Summary Basis of Decision for Nexavar ®
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:
Nexavar®
Sorafenib (as sorafenib tosylate), 200 mg sorafenib (as 274 mg sorafenib tosylate), Tablets, Oral
Bayer Inc.
Submission control no: 102070
Date issued: 2007-05-22
Health Products and Food Branch
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Health Products and Food Branch
Également disponible en français sous le titre : Sommaire des motifs de décision (SMD), PrNEXAVARMD, Sorafénib, 200 mg, comprimés, Bayer Inc., N° de contrôle de la présentation 102070
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):
- 02284227
Therapeutic Classification:
Non-medicinal ingredients:
Tablet core: croscarmellose sodium, microcrystalline cellulose, hydroxypropylmethyl cellulose, sodium lauryl sulfate, magnesium stearate
Film-coating: hydroxypropylmethyl cellulose, macrogol, titanium dioxide, iron oxide red
Submission type and control no:
Date of Submission:
Date of authorization:
© 2006, Bayer Inc.
Nexavar is a trademark of Bayer AG, used under license by Bayer Inc.
2 Notice of decision
On July 28, 2006, Health Canada issued a Notice of Compliance with Conditions to Bayer Inc. for the drug product Nexavar. The product was authorized under the NOC/c Policy on the basis of the promising nature of the clinical evidence, and the need for confirmatory studies to verify the clinical benefit. Patients should be advised of the fact that the market authorization was issued with conditions.
Nexavar contains the medicinal ingredient sorafenib (as sorafenib tosylate) which is a multikinase inhibitor and antineoplastic agent.
Nexavar is indicated for treatment of locally advanced/metastatic renal cell (clear cell) carcinoma (RCC) in patients who failed prior cytokine therapy or are considered unsuitable for such therapy. Nexavar has demonstrated anticancer activity due to its inhibitory effects on cellular pathways involved in tumour growth and tumour angiogenesis.
The market authorization with conditions was based on submitted data from quality control studies, pre-clinical and clinical studies. The evidence of clinical efficacy and safety was based on the interim analysis of a randomized controlled Phase III clinical study involving a total of 903 RCC patients, as well as a supportive Phase II trial involving 202 patients. The results of the two studies clearly indicated that patients randomized to Nexavar had a significantly longer median progression-free survival compared to patients randomized to placebo.
Nexavar (200 mg, sorafenib [as sorafenib tosylate]) is presented in tablet form. The recommended daily dose of Nexavar is 400 mg (2 x 200 mg tablets) taken twice a day (equivalent to a total daily dose of 800 mg) without food. Treatment should be continued until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs. Dosing guidelines are available in the Product Monograph.
Nexavar is contraindicated for patients with known severe hypersensitivity to sorafenib or to any of the excipients. Nexavar 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 Nexavar are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of Nexavar is favourable for the treatment of locally advanced/metastatic renal cell (clear cell) carcinoma in patients who failed prior cytokine therapy or are considered unsuitable for such therapy.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
Manufacturing Process and Process Controls
The drug substance (sorafenib tosylate) is manufactured via a multi-step synthesis. Each step of the manufacturing process is considered to be controlled within acceptable limits:
- The sponsor has provided information on the quality and controls for all materials used in the manufacture of the drug substance.
- The drug substance specifications are found to be satisfactory. Impurity limits meet ICH requirements.
- The processing steps have been evaluated and the appropriate ranges for process parameters have been established.
Characterisation
The structure of sorafenib tosylate was derived from the route of synthesis and from experimental analysis and spectral data. All data are consistent with the assigned chemical structure. The structure ofsorafenib tosylate is considered to be adequately elucidated.
Impurities arising from manufacturing and/or storage were reported and characterized. These products were found to be within ICH established limits or were toxicologically qualified and therefore, considered to be acceptable.
Control of Drug Substance
The analytical methods and validation reports are considered satisfactory for all analytical procedures used for release and stability testing ofsorafenib tosylate.
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 to be acceptable.
