Technical review report for medical device product registrationChinese name of product: absorbable bone wax.
Product Management Category: Category III.
Name of applicant: Shanghai Pengguan Biomedical Technology Co., Ltd. ***
Center for Technical Evaluation of Medical Devices, National Medical Products AdministrationBasic Information1. Name of the applicant.
Shanghai Pengguan Biomedical Technology Co., Ltd
2. The applicant's residence.
1st Floor, Building 2, No. 168, 178 Banxia Road, Pudong New Area, Shanghai.
3. Production address.
1st Floor, Building 2, No. 168, 178 Banxia Road, Pudong New Area, Shanghai.
Overview of the technical evaluation1. Product Overview.
1) Product structure and composition.
The product is made of a certain proportion of polyethylene glycol 1500, polyethylene glycol 600, and sodium carboxymethylcellulose, irradiated and sterilized packaging, and has a sterile expiration date of 35 years.
2) Scope of application of the product.
It is suitable for hemostasis of capillary bone wounds of hemorrhage of limb bones and thoracolumbar cortical bone and cancellous bone.
3) Model specifications.
gl2、gl3、gl4
4) How it works.
After the product is rubbed and softened, it stops the bleeding process by sealing the bleeding pathway between the bones (cancellous spongy mesh or drilling bone hole), and then activates the intravascular and external coagulation pathways to achieve hemostasis.
2. Overview of preclinical studies.
1) Product performance research.
1.Research on product technical requirements.
The technical requirements study items are shown in Table 1.
2.Product performance evaluation.
1) Mechanism of action and review: The product is made of polyethylene glycol and sodium carboxymethylcellulose mixed in a certain proportion. The formulation research data of absorbable bone wax of the declared product were provided, and the mass percentages of polyethylene glycol 1500, polyethylene glycol 600 and sodium carboxymethylcellulose were determined. Polyethylene glycol 1500 is the base and plays the main blocking role, polyethylene glycol 600 is a plasticizer to adjust the softness and hardness of the formulation, and sodium carboxycellulose can improve the blocking performance of the formulation.
2) Chemical material characterization: provide the quality control standards of raw materials and the inspection indicators and control requirements in the production process, and submit the inspection report of the raw materials provided by the first supplier that meet the requirements of the corresponding Chinese Pharmacopoeia and the applicant's purchase inspection report, the qualification certificate of the raw material manufacturer, and the main batch outsourcing agreement. The inspection reports of the intermediate products refined polyethylene glycol 1500 and refined polyethylene glycol 600, the infrared spectrogram before and after refining, the control index and determination basis of the finished product, the inspection report of the finished absorbable bone wax product, the verification data such as infrared spectrum and quantitative analysis and component identification of absorbable bone wax components were provided.
3) Product performance research: the research data on the effectiveness of physical blockade of absorbable bone wax for hemostasis were provided, and the in vitro simulated plugging test of the product and the hemostatic effectiveness test in animals were carried out; The research data on the dissolution and absorption time of the product were provided, and the simulated dissolution or swelling test of the product in vitro, the degradation test after the product was implanted into the bone wound of animals, and the in vitro degradation test of absorbable bone wax (including short-term dissolution test) were carried out. Physical and mechanical properties including appearance, weight, melting point, solubility or swelling, moisture content, penetration, dispersibility, pressure plugging resistance (pressure resistance and wound adhesion), rubbing performance, viscosity, electrocautery compatibility tests, compared to marketed non-absorbable bone waxes.
b) Biocompatibility.
