IVD Reagent Registration Change Review Draft Guidelines have been issued by China’s Center for Medical Device Evaluation (CMDE) for industry comment. The Draft Guidelines provide regulatory affairs professionals with a comprehensive framework for managing changes to in vitro diagnostic reagents after they have been launched in the market. The draft guidelines outline the scope of application, principles of change management, evaluation process, and declaration materials required for change registration.
Changes to the contents specified in the medical device registration certificate and its attachments may require submitting a product filing or product registration change application or indeed they may require a new product to be filed or registered if the risk is deemed to be considerable.
The draft guidelines provide example case studies of circumstances that do not increase risks, such as text changes, packaging specification changes that do not affect performance or stability, and the addition or deletion of applicable models.
Most of the changes are potentially risky situations, that is, changes in the product may lead to new risks or change existing risks. Non-clinical studies and/or clinical evaluations are required to determine that the risk is not increased, or that although the risk is partially increased, the residual risk is acceptable and the benefit is significantly increased. In this case, it is recommended to change the registration. If the product change results in an increase in risk and does not significantly improve the benefits, such as a decrease in product performance indicators, the change is not recommended.
Non-clinical research involves studying various aspects such as raw materials, production process, reaction system, test reports, analytical performance, stability, positive judgment value, and reference interval.
Clinical evaluation methods include clinical trials and evaluations exempted from trials for in vitro diagnostic reagents. The choice of non-clinical studies and/or clinical evaluations is based on the potential risks associated with the specific change.
Various scenarios are listed here with suggested studies to evaluate the risk:
- Changes in packaging specifications: When altering packaging specifications, it is important to identify potential risks based on specific differences and verify these risk factors. For example, changes in packaging form or reaction form may require studying the analytical performance of the modified packaging specifications. Additionally, changes that affect evaporation, loss, and other risks may necessitate considering the product’s shelf life and use stability through corresponding stability studies.
- Changes in product storage conditions and validity period: Changes in storage conditions and expiration dates require stability studies to ensure the product remains stable and effective under the new conditions.
- Applicable instrument changes: Adding new applicable models requires performance research using these models. Performance establishment can be conducted, and the performance indicators of approved products can be reasonably verified based on risk analysis, as long as the working principle, detection method, reaction condition control, and signal processing of the new model align with the previous model. Precision studies using the new model are recommended for both performance establishment and verification. An airborne stability study should also be conducted. Any differences in measured values or signal values between the models before and after the change should be considered, along with potential changes in the positive judgment value.
- Change of positive judgment value or reference interval: Changes to the positive judgment value generally require studying the positive judgment value and clinical evaluation. If the reference interval is modified, it should be established or verified.
- Changes in raw materials of Class III in vitro diagnostic reagents: When changing specified raw materials, the impact on the product’s quality standards should be studied. The change may affect the production process, reaction system, analytical performance, positive judgment value or reference interval, stability, and clinical performance. Risk analysis should guide the re-evaluation of the combination of raw materials, and relevant research data, including main raw materials, product technical requirements, and inspection reports, should be submitted.
- Changes in the production process of Class III in vitro diagnostic reagents: Any changes in the production process specified in the technical requirements for Class III IVD reagent products require a production process study to confirm the rationality of the modified process. Non-clinical studies and clinical evaluations may be necessary.
- Change of reaction system: The reaction system encompasses various factors such as sample preparation, sample requirements, reagent dosage, reaction conditions, calibration method, quality control method, and result interpretation. Changes to the reaction system stated in the product specification should be studied to confirm their rationality and analyze the impact on performance. A comparison of product performance and magnitude/signal value before and after the change should be conducted, considering any changes to the positive judgment value. Significant changes, such as in sample dosage, reagent dosage, and reaction conditions, may require clinical evaluation. If the product composition changes, a stability study should also be considered.
- Change of production address of imported in vitro diagnostic reagents: When the production site of imported reagents changes, the reagents produced at the new site should be used for analytical performance studies.
- Change in the type of sample applied: Comparable samples share the same performance indicators, positive judgment value or reference interval, expected population, and clinical significance. Incomparable samples require analytical performance evaluation, positive judgment value or reference interval study, and clinical evaluation for each sample type. The stability of added sample types should also be studied.
- Changes in the applicable population and clinical indications: Changes in applicable population and clinical indications generally require clinical evaluation. Research should be conducted on product analytical performance, positive judgment value or reference interval, and enterprise reference product to support the change.
- Changes in product technical requirements and specifications: Changes in technical requirements and specifications may involve any of the aforementioned situations, which should be assessed based on the specific changes. If there are changes to performance indices or inspection methods, an inspection report must be submitted. Changes affecting the clinical performance of the product, as indicated by non-clinical study results, require clinical evaluation.
Scenarios that substantially constitute a new product
For changes that substantially constitute a new product, such as changes to the core reaction system, the draft guidelines state that re-verification and confirmation are necessary, and the change should be handled according to product registration requirements. They also provide a reference for analyzing and evaluating changes not covered in the document.
If changes involve altering the source of antigen and antibody or modifying the nucleic acid sequence of primer and probe, the core reaction of the product will change, essentially constituting a new product. Such changes require re-verification and confirmation, following the procedures for product registration.
If the core technical principles or other major changes significantly impact the safety and effectiveness of the product, constituting a new product, change registration is not applicable, and the product should be handled according to the standard product registration process.
They provide analysis and evaluation ideas for most change registrations. For changes not covered in the document that may impact the safety and effectiveness of products, professionals can refer to the evaluation process and cases outlined for analysis and evaluation or please contact your Cisema consultant for advice.
How to submit comments
If you have any comments and suggestions, please fill in the feedback form and name the email subject and file name in the format of “Guidelines for the Review of Changes in Vitro Diagnostic Reagents (Draft for Comments)”. Send the feedback before June 30, 2023, together with your company name to: Bao Wen email@example.com or Cheng Xi firstname.lastname@example.org.
Read the original IVD Reagent Registration Draft Guidelines.
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