Summary Basis of Decision for Darzalex

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

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Post-Authorization Activity Table (PAAT) for Darzalex

Updated:

2023-06-02

The following table describes post-authorization activity for Darzalex, a product which contains the medicinal ingredient daratumumab. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.

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

Drug Identification Numbers (DINs):

  • DIN 02455951 (Darzalex) – 100 mg/5 mL, daratumumab, solution, intravenous administration
  • DIN 02455978 (Darzalex) – 400 mg/20 mL, daratumumab, solution, intravenous administration
  • DIN 02502712 (Darzalex SC) - 1800 mg/15 mL, daratumumab, solution, subcutaneous administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
SNDS # 265459 2022-06-22 Issued NOC 2023-05-29 Submission filed as a Level I – Supplement to update the Darzalex and Darzalex SC PMs with data from studies MMY3003, MMY3004, and MMY3008. As a result of the SNDS, modifications were made to the Clinical Trials section of the PMs. An NOC was issued.
SNDS # 264517 2022-05-20 Issued NOC 2022-12-22 Submission filed as a Level I – Supplement to add a manufacturing site for the production of the drug substance for Darzalex SC. The data were reviewed and considered acceptable, and an NOC was issued.
SNDS # 259880 2021-12-21 Issued NOC 2022-12-08 Submission filed as a Level I – Supplement for a new indication for Darzalex and Darzalex SC. The indication authorized was: in combination with Kyprolis and dexamethasone (DKd) for the treatment of patients with relapsed multiple myeloma who have received 1 to 3 prior lines of therapy. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
SNDS # 265885 2022-07-05 Issued NOC 2022-11-15 Submission filed as a Level II – Supplement (Safety) to update the Darzalex and Darzalex SC PMs 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.
NC # 267106 2022-08-17 Issued NOL 2022-09-26 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to extend the shelf-life of Darzalex SC to 24 months. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 257728 2021-10-18 Issued NOC 2022-09-12 Submission filed as a Level I – Supplement to update the Darzalex and Darzalex SC PMs with updated analyses from studies MMY3008 and MMY3012. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Clinical Trials section of the PMs. An NOC was issued.
NC # 263554 2022-04-20 Issued NOL 2022-07-26 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for Darzalex SC to extend the drug product shelf-life to 18 months and to change the drug substance purification process. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 263901 2022-04-29 Issued NOL 2022-06-22 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to extend the in-use shelf-life of the prepared syringe of Darzalex SC. The submission was considered acceptable, and an NOL was issued.
SNDS # 256183 2021-08-27 Issued NOC 2022-04-13 Submission filed as a Level I – Supplement for an alternate manufacturing site and to extend the shelf-life, for the Darzalex SC drug substance. The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS # 249815 2021-02-25 Issued NOC 2022-01-21 Submission filed as a Level I – Supplement for a new indication for Darzalex SC. The indication authorized was: in combination with pomalidomide and dexamethasone, the treatment of patients with multiple myeloma who have received at least one prior line of therapy, including lenalidomide and a proteasome inhibitor. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
SNDS # 255187 2021-07-28 Issued NOC 2021-12-08 Submission filed as a Level II – Supplement (Safety) to update the Darzalex and Darzalex PMs with new safety information and to migrate the Darzalx SC PM to the 2020 format. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Adverse Reactions section of the PMs. An NOC was issued.
NC # 256509 2021-09-08 Issued NOL 2021-11-18 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in scale of the manufacturing process of the drug substance and to introduce a new working cell bank, for Darzalex SC. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 249604 2021-02-16 Issued NOC 2021-06-30 Submission filed as a Level II – Supplement (Safety) to update the Darzalex PM with new safety information and to migrate the PM to the 2020 format. 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 a Serious Warnings and Precautions Box was added. An NOC was issued.
SNDS # 244119 2020-09-18 Issued NOC 2021-04-12 Submission filed as a Level I – Supplement for a new indication for Darzalex SC. The indication authorized was: the treatment of adults with newly diagnosed light chain amyloidosis in combination with a background regimen of cyclophosphamide, bortezomib, and dexamethasone. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
SNDS # 245374 2020-10-21 Issued NOC 2021-03-17 Submission filed as a Level II – Supplement (Safety) to update the Darzalex and Darzalex SC PMs 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 PMs, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
SNDS # 238979 2020-08-28 Issued NOC 2021-03-09 Submission filed as a Level I – Supplement to update the product labels for Darzalex, as requested by Health Canada on 2020-05-01. The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS # 235655 2020-01-30 Issued NOC 2020-12-23 Submission filed as a Level I – Supplement to update the Darzalex PM with new efficacy data from studies MMY3003, MMY3004 and MMY3007. 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 # 234407 2019-12-12 Issued NOC 2020-11-17 Submission filed as a Level I – Supplement for a new indication for Darzalex. The indication authorized was: in combination with bortezomib, thalidomide and dexamethasone, the treatment of patients with newly diagnosed multiple myeloma who are eligible for an autologous stem cell transplant. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
