Summary Basis of Decision for Picato
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Picato is located below.
Recent Activity for Picato
SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
Post-Authorization Activity Table (PAAT) for Picato
Updated:
The following table describes post-authorization activity for Picato, a product which contains the medicinal ingredient ingenol mebutate. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.
For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.
Drug Identification Numbers (DINs):
- DIN 02400987 - 150 µg/g (0.015%) ingenol mebutate, gel, topical administration
- DIN 02400995 - 500 µg/g (0.05%) ingenol mebutate, gel, topical administration
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| Health Professional Risk Communication | Not applicable | Posted 2020-10-27 | Health Professional Risk Communication posted (Picato [ingenol mebutate gel, 0.015% and 0.05%] - Product withdrawal in Canada due to potential increased risk of skin cancer), containing information on product withdrawal and important safety information for healthcare professionals. |
| Information Update | Not applicable | Posted 2020-10-27 | Information Update posted (LEO Pharma Inc. is withdrawing the drug Picato [ingenol mebutate], used to treat skin lesions, due to the potential increased risk of skin cancer), containing information on product safety for the general public and healthcare professionals. |
| Drug Recall | Not applicable | Posted 2020-10-26 | Drug Recall posted on the Healthy Canadians website for Picato, for the general public, healthcare professionals, and hospitals. |
| DINs 02400987, 02400995 cancelled (post-market) | Not applicable | Discontinuation date: 2020-10-14 | The manufacturer notified Health Canada that sale of the drug has been discontinued post-market. Health Canada cancelled the DINs pursuant to section C.01.014.6(1)(a) of the Food and Drug Regulations. |
| Information Update | Not applicable | Posted 2020-07-02 | Information Update posted (Use of the drug Picato may increase the risk of skin cancer), containing information about product safety for the general public and healthcare professionals. |
| Summary Safety Review | Not applicable | Posted 2020-07-02 | Summary Safety Review posted for Picato (Assessing the potential risk of skin cancer). |
| NC # 233545 | 2019-11-15 | Issued NOL 2020-02-21 | Submission filed as a Level II (90 day) Notifiable Change to update the PM with new safety information. As a result of the NC, modifications were made to the Adverse Reactions section of the PM, and corresponding changes were made to Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued. |
| New safety review | Not applicable | Started between 2019-12-01 | Health Canada started a safety review for Picato related to skin cancer. |
| NC # 218185 | 2018-07-13 | Issued NOL 2018-10-12 | Submission filed as a Level II (90 day) Notifiable Change to update the PM with new safety information. As a result of the NC, modifications were made to the Warnings and Precautions section of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued. |
| NC # 198249 | 2016-09-09 | Issued No Objection Letter 2016-11-28 | Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the Product Monograph (PM) to reflect revisions in the company core data sheet. As a result of the NC, modifications were made to the Warnings and Precautions, and Adverse Reactions sections of the PM, and corresponding changes were made to the PM Part III: Consumer Information. |
| NC # 191625 | 2016-01-25 | Issued No Objection Letter 2016-06-07 | Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the Product Monograph (PM) with new safety information. As a result of the NC, modifications were made to the Warnings and Precautions, Adverse Reactions, and Dosage and Administration sections of the PM, and corresponding changes were made to the PM Part III: Consumer Information. |
| Drug product [Drug Identification Numbers (DINs) 02400987, 02400995] market notification | Not applicable | Date of first sale: 2013-03-21 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 153285 | 2012-02-09 | Issued NOC 2013-01-30 | Notice of Compliance issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Picato
Date SBD issued: 2013-03-11
The following information relates to the new drug submission for Picato.
Ingenol mebutate, 150 µg/g (0.015%) and 500 µg/g (0.05%), gel, topical
Drug Identification Number (DIN):
- DIN 02400987 - 150 µg/g (0.015%) ingenol mebutate, gel, topical
- DIN 02400995 - 500 µg/g (0.05%) ingenol mebutate, gel, topical
LEO Pharma Inc.
New Drug Submission Control Number: 153285
On January 30, 2013, Health Canada issued a Notice of Compliance to LEO Pharma Inc. for the drug product, Picato.
The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology, and toxicology), and clinical (safety and efficacy) information submitted. Based on Health Canada's review, the benefit/risk profile of Picato is favourable for the topical treatment of non-hyperkeratotic, non-hypertrophic actinic keratosis in adults.
