How to prepare overseas clinical trial data of sodium hyaluronate products for Chinese registration

1. Introduction

Imported sodium hyaluronate gel for clinical trials abroad, if its clinical trial meets the relevant technical requirements in China's relevant regulations and registration technical guidelines, such as sample size, control group selection, evaluation indicators and evaluation principles, efficacy evaluation indicators, etc. The registered applicant may submit the clinical trial data submitted to the overseas medical device authority when the company is in the China registration process.

The information should at least include:

(1) Opinions of the Ethics Committee;

(2) Clinical trial plan and clinical trial report;

(3) Applicants are also required to submit relevant supporting information to demonstrate whether there are ethnic differences in clinical performance and/or safety of the product.

2. Sodium hyaluronate facial filling material

If the applicant applies for registration using clinical trial data submitted to the overseas medical device authority, the relevant overseas clinical trials shall in principle not be lower than the requirements of the ‘Guiding Principles for Clinical Trial of Sodium Hyaluronate Face Filling Materials’. It is also necessary to consider the impact of the ethnic differences between the test population and the domestic population on the safety and effectiveness of the clinical use of the product.

2.1 Overall design

Clinical trial requirements for such products for the purpose of applying for initial registration:

(1) Prospective, randomized controlled clinical trials;

(2) Clinical trials should be conducted in two or more clinical trials of medical devices.

(3) It is necessary to use the similar products already on the market as control instruments, and it is preferred to select the control devices with similar composition and performance.

(4) Select the appropriate type of test (excellent/equivalent/non-inferior) according to the clinical significance of the design and the performance of the test instrument.

(5) Appropriate control methods should be considered to ensure the consistency of the baseline between the test group and the control group, such as randomized control of subjects.

(6) Blind methods should be used as much as possible to avoid subjective influencing factors, such as blinding subjects and blinding third-party evaluators. Injection operators can also be blinded if feasible.

2.2 Product target scope

Specific injection levels should be identified (e.g., dermal tissue superficial, dermal tissue middle to deep, dermal tissue deep to subcutaneous shallow, etc.).

2.3 Clinical evaluation criteria

2.3.1 Main effectiveness evaluation indicators

The effectiveness of the wrinkle correction at the point of effect duration stated is set as the main effectiveness evaluation index.

"Efficacy" is generally defined as the percentage of subjects with a 5-point scale of wrinkle severity (such as WSRS) compared to at least one grade before surgery, as evaluated by a professional independent of the injection operator.

For the bilateral data of the same subject, take the data on the side with poor effect. Table 1 provides an example of the amount of evaluation of the severity of nasolabial folds.

Other wrinkle severity reference scales should be validated and recommended to provide clinical institutions with corresponding wrinkle images for each grade to facilitate reference judgment.

Table 1 Reference scale for evaluating the degree of nasolabial wrinkles

Level

Degree

Description

1

No

No visible creases; only continuous skin lines.

2

Mild

The wrinkles are shallow, but visible, with slight dents; the facial folds are fine.

3

Moderate

Deeper wrinkles; clear facial folds; pleats are visible under normal conditions. But the           crease disappears when stretched.

4

Severe

Very long and deep wrinkles; facial folds are noticeable; visible folds of less than 2 mm          when stretched.

5

Extreme

Extremely deep and long wrinkles, severely damaging the face; 2-4mm clearly visible            V- shaped creases when stretched.

 

2.3.2 Secondary effectiveness evaluation indicators

The evaluation includes the severity of wrinkles at other time points except the time point of observation of the main effectiveness evaluation, the evaluation of the global cosmetic effect by the researcher, and the evaluation of the overall cosmetic effect by the subject.

Table 2 provides an example of a global beauty effect evaluation rating.

Table 2 General Beauty Effect Grading Reference Scale

Level

General beauty effect

1

Very obvious improvement

2

Significant improvement

3

A certain degree of improvement

4

No change

5

Worse than before

 

2.3.3 Safety evaluation indicators

Includes side effects (such as induration, itching, pain, redness, bruises, congestion, ecchymoses, infections, local inflammatory reactions, scar formation, nodules, granulomas, allergies, etc.), adverse events, essential vital signs, pre-injection and Laboratory tests at the time of main efficacy evaluation after injection (such as blood, urine routine examination, liver function test, renal function test).

 

2.3.4 Other functional evaluation indicators

For the addition of pharmaceutical ingredients (such as lidocaine) or other functional ingredients in the product, it is necessary to set the corresponding indicators in clinical trials to evaluate their functions.

Remarks: If sodium hyaluronate containing lidocaine is registered in China, the added lidocaine needs to be listed in China (obtaining the Chinese drug approval).

2.4 Clinical trial duration

The observation time after injection in a clinical trial is determined by the time it takes for the product to remain effective and the time required to observe product safety.

The observation period of uncross-linked sodium hyaluronate products should be no less than 6 months. The cross-linked sodium hyaluronate gel product should be observed for no less than one year.

If the effect claimed by the applicant is longer than the above time, then the claimed effect retention time needs to be observed.

If the applicant's stated effect retention time is shorter than the above time, the safety evaluation is mainly performed after the claimed effect retention time is exceeded.

2.5 Test sample size

The sample size should be determined according to the purpose of the test, the type of test (superior, non-inferior, equivalent), the main effectiveness evaluation index, the control group, and meet the statistical requirements. In addition, the subject's shedding/missing during the clinical trial should be considered and the initial sample size should be further expanded according to the estimated shedding/loss of follow-up.

Note:

(1) The above sample size is based on the target range for correcting nasolabial folds.

(2) If the target range of the declared product exceeds the above range (such as increasing the correction of apple muscle), the calculation of the sample size needs to be reconsidered.

(3) For the addition of pharmaceutical ingredients (such as lidocaine) or other functional ingredients in the product, the sample size should be calculated with the corresponding functional indicators and compared with the sample size calculated by the main effectiveness evaluation index. The larger sample size was used to ensure that the clinical trial data of the main efficacy evaluation indicators and functional indicators were statistically significant.

(4) When determining the sample size, it is also necessary to consider sufficient clinical evidence to support the time that most patients described in the product manual can remain effective after the injection of the product.

2.6 Inclusion/Exclusion Criteria

Clear inclusion/exclusion criteria are required in clinical trial protocols. The inclusion criteria must be tailored to the scope of the target. The inclusion/exclusion criteria of the test group and the control group should be uniform.

2.7 Auxiliary supportive clinical data

If applicable, applicants are advised to submit clinical research data, clinical follow-up data/documents, and current sales, complaints, complaints, and adverse events records, causes, and treatments of the products after they are listed in other countries or regions. Methods and treatment results, etc., as auxiliary supporting clinical data.

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