NMPA releases guidelines for technical review of intravascular catheters compared with the same type of clinical evaluation

The purpose of comparison of the same variety is to reasonably use the clinical data of the same variety of products as evidence to support the clinical safety and effectiveness of the declared products
.
Therefore, the process of comparing whether a product of the same variety and the declared product are basically equivalent is also a process to determine the extent to which the clinical data of the same product can be used to support the clinical safety and effectiveness of the declared product
.
The "Technical Guidelines for Clinical Evaluation of Medical Devices" has elaborated on the definition, determination principles, evaluation paths of the same types of medical devices, the collection methods and analysis and evaluation methods of clinical data of the same types, and the principles of clinical evaluation of the same types of medical devices.
The above should meet the requirements of "Technical Guidelines for Clinical Evaluation of Medical Devices"
.

When comparing intravascular catheter products with the same variety, the products of the same variety selected should be products that have been on the market and have basically the same expected use and similar technical characteristics
.
It should be compared from the three aspects of intended use, technical characteristics, and biological characteristics, and preferentially select products with higher homogeneity
.
It is recommended to first consider choosing similar products as products of the same variety.
If there is indeed a need to choose different types of products as the same variety, or when multiple products of the same variety need to be selected, the reasons should be fully explained
.
The comparison of the same type of intravascular catheter requires a comprehensive evaluation.
Therefore, it is recommended to consider all items when comparing with each product of the same type, except for components with completely independent functions
.

Fourth, the basic requirements of the comparison project

The specific comparison items with products of the same variety should meet the requirements in the "Technical Guidelines for Clinical Evaluation of Medical Devices", and the following content under the subdivided items should be paid attention to:

(1) Basic principles

The basic principle of intravascular catheter products is mainly to establish the passage of liquid or other substances between the blood vessel and the outside.
However, due to the different anatomical positions of the catheter placement and the tip end of the catheter in the human body, the clinical expected uses and risks are different, so detailed explanation is required.
And compare the anatomical parts of the catheter, which should also focus on the anatomical parts that the tip of the catheter reaches
.
In addition, due to the different functions brought about by the differences in product design, the principles of the realization of the functions should also be compared in detail
.
For example, the specially designed head-end configuration realizes the principle of reducing blood vessel damage, or the principle of reducing fibrin adhesion/catheter-related thrombosis with a coating design
.

(2) Structural composition

At present, the basic structure of the same kind of catheters that have been registered is relatively fixed.
The main differences are the number of sub-lumens, the size distribution of each lumen; the difference in the types of joints; the difference in the position and number of the openings at the tip of the catheter, and the difference in the coating
.

(3) Production process and manufacturing materials

Intravascular catheters should mainly be compared with the raw materials that the product directly or indirectly contacts the human body, including the chemical names of materials such as catheters, extension tubes, joints, coatings, and radiopaque substances
.
At the same time, the manufacturing, sub-lumen, tip treatment, coating and other processes of the intravascular catheter will affect the performance of the product, and may also directly affect the clinical safety and effectiveness of the product
.
The registration applicant can analyze the differences in the process and submit supporting materials to prove that the differences do not have an adverse effect on the clinic, and can also evaluate whether the product meets the requirements through the non-clinical and/or clinical evidence of the declared product
.

(4) Performance requirements

Intravascular catheters should meet the applicable mandatory industry standards in the YY0285 series according to the product type, and then compare the corresponding technical requirements according to the design features of the product
.
In most cases, when there is a clear acceptance threshold in the industry standard, the performance does not need to be compared.
For example, the UV absorbance in the chemical performance, the residual amount of ethylene oxide, and the bacterial endotoxin in the biological performance.
Other commonly used items need to be carried out.
Depending on the type of product, the performance comparison may include:

·Catheter size (should include inner diameter, outer diameter, and effective length
.
Hydration catheter should provide effective length before and after hydration)

·Sub-cavity condition (including quantity, shape, inner diameter)

·Head end configuration (including head end shape, opening shape, number of openings, opening position, etc.
)

·Whether it is a hydration catheter

·Catheter rigidity

·Catheter elongation

·Ray detectable

·Corrosion resistance

·Flow rate (should include the flow rate of each lumen and each rated pressure)

·Lumen identification

·Distance Mark

·Peak tension of each part of the catheter (including the head end, the tubular part, each connection between the pipe socket or the connector and the pipeline and the connection between each tubular part)

·Connectors (including type, size, shape, etc.
)

·Seat configuration

·Pressure resistance/burst strength

·Anti-negative pressure performance/catheter flattening

·Bending fatigue resistance

·Coating performance (including coating uniformity, reliability, coating function related indicators, etc.
)

(5) Scope of application

The comparison should include: applicable population, applicable part, contact method with human body, indications, applicable disease stage and degree, and use environment
.