1 What was approved?
Picato, a chemotherapeutic for topical use, was authorized for the topical treatment of non-hyperkeratotic, non-hypertrophic actinic keratosis (AK) in adults.
No overall differences in safety or efficacy were observed between patients aged 65 years and over compared with younger patients. The safety and efficacy of Picato in patients <18 years of age have not been established.
Picato is contraindicated for patients who have hypersensitivity to ingenol mebutate or to any of the excipients. Picato was approved for use under the conditions stated in the Picato Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Picato (150 µg/g and 500 µg/g ingenol mebutate) is presented as a gel for topical use. In addition to the medicinal ingredient, the gel contains isopropyl alcohol, hydroxyethyl cellulose, benzyl alcohol, citric acid monohydrate, sodium citrate, and purified water.
For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
Additional information may be found in the Picato Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Picato approved?
Health Canada considers that the benefit/risk profile of Picato is favourable for the topical treatment of non-hyperkeratotic, non-hypertrophic actinic keratosis (AK) in adults.
Actinic keratosis (AK) is a common skin condition visible as thickened, cornified, scaly lesions and characterised histologically by atypical epithelial proliferation. Actinic keratoses usually develop on areas that are frequently exposed to the sun (for example; face, lips, ears, scalp, neck, forearms, and back of the hands). If left untreated, AK may progress to invasive squamous cell carcinoma (SCC).
Picato has been shown to be efficacious in the topical treatment of non-hyperkeratotic, non-hypertrophic AK. Four Phase III pivotal studies supported the market authorization of Picato. All four studies met the primary efficacy endpoint (complete clearance rate, defined as the proportion of patients at Day 57 with no clinically visible AK lesions in the selected treatment area). Patients treated with Picato had statistically significant higher rates of complete clearance and partial clearance than patients treated with vehicle gel (control group). However, while it is important to treat AK as some lesions may progress to SCC, the efficacy of Picato in the prevention of SCC associated with AK has not been adequately studied, and furthermore, the rate of SCC reported in the treatment area was not different between patients treated with Picato and patients treated with vehicle in the short-term clinical studies.
During long-term (12 months) observational follow-up studies, no SCCs were reported. However these studies followed only those patients who successfully responded to treatment in the initial treatment studies; patients who did not respond to Picato gel and who may potentially be at a higher risk of occurrence of SCC were not followed. Therefore, the available data do not allow a conclusion on the efficacy of Picato in the prevention of SCC.
The most frequently reported adverse events occurred at the application site: pruritus; pain; and irritation. Local skin responses included erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, and erosion/ulceration. These events were transient and typically occurred within 1 day of treatment initiation and peaked in intensity up to 1 week following completion of treatment. The noted effects were generally resolved within 2 weeks for areas treated on the face and scalp and within 4 weeks for areas treated on the trunk and extremities. Systemic exposure of the medicinal ingredient, ingenol mebutate, was not detected following topical treatment with Picato.
In patients treated on the face or scalp, severe eye disorders, including periorbital edema, eyelid edema, eye edema, eye pain, and eyelid ptosis, occurred more frequently in Picato-treated patients compared to vehicle-treated patients. These events were not related to accidental eye exposure. All eye disorders resolved without sequelae and labelling adequately warns patients and medical professionals regarding these events.
A Risk Management Plan (RMP) for Picato was submitted by LEO Pharma Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will put in place to minimize risks associated with the product.
Overall, the therapeutic benefits seen in the pivotal studies are positive and the benefits of Picato treatment are considered to outweigh the risks. Picato has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and pharmacovigilance. Appropriate warnings and precautions are described in the Picato Product Monograph and address the identified safety concerns.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of Picato?
Submission Milestones: Picato
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2011-10-27 |
| Submission filed: | 2012-02-09 |
| Screening | |
| Screening Acceptance Letter issued: | 2012-04-05 |
| Review | |
| Quality Evaluation complete: | 2013-01-15 |
| Clinical Evaluation complete: | 2013-01-29 |
| Labelling Review complete: | 2013-01-25 |
| Notice of Compliance issued by Director, Therapeutic Products Directorate: | 2013-01-30 |
The Canadian regulatory decision on the non-clinical and clinical review of Picato was based on a critical assessment of the Canadian data package. The foreign reviews completed by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) were used as an added reference.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
4 What follow-up measures will the company take?
Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Picato Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada and have been market notified (that is, the company has told Health Canada the product is being marketed).
