Summary Basis of Decision for Xiaflex ™
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:
XiaflexTM
Collagenase clostridium histolyticum, 0.9 mg/vial, Lyophilized Powder for Solution, Intralesional
Auxilium Pharmaceuticals, Inc.
Submission control no: 147788
Date issued: 2012-10-05
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):
- 02388316
Therapeutic Classification:
Non-medicinal ingredients:
Diluent: calcium chloride dehydrate and 0.9% sodium chloride
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On July 5, 2012, Health Canada issued a Notice of Compliance to Auxilium Pharmaceuticals, Inc. for the drug product, Xiaflex.
Xiaflex contains the medicinal ingredient collagenase clostridium histolyticum, consisting of two microbial collagenases in a defined mass ratio, Collagenase AUX-I and Collagenase AUX-II, which are isolated and purified from the fermentation of Clostridium histolyticum bacteria. A collagenase is an enzyme that recognizes and binds to collagen in its native conformation and cleaves peptide bonds resulting in collagen breakdown. Collagenase AUX-I belongs to the class I Clostridium histolyticum collagenases. Collagenase AUX-II belongs to the class II Clostridium histolyticum collagenases.
Xiaflex is indicated for the treatment of adult patients with Dupuytren's contracture with a palpable cord. Dupuytren's disease is an inherited connective tissue disorder of the palmar fascia of the hand where fingers bend towards the palm and cannot be fully extended. The ring finger and little finger are most commonly affected. Abnormal collagen deposition results in nodule and cord formation. When the fibrous cord retracts the finger toward the palm in the advanced stage of the disease, the resulting pathology is known as Dupuytren's contracture. Injection of Xiaflex into a Dupuytren's cord, which is comprised mostly of collagen, may result in enzymatic disruption of the cord.
The market authorization was based on quality, non-clinical, and clinical information submitted. The efficacy and safety of Xiaflex were evaluated in two randomized, double-blind, placebo-controlled, multicentre studies in 374 adult patients with Dupuytren's contracture. The cord affecting the selected primary joint received up to 3 injections of 0.58 mg of Xiaflex or placebo on Days 0, 30, and 60. The proportion of patients who achieved a reduction in contracture of the selected primary joint to within 0° to 5° of normal, 30 days after the last injection, was 64% and 7% in Study 1, and 44% and 5% in Study 2; in the Xiaflex and placebo groups respectively. The safety profile was considered to be acceptable for the requested indication.
Xiaflex (0.9 mg/vial, collagenase clostridium histolyticum) is presented as a lyophilized powder for injection. Xiaflex must be reconstituted with the provided sterile diluent prior to use. The dose of Xiaflex is 0.58 mg per injection into a palpable cord with a contracture of a metacarpophalangeal (MP) joint or a proximal interphalangeal (PIP) joint. Xiaflex should be administered by a health professional experienced in injection procedures of the hand and in the treatment of patients with Dupuytren's contracture. Dosing guidelines are available in the Product Monograph.
Xiaflex is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. Xiaflex 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 Xiaflex 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 Xiaflex is favourable for the treatment of adult patients with Dupuytren's contracture with a palpable cord.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Dupuytren's disease is an inherited connective tissue disorder of the palmar fascia of the hand where fingers bend towards the palm and cannot be fully extended. The ring finger and little finger are most commonly affected. Abnormal collagen deposition results in nodule and cord formation. When the fibrous cord retracts the finger toward the palm in the advanced stage of the disease, the resulting pathology is known as Dupuytren's contracture. This disease progresses slowly and is usually painless. It is believed to be one of the most common hereditary connective tissue disorders in Caucasians, with prevalence of 13.6% in Canada and at 3.4% in the United States.
Collagenase clostridium histolyticum, the medicinal ingredient of Xiaflex is a combination of two microbial collagenases in a defined mass ratio, Collagenase AUX-I and Collagenase AUX-II, which are isolated and purified from the fermentation of Clostridium histolyticum (C. histolyticum) bacteria. A collagenase is an enzyme that recognizes and binds to collagen in its native conformation and cleaves peptide bonds resulting in collagen breakdown.
