Summary Basis of Decision for Keytruda

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:

Drug

Contact: Office of Regulatory Affairs, Biologic and Radiopharmaceutical Drugs Directorate

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Keytruda is located below.

Recent Activity for Keytruda

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) 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. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.

Post-Authorization Activity Table (PAAT) for Keytruda

Updated: 2024-12-20

The following table describes post-authorization activity for Keytruda, a product which contains the medicinal ingredient pembrolizumab. 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 found in Post-Authorization Activity Tables (PAATs).

For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.

Drug Identification Number (DIN):

DIN 02441152 – 50 mg/vial pembrolizumab, powder for solution, intravenous administration

DIN 02456869 – 25 mg/mL pembrolizumab, solution, intravenous administration

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number	Date Submitted	Decision and Date	Summary of Activities
NC # 289313	2024-08-02	Issued NOL 2024-12-05	Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change to the drug substance fermentation process, a change in cell bank/seed bank qualification protocol, and a change in the controls (in-process tests and/ or acceptance criteria) applied during the drug substance manufacturing process or on intermediates. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 289527	2024-08-13	Issued NOL 2024-12-02	Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes in the labelled storage conditions for the drug product or the diluted or reconstituted product. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 291062	2024-10-04	Issued NOL 2024-10-29	Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in cell bank/seed bank testing site. The submission was considered acceptable, and an NOL was issued.
SNDS # 279533	2023-09-28	Issued NOC 2024-09-09	Submission filed as a Level I – Supplement to update the PM based on overall survival data from Study KEYNOTE-581. Additionally, to fulfill comment 1a of the Post-Decision Letter issued on May 5, 2022 under SNDS # 253060, final safety and efficacy results from Study KEYNOTE-555 were provided. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Clinical Trials section of the PM. An NOC was issued.
SNDS # 278399	2023-08-21	Issued NOC 2024-08-29	Submission filed as a Level I – Supplement for a new indication. The indication authorized was: Keytruda for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumours, as determined by a validated test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
SNDS # 282981	2024-01-19	Issued NOC 2024-08-20	Submission filed as a Level I – Supplement for a new indication. The submission was reviewed under the Priority Review of Drug Submissions Policy. The indication authorized was: Keytruda, in combination with enfortumab vedotin, is indicated for the treatment of adult patients with unresectable locally advanced or metastatic urothelial cancer (mUC) with no prior systemic therapy for mUC. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
SNDS-C # 279168	2023-09-15	Issued NOC 2024-08-16	Submission filed as a Level I – Supplement in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). The submission provided the results from studies KEYNOTE-052 and KEYNOTE-361, as outlined in the LOU dated March 8, 2019, and requested the removal of the conditions associated with the following indication: Keytruda is indicated for the treatment of adult patients with locally advanced unresectable or metastatic urothelial carcinoma, as monotherapy, who are not eligible for any platinum-containing chemotherapy. As a result of the submission, the conditions were removed from the NOC that had been issued on 2019-04-11 under SNDS # 209011.
SNDS # 278305	2023-08-16	Issued NOC 2024-08-07	Submission filed as a Level I – Supplement to update the PM with clinical efficacy data from Study KEYNOTE-826 and with updated dosing recommendations for patients with moderate hepatic impairment. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions; Dosage and Administration; Clinical Pharmacology; and Clinical Trials sections of the PM. An NOC was issued.
SNDS # 283423	2024-02-02	Issued NOC 2024-06-20	Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions section of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
PSUR-C # 280766	2023-11-03	Filed 2024-06-10	Submission filed in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). PSUR-C for the period 2022-09-04 to 2023-09-03. The information was reviewed and found acceptable.
SNDS # 276501	2023-06-23	Issued NOC 2024-05-29	Submission filed as a Level I – Supplement to expand the indication. The indication authorized was: Adjuvant treatment of adult and pediatric (12 years and older) patients with stage IIB, IIC or III melanoma following complete resection. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
SNDS # 281466	2023-11-23	Issued NOC 2024-05-14	Submission filed as a Level I – Supplement for a change in the drug substance manufacturing process. The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS # 275053	2023-05-05	Issued NOC 2024-04-12	Submission filed as a Level I – Supplement for a new indication. The indication authorized was: Keytruda, in combination with gemcitabine-based chemotherapy, is indicated for the treatment of adult patients with locally advanced unresectable or metastatic biliary tract carcinoma (BTC). The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
SNDS # 273487	2023-03-20	Issued NOC 2024-03-21	Submission filed as a Level I – Supplement for a new indication. The indication authorized was: Keytruda, in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adult patients with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or GEJ adenocarcinoma. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
SNDS # 280066	2023-10-17	Issued NOC 2024-03-14	Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions section of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
SNDS # 272409	2023-02-14	Issued NOC 2024-02-06	Submission filed as a Level I – Supplement for a new indication. The indication authorized was: Keytruda, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adult patients with locally advanced unresectable or metastatic HER2 positive gastric or gastroesophageal junction (GEJ) adenocarcinoma, whose tumors express PD-L1 (Combined Positive Score [CPS] ≥1) as determined by a validated test. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
SNDS # 276627	2023-08-15	Issued NOC 2023-12-12	Submission filed as a Level I – Supplement to update the PM with new safety information. The changes were in response to an Advisement Letter issued by Health Canada, dated June 27, 2023, requesting an update the safety labeling by including the risk of aplastic anemia as an adverse drug reaction. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions section of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.
SNDS # 275259	2023-05-12	Issued NOC 2023-12-15	Submission filed as a Level I – Supplement for a new drug substance manufacturing site. The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS-C # 272398	2023-02-14	Issued NOC 2023-11-30	Submission filed as a Level I – Supplement in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). The SNDS-C is in response to commitments 2 (a & b) (and by extension 2c) of the LOU, dated April 10, 2019, issued under SNDS # 218779, and to support the removal of the conditions for Keytruda as monotherapy for the treatment of patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer progressed after first line treatment or endometrial cancer progressed after prior therapy with no satisfactory alternative treatment options. The data were reviewed and considered acceptable. As a result of the submission, the conditions were removed from the NOC that had been issued April 18, 2019.
SNDS-C # 269318	2022-11-01	Issued NOC under NOC/c Guidance 2023-10-19	Submission filed as a Level I – Supplement in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). The purpose of the SNDS-C was to fulfill commitment 2c of the LOU dated August 16, 2018, under SNDS # 212388. The sponsor provided the completed clinical report for Study KEYNOTE-051. Based on the evaluation of the data submitted, this SNDS-C fulfills Condition 2c for the treatment of adult and pediatric patients with refractory Primary Mediastinal B-cell Lymphoma (PMBCL), or who have relapsed after 2 or more lines of therapy. No new safety signals were identified and an NOC was issued under the Guidance Document: Notice of Compliance with Conditions (NOC/c).
Summary Safety Review	Not applicable	Posted 2023-08-17	Summary Safety Review posted for Keytruda (pembrolizumab) and Tecentriq (atezolizumab) (Assessing the Potential Risk of Aplastic Anemia).
SNDS # 273875	2023-03-30	Issued NOC 2023-08-17	Submission filed as a Level I – Supplement to update the outer labels. The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS-C # 267365	2022-08-26	Issued NOC 2023-07-20	Submission filed as a Level I – Supplement in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). The purpose of the SNDS-C was to fulfill commitment 2a in the Letter of Undertaking, dated September 17, 2019, under SNDS # 228721, and to support the removal of the conditions from the NOC. The sponsor provided the results from the first efficacy interim analysis of Study 309/KEYNOTE-775. The data were reviewed and considered acceptable. As a result of the submission, the conditions were removed from the NOC that had been issued September 20, 2019.
SNDS # 264318	2022-05-16	Issued NOC 2023-04-19	Submission filed as a Level I – Supplement for a new indication. The indication authorized was: Keytruda as monotherapy is indicated for the adjuvant treatment of adult patients with Stage IB (T2a ≥ 4 cm), II, or IIIA NSCLC who have undergone complete resection and platinum-based chemotherapy. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
SNDS # 269692	2022-11-14	Issued NOC 2023-04-06	Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Adverse Reactions section of the PM. An NOC was issued.
