Summary Basis of Decision for Cimzia ™
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:
CimziaTM
Certolizumab pegol, 200 mg/mL, Solution, Subcutaneous
UCB Canada Inc.
Submission control no: 120296
Date issued: 2010-03-11
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02331675
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
™Cimzia is a trademark of the UCB Group of Companies
2 Notice of decision
On August 12, 2009, Health Canada issued a Notice of Compliance to UCB Canada Inc. for the drug product Cimzia.
Cimzia contains the medicinal ingredient certolizumab pegol which is a biological response modifier that belongs to the tumour necrosis factor (TNF)-blocker class of drugs.
Cimzia in combination with methotrexate (MTX) is indicated for:
- reducing signs and symptoms, inducing major clinical response, and reducing the progression of joint damage as assessed by X-ray, in adult patients with moderately to severely active rheumatoid arthritis (RA).
Cimzia may be used alone for reducing signs and symptoms in adult patients with moderately to severely active RA who do not tolerate MTX.
Rheumatoid arthritis is an autoimmune disorder of unknown etiology, however, it is known that the pro-inflammatory cytokine tumour necrosis factor-alpha (TNF-α) mediates inflammation in this condition. Cimzia is a recombinant humanized antibody Fab' fragment that has a high affinity for and selectively neutralizes human TNF-α, thereby inhibiting its role as a key mediator of the inflammation and joint destruction associated with RA.
The market authorization was based on quality, non-clinical, and clinical information submitted. The efficacy and safety of Cimzia were assessed in three pivotal, randomized, placebo-controlled, double-blind studies (RA-I, RA-II, and RA-III) that enrolled 1821 patients. Enrolled patients were ≥18 years of age with moderately to severely active RA as diagnosed according to American College of Rheumatology (ACR) criteria. For Studies RA-I and RA-II, Cimzia was administered subcutaneously in combination with MTX at stable doses of at least 10 mg weekly. Patients had received MTX for at least 6 months prior to receiving study medication in Study RA-I and RA-II but still had an incomplete response to MTX alone. Cimzia was administered as a monotherapy in Study RA-III.
In all three studies, patients were evaluated for treatment of signs and symptoms of active RA as measured by the primary endpoint of ACR 20 response at Week 24. An ACR 20 response requires a patient to have a 20% reduction in the number of swollen and tender joints, and a 20% reduction in three of the following five parameters: physician global assessment of disease, patient global assessment of disease, patient assessment of pain, C-reactive protein or erythrocyte sedimentation rate, and degree of disability in Health Assessment Questionnaire (HAQ) score. In Study RA-I, patients were also evaluated for inhibition of progression of structural joint damage (modified Total Sharp Score [mTSS]) at Week 52.
ACR response rates and improvement in all components of ACR response were seen as early as Week 1 and were maintained through to the end of each of the three studies. Statistically significantly greater ACR 20 responses at Week 24 were observed in patients treated with Cimzia as compared to placebo. In all studies, Cimzia-treated patients reported pain-relief, as assessed by the Patient Assessment of Arthritis Pain, as early as the first assessment at Week 1 through to the end of all three studies, demonstrating durability of the results. In Study RA-I, significantly less radiographic progression (mTSS) and joint damage was observed with Cimzia compared with placebo at Week 52.
In the placebo-controlled studies, 71% of patients treated with Cimzia experienced an adverse event (AE) as compared to 62% in the placebo group. Serious AEs occurred in 10.7% of Cimzia-treated patients as compared to 6.5% of placebo-treated patients. The most serious AEs were infections, malignancy, and cardiovascular disorders.
Cimzia (200 mg/mL, certolizumab pegol) is presented as a solution for subcutaneous (SC) injection in a single-use pre-filled syringe. The recommended dose of Cimzia for adult patients with RA is 400 mg (given as two SC injections of 200 mg) at Weeks 0, 2, and 4, followed by 200 mg every other week. For maintenance dosing, Cimzia 400 mg every 4 weeks may be considered. Dosing guidelines are available in the Product Monograph.
Cimzia is contraindicated for patients with known hypersensitivity to Cimzia (certolizumab pegol) or any of its components and in patients with active tuberculosis or other severe infections such as sepsis, abscesses, and opportunistic infections. Cimzia should not be used in combination with other biologic disease modifying anti-rheumatic drugs (DMARDs) or other TNF-blocking agents. Cimzia should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Cimzia are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Cimzia is favourable for the indications stated above.
