regarded as having been cured was 90% for both studies.

Table 1: Percentage of patients whose lesions completely disappeared (based on histological and
clinical assessment or on histological assessment alone)
Histological and clinical efficacy Histological efficacy
Imiquimod Excipient Imiquimod Excipient
5 times/week 5 times/week
N = 94 N = 89 N = 94 N = 89 (1)
1393-IMIQ
70% 2% 78% 6%
N = 91 N = 90 N = 91 N = 90 (2)
1408-IMIQ
80% 1% 87% 1%
(1) (2)
p < 0.001 (difference between the group receiving the active treatment and the group receiving
the excipient)

Result of study 1412-IMIQ: long-term (5 years) monitoring data
This study was conducted on 162 patients who had taken part in studies 1393-IMIQ and
1408-IMIQ, previously been treated with imiquimod and whose lesions were regarded by the
investigator as clinically cured. Patients were seen after 3 months, 6 months, 1 year and
thereafter once a year in order to measure tumour relapse and local tolerance of imiquimod.
The average age of the patients was 65, and 65% of them were men.
A Kaplan-Meier analysis was performed on the ITT population (n = 162) taking the most
recent value available into account.




8 Assessment 1 and 2 years after the end of treatment:
Of the 162 patients included in the monitoring period, the percentage of patients regarded as
cured on clinical examination and remaining so one year after the end of treatment was
93.7% (95%CI = 89.9% - 97.5%).
The figure after two years was 91.1% (95%CI= 86.6% - 95.5%).

Assessment 5 years after the end of treatment:
Of the 162 patients included, 125 completed the five years of monitoring without relapse and
contact was lost with 19 patients who had not had a relapse by the time of their last
appointment.
After 5 years monitoring, 84.5% of patients were still cured (95%CI= [74.8% - 94.2%]).

4.2. Adverse effects/tolerance
Tolerance results for imiquimod used as pre-treatment prior to ablation of external
condylomata acuminata (study 1526-IMIQ)
Among the 128 patients taking part, treatment-related adverse events were observed in
20.9% of patients being treated with imiquimod and 6.7% of those on placebo.
Most of these adverse events were of mild to moderate intensity. Local skin reactions such
as erythema were more common among patients treated with imiquimod than among those
treated with placebo (45.0% versus 13.3%, p<0.0001). Other skin manifestations were
observed (oedema, induration, erosion, ulceration, desquamation, scabs), but there was no
statistically significant difference between the groups. These effects disappeared when
treatment was suspended.
Ten severe adverse events occurred in 6 patients in the imiquimod group: 2 infections, 2
headaches, 1 dysmenorrhoea, 1 cervical dysplasia, 1 earache, 1 palpebral cyst, 1 attack of
haemorrhoids and 1 erythema.
Only one serious adverse event was reported in the imiquimod group: pregnancy identified
by a urine test five days after the end of treatment, with ultrasound one month later revealing
an embryo 4 mm long with no cardiac activity (it was unclear whether this could be attributed
to the treatment).
No definitive withdrawal of treatment took place. In addition to the treatment-free intervals
specified by the protocol in the event of irritation, two temporary suspensions were
necessary: one because of moderate fever and one because of a moderate burn.


Long-term tolerance results following the cessation of imiquimod in the treatment of
small superficial basal cell carcinomas (study 1412-IMIQ)
111 of the 182 patients taking part in this open-label study (61%) reported at least one
adverse event during the 6-week treatment period, the following 12 weeks, or the five-year
follow-up period.

6-week treatment period
89 patients (49%) reported at least one adverse event during the treatment period, and 2
patients withdrew from the trial as a result of non-serious adverse events (tachycardia and
fever).
34 patients (19%) needed a treatment-free interval during the treatment period, with an
average of 5 applications skipped (ranging from 1 to 15).
Reactions at the application site were the adverse events most frequently reported (59
patients, 32%) during the treatment period. Most of these reports were of pruritis (19%).
None of the other skin manifestations at the application site were reported by more than 5%
of patients. Headaches were the second most common adverse event (5%).
Two patients had what was presumed to be an infection at the application site. However, this
was not confirmed by the samples taken, so may have been confused with a local skin
reaction. The patients responded well to treatment with fusidic acid.

9 12-week post-treatment period
49 patients (27%) had at least one adverse event during the first 12 weeks after treatment.
The most common events were skin disorders (12 patients, 7%), digestive problems (9
patients, 5%) and respiratory disorders (8 patients, 4%). Reactions at the application site that
appeared more than 7 days after the last application of imiquimod were observed in 6
patients (3%).

5-year follow-up period
Only serious adverse events were recorded during the 5-year follow-up period. Thirty-six (36)
patients experienced 74 serious adverse events, including 9 deaths. None of the events were
regarded as treatment-related. No biological adverse events were recorded.

Local skin reactions
Most of the local skin reactions observed were mild to moderate in intensity, and in all but
two cases consisted of erythema. This was the only local reaction which reached moderate
to severe intensity in more than 50% of patients, and the reaction which persisted most after
the treatment period.

Pigmentation disorders
The monitoring activities carried out between the 12th week and the 60th month after
treatment show a trend towards greater hypopigmentation compared to the baseline situation
on inclusion (affecting between 24 and 51 of the 178 patients treated, depending on the
assessment time point). However, a decline in hypopigmentation was observed in 5 to 7 of
the 178 patients, as was a reduction in hyperpigmentation (among 20 to 29 of the 178
patients, depending on the assessment time point) along with other skin surface defects.

Basal cell carcinomas outside the treatment target area
Seventy-seven patients (42%) had at least one basal cell carcinoma suitable for clinical
treatment outside the treated area. However, new basal cell carcinomas are to be expected
in this medical condition which is related to exposure to light.


Pharmacovigilance results
As of the last PSUR (January 2008), total exposure to imiquimod cream amounted to 181
million patient-days.
400 serious adverse event reports have been submitted, of which 306 related to unexpected
adverse events. However, analysis of all these cases did not show any new risks over and
above those referred to in the SPC.
Local reactions at the application site were the most frequently reported expected adverse
events.

Particular monitoring as part of the Risk Management Plan (RMP)
Analysis of monitoring data from the RMP did not show any new risks over and above those
already referred to in the SPC.

4.3. Conclusion
A randomised, double-blind, placebo-controlled study performed on adults assessed the
efficacy of imiquimod administered as pre-treatment (3 applications per week for 4 weeks)
prior to ablation of condylomata using laser CO or electrocoagulation techniques (1526-2
IMIQ). The primary efficacy endpoint of the study was the percentage of relapse of
condylomata 24 weeks after ablation. Relapse was defined as the presence of a lesion in the
area which was originally treated or the need for a second intervention two weeks after the
first in order to completely eliminate the lesions. This study did not show imiquimod to be
beneficial as pre-treatment prior to ablation of condylomata acuminata. The relapse rates
were 24.2% in the imiquimod group and 17.5% in the placebo group, with no statistically
significant difference between the groups.
10

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