Manufacturing Process and Process Controls
The drug substance (collagenase clostridium histolyticum) is produced by the anaerobic fermentation of C. histolyticum, subsequent purification of Collagenase AUX-I and Collagenase AUX-II intermediates, and final mixing of the two intermediates in an approximate 1:1 ratio.
The production cell line is C. histolyticum, a Biosafety Level 2, gram-positive bacterium. Clostridium histolyticum is known to produce toxins that cause gas gangrene; therefore, careful evaluation of the production clone, the potential for sporulation, and the processes to eliminate the carryover of cells and to remove known toxins was necessary.
The manufacturing process is considered to be adequately controlled within justified limits. In-process controls performed during 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 the components (Collagenase AUX-I and Collagenase AUX-II) of the collagenase clostridium histolyticum drug substance consistently exhibit the desired characteristic structure and biological activity. Appropriate tests are adequately controlling the levels of product- and process-related impurities.
Control of Drug Substance
The drug substance specifications and analytical methods used for quality control of collagenase clostridium histolyticum are considered acceptable. Copies of the analytical methods and, where appropriate, validation reports were provided and are considered satisfactory for all analytical procedures used for release and stability testing of collagenase clostridium histolyticum.
Batch analysis results were reviewed and all results comply with the specifications and demonstrate consistent quality of the batches produced.
The levels of product- and process-related impurities were adequately monitored throughout the manufacturing process. Results from process validation reports and in-process controls indicated that the impurities of the drug substance were adequately under control. The level of impurities reported for the drug substance was found to be within the established limits.
The proposed packaging components are considered acceptable.
Stability
Based on the real-time and accelerated stability data submitted, the proposed storage conditions for the drug substance were supported and are considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Xiaflex is a lyophilized powder filled at a concentration of 0.9 mg/vial consisting of 10 mM Tris and 60 mM sucrose, pH 8.0. It is reconstituted using a sterile diluent provided as a single-use, 5 mL/20 mm Type 1 glass vial containing 3 mL of 0.3 mg/mL (2 mM) calcium chloride dihydrate in 0.9% (154 mM) sodium chloride. Each vial is stoppered and sealed with an aluminum flip-off overseal.
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 collagenase clostridium histolyticum with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Pharmaceutical development data, including development of the container closure system, are considered acceptable. Data provided in this section include composition of Xiaflex, rationale for choice of formulation, manufacturing process including packaging, information on batches used in in vitro studies for characterization, and discussion on the effect of formulation change on the safety and/or efficacy of Xiaflex. 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.
Manufacturing Process and Process Controls
To produce Xiaflex, unopened bottles of drug substance are thawed at room temperature, pooled into a 20 L glass vessel, mixed and sterile filtered, and filled. Partially stoppered vials are lyophilized after which the stoppers are fully seated and the vials capped.
The sterile diluent is produced through compounding/formulation, sterile filtration, filling, and terminal sterilization.
Labelling and bulk packaging of the Xiaflex and the diluent are performed at a separate facility.
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 method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
Control of Drug Product
Xiaflex is tested to verify that its purity, potency, identity, appearance, pH, particulates, concentration, moisture content, osmolality, colour, clarity and opalescence, reconstitution time, product-related impurities, product-related substances, and microbiological contaminants are within acceptance criteria. Validation results of the analytical method used for the determination of collagenase clostridium histolyticum and the drug-related impurities are considered acceptable.
Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.
Through Health Canada's lot release testing and evaluation program, final product lots were tested, evaluated, and found to meet the specifications of the drug product.
Three conformance batches of the sterile diluent were manufactured to validate the process and to provide stability information. Critical Process Parameters for all major manufacturing steps (compounding, filling, terminal sterilization) were established, monitored and recorded, as well as conformance to in-process and final product specifications. All quality control in process and final product vial testing results were within specifications.