Stability
Based on the long-term and accelerated stability data submitted, the proposed retest period, storage, and shipping conditions for the drug substance were supported and considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Nexavar (sorafenib tablets) is supplied as round, biconvex, red film-coated tablets with a diameter of 10 mm, a thickness of 4.2-4.8 mm and a weight of 348.0-352.85 mg. Tablets are debossed with "Bayer cross" on one side and "200" on the other side.
Each tablet contains 200 mg of sorafenib (as 274 mg of sorafenib tosylate). The tablet core also contains croscarmellose sodium, microcrystalline cellulose, hydroxypropylmethyl cellulose, sodium lauryl sulfate, and magnesium stearate. The film-coating contains hydroxypropylmethyl cellulose, macrogol, titanium dioxide, and iron oxide red.
The tablets are packaged in 90 cc high-density polyethylene bottles (120 tablets per bottle).
All excipients found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of sorafenib tosylate with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
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.
Manufacturing Process and Process Controls
The manufacturing process uses conventional manufacturing techniques, namely: mixing, wet granulation, wet sizing, drying, sieving, blending, tabletting, and film-coating. The specifications for all the ingredients are approved in accordance with either USP/NF or Ph. Eur. standards.
The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
Control of Drug Product
Sorafenib tablets are tested to verify that their identity, appearance, concentration, water content, weight, uniformity, dissolution, and levels of degradation products and microbiological impurities are within acceptance criteria. The test specifications are considered acceptable to control the drug product, and the impurity limits were set according to ICH recommendations.
The validation process is considered to be complete. Validation reports were submitted for release testing of the drug product, and no anomalies were present. The results for all batches were within the proposed specification limits.
Stability
Based on the real-time and accelerated stability data submitted, the proposed 36-month shelf-life for Nexavar is considered acceptable when the product is stored in a dry place at 15-30°C.
3.1.3 Facilities and Equipment
The design, operations and controls of the facility and equipment that are involved in the production are considered suitable for the activities and products manufactured. All of the proposed manufacturing sites comply with the requirements of Division 2 of the Food and Drug Regulations.
3.1.4 Adventitious Agents Safety Evaluation
N/A
3.1.5 Summary and Conclusion
The Chemistry and Manufacturing information submitted for Nexavar 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
Non-clinical studies were performed to characterize the biopharmaceutical properties and pharmacodynamics of sorafenib. The pharmacology data for sorafenib included a description of the kinase inhibitory activities in biochemical and cellular assays. Functional effects of sorafenib on the proliferation of tumour cell lines and tumour growth inhibitory effects, when administered to immunodeficient mice bearing murine renal cell carcinoma, renal cancer cells, or human tumour xenografts, were also investigated.
Sorafenib was shown to be a multikinase inhibitor. The therapeutic targets of sorafenib were in tyrosine kinase receptors (RTKs) present in the tumour cell (c-KIT and FLT-3) and in the tumour vasculature (VEGFR-2, VEGFR-3 and PDGFR-β). In addition to RTKs, sorafenib inhibited serine/threonine RAF kinases implicated in tumour cell proliferation (CRAF, BRAF, V600E BRAF). Sorafenib did not inhibit the following kinases: MEK-1, ERK-1, EGFR, HER2/NEU, c-MET, PKA, PKB, IGFR-1, Cdk-1/cyclin B, PIM-1, GSK 3-b, CK-2, or PKC- at concentrations as high as 10 μM. The therapeutic targets of Nexavar in renal cell carcinoma (RCC) have not yet been clearly defined.
Based on the in vivo pharmacology studies, sorafenib inhibited tumour progression in transplantable tumour models of multiple histological types. The anti-tumour activity of sorafenib can be attributed to the anti-proliferative and/or anti-neoangiogenic mechanism of action.
3.2.2 Pharmacokinetics
The in vivo pharmacokinetics of sorafenib administered as a tosylate salt were investigated in Wistar rats, CD-1 mice, and Beagle dogs. Additional in vitro studies were performed to investigate plasma protein binding, blood cell/plasma partitioning and drug metabolism in several species, including man.
Absorption
The absorption of radiolabelled sorafenib was high in rats and mice (approx. 80% and 92%, respectively) and limited in dogs (68%). Peak plasma concentrations following an oral dose were also variable across the species for the unchanged compound.