3 Scientific and Regulatory Basis for Decision
A Notice of Deficiency (NOD) was issued on September 17, 2008 for this New Drug Submission (NDS) as bioequivalence between the formulations used in the Phase III clinical studies (lyophilized formulations and the to-be-marketed liquid formulation) had not been established.
In their response to the NOD, the sponsor addressed the issues of concern and supplied new clinical pharmacological bioequivalence data. The response to the NOD was accepted on October 17, 2008 and a screening acceptance letter was issued.
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Certolizumab pegol, the medicinal ingredient of Cimzia, is a recombinant, humanized, monoclonal antibody Fab′ fragment, with specificity for human TNF-α. Certolizumab pegol binds to TNF-α, inhibiting its role as a key mediator of the inflammation and joint destruction associated with rheumatoid arthritis (RA).
Manufacturing Process and Process Controls
The drug substance is generated by recombinant technology.
Certolizumab is manufactured using a bacterial cell culture process. The purification process consists of a combination of chromatography steps and a PEGylation step. Process validation data demonstrate that the manufacturing process operates in a consistent manner, yielding product of acceptable quality.
The drug substance manufacturing process has been scaled-up and optimized during development. The process changes introduced at each generation of the process were adequately described and comparatively assessed. Lot release, stability, and characterization data have also been used to support the comparability assessment.
The materials used in the manufacture of the drug substance are considered to be suitable and/or meet standards appropriate for their intended use. In-process controls performed during the manufacture were reviewed and are considered acceptable. The specifications for the raw materials used in manufacturing the drug substance are also considered satisfactory.
Characterization
Detailed characterization studies were performed to provide assurance that certolizumab pegol consistently exhibits the desired characteristic structure and biological activity.
Comparability of certolizumab pegol lots produced by different processes was performed and comparable physicochemical characteristics were demonstrated.
Control of Drug Substance
The drug substance specifications and analytical methods used for quality control of certolizumab pegol are considered acceptable.
The levels of product- and process-related impurities were adequately monitored throughout the manufacturing process. Results from process validation reports and in-process controls indicate that the impurities of the drug substance were adequately under control.
Batch analysis results were reviewed and all results comply with the specifications and demonstrate consistent quality of the batches produced.
The drug substance packaging is considered acceptable.
Stability
Based on the real-time and accelerated stability data submitted, the proposed shelf-life, storage conditions, and shipping conditions for the drug substance were supported and are considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Cimzia (200 mg/mL, certolizumab pegol) is supplied as a sterile, preservative-free solution for SC administration in a single-use, Type I glass 1-mL pre-filled syringe, with a fixed 25-gauge, half-inch needle. The solution of Cimzia is clear and colourless to pale yellow and is essentially free of particulates, with a pH of 4.7. The syringe is stoppered with a coated stopper and the needle is covered with a rigid shield. The syringe components do not contain any latex or dry natural rubber.
Each 1.0 mL of Cimzia contains: 200 mg of certolizumab pegol, 1.36 mg of sodium acetate, 7.31 mg sodium chloride, and water for injection.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of certolizumab pegol with the excipients is demonstrated by the stability data presented on the proposed commercial formulation. The formulation is simple and the proposed excipients are widely used in injectable preparations.
Pharmaceutical Development
Pharmaceutical development data, including development of the container closure system, are considered acceptable. Data provided in this section include the composition of Cimzia, a rationale for the choice of formulation, the manufacturing process including packaging, information on batches used in in vitro studies for characterization, and a discussion on the effect of formulation change on the safety and/or efficacy of Cimzia. Studies which justified the type and proposed concentration of excipients to be used in the drug product were also reviewed and are considered to be acceptable.
Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Parameters relevant to the performance of the drug product were not affected by the changes described.
Data pertaining to the physico-chemical characteristics and biological activity demonstrated biocomparability between the development and commercial batches.
Manufacturing Process and Process Controls
The manufacturing formula for Cimzia is identical to that of the drug substance certolizumab pegol.
The manufacturing process for Cimzia essentially consists of pooling of the formulated bulk drug substance, filtration, and filling into 1-mL glass syringes. The validated process is capable of consistently generating product that meets release specifications.