(6) How to use

For example, attention should be paid to the differences in pretreatment methods used in different catheters.
The pretreatment of catheters may include bending, shearing, and coating activation
.
Another example is to pay attention to the comparison of different catheter placement methods, the use of puncture plus X-ray positioning method and the comparison of catheter placement under ECG monitoring, there will be differences in the equipment, the time and accuracy of the catheter placement operation
.
The differences in the above-mentioned operation methods may lead to different clinical risks and benefits
.

(7) Contraindications

According to the type of intravascular catheter, compare absolute contraindications and relative contraindications (if applicable)
.

(8) Preventive measures and warnings

The comparison includes but is not limited to: known adverse reactions such as complications (intraoperative and postoperative), drug compatibility warning information, compatibility warning information with other prescribed drugs such as disinfectants, plasticizer warning information, possible Misoperation or performance failure (such as the failure of acupuncture prevention function)
.

(9) Instructions

Should focus on contraindications, warning information, operating precautions, known adverse events, and differences in drug compatibility
.

In addition to the required comparison content, it is necessary to consider the addition of the characteristics of the declared product and the product of the same variety or the selection of comparison items
.
For inapplicable items, the reasons for their inapplicability should be elaborated
.

5.
Difference analysis and evidence provision

After detailed comparison with products of the same variety, all differences should be analyzed one by one, supporting information should be provided, and corresponding non-clinical or clinical evidence should be submitted to prove that the differences do not have an adverse effect on the clinical use of the product.
The submission form and requirements of the information should meet "Technical Guidelines for Clinical Evaluation of Medical Devices
.
" Similar intravascular catheters (such as CVC, PICC) often have differences in performance indicators, and sometimes these differences may not have absolute advantages and disadvantages
.
For example, some products will reduce the wall thickness and peak tension of the catheter in order to achieve a higher lumen flow rate; some products in order to achieve a higher burst pressure, use a harder catheter material, so the catheter may be increased Risk of damage to the blood vessel wall from the tip
.
Therefore, clinical evaluation needs to comprehensively consider the clinical risk and benefit of the product
.
When analyzing these differences, firstly, whether the product meets the needs of clinical use can be explained by whether the product meets the performance requirements in the applicable national and/or industry standards
.
Second, if the difference exists in some indicators that do not give limit values ​​in national and/or industry standards, the registration applicant can choose to compare the measured values ​​under the same testing method, or whether it can meet the needs of clinical use.
Discuss whether the difference has an adverse effect on clinical use
.
Such as flow requirements, usually the standard specifies the target nominal value tolerance and measurement method, but does not specify the nominal value of the flow.
The registration applicant defines the limit according to the product design.
The registration applicant can measure under the same method Comparing the actual measured values ​​of the declared product with the products of the same variety, you can also provide your own data of the declared product to prove its safety and effectiveness
.
Third, some indicators that are not listed in the standards or product technical requirements, but are extremely important for product performance, production control or clinical use, should also be compared and analyzed
.

 6.
Use of product data of the same type

Because the principle of intravascular catheters to achieve clinical functions is mainly to establish human blood vessels and external pathways that meet clinical flow requirements or other material delivery requirements, it is easier to draw conclusions from the comparison of products of the same variety in terms of effectiveness
.
Under normal circumstances, in addition to claiming the safety and effectiveness of anti-infective and anti-thrombotic functional coatings, in most cases, non-clinical data can be used to prove that differences with products of the same variety do not cause adverse effects
.

The safety indicators of intravascular catheters, such as catheter-related infections, thrombosis rate, etc.
, as well as the aforementioned effectiveness indicators that claim to have anti-infection and anti-thrombotic functional coatings, usually require a large sample size to be able to draw statistical conclusions.
And the clinical outcome is closely related to the patient's condition, surgical methods, and postoperative care.
It is not easy to reflect the use of the product in the real world in a rigorously designed pre-market clinical trial
.
Therefore, compared with the small-scale clinical data generated by the clinical trials of the same product before the market, the data generated in the clinical application after the market is more suitable for assisting in determining the safety of the product
.
Due to the complex influencing factors of infection and thrombosis, when evaluating the clinical data of products of the same product, the description and basis for determining the correlation between adverse events and catheters are particularly important
.
In addition, epidemiological data has good guiding significance for the safety evaluation of the clinical use of intravascular catheter products.
It is recommended that the registration applicant collect the latest data on the incidence of infection and mortality of the intravascular catheter or one of its products.
Compare with the existing safety clinical data of the same product or declared product
.