SNDS # 263005	2022-04-06	Issued NOC 2023-03-21	Submission filed as a Level I – Supplement to update the PM based on the final analysis of Study KEYNOTE-177. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to Clinical Trials section of the PM. An NOC was issued.
SNDS-C # 261947	2022-03-01	Issued NOC 2023-01-25	Submission filed as a Level I – Supplement in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). The submission provided clinical data from Study KEYNOTE-355 to fulfill Commitment 2a (i & ii) of the Letter of Undertaking (LOU) dated October 14, 2021 under SNDS-C # 246373, and to support the removal of the conditions from the NOC for this indication. Based on the data submitted, the sponsor has fulfilled commitments 2a (i & ii) of the LOU to confirm the clinical benefit of Keytruda for the following indication: Keytruda, in combination with chemotherapy, is indicated for the treatment of adult patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC), who have not received prior chemotherapy for metastatic disease and whose tumors express PD-L1 (Combined Positive Score [CPS] ≥ 10) as determined by a validated test. As a result of the submission, the conditions for that indication were removed from the NOC that had been issued November 19, 2021.
PSUR-C # 269822	2022-11-16	Filed 2023-01-19	Submission filed in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). PSUR-C for the period 2021-09-04 to 2022-09-03. The information was reviewed and found acceptable.
SNDS-C # 248082	2021-01-05	Issued NOC under NOC/c Guidance 2022-12-29	Submission filed as a Level I – Supplement in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). The submission provided data from Study KEYNOTE-361 to fulfil commitment 2a outlined in the Letter of Undertaking dated March 8, 2019, issued under SNDS # 209011, and a revision of an indication. The indication authorized was: Adult patients with locally advanced unresectable or metastatic urothelial carcinoma, as monotherapy, who are not eligible for any platinum-containing chemotherapy. The submission was reviewed and considered acceptable, and an NOC was issued under the Guidance Document: Notice of Compliance with Conditions (NOC/c) .
SNDS # 259731	2021-12-17	Issued NOC 2022-11-09	Submission filed as a Level I – Supplement to update the PM with the addition of follow-up data from Study KEYNOTE-426 for the first-line treatment of metastatic Renal Cell Carcinoma. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Clinical Trials section of the PM. An NOC was issued.
New safety and effectiveness review	Not applicable	Started between 2022-09-01 to 2022-09-30	Health Canada started a new safety and effectiveness review for Keytruda related to aplastic anemia (disease when the body stops producing enough new blood cells).
SNDS # 263895	2022-05-02	Issued NOC 2022-09-14	Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions, and Adverse Reactions sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
SNDS # 256537	2021-09-09	Issued NOC 2022-08-18	Submission filed as a Level I – Supplement for a new indication. The indication authorized was: the adjuvant treatment of patients with renal cell carcinoma (RCC) at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS # 258432	2021-11-05	Issued NOC 2022-07-20	Submission filed as a Level I – Supplement to update the PM with data from Study KEYNOTE-054. The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS # 259703	2021-12-17	Issued NOC 2022-07-05	Submission filed as a Level I – Supplement for a new indication. The submission was reviewed under the Priority Review of Drug Submissions Policy. The indication authorized was: the adjuvant treatment of adult and pediatric (12 years and older) patients with Stage IIB or IIC melanoma following complete resection. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
SNDS # 253060	2021-05-25	Issued NOC 2022-05-04	Submission filed as a Level I – Supplement for a new indication. The indication authorized was: in combination with lenvatinib, the treatment of adult patients with advanced (not amenable to curative surgery or radiation) or metastatic renal cell carcinoma (RCC) with no prior systemic therapy for metastatic RCC. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
SNDS # 256659	2021-09-15	Issued NOC 2022-04-12	Submission filed as a Level I – Supplement for a new indication. The submission was reviewed under the Priority Review of Drug Submissions Policy. The indication authorized was: the treatment of adult patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as monotherapy as adjuvant treatment after surgery. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
SNDS # 257236	2021-10-04	Issued NOC 2022-04-07	Submission filed as a Level I – Supplement for a new indication. The submission was reviewed under the Priority Review of Drug Submissions Policy. The indication authorized was: the treatment of adult patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (Combined Positive Score ≥1) as determined by a validated test, in combination with chemotherapy with or without bevacizumab. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
SNDS-C # 251499	2021-04-07	Issued NOC under NOC/c Guidance 2022-03-09	Submission filed as a Level I – Supplement in response to commitments made as per the provisions of the NOC/c Guidance for SNDS # 212388. The submission provided data from Study KEYNOTE-204. The data were reviewed and considered acceptable, and an NOC was issued under the NOC/c Guidance.
SNDS # 252263	2021-05-03	Cancellation Letter Received 2022-02-24	Submission filed as a Level I – Supplement for a new indication: the treatment of patients with advanced endometrial carcinoma who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation, when used in combination with lenvatinib. A Summary of Cancellation was published.
PSUR-C # 258274	2021-11-02	Filed 2021-12-20	Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PSUR-C for the period 2020-09-04 to 2021-09-03. The information was reviewed and found acceptable.
SNDS-C # 247393	2020-12-10	Issued NOC under NOC/c Guidance 2021-11-24	Submission filed as a Level I – Supplement in response to commitments made as per the provisions of the NOC/c Guidance for SNDS # 212388. The submission provided final data from Study KEYNOTE-170. The data were reviewed and considered acceptable, and an NOC was issued under the NOC/c Guidance.
SNDS # 246373	2020-11-16	Issued NOC under NOC/c Guidance 2021-11-19	Submission filed as a Level I – Supplement for a new indication. The indication authorized was: for the treatment of patients with locally advanced unresectable or metastatic triple-negative breast cancer (TNBC) who have not received prior chemotherapy for metastatic disease and whose tumors express programmed death-ligand 1 (PD-L1) (Combined Positive Score [CPS] ≥10) as determined by a validated test. The submission was reviewed and considered acceptable, and an NOC was issued was issued under the NOC/c Guidance.
SNDS # 253346	2021-06-02	Issued NOC 2021-11-17	Submission filed as a Level I – Supplement to remove information related to discontinued DIN 02441152 from the PM. The submission was reviewed and considered acceptable, and an NOC was issued.
PSUR-C # 245980	2020-10-30	Filed 2021-10-29	Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PSUR-C for the period 2019-09-04 to 2020-09-03. The information was reviewed and found acceptable.
NC # 253486	2021-06-04	Issued NOL 2021-08-13	Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for an alternate site for quality control testing of the drug substance and drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 249619	2021-02-19	Issued NOC 2021-07-15	Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions section of the PM. An NOC was issued.
SNDS # 246922	2020-11-30	Issued NOC 2021-06-04	Submission filed as a Level I – Supplement for a new indication. The submission was reviewed under the Priority Review of Drug Submissions Policy. The indication authorized was: in combination with platinum and fluoropyrimidine based chemotherapy, the first-line treatment of adult patients with locally advanced unresectable or metastatic carcinoma of the esophagus or human epidermal growth factor receptor 2 (HER2)-negative adenocarcinoma of the esophagogastric junction (tumour centre 1 to 5 centimetres above the gastric cardia). The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
SNDS # 240386	2020-06-09	Issued NOC 2021-04-29	Submission filed as a Level I – Supplement for an alternate dosing regimen of 400 mg every 6 weeks for all approved indications in adults. The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS # 242370	2020-07-31	Issued NOC 2021-04-20	Submission filed as a Level I – Supplement to update the PM with data from studies KEYNOTE-189 and KEYNOTE-407. The submission was reviewed and considered acceptable, and an NOC was issued.
NC # 247668	2020-12-16	Issued NOL 2021-03-16	Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in supplier for a primary container closure component. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 240864	2020-06-19	Issued NOC 2021-03-03	Submission filed as a Level I – Supplement for a new indication. The indication authorized was: as monotherapy, the first-line treatment of adult patients with metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer (CRC). The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS # 239505	2020-05-15	Issued NOC under NOC/c Guidance 2021-02-05	Submission filed as a Level I – Supplement for a new indication. The indication authorized was: as monotherapy, the treatment of adult and pediatric patients with refractory or relapsed classical Hodgkin Lymphoma (cHL) who have failed autologous stem cell transplant (ASCT), or who are not candidates for multi-agent salvage chemotherapy and ASCT. The submission was reviewed and considered acceptable, and an NOC was issued under the NOC/c Guidance. A Regulatory Decision Summary was published.
SNDS # 236910	2020-03-05	Issued NOC under NOC/c Guidance 2020-12-14	Submission filed as a Level I – Supplement for a new indication. The indication authorized was: treatment of adult patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in-situ (CIS) with or without papillary tumours who are ineligible for or have elected not to undergo cystectomy. The submission was reviewed and considered acceptable, and an NOC was issued under the NOC/c Guidance. A Regulatory Decision Summary was published.