Sorafenib was found to have an oral bioavailability of 80% in rats and mice and 60% in dogs. In man, sorafenib bioavailability of 38-49% in fasted state was reduced by 29% with a high-fat meal.
Distribution
The volume of distribution for rats, mice, and dogs was 0.7 L/kg, indicating a moderate distribution to the tissues. The peak plasma concentration occurred within 1 hour in mice, 1.6 hours in rats and 2 hours in dogs (3 hours in humans). Sorafenib binding to plasma proteins in vitro was high: 99.5% (humans, rats, mice) and 98.0% (dogs, rabbits). The radiolabelled sorafenib was rapidly and homogeneously distributed to almost all organs and tissues. Blood/brain penetration was low to moderate.
Metabolism
Comparison of thein vitro tests based on liver microsomal incubations revealed N-oxidation (M-2) to be prominent in humans, monkeys, and mice, whereas rats and dogs preferentially formed the metabolite M-3 by N-methylhydroxylation.
In humans, CYP3A4 was the enzyme responsible for oxidative metabolism yielding N-oxide as the major metabolite (M-2). UDP-glucuronosylransferase UGT 1A9 was responsible for the conjugation of sorafenib with glucuronic acid yielding the drug glucuronide (M-7).
Excretion
After oral administration of radiolabelled sorafenib, renal excretion of radioactivity was more pronounced in humans than in rats and dogs. In humans, 77% of radiolabelled sorafenib was excreted in the faeces. Urinary elimination was a minor route of excretion.
Drug Interactions
The results of the in vitro studies suggest that sorafenib has no potential to induce metabolic clearance of drugs that are substrates for major CYP450 enzymes at clinically relevant concentrations. Systemic exposure to substrates of UGT1A1 and UGT1A9 may be increased when co-administered with sorafenib which inhibits glucuronidation by the UGT1A1 and UGT1A9 pathways. Sorafenib has a potential to affect the pharmacokinetics of CYP2B6, CYP2C8, and CYP2C9 substrates.
Sorafenib in combination with a variety of standard cancer chemotherapy agents was shown to be safe and effective in animal models.
Safety Pharmacology
Two rodent and one non-rodent species were used for the non-clinical safety evaluation. Based on the safety pharmacology studies, sorafenib demonstrated potential effects on nociception, blood glucose, and heart rate. The in vitro electrophysiological studies indicated a potential of sorafenib to exhibit cardio toxicity by blocking a potassium channel and the Ca2+-inward current within the 1-10 μM concentration range.
3.2.3 Toxicology
Acute Toxicity
Acute toxicity studies revealed that the gastrointestinal tract (GI) and liver are potential targets of sorafenib toxicity.
Long-Term Toxicity
Repeat-dose toxicity studies with sorafenib were performed in mice, rats, and dogs with the appropriate route of administration (oral), long-term exposure and at adequate doses compared to the proposed human dose. Due to the pharmacological actions of the drug, sorafenib affected generally all types of tissues. The observed toxicities were dose- and time-related. The non-clinical findings indicate possible impact on the liver, kidneys, GI-tract, cardio vascular system, lymphoreticular/hematopoietic system, adrenals, reproductive organs, teeth, bone, and skin in humans.
Sorafenib toxicities with possible impact on the human risk assessment were as follows:
- GI-tract including Exocrine Pancreas: emesis, bloody diarrhea, inflammation, necrosis.
- Liver: cirrhosis, hypertrophy, bile duct proliferation, increased liver related enzymes/toxicity markers (in particular ALT, AST, GLDH, ALP, GGT).
- Kidneys: hypertrophy, nephropathy, basophilic tubules and tubular dilation, an anti-diuretic effect, high protein (urinalysis).
- Lymphoreticular/Hematopoetic System: morphological changes in the blood-forming elements (bone marrow, spleen) and immune organs (thymus, spleen).
- Adrenals: hypertrophy, hemorrhage, necrosis.