Stability
Based on the real-time and accelerated stability data submitted, the proposed 36-month shelf-life at 2 to 8°C for Xiaflex is considered acceptable.
Based on the available stability data, a shelf-life of 36 months stored at 2 to 30°C is proposed for the sterile diluent.
The data obtained from the reconstitution stability studies show that following reconstitution, the drug product is able to maintain chemical and physical stability for at least 1 hour at room temperature. As there is no preservative, the reconstituted Xiaflex solution should be used immediately (within 3 hours). The reconstituted Xiaflex solution can be kept at room temperature (20º to 25ºC) for up to one hour or refrigerated at 2º to 8°C for up to 3 hours prior to administration.
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
At the outset of the review, it was decided that an On-Site Evaluation (OSE) of the sponsor's drug substance manufacturing and testing facility was warranted. As the OSE could not be scheduled at an appropriate time in the review period, the submission was placed on regulatory hold as of May 10, 2012 to allow for completion of the OSE.
An OSE of the facilities involved in the manufacture and testing of the drug substance was successfully conducted from May 14 to 18, 2012 by the Biologics and Genetic Therapies Directorate (BGTD), Health Canada. All observations made during the OSE were successfully resolved.
An OSE of the facilities involved in the manufacture of the drug product was not warranted as a satisfactory OSE was conducted in 2009.
The design, operations, and controls of the facilities and equipment that are involved in the manufacture and testing of Xiaflex are considered suitable.
3.1.4 Adventitious Agents Safety Evaluation
Raw materials of biological 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.
The only animal-derived raw material used in the production of the drug substance is Proteose Peptone #3 (PP3). To date, there is no known risk of Bovine Spongiform Encephalopathy (BSE)/Transmissible Spongiform Encephalopathy (TSE) transmission from non-ruminant (porcine) raw material sources. Control over the source and release of materials prior to Good Manufacturing Practice production activities, and the continued use and maintenance of qualified vendors, is guided by strict quality assurance policies and procedures.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Xiaflex 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 studies conducted in animals demonstrated that clostridial collagenase is active against the collagen types that predominate in Dupuytren's disease. Effects were confined to the injection site and were qualitatively similar in all species. Complete or partial reversal (with evidence of progression towards complete reversal) was observed following recovery periods of up to eight weeks.
Secondary Pharmacodynamics
Local secondary pharmacodynamic responses (alterations in vascular permeability, inflammatory responses, and proliferative changes reflecting enhanced wound healing responses) are most likely mediated by the in situ generation of collagen fragments as a reflection of the primary pharmacodynamic activity of collagenase clostridium histolyticum. These are well characterized and anticipated physiologic responses to the unmasking of hidden (cryptic) pharmacologically active sites within collagen molecules. Because collagenase clostridium histolyticum is not intended for systemic use and due to the absence of quantifiable systemic exposure from clinically relevant routes of administration, there are no systemic primary or secondary pharmacodynamic actions of relevance and no systemic safety pharmacology concerns.
No significant drug interactions have been identified, although tetracycline antibiotics may have the potential to inhibit collagenase clostridium histolyticum activity. While inhibition of clostridial collagenase activity by anthracycline antibiotics has been demonstrated, the clinical use of these agents in oncology chemotherapy protocols makes it unlikely that a patient will undergo concomitant treatment with collagenase clostridium histolyticum.
3.2.2 Pharmacokinetics
Administration of collagenase clostridium histolyticum by local injection (single dose or repeat dose) does not result in any systemic toxicity or significant systemic exposure to collagenase clostridium histolyticum components when administered to rats, guinea pigs, dogs, rabbits or mini-pigs at any injection site or dose level.
