Summary Basis of Decision for Ibrance

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 Ibrance is located below.

Recent Activity for Ibrance

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 Ibrance

Updated:

2023-02-23

The following table describes post-authorization activity for Ibrance, a product which contains the medicinal ingredient palbociclib. 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 Number(s) (DINs):

  • DIN 02453150 – 75 mg palbociclib, capsule, oral administration
  • DIN 02453169 – 100 mg palbociclib, capsule, oral administration
  • DIN 02453177 – 125 mg palbociclib, capsule, oral administration
  • DIN 02493535 – 75 mg palbociclib, tablet, oral administration
  • DIN 02493543 – 100 mg palbociclib, tablet, oral administration
  • DIN 02493551 – 125 mg palbociclib, tablet, oral administration

 

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
New safety and effectiveness review Not applicable Started between 2022-01-01 and 2022-01-31 Health Canada started a safety and effectiveness review for Ibrance related to venous thromboembolic events (blood clots that form in a deep vein).
SNDS # 243405 2020-08-27 Issued NOC 2021-07-16 Submission filed as a Level I – Supplement to update the PM with data regarding use of Ibrance in pediatric patients. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Indications and Clinical Use, Warnings and Precautions, and Action and Clinical Pharmacology sections of the PM. An NOC was issued.
Drug product (DINs 02493535, 02493543, 02493551) market notification Not applicable Date of first sale: 2020-09-21 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NC # 234582 2019-12-19 Issued NOL 2020-01-27 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 Warnings and Precautions section of the PM. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 232295 2019-10-07 Issued NOC 2019-11-07 Submission filed as a Level I – Supplement to revise the outer labels for the capsules. The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS # 226755 2019-04-11 Issued NOC 2019-10-31 Submission filed as a Level I – Supplement for a new tablet formulation (75 mg, 100 mg, and 125 mg strengths). The data were reviewed and considered acceptable, and an NOC was issued. New DINs (02493535, 02493543, 02493551) were issued for the tablets.
SNDS # 223264 2018-12-21 Issued NOC 2019-10-15 Submission filed as a Level I – Supplement to update the PM with results from study PALOMA-3. 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.
PBRER-C # 226836 2019-04-15 Filed 2019-09-16 Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C for the period 2018-08-03 to 2019-02-02. The information was reviewed and found acceptable. No further action was required.
SNDS # 219500 2018-08-24 Issued NOC 2019-08-06 Submission filed as a Level I – Supplement to update the PM with new data, and to expand the indication. The indication was expanded to allow use in male patients with advanced breast cancer. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
NC # 227077 2019-04-23 Issued NOL 2019-07-26 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, and corresponding changes were made to Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.
PSUR-C # 209992 2017-10-06 Filed 2018-08-19 Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PSUR-C for the period 2017-02-03 to 2017-08-03. The information was reviewed and found acceptable. No further action was required.
PSUR-C # 217609 2018-06-26 Filed 2018-07-23 Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PSUR-C for the period 2017-08-03 to 2018-02-02. The information was reviewed and found acceptable. No further action was required.
SNDS # 207909 2017-07-26 Issued NOC
2018-06-06		 Submission filed as a Level I - Supplement to propose revisions to the approved indications of Ibrance including an expansion from the currently approved combination with letrozole to include combination of Ibrance with all aromatase inhibitors, as well as to indicate treatment for patients with hormone receptor (HR)-positive advanced breast cancer instead of the current restriction to patients with estrogen receptor (ER)-positive disease. Additionally, updates to the PM to include dosing recommendations for patients with mild, moderate or severe hepatic or renal impairment were proposed. Regulatory Decision Summary published.
PBRER-C # 182048 2016-04-11 Cleared
2018-01-26		 Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C for the period 2015-02-03 to 2016-02-02. The information was reviewed and found acceptable. No further action was required.
SNDS-C 200851 2016-12-02 Issued NOC
2017-11-17		 Submission filed as a Level I - Supplement in response to commitments made as per the provisions of the NOC/c Guidance. This SNDS-C was submitted to provide the final study report for the Phase III confirmatory study, Study 1008 (PALOMA-2), and to update the Ibrance PM with the data from this study. 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 Ibrance, and together, the data support the favourable benefit/risk profile of Ibrance in combination with letrozole for the treatment of women with ER-positive, HER2-neative advanced breast cancer who had not received any prior systemic anticancer treatment for advanced disease. The data were reviewed and considered acceptable. As a result of the submission, the conditions were removed from the NOC that had been issued on 2016-03-16.
SNDS # 195948 2016-06-14 Issued NOC
2017-05-19		 Submission filed as a Level I - Supplement for a new indication for Ibrance for use in combination with fulvestrant for the treatment of women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer whose disease progressed after prior endocrine therapy.