All manufacturing equipment, in-process manufacturing steps, and detailed operating parameters were adequately described in the submitted documentation and are found to be acceptable. The manufacturing process is considered to be adequately controlled within justified limits.
Control of Drug Product
Cimzia is tested to verify that its identity, appearance, assay, pH, particulates, sterility, protein content, osmolality, colour, clarity, levels of degradation products, drug-related impurities, bacterial endotoxins, and microbiological impurities are within acceptance criteria. The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits, for individual and total degradation products are within acceptable limits.
The validation process is considered to be complete. Validation reports were submitted for in-process and release testing of the drug product, and no anomalies were present. The results for all of the batches were within the proposed specification limits.
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
Based on the real-time and accelerated stability data submitted, the proposed 24-month shelf-life for Cimzia when stored between 2 to 8°C protected from light is considered acceptable.
The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.
3.1.3 Facilities and Equipment
Each of the facilities involved in the manufacture of the drug substance and drug product was inspected by a qualified team of inspectors from the Biologics and Genetic Therapies Directorate, Health Canada. On-site evaluations were waved for both the drug substance and the drug product because of relatively recent and successful inspections of both facilities.
The design, operations, and controls of the facilities and equipment that are involved in the production of Cimzia are considered suitable for the activities and products manufactured. All sites are compliant with Good Manufacturing Practices.
3.1.4 Adventitious Agents Safety Evaluation
Raw materials of animal and recombinant origin used in the manufacturing process are adequately tested to ensure freedom from adventitious agents. The excipients used in the drug product formulation are not from animal or human origin.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Cimzia 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.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
Pharmacodynamic (PD) studies conducted in vitro demonstrated that certolizumab pegol binds with high affinity to soluble recombinant human TNF-α (rhuTNF-α) and is effective at inhibiting TNF-α from binding to human p55 and p75 TNF receptors. Certolizumab pegol selectively neutralized human TNF-α with an IC90 (the concentration at which 90% inhibition is achieved) of approximately 4 ng/mL.
Certolizumab pegol did not bind to lymphotoxin-alpha (LT-α) [a related cytokine that utilizes the same receptors (p55 and p75) as TNF-α]. Certolizumab pegol inhibited the lipopolysaccharide (LPS)-driven production of TNF-α and interleukin-1β (IL-1β) by the human monocytic cell line MM6 and primary human monocytes in vitro.
The pharmacodynamics of certolizumab pegol were compared to other licensed anti-TNF-α reagents including infliximab, adalimumab, and etanercept in vitro. All anti-TNF-α reagents were potent neutralizers of soluble rhuTNF-α and all bound to and neutralized membrane TNF-α. Infliximab, adalimumab, and etanercept mediated complement lysis and antibody dependent cell-mediated cytotoxicity (ADCC) whereas certolizumab pegol did not mediate complement lysis or ADCC, even at concentrations of 100 µg/mL. In human peripheral blood-derived monocytes, certolizumab pegol did not cause an increase in cells exhibiting an apoptotic phenotype and did not induce degranulation of peripheral blood-derived neutrophils or cell death, as was observed with infliximab, adalimumab, and etanercept.
In vivo studies were conducted in mice and rabbits. In an in vivo mouse bioassay, certolizumab pegol inhibited rhuTNF-α-induced neutrophil recruitment in a dose-dependent manner with a median effective dose (ED50; the concentration that produces a therapeutic response in 50% of those treated) value of 0.052 mg/mL.
In a transgenic mouse model (Tg197 mice) of inflammatory polyarthritis, certolizumab pegol was shown to be effective in preventing disease development. Further studies in New Zealand White rabbits confirmed the efficacy of certolizumab pegol, demonstrating that it neutralizes plasma rhuTNF-α and reduces the rhuTNF-α-induced pyrogenic response in a dose-dependent manner with an ED50 of approximately 3 µg/mL. Certolizumab pegol did not mediate ADCC or activate complement-mediated lysis, did not cause changes in the levels of markers for apoptosis and cell death, and did not show changes in the levels of neutrophil degranulation or cell death.
3.2.2 Pharmacokinetics
At the time of review, pharmacokinetic (PK) studies in humans had been completed which were considered more relevant than the non-clinical PK studies. As a result, the non-clinical PK studies were not reviewed for this submission.