- Thyroid and Parathyroid: hypothyroidism, parathyroid fibrosis, hypophosphatemia, increased blood alpha amylase activities.
- Skin: marked skin lesions with hair loss and inflammatory processes, red/blue spots on skin, atrophy/degeneration of the hair follicles, alopecia, dermatitis, acanthosis.
- Bone, Teeth: irregular thickening of the femoral growth plate, hypocellularity of the bone marrow, altered growth plate and dentin composition in the teeth (a potential risk for children or adolescents).
The risks of inhibition of multiple cellular pathways in humans are not known and it appears difficult to evaluate and predict the consequences in a non-clinical model. Special attention should be given to monitoring of cardiovascular toxicities.
Sorafenib can affect thyroid/parathyroid functions indirectly increasing the potential to cause cardiovascular toxicities. In addition, cancer patients are prone to electrolyte imbalances which may augment the GI toxicity.
Carcinogenicity
Carcinogenicity studies were not conducted with sorafenib.
Genotoxicity
Sorafenib demonstrated positive genotoxic effects with the in vitro chromosome aberration test with Chinese hamster cells. Also, one of the formulation impurities present in the final drug substance was positive for mutagenesis in the Ames test.
Reproductive and Development Toxicity
Sorafenib demonstrated a potential to impair reproductive function in both males and females. Various effects including retardation and degradation were observed in the reproductive organs of male rats (tubular degeneration in the testes, epididymidal oligospermia) and female rats (retarded ovaries, central necrosis of corpora lutea) in the pivotal toxicity studies, with clear treatment-related effects. Dogs showed tubular degeneration and oligospermia in the epididymus in the 12-month toxicity study. Due to the reproductive toxicity seen in animal studies, women of child-bearing potential should be advised to avoid becoming pregnant. Sorafenib crossed the blood/brain and placental barriers. The fetotoxic and teratogenic effects occurred at doses considerably below the human therapeutic clinical doses.
In lactating rats, concentration of sorafenib and its metabolites were increased 5-fold in milk compared to plasma. Women should discontinue breast-feeding during sorafenib treatment.
3.2.4 Summary and Conclusion
Nexavar (sorafenib) is a multikinase inhibitor. The mode of cytostatic action of Nexavar in RCC has not yet been clearly defined, however there is evidence that the drug inhibits neo-angiogenesis, thus preventing tumour growth.
The safety pharmacology studies have indicated that Nexavar has the potential to cause hypoglycemia, sensory neuropathy, and cardiac toxicity. Acute toxicity studies revealed GI tract and liver toxicity. Repeat-dose toxicity studies revealed skin reactions, gastrointestinal, and liver toxicity. Histopathology indicated morphological lesions in multiple organ systems including liver, kidneys, lymphoreticular/hematopoietic system, gastrointestinal tract, pancreas, adrenals, reproductive organs, skin, teeth, and bones. The majority of these lesions were reversible or showed a tendency for recovery.
Significant toxicities in animals were observed at doses and plasma concentrations that were less than or equal to the recommended daily dose of Nexavar in cancer patients (400 mg b.i.d.). Sorafenib and one of its impurities were genotoxic. Various reproductive and fertility abnormalities were observed in the repeat-dose toxicity studies. Clear embryo-fetal toxicity and teratogenicity were demonstrated in rats and rabbits. Based on findings in the repeat-dose toxicity studies, there seems to be a potential risk to children and adolescents regarding effects on structure and composition of bone and teeth.
All toxicities described may occur in humans, and as such the corresponding parameters should be monitored. The results of the non-clinical studies as well as the potential risks to humans have been included in the Product Monograph. In view of the intended use of Nexavar, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product for the requested indication.
3.3 Clinical basis for decision
3.3.1 Human Pharmacology
Studies conducted to support the clinical pharmacology development of sorafenib included dose selection studies, biopharmaceutical studies, metabolism studies, special population studies, and evaluation of the safety and pharmacokinetics of sorafenib in combination with authorized anti-cancer agents.
Sorafenib was primarily administered as sorafenib tosylate tablets in the clinical trials. The dosage of sorafenib and the reported plasma sorafenib concentrations are expressed as the free base of sorafenib.
