Summary Basis of Decision for Recothrom ®
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:
Recothrom®
Thrombin alfa (Recombinant), 6,000 IU/vial and 24,000 IU/vial, Powder for solution, Topical
Bayer Inc.
Submission control no: 125888
Date issued: 2010-08-30
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):
- 02339277- 6,000 IU/vial
- 02339285- 24,000 IU/vial
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
® RECOTHROM is a trademark of ZymoGenetics, Inc., used under license by Bayer Inc.
® Bayer and Bayer Cross are registered trademarks of Bayer AG, used under license by Bayer Inc.
2 Notice of decision
On December 15, 2009, Health Canada issued a Notice of Compliance to Bayer, Inc. for the drug product Recothrom.
Recothrom contains the medicinal ingredient thrombin alfa (recombinant) which is a coagulation factor produced via recombinant deoxyribonucleic acid (DNA) technology. Thrombin alfa is comparable to human thrombin with respect to amino acid sequences, disulfide linkages and higher order structure.
Recothrom is indicated as an aid to haemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques is ineffective or impractical. Recothrom activates platelets and catalyzes the conversion of fibrinogen to fibrin, which are steps that are essential for blood clot formation. The effectiveness of Recothrom was only evaluated in surgical settings where adjuncts to hemostasis are frequently required: hepatic resection, peripheral arterial bypass surgery, arteriovenous graft formation for hemodialysis access, and spinal surgery.
The market authorization was based on quality, non-clinical, and clinical information submitted. The safety and efficacy evaluation of Recothrom included four Phase II clinical studies and one pivotal Phase III, randomized, double-blind, controlled study which compared Recothrom to bovine thrombin (bThrombin) as adjuncts to achieving haemostasis in surgery. In the Phase III study, the efficacy of Recothrom was evaluated in a total of 401 patients who underwent one of the following surgical procedures: spinal surgery, hepatic resection, peripheral arterial bypass surgery, or arteriovenous graft formation for haemodialysis access, upon which the bleeding site was then treated with either Recothrom (1000 IU/mL) or bThrombin (1000 IU/mL). The primary objective of the trial was to evaluate the efficacy of Recothrom versus bThrombin as adjuncts to achieving haemostasis in surgery by measuring the incidence of haemostasis achieved within 10 minutes. Only one bleeding site per patient was used to determine primary effectiveness. Results from the study showed that the overall incidence of haemostasis within 10 minutes was 95.4% for subjects in the Recothrom group and 95.1% for subjects in the bThrombin group. This represents a 0.3% difference in the incidence of haemostasis within 10 minutes in subjects receiving Recothrom compared to those receiving bThrombin, demonstrating that the two treatments have comparable efficacy. However, the evidence to support the efficacy of Recothrom as an aid to haemostasis in patients undergoing spinal surgery was not established from Phase II and III studies. These studies were not of sufficient size to draw specific conclusions regarding the safety or efficacy of Recothrom within each of the surgical settings investigated.
Recothrom [6000 IU and 24,000 IU, thrombin alfa (recombinant)] is presented as a powder for solution to be reconstituted with sterile sodium chloride solution before use. Recothrom may be applied directly to the bleeding site or used in conjunction with a compatible absorbable gelatine sponge. The amount of Recothrom required to stop bleeding depends upon the area of tissue to be treated and the method of application. Recothrom is indicated for topical use only. Application guidelines are available in the Product Monograph.
Recothrom is contraindicated for use in patients who are hypersensitive to this drug or to any ingredient in the formulation or any component of the container. Recothrom contains the medicinal ingredient thrombin alfa which is produced via recombinant DNA technology in Chinese Hamster Ovary Cells. Consequently, Recothrom is also contraindicated in patients who are hypersensitive to hamster protein. Recothrom should not be used for treatment of massive or brisk arterial bleeding.
Recothrom 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. Recothrom must not be injected directly into the bloodstream. Intravascular injection of thrombin-containing haemostats may result in life-threatening intravascular coagulation or death. Detailed conditions for the use of Recothrom 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 Recothrom is favourable as an aid to haemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques is ineffective or impractical.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
General Information
Thrombin alfa (recombinant), the medicinal ingredient of Recothrom, is a recombinant coagulation factor identical in amino sequence to natural human thrombin. Thrombin alfa efficiently activates platelets and catalyzes the conversion of fibrinogen to fibrin, which are steps that are essential for blood clot formation.
Manufacturing Process and Process Controls
Thrombin alfa is produced by recombinant deoxyribonucleic acid (DNA) technology using a genetically stable Chinese hamster ovary (CHO) cell line known to be free of adventitious agents/viral contaminants.
The CHO cells secrete a precursor into the culture medium which is recovered by a series of filtration steps, subjected to viral inactivation, chromatographically purified, and then concentrated by ultrafiltration.