3.2.3 Toxicology
Toxicology studies for certolizumab pegol were conducted in cynomolgus monkeys as it was demonstrated that certolizumab pegol neutralizes the activity of native cynomolgus TNF-α. It was also shown that certolizumab pegol binds to membrane TNF-α (mTNF-α) and saturates mTNF-α on cynomolgus monkey monocytes, lymphocytes and granulocytes at concentrations of approximately 10 μg/mL and higher. These levels are comparable to the concentrations required to saturate mTNF-α on the same human cell populations [the high dose of 100 mg/kg bodyweight (bw)/week in the 13-, 26-, and 52-week cynomolgus monkey studies is approximately 70-times the expected maximum recommended human dose (MRHD) on a mg/kg bw/month basis].
The formulation was originally intended for intravenous (IV) administration, and hence the early non-clinical studies were conducted via this route. However, as development progressed, the SC route was preferred and so most of the later studies were conducted via SC administration.
Acute Toxicity
An acute IV toxicity study was conducted at dose levels of 50, 100 and 400 mg/kg bw. There were no mortalities and all dose levels were well-tolerated. The median lethal dose (LD50) and the no observable adverse effect level (NOAEL) were therefore both determined to be >400 mg/kg bw.
Repeat-Dose Toxicity
Sub-chronic testing in cynomolgus monkeys was carried out for 4 weeks by IV administration (0, 50, 100 and 400 mg/kg bw/week), for 13 and 26 weeks by SC administration (10 and 100 mg/kg bw/week), and for 52 weeks by SC administration (50 and 100 mg/kg bw/week). Endpoints to study the effects on the cardiovascular system were incorporated into the design of the 13/26-week study, and included evaluation of electrocardiograms (ECGs), blood pressure and heart rate. Results of the sub-chronic studies indicated that certolizumab pegol was generally well-tolerated at all dose levels.
The primary finding after 4, 13, 26, and 52 weeks of treatment was the presence of histiocyte vacuolation/foamy macrophages. The observation of histiocytic vacuolation in all of the repeat-dose toxicity studies was considered to be part of the physiological processing of high molecular weight polyethylene glycol molecules (PEGs), reflecting phagocytic uptake of the test material by the affected cells. Therefore, this was not considered to be an adverse, toxicologically significant finding.
Carcinogenicity
Carcinogenicity studies have not been conducted with certolizumab pegol in accordance with International Conference on Harmonisation (ICH) S6 guidelines. The primary justification for this was the lack of pharmacological activity and immunogenicity of certolizumab pegol in species normally used for such testing.
No specific concerns regarding carcinogenicity were identified in the 13/26-week repeat-dose toxicity study conducted in cynomolgus monkeys at doses up to 100 mg/kg bw/week. There were no morphological changes, particularly no inflammatory, proliferative or pre-malignant changes indicative of carcinogenic potential. In addition, there were no treatment-related changes to the lymphoid tissue or lymphocyte subsets, and there were no findings of toxicological significance observed in the 52-week cynomolgus monkey study.
Mutagenicity
Certolizumab pegol demonstrated no evidence of mutagenicity, clastogenicity or aneugenicity, using a standard battery of in vitro [such as (i.e.) reverse mutation assay and chromosomal aberration assay] and in vivo (i.e. bone marrow micronucleus assay) genotoxicity tests.
Reproductive and Developmental Toxicity
Reproductive and developmental toxicity studies were conducted in Sprague-Dawley rats to evaluate the effect of certolizumab pegol on fertility, embryo-foetal development, and peri-postnatal development. The studies used cTN3 PF (a homologous PEGylated Fab′ of an antibody raised to murine TNF-α).
There was no evidence of treatment-related effects on male or female fertility, embryo-foetal development, pre- and post-natal development (including an assessment of immune system development and function) nor on maternal function. In addition, cTN3 PF was not teratogenic at any dose level tested (up to 100 mg/kg bw).
Local Tolerance
Local tolerance was evaluated in rats after a single SC injection of certolizumab pegol at dose levels of 160 or 800 mg/kg bw, followed by a 28-day observation period. Certolizumab pegol was well tolerated and did not demonstrate any clinical reaction at the injection site. Transient oedema, slight haemorrhage, and cellulitis were observed at microscopic examination on Days 2 and 8, with resolution by Day 29 in all groups.