SNDS # 232775	2019-11-14	Issued NOC 2020-10-09	Submission filed as a Level I – Supplement to for a new indication. The indication authorized was: first-line treatment of metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC), as monotherapy in adults whose tumors have programmed death-ligand 1 (PD-L1) expression (Combined Positive Score [CPS] ≥1) as determined by a validated test first-line treatment of metastatic or unresectable recurrent HNSCC, in combination with platinum and fluorouracil chemotherapy in adults. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
NC # 239815	2020-05-22	Issued NOL 2020-06-26	Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for an alternate site for quality control testing of the drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 235931	2020-02-07	Issued NOL 2020-05-12	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. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 237478	2020-03-25	Issued NOL 2020-05-06	Submission filed as a Level II (120 day) Notifiable Change to migrate the PM to the 2016 format. The submission was reviewed and considered acceptable, and an NOL was issued.
PSUR-C # 233325	2019-11-07	Cleared 2020-05-01	Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PSUR-C for the period 2018-09-04 to 2019-09-03. The information was reviewed and found acceptable.
SNDS # 219213	2018-08-15	Issued NOC 2020-03-16	Submission filed as a Level I – Supplement for a new indication. The indication authorized was: as monotherapy, for the first-line treatment of adults with metastatic non-small cell lung carcinoma (NSCLC) or stage III disease where patients are not candidates for surgical resection or definitive chemoradiation, expressing programmed death-ligand 1 (PD-L1) (Tumour Proportion Score [TPS] ≥1%) as determined by a validated test, with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumour aberrations. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
NC # 233788	2019-11-21	Issued NOL 2020-02-27	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. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 223819	2019-01-18	Issued NOC 2019-12-13	Submission filed as a Level I – Supplement for a new indication. The indication authorized was: treatment of patients with advanced or metastatic renal cell carcinoma (RCC) in combination with axitinib, in adults with no prior systemic therapy for metastatic RCC. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
DIN 02441152 cancelled (post-market)	Not applicable	Discontinuation date: 2019-12-04	The manufacturer notified Health Canada that sale of the drug has been discontinued post market. Health Canada cancelled the DIN pursuant to section C.01.014.6(1)(a) of the Food and Drug Regulations.
SNDS # 232724	2019-10-18	Issued NOC 2019-12-27	Submission filed as a Level I – Supplement to update the format and presentation of the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOC was issued.
NC # 231436	2019-09-06	Issued NOL 2019-12-06	Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the storage conditions for the drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 230027	2019-07-24	Issued NOL 2019-11-04	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, Adverse Reactions, and Drug Interactions sections of the PM. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 228721	2019-06-17	Issued NOC under NOC/c Guidance 2019-09-20	Submission filed as a Level I – Supplement for a new indication. The indication authorized was: in combination with lenvatinib, treatment of adult patients with advanced endometrial carcinoma (EC) that is not microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR), who have disease progression following prior platinum-based systemic therapy, and are not candidates for curative surgery or radiation. The submission was reviewed and considered acceptable, and an NOC was issued under the NOC/c Guidance. A Regulatory Decision Summary was published.
SNDS-C # 220544	2018-09-28	Issued NOC 2019-09-10	Submission filed as a Level I – Supplement in response to commitments made as per the provisions of the NOC/c Guidance for SNDS # 186275. The submission provided a summary of exploratory biomarker data from Study KEYNOTE-001. The data were reviewed and considered acceptable. As a result of the submission, the conditions were removed from the NOC that had been issued 2016-04-15. An NOC was issued.
NC # 227868	2019-05-17	Issued NOL 2019-07-22	Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the drug product manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 219700	2018-08-30	Issued NOC 2019-07-04	Submission filed as a Level I – Supplement for a new indication. The indication authorized was: treatment of patients with metastatic squamous non-small cell lung carcinoma (NSCLC) in combination with carboplatin and either paclitaxel or nab-paclitaxel, in adults with no prior systemic chemotherapy treatment for metastatic NSCLC. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
SNDS # 218226	2018-07-13	Issued NOC 2019-06-11	Submission filed as a Level I – Supplement to update the PM with final data from Study KEYNOTE-045. The submission was reviewed and considered acceptable, and an NOC was issued.
PSUR-C # 221756	2018-11-07	Cleared 2019-05-01	Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PSUR-C for the period 2018-03-04 to 2018-09-03. The information was reviewed and found acceptable.
NC # 223963	2019-01-23	Issued NOL 2019-04-26	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, and Adverse Reactions sections of the PM. The submission was reviewed and considered acceptable, and an NOL was issued.
Drug Recall	Not applicable	Posted 2019-04-23	Drug Recall posted on the Healthy Canadians website for the general public, healthcare professionals, and hospitals.
SNDS # 218779	2018-07-31	Issued NOC under NOC/c Guidance 2019-04-18	Submission filed as a Level I – Supplement for a new indication. The indication authorized was: treatment of adults with unresectable or metastatic microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR): colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, or endometrial cancer that has progressed following prior therapy and who have no satisfactory alternative treatment options. The submission was reviewed and considered acceptable, and an NOC was issued under the NOC/c Guidance. A Regulatory Decision Summary was published.
SNDS # 209011	2017-09-01	Issued NOC under NOC/c Guidance 2019-04-11	Submission filed as a Level I – Supplement for a new indication. The indication authorized was: treatment of patients with locally advanced unresectable or metastatic urothelial carcinoma, as monotherapy, in adults who are not eligible for cisplatin-containing chemotherapy and whose tumors express programmed death-ligand 1 (PD-L1) (Combined Positive Score [CPS] ≥10) as determined by a validated test, or in adults who are not eligible for any platinum containing chemotherapy regardless of PD-L1 status. The submission was reviewed and considered acceptable, and an NOC was issued under the NOC/c Guidance. A Regulatory Decision Summary was published.
SNDS # 216451	2018-05-18	Issued NOC 2019-04-02	Submission filed as a Level I – Supplement for a new indication. The indication authorized was: adjuvant treatment of patients with stage III melanoma with lymph node involvement who have undergone complete resection. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
SNDS # 215699	2018-04-23	Issued NOC 2019-03-13	Submission filed as a Level I – Supplement for a new indication. The indication authorized was: in combination with pemetrexed and platinum chemotherapy, treatment of metastatic non-squamous non-small cell lung carcinoma (NSCLC) in adults with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumour aberrations, and no prior systemic chemotherapy treatment for metastatic NSCLC. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
SNDS # 215119	2018-04-03	Issued NOC 2019-01-15	Submission filed as a Level I – Supplement to update the PM with data from Study KEYNOTE-024. The submission was reviewed and considered acceptable, and an NOC was issued.
PSUR-C # 216115	2018-05-09	Cleared 2018-11-21	Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PSUR-C for the period 2017-09-04 to 2018-03-03. The information was reviewed and found acceptable.
NC # 216802	2018-05-31	Issued NOL 2018-10-01	Submission filed as a Level II (120 day) Notifiable Change to update the PM. As a result of the NC, modifications were made to the Action and Clinical Pharmacology section of the PM. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 212388	2018-01-02	Issued NOC under NOC/c Guidance 2018-09-21	Submission filed as a Level I – Supplement for new indication: Treatment of adult and pediatric patients with refractory Primary Mediastinal B-cell Lymphoma (PMBCL) or who have relapsed after 2 or more lines of therapy, as monotherapy. Regulatory Decision Summary published.
SNDS # 209481	2017-09-19	Issued NOC 2018-08-31	Submission filed as a Level I – Supplement to change the recommended dose of Keytruda for the treatment of unresectable or metastatic melanoma and previously-treated metastatic non-small cell lung carcinoma (NSCLC). No major issues concerning the change from the currently approved weight based dose to the proposed fixed dose were identified during the review of this submission. Health Canada did not anticipate a change to the benefit/risk profile based upon the population pharmacokinetic model presented. A revised Package Insert (PI) to align with the PM revisions made throughout the course of this submission was requested from the sponsor. An NOC was issued.