The precursor is converted to thrombin alfa by passing over a solid phase reagent. The resulting recombinant product is identical in amino acid sequence, disulfide linkage and higher ordered structure to human α thrombin.
The conversion to thrombin alfa is followed by orthogonal chromatography steps, nanofiltration and formulation with excipients (mannitol, histidine, sucrose, polyethylene glycol 3350, sodium chloride, and calcium chloride dehydrate).
Characterization
Structural elucidation/confirmation was accomplished by a number of techniques including amino acid sequencing, mass spectrometry, and ultraviolet spectroscopy.
Biologic activity was verified using enzyme kinetic analysis, inhibition kinetics, clotting assays, and chromogenic assays.
Control of Drug Substance
The drug substance specifications and analytical methods used for quality control of thrombin alfa are considered acceptable.
Results from process validation reports and in-process controls indicate that the impurities of the drug substance are adequately under control.
Batch analysis results were reviewed and all results comply with the specifications and demonstrate consistent quality of the batches produced.
The proposed packaging components are considered acceptable.
Stability
Sufficient long-term and accelerated stability data were submitted to support the proposed retest period when the substance is packaged in polyethylene terephthalate glycol (PETG) bottles sealed with high-density polyethylene (HDPE) screw closures and stored at the proposed temperature.
3.1.2 Drug Product
Description and Composition
The drug product, Recothrom, is manufactured by diluting the bulk drug substance to a target concentration, aseptically filling into glass vials and lyophilizing. The vials are closed with a bromobutyl stopper and a flip-off, tear-off seal. The drug product is a preservative-free formulation and the vials are single-use only. Recothrom packaging includes a sterile diluent, 0.9% sodium chloride in water for injection in a blow-molded plastic ampoule with a Luer fitting, along with a vial adapter and syringe for reconstituting the product.
Recothrom is a sterile, lyophilized, white to off-white powder for solution and is filled in two sizes, 6000 IU/vial and 24000 IU/vial. Both sizes have identical formulations, that is (i.e.) only the net contents are different. Following reconstitution with the 0.9% sodium chloride solution, the formulated product is a clear, colourless solution with a strength of 1200 IU/mL.
All of the non-medicinal ingredients (excipients) found in Recothrom are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of thrombin alfa with the excipients is demonstrated by the stability data presented for the proposed commercial formulation.
Pharmaceutical Development
Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable.
Manufacturing Process and Process Controls
The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
The validated process is capable of consistently generating product that meets release specifications.
Control of Drug Product
Recothrom is tested to verify that its identity, appearance, content uniformity, assay, pH, dissolution, sterility, moisture content, osmolality, colour, clarity, drug-related impurities, bacterial endotoxins, specific activity, and total activity are within acceptance criteria.
The Recothrom specifications are considered acceptable; the analytical methods and test criteria constitute appropriate controls for drug product release and stability.
The Sponsor provided sufficient batch data to support the proposed manufacturing process and specifications.
Four sample lots (two of each drug product size) were received by the Biologics and Genetic Therapies Directorate, Health Canada for consistency testing. The results of the laboratory testing were found to be acceptable to support the submission.
Stability
Based on the long-term and accelerated stability data submitted, the proposed 24-month shelf-life for Recothrom when stored at 2°C to 25°C 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 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. The on-site evaluation and the review of the responses to the Exit Notice observations were found to be satisfactory.
All sites are compliant with Good Manufacturing Processes.
3.1.4 Adventitious Agents Safety Evaluation
The CHO cell line was known to be free of adventitious agents. Pre-harvest culture fluid from each lot is tested to ensure freedom from adventitious microorganisms. Orthogonal viral reduction and inactivation steps included in the bulk drug substance manufacturing process were adequately validated.
Raw materials of animal and recombinant origin used in the manufacturing process are adequately tested to ensure freedom from adventitious agents.
3.1.5 Conclusion
The chemistry and manufacturing information submitted for Recothrom 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
In vitro and in vivo studies demonstrated that Recothrom is enzymatically active and can convert autologous fibrinogen to fibrin as well as activate Factor XIII and platelets. In animal models of surgical bleeding, Recothrom applied at a concentration of 1000 IU/mL was consistently superior to placebo in decreasing time to haemostasis (TTH).
Based on TTH, Recothrom controlled bleeding comparable to bovine thrombin in the animals tested. In both rabbit and rat bleeding models, TTH was dramatically reduced with Recothrom compared to saline when both were applied using Gelfoam®. Another study assessed the use of Recothrom with different sponges and there were no significant differences in TTH between Recothrom and bovine thrombin when comparing TTH within similar sponge groups.
3.2.2 Pharmacokinetics
Two studies were conducted to monitor the bioavailability and clearance of Recothrom in its free and complex forms in monkeys and rabbits.