Regulatory Decision Summary published.
SNDS # 198800 2016-09-30 Issued NOC
2017-02-23		 Submission filed as a Level I - Supplement for the addition of an alternate encapsulator in addition to the previously approved encapsulator. The information was reviewed and considered acceptable. An NOC was issued.
SNDS-C # 195710 2016-06-06 Issued NOC under NOC/c Guidance
2016-10-06		 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 Top Line Summary for the confirmatory Phase III study for the use of Ibrance in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. Based on these results, the caveat associated with the indication was removed from the Indications and Clinical Use section of the Product Monograph.
Drug product (DIN 02453150) market notification Not applicable Date of first sale:
2016-04-20		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
Drug product (DINs 02453169, 02453177) market notification Not applicable Date of first sale:
2016-04-19		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 182048 2015-02-12 Issued NOC
2016-03-01		 Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Ibrance

Date SBD issued: 2016-05-19

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

Palbociclib, 75 mg, 100 mg, and 125 mg, capsules, oral

Drug Identification Number (DIN):

  • DIN 02453150 - 75 mg, capsule
  • DIN 02453169 - 100 mg, capsule
  • DIN 02453177 - 125 mg, capsule

Pfizer Canada Inc.

New Drug Submission Control Number: 182048

On March 16, 2016, Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance to Pfizer Canada Inc. for the drug product Ibrance. 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 Ibrance is favourable for use in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. While clinical effectiveness of Ibrance is based on a relatively large observed progression-free survival (PFS) benefit in a single, open label randomized Phase II clinical study, study design limitations precluded statistical inference, and internal inconsistencies within the study results suggested possible investigator bias favouring the Ibrance (palbociclib) arm. The magnitude of benefit may differ in the ongoing placebo-controlled Phase III study. Continued approval for this indication is contingent upon verification and description of clinical benefit in the confirmatory trial.

1 What was approved?

Ibrance, a protein kinase inhibitor, was authorized for use in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. While clinical effectiveness of Ibrance is based on a relatively large observed progression-free survival (PFS) benefit in a single, open label randomized Phase II clinical study, study design limitations precluded statistical inference, and internal inconsistencies within the study results suggested possible investigator bias favouring the Ibrance (palbociclib) arm. The magnitude of benefit may differ in the ongoing placebo-controlled Phase III study. Continued approval for this indication is contingent upon verification and description of clinical benefit in the confirmatory trial.

In the Phase II study of Ibrance plus letrozole in advanced breast cancer patients, 46% of the patients were ≥65 years of age. No overall differences in the efficacy of Ibrance plus letrozole treatment were observed between these patients and younger patients.  Neutropenia and leukopenia (all grades and Grades 3 and 4) were reported more frequently in patients ≥65 compared to <65 years of age.

The safety and efficacy of Ibrance in children and adolescents <18 years have not been studied.

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

Ibrance (75 mg, 100 mg, and 125 mg, palbociclib) is presented as capsules. In addition to the medicinal ingredient, the capsules contain ammonium hydroxide, colloidal silicon dioxide, gelatin, lactose monohydrate, magnesium stearate, microcrystalline cellulose, propylene glycol, red iron oxide, shellac, simethicone, sodium starch glycolate, titanium dioxide, and yellow iron oxide.

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

2 Why was Ibrance approved?

Health Canada considers that the benefit/risk profile of Ibrance is favourable for use in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. While clinical effectiveness of Ibrance is based on a relatively large observed progression-free survival (PFS) benefit in a single, open label randomized Phase II clinical study, study design limitations precluded statistical inference, and internal inconsistencies within the study results suggested possible investigator bias favouring the Ibrance (palbociclib) arm. The magnitude of benefit may differ in the ongoing placebo-controlled Phase III study. Continued approval for this indication is contingent upon verification and description of clinical benefit in the confirmatory trial. Ibrance 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.

Breast cancer is the most common cancer in women worldwide. According to current Canadian cancer statistics, it is the most frequently diagnosed cancer and the second leading cause of cancer death in females. The lifetime risk of women developing breast cancer is estimated to be 1 in 9, and the lifetime probability of dying from the disease is 1 in 29. The median age of patients at breast cancer diagnosis is 61. Although age-adjusted mortality from breast cancer has been decreasing since 1990, metastatic breast cancer still remains a life-threatening disease for which no cure is currently available.

Breast cancer is a heterogeneous disease, with subtypes that can be characterized based on their hormonal receptor status and human epidermal growth factor receptor 2 (HER2) receptor status.

The specific type of breast cancer of interest for the current submission is estrogen receptor (ER)-positive, HER2-negative advanced breast cancer in postmenopausal women.

Palbociclib, the medicinal ingredient in Ibrance, is a first in class inhibitor of cyclin-dependent kinase (CDK) 4 and CDK 6 that prevents cellular proliferation by prohibiting progression of the cell cycle from G1 into the S phase, thereby inhibiting cell division.