Most intravascular catheter products are widely used in clinical applications and are used in large quantities.
At the same time, the product design is relatively mature.
The difference in comparison is not necessarily a problem faced by a single product, but a problem faced by similar products with the same characteristics.
Therefore, products of the same variety are listed on the market.
In addition to searching for the clinical data of products of the same variety that have been selected for the subsequent clinical data, it is recommended to collect data on similar products with the same characteristics to support the clinical safety and effectiveness of the declared products
.
For example, the clinical effect of anti-infective coatings can be evaluated by simulation experiments and/or pre-market clinical trials on bacterial colonization after extubation, but whether the reduction of bacterial colonization is related to the reduction of catheter-related infection rate This clinical outcome is related, and it is difficult to draw conclusions only through pre-marketing clinical trials whether to reduce the rate of catheter-related infections
.
If the registration applicant claims that the coating has the effect of reducing infection, the clinical data on intravascular catheters with similar coatings can be considered, combined with the epidemiological report of intravascular catheters, to obtain appropriate evidence
.
Comparative clinical evaluation of the same species is one of the ways of clinical evaluation, which can be used together with other paths such as clinical trials to conduct comprehensive clinical evaluation of products
.

Seven, references

1.
"Notice of the State Food and Drug Administration on Issuing Technical Guidelines for Clinical Evaluation of Medical Devices" (2015 No.
14)

2.
"Guidelines for the Prevention and Treatment of Intravascular Catheter-related Infections" (2007 Edition)

3.
"Guidance On Premarket notification [510(K)] Submission For Short-Term and Long-Term Intravascular Catheters" (1997) FDA

4.
"Practical Standards for Infusion Therapy" American Infusion Nursing Society (INS)

5.
Implanted Blood Access Devices for Hemodialysis- Draft Guidance for Industry and Food and Drug Administration Staff; June 28, 2013; CDRH FDA.

6.
"Standard Operating Procedures for Blood Purification" (2015 Edition)

7.
"Clinical Practice Guidelines for Hemodialysis Vascular Access"

8.
"Expert consensus on vascular access for hemodialysis in China" (1st edition)

9.
"Guidelines for Diagnosis and Treatment of Intravascular Catheter-related Infections" IDSA (2009 Supplementary Edition)

8.
Drafting unit

Medical Device Technology Evaluation Center of the State Drug Administration
.

Appendix 1: Examples of some common situations in the comparison of intravascular catheter products with the same variety

(1) Comparison of intravascular catheters with different indwelling times

For example, CVC can be divided into tunnel type and non-tunnel type according to the catheter placement method and indwelling time.
Under normal circumstances, the company claims that the implantation time of tunnel catheter is more than 30 days, and the implantation time of some products can exceed 1 year.
Non-tunnel catheter implantation The time is less than 30 days
.
Since the clinical and non-clinical indicators related to the effectiveness of these two products are comparable, and the short-term observation time points and safety indicators in clinical trials are the same, the two can be considered as products of the same variety
.
Because the tunnel catheter takes a long time to implant in the body, when selecting non-tunnel catheters for comparison of products of the same variety, additional evidence should be added to prove the safety and effectiveness of implantation for more than 30 days
.

(2) Comparison between coated and uncoated intravascular catheters

At present, the coating has three functions: increasing lubricity, anti-bacterial colonization, anti-infection, and anti-thrombosis
.
When an intravascular catheter without a coating is used as a product of the same product, whether the difference in the coating brings about adverse effects can be determined by the internal data of the coated intravascular catheter or other evidence (similar to the clinical data of the coating, etc.
).
) Prove it
.

(3) Comparison between intravascular catheters using different main raw materials

In general, the same kind of intravascular catheters of different materials need to comply with the YY0285 series related standards due to their physical, chemical, and biological properties.
The performance of the same kind of catheters is comparable, so the same kind of catheters of different materials can be used as the same variety of products.