- See the NOC/c-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision
Clinical Pharmacology
Picato (ingenol mebutate) is indicated for the topical treatment of non-hyperkeratotic, non-hypertrophic actinic keratosis (AK) in adults. Actinic keratoses have the potential to progress to squamous cell carcinoma (SCC), a non-melanoma skin cancer.
The mechanism of action of ingenol mebutate in AK has not been fully characterized. However, studies with tumour cell lines, including squamous cell carcinoma, have shown a dual mechanism of action: direct cytotoxicity and promotion of an inflammatory response characterized by the release of inflammatory cytokines and infiltration of immunocompetent cells.
The clinical pharmacology program consisted of two dedicated pharmacokinetic studies. Results showed that the systemic exposure of ingenol mebutate (or its two isomers) was below the lower limit of quantification in all of the blood samples collected. Due to the lack of systemic absorption, there were no dedicated clinical studies investigating the drug's metabolism, distribution, excretion, or drug-drug interactions. The sponsor also did not conduct a thorough QT/QTc study due to the lack of quantifiable levels of ingenol mebutate in the pharmacokinetic studies. Instead, electrocardiographic data were obtained from four clinical studies, and a non-clinical human ether-à-go-go-related gene (hERG) study was performed. Ingenol mebutate exhibited neither non-clinical nor clinical effects consistent with QTc prolongation.
The clinical pharmacological data support the use of Picato for the indication stated above.
For further details, please refer to the Picato Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The efficacy and safety of Picato (ingenol mebutate) 150 µg/g (0.015%) administered on the face or scalp for 3 consecutive days, and 500 µg/g (0.05%) administered on the trunk or extremities for 2 consecutive days was studied in four Phase III multicentre, double-blind, randomized, parallel group, vehicle-controlled studies. The two Phase III studies evaluating the efficacy on the face and scalp included 547 patients, while the other two Phase III studies evaluating the efficacy on the trunk or extremities included 458 patients (98% completed the studies). For both treatment locations (head and non-head), eligible patients had 4 to 8 clinically typical, visible, discrete, non-hyperkeratotic, non-hypertrophic actinic keratosis (AK) lesions within a contiguous 25 cm2 treatment area. On each scheduled dosing day, the study gel was applied to the entire treatment area (25 cm2). Patients continued in the studies for an 8-week follow-up period during which they returned for clinical observations and safety monitoring.
The proposed indication for Picato by the sponsor was the topical field treatment of AK on the face and scalp, and on the trunk and extremities in adults. However, the design of the Phase III pivotal studies did not support this indication in its current form. Since AKs were clinically assessed, not histologically assessed, and field-directed treatment was not compared to lesion-directed treatment, the 'field-treatment' effect of treating subclinical lesions could not be sufficiently demonstrated. Also, exclusion criteria prohibited lesions that had an atypical clinical appearance (for example, hypertrophic, hyperkeratotic). Therefore, Health Canada recommended that the indication not reference field treatment and be restricted to patients with clinically typical (non-hypertrophic, non-hyperkeratotic) lesions. As a result, the following indication was approved: the topical treatment of non-hypertrophic, non-hyperkeratotic actinic keratosis in adults.
The primary efficacy endpoint was complete clearance rate, defined as the proportion of patients at Day 57 with no clinically visible AK lesions in the selected treatment area. The secondary endpoint was partial clearance rate, defined as the proportion of patients at Day 57 with a 75% or greater reduction in the number of clinically visible AK lesions identified at baseline in the selected treatment area. The median percent reduction from baseline in the total number of AK lesions at Day 57 was also determined.
The study designs for the Phase III studies were appropriate. The selection of a vehicle control rather than an active control in the Phase III studies is acceptable. The duration and frequency of study visits, safety assessments, and efficacy assessments were supported by data from Phase II studies.
Two Phase III studies (PEP005-16 and PEP005-25) evaluated the efficacy of Picato for AK lesions on the face and scalp. On Day 57, compared to patients treated with vehicle gel, the patients who were treated with Picato had higher rates of complete clearance [37% and 47% versus (vs.) 2% and 5%] and partial clearance (60% and 68% vs. 7% and 8%). When both studies were combined, the Picato-treated patients had higher clearance rates for the face compared to the scalp (complete clearance rate 47% vs. 23%; partial clearance rate 71% vs. 35%). In both studies combined, the median percent reduction in AK lesions was higher in the groups treated with Picato compared to the vehicle groups (83% vs. 0%).