3.2.4 Conclusion
In conclusion, the non-clinical toxicology database is considered adequate to assess the safety profile of Cimzia (certolizumab pegol) and to support its use for the treatment of RA in humans. The toxicity database for Cimzia is complete, and is in accordance with the ICH Guidance S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals document.
3.3 Clinical basis for decision
3.3.1 Human Pharmacology
Different formulations were developed during the clinical program. The following formulations were used in the three pivotal, Phase III clinical studies:
- a lyophilized formulation (Studies RA-I and RA-III)
- a liquid formulation - intended for commercial use (Study RA-II)
3.3.2 Pharmacodynamics
The pharmacodynamics of Cimzia were investigated in in vitro studies involving rhuTNF-α and cell-lines transfected with human TNF-α, as well as some isolated human cells, and two studies on human tissues. A description of these studies is found in section 3.2.1 Pharmacodynamics.
3.3.3 Pharmacokinetics
In healthy subjects, single IV injections of Cimzia resulted in a linear relationship between the dose administered, the maximum plasma concentration (Cmax) and the area under the plasma concentration time curve (AUC). The terminal elimination phase half-life (T1/2z) was approximately 14 days for all dose levels tested. Cimzia demonstrated a bioavailability of approximately 80% when given by the SC route.
Only one clinical pharmacology study was conducted in patients with RA. The study investigated the interaction between Cimzia and MTX. In RA patients who were currently on stabilized weekly oral doses of MTX, Cimzia had no significant effect on the overall exposure or the Cmax of MTX. It is not known if MTX affects the PK profile of Cimzia. Following multiple SC administration in patients with RA, mean peak plasma levels of Cimzia were observed approximately 7 days post-injection. The mean terminal half-life was approximately 14 days and the clearance was estimated to be 21.0 mL/h based on population PK analysis. As estimated from studies, following a single SC administration, the mean time to reach Cmax (Tmax) and the mean terminal half-life (T1/2) of Cimzia were comparable in RA patients and in healthy subjects.
A bioavailability study was conducted to compare three dosage forms of Cimzia: lyophilized, liquid in vial (LIV), and liquid in pre-filled syringe (PFS). A total of 149 healthy subjects received a single administration of 400 mg of Cimzia (lyophilized, n = 50; PFS, n = 50; and LIV, n = 49). The standard criteria for bioequivalence were met for both the LIV and PFS dosage forms as compared to the lyophilized formulation. Based on the results of the bioavailability study, bioequivalence between liquid and lyophilized formulations was established.
3.3.4 Clinical Efficacy
The efficacy of Cimzia for the proposed indication was primarily evaluated in three pivotal, randomized, placebo-controlled, double-blind, parallel-group, multicentre studies (RA-I, RA-II, and RA-III). All enrolled patients were ≥18 years of age with moderately to severely active RA diagnosed according to ACR criteria. Patients had at least nine swollen and tender joints and had active RA for at least 6 months prior to baseline.
Combination Therapy with Methotrexate
For Studies RA-I and RA-II, RA patients were subcutaneously administered either a placebo in combination with MTX, or 200 mg or 400 mg of Cimzia in combination with MTX. Enrolled patients had active RA despite ≥6 months of treatment with MTX (including stable dose ≥2 months prior to study enrolment).
Of note, since different formulations were used in these two studies, efficacy and safety data collected from each study over 24-weeks of Cimzia treatment were compared. The results supported the therapeutic similarity of both formulations (lyophilized and liquid).
Study RA-I
Study RA-I was a 52-week study conducted to assess the efficacy and safety of two dose regimens of lyophilized Cimzia given as an additional medication to MTX as compared to placebo + MTX.
Patients were randomized to receive Cimzia (200 mg) SC every other week (EOW) + MTX (n = 393), Cimzia (400 mg) SC EOW + MTX (n = 390), or placebo EOW + MTX (n = 199). Patients assigned to the Cimzia (200 mg) group, received three loading doses of Cimzia (400 mg) at Weeks 0, 2 and 4, followed by Cimzia (200 mg) SC EOW for the remainder of the study.