NC # 217912	2018-07-04	Issued NOL 2018-07-23	Submission filed as a Level II (90 day) Notifiable Change (Risk Management 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 # 216567	2018-05-24	Issued NOL 2018-07-09	Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to add a new testing site. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 215765	2018-04-25	Issued NOL 2018-06-07	Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM with new safety information. As a result of the NC modifications were made to the Dosage and Adminstration section of the PM. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS-C # 208997	2017-08-29	Issued NOC under NOC/c Guidance 2018-05-23	Submission filed as a Level I – Supplement in response to commitments made as per the provisions of the NOC/c Guidance. The submission provided the final clinical study report for KEYNOTE-001. The data continues to support an acceptable safety profile for the use of Keytruda, and together, the data support the favourable benefit/risk profile of Keytruda for the treatment of metastatic NSCLC patients whose tumours express PD-L1 and who have tumour progression on or after platinum-containing chemotherapy. The data were reviewed and considered acceptable. An NOC under the NOC/c Guidance was issued.
PSUR-C # 211118	2017-11-07	Cleared 2018-05-17	Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PSUR-C for the period 2017-03-04 to 2017-09-03. The information was reviewed and found acceptable.
NC # 212769	2018-01-16	Issued NOL 2018-04-18	Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to revise specifications and testing procedures for the drug substance and drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 213539	2018-02-08	Issued NOL 2018-03-23	Submission filed as a Level II (90 day) Notifiable Change (Risk Management 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. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 201200	2016-12-15	Issued NOC under NOC/c Guidance 2017-09-08	Submission filed as a Level I – Supplement to seek extension of the use of Keytruda as monotherapy, for the treatment of adult patients with refractory, relapsed classical Hodgkin Lymphoma who have failed autologous stem cell transplant (ASCT) and brentuximab vedotin (BV) or who are not ASCT candidates and have failed BV. Regulatory Decision Summary published.
NC # 211484	2017-11-21	Issued NOL 2018-02-21	Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM with new safety information. As a result of the NC modifications were made to the Warnings and Precautions, and Dosage and Administration sections of the PM. Corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS-C # 202247	2017-01-25	Issued NOC 2017-12-22	Submission filed as a Level I – Supplement in response to commitments made as per the provisions of the NOC/c Guidance. The submission provided the final clinical study reports for studies KEYNOTE-001 and KEYNOTE-002. Overall the benefit/risk analysis is considered favourable for the use of Keytruda in patients with unresectable or metastatic melanoma who have disease progression following ipilimumab therapy and, if BRAF V600 mutation positive, following a BRAF or MEK inhibitor. The data were reviewed and considered acceptable. As a result of the submission, the conditions were removed from the NOC that had been issued 2015-05-19. An NOC was issued.
NC # 209565	2017-09-21	Issued NOL 2017-12-21	Submission filed as a Level II (90 day) Notifiable Change (Risk Management 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.
SNDS # 202056	2017-01-18	Issued NOC 2017-12-08	Submission filed as a Level I – Supplement to review the final study report of KEYNOTE-006 and update the PM for the treatment of unresectable or metastatic melanoma who have not received prior treatment with ipilimumab. Overall the benefit/risk analysis is considered favourable for the use of pembrolizumab in patients with unresectable or metastatic melanoma who have not received prior treatment with ipilimumab. The data were reviewed and considered acceptable. As a result of the study, the PM was updated. An NOC was issued.
SNDS # 203157	2017-02-22	Issued NOC 2017-09-20	Submission filed as a Level I – Supplement for new indication: for the use of Keytruda in the treatment of patients with locally advanced or metastatic urothelial carcinoma who have received platinum-containing chemotherapy. Regulatory Decision Summary published.
NC # 208125	2017-08-02	Issued NOL 2017-08-22	Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to make changes regarding the reference standard. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS-C # 197355	2016-08-04	Issued NOC under NOC/c Guidance 2017-07-20	Submission filed as a Level I – Supplement in response to commitments made as per the provisions of the NOC/c Guidance. The sponsor provided a final confirmatory report from KEYNOTE-010, data from the interim report of the NSCLSC cohorts of KEYNOTE-001, and updated immunogenicity data KEYNOTE-001 for both melanoma and NSCLC, and from KEYNOTE-010 for NSCLC. Overall the benefit/risk analysis is considered favourable for the use of Keytruda for the treatment of metastatic NSCLC as monotherapy, in adults whose tumours express PD-L1 (TPS ≥1%) as determined by a validated test and who have disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumour aberrations should have received authorized therapy for these aberrations prior to receiving Keytruda. The data were reviewed and considered acceptable. An NOC under the NOC/c Guidance was issued.
SNDS # 198839	2016-10-03	Issued NOC 2017-07-12	Submission filed as a Level I – Supplement for new indication: For the treatment of patients with metastatic non-small cell lung carcinoma (NSCLC) as monotherapy, in adults whose tumours have high PD-L1 expression [(Tumour Proportion Score (TPS) ≥50%)] as determined by a validated test, with no EGFR or ALK genomic tumour aberrations, and no prior systemic chemotherapy treatment for metastatic NSCLC. Regulatory Decision Summary published.
PSUR-C # 205604	2017-05-12	Cleared 2017-06-15	Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PSUR-C for the period 2016-09-04 to 2017-03-03. The information was reviewed and found acceptable.
NC # 204869	2017-04-19	Issued NOL 2017-05-05	Submission filed as a Level II (90 day) Notifiable Change (Risk Management 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 # 203048	2017-02-20	Issued NOL 2017-04-10	Submission filed as a Level II (90 day) Notifiable Change (Risk Management 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.
Dear Healthcare Professional Letter	Not applicable	Posted 2017-03-16	Dear Healthcare Professional Letter posted, containing important safety information for healthcare professionals.
NC # 202675	2017-02-08	Issued NOL 2017-03-15	Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM with new safety information. As a result of the NC modifications were made to the Warnings and Precautions, and Dosage and Administration sections of the PM. Corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.
PSUR-C	2016-11-04	Cleared 2016-12-20	Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PSUR-C for the period 2016-03-04 to 2016-09-03. The information was reviewed and found acceptable.
NC # 200124	2016-11-09	Issued NOL 2016-12-19	Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to extend the shelf-life of the drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 197815	2016-05-22	Issued NOL 2016-11-24	Submission filed as a Level II (90 day) Notifiable Change (Risk Management 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 # 196331	2016-06-27	Issued NOL 2016-10-04	Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes related to a release test for the drug substance and drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS-C # 191746	2016/01/29	Issued NOC under NOC/c Guidance 2016/09/02	Submission filed as a Level I – Supplement in response to commitments made as per the provisions of the Notice of Compliance with Conditions (NOC/c) Guidance. The submission included the final report from an animal study measuring the effect of programmed cell death 1 receptor (PD-1) inhibition on the magnitude of primary and recall antibody responses to antigen challenge. The information was reviewed and considered acceptable, and an NOC was issued under the NOC/c guidance. No changes to the Product Monograph were required.
SNDS # 189009	2015/10/30	Issued NOC 2016/08/09	Submission filed as a Level I – Supplement for a new dosage form (solution for infusion), an alternate drug substance manufacturing and test site, a new drug product manufacturing site, a revised specification for the drug substance, and an extension of shelf life of the drug substance. The data were reviewed and considered acceptable, and an NOC was issued. DIN 02456869 was issued.
PSUR-C # 194977	2016/05/11	Cleared 2016/07/15	Submission filed in response to commitments made as per the provisions of the Notice of Compliance with Conditions (NOC/c) Guidance. The PSUR-C for the period 2015/09/04 to 2016/03/03 was reviewed and found acceptable.
SNDS-C # 185303	2015/06/24	Issued NOC under NOC/c Guidance 2016/06/22	Regulatory Decision Summary published.
PSUR-C # 189385	2015/11/10	Cleared 2016/06/08	Submission filed in response to commitments made as per the provisions of the Notice of Compliance with Conditions (NOC/c) Guidance. The PSUR-C for the period 2014/09/04 to 2015/09/03 was reviewed and found acceptable.
SNDS # 187844	2015/09/18	Issued NOC 2016/05/06	Regulatory Decision Summary published.
SNDS # 186275	2015/07/16	Issued NOC under NOC/c Guidance 2016/04/15	Regulatory Decision Summary published.
NC # 189354	2015/11/05	Issued No Objection Letter 2016/02/15	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 Notifiable Change, modifications were made to the Warnings and Precautions section of the PM, and corresponding changes were made to the PM Part III: Consumer Information/Patient Medication Information. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
NC # 189982	2015/11/27	Issued No Objection Letter 2016/02/12	Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to extend the shelf life of the drug substance and drug product. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
NC # 186466	2015/07/24	Issued No Objection Letter 2015/10/01	Submission filed as a Level II (90 day) Notifiable Change (Safety Change) to update the Warnings and Precautions, Dosage and Administration, and Part III Patient Medication Information sections of the Product Monograph. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
Drug product (DIN) 02441152) market notification	Not applicable	Date of first sale: 2015/06/01	The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 175884	2014/06/26	Issued NOC under the NOC/c Guidance 2015/05/19	Notice of Compliance issued for New Drug Submission under the Notice of Compliance with Conditions Guidance.