Recothrom did not circulate in the blood as a free, active molecule. Results from the study in monkeys indicate that radiolabelled Recothrom administered intravenously or subcutaneously rapidly became inactive by forming complexes with endogenous inhibitors [for example (e.g.) antithrombin III] and these complexes were cleared by the liver.
Radiolabelled Recothrom, administered via a Gelfoam® sponge to a rabbit liver wound, remained in the vicinity of the sponge application site, and the small amount of Recothrom-associated radioactivity was absorbed.
3.2.3 Toxicology
Single-Dose Toxicity
Single-dose toxicity studies were conducted in monkeys using a surgical liver wound healing model. Recothrom was applied topically (approximately 500 IU/kg using a 1000 IU/mL formulation). No treatment-related effects were reported with the use of Recothrom.
Repeat-Dose Toxicity
Female rats tolerated subcutaneous (SC) injections of up to 992 IU/kg Recothrom given once-weekly for two weeks, as well as a single intravenous bolus injection of 158 IU/kg Recothrom. In contrast, female rats did not tolerate a single intravenous (IV) dose of either 178 or 341 IU/kg bovine thrombin.
Monkeys received SC injections of 346 IU/kg Recothrom or bovine thrombin once weekly for 4 consecutive weeks. Both products were well-tolerated; there were no signs of test-related toxicity in any animal. No animals developed specific antibodies to Recothrom or potential trace prothrombin activator (PTA) impurities. One animal had low levels of specific antibodies to CHO impurities at 2 of 9 non-consecutive time points.
Genotoxicity
Genotoxicity studies were not performed. These studies are not required as thrombin alfa is a correlate of naturally existing plasma thrombin.
Carcinogenicty
Carcinogenicity studies were not performed.
Reproductive and Developmental Toxicity
Reproductive and developmental toxicity studies were not performed. The animal toxicity studies showed no signs of organ toxicity, including the reproductive tissues.
Local Tolerance
Recothrom was found to be non-irritating when instilled in the eyes or applied to normal or abraded skin of rabbits.
3.2.4 Conclusion
The pharmacological activity of Recothrom as a coagulation factor has been demonstrated in the non-clinical studies. The pharmacology and toxicology studies for this drug submission are considered acceptable. No major concerns were identified. The non-clinical studies support the use of Recothrom for the proposed indication.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
Pharmacodynamic studies were not conducted in humans. Instead, the pharmacodynamics of Recothrom were extensively characterized in vitro. Four in vitro studies have shown that Recothrom and bovine thrombin have approximately equal activity in vitro. Results showed that Recothrom was capable of activating recombinant human Factor XIII (rhFXIII) at concentrations equivalent to that of bovine thrombin.
3.3.2 Pharmacokinetics
Clinical pharmacokinetic studies were not conducted due to the fact that Recothrom acts locally, does not appreciably enter the circulation when applied topically, and is rapidly bound to endogenous inhibitors upon entry into the circulation.
3.3.3 Clinical Efficacy
The clinical studies consisted of one pivotal Phase III study, four Phase II controlled studies, one Phase I study, and one non-controlled Phase II study using a different mode of application. The program of controlled studies examined the use of Recothrom in four diverse surgical settings where adjunctive therapies for haemostasis are often required: spinal surgery, major hepatic segment resection, peripheral arterial bypass (PAB) surgery, and arteriovenous (AV) graft formation for haemodialysis access. During the clinical studies, a total of 374 patients received Recothrom topically applied with an absorbable gelatin sponge or a spray applicator. For 368 of these patients, Recothrom was applied at a dose level of 1000 IU/mL.
The pivotal Phase III study was a multicentre, randomized, double-blind, active-controlled study comparing Recothrom to bovine thrombin, each applied topically to bleeding sites with an absorbable gelatin sponge, at a nominal concentration of 1000 IU/mL. The study was conducted with 411 patients undergoing surgery in one of the four surgical settings mentioned above. Efficacy was evaluated by the incidence of haemostasis within 10 minutes.
In the pivotal study, the overall incidence of haemostasis within 10 minutes was 95.4% for patients in the Recothrom group and 95.1% for patients in the active control group. There was a 0.3% difference in patients receiving Recothrom compared to those receiving bovine thrombin. The proportion of patients achieving haemostasis was similar for both the Recothrom group and bovine thrombin group at 1.5 minutes, slightly higher in the Recothrom group at 3 and 6 minutes, and was similar at 10 minutes. These results demonstrate that Recothrom and bovine thrombin provide comparable effects as general adjuncts to haemostasis.