The co-primary efficacy endpoints were ACR-20 response rates at Week 24 and changes from baseline in mTSS at Week 52. The ACR-20 response rates at Week 24 were 59% and 61% for the Cimzia (200 mg) + MTX and Cimzia (400 mg) + MTX groups, respectively, compared to 14% in the placebo + MTX group. Analysis of the radiographic change from baseline at Week 52 as measured by mTSS demonstrated significantly less radiographic progression and joint damage with Cimzia as compared to the placebo group. In general, small differences between the active groups were not significant for any of the efficacy parameters tested, suggesting that the higher dose of Cimzia is not associated with additional benefit.
Study RA-II
Study RA-II was a 24-week study conducted to assess the efficacy and safety of two dose regimens of liquid Cimzia given as an additional medication to MTX as compared to placebo + MTX.
Patients were randomized to receive Cimzia (200 mg) SC EOW + MTX (n = 246), Cimzia (400 mg) SC EOW + MTX (n = 246), or placebo EOW + MTX (n = 127). Patients assigned to the Cimzia (200 mg) group, received three loading doses of Cimzia (400 mg) at Weeks 0, 2 and 4, followed by Cimzia (200 mg) SC EOW for the remainder of the study.
The primary efficacy endpoint was the ACR-20 response rate at Week 24. The ACR-20 response rates at Week 24 were 57% and 58% for the Cimzia (200 mg) + MTX and Cimzia (400 mg) + MTX groups, respectively, compared to 9% in the placebo + MTX group. The efficacy results do not demonstrate additional benefit of a 400 mg EOW maintenance dose of Cimzia compared to the 200 mg EOW maintenance dose regimen.
Monotherapy
Study RA-III
Study RA-III was a Phase III multicentre, double-blind, placebo-controlled, parallel group, 24-week study to compare the efficacy and safety of Cimzia (400 mg) given SC every 4 weeks versus (vs.) placebo. Enrolled patients had active RA and had previously failed to exhibit a response from at least one disease-modifying anti-rheumatic drug (DMARD) with discontinuation of DMARD treatment at least 1 month prior to study treatment.
Patients were randomized to receive Cimzia (400 mg) SC (n = 111) or placebo (n = 109) every 4 weeks.
The primary efficacy endpoint was the ACR-20 response rate at Week 24. The ACR-20 response rates at Week 24 were 46% for the Cimzia (400 mg) group vs. 9% for the placebo group. The ACR-20 response rate was statistically significantly greater for Cimzia (400 mg) with every 4 weeks of dosing as compared to the placebo group. This study demonstrated that Cimzia administered as monotherapy is effective in the treatment of the signs and symptoms of patients with active RA who had previously failed at least one DMARD.
3.3.5 Clinical Safety
The safety of Cimzia was evaluated based on an integrated review of data collected from both controlled and uncontrolled studies (open-labelled extension studies with a cut-off date of January 31, 2007) conducted in the RA clinical program. A description of the pivotal clinical studies is described in section 3.3.4 Clinical Efficacy.
A total of 2,367 patients received at least one dose of Cimzia (including 1,774 in placebo-controlled studies) and 647 received at least one dose of placebo. In four Phase III studies, 1,510 patients received at least one dose of Cimzia, including 998 patients who were exposed to Cimzia for at least 24 weeks and 521 patients who were exposed for 52 weeks. The majority of RA patients recruited for the clinical studies were female (about 70 to 83%) and Caucasian (80 to 99%), with an age range of 18 to 83 years.
In the placebo-controlled studies, a greater percentage of patients in the Cimzia-treatment groups (71%), experienced AEs as compared to the placebo group (62%). In addition, serious AEs (SAEs) were more common in Cimzia-treated patients (10.7%) as compared to the placebo group (6.5%). Adverse events leading to death were also higher in the Cimzia-treated groups (0.5%) vs. placebo (0.2%) as were AEs leading to withdrawal (5.0%) vs. placebo group (2.5%). The Cimzia (400 mg) every 4 weeks treatment group had a higher incidence of AEs (77.7%), and SAEs (11.5%) than the other Cimzia groups.
Antigenicity
A total of 6.9% of patients treated with Cimzia during four Phase III studies developed antibodies to Cimzia. Approximately 3% of these patients had antibodies capable of neutralizing Cimzia bioactivity in vitro. Patients who received Cimzia monotherapy had a higher rate of antibody development than did patients who received Cimzia in combination with MTX.