Summary Basis of Decision (SBD) for Keytruda

Date SBD issued: 2015-07-23

The following information relates to the New Drug Submission for Keytruda.

Pembrolizumab, 50 mg, powder for solution, intravenous

Drug Identification Number (DIN):

02441152

Merck Canada Inc.

New Drug Submission Control Number: 175884

On May 19, 2015, Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance to Merck Canada Inc. for the drug product Keytruda. The product was authorized under the NOC/c Guidance on the basis of the promising nature of the clinical evidence, and the need for further follow-up to confirm the clinical benefit. Patients should be advised of the fact that the market authorization was issued with conditions.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit/risk profile of Keytruda is favourable for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab therapy and, if BRAF V600 mutation positive, following a BRAF or MEK inhibitor. An improvement in survival or disease-related symptoms has not yet been established.

1 What was approved?

Keytruda, a monoclonal antibody and antineoplastic agent, was authorized for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab therapy and, if BRAF V600 mutation positive, following a BRAF or MEK inhibitor. An improvement in survival or disease-related symptoms has not yet been established. Keytruda has been issued marketing authorization with conditions, pending the results of studies to verify its clinical benefit. Patients should be advised of the nature of this authorization.

At the time of authorization, no overall differences in safety or efficacy have been reported between elderly patients (65 years and over) and younger patients (less than 65 years). The safety and efficacy of Keytruda in children under 18 years of age have not been established.

Keytruda is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. Keytruda was approved for use under the conditions stated in the Keytruda Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Keytruda (50 mg pembrolizumab) is presented as a powder for solution. In addition to the medicinal ingredient, the powder for solution contains L-histidine, polysorbate-80, and sucrose.

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 Keytruda Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Keytruda approved?

Health Canada considers that the benefit/risk profile of Keytruda is favourable for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab therapy and, if BRAF V600 mutation positive, following a BRAF or MEK inhibitor. An improvement in survival or disease-related symptoms has not yet been established. Keytruda was authorized under the Notice of Compliance with Conditions (NOC/c) Guidance on the basis of the promising nature of the clinical evidence, and the need for further follow-up to confirm the clinical benefit.

Melanoma is a malignant tumour of melanocytes, which are cells derived from the neural crest that create the pigment melanin. The current recommended systemic treatment options for newly diagnosed unresectable or metastatic melanoma patients include ipilimumab and, for patients with BRAF-mutant disease, either a BRAF inhibitor (vemurafenib or dabrafenib) or the MEK inhibitor trametinib. For patients that progress after these regimens there is no standard of care treatment and therefore there is an unmet medical need for this patient population.

The market authorization with conditions was based primarily on Part B2 of one Phase I, multicentre, open-label study (KEYNOTE-001) in patients with unresectable or metastatic melanoma resistant to ipilimumab, and if BRAF V600 mutation positive, who progressed after treatment with a BRAF or MEK inhibitor. There were 173 patients enrolled in this study, of which 89 received Keytruda 2 mg/kg every 3 weeks (Q3W) and 84 received Keytruda 10 mg/kg Q3W. The primary efficacy outcome measure was overall response rate (ORR) as assessed by independent radiology and oncology reviews, using confirmed responses and Response Evaluation Criteria in Solid Tumours (RECIST) 1.1. Keytruda was shown to be efficacious in the 2 mg/kg arm with an overall response rate (ORR) of 24% (95% confidence interval: 15%, 34%). This consisted of one patient with a complete response and 20 patients who experienced partial responses.

The most commonly reported adverse events (AEs) for the 89 patients in the 2 mg/kg Q3W arm of the Part B2 group, that occurred in a total of at least 15% of patients, were: fatigue (47.2%), cough (30.3%), pruritus (30.3%), nausea (28.1%), decreased appetite (24.7%), rash (21.3%), diarrhea (19.1%), arthralgia (19.1%), constipation (18.0%), dyspnea (16.9%), pain in extremity (16.9%) and peripheral edema (15.7%).

The identified safety concerns also include immune-mediated adverse events (irAEs). These include pneumonitis, colitis, hepatitis, nephritis, endocrinopathies (hypophysitis, type I diabetes mellitus, hyperthyroidism, hypothyroidism), and others (uveitis, myositis and severe skin reactions). In the clinical studies, most irAEs were reversible and could be managed with interruptions of Keytruda, administration of corticosteroids and/or supportive care. Overall, irAEs were reported for 14 of the 89 patients in the 2 mg/kg Q3W group (15.7%). The most commonly reported irAE was hypothyroidism in 3 patients (3.4%). There was one Grade 4 irAE of drug-related autoimmune hepatitis. Infusion-related reactions have been reported in less than 0.1% of patients receiving Keytruda.

Keytruda has not been studied in pregnant or nursing patients, children under the age of 18, patients with moderate or severe hepatic impairment, or in patients with severe renal impairment.

Thyroid and liver function tests (transaminase and bilirubin levels) should be performed at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation. These issues have been addressed through appropriate labelling in the Keytruda Product Monograph.

A Risk Management Plan (RMP) for Keytruda was submitted by Merck Canada 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 be put in place to minimize risks associated with the product.

A brand name assessment was performed and the proposed name Keytruda has been deemed appropriate and acceptable.

As part of the sponsor's post-authorization commitments to Health Canada, in order to confirm the efficacy of Keytruda, the final report for Study P002 entitled, "A Randomized, Phase II Study of Keytruda versus Chemotherapy in Patients with Advanced Melanoma" will be submitted to Health Canada within 5 years of the completion of the study.

The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Keytruda Product Monograph to address the identified safety concerns, including the potential risk of irAEs. As described within the framework of the NOC/c Guidance, safety monitoring on the use of Keytruda will be ongoing. Further evaluation will take place upon the submission of requested studies after they become available.

Based on the promising efficacy findings for this population, in combination with an overall safety profile that is considered manageable, Keytruda meets the NOC/c criteria of promising clinical benefit as a second- or third-line (if BRAF V600 mutation) treatment for unresectable or metastatic melanoma which is a life threatening disease.

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 thee Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3 What steps led to the approval of Keytruda?

The sponsor filed a request for Advance Consideration under the Notice of Compliance with Conditions (NOC/c) Guidance for the review of the new drug submission (NDS) for Keytruda. An assessment was conducted and it was determined there was promising evidence of clinical effectiveness that the drug has the potential to provide a significant increase in efficacy such that the overall benefit/risk profile is improved over existing therapies for a disease or condition that is not adequately managed by a drug marketed in Canada.

Subsequent review led to the decision to issue the sponsor market authorization under the (NOC/c) Guidance, in recognition of the promising but unconfirmed evidence of clinical effectiveness in the submission. In keeping with the provisions of the NOC/c Guidance, the sponsor agreed to provide additional information to confirm the clinical benefit.

Submission Milestones: Keytruda

Submission Milestone	Date
Pre-submission meeting 1:	2014-02-21
Pre-submission meeting 2:	2014-04-10
Acceptance of Advance Consideration under the Notice of Compliance with Conditions (NOC/c) Guidance:	2014-05-21
Submission filed:	2014-06-23
Screening
Screening Deficiency Notice issued:	2014-07-31
Response filed:	2014-08-22
Screening Acceptance Letter issued:	2014-09-23
Review
Biopharmaceutics Evaluation complete:	2015-03-27
Quality Evaluation complete:	2015-04-10
Clinical Evaluation complete:	2015-03-27
Biostatistics Evaluation complete:	2015-03-27
Labelling Review complete:	2015-03-06
Notice of Compliance with Conditions (NOC/c) Qualifying Notice issued:	2015-04-10
Response filed (Letter of Undertaking):	2015-04-16
Revised Qualifying Notice issued:	2015-05-08
Response filed (Letter of Undertaking):	2015-05-11
Notice of Compliance (NOC) issued by Director General under the Notice of Compliance with Conditions (NOC/c) Guidance:	2015-05-19

The Canadian regulatory decision for the quality and non-clinical components of the review of Keytruda was based on a critical assessment of the Canadian data package. The statistical review completed by the United States Food and Drug Administration (FDA) were used as an added reference.