Drug product (DIN 02502712) market notification Not applicable Date of first sale: 2020-08-12 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
SNDS # 231031 2019-08-22 Issued NOC 2020-07-29 Submission filed as a Level I – Supplement to add a new subcutaneous formulation of daratumumab. The submission was reviewed and considered acceptable, and an NOC was issued. A new DIN (02502712) was issued for Darzalex SC, the subcutaneous formulation. A Regulatory Decision Summary was published.
NC # 237557 2020-03-25 Issued NOL 2020-05-22 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 Indications and Clinical Use, Warnings and Precautions, Adverse Reactions, and Action and Clinical Pharmacology sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 237403 2020-03-23 Issued NOL 2020-04-16 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 # 236633 2020-02-08 Issued NOL 2020-04-03 Submission filed as a Level II (90 day) Notifiable Change to update the PM with new safety information. As a result of the NC, modifications were made to the Adverse Reactions section of the PM, and corresponding changes were made to Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 226512 2019-04-03 Issued NOC 2019-10-25 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 lenalidomide and dexamethasone, the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
SNDS # 222959 2018-12-12 Issued NOC 2019-07-11 Submission filed as a Level I – Supplement to add an alternate manufacturing site for the production of the drug product. The data were reviewed and considered acceptable, and an NOC was issued.
NC # 224102 2019-01-25 Issued NOL 2019-05-07 Submission filed as a Level II (90 day) Notifiable Change to update the PM with new safety information related to hepatitis B virus (HBV) reactivation. As a result of the NC, modifications were made to the Warnings and Precautions and Adverse Reactions sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.
Dear Healthcare Professional Letter Not applicable Posted 2019-03-25 Dear Healthcare Professional Letter posted (Darzalex [daratumumab] and Hepatitis B Virus Reactivation), containing important safety information for healthcare professionals.
SNDS # 216806 2018-10-18 Issued NOC 2019-03-04 Submission filed as a Level I – Supplement to add an alternate manufacturing site for the production of the drug substance. The data were reviewed and considered acceptable, and an NOC was issued.
PBRER-C # 218253 2018-07-16 Cleared
2019-01-10		 Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C for the period 2017-11-16 to 2018-05-15. The information was reviewed and found acceptable.
SNDS # 212559 2018-01-03 Issued NOC
2018-11-27		 Submission filed as a Level I - Supplement for a new indication for Darzalex (daratumumab) in patients with previously untreated multiple myeloma who are ineligible for autologous stem cell transplant. Regulatory Decision Summary published.
NC # 219648 2018-09-04 Issued NOL
2018-12-06		 Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM to reflect revisions in the company core data sheet. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS-C # 210968 2017-11-03 Issued NOC
2018-10-10		 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 the confirmatory studies MMY3003 and MMY3004. The sponsor also provided final analyses from studies MMY1002, MMY2002, GEN501, and GEN503. Based on these data, this submission also requested the removal of the conditions from the NOC for this indication. The data continues to support an acceptable safety profile for the use of Darzalex, and together, the data support the favourable benefit/risk profile. The data were reviewed and considered acceptable. As a result of the submission, the conditions were removed from the NOC that had been issued 2016-06-29.
PBRER-C # 213082 2018-01-24 Cleared
2018-07-16		 Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C for the period 2016-05-20 to 2017-05-15. The information was reviewed and found acceptable.
SNDS # 210688 2017-11-01 Issued NOC
2018-05-24		 Submission filed as a Level I - Supplement for changes to the manufacture of the drug product. The information was reviewed and considered acceptable. An NOC was issued.
NC # 211789 2017-12-01 Issued NOL
2018-02-26		 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 Adverse Reactions sections 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.
PBRER-C # 207588 2017-07-17 Cleared
2017-09-01		 Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C for the period 2016-05-20 to 2017-05-15. The information was reviewed and found acceptable.
NC # 206253 2017-06-02 Issued NOL
2017-06-15		 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 an NOL was issued.
SNDS # 198647 2016-09-26 Issued NOC
2017-04-13		 Regulatory Decision Summary published.
NC # 202332 2017-01-27 Issued No Objection Letter
2017-04-05		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change to a drug substance manufacturing facility and to change the drug substance purification process. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
Drug product (DINs 02455951, 02455978) market notification Not applicable Date of first sale:
2016-07-12		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 187648 2015-09-14 Issued NOC
2016-06-29		 Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Darzalex