The probability of antibody formation appeared to be higher in the lower dose groups. Antibody formation has been shown to lower the plasma concentration of Cimzia and reduce its efficacy. Following the recommended dose (200 mg EOW + MTX after three loading doses), patients who tested positive for Cimzia antibodies (Ab+) had approximately 3- to 5-fold lower mean plasma concentrations of Cimzia as compared to patients who tested negative (Ab-). The ACR-20 response was numerically 11-22% lower among Ab+ patients than among Ab- patients. No clear trend of antibody development and the occurrence of AEs was observed.
Infection
In the controlled portions of the studies, an increased risk for infection was observed in patients receiving Cimzia (37.6%; 0.91 per patient-year) vs. placebo (22.9%; 0.72 per patient-year), as well as an increased risk of serious infections (3.5% Cimzia; 0.06 per patient-year vs. 0.6% placebo; 0.02 per patient-year). The most frequent infections were upper respiratory tract infections (17.6% Cimzia vs. 9.4% placebo), urinary tract infections (5.8% Cimzia vs. 4.5% placebo), and lower respiratory tract and lung infections (5.6% Cimzia vs. 3.4% placebo). The most frequent serious infections in the Cimzia treatment groups were tuberculosis infections (0.6% Cimzia vs. 0% placebo), upper respiratory tract infection (0.5% Cimzia vs. 0% placebo), and lower respiratory tract and lung infections (0.5% Cimzia vs. 0.2% placebo). Six patients who received Cimzia in the controlled and uncontrolled studies had fatal infections, including pneumonia or bronchopneumonia, septic shock, and peritoneal infection/peritonitis. The incidence of serious infections was similar in women (3.6%) as compared to men (3.0%).
Malignancies
In the controlled and uncontrolled studies, by the data cut-off date, a total of thirty patients developed malignancies (including 3 cases of lymphoma); twenty-nine in the Cimzia-treatment group and one case in the placebo group. Eleven cases (including two cases of non-melanoma skin cancer) occurred in the controlled portion of the studies and nineteen in the open-label portions of the studies. Malignancies other than lymphomas and non-melanoma skin cancers were observed at a rate of 0.61/100 patient-years among 2,367 Cimzia-treated patients and 0.41/100 patient-years among 647 placebo-treated patients. In comparison, the reported overall exposure-adjusted incidence of malignancy incidence rates (excluding non-melanoma skin cancer and lymphoma) per 100 patient-years for TNF-blocking therapy are 0.6 for etanercept and 0.80 for adalimumab.
Taking into consideration published malignancy rates to compare RA patients with the general population, it is suggested that patients with RA, particularly those with highly active disease, are at a higher risk for the development of lymphoma as compared to the general population.
The possible risk for the development of lymphomas or other malignancies in patients treated with TNF-blocking therapy cannot be excluded. The potential role of TNF-blocking therapy in the development of malignancies is unknown.
Cardiovascular Events
In the controlled portion of the studies, the percentage of patients with cardiovascular AEs was 3.4% in the Cimzia group (1.60 events per 100 patient-years) and 2.0% in the placebo group (1.23 events per 100 patient-years). The most frequent serious cardiac AEs were ischaemic coronary artery disorders (0.4% Cimzia vs. 0.3% placebo) and supraventricular arrhythmias (0.3% Cimzia vs. 0% placebo).
Four patients (0.2%) experienced cerebrovascular accidents and four patients (0.2%) experienced transient ischaemic attacks (TIAs) in the Cimzia group, compared with only one patient (0.2%) who experienced a cerebrovascular incident in the placebo group. One patient in both the Cimzia (400 mg) every 2 weeks and the placebo group experienced a pulmonary embolism.
Three patients in the Cimzia group experienced hypertension SAEs, including two cases of vascular hypertension and one malignant hypertension event. No patients in the placebo group were affected by these types of AEs. There was an increased percentage of patients with hypertension in the Cimzia group (5.1%) compared to the placebo group (1.2%).
Concerns regarding a potential cardiovascular safety signal of Cimzia in treatment of RA were raised based on the following observations during the review cycle:
- In the controlled portion, serious cardiac AEs occurred in sixteen patients (0.9%; 1.63 per 100 patient-years) in the Cimzia group, compared with only three patients (0.5%; 1.69 per 100 patient-years) in the placebo group.