A revised Qualifying Notice (QN) was issued for Keytruda on May 8, 2015 to clarify that only one of the in-progress Phase III studies will be submitted and reviewed as the other study was performed in a different population than that for which the NOC/c was authorized. No other changes were made to the NOC/c commitments.

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?

In addition to requirements for post-market commitments outlined in the Food and Drugs Act and Regulations, and in keeping with the provisions outlined in the Notice of Compliance with Conditions (NOC/c) Guidance, Health Canada has requested that the sponsor agree to undertake several NOC/c commitments. Some of these commitments are listed below.

Confirmatory Study

The sponsor will submit as a Supplemental New Drug Submission - Confirmatory (SNDS-C), the results from Study P002: "A Randomized, Phase II Study of Keytruda versus Chemotherapy in Patients with Advanced Melanoma", which is performed in the same population as the pivotal study (KEYNOTE-001, Part B2) submitted for the Keytruda New Drug Submission.

The completed study will be submitted within five years of the issuance of the NOC/c. The sponsor has acknowledged that the indication for Keytruda can be withdrawn if the confirmatory study cited above is unsuccessful.

Status reports on the progress of the ongoing confirmatory study cited above, as per section 3.2 and Appendix 4 of the NOC/c Guidance, will be submitted on an annual basis, within 60 days of the market authorization anniversary and until Merck Canada Inc. has submitted an SNDS-c containing the final clinical study report of the confirmatory study to Health Canada.

Commitments

In addition to the confirmatory study, Health Canada has requested that the sponsor commit to providing additional information from other ongoing studies including:

Study KEYNOTE-001: "Phase I Study of Single Agent Keytruda in Patients with Progressive Locally Advanced or Metastatic Carcinoma, Melanoma, and Non-Small Cell Lung Carcinoma."
- An SNDS-c, for the final clinical study report of the completed study.
An SNDS-c, for the final study report from an animal study that will measure the effect of programmed cell death 1 receptor (PD-1) inhibition on the magnitude of primary (first vaccination) and recall (second vaccination) antibody responses to antigen challenge [for example (e.g.), tetanus toxoid or keyhole limpet hemocyanin (KLH)].
Any other analyses that have been designated as post-marketing commitments to other international market authorization granting agencies.

Post-Market Safety Monitoring

The sponsor agrees to submit:

All serious adverse reactions (ARs) that occur in Canada and all serious unexpected ARs that occur outside of Canada within 15 days to Health Canada, in accordance with current regulations.
All adverse events (AEs) and ARs reports on marketed drugs occurring as part of confirmatory trials to Health Canada.
The Periodic Safety Updates Reports-Confirmatory (PSUR-Cs) for Keytruda to Health Canada on an annual basis until such time as conditions associated with the market authorization are removed. The PSUR-Cs should include an analysis of the adverse drug reactions as per the Pharmacovigilance Plan and safety updates from all ongoing clinical studies with Keytruda. The PSUR-Cs will be prepared in accordance with the International Conference on Harmonisation (ICH) E2C Guideline, including format and content.
The sponsor agrees to implement the Risk Management Plan (RMP) in Canada and provide any update to the Canadian RMP when available.
In the event of Specific Issues of Concern as outlined in section 3.4.4 of the NOC/c Guidance, the sponsor agrees to the following:
1. Notify Health Canada within 15 days when, on the basis of safety, efficacy or quality concerns related to the product, an expert panel or advisory committee has been struck in a foreign jurisdiction to address an issue, or, when there has been significant regulatory action in another jurisdiction including a direction to issue warnings, a health advisory or the removal of a product from the market; and
2. Prepare and submit a report on the issue that prompted the action in the foreign jurisdiction. The report should be available to Health Canada within 30 days of the notification. This time frame may be subject to negotiation with Health Canada when the scope of the issue under investigation warrants additional time to gather the necessary information.

5 What post-authorization activity has taken place for Keytruda?

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decision was negative or positive. The PAAT will continue to be updated during the product's lifecycle.

The PAAT for Keytruda is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

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 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 Notice of Compliance with Conditions (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 Document, 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

Melanoma is a malignant tumour of melanocytes, which are cells derived from the neural crest that are responsible for producing the pigment melanin.

Keytruda is a highly selective humanized monoclonal antibody that binds to human programmed cell death 1 receptor (PD-1) and blocks the interaction between PD-1 receptor and its ligands, PD-L1 and PD-L2. These ligands are constitutively expressed or can be induced in various tumours including melanoma.

The PD-1 pathway represents a major immune control switch which may be engaged by tumour cells to overcome active T-cell immune surveillance. By inhibiting the PD-1 receptor from binding to its ligands, Keytruda reactivates tumour-specific cytotoxic T lymphocytes in the tumour microenvironment and reactivates anti-tumour immunity.

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies.

The effects of various covariates on the pharmacokinetics of pembrolizumab, the medicinal ingredient of Keytruda were assessed in population pharmacokinetic analyses using a two compartment model with linear clearance from the central compartment. The clearance of Keytruda increased with increasing body weight. The resulting exposure differences are adequately addressed by the administration of Keytruda using weight-based dosing on a mg/kg basis. The following factors had no clinically important effect on the clearance of Keytruda: age (range 18-94 years), gender, mild or moderate renal impairment, mild hepatic impairment, and tumour burden. The effect of race could not be assessed due to limited data available in non-Caucasian ethnic groups.

Keytruda has not been studied in patients with moderate or severe hepatic impairment or in patients with severe renal impairment. For further information, please consult the Warnings and Precautions and Dosage and Administration sections of the Keytruda Product Monograph.

The clinical pharmacological data support the use of Keytruda for the recommended indication. For further details, please refer to the Keytruda Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy of Keytruda was primarily evaluated in one Phase I, multicentre, open-label, dose-comparative, randomized study, Study KEYNOTE-001, Part B2. Patients who enrolled in this study had locally advanced or metastatic melanoma (ipilimumab-naïve or previously treated with ipilimumab), non-small cell lung cancer (NSCLC), or advanced solid tumours. The study was designed to evaluate the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of Keytruda in this patient population.

The primary efficacy endpoint of this study was overall response rate (ORR) by independent central review using Response Evaluation Criteria in Solid Tumours (RECIST) 1.1. The primary method of analysis included the review of images by independent radiologists and review of objective clinical data [for example (e.g.) qualitative skin photographs and biopsy reports from suspicious lesions if performed) by independent oncologists when such data were available, referred to as the integrated radiology and oncology (IRO) assessment.

Part B2 of the study focused on patients with unresectable or metastatic melanoma that was resistant to ipilimumab (100% of enrolled patients), and if BRAF V600 mutation positive, progressed after treatment with a BRAF or MEK inhibitor (72% of enrolled patients). Among the 173 patients enrolled, 89 patients received Keytruda 2 mg/kg every 3 weeks (Q3W) and 84 patients received Keytruda 10 mg/kg Q3W. The duration of exposure for the 89 patients treated with 2 mg/kg Q3W ranged from 1 to 402 days with a mean duration of 176 days on treatment. Baseline characteristics were generally well-balanced between the treatment arms in Part B2. Considering all 173 patients (in both arms), the median age was 61 years (range 18 to 88 years), and 36% of patients were age 65 or older. Sixty-one percent (61%) of patients were male, and almost all were Caucasian, as expected for a melanoma population. All patients had a reported Eastern Cooperative Oncology Group (ECOG) performance status of 0 (67%) or 1 (33%) at study entry. The ECOG performance status is a measure of how a patient's disease is progressing and how the disease affects their daily living abilities. Over one-half of patients (57%) were stage M1c (metastases to any other organs) at baseline, and 9% had brain metastasis at the time of enrollment. Lactate dehydrogenase (LDH) was elevated at baseline in 39% of patients. Eighteen percent (18%) of patients had a BRAF mutation. The median baseline tumour size was 132 mm (range 14 to 895 mm).