3.3.2 Pharmacodynamics
The drug substance sorafenib tosylate acts as a multikinase inhibitor and targets kinases that are involved in tumour cell signal transduction and tumour angiogenesis. Sorafenib was originally identified as a potential anticancer agent due to its inhibitory effects on Raf-1, a serine/threonine kinase and a member of the RAF/MEK/ERK signalling pathway with an important role in mediating cell proliferation and survival responses to growth factor stimulation. Subsequent biochemical and cellular mechanistic assays demonstrated activity against B-RAF and additional receptor tyrosine kinases, including vascular endothelial growth factor receptor-2 (VEGFR-2), platelet-derived growth factor receptor (PDGFR), both associated with the process of angiogenesis, as well as FLT-3 and c-KIT.
3.3.3 Pharmacokinetics
Absorption
With sorafenib 400 mg b.i.d. (the therapeutic dose), the drug reached its maximum plasma levels (6-10 mg/L) in approximately 3 hours. Based on the pharmacokinetic (PK) drug exposure parameter (AUC), the relative bioavailability of sorafenib was up to 49% for a 400 mg tablet dose. When given with a high-fat meal (50% of calories from fat), sorafenib absorption was reduced by 29%compared to administration in the fasted state. When administered with a moderate-fat meal (approximately 30% of calories from fat), bioavailability was similar to that in the fasted state.
Distribution
Sorafenib was shown to 99.5% bound to plasma proteins and the binding was independent of sorafenib concentration. Sorafenib was distributed almost equally between red blood cells and plasma with an average plasma to blood concentration ratio of 1.33.
Metabolism
Sorafenib is metabolized primarily in the liver through two pathways, glucuronidation (UGT1A9) and oxidation (CYP3A4). Eight metabolites were identified, of which five were detected in the plasma. Experiments with radiolabelled sorafenib indicated that sorafenib accounted for most (73% of AUC) of the radioactivity in plasma with M-2 accounting for 16.7% of the radioactivity (20.2% of AUC). The sum of minor metabolites M-1, M-3, M-4, and M-5 represented less than 5% of total radioactivity or 6.3% of the sum of AUC values. Sorafenib appears to be subjected to enterohepatic re-circulation as indicated by a second peak in plasma at 12 hr following administration. Additional sorafenib plasma concentration peaks were also observed.
Elimination
Following oral administration, the radiolabelled sorafenib was primarily eliminated in the faeces. A total of 77.1% of sorafenib or its metabolites were excreted in the faeces and 19.2% were excreted in the urine.
Drug-Drug Interactions
Ketoconazole, a potent CYP3A4 inhibitor, did not alter the drug exposure levels (AUC) and maximum plasma concentration values (Cmax) of sorafenib.
Co-administration of sorafenib with substrates of CYP2C19 (omeprazole), CYP2D6 (dextromethorphan), or CYP3A4 (midazolam) also demonstratedno significant or consistent change in the pharmacokinetics of the substrates. Sorafenib is not expected to significantly increase or decrease the exposure of co-administered compounds metabolized by these pathways. Sorafenib also showed no significant effect on the activity of the CYP2C9 substrate, warfarin.
Co-administration of sorafenib with gemcitabine or oxaliplatin showed no consistent or clinically significant interaction. There was a moderate increase of doxorubicin AUC and Cmax values when doxorubicin was administered concomitantly with sorafenib. However, the clinical relevance of this increase in doxorubicin exposure was not investigated. Administration of sorafenib and irinotecan resulted in increases in the AUC of irinotecan and its active metabolite. There was no significant effect of irinotecan on the PK of sorafenib. The clinical relevance of these changes is unknown.
Special Populations
Japanese Patients
The PK studies indicate that AUC values were much lower (45% lower) in Asian patients (N = 6) compared to data from 25 Caucasians. The metabolic pathways followed by sorafenib are not prone to ethnic differences. Nevertheless, additional data should be collected to either verify the accuracy of these PK differences or to provide data showing that sorafenib, at 400 mg b.i.d., produced similar exposure in Caucasians and Asian patients. Efficacy data on sorafenib treatment on Japanese and other Asian populations should be provided.