.
Differences caused by material characteristics, such as material safety and other indicators, can be used to declare the product's own data or other evidence, such as the clinical application of the material, to prove that the above-mentioned differences do not bring adverse effects
.

When it is difficult to obtain some raw material information of the same product, the part that cannot be compared can also be regarded as the difference item, and the data of the declared product itself or other evidence shall be provided with reference to the above principles to prove that the difference does not bring adverse effects
.

(4) Comparison of intravascular catheters in different clinical catheter placement methods

For example, PICC products can use conventional tube placement in X-ray positioning (puncture method) and tube placement under ECG monitoring.
The former highly depends on the doctor’s clinical operating experience, while the latter can reach expectations at the tip of the guide wire.
Provide ECG signal guidance when the location is nearby
.
If the registration applicant claims that the latter method can reduce the risk of intraoperative complications such as ectopic catheters, improve the accuracy of the catheter tip to the expected position, reduce the operation time, and reduce the radiation exposure time of the doctor and the patient, etc.
, it should be provided separately Evidence of the effectiveness of intubation
.
However, the evaluation of the clinical safety and effectiveness of CVC after the operation of the two is basically not directly related to the difference of intraoperative guidance measures, so they can be used as products of the same variety
.

(5) Comparison between catheter package products and individual intravascular catheter products

In general, the intravascular catheter is the most important component in the catheter package, and the same single intravascular catheter product can be used as the same product
.
The intravascular catheter in the catheter package may be sterilized again, which is different from the product of a single intravascular catheter.
The sterilization verification report can prove that the second sterilization does not adversely affect the CVC
.
Most of the accessories in the catheter kit have been included in the list of exempt clinical trials, so the accessories can also be evaluated by other evaluation paths
.

(6) Comparison of different catheter tip implant positions of implantable drug delivery device

The tip end of the catheter of the implantable drug delivery device can be implanted into veins, arteries, intraperitoneal or intraspinal (intrathecal/epidural) and other parts.
Products that are only used for non-intravascular indications can also refer to this guide.
Principles for clinical evaluation
.
Products with different catheter tip implant positions can also be compared as products of the same variety.
The differences in indications, product structure, tip configuration, flow rate, etc.
should be focused on to provide evidence that does not adversely affect clinical use
.

(7) Circumstances that are not suitable as products of the same variety

CVC for blood purification and CVC for infusion are different in indications, applicable population, test items, biological evaluation, clinical use, and known adverse events.
They are two different products, so blood purification CVC and CVC for infusion are not suitable for each other as products of the same variety
.

Appendix 2: Overview of typical products of intravascular catheters

(1) Central venous catheter (CVC)

CVC refers to an intravascular catheter that can be inserted into the central venous system through the internal jugular vein, femoral vein, or subclavian vein for blood purification, fluid infusion, blood sampling, and measurement of central venous pressure
.
The catheter can be divided into a tunnel and non-tunnel, according to the product structure can be divided into single chamber, dual chamber, the three chambers and the like
.
According to its use, it can be divided into CVC for blood purification and CVC for infusion.
The former includes CVC for blood purification such as hemodialysis and diafiltration, and the latter includes CVC for infusion and pressure measurement
.

(2) Via peripheral central venous catheter (PICC)

PICC refers to an intravascular catheter that can be inserted into the central venous system through peripheral veins, such as the expensive vein, median cubital vein, cephalic vein, and brachial vein for liquid infusion and blood sampling
.

(3) Implantable drug delivery device (TIAP)

Implantable drug delivery device or fully implanted infusion port (TIAP) (referred to as "infusion port") is an infusion device that is left in the human body for a long time.
”), the conduit consists of two parts, and some products have independent connectors
.
The port body and the connector are implanted subcutaneously, and the catheter can be implanted in veins, arteries, intraperitoneal or intraspinal (intrathecal/epidural) and other places to establish long-term fluid access for patients.
The port can be repeatedly punctured through the skin The injection seat is suitable for patients who need chemotherapy, nutritional support, ascites or pleural effusion suction and drainage, pain management, blood sampling and other clinical need for repeated infusion or aspiration
.

(4) Intravenous indwelling needle (IV-Caths.
)

Intravenous indwelling needle or intravenous trocar.
After the core and the outer tube are punctured into the peripheral vein, the needle core is drawn out, and the outer tube is indwelled in the blood vessel to establish a fluid pathway with the outside world for infusion or blood sample collection
.
The general retention time is 72 hours
.