The market authorization with conditions was based primarily on efficacy and safety data from one Phase I/II study (Study 1003 - PALOMA-1) performed in the target patient population. The assessment of efficacy relied on the randomized, open-label, Phase II portion of this study, which evaluated the use of Ibrance in combination with letrozole, compared to single agent letrozole, for the first-line treatment of ER-positive, HER2-negative advanced breast cancer in postmenopausal women. The results of the Phase II portion of Study 1003 suggested a 10-month improvement in the primary efficacy endpoint, investigator-assessed progression-free survival (PFS) in patients treated with Ibrance plus letrozole compared to patients treated with letrozole alone (20.2 months versus 10.2 months, respectively; Hazard Ratio [HR] = 0.49). However, there were many sources of uncertainty in this study, including the likely presence of bias and the implementation of data-driven protocol amendments that precluded statistical inference. While a statistically significant benefit of Ibrance plus letrozole (over letrozole alone) has not been demonstrated and the magnitude of the benefit is uncertain, Health Canada considered that the reported point estimate for the PFS hazard ratio provided promising evidence of clinical efficacy in the target patient population. Health Canada noted that patients who may be treated with the Ibrance plus letrozole combination will also be receiving a standard of care (letrozole) for their disease. Health Canada also noted that an additional clinical trial has been reported in the medical literature to show that palbociclib combined with fulvestrant resulted in longer PFS than fulvestrant alone among patients with hormone-receptor-positive metastatic breast cancer who had progression of disease during or after completion of prior endocrine therapy. In order to confirm the clinical benefit of Ibrance, the results of the confirmatory trial, a currently ongoing Phase III study in the same patient population (Study 1008: PALOMA-2) will be submitted for evaluation to Health Canada as part of the post-approval commitments.

The assessment of the safety profile demonstrated that the addition of Ibrance to letrozole treatment increased reports of cytopenias (especially neutropenia), infections, diarrhea, nausea, eye disorders, and pulmonary embolism. Neutropenia was the most frequently reported treatment-emergent adverse event in both phases of the pivotal study, reported by 92% of patients in the Phase I portion and 75% of patients in the Phase II portion of the study, compared to 5.2% in the letrozole-alone arm. There were also more reports of infections in the Ibrance plus letrozole treatment arm compared to letrozole alone. There were no reports of febrile neutropenia or neutropenic sepsis in either treatment arm of the pivotal study.

Pulmonary embolism was the most significant serious adverse event, reported more frequently in the Ibrance plus letrozole arm than in the letrozole only arm; however, 80% (4/5) of the reported cases were detected through imaging only and were asymptomatic in the affected patients.

Neutropenia was identified as a serious adverse drug reaction (ADR) in patients using Ibrance and is the only ADR included in the Serious Warnings and Precautions Box in the Ibrance Product Monograph.

A Risk Management Plan (RMP) for Ibrance was submitted by Pfizer 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 Look‑alike Sound‑alike brand name assessment was performed and the proposed name Ibrance has been deemed acceptable.

Overall, the therapeutic benefits seen in the pivotal study are promising and the benefits of Ibrance therapy in combination with letrozole are considered to potentially provide a significant increase in efficacy such that the overall benefit/risk profile is improved over the existing therapy of letrozole alone. The submitted data and supportive evidence from the literature provide promising evidence of the clinical effectiveness of Ibrance in combination with letrozole for the treatment of postmenopausal women with ER-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. Clinical effectiveness of Ibrance is based on an observed PFS benefit in a single, open-label randomized Phase II clinical study that had design flaws precluding statistical inference and evidence of investigator bias favouring the Ibrance plus letrozole arm. Continued approval for this indication is contingent upon verification and description of clinical benefit in a confirmatory Phase III trial.

Ibrance 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 Ibrance Product Monograph to address the identified safety concerns. As described within the framework of the NOC/c Guidance, safety monitoring on the use of Ibrance 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 Ibrance?

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 Ibrance. An assessment was conducted to determine whether it provided 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. As a result of this assessment, Health Canada considered that the criteria were not met based the information provided. The sponsor was advised that it could file the submission as a regular NDS.

The sponsor subsequently filed a standard NDS, which included a detailed document to specifically address the issues outlined by Health Canada that precluded filing of the NDS under the NOC/c Guidance. The main deficiencies included the small size of the study population in the single Phase I/II trial, which might not adequately establish the safety profile of Ibrance, and in which there was the potential for investigator bias due to the open-label study design. There was also concern that the observed benefit may not translate to equally positive Phase III trial results. Furthermore, the efficacy was greater in an unselected patient population compared to the subgroup of patients identified as biomarker positive, suggesting that the mechanism of action of the drug may not be well understood. Health Canada was also not convinced that Ibrance was meeting an unmet medical need for the target patient population, given the availability of other therapies (for example [e.g.], anastrozole, tamoxifen, and chemotherapy) for first-line treatment of advanced breast cancer.