Hepatic Impairment
Mild to moderate hepatic impairment did not significantly affect sorafenib steady state PK.
Renal Impairment
All dose levels of sorafenib indicated no clear relationship between drug exposure and creatinine clearance. A thorough study on sorafenib PK in renal patients is recommended.
3.3.4 Clinical Efficacy
The efficacy and safety of Nexavar (sorafenib) were evaluated in one pivotal study and a supportive study. The pivotal study was a Phase III, double-blind, international, randomized, parallel-group, multicentre study comparing sorafenib with placebo in patients with advanced RCC who received one prior regimen of chemotherapy or immunotherapy. Prior therapy must have been completed at least 30 days but no more than 8 months prior to randomization. Concomitant treatment with other cytotoxic or cytostatic agents was prohibited. All patients who met the entry criteria were randomized to receive 400 mg sorafenib (2 x 200 mg tablets) or matching placebo administered orally, twice daily (b.i.d.). At the time of data cut-off, 769 patients were randomized at 117 centres in 19 countries. The study excluded "High Risk" patients (defined by the Motzer Prognostic Score) and therefore it is not known if Nexavar would be efficacious in this group of patients. The supportive Phase II study consisted of a 12-week induction (sorafenib, 400 mg twice daily) phase followed by a randomization phase. After 12 weeks of therapy with sorafenib, 65 patients with stable disease were randomized to receivesorafenib or placebo. The efficacy data, although significant, came from a very small group of RCC patients.
For both studies, the primary efficacy endpoint was progression-free survival (PFS). Originally, the primary efficacy endpoint in the pivotal study was to compare the overall survival (OS) between patients treated with sorafenib and those treated with placebo. However, at the time of the drug submission, the OS data was not mature enough. Although there were some improvements in OS for patients treated with sorafenib at the two interim analyses, neither analysis result reached statistical significance. The second interim analysis indicated 171 deaths in thesorafenib group and 196 deaths in the placebo group. The Kaplan-Meir curves for OS constructed at this time showed that the two survival curves (sorafenib and placebo) cross at day 696. Furthermore, the OS rate at 6 months was 87.1% for the sorafenib group and 80.1% for the placebo group. The OS rate at 12 months was 64.9% for the sorafenib group and 59.0% for the placebo group. Although the OS was greater in the sorefenib group, the difference in the results was not statistically significant. Additional data will be submitted with the final analysis after approximately 540 deaths are observed. The results of the final analysis for OS and an explanation of its significance at a later date are part of the conditions of marketing authorization. PFS is an acceptable endpoint for the authorization of antineoplastic cytostatic agents and a good indicator of a drug's clinical response in randomized Phase III trials.
In the pivotal study, median PFS was 84 days for patients randomized to placebo and 167 days for patients randomized to sorafenib. The PFS results were highly significant in favour of the sorafenib arm. Similarly, highly significant differences were observed when Time to Disease Progression was evaluated.
Among 335 sorafenib patients, 268 (80.0%) of the patients had a best overall tumour response of stable disease or better. Overall, 186/337 (55.2%) of the placebo patients had at least stable disease. Of the 574 patients with a post-baseline tumour evaluation, 293 were in the sorafenib group and 281 were in the placebo group. There was a trend towards increased tumour shrinkage in the treated patients; 74% of the sorafenib patients had some degree of tumour shrinkage, compared to 20% of the placebo patients. The sponsor plans to provide the results of the final analysis for OS when approximately 540 deaths are observed, as part of the marketing authorization with conditions. Patients should be advised of the nature of the authorization.
From the small population of patients in the supportive study, there was a statistically significant difference in progression-free rate: 50% (16/32) of the RCC patients randomized to sorafenib were progression-free at 12 weeks post-randomization, as compared to 18% (6/33) of the patients randomized to placebo. The median progression-free survival post-randomization was 163 days for sorafenib and 41 days for placebo.