- In both the controlled and uncontrolled portions of the studies, fatal cardiovascular events (including cardiac failure, congestive heart failure and atrial fibrillation, cardiac arrest, myocardial infarction/necrosis/ischaemia, cardiopulmonary failure, cardiogenic shock, cerebrovascular accident, and pulmonary embolism) occurred in eighteen patients treated with Cimzia (eight in the controlled studies and ten in the uncontrolled studies).
Upon review of an overall analysis of the cardiovascular AE data (including correction for exposure differences between the Cimzia and placebo treatment groups), it is considered that a signal for increased cardiovascular risk does not exist at this time based on the available Cimzia data. A post-market registry is intended to evaluate this.
Deaths
There were a total of twenty-nine deaths in the controlled and uncontrolled RA studies as of the data cut-off date.
In the placebo-controlled studies, 9 of 1774 patients (0.51%) who received Cimzia at any dose, compared with 1 of 647 patients (0.15%) who received placebo, died. The most common causes leading to death in patients who received Cimzia were cardiovascular events and/or infections. All seven cardiovascular deaths were in patients with pre-existing history of cardiovascular conditions.
In the combined placebo-controlled and open-label studies in patients with RA, 28 deaths occurred in patients who received Cimzia over 3218.0 patient-years of exposure (1 death per 115 patient-years) and 1 death occurred in a placebo-treated patient over 224.9 patient-years of exposure (1 death per 225 patient-years). Cardiovascular (primarily in predisposed patients) and/or infectious events were the most common causes leading to death in patients who received Cimzia.
The incidence of deaths per 100 patient-years exposure in the controlled portions of the Phase III studies was 0.9 for Cimzia vs. 0.4 for placebo. The estimated standardized mortality ratio (SMR) was 1.02 which is comparable to the literature-reported SMR estimated for the RA population.
3.3.6 Additional Issues
As part of the marketing authorization for Cimzia, Health Canada requested that the sponsor agree to several commitments to be addressed post-market. Commitments include (but are not limited to) providing a Canadian Risk Management Plan for Cimzia (certolizumab pegol).
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
The clinical efficacy evidence provided from studies RA-I, RA-II, and RA-III demonstrated statistically significant differences between Cimzia-treated patients and control-treated patients, with or without MTX, for ACR-20 response rates in patients with active RA who only partially responded to conventional therapy. Based on the results of Study RA-I, Cimzia in combination with MTX is efficacious in inducing a major clinical response (defined as achieving an ACR 70 response over a continuous 6-month period) and inhibiting radiographic progression.
The safety profile for Cimzia indicates serious risks associated with its use in adult RA patients including increased life-threatening serious infections and malignancies. These events do not appear to occur more frequently than those that occur with the other approved TNF-α blockers. The efficacy data provided demonstrates sufficient evidence to support the use of Cimzia as an effective treatment for patients with RA, who only partially respond to conventional therapy. Therefore, the benefit/risk ratio has been judged acceptable.
Taking into consideration the available clinical efficacy and safety data, the benefit/risk is favourable for the use of Cimzia as an alternative biologic therapy for adult patients with RA.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Cimzia in combination with methotrexate is favourable for the treatment of:
- reducing signs and symptoms, inducing major clinical response, and reducing the progression of joint damage as assessed by X-ray, in adult patients with moderately to severely active rheumatoid arthritis.
Cimzia may be used alone for reducing signs and symptoms in adult patients with moderately to severely active rheumatoid arthritis.
The NDS complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance (NOC) pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: CimziaTM
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2007-08-23 |
| Submission filed: | 2008-03-12 |
| Screening | |
| Screening Acceptance Letter issued: | 2008-04-25 |
| Review | |
| Notice of Deficiency (NOD) issued by Director General (biophamaceutics issues): | 2008-09-17 |
| Response filed: | 2008-10-15 |
| Screening | |
| Screening Acceptance Letter issued: | 2008-10-17 |
| Review | |
| Quality Evaluation complete: | 2009-07-27 |
| Clinical Evaluation complete: | 2009-08-07 |
| Labelling Review complete: | 2009-07-21 |
| Notice of Compliance (NOC) issued by Director General: | 2009-08-12 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| CIMZIA | 02331675 | UCB CANADA INC | CERTOLIZUMAB PEGOL 200 MG / ML |