Plasma kinetics following either intravenous (IV) or local administration of collagenase clostridium histolyticum are consistent with the inactivation of collagenase clostridium histolyticum by plasma proteins, as a result of complex formation with α-2-macroglobulin (α2M) (endogenous protease inhibitor, either secreted locally or derived from the serum) or other plasma proteases followed by rapid removal of the complexes by fixed tissue phagocytes in the injection site, liver and/or spleen.
The ability of human α2M to inactivate AUX-I and AUX-II has been directly examined. Inactivation of commercial research-grade purified collagenase either by the α2M serum fraction from a number of species or by purified human α2M has been demonstrated.
In vitro studies provide a basis for limited systemic circulation of AUX-I and AUX-II, showing that at physiological concentrations:
- human plasma inhibits AUX-I and AUX-II enzymatic activities by up to 32% and 65% respectively; and
- α2M inhibited activities by 90% and 88%, respectively.
3.2.3 Toxicology
The non-clinical safety program for Xiaflex was designed in accordance with the International Conference on Harmonisation (ICH) S6 guidelines. Toxicology studies were conducted using rats, dogs, mini-pigs, and guinea pigs.
Acute Toxicity
Acute studies revealed median lethal dose (LD50) values of ≥80 U/mouse, and ≥5,000 U/rat. Necropsy revealed evidence of haemorrhage into body cavities and/or increased friability of the liver and/or spleen.
In single-dose studies, Xiaflex was administered to rats by injection into the metatarsal phalangeal area at dose levels of 0, 0.015 (~1.3 times the clinical dose), 0.030, 0.060 and 0.150 mg/animal with a 28 day recovery period; and was administered to dogs by intra-tendon injection at dose levels of 0, 0.075 (half the clinical dose), 0.15 or 0.30 mg/animal, or by deep subcutaneous injection at dose levels of 0, 0.15 (~ equal to the clinical dose), 0.45 or 0.75 mg/animal with an 8-week recovery period. Treatment-related findings were observed at all dose levels and were similar for both species and included swelling and purple discoloration at the injection site; increased hind paw circumference; gross necropsy observations of red discoloration; swelling and enlarged and/or dark red discoloration of the right axillary lymph nodes (dogs only); and histopathological findings of haemorrhage; oedema, inflammation; collagen lysis; fibroplasia/neovascularization; skeletal muscle necrosis; arterial changes, and/or lysis of collagen and/or sinus erythrocytosis of the right axillary lymph node (dogs only). At the end of the recovery period for both rats and dogs, the only findings were mild to severe fibrosis at the injection site in both sexes, at all dose levels and by both injection routes which were considered indicative of ongoing reversal of the treatment-related findings observed at the primary necropsy.
Repeat-Dose Toxicity
In a 3-month repeat dose study conducted in rats, Xiaflex was administered every other week for 3 months by injection into the metatarsal phalangeal area at dose levels of 0, 0.015 (~1.3 times the clinical dose), 0.030, 0.060 and 0.150 mg/animal, followed by a 28 day recovery period. Clinical observations of swelling; reddening; and purple discoloration; increased hind paw circumference; gross necropsy observations of red discoloration and swelling; and histopathological findings of haemorrhage; oedema; inflammation; collagen lysis; fibroplasia/neovascularization; skeletal muscle necrosis, and/or arterial changes were detected in both sexes at all dose levels. Additional Xiaflex-related changes observed at ≥0.030 mg/animal included transient impaired use or scabbing of the right hindlimb. Following a 28 day recovery period, all in-life and gross necropsy findings had completely reversed, and nearly complete resolution of the histopathological changes seen at the injection site.
A 16 day repeat dose IV toxicity study was conducted in rats, with administration of Xiaflex every other day during a 16 day period at dose levels of 0 (placebo control), 0.0029 (~ equal to the clinical dose), 0.0087 or 0.029 mg/dose. An additional group was administered collagenase clostridium histolyticum (manufactured according to one of the earlier manufacturing processes) at the dose level of 0.029 mg/dose. Xiaflex and collagenase clostridium histolyticum produced using the earlier process were well tolerated in both male and female rats. There was no evidence of systemic toxicity following IV administration of either dose material and in both cases administration resulted in comparable effects. The only treatment-related findings were minimal to mild chronic perivascular inflammation and minimal to mild perivascular haemorrhage at the site of injection.