Date SBD issued: 2016-09-08

The following information relates to the new drug submission for Darzalex.

Daratumumab, 20 mg/mL, solution, intravenous

Drug Identification Number (DIN):

  • 02455951 - 100 mg/5 mL
  • 02455978 - 400 mg/20 mL

Janssen Inc.

New Drug Submission Control Number: 187648

 

On June 29, 2016, Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance to Janssen Inc. for the drug product Darzalex. 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 Darzalex is favourable for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or who are refractory to both a PI and an IMiD.

1 What was approved?

Darzalex (daratumumab), an antineoplastic agent, was authorized for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or who are refractory to both a PI and an IMiD. Darzalex is an IgG1k (immunoglobulin G, subclass 1, kappa light chain) human monoclonal antibody that targets the CD38 protein expressed at a high level on the surface of cells in a variety of hematological malignancies, including multiple myeloma tumour cells. The CD38 protein has multiple functions such as receptor-mediated adhesion, signalling, and enzymatic activity. Daratumumab inhibits the in vivo growth of CD38-expressing tumour cells. Based on in vitro studies, daratumumab may utilize multiple effector functions, resulting in immune-mediated tumour cell death.

Marketing authorization with conditions was based on the primary efficacy endpoint of objective response rate demonstrated in a single-arm study.

No overall differences in safety or effectiveness were observed between elderly (≥65 years of age) and younger patients. No dose adjustments are considered necessary.

The safety and efficacy of Darzalex have not been established in pediatric patients (<18 years of age).

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

Darzalex (20 mg/mL daratumumab) is presented as a liquid concentrate that must be diluted in a sodium chloride solution before being administered by intravenous infusion. In addition to the medicinal ingredient, daratumumab, Darzalex contains glacial acetic acid, sodium acetate trihydrate, sodium chloride, mannitol, polysorbate 20, and water for injection.

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

2 Why was Darzalex approved?

Health Canada considers that the benefit/risk profile of Darzalex is favourable for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or who are refractory to both a PI and an IMiD. Darzalex 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.