In its rationale supporting the request for authorization, the sponsor emphasized that there are over 1,000 patients/subjects who have received Ibrance, either as a single agent or in combination with other therapies in the safety database as of the cut-off date (November 29, 2013), suggesting that there is a sufficiently large population to assess the safety of the drug. Furthermore, in accordance with Health Canada's NOC/c Guidance, the ongoing Phase III trial (Study 1008 - PALOMA-2) is designed to confirm the results of Study 1003 PALOMA-1, and the sponsor has indicated that it will withdraw the indication should the primary endpoint of the Phase III trial not reach statistical significance. It was emphasized that the mechanism of action of palbociclib, in terms of cyclin-dependent kinase (CDK) 4/6 inhibition and interaction with estrogen, is well-established; however, breast cancer is a heterogeneous disease, and the ongoing Phase III study is also actively evaluating the biomarker hypothesis.

Importantly, the sponsor also provided further rationale supporting the view that there is an unmet medical need for postmenopausal women with advanced breast cancer. A clinical expert explained that despite the number and variety of therapeutic agents available to treat advanced breast cancer, resistance to endocrine therapy remains a substantial clinical concern in this setting, as all patients eventually develop progressive disease. Also, as the extent of established endocrine therapy use increases in the (neo)adjuvant setting, there is a clinical need for additional effective, minimally toxic therapies that overcome endocrine therapy resistance, or act synergistically with endocrine therapy, to prolong progression-free survival (PFS) in the first-line setting. In this context of unmet medical need in the treatment of advanced breast cancer, where palbociclib, a reversible inhibitor of CDK4 and CDK6, has a novel mechanism of action involved in cell cycle regulation, the sponsor sufficiently justified its position that an NOC/c could be an appropriate recommendation if the submitted safety, efficacy, and chemistry data were determined to be acceptable upon a complete benefit-harm-uncertainty assessment.

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: Ibrance

Submission Milestone Date
Pre-submission meeting 1: 2013-05-02
Pre-submission meeting 2: 2014-10-08
Refusal of Advance Consideration under the Notice of Compliance with Conditions (NOC/c) Guidance: 2014-12-05
Submission filed: 2015-02-12
Screening  
Screening Acceptance Letter issued: 2015-03-27
Review  
Biopharmaceutics Evaluation complete: 2015-12-01
Quality Evaluation complete: 2016-01-08
Clinical Evaluation complete: 2016-01-20
Labelling Review complete: 2016-01-20
Notice of Compliance with Conditions (NOC/c) Qualifying Notice issued: 2016-01-21
Response filed (Draft Letter of Undertaking): 2016-02-11
Response filed (Letter of Undertaking): 2016-03-14
Notice of Compliance (NOC) issued by Director General, Therapeutic Products Directorate, under the Notice of Compliance with Conditions (NOC/c) Guidance: 2016-03-16

The Canadian regulatory decision on the non-clinical and clinical review (with the exception of the review of the pharmacodynamic studies) of Ibrance was based on a critical assessment of the Canadian data package. The foreign reviews completed by the United States Food and Drug Administration (FDA) were used as an added reference. The Canadian regulatory decision on the review of the clinical pharmacodynamic studies was based on the United States FDA review, referring to the data filed in Canada as necessary.

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 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 Studies

Study 1008 (PALOMA-2): A randomized, multicentre, double-blind, Phase III Study of Ibrance plus letrozole versus placebo plus letrozole for the treatment of postmenopausal women with ER-positive, HER2-negative breast cancer who have not received any prior systemic anti-cancer treatment for advanced disease.

To confirm the clinical benefit of Ibrance for the treatment of these patients, as initial endocrine-based therapy for their metastatic disease, Pfizer Canada Inc. will submit the following:

The sponsor will submit as a Supplemental New Drug Submission-Confirmatory (SNDS-C) Study:

  • High level results for Study 1008 (PALOMA-2). These results will be provided at their earliest availability. Pfizer has indicated that it will withdraw the indication should the primary endpoint of the Phase III trial not reach statistical significance.
  • The final study report for Study 1008 (PALOMA-2). This report will be submitted at its earliest availability.

Post-Market Safety Monitoring

The sponsor agrees to submit:

  • All serious adverse drug reactions (ADRs) that occur in Canada and all serious unexpected ADRs that occur outside of Canada within 15 days to Health Canada, in accordance with the current regulations and guidance documents.
  • Conclusions from the analysis of Pfizer's Annual Safety Summary Reports to Health Canada in a manner deemed consistent with the NOC/c Guidance.
5 What post-authorization activity has taken place for Ibrance?

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 Ibrance 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

Palbociclib is a selective inhibitor of cyclin-dependent kinases (CDK) 4 and 6. Cyclin D1 and CDK4/6 are downstream of multiple signaling pathways which lead to cellular proliferation. Through inhibition of cyclin D-CDK4/6 complex activity, palbociclib inhibits the phosphorylation of retinoblastoma (Rb) protein, blocking cell cycle progression from G1 into S phase. In a panel of molecularly profiled breast cancer cell lines, palbociclib exhibited the greatest efficacy towards the luminal estrogen receptor (ER)-positive subtype. In combination with anti-estrogen agents, palbociclib demonstrated enhanced inhibition of cell proliferation and induction of cell senescence in ER-positive breast cancer models.