3.3.5 Clinical Safety
The clinical safety of Nexavar (sorafenib) was assessed from interim results of the pivotal study, as well as the supportive study, described in Section 3.3.4 Clinical Efficacy. Later in the submission review process, updated information from the pivotal study was submitted along with additional data for the safety analysis.
Overall, 903 patients were randomized in the pivotal study; 451 patients in the sorafenib group and 452 patients in the placebo group. Treatment-emergent adverse events, most of which were Grades I or II, were reported in 428 (94.9%) of the sorafenib-treated patients and 387 (85.8%) of the placebo patients. The most common treatment emergent adverse events reported with Sorafenib versus placebo were rash (40% vs 16%), diarrhea (43% vs 13%), hand-foot skin reaction (30% vs 7%), fatigue (37% vs 28%), and hypertension (17% vs 2%).
In the pivotal study, a higher number of treatment-emergent cardiac ischemia/infarction events were reported in the sorafenib group [13 (2.9%)] than in the placebo group [2 (0.4%)]. The cardiac ischemia/infarction events are described in the warnings and precautions section of the Nexavar Product Monograph.
The incidence of deaths within 30 days of the study drug in the pivotal study was higher in the sorafenib group (48 patients, 10.6%) than in the placebo group (28 patients, 6.2%). The sponsor has stated that this is likely, because patients who were treated with sorafenib had the option of continuing sorafenib therapy after progression of disease and many patients continued on sorafenib therapy until close to the time of death. In the placebo group, patients stopped therapy upon disease progression, in many cases more than 30 days prior to death. Most deaths in both treatment groups were due to progressive disease.
3.3.6 Issues Outstanding
In keeping with the provisions outlined in the Notice of Compliance with Conditions (NOC/c) Policy, the sponsor has agreed to provide the following:
- To complete and submit final overall survival (OS) data from the Phase III pivotal study 11213. The final analysis of OS will be conducted when approximately 540 deaths are observed and it will be performed following the statistical analysis plan as outlined in the Clarifax of May 15, 2006.
- To complete and submit final data from the Phase I study 11497 in order to evaluate PK and safety following continuous administration of 400 and 600 mg b.i.d. sorafenib to Japanese cancer patients. If further data are necessary, new studies will be performed to verify the PK and/or efficacy of sorafenib in Asian patients.
- To complete and submit data from the biomarkers studies 10874, 100391 and 11213 to determine whether these markers can be used as an index of patient response to sorafenib.
- To perform, complete, and submit study 11804 on sorafenib PK on patients with mild, moderate, and severe renal function impairment.
- To perform, complete, and submit studies to elucidate the mechanisms of sorafenib-induced hypophosphatemia.
- To complete study 11883 and submit data on the effect of rifampin on sorafenib PK.
The sponsor has agreed to submit Periodic Safety Update Reports (PSURs) semi-annually for the next three years. The PSURs should contain cumulative data on relevant listed and unlisted adverse reactions from the day of marketing to the date of the report. Every PSUR should also contain cumulative data on hypertension, cardiac ischemia/infarction, hypophosphatemia, thrombosis, and bleeding episodes.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Nexavar (sorafenib) in a Phase III pivotal study and a Phase II supportive study has shown promising evidence of clinical effectiveness, and an acceptable safety profile for a disease (RCC) that is serious and life-threatening. In order to complete the assessment, confirmatory studies are required. As part of the NOC/c Policy, additional information, such as overall survival (OS) data, will be submitted within an agreed timeframe to verify the clinical benefit of Nexavar. Patients should be aware of the nature of the market authorization.
The results from the Phase III pivotal study on Nexavar versus placebo clearly demonstrated that sorafenib, a cytostatic agent inhibitor of Raf-1 kinase, prolonged the progression free survival (PFS, 167 vs. 84 days) of patients with advanced RCC. The study also indicated a consistent benefit for Nexavar over placebo for all subgroups studied (age, gender, low and intermediate score patients, prior or no prior therapy, and time from diagnosis). The Phase II supportive study was a small study because of the way the protocol was designed. Here again, a significant advantage in PFS for Nexavar was observed. The supportive study will not provide OS data, however the sponsor has agreed to provide future OS data from the pivotal study. Interim analysis from the pivotal study did not provide a statistically significant advantage in OS for Nexavar. Nevertheless, using the surrogate PFS, the studies demonstrated a clinical benefit for Nexavar in "Low" and "Intermediate Risk" (Motzer Risk Category) RCC patients. "High Risk" patients as well as patients with brain metastasis were excluded from the studies.