All patients in Part B2 had received prior treatment with ipilimumab. Twenty-eight percent (28%) of patients had only one prior systemic therapy, (ipilimumab), while 72% of patients had received two or more prior therapies. There were 35% of patients who had received three or more prior therapies. Other prior treatments included chemotherapy (46%), BRAF and/or MEK inhibitors (20%), other immunotherapies (31%), and other types of agents, including experimental agents (21%). Prior BRAF and/or MEK inhibitors were required for patients with a known BRAF mutation, of which there were 31/173 patients in Part B2.

While Part B2 studied two doses of Keytruda (2 mg/kg Q3W and 10 mg/kg Q3W), the sponsor only submitted an NDS seeking authorization of the 2 mg/kg dose. At the time of submission, support for the clinical efficacy of Keytruda was only reviewed for this dose.

The ORR was 24% (95% confidence interval: 15, 34) in the 2 mg/kg arm, consisting of 1 complete response and 20 partial responses. Among the 21 patients with an objective response, 3 (14%) had progression of disease, 2.8, 2.9, and 8.2 months after initial response. Approximately 47% of patients achieved disease control, with a best response of stable disease or better. Sixty-one percent (61%) of the 89 patients discontinued treatment, including 5 (6%) for AEs and 34 (38%) for progressive disease. Objective responses were reported in ipilimumab-refractory patients with and without BRAF mutations.

The secondary efficacy outcome measure was response duration. The median response duration was not reached at the time of analysis for the population for Part B2 of the KEYNOTE-001 Study.

Of the 173 patients enrolled, 73 patients (42%) remained on study treatment at the time of the data cutoff. Progressive disease was the most frequent reason for discontinuing study treatment (34%), with 17% discontinuing due to an adverse event (AE). Four, patients discontinued due to physician decision, 4 patients discontinued due to patient decision, 2 patients were lost to follow-up, and 2 patients discontinued due to a protocol violation.

Indication

The indication for Keytruda originally sought by the sponsor was for the treatment of patients with unresectable or metastatic melanoma. Health Canada narrowed this indication as there is currently first-line treatment for metastatic/unresectable melanoma in Canada authorized for market. The revised indication authorizes the use of Keytruda for patients with unresectable or metastatic melanoma and disease progression following ipilimumab therapy and, if BRAF V600 mutation positive, following a BRAF or MEK inhibitor. The indication was also revised to include a statement that an improvement in survival or disease-related symptoms has not yet been established.

Overall Analysis of Efficacy

For the population of patients studied in the pivotal study KEYNOTE-001- Part B2 who have progressed after ipilimumab, and BRAF or MEK inhibitors for BRAF-mutant disease very few treatment options remain. Based on the promising efficacy findings for this population, Keytruda meets the Notice of Compliance with Conditions (NOC/c) criteria of promising clinical benefit as a second- or third-line (if BRAF V600 mutation) treatment for unresectable or metastatic melanoma which is a life threatening disease.

For more information, refer to the Keytruda Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Keytruda was primarily evaluated in Part B2 of the pivotal study (cut-off date of October 18, 2013) described in the Clinical Efficacy section.

The most commonly reported adverse events (AEs) for the 89 patients in the 2 mg/kg Q3W group, occurring in a total of at least 15% of patients were: fatigue (47.2%), cough (30.3%), pruritus (30.3%), nausea (28.1%), decreased appetite (24.7%), rash (21.3%), diarrhea (19.1%), arthralgia (19.1%), constipation (18.0%), dyspnea (16.9%), pain in extremity (16.9%) and peripheral edema (15.7%). Grade 3-4 AEs occurred in 38.2% of patients (2 mg/kg Q3W). The most frequent Grade 3-5 AEs reported for at least 2% of patients were: anemia (3.4%), pneumonia (4.5%), dehydration (3.4%), dyspnea (2.2%), hyponatremia (2.2%), muscular weakness (2.2%), tumour pain (2.2%), and fatigue (6.7%). Grade 3-5 AEs did not cluster in any particular system organ class.

Drug-related AEs were reported for 82.0% of patients in the 2 mg/kg Q3W group. The most frequently reported drug-related AEs in the pooled 2 mg/kg Q3W group (n = 162) for at least 10% of patients, were: fatigue (30.2%), pruritus (22.8%), rash (18.5%), diarrhea (14.8%), arthralgia (13.6%), and nausea (10.5%). Drug-related Grade 3-4 AEs were experienced in 14.6% of patients taking 2 mg/kg of Keytruda Q3W, with fatigue being the most commonly reported (5.6%). There were 2 Grade 4 drug-related AEs (1.2%) each occurring in 1 patient: hypophysitis and autoimmune hepatitis.

Immune-mediated adverse events (irAEs) can occur in patients treated with Keytruda. The identification of these AEs is based on ongoing monitoring for Study KEYNOTE-001 AEs and the published literature on irAEs for other cancer immunotherapies. These irAEs are listed in the Product Monograph and include pneumonitis, colitis, hepatitis, nephritis, endocrinopathies (hypophysitis, type I diabetes mellitus, hyperthyroidism, hypothyroidism), and others (uveitis, myositis and severe skin reactions). Immune-mediated adverse events were reported for 14/89 patients (15.7%) in Part B2 of the study in the 2 mg/kg Q3W group. The most commonly reported irAE was hypothyroidism in 3 patients (3.4%). There was one Grade 4 irAE of drug-related autoimmune hepatitis.

No post marketing safety data is currently available.

Supportive Studies

Information to support safety for the use of Keytruda in patients with unresectable or metastatic melanoma was provided by combining safety data from all advanced melanoma patients treated in different parts of KEYNOTE-001. Study KEYNOTE-001 was initially designed as a standard dose-escalation trial, and was the first in-human study of Keytruda. This original part of the study is referred to as Part A of KEYNOTE-001 (n = 30). During Part A, several patients with melanoma had an objective response to treatment, so the study was expanded to evaluate efficacy in melanoma [now Part B1, advanced melanoma patients (ipilimumab naïve and ipilimumab treated), non-randomized cohort (n = 135)]. Through a series of protocol amendments, KEYNOTE-001 evolved into 4 Phase II-like melanoma sub-studies, known as Parts B1, B2, B3, and D.

The combination of Part B1 and Part D of the KEYNOTE-001 Study along with Part B2 provided supportive data for the evaluation of the safety of Keytruda. Part B1 studied patients who were naïve or previously exposed to ipilimumab while Part D enrolled patients with a diagnosis of melanoma who were naïve to ipilimumab. Within these three parts, B1, B2 and D, there were 411 patients treated at all doses, comprising 162 patients at 2 mg/kg Q3W, 192 patients at 10 mg/kg Q3W and 57 at 10 mg/kg Q2W.

While Part B2 studied two doses of Keytruda (2mg/kg Q3W and 10 mg/kg Q3W), the sponsor only submitted an NDS seeking authorization of the 2 mg/kg dose. At the time of submission, support for the clinical efficacy of Keytruda was only reviewed for this dose.

Of the 162 patients treated with Keytruda for melanoma at 2 mg/kg Q3W irrespective of previous ipilimumab treatment, 36.4% of patients experienced Grade 3-4 AEs and 16.0% of patients experienced Grade 3-4 drug-related AEs. IrAEs were reported for19.1% of patients. The most commonly reported irAEs were hypothyroidism (4.3%), pruritis (3.1%), arthralgia (2.5%), and vitiligo (2.5 %). Five out of 162 patients (3.1%) experienced a Grade 3-4 irAE. These included 2 cases of colitis (1.2%), one case of autoimmune hepatitis (0.6%), 1 case of pleural effusion (0.6%), and one case of diarrhea (0.6%).

There were 4 deaths that occurred due to AEs in these 411 patients, all considered by the investigator to be not related to the study drug. One patient in Part B2 in the 2 mg/kg Q3W treatment group died due to septic shock which occurred 38 days after the first and only dose of study drug. The other three deaths occurred in Part B1 patients receiving Keytruda at the higher dose and frequency of 10 mg/kg Q2W.

Special Populations

Keytruda has not been studied in children under the age of 18, patients with moderate or severe hepatic impairment, or in patients with severe renal impairment. These issues have been addressed through appropriate labelling in the Keytruda Product Monograph.