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

The single- and multiple-dose pharmacokinetics of palbociclib were evaluated in patients with solid tumors including advanced breast cancer. Following oral administration to patients with advanced breast cancer, peak plasma levels of palbociclib were observed within 4 to 8 hours, with a mean half-life of 28.8 hours. The mean apparent oral clearance was 63.1 L/hr. In the dosing range of 25 mg to 225 mg, palbociclib exposure increased proportionally with dose in general. Steady state was achieved within 8 days following repeated once-daily dosing, with a median accumulation ratio of 2.4.

Palbociclib is primarily eliminated by hepatic metabolism. Population pharmacokinetic analysis indicated that mild hepatic impairment or mild to moderate renal impairment has no impact on the exposure of palbociclib. Ibrance has not been studied in patients with moderate or severe hepatic impairment or severe renal impairment. Palbociclib is a substrate and weak inhibitor of cytochrome P450 (CYP) 3A. Drug-drug interactions were observed when Ibrance was coadministered with a strong CYP3A inhibitor and a strong CYP3A inducer. No study of the effect of moderate CYP3A inducers on palbociclib exposure was submitted. Concomitant use of strong CYP3A inhibitors or moderate to strong CYP3A inducers should be avoided. Concomitant use of Ibrance and a CYP3A substrate may increase exposure to the CYP3A substrate. Caution is warranted when Ibrance is co-administered with CYP3A substrates of narrow therapeutic index.

The effect of food on palbociclib exposure was evaluated in healthy volunteers. Compared to Ibrance given under overnight fasted conditions, the area under the concentration time curve (AUCinf) and maximum concentration (Cmax) of palbociclib increased by 21% and 38% when given with high-fat food, by 12% and 27% when given with low-fat food, and by 13% and 24% when given with moderate-fat food 1 hour before and 2 hours after Ibrance dosing. In addition, food intake significantly reduced the inter-subject and intra-subject variability of palbociclib exposure. Based on these results, Ibrance should be taken with food.

A pharmacokinetic/pharmacodynamic analysis was conducted using data from 184 patients with advanced cancer to evaluate the relationship between heart rate‑corrected QT interval according to study-specific criteria (QTcS) and palbociclib concentration. A positive correlation was observed between QTcS and palbociclib concentration, with a mean QTcS increase of 5.60 msec, and upper bound 1-sided 95% confidence interval of 8.72 msec at the mean observed maximal steady-state palbociclib concentration following a therapeutic schedule (that is [i.e.], 125 mg daily for 21 consecutive days followed by 7 days off to comprise a complete cycle of 28 days). Despite the slight linear relationship between palbociclib concentration and QTcS, at the mean or median maximal steady-state palbociclib concentrations, the upper bound of the one-sided 95% confidence interval for the increase in QTcS did not exceed the threshold of 10 msec, suggesting that clinically relevant QT prolongation due to palbociclib at the recommended therapeutic dose is unlikely. This information is included in the proposed Product Monograph. A dedicated electrocardiogram (ECG) substudy is currently being performed by the sponsor.

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

Clinical Efficacy

The efficacy of Ibrance (palbociclib) for the first-line treatment of estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer in postmenopausal women was supported by Study 1003 (PALOMA-1), a Phase I/II open-label, randomized study, comparing Ibrance plus letrozole against letrozole alone. The patients studied had not previously received any anticancer therapies for advanced disease.

The Phase I portion of the study enrolled 12 patients to assess the safety and tolerability of the combination of Ibrance and letrozole and to exclude a drug-drug interaction with the combination. This portion of the study did not contribute to the efficacy conclusions. The Phase II portion of the study was randomized, open-label, and was divided into two parts to assess the efficacy and safety of Ibrance in combination with letrozole versus (vs.) letrozole-alone in the first-line treatment of ER-positive, HER2-negative, postmenopausal patients with advanced breast cancer in:

  • a biomarker-unselected population (Phase II Part I [Ph2P1]; total number [n] = 66); and
  • a biomarker-selected population; a prospectively defined population of patients whose tumours additionally demonstrated genomic amplification of cyclin D1 (CCND1) and/or loss of CDKN2A/p16 gene (Phase II Part II [Ph2P2]); n = 99).

All patients were randomized with two stratification factors: disease site and disease-free interval from adjuvant therapy to recurrence. An interim analysis of Ph2P1 data was performed and showed that the clinical activity of Ibrance in combination with letrozole was independent of patients' biomarker (CCND1/p16) status. After these interim results, accrual to Ph2P2 was terminated, and the protocol was amended to determine the clinical benefit in patients randomized to both Ph2P1 and Ph2P2 combined for the primary efficacy endpoint, with secondary analyses performed for Ph2P1 and Ph2P2 separately. The primary endpoint of the study was investigator-assessed progression-free survival (PFS) evaluated according to Response Evaluation Criteria in Solid Tumours Version 1.0 (RECIST 1.0). The data showed a 10 month improvement in investigator-assessed PFS in patients treated with Ibrance plus letrozole compared to patients treated with letrozole alone (20.2 months versus [vs.] 10.2 months, respectively; Hazard Ratio [HR] = 0.49). Although p-values and 95% confidence intervals were provided in the study report, it was not possible to make statistical inferences due to the data-driven protocol amendments and these statistics were not included in the Clinical Trials section of the Product Monograph.