In the four Phase II studies, a total of 130 patients received blinded study drug (64 subjects in the Recothrom group and 66 in the placebo group). Eighty-eight patients received Recothrom (45 received blinded Recothrom only and 43 received Recothrom as rescue therapy) and 42 subjects received placebo only. The incidence of haemostasis within 10 minutes was numerically greater in patients receiving Recothrom compared to those receiving placebo when the results for all surgery types were combined (90% vs. 80%). However, in the Phase II study 499C05 in spinal surgery, 86% of patients in both the Recothrom group (n=21) and the placebo group (n=21) achieved haemostasis within 10 minutes indicating that the efficacy of Recothrom was not different from placebo in spinal surgery.
Combining the data collected from the Phase III study and four Phase II studies, the evidence to support the efficacy of Recothrom as an aid to haemostasis in patients undergoing surgery is limited for each individual surgery type. In particular, the evidence to support the efficacy of Recothrom in patients undergoing spinal surgery is not considered to be substantial.
3.3.4 Clinical Safety
In the pivotal Phase III study, the safety analysis set was taken from the 205 patients that were treated with Recothrom and the 206 patients that were treated with bovine thrombin. Similar volumes of study drug were administered to both treatment groups for each type of surgery. A safety evaluation was conducted on Day 2 (16 to 48 hours post-surgery) and a final safety and immunogenicity follow-up evaluation was conducted on Day 29 (end of study).
Nearly all patients reported at least one adverse event (AE). The overall incidence of
AEs and serious adverse events (SAEs) was similar between treatment groups. Investigators assessed most AEs as moderate in severity. The severity of AEs was generally similar between treatment groups. The most common AEs were incision site complications, procedural pain, and nausea. A slightly higher incidence of peripheral oedema was observed in the Recothrom group, and slightly higher incidences of procedural pain and nausea were observed in the bovine thrombin group. Few patients experienced AEs that were considered to be treatment-related (overall n=9, 2%; Recothrom, n=7, 3%; bovine thrombin, n=2, 1%). Recothrom had no effect on standard laboratory parameters or system coagulation.
Serious adverse events were reported for patients in both groups [overall, number (n) =82, 20%; Recothrom, n=36, 18%; bovine thrombin, n=46, 22%]. Serious adverse events were those expected for a surgical population. Two SAEs were assessed by investigators as treatment-related. Each of these events occurred in one patient from the Recothrom group and included arteriovenous graft thrombosis and a pulmonary embolism.
Three patients died. No deaths were considered related to study treatment.
Certain AEs were prospectively defined in the Phase III study as "adverse events of heightened surveillance" based on the mechanism of action of Recothrom or bovine thrombin, historical reporting in association with cross-reacting antibodies to bovine thrombin, use of a gelatin sponge for delivery of Recothrom or bovine thrombin, or results obtained from the Phase II studies. Throughout the Phase III study, "adverse events of heightened surveillance" occurred with a similar incidence between the two treatment groups (Recothrom n=124, 60%; bovine thrombin n=136, 66%).
The development of anti-thrombin alfa product antibodies was monitored in the Phase III study. Recothrom had a lower rate of immunogenicity compared to bovine thrombin; antibody development occurred in 1.5% of the patients in the Recothrom group compared to 22% in the bovine thrombin group.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Recothrom has been shown to act as an aid to haemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques is ineffective or impractical. Overall efficacy was demonstrated in patients undergoing spinal surgery, hepatic resection, PAB surgery, or AV graft formation, although the evidence to support the efficacy of Recothrom is limited for each individual surgery type. In the pivotal study, an overall incidence of haemostasis within 10 minutes was achieved in 95.4% of the patients that were treated with Recothrom compared to 95.1% for the patients in the active control group.
When topically administered, Recothrom is well-tolerated. Observed rates of AEs of interest, such as thromboembolic events, cardiac events, bleeding, and infection, were similar between treatment arms, and were consistent with expected rates for patients undergoing surgical procedures. Recothrom had a low rate of immunogenicity compared with bovine thrombin.
Overall, the benefits of Recothrom outweigh the risks when topically administered locally as an adjunct treatment for bleeding in surgical settings.
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 Recothrom is favourable as an aid to haemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques is ineffective or impractical. The New Drugs 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: Recothrom®
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2008-04-24 |
| Submission filed: | 2008-11-06 |
| Screening | |
| Screening Acceptance Letter issued: | 2008-12-19 |
| Review | |
| On-Site Evaluation: | 2009-09-28 |
| Quality Evaluation complete: | 2009-10-15 |
| Clinical Evaluation complete: | 2009-12-04 |
| Biostatistics Evaluation complete: | 2009-12-04 |
| Labelling Review complete: | 2009-10-14 |
| Notice of Compliance (NOC) issued by Director General: | 2009-12-15 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| RECOTHROM | 02339277 | BAXTER CORPORATION | THROMBIN ALFA 6000 UNIT / VIAL |
| RECOTHROM | 02339285 | BAXTER CORPORATION | THROMBIN ALFA 24000 UNIT / VIAL |