Phase III studies PEP005-14 and PEP005-28 evaluated the efficacy of Picato for AK lesions on the trunk and extremities. On Day 57, compared to patients treated with vehicle gel, patients treated with Picato had higher complete clearance rates (28% and 42% vs. 5% and 5%) and partial clearance rates (44% and 55% vs. 7% and 7%). When both studies were combined, the Picato-treated patients had the highest complete and partial clearance rates for the lesions on the chest (79% and 86%), and the lowest rates were for the back of the hand (19% and 30%). In both studies combined, the median percent reduction in AK lesions was higher in the groups treated with Picato compared to the vehicle groups (75% vs. 0%).
Although all four Phase III pivotal studies showed that the efficacy varied between anatomical locations, it is common clinical experience that AKs on the scalp and on the back of the hand are often recalcitrant to treatment. Furthermore, within each anatomical location group, the complete and partial clearance rates were higher in patients treated with Picato gel than patients treated with vehicle gel.
Three follow-up studies provided data on the recurrence of AK lesions following Picato treatment. The estimated recurrence rates were high with more than 50% of patients who achieved complete clearance having recurrences within one year. However, the recurrence rate was similar to those reported for other currently approved AK topical therapies.
While it is important to treat AK as some lesions may progress to squamous cell carcinoma (SCC), the efficacy of Picato in the prevention of SCC associated with AK has not been studied. The rate of SCC reported in the treatment area was not different between patients treated with Picato (0.3%) and patients treated with vehicle gel (0.3%) in the short-term AK clinical studies.
Overall, the efficacy results are statistically significant, clinically relevant, and acceptable for approval for the topical treatment of non-hyperkeratotic, and non-hypertrophic AK in adults.
For more information, refer to the Picato Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
Across the 13 studies that evaluated Picato for the topical treatment of AK, 1,165 patients received Picato and 632 patients received vehicle treatment. In the controlled Phase III studies (described in Clinical Efficacy), 499 patients were treated with Picato and 503 were treated with vehicle gel.
Overall, demographics, baseline characteristics, and medical histories were similar between patients treated with Picato and the vehicle gel. The demographics were representative of those observed for the general population of patients diagnosed with AK. Results from clinical studies showed that the systemic exposure of topical Picato (ingenol mebutate, or its two isomers) was below the lower limit of quantification in all of the blood samples collected.
The System Organ Class (SOC) of General Disorders and Administration Site Disorders had the highest incidence of adverse events (AEs) for patients treated with Picato (22.7% vs. 2.8% for patients treated with vehicle gel). The most frequently reported AEs occurred at the application site: pruritus; pain; and irritation.
Some differences were noted with respect to the incidence of treatment-related AEs between the two treatment locations (head and non-head). In the controlled Phase III studies, patients treated with Picato on the face or scalp had a higher incidence of application site pain than patients treated on the trunk or extremities (13.9% vs. 1.8%, respectively). Similarly, patients treated on the face or scalp had eye-associated disorders, such as eyelid edema (1.1%) and periorbital edema (2.6%), whereas patients who received Picato on the trunk or extremities had no report of these events. Appropriate warnings and precautions are in place in the approved Picato Product Monograph to address the identified safety concerns.
Local Skin Responses (LSRs) within the treatment area were assessed independently of AEs in an effort to provide a better profile of the specific types of visible local skin reactions. The LSRs included erythema, flaking/scaling, crusting, swelling, vesiculation/postulation and erosion/ulceration, and were graded by the investigator on a scale of 0 to 4. Most Picato-treated patients showed an increase in LSR scores relative to baseline (95%), whereas most patients treated with vehicle gel showed no change from baseline LSR score (64%). Localised skin responses were transient and typically occurred within 1 day of treatment initiation and peaked in intensity up to 1 week following completion of treatment. Localised skin responses typically resolved within 2 weeks of treatment initiation when areas on the face and scalp were treated and within 4 weeks of treatment initiation when the trunk and extremities were treated. For both treatment locations (head and non-head), erythema and flaking/scaling were the most common LSRs, followed by crusting and swelling. Grade 4 responses were observed more frequently for erythema than the other LSRs, independent of treatment location.