The secondary efficacy endpoint, overall response rate (ORR), favoured the Ibrance plus letrozole treatment arm compared to letrozole alone (55% vs. 39%, respectively) in patients with measurable disease. Overall survival data were not yet mature, with events having been reported for only 37% of patients.

Limitations of Study 1003 (PALOMA-1)

There were multiple significant data-driven protocol amendments implemented during conduct of the study, including:

  • Amendment 3: Phase II was split into two parts as a result of pre-clinical data, where Cohort 2 (Ph2P2) was to enroll only patients with biomarker-positive disease;
  • Amendment 5: the primary endpoint was changed from PFS from the Ph2P2 Cohort to PFS from both Ph2P1 and Ph2P2 Cohorts; and
  • Amendment 7: the timing of the final analysis was changed, to be performed when approximately 95 events had been accumulated, instead of the previously-determined 114 PFS events.  

The fact that these protocol amendments were data-driven precluded statistical inference of the resulting data and limited the overall conclusions that could be made. As there are no statistical methods that can take into account the clinical and operational aspects of these amendments, Health Canada considered that no statistical conclusions could be made from the study, the reported p-values and 95% confidence intervals are not meaningful, and the magnitude of difference between letrozole alone and Ibrance in combination with letrozole in PFS is uncertain. 

There were a high number of protocol deviations in the Phase II portion of the study, including significant protocol deviations to the inclusion/exclusion criteria. There were also imbalances in some baseline characteristics, including those with prognostic implications (for example [e.g.], bone-only disease vs. visceral disease and prior anticancer treatments patients received) between the Ibrance plus letrozole treatment arm compared to the letrozole-alone arm.

The primary endpoint of investigator-assessed PFS was not confirmed by Blinded Independent Central Review (BICR) analysis of the combined Ph2P1 + Ph2P2 dataset, which resulted in a HR of 0.62 (compared to the investigator-assessed HR of 0.49). This inconsistency appears to be due to informative censoring, where there was a much larger percentage of patients in the letrozole only arm (41%) compared to the Ibrance plus letrozole arm (12%) who discontinued due to relapse that was not confirmed by BICR. When looking at the two cohorts separately, Ph2P1 shows a large discrepancy between the two analyses, suggesting there may be a major bias associated with the investigator results, specifically in the biomarker-unselected patient population:

  • In Ph2P1: BICR HR = 0.73; investigator HR = 0.30
  • In Ph2P2: BICR HR = 0.58; investigator HR = 0.51

This censoring of the BICR data results in investigator-reported efficacy data for PALOMA-1 that may not be reliable, as the magnitude of benefit seen in the full Phase II population is largely driven by the Ph2P1 data.

In an attempt to partially address some of the limitations of the study, the sponsor provided additional analyses. Both pre-planned and ad hoc sensitivity analyses were performed, all of which supported the primary efficacy data favouring the Ibrance plus letrozole treatment arm. A number of sensitivity analyses were also performed independently by the United States Food and Drug Administration (FDA); including a "worst case" analysis of PFS in which patients who discontinued treatment without a documented PFS event were censored in the control arm but were considered as having a PFS event in the combination treatment arm. Although the results of all sensitivity analyses were supportive of the primary efficacy analysis, suggesting a longer PFS in the Ibrance plus letrozole arm compared to letrozole alone, they were performed on the full Phase II population, despite the likely investigator bias in the Part 1 portion of the population.

Overall Analysis of Efficacy

Overall, there were many sources of uncertainty in the Phase II portion of Study 1003 (PALOMA-1), including the presence of bias and the implementation of significant protocol amendments. A statistically significant benefit of Ibrance plus letrozole (over letrozole alone) has not been demonstrated. It is considered that the point estimate for the PFS hazard ratio reported in the Phase II portion of the Study 1003 provides promising evidence of clinical efficacy in the context of the treatment for first-line treatment of advanced breast cancer in postmenopausal patients with ER-positive, HER2-negative disease. Given the serious nature of the disease and the medical need for therapy to prolong life and delay disease progression, it is considered that, despite the study limitations, the data from the Phase II portion of Study 1003 are sufficient to conclude that the addition of Ibrance to letrozole provides a clinical benefit to the target patient population; however, additional data, from the ongoing Phase III trial in the same patient population (Study 1008: PALOMA-2), are required in order to confirm the effectiveness of Ibrance as a first-line treatment in postmenopausal women with ER-positive, HER2-negative advanced breast cancer.