Multiple myeloma is a malignant disorder of the plasma cells, characterized by uncontrolled and progressive proliferation of a plasma cell clone. Current treatments include proteasome inhibitors (PIs; for example [e.g.], bortezomib or carfilzomib), immunomodulators (IMiDs; e.g., lenalidomide, pomalidomide, thalidomide), alkylating agents, anthracyclines, and/or corticosteroids. The PIs and IMiDs are typically employed as backbone agents in combination regimens. Chemotherapy with an autologous stem cell transplant is also used as a front-line treatment for patients eligible for transplantation. Despite these treatment modalities, all patients eventually progress, and after relapse following treatment with PIs and IMiDs, the disease ultimately becomes refractory. Following several relapses, very limited therapeutic options remain for these heavily pre-treated and refractory patients; therefore, there remains a high unmet medical need for these patients.

Darzalex has been shown to be efficacious in patients with multiple myeloma who have received at least three prior lines of therapy including a PI and an IMiD, or who are refractory to both a PI and an IMiD. The market authorization with conditions was based on the primary efficacy endpoint of objective response rate demonstrated in a Phase II open-label, two-part, single-arm study (Study MMY2002). This pivotal study demonstrated a promising objective response rate (ORR) of 29.2% in patients with multiple myeloma who received at least three prior lines of therapy including a PI and an IMiD, or who were refractory to both a PI and an IMiD. Among the 31 responders, the median duration of response was 7.4 months (range 5.5 - not reached). This efficacy result was further supported by an ORR of 36% achieved in patients treated with 16 mg/kg of Darzalex in a Phase I/II study (Study GEN501). In order to confirm the clinical benefit of the product, additional data will be submitted for evaluation to Health Canada as part of the post-approval commitments.

The safety profile of Darzalex is considered manageable in the context of relapsed/refractory multiple myeloma. The most common adverse events (AEs) were infusion-related reactions (IRRs), fatigue, pyrexia, cough, nasal congestion, dyspnea, back pain, arthralgia, upper respiratory tract infection, nasopharyngitis, diarrhea, anemia, neutropenia and thrombocytopenia. Severe IRRs included bronchospasm, hypertension, dyspnea and hypoxia. The most frequently reported serious AEs were infections (e.g., pneumonia and herpes zoster), general physical health deterioration, pyrexia, hypercalcemia and crossmatch incompatible. Darzalex binds to CD38 on red blood cells and may result in a positive indirect Coombs test that may persist for up to 6 months after the last Darzalex infusion.

A Risk Management Plan (RMP) for Darzalex was submitted by Janssen Inc. to Health Canada. Upon review, the RMP was considered to be acceptable at this stage. 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 Look-alike Sound-alike brand name assessment was performed and the proposed name Darzalex was accepted.

Overall, the therapeutic benefits seen in the pivotal study are promising and the benefits of Darzalex therapy are considered to outweigh the potential risks. Darzalex has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling, and adequate monitoring. Appropriate warnings and precautions are in place in the Darzalex Product Monograph to address the identified safety concerns. As described within the framework of the NOC/c Guidance, safety monitoring on the use of Darzalex will be ongoing. Further evaluation will take place upon the submission of the requested studies after they become available.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3 What steps led to the approval of Darzalex?

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 Darzalex. An assessment was conducted and it was determined there was promising evidence of clinical effectiveness that the drug has the potential to provide:

  1. Effective treatment, prevention or diagnosis of a disease or condition for which no drug is presently marketed in Canada; or
  2. A significant increase in efficacy and/or significant decrease in risk such that the overall benefit/risk profile is improved over existing therapies, preventatives or diagnostic agents for a disease or condition that is not adequately managed by a drug marketed in Canada.

Submission Milestones: Darzalex

Submission Milestone Date
Pre-submission meeting: 2015-06-24
Submission filed: 2015-09-14
Screening  
Screening Deficiency Notice issued: 2015-10-16
Response filed: 2015-11-02
Screening Acceptance Letter issued: 2015-11-10
Review  
On-Site Evaluation:  
Quality Evaluation complete: 2016-05-16
Clinical Evaluation complete: 2016-06-09
Biostatistics Evaluation complete: 2016-06-09
Labelling Review complete: 2016-06-09
Notice of Compliance with Conditions (NOC/c) Qualifying Notice issued: 2016-05-27
Response filed (Letter of Undertaking): 2016-06-01
Notice of Compliance (NOC) issued by Director General, Biologics and Genetic Therapies Directorate under the Notice of Compliance with Conditions (NOC/c) Guidance: 2016-06-29

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

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

4 What follow-up measures will the company take?

As part of the marketing authorization for Darzalex, Health Canada requested and the sponsor agreed to several commitments to be addressed post-market. In addition to requirements 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, commitments include (but are not limited to) the following reports.