In a 3-month repeat dose study conducted in dogs, Xiaflex was administered at dose levels of 0, 0.15, 0.225 or 0.375 mg/protein once a month for 4 injections by deep subcutaneous injection into the peri-digital flexor tendon fascia/connective tissue area of the right forelimb, followed by a 28 day recovery period. Clinical observations of swelling; reddening; and purple discoloration; hardened area at the injection site; increased forepaw circumference; gross necropsy observations of red discoloration and swelling; and histopathological findings of haemorrhage; oedema; inflammation; collagen lysis; fibroplasia/neovascularization, and arterial changes were detected in both sexes at all dose levels. At the end of the 28 day recovery period, changes still evident were hardened areas at the injection site, and histopathological changes indicative of ongoing resolution, such as (i.e.), residual haemorrhage, fibrosis and neovascularization.
After repeated IV administration, systemic toxicity in rats was manifest as reversible liver pathology, which should not occur under conditions of clinical use. In the unlikely event that a single dose is inadvertently administered by IV bolus, adequate safety margins exist based on the rat study findings. The systemic effects on the liver are therefore not considered to represent safety concerns for the clinical use of Xiaflex.
Mutagenicity and Clastogenicity
A battery of mutagenicity studies were conducted with Xiaflex. Xiaflex was neither mutagenic nor clastogenic either in vivo or in vitro.
Carcinogenicity
Carcinogenicity studies were not performed with Xiaflex, based on the fact that the intended clinical use is only for intermittent local administration of single doses at monthly intervals with a limit to the total number of doses that may be administered to each cord; the nature of the drug product (non-endogenous protein with no known growth factor activity relevant to carcinogenesis); and the absence of systemic exposure under conditions of clinical use.
Reproductive and Developmental Toxicity
Xiaflex was not a reproductive toxicant in male and female rats and did not affect the development of rat embryos or foetuses (i.e., was not teratogenic) in rats.
An IV fertility and general reproduction toxicity study, and an IV embryo-foetal developmental toxicity study were conducted in rats at dose levels of 0, 0.0145, 0.0435 and 0.13 mg/dose. Results from these studies revealed that Xiaflex is not a reproductive toxicant in male and female rats and is without effect on the development of, and is not teratogenic to rat embryos or foetuses.
3.2.4 Summary and Conclusion
In summary, administration of Xiaflex by single- or repeat-dose local injection did not result in any systemic toxicity or significant systemic exposure when administered to rats, guinea pigs, dogs, rabbits or mini-pigs, at any injection site or at any dose level tested. Effects following local administration were confined to the injection site and were qualitatively similar in all species. Findings were characterized by transient swelling and/or bruising adjacent to the site of injection and haemorrhage, acute to sub-acute inflammation progressing to chronic (mononuclear) inflammation, and neovascular proliferation. There were no effects noted on adjacent nerves, blood vessels with smooth muscle-containing walls, or epithelial or mesenchymal cells. Complete or partial reversal (with evidence of progression towards complete reversal) occurred following a recovery period of up to 8 weeks.
In conclusion, the non-clinical pharmacodynamics, pharmacokinetics, and toxicology database was considered adequate to assess the safety profile of Xiaflex in the treatment of patients with contracture caused by advanced Dupuytren's disease.
3.3 Clinical basis for decision
3.3.1 Human Pharmacology
Because the therapeutic activity of Xiaflex is localized to the injection site and does not require or result in systemic exposure, the primary pharmacodynamic activity of the drug could not be evaluated in subjects and, therefore, such studies have not been undertaken.