The applicant adopts GB T 168861. The evaluation flow chart given in the standard "Biological Evaluation of Medical Devices Part 1 Evaluation and Testing in the Risk Management Process" is used as the evaluation route, and the cytotoxicity, sensitization, irritation or intradermal reaction, acute systemic toxicity, subacute systemic toxicity (28-week bone implantation), genotoxicity (chromosomal aberration test, gene mutation, Salmonella typhimurium revert mutation), bone implantation (4 weeks), pyrogen test report carried out by Shanghai Medical Device Testing Institute is submitted. A bacterial endotoxin test report was provided, a cytotoxicity test report for cell fusion rate was submitted, a 13-week rabbit tibial bone implantation test was supplemented, and the toxicokinetic evaluation data of PEG1500 and PEG600 were provided.
c) Sterilization. The product was sterilized by electron beam irradiation, and the verification report of absorbable bone wax dose setting, the maximum tolerable dose verification report of absorbable bone wax, and the verification report of absorbable bone wax sterilization dose distribution program were provided. The effect of irradiation sterilization dose on the properties of absorbable bone wax components and the effect on the performance of resorbable bone wax products are provided.
4) Product expiration date and packaging.
The 2-year accelerated aging test report of absorbable bone wax, the 2-year real-time aging test report and the 3-year and 8-month real-time aging test report have been provided to verify the performance stability of the product after aging.
The initial packaging of the product adopts double-layer aseptic packaging, and aseptic packaging of paper-plastic bags is added to the aluminum foil bag packaging. It provides the sealing verification scheme and report of absorbable bone wax paper plastic bag, the sealing verification scheme and report of absorbable bone wax aluminum foil bag, and the test plan and report of absorbable bone wax packaging integrity and packaging simulation transportation.
5) Animal research.
The applicant provided animal tests on rabbit femoral hemorrhage model, rabbit sternotomy model, and pig scapula wound bleeding model, and verified the effectiveness of the maximum dose and maximum bleeding wound that can be used in clinical practice.
3. Overview of clinical evaluation.
The applicant chose the clinical trial as the path of this clinical evaluation. The applicant conducted clinical trials of the product in 6 institutions: Shanghai Sixth People's Hospital, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Taiyuan Central Hospital, Changzhi People's Hospital, Hebei PetroChina Central Hospital, and Baoding First Hospital of Traditional Chinese Medicine. A total of 240 subjects completed the clinical trial to evaluate the safety and efficacy of intraoperative absorbable bone wax in capillary bone wounds of limb bones and thoracolumbar cortical bone and cancellous bone bleeding using randomized, single-blind, parallel, positive-controlled, non-inferiority design, with a total of 240 subjects. The main evaluation indicators were the effective rate of hemostasis in 3 minutes, and the secondary effectiveness evaluation indicators included secondary efficacy indicators: (1) intraoperative evaluation of adhesion non-spillage rate (overflow rate), the number and amount of device application, the time to achieve effective hemostasis, and product performance evaluation; (2) evaluation of bone clinical healing before surgery and 12 weeks after surgery; (3) Incision grade A healing rate. Safety measures included changes in vital signs, adverse events, clinical laboratory data, and death and surgery-related complications. The results of the study showed that the results of FAS analysis: the effective rate of hemostasis in the experimental group for 3 minutes was 10000%；The effective rate of hemostasis in the control group for 3 minutes was 10000%, with a 95% confidence interval of (-0.)03%,0.03%)。PPS analysis results: the effective rate of hemostasis in the experimental group for 3 minutes was 10000%；The effective rate of hemostasis in the control group for 3 minutes was 10000%, with a 95% confidence interval of (-0.)03%,0.03%)。The experimental group was not inferior to the control group. The results of FAS and PPS analysis showed that the adhesion non-spillage rate (overflow rate) of the experimental group and the control group was 100%, that is, there was no bone wax secretion at the surgical wound. There were no statistically significant incision healing at 12 weeks after surgery, 3 days after surgery, and incision healing at 2 weeks after surgery in the experimental group and the control group. There was no statistical significance in the number of application times and product performance evaluation (including dosage, product texture, granularity and viscosity) of bone wax used in the experimental group and the control group, but the softening time of the product in the experimental group (6397 ± 41.98) were statistically significant longer than the control group (2984 ± 23.45), the product of the experimental group was statistically significantly harder than that of the control group. Regarding safety outcomes, there were 53 adverse events in the control group, with an incidence of 438%, and 55 patients in the trial group had adverse events, with an incidence of 4622%。Seven serious adverse events (SAEs) occurred during the course of the study, and no adverse events and serious adverse events related or potentially related to the trial device were observed. Statistically speaking, there was no statistical significance in the two groups. In addition, the applicant also searched for clinical data supplemented by the R&D reference product Absorbable Hemostatic Bone Wax (Orthocon Company), which has similar composition materials to the declared product, and no adverse events were reported in the FDA database. In summary, absorbable bone wax meets the current clinical approval requirements.