Confirmatory Studies

  • 1. Study MMY3003: Submit by the end of 2016, the interim analysis report of the confirmatory study (MMY3003) entitled Phase III, Randomized, Open-label, Active-controlled, Parallel-group, Multicentre Study of Daratumumab, Lenalidomide, and Low-dose Dexamethasone (DRd) Compared with Lenalidomide and Low-dose Dexamethasone (Rd) in Subjects with Relapsed or Refractory Multiple Myeloma. The final report will be submitted when available.

It was recommended that the study be sufficiently powered for the key secondary endpoint, overall survival (OS). The sponsor is aware that the indication for Darzalex can be withdrawn in the event of an unsuccessful study.

  • 2. Study MMY3004: Submit by the end of 2016, the interim analysis report of the confirmatory study (MMY3004) entitled Phase III Study Comparing Daratumumab, Bortezomib and Dexamethasone (DVd) versus (vs.) Bortezomib and Dexamethasone (Vd) in Subjects With Relapsed or Refractory Multiple Myeloma. The final report will be submitted when available.

It was recommended that the study be sufficiently powered for the key secondary endpoint OS. The sponsor is aware that the indication for Darzalex can be withdrawn in the event of an unsuccessful study.

  • 3. Studies MMY3003 and MMY3004: Provide a subgroup analysis of objective response rate (ORR) by the International Staging System (ISS) for both confirmatory studies MMY3003 and MMY3004. The role of disease stage as a potential prognostic and/or predictive marker of response should be further investigated in the confirmatory studies.

Final Reports

The following reports should be submitted when available:

  1. The final report of the completed study MMY2002 entitled An Open-label, Multicentre, Phase II Trial Investigating the Efficacy and Safety of Daratumumab in Subjects With Multiple Myeloma Who Have Received at Least 3 Prior Lines of Therapy (Including a Proteasome Inhibitor and IMiD) or are Double Refractory to a Proteasome Inhibitor and an IMiD.
  2. The final report of the completed study GEN501 entitled Daratumumab (HuMax-CD38) Safety Study in Multiple Myeloma, Open-label, Dose-Escalation Followed by Open-Label, Single-Arm Study.
  3. The final report of the completed study MMY1001 entitled An Open-label, Multicentre, Phase 1b Study of JNJ-54767414 (HuMax CD38) (Anti-CD38 Monoclonal Antibody) in Combination with Backbone Regimens for the Treatment of Subjects with Multiple Myeloma.
  4. The final report of the completed study MMY1002 entitled A Phase 1 Study of JNJ-54767414 (Daratumumab) in Japanese Patients with Relapsed or Refractory Multiple Myeloma.
  5. The final report of the completed study GEN503 entitled An Open-label, International, Multicentre, Dose Escalating Phase I/II Study Investigating the Safety of Daratumumab in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed or Relapsed and Refractory Multiple Myeloma.
  6. The validation reports to accurately detect binding antibodies and neutralizing antibodies to Darzalex with an appropriate level of tolerance to concentrations of Darzalex in clinical study serum samples. Along with these validation reports, an evaluation of antibody-drug antibodies response to Darzalex (both binding and neutralizing) in clinical studies should be performed.