Data from one Phase I and one Phase II Study confirmed that there is no quantifiable systemic exposure following a single injection of Xiaflex (0.58 mg) into the cord of the affected finger in subjects with advanced Dupuytren's disease or following the subsequent procedure to disrupt the cord. There has been no evidence of systemic toxicity to date in the clinical studies conducted with Xiaflex administered through localized injection into the Dupuytren's cord. Results from the aforementioned clinical Phase I and II studies indicate that no detectable absorption of any Xiaflex-derived components occurs in subjects under the conditions of clinical use.
For these reasons, no clinical studies pertaining to tissue distribution, metabolism, excretion, plasma concentration-effect relationship, dose and time dependency, effect on hepatic or renal function, and drug-drug interactions have been performed with Xiaflex.
3.3.2 Clinical Efficacy
The clinical development program for Xiaflex included 13 clinical studies. None of these studies were conducted in Canada; however, the characteristics of the population recruited are considered to be similar to those of Canadian patients. The results of two Phase III studies are the basis of the recommendation for the approval of this submission: Study AUX-CC-857 (herein referred to as Study 1); and Study AUX-CC-859 (herein referred to as Study 2). Both studies were pivotal, multi-center, double-blind, placebo-controlled studies, and both were followed by open-label extensions. One additional Phase III, double-blind, placebo-controlled study (Study DUPY-303) supports the efficacy findings from the two pivotal studies. Five Phase III open-label studies (Studies DUPY-404, AUX-CC-854, AUX-CC-856, AUXCC-858, and AUX-CC-859 open-label phase) were primarily designed to examine the safety of the drug; they also provided supportive efficacy data.
The data described below are based on two randomized, double-blind, placebo-controlled studies through Day 90 in patients with Dupuytren's contracture (Studies 1 and 2). In these studies, patients were treated with up to 3 injections of 0.58 mg of Xiaflex or placebo with approximately 4 week intervals between injections. Each patient had finger extension procedures the day after injection, if needed, to facilitate disruption of the cord. These trials were comprised of 374 patients of whom 249 and 125 received 0.58 mg of Xiaflex and placebo, respectively. The mean age was 63 years, 80% were male and 20% were female, and 100% were Caucasian.
Pivotal Studies
In Study 1, 191 of the 204 patients in the treatment arm, and 100 of 104 patients in the placebo arm, completed the clinical study. In Study 2, all 45 patients in the treatment arm, and 19 of the 21 patients in the placebo arm, completed the clinical study. The patients in both studies were males or females ≥18 years of age, with Dupuytren's contracture with a palpable cord, with a primary metacarpo-phalangeal (MP) or proximal inter-phalangeal (PIP) joint contracture suitable for injection and evaluation. The primary endpoint in both studies was the reduction of contracture to 5° or less in the primary joint at the Day 30 of evaluation after the last injection of study drug. For the MP and PIP joints involved, the surrogate endpoint for determining the outcome of treatment of the cord affecting the joint was the contracture angle (degrees).
The primary endpoint was achieved in both studies. The proportion of patients who achieved a total reduction in contracture of the selected primary joint to within 0° to 5° of normal within 30 days of the last injection was 64% and 7% in Study 1, and 44% and 5% in Study 2; in the Xiaflex and placebo groups respectively. Efficacy results were consistent across the studies and were clinically and statistically significant.
Secondary endpoints included the percent reduction in baseline contracture, change from baseline in range of motion, time to achieve clinical success, and clinical improvement. Evaluation of efficacy by joint type (MP and PIP) and baseline severity was also performed. Most of the secondary endpoints were achieved.
Non-Pivotal Studies
The results of the non-pivotal/supportive trials were consistent with those obtained in pivotal trials.