Like most anti-cancer agents, Nexavar is not free from unwanted effects and some of these adverse events seem to be specific for this agent. The main adverse events are diarrhoea, hand-foot skin reactions, hypertension, and hypophosphatemia. Hand-foot skin reactions were the only dermatologic condition that led to permanent discontinuation in a small number of patients and was the most frequent reason for drug interruption or dose reduction. The hypertension observed and considered clinical relevant was well managed in most cases with standard anti-hypertensive therapy. Hypertension led to permanent drug discontinuation in only one case in the pivotal trial. There were no clinical sequelae associated with hypophosphatemia and no apparent evidence of renal disorders associated with it. The mechanism of sorafenib associated with hypophosphatemia remains unknown and in view of this, the sponsor plans to conduct studies to elucidate the mechanisms responsible for the development of this condition.
In conclusion, the benefits of Nexavar therapy in RCC appear to outweigh the risks. To complete the benefit/risk assessment, the sponsor is required to submit OS data, additional PK data in Asian patients, report all adverse events following a careful post-market surveillance program, and initiate studies to determine the mechanisms of sorafenib-induced hypophosphatemia.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and effectiveness, Health Canada considers that the benefit/risk profile of Nexavar is favourable in the treatment of locally advanced/metastatic renal cell (clear cell) carcinoma in patients who failed prior cytokine therapy or are considered unsuitable for such therapy.
This New Drug Submission (NDS) qualifies for authorization under the Notice of Compliance with Conditions (NOC/c) Policy. 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 pursuant to section C.08.004 of the Food and Drug Regulations.
In keeping with the provisions outlined in the NOC/c Policy, the sponsor has agreed to provide the following:
- To complete and submit final overall survival (OS) data from the Phase III pivotal study 11213. The final analysis of OS will be conducted when approximately 540 deaths are observed and it will be performed following the statistical analysis plan as outlined in the Clarifax of May 15, 2006.
- To complete and submit final data from the Phase I study 11497 in order to evaluate PK and safety following continuous administration of400 and 600 mg b.i.d. sorafenib to Japanese cancer patients. If further data are necessary, new studies will be performed to verify the PK and/or efficacy of sorafenib in Asian patients.
- To complete and submit data from the biomarkers studies 10874, 100391, and 11213 to determine whether these markers can be used as an index of patient response to sorafenib.
- To perform, complete and submit study 11804 on sorafenib PK on patients with mild, moderate and severe renal function impairment.
- To perform, complete and submit studies to elucidate the mechanisms of sorafenib-induced hypophosphatemia.
- To complete study 11883 and submit data on the effect of rifampin on sorafenib PK.
The sponsor has agreed to submit Periodic Safety Reports (PSURs) semi-annually for the next three years. The PSURs should contain cumulative data on relevant listed and unlisted adverse reactions from the day of marketing to the date of the report. Every PSUR should also contain cumulative data on hypertension, cardiac ischemia/infarction, hypophosphatemia, thrombosis, and bleeding episodes.
4 Submission Milestones
Submission Milestones: Nexavar®
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2005-09-20 |
| Acceptance for Advance Consideration under the NOC/c Policy: | 2005-11-02 |
| Submission filed: | 2005-11-04 |
| Screening | |
| Screening Acceptance Letter issued: | 2005-12-13 |
| Review | |
| Quality Evaluation complete: | 2006-06-23 |
| Clinical Evaluation complete: | 2006-06-26 |
| Biostatistics Evaluation complete: | 2006-04-21 |
| Labelling Review complete: | 2006-06-27 |
| NOC/c-QN issued: | 2006-06-30 |
| Response filed: | 2006-07-10 |
| NOC issued by Director General under the NOC/c Policy: | 2006-07-28 |