Safety Monitoring

  1. Submit when available the safety analysis of Darzalex in multiple myeloma patients with baseline hepatic impairment from clinical studies MMY3003 and MMY3004.
  2. If the results of the confirmatory studies MMY3003 or MMY3004, and/or of other Darzalex clinical studies reveal greater safety risks for any subgroups and/or adverse events (AEs; for example [e.g.] cardiac AEs), appropriate risk mitigation strategies will be required (e.g. Product Monograph labelling and Risk Management Plan).
  3. Provide an evaluation of the relationship between daratumumab and QT from study SMm2001 when the SMm2001 study report is available.
  4. Based on the mechanism of action of Darzalex, there is a potential risk of hemolysis. Continue to monitor this as a potential safety signal in clinical studies and post-marketing safety data.
  5. Submit to Health Canada education materials for Darzalex regarding the interference with blood compatibility testing within 2 months after product launch.
5 What post-authorization activity has taken place for Darzalex?

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 Darzalex 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:

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision

 

Clinical Pharmacology

The medicinal ingredient of Darzalex, daratumumab, is an IgG1k (immunoglobulin G, subclass 1, kappa light chain) human monoclonal antibody (mAb) that targets the CD38 protein expressed at a high level on the surface of cells in a variety of hematological malignancies, including multiple myeloma tumour cells, as well as other cell types and tissues at various levels. The CD38 protein has multiple functions such as receptor-mediated adhesion, signalling and enzymatic activity. Daratumumab has been shown to inhibit the in vivo growth of CD38-expressing tumour cells.

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies. The clinical pharmacological data support the use of Darzalex for the specified indication.

In the 1 to 24 mg/kg cohorts, peak serum concentrations increased in a dose-proportional manner after the first dose, and volume of distribution was consistent with initial distribution into the plasma compartment.

Non-compartmental analysis was based on intensive sampling of approximately 39 subjects over a dosing range of 1 to 24 mg/kg. The systemic drug exposure calculated as area under the curve (AUC) increased more than proportionately with increasing dose, while the drug clearance decreased with increasing dose and repeated dosing. This response pattern suggests a target-mediated drug disposition (TMDD) which the sponsor attributes to linear and non-linear elimination pathways. At the recommended dosing level of 16 mg/kg, the non-linear pathway was saturated and only the linear elimination pathway with an estimated half-life of 18 days was considered relevant.

For further details, please refer to the Darzalex Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Darzalex was demonstrated in one pivotal study (MMY2002), and one key supportive study (GEN501).

Pivotal Study

Study MMY2002 was a Phase II, open-label, multicentre, single-arm, two-part study that enrolled patients with multiple myeloma who received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or who were refractory to both a PI and an IMiD. A total of 106 patients received 16 mg/kg of Darzalex monotherapy weekly for 8 weeks, then every two weeks for 16 weeks, and every four weeks thereafter until disease progression or unacceptable toxicity. The primary efficacy endpoint was objective response rate (ORR) according to the International Myeloma Working Group (IMWG) 2011 criteria as assessed by an Independent Review Committee (IRC). Tumour assessment was performed every 28 days (± 3 days) until disease progression. The key secondary endpoint was duration of response.

The median patient age was 63.5 years, 49% were male, and 79% were Caucasian. Patients received a median of 5 prior lines of therapy. Prior therapies included bortezomib (99%), lenalidomide (99%), pomalidomide (63%) and carfilzomib (50%). At baseline, 97% of patients were refractory to the last line of treatment, and 95% were refractory to both, a PI and an IMiD.

After a median duration follow-up of 9.3 months, patients treated with 16 mg/kg of Darzalex achieved an ORR of 29.2% (31/106 patients; 95% Confidence Interval [CI]: 20.8, 38.9%). The lower bound of the CI exceeded the protocol pre-specified lower bound of the 95% CI of 15%. Among the responders, 3 patients (2.8%) had a stringent complete response, none had a complete response, 10 patients (9.4%) had a very good partial response, and 18 patients (17.0%) had a partial response. The median duration of response was 7.4 months (range: 5.5 - not reached).

Several sensitivity analyses were performed and supported the robustness of the primary analysis. Additional secondary endpoints were assessed such as progression-free survival and overall survival. However, in the absence of a comparator arm, the results of these time-to-event endpoints cannot be reliably interpreted. Therefore, an improvement in survival or disease-related symptoms has not yet been established.