Pregnant and Nursing Women

There are no data on the use of Keytruda in pregnant and nursing women. Animal reproduction studies have not been conducted with pembrolizumab (the medicinal ingredient of Keytruda); however, blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus and to result in an increase in fetal loss. These results indicate a potential risk that treatment with Keytruda during pregnancy could cause fetal harm, including increased rates of abortion or stillbirth.

Human immunoglobulin G4 (IgG4) is known to cross the placental barrier. Pembrolizumab is an IgG4; therefore pembrolizumab has the potential to be transmitted from mother to the developing fetus.

Keytruda is not recommended during pregnancy unless the clinical benefit outweighs the potential risk to the fetus. Women of childbearing potential should use effective contraception during treatment with Keytruda and for 4 months after the last dose of Keytruda.

It is not known if Keytruda is secreted in human milk. As many drugs are secreted in human milk, a decision to discontinue breast-feeding or to discontinue Keytruda should be made, taking into account the benefit of breast-feeding to the child and the benefit of Keytruda therapy for the mother.

Overall Analysis of Safety

The safety data presented in Part B2 of the KEYNOTE-001 Study relevant to the proposed indication demonstrate AEs common to chemotherapy such as fatigue, nausea, anorexia, diarrhea, rash, and pruritis. The Grade 3-4 AEs did not cluster in any particular system organ class. Immune-mediated adverse events (irAEs) can occur in patients receiving Keytruda. They include pneumonitis, colitis, hepatitis, nephritis, endocrinopathies (hypophysitis, type I diabetes mellitus, hyperthyroidism, hypothyroidism), and others (uveitis, myositis and severe skin reactions.) In clinical trials, most irAEs were reversible and could be managed with interruptions of Keytruda, administration of corticosteroids and/or supportive care. Overall, irAEs were reported for 14 of 89 patients in the 2 mg/kg Q3W arm (15.7%) of Part B2. The most commonly reported irAE was hypothyroidism in 3 patients (3.4%). There was one Grade 4 irAE of drug-related autoimmune hepatitis.

A similar safety profile to that of Part B2 was observed in the pooled analysis of all patients with melanoma (Parts B1, B2, and D).

All of the currently known potential irAEs are clearly identified in the Warning and Precautions section of the Keytruda Product Monograph. The safety profile is considered acceptable for this stage of treatment in this group of melanoma patients.

Appropriate warnings and precautions are in place in the approved Keytruda Product Monograph to address the identified safety concerns. For more information, refer to the Keytruda Product Monograph, approved by Health Canada and available through the Drug Product Database.

In addition, to verify the clinical benefit of Keytruda, additional safety data will be submitted at the request of Health Canada as part of the NOC/c commitments.

For more information, refer to the Keytruda Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.2 Non-Clinical Basis for Decision

The non-clinical program for Keytruda is complete and in compliance with the International Conference on Harmonisation (ICH) S6 (R1) and ICH S9 guidelines for pre-clinical safety evaluation of biotechnology-derived and anti-cancer pharmaceuticals.

T-cell engagement and modulation were demonstrated in in vitro assays in which PD-1 blockade increased secretion of IL-2 and other cytokines from peripheral blood mononuclear cells that were pre-stimulated with Staphylococcus enterotoxin B (SEB). The SEB assay also demonstrated complete PD-1 target saturation at all dose levels administered in repeat-dose toxicology studies. Cytokine release assays demonstrated that Keytruda was not capable of eliciting cytokine release when administered in the absence of pre-stimulation.

In vivo studies conducted in mice investigated the effect of a mouse anti-PD-1 surrogate of Keytruda on syngeneic colon adenocarcinoma tumour growth. In these studies, PD-1 blockade slowed tumour growth and extended life when the antibody was administered alone or in combination with 5-fluorouracil.

Keytruda binds with high affinity to both human and cynomolgus monkey PD-1. It is cross-reactive with human, cynomolgus monkey and rhesus macaque PD-1, but not with mouse or rat PD-1. Thus, cynomolgus monkey was considered the relevant species for further non-clinical testing. One and six month repeat-dose toxicology studies with four-month recovery periods did not reveal any significant treatment-related findings in cynomolgus monkeys.

Developmental studies were not performed; however, as PD-1 plays a role in maternal acceptance of the fetal allograft, Keytruda should not be administered to women who are pregnant or are trying to become pregnant.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Keytruda Product Monograph. In view of the intended use of Keytruda, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product. Appropriate warnings and precautionary measures are in place in the Keytruda Product Monograph to address the identified safety concerns.

For more information, refer to the Keytruda Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.3 Quality Basis for Decision

Keytruda (pembrolizumab) is a selective humanized monoclonal antibody designed to block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Pembrolizumab is an immunoglobulin G4 (IgG4) kappa immunoglobulin.

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that pembrolizumab, the drug substance, consistently exhibits the desired characteristic structure and biological activity.

Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established limits.

Manufacturing Process and Process Controls of the Drug Substance and Drug Product

The drug substance, pembrolizumab, is manufactured based on a master and working cell bank system, where the master and working cell banks have been thoroughly characterized and tested for adventitious contaminants and endogenous viruses in accordance with International Conference on Harmonisation (ICH) guidelines. Results from genetic characterization studies also demonstrated stability of these cell banks.

The manufacturing process of the drug substance consists of a series of stages which include cell culture, harvest, purification stages including viral inactivation/removal steps, and formulation. The materials used in the manufacture of the drug substance are considered suitable and/or meet standards appropriate for their intended use.

The drug product, Keytruda, is supplied as lyophilized powder for single-use and contains 50 mg of pembrolizumab and compendial grade L-Histidine, polysorbate 80, and sucrose as excipients. Keytruda is reconstituted with sterile water for injection and is further diluted with normal saline (0.9% sodium chloride injection) or 5% dextrose (5% dextrose injection) prior to intravenous (IV) administration.

The Keytruda drug product manufacturing process includes drug substance thawing and pooling, sterile filtration, aseptic filling into vials, lyophilization, capping, and visual inspection using conventional pharmaceutical equipment and facilities.

Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.

In-process controls and lot release tests for the drug substance and drug product were established and validated.

The materials used in the manufacture of the drug substance and drug product (including biological-sourced materials) are considered to be suitable and/or meet standards appropriate for their intended use. The manufacturing processes are considered to be adequately controlled within justified limits.

All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of the pembrolizumab with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications and analytical procedures are validated and in compliance with ICH guidelines.

Each lot of Keytruda drug product is tested for appearance, content, identity, potency, purity, and impurities. Established test specifications and validated analytical test methods are considered acceptable.

Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested, evaluated, and found to meet the specifications of the drug product and demonstrate consistency in manufacturing.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf lives and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed shelf life of 18 months for the drug substance at -40°C and the proposed shelf life at 2-8°C for the drug product Keytruda are considered acceptable.

The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.

Constitution stability studies support that the reconstituted drug product solutions may be stored at room temperature for a cumulative time of up to 6 hours. In addition, reconstituted vials and/or IV bags may be stored under refrigeration at 2-8°C for up to a cumulative time of 24 hours.

Facilities and Equipment

The design, operations, and controls of the facilities and equipment that are involved in the production are considered suitable for the activities and products manufactured.

An On-Site Evaluation (OSE) of the facilities involved in the manufacture and testing of the pembrolizumab drug substance was not conducted as the facility was not in production during the review period and there were no critical manufacturing issues identified from the submission review. Also, an OSE of the facility involved in the manufacture and testing of the Keytruda drug product was not conducted due to restrictive resources. In both cases, an inspection history by competent regulatory agents, including the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the last five years and the most recent inspection observations with answers for the facilities were requested to support the review of this submission.

Both sites involved in production are compliant with Good Manufacturing Practices.

Adventitious Agents Safety Evaluation

The pembrolizumab manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Pre-harvest culture fluid from each lot is tested to ensure freedom from adventitious microorganisms (bioburden, mycoplasma, and viruses). Purification process steps designed to remove and inactivate viruses are adequately validated.

The excipients used in the Keytruda product formulation are not of animal or human origin.

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Product name	DIN	Company name	Active ingredient(s) & strength
KEYTRUDA	02456869	MERCK CANADA INC	PEMBROLIZUMAB 25 MG / ML

Date modified:: 2026-04-19

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