Fourth, the product benefit risk determination.
The applicant conducts a risk analysis of the product with reference to YY T 0316 "Application of Medical Device Risk Management to Medical Devices". Risk control measures have been taken for the currently known and can be the best risks, after comprehensive evaluation, at the current level of cognition, it is believed that the benefits of the product on the market outweigh the risks, in order to ensure the safety of the equipment, the following information needs to be prompted in the manual:
a) Instructions for use.
1.Select the appropriate model and specification according to the surgical site where the absorbable bone wax is intended to be used, check the integrity of the initial packaging, and check whether the product is within the validity period.
2.After the inspection is correct, unpack it from the tear site, take an appropriate amount of bone wax according to the size of the bone wound, rub it appropriately to soften, shape it to the desired shape, and apply it to the bone wound area.
3.Observe the hemostasis of the wound, apply it many times if necessary, and wipe off the excess bone wax after the hemostasis is completed, and the specific use method is the same as that of the traditional bone wax.
4.Intramedullary hemorrhage, bleeding in neurosurgical areas such as important nerve centers, spinal canals, intervertebral foramina, dural sacs, etc., has limited clinical evidence, and this product is not recommended.
2) Precautions Warning.
1.Use of this product by trained physicians or paramedic is restricted to those who have been trained.
2.Please use the small package immediately after opening, if the small package is damaged or there are foreign objects in the package, it is strictly forbidden to use it.
3.This product is for one-time use only (repeated use may cause cross-infection), and should be harmless and centralized destruction after use.
4.It is forbidden to use the product beyond the expiration date.
5.This product is strictly forbidden to contact the high-frequency electric knife, if you accidentally contact the high-frequency electric knife, you should immediately cut off the power supply, and wipe the product residue on the surface of the electric knife.
6.This product is strictly forbidden to be used as a bone structure support.
7.Bleeding conditions that are not applicable (e.g., intramedullary hemorrhage, neurosurgical bone wounds such as spinal canal and intervertebral foramina, craniomaxillary wounds).
8.The recommended maximum dosage of this product for a single surgical site does not exceed 6g, that is, the maximum dosage of GL2 does not exceed 3 tablets, the maximum dosage of GL3 does not exceed 2 tablets, and the maximum dosage of GL4 does not exceed 1 tablet.
Please refer to the manual for other details.
3) Contraindications.
1.It is strictly forbidden for those who are allergic to polyethylene glycol and sodium carboxymethyl cellulose materials;
2.It is strictly forbidden to use in case of bone wound infection;
3.It is contraindicated in patients with severe coagulopathy.
4.This product is for ** use only, and the use of children is not yet clear.
5.This product should not be used when bleeding is stopped during surgery and it is necessary to prevent bone regeneration.
Please refer to the manual for other details.
Comprehensive evaluation opinionsThe registration applicant applies for the registration of Class III medical devices in China, and the product registration application materials provided are complete. According to the Regulations on the Supervision and Administration of Medical Devices (Order No. 739), the Administrative Measures for the Registration and Filing of Medical Devices (Order No. 47 of the State Administration for Market Regulation) and other relevant medical device regulations and supporting regulations, after systematic evaluation of the registration application materials, at the current level of cognition, the benefits brought by the listing of the product outweigh the risks, and it is recommended to register it in line with the current technical review requirements.
January 16, 2024**: CMDE