3.3.3 Clinical Safety
The safety profile of Xiaflex was established in 13 clinical studies. Out of 1,082 patients who received at least one dose of Xiaflex (0.58 mg) in the controlled and uncontrolled portions of the clinical studies (2,630 Xiaflex injections), 61.2% received 1 or 2 injections of the study drug. Of these 1,082 patients, 3 (0.3%) had a flexor tendon rupture of the treated finger within 7 days of the injection. A statement has been included in the Warnings and Precautions section of the Product Monograph that recommends that Xiaflex should be injected only into the collagen cord with a MP or PIP joint contracture, and care should be taken to avoid injecting into tendons, nerves, blood vessels, or other collagen-containing structures of the hand. Further details are discussed in the Warnings and Precautions section of the Product Monograph.
In the placebo-controlled portions of Studies 1 and 2 through Day 90, 98% and 51% of Xiaflex-treated and placebo-treated patients, respectively, had an adverse reaction after up to 3 injections. Approximately 81% of these local reactions resolved without intervention within 4 weeks of Xiaflex injections. The adverse reaction profile was similar for each injection, regardless of the number of injections administered; however, the incidence of pruritus increased with more injections. A statement has been added to the Warnings and Precautions section of the Product Monograph describing that Xiaflex contains foreign proteins and patients develop anti-drug antibodies in greater proportions and higher titers with successive Xiaflex injections. Although there were no severe allergic reactions observed in the Xiaflex studies, severe reactions including anaphylaxis could occur following Xiaflex injections. Health professionals should be prepared to address severe allergic reactions following Xiaflex injections.
The most frequently reported adverse drug reactions (ADRs) (>25%) in the Xiaflex clinical studies included oedema peripheral (mostly swelling in the injected hand) [73.5% - Xiaflex versus (vs.) 4.8% - placebo]; contusion (69.5% - Xiaflex vs. 3.2% - placebo); injection-site haemorrhage (38.2% - Xiaflex vs. 3.2% - placebo); injection-site reaction (34.9% - Xiaflex vs. 5.6% - placebo); and pain in the treated extremity (34.1% - Xiaflex vs. 3.2% - placebo). Other ADRs occurring 25% to 5% more commonly in the Xiaflex arm included injection-site swelling; pruritus and tenderness; skin laceration; blisters and axillary pain.
Serious ADRs in the Xiaflex-treated patients included: injection-site reaction, pain in extremity (2%); peripheral oedema, contusion (1.6%); injection-site haemorrhage (1.2%); and tenderness; injection-site cellulitis; ligament injury; skin laceration requiring skin graft; tendon rupture; chest wall pain; and irritability. A statement has been added to the Warnings and Precautions section of the Product Monograph recommending that care be taken during release of the contracture to help prevent tendon and skin ruptures.
Distal adverse events (AEs) (i.e., those beyond the hand) occurred more often in the Xiaflex-treated patients vs. placebo-treated patients. These included lymphadenopathy and lymph node pain (21.3% vs. 0%), cardiovascular/respiratory disorders (2.0% vs. 0%), and psychiatric disorders (2.0% vs. 0%).
For a more complete list of ADRs occurring during the clinical trials, see the Product Monograph.
While it is an injectable product, Xiaflex has a local destructive effect on the tissues; this is the basis of its pharmacodynamic mechanism. In order to minimize risk and maximize therapeutic benefit, Xiaflex should be administered correctly, by trained healthcare professionals.
Based on pre-market clinical study data and post-marketing data collected over a one-year time interval, the safety profile of Xiaflex is considered to be acceptable for the indication sought.
The Risk Management Plan (RMP) for Xiaflex and the Training Guide for the Administration of Xiaflex (United States version) have been reviewed by Health Canada.
3.3.4 Additional Issues
As a post-marketing commitment, the sponsor will provide Health Canada with the Xiaflex training materials for healthcare professionals in Canada within an agreed upon timeframe.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Xiaflex is a new type of therapy for the treatment of patients with Dupuytren's contracture with a palpable cord. Existing therapeutic options involve surgery and have a relatively high rate of recurrence. Currently there are no approved pharmacological treatments for Dupuytren's contracture in Canada. The proposed novel therapy, Xiaflex, consists of injecting bacterial collagenases into the fibrous cord to disrupt its anatomical structure.