Key Supportive Study

Study GEN501 was a Phase I/II, first-in-human, single-arm, dose-escalation (Part 1) and cohort expansion (Part 2) study investigating Darzalex for the treatment of refractory or relapsed multiple myeloma. The primary efficacy endpoint was the ORR in patients who had received at least 2 previous lines of therapy including a PI and an IMiD. An ORR of 36% (95% CI: 21.6-52.0%) was observed in a cohort of 42 patients who received 16 mg/kg of Darzalex monotherapy. The median duration of response was not reached after 10.2 months of follow-up.

Overall Analysis of Efficacy

Overall, the efficacy data demonstrated promising evidence of the clinical effectiveness of Darzalex. Darzalex was authorized with conditions, pending the results of studies to verify its clinical benefit. Further evaluation will take place upon the submission of the requested studies after they become available.

The pivotal study MMY2002 demonstrated a promising ORR of 29.2% in patients with multiple myeloma, who have received at least three prior lines of therapy including a PI and an IMiD, or who are refractory to both a PI and an IMiD. Among the 31 responders, the median duration of response was 7.4 months. This efficacy result was further supported by an ORR of 36% achieved in patients treated with 16 mg/kg of Darzalex in Study GEN501.

The recommended indication is: "Darzalex is indicated for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or who are refractory to both a PI and an IMiD."

Clinical Safety

The integrated safety analysis was based on 156 patients with multiple myeloma, who received at least one dose of 16 mg/kg of Darzalex monotherapy from three clinical studies: MMY2002, GEN501 and MMY1002. The most commonly reported treatment-emergent adverse events (TEAEs, =15%) were infusion-related reactions (IRRs), fatigue, pyrexia, cough, nasal congestion, dyspnea, back pain, arthralgia, upper respiratory tract infection, nasopharyngitis, nausea, diarrhea, anemia, neutropenia and thrombocytopenia. Bleeding events also occurred in patients treated with Darzalex (15.1% in Study MMY2002 and 4.4% in Study GEN501). A total of 29% of the patients received a red blood cell transfusion. Treatment-emergent adverse events of Grade 3-4 were reported in 55.8% of the patients. Serious TEAEs were observed in 32.7% of the patients including pneumonia, general physical health deterioration, hypercalcemia, crossmatch incompatible and herpes zoster. Six patients discontinued treatment due to a TEAE including general physical health deterioration, H1N1 influenza, hypercalcemia, pyrexia, pneumonia and spinal cord compression. Four deaths due to TEAEs, pneumonia (number of patients [n] = 2), cardio-respiratory arrest (n = 1), and general physical health deterioration (n = 1), occurred within 30 days of the last dose of Darzalex.

Infusion-related reactions (IRRs) were one of the most important identified risks associated with Darzalex. A total of 48.1% of the patients experienced IRRs. Most of the IRRs (95%) occurred during the first infusion. The most common IRRs were nasal congestion, cough, allergic rhinitis, throat irritation, dyspnea, bronchospasm, hypertension, hypoxia, chills, pyrexia, nausea and vomiting. Severe IRRs included bronchospasm, hypertension, dyspnea and hypoxia. All patients received pre-medications to reduce the risk of IRRs prior to treatment with Darzalex. Patients also received post-medications to prevent delayed IRRs

Infections (any grade) were reported in 59% of patients. The most commonly reported infection (any grade) was respiratory tract infection (including upper respiratory tract infections and pneumonia) (47.4%). A total of 10.3% of the patients had Grade 3-4 infections, and pneumonia (5.8%) was the most commonly observed Grade 3-4 infection. Opportunistic infections were reported in 10.1% of the patients.

Darzalex binds to CD38 protein on red blood cells and may result in a positive indirect Coombs test that may persist for up to 6 months after the last Darzalex infusion. Crossmatch incompatibility was reported in patients treated with Darzalex. Additionally, Darzalex can be detected in serum protein electrophoresis assays and immunofixation assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in patients with IgGk myeloma protein.