The majority of patients had an AE with a maximum severity of mild or moderate intensity; 3.2% of Picato-treated patients and 1.6% of vehicle-treated patients had a severe AE. The emergence of an AE resulting in discontinuation of treatment was 3.2% and 0% of Picato-treated patients and vehicle-treated patients, respectively, and discontinuation from the study was 0.3% and 0.5%, respectively. There was one reported death in a patient who had been treated with Picato; the death was attributed to coronary artery atherosclerosis and hypertension, considered unrelated to study medication.
Serious adverse events (SAEs) were reported for 4.2% of Picato-treated patients and 3.6% of vehicle-treated patients; 3 SAEs (all occurring in Picato-treated patients and all SCC-type lesions) were considered related to study medication.
Neoplasms (arising at any location, that is, outside or inside the treatment area) were reported for a similar proportion of patients treated with Picato and vehicle gel (3.0% vs 2.7%). The majority of neoplasms were graded as mild or moderate. Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) were the more frequently reported types of neoplasms and occurred with similar frequency between groups (BCC: 1.5% vs. 1.1% for Picato vs. vehicle; SCC: 0.9% vs. 0.8% for Picato vs. vehicle). Among these patients, SCC was determined to be inside or possibly inside the treatment area for 3 (0.3%) Picato-treated patients and for 2 (0.3%) vehicle-treated patients. Despite certain non-clinical findings, carcinogenic and mutagenic risks to humans receiving treatment with Picato are considered unlikely due to the short duration of treatment (2-3 days) and the lack of systemic exposure of ingenol mebutate following topical treatment.
Long-term safety was assessed in three observational, long-term, 1-year follow-up studies. Only patients who achieved complete clearance in the Phase III studies were followed. No patients received treatment during follow-up. Over the 12 months of follow-up, 3 of 198 patients experienced AEs in the treatment area, which were mild sunburn, moderate hematoma, and a mild rash. All events occurred 8-9 months after the start of follow-up (10-11 months after initial treatment). All events resolved within two weeks of onset and were considered not related to the study drug.
For more information, refer to the Picato Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
Picato (ingenol mebutate) was shown to inhibit tumour growth in in vivo and in vitro models using tumour cell lines, including squamous cell carcinoma lines. A direct cytotoxic effect on tumour cells was observed with high doses of ingenol mebutate (100 µg/mL). At lower concentrations (10 to 100 ng/mL), ingenol mebutate activates both novel and classical protein kinase C (PKC) and is associated with immunostimulatory effects. Some classes of PKC activators, such as phorbol esters, are known to be tumour promoters. Ingenol mebutate is structurally related to phorbol esters. The clinical significance of potential proliferative effects via activation of PKC by ingenol mebutate is unknown. However, ingenol mebutate was positive in the Syrian hamster embryo (SHE) cell transformation test, which detects both genotoxic and epigenetic carcinogens. In addition, a 6-month repeat-dose intravenous study in rats found isolated reports of tubular hyperplasia of the kidney, renal and pituitary adenoma, and thyroid follicular cell carcinoma. Conversely, ingenol mebutate was not genotoxic or clastogenic in a bacterial mutation (Ames) assay, mouse lymphoma cell assay, or rat in vivo micronucleus assay and no evidence of neoplasia was noted in 6 and 9-month dermal repeat-dose studies in rats and minipigs (cyclic administration). The risk of tumour induction in humans receiving treatment with Picato is considered very unlikely due to the short duration of treatment (2-3 days).
Absorption of ingenol mebutate following dermal administration was very low. After in vitro applications of 0.01%, 0.1%, or 0.05% Picato to rat, mini-pig, and human skin preparations, the percutaneous absorption of ingenol mebutate expressed as percentage of dose applied was generally low in all studies, with a range of 0.04% (mini-pig) to 8.68% (rat) across animal species and 0.16% to 1.93% in human skin preparations. Single and repeat dermal dose toxicity studies revealed dermal responses that included erythema, oedema, and scab formation which were seen histopathologically as ulcerative dermatitis and acanthosis. The incidence and severity of the findings were dose-related.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Picato Product Monograph. In view of the intended use of Picato, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product for the specified indication.
For more information, refer to the Picato Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
The Chemistry and Manufacturing information submitted for Picato has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf-life for the drug substance and drug product is supported and considered to be satisfactory.
All sites involved in the production are compliant with Good Manufacturing Practices.
The proposed limits of drug-related impurities are considered adequately qualified from toxicological studies.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The excipients used in the product formulation are not from animal or human origin.