The efficacy of Xiaflex was demonstrated in two Phase III double-blinded clinical studies, and several supportive studies. In the controlled studies, Xiaflex demonstrated superior efficacy to placebo. In one study 64% (130/203) of the patients treated with Xiaflex achieved a reduction in contracture to ≤5º vs. 6.8% (7/103) of the patients treated with placebo. In the second study, 44.4% (20/45) of the patients receiving Xiaflex achieved a similar reduction in contracture vs. 4.8% (1/21) of the patients receiving placebo. These results were clinically and statistically significant. The rationale for selecting a placebo as a comparator is that choosing standard treatment options, such as needle aponeurotomy and open fasciectomy, would have made study blinding impossible.
The safety profile of Xiaflex was established in 13 clinical studies where 1,082 patients received Xiaflex. Most subjects (61.2%) received 1 or 2 injections of study drug. The most frequently reported (≥10.0%) treatment-emergent AEs and treatment-related AEs were: peripheral oedema; contusion; injection-site pain; pain in extremity; injection-site haemorrhage; swelling and tenderness; and pruritus. The majority of treatment-related serious AEs were related to events of the hand: injection-site reaction; pain oedema; contusion and injection-site haemorrhage; cellulitis; ligament injury; tendon ruptures; ligament injuries; and skin lacerations requiring skin graft, as well as lymphadenopathy; axillary and chest-wall pain; and irritability.
In the Phase III controlled studies, up to 92% of the patients receiving Xiaflex developed anti-drug antibodies (ADA). There was no apparent correlation of antibody frequency, antibody titers, or neutralizing status to clinical efficacy or adverse reactions, although the potential for ADA to result in reduced efficacy cannot be excluded. Xiaflex is generally expected to be confined to the injection site rather than to undergo systemic distribution; however, extravasation could occur. Injection-site reactions occurred in 35% of the patients who received Xiaflex vs. 5.6% placebo.
It should be emphasized that the pharmacodynamic mechanism of action of Xiaflex is the destruction/digestion of collagen. As long as this process is controlled and remains localized to the tissue area/volume of interest the risk/benefit profile of this therapy could be acceptable. However, should the drug reach adjacent tissues, such as nerves; blood vessels; cartilage and bone; or muscle, the risk of extensive irreversible damage cannot be ruled out.
Based on the clinical data provided in the submission, Xiaflex is an acceptable medical treatment for Dupuytren's contracture. However, Xiaflex has not been directly compared to standard surgical techniques and due to the safety concerns identified and potential pitfalls related to this novel therapy, Xiaflex should be administered only by health professionals experienced in injection procedures of the hand and in the treatment of patients with Dupuytren's contracture.
The benefits of Xiaflex for the treatment of Dupuytren's contracture with palpable cord were judged to outweigh the risks. In order to monitor whether the benefits of Xiaflex continue to outweigh any risk, a Risk Management Plan has been requested by Health Canada. Also, as a post-marketing commitment, the sponsor will provide Health Canada with the Xiaflex training materials for healthcare professionals in Canada within an agreed upon timeframe.
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 Xiaflex is favourable in the treatment of adult patients with Dupuytren's contracture with palpable cord. The New Drug Submission (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: XiaflexTM
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2011-01-13 |
| Request for priority status | |
| Filed: | 2011-03-25 |
| Rejection issued by Director, Centre for the Evaluation of Radiopharmaceuticals and Biotherapeutics: | 2011-04-19 |
| Submission filed: | 2011-06-07 |
| Screening | |
| Screening Acceptance Letter issued: | 2011-07-29 |
| Review | |
| On-Site Evaluation: | 2012-05-14 - 2012-05-18 |
| Quality Evaluation complete: | 2012-05-09 |
| Clinical Evaluation complete: | 2012-05-09 |
| Labelling Review complete: | 2012-04-30 |
| Notice of Compliance issued by Director General | 2012-07-05 |