In Study MMY2002, none of the 111 evaluable patients were tested positive for anti-Darzalex antibodies. However, the immunogenicity data cannot be reliably determined because the immunogenicity assay used in the pivotal study had limitations in detecting anti-Darzalex antibodies in the presence of high concentrations of Darzalex.

Overall, the safety profile of Darzalex is considered manageable. All identified and potential risks associated with Darzalex have been adequately captured in the Darzalex Product Monograph.

Darzalex 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. As described within the framework of the NOC/c Guidance, safety monitoring on the use of Darzalex will be ongoing. Further evaluation will take place upon the submission of the requested studies after they become available.

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

7.2 Non-Clinical Basis for Decision

The non-clinical pharmacology and toxicology studies support the use of Darzalex for the specified indication.

Darzalex binds to human and chimpanzee CD38 protein, but not to CD38 protein of other species. For this reason, non-clinical toxicity was assessed in a 6-week repeat-dose study in chimpanzees and in a 2-week repeat-dose study using a surrogate anti-CD38 antibody in monkeys. Darzalex was found to target primarily the hematopoietic and lymphatic systems, resulting in decreases in red blood cells, hemoglobin, white blood cells and platelets, and in lymphoid depletion. Infusion reactions and cytokine release syndrome, with one fatal event, were reported in chimpanzees that did not receive pre-infusion medication. Mild spinal cord inflammation was observed in one monkey treated with 100 mg/kg of a surrogate anti-CD38 antibody.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Darzalex Product Monograph. In view of the intended use of Darzalex, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.

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

7.3 Quality Basis for Decision

Darzalex (daratumumab drug substance) is a first-in-class, human IgG1 monoclonal antibody that binds CD38-expressing malignant cells with high affinity, inducing tumour cell death through diverse mechanisms of immune-mediated action; complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, as well as induction of apoptosis. Plasma cells from patients with multiple myeloma express high levels of CD38 protein. This target is distinct from those of other approved agents for multiple myeloma therapy.

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that daratumumab consistently exhibits the desired characteristic structure and biological activity.

Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within established limits and are considered to be acceptable.

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

Drug Substance

The drug substance, daratumumab, is produced in a mammalian cell line (Chinese Hamster Ovary) using recombinant deoxyribonucleic acid (DNA) technology. The manufacture is 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 Council for 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, pre-culture expansion, bioreactor production, harvesting, clarification, chromatography, viral inactivation, ultrafiltration, purification, 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 overall process validation and evaluation studies of the drug substance manufacturing process were performed using manufacturing scale batches and small-scale studies, representative of the manufacturing process and conditions. The entire validation process resulted in four process validation batches. All data from the process validation indicate that the manufacturing process is consistent; all batches were manufactured within the pre-set validation limits and met the acceptance criteria for in-process controls and quality attributes.

Drug Product

Darzalex is supplied as a colourless to yellow, sterile, preservative-free liquid concentrate in a Type 1 single-use glass vial. Each vial of Darzalex (100 mg/5 mL or 400 mg/20 mL) is individually packaged in a carton. Following dilution in commercially available 0.9% sodium chloride, the product is intended for intravenous infusion.

The method of manufacturing and the controls used during the manufacturing process for the drug product are valid and considered to be adequately controlled within justified limits.

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 International Council for Harmonisation (ICH) guidelines.

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-life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 18-month shelf-life at 2°C-8°C for Darzalex is considered acceptable when the product is protected from light.

The proposed packaging and components are considered acceptable.

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.

On-Site Evaluations of the facilities involved in the manufacture and testing of Darzalex drug substance and drug product were not warranted since the facilities were recently evaluated in good standing.

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

Adventitious Agents Safety Evaluation

The drug substance manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. The manufacturing process provides sufficient capacity 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 formulation are not of animal or human origin.

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