Indication

The sponsor proposed the following indication:

Ibrance (palbociclib) is indicated in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease.

To ensure the safe and effective use of the product, Health Canada requested that the following additional paragraph be included with the above indication:

While clinical effectiveness of Ibrance is based on a relatively large observed PFS benefit in a single, open label randomized Phase II clinical study, study design limitations precluded statistical inference, and internal inconsistencies within the study results suggested possible investigator bias favouring the palbociclib arm. The magnitude of benefit may differ in the ongoing placebo-controlled Phase III study. Continued approval for this indication is contingent upon verification and description of clinical benefit in the confirmatory trial.

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

Clinical Safety

The clinical safety of Ibrance was primarily evaluated in Study 1003 (PALOMA-1) described in the Clinical Efficacy section. Additional safety data were also evaluated from clinical studies of Ibrance in ongoing trials and in other indications.

A total of 851 subjects/patients (from the Phase I-III studies) were evaluated for safety, including 393 healthy volunteers (46.2%), 255 patients (30.0%) with malignant disease who received at least one dose of Ibrance, 77 patients (9.0%) who received a comparator, and 126 patients (14.8%) who were randomized to blinded therapy. Of the 255 patients with malignant disease who received at least one dose of Ibrance, 101 patients were postmenopausal women with advanced breast cancer who received Ibrance in combination with letrozole in the pivotal Study 1003 (n = 95) and Part 2 of ongoing Study 1010 (n = 6) comprising the target population and the recommended dosing regimen for palbociclib treatment. The most relevant safety data for this submission comes from Study 1003, which also had a comparator treatment arm, and was the focus of the safety review for this file. This is a relatively small patient population, especially given the frequency of the disease (advanced breast cancer) in the Canadian population, although the supportive safety data from other studies does contribute to the overall safety profile of the drug, and helps to alleviate concerns regarding the size of the safety database.

In the Phase I portion of Study 1003 (n = 12), the average daily dose of palbociclib administered was 125 mg (range: 102 to 129 mg) and the average daily dose of letrozole was 2.5 mg (range: 2.5 mg). The median duration of treatment was 374 days and 353 days for palbociclib and letrozole, respectively. The median relative dose intensity was 90% and 100% for palbociclib and letrozole, respectively.

In Phase II (Ph2P1 + Ph2P2), the average daily dose of palbociclib was 125 mg (range: 80 to 267 mg). The average daily dose of letrozole was 2.5 mg (range: 2.5 mg) in both the palbociclib plus letrozole arm and the letrozole-alone arm. The median duration of treatment was longer in the palbociclib plus letrozole arm (420 days for palbociclib and 428 days for letrozole) than in the letrozole-alone arm (231 days).

The results of Study 1003 showed that Ibrance in combination with letrozole was associated with an increased frequency of adverse events (AEs), serious adverse events (SAEs), and (permanent as well as temporary) drug discontinuations compared to letrozole-alone treatment. 

Neutropenia (decreased neutrophil counts) was the most frequently reported treatment-emergent adverse event (TEAE) in both phases of the study:

  • Phase I - 92% of patients receiving Ibrance plus letrozole reported neutropenia
  • Phase II - 75% of patients receiving Ibrance plus letrozole vs. 5% in the letrozole-alone arm (Ph2P2). 

The remaining frequently reported TEAEs were fatigue (41%; Grade 3, 2% and Grade 4, 2%), anemia (35%, Grade 3, 5% and Grade 4, 1%), nausea (25%), arthralgia (23%), alopecia (22%), diarrhea and hot flush (21% each), and thrombocytopenia (17%). In the Phase II portion of Study 1003, there were significantly more reports of Grade 3 neutropenia (48%) than any other grade in the Ibrance plus letrozole treatment arm. Leukopenia (decreased leukocyte counts) was also frequently reported in the Phase II portion (43% of patients in the palbociclib plus letrozole treatment arm), with a large percentage of patients reporting Grade 3 leukopenia (19%); however, despite the high number of reports of neutropenia, anemia, leukopenia, and thrombocytopenia, there were no SAEs reported for any of these AEs. A Serious Warnings and Precautions Box has been included in the Product Monograph for Ibrance to warn of the possibility of neutropenia.

There were also more reports of infections in the Ibrance plus letrozole treatment arm compared to letrozole alone (55% vs. 34%, respectively). There were no reports of febrile neutropenia or neutropenic sepsis in either treatment arm in Study 1003, although there were two reports of febrile neutropenia in Ibrance-treated patients from other studies in the Ibrance clinical trial safety database. The Warnings and Precautions section of the Product Monograph provides the frequency of infection in Study 1003, and also recommends monitoring and treatment for these patients.

Significantly more patients reported SAEs in the Ibrance plus letrozole treatment arm (22%) compared to letrozole alone (7%). Pulmonary embolism was reported more frequently in the palbociclib plus letrozole treatment arm (5%) compared to the letrozole only treatment arm (0%); however, 4 of the 5 cases were detected through imaging and were asymptomatic. It has been suggested by a clinical expert, and supported by published literature, that this rate may be within the range of pulmonary embolism incidence in a typical advanced breast cancer population, and it was hypothesized that the higher incidence compared to the control arm reported in this study was related to the prolonged exposure to treatment in the Ibrance plus letrozole treatment arm compared to the control arm. Pulmonary embolism is included in the Warnings and Precautions section of the Product Monograph.

There were more patients who permanently discontinued from study treatment in the Ibrance plus letrozole treatment arm (15%) compared to the letrozole-alone treatment arm (3%). The only AE that led to discontinuation in more than one patient was neutropenia, which led to permanent discontinuation in 5 patients (6%), all of whom were in the Ibrance plus letrozole treatment arm. There were 32 patients (39%) who had their Ibrance dose reduced due to AEs, and 42 patients (51%) who required temporary drug discontinuation. Most patients, however, did not require permanent discontinuation, suggesting that temporary discontinuation and/or dose reductions were frequently sufficient for the management of AEs. The Ph2P2 cohort of patients experienced a lower frequency of discontinuations due to neutropenia compared to the Ph2P1 cohort, suggesting that dose modifications were optimized during Ph2P1 and were effective at reducing the incidence of neutropenia requiring discontinuation.

Overall Analysis of Safety

The safety profile of Ibrance used in combination with letrozole comes predominantly from the pivotal study for the target indication (advanced breast cancer) for this submission. Supportive safety studies submitted contributed to the overall safety profile; however, in these other studies, Ibrance was used either as a single agent or in combination with other agents. Despite the different conditions of use, the supportive studies were generally consistent in the AEs reported.

Overall, Ibrance treatment increased the reports of cytopenias (especially neutropenia), infections, diarrhea, nausea, eye disorders, and pulmonary embolisms. Given that advanced breast cancer is a serious, life-threatening disease, the toxicity profile is considered to be tolerable and manageable for the target patient population.

The following warning has been included in a Serious Warnings and Precautions box in the Product Monograph for Ibrance: Neutropenia.

Appropriate warnings and precautions are in place in the approved Ibrance Product Monograph to address the identified safety concerns.

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

7.2 Non-Clinical Basis for Decision

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

The non-clinical review of Ibrance included the evaluation of non-clinical and safety pharmacology, pharmacokinetic, general toxicology, genetic toxicology, and reproductive and developmental toxicology studies.

The non-clinical pharmacodynamic studies support the use of Ibrance (palbociclib) in postmenopausal women with ER-positive, HER2-negative breast cancer. An in vitro study from the literature showed that ER-positive breast cancers with increased retinoblastoma protein (pRb) and cyclin D1 and decreased cyclin-dependent kinase inhibitor 2A (p16) were most sensitive to palbociclib; however, the expression levels of cyclin D1 and p16 were not measured in the breast cancer models used in non-clinical pharmacodynamic studies. It is uncertain if the biomarker (cyclin D1 amplification and/or p16 loss) would predict a better clinical response to palbociclib treatment.

In cardiovascular safety pharmacology studies in dogs, QTc interval prolongation was highly correlated with the plasma exposure to palbociclib.

In repeat dose toxicology studies, the primary palbociclib-related toxicities were observed in the bone marrow, lymphoid tissues and male reproductive organs, consistent with the pharmacological action of palbociclib. In addition, altered glucose metabolism and secondary changes in the eye (cataracts/lens degeneration), incisor teeth (ameloblast degeneration), kidney (tubule vacuolation) and adipose tissue (atrophy) were observed in longer term studies (≥ 15 weeks) in the rat, but not in dog. Changes attributable to hyperglycemia were not reversible. The mechanism and human relevance of alterations in glucose metabolism remain unclear.

Non-reversible effects on bone (decrease in trabeculae in the femur) were observed in male rats following 27 weeks of intermittent dosing. These effects are considered of potential relevance to humans. The risk to an adult population with mature trabeculae is unclear, but a risk is considered to exist for a pediatric population.

Palbociclib was shown to be aneugenic in in vitro and in vivo genotoxicity studies. In developmental toxicity studies in rats and rabbits, palbociclib was shown to be fetotoxic.

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

7.3 Quality Basis for Decision

The Chemistry and Manufacturing information submitted for Ibrance has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. The pharmaceutical development was considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 24 months when stored between 20-25°C is acceptable.

Proposed limits of drug-related impurities are considered adequately qualified (that is ([i.e.] within International Council for Harmonisation [ICH] limits and/or qualified from toxicological studies).

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

All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.

Two excipients in the hard capsule shell, gelatin and lactose monohydrate, are of animal origin. Letters of attestation confirming that the materials are not from a bovine spongiform encephalopathy and transmissible spongiform encephalopathy (BSE/TSE) affected country/area have been provided for this product indicating that it is considered to be safe for human use. The magnesium stearate is of vegetable origin.

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