This guideline is to inform the applicants on the Clinical Evaluation of Proton and Carbon Ion Therapy System. This document does not fully cover the clinical evaluation data that may be necessary to support approval. Applicants must substantiate and detail the content for clinical evaluation. If some requirements are not applicable, manufacturers must demonstrate the scientific reasons. This guidance is not intended for administrative affairs such as registration and approval, and it is not legally enforceable. Applicants can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. The agency would need to issue updated guidance to reflect the new statutory provision, technological advances and development in standard system
This guidance is for Proton/Carbon Ion Therapy System. It is classed as medical high-energy radiation therapy equipment （regulation number: 6832）according to Medical Devices Classification, version of 2002. In Medical Devices Classification, version of 2002, it is 05 Radiation Therapy Devices, including class 1 device, Radiation Therapy Device, and class 2 device, Medical Light Ion Therapy System. The facilities use either cyclotron or synchrotron to accelerate the protons or carbon ions. The particle therapy system should also refer to this guidance.
II. Basic Requirement
1) Description of Clinical Evaluation
Clinical evaluation is the assessment and analysis of non-clinical and clinical data pertaining to a medical device to verify its clinical safety and performance. The evaluation is based on literature review, clinical data and clinical experience relevant to the intended use.
In clinical evaluation, the scope of application (population, site in the body, interaction with the body, intended use, severity and stage of disease, use requirement, use environment), instructions, contraindications, precautions and warnings and other possible aspects should be verified.
2) Qualification Requirement for Clinical Evaluation Personnel
Clinical evaluation should be conducted by qualified personnel. Credential and certificate for experience can be used to evaluate the qualification. Generally, clinical evaluation personnel for proton/carbon ion therapy system should have:
- Technical knowledge about proton/carbon ion therapy system and other similar systems;
- Clinical experience for proton/carbon ion therapy system such as instructions, intended use and precautions;
- Research methods for clinical evaluation, such as design method for clinical trial, methodology for literature review, methodology of statistics and method of efficacy evaluation.
3) Procedure of Clinical Evaluation
- Verify technical characteristics and intended use;
- Collect data for intended use in pre-clinical and clinical trials, post market data, domestic use data and international use data;
- Conduct assessment for safety and efficacy based on data;
- Summarize all data to concluding and reporting.
Summary of Product Information
Applicants must brief the product information, and give detailed introduction for specific Essential Requirements concerning safety and efficacy, including:
1) Particle type, beam distribution (scanning or scattering), gantry type (rotating, fixed or eye bundle), rotating scope of gantry and angle of fixed gantry;
2) Energy scope, hodoscope, Radiation field range, dose rate, spot size, Penumbra width, beam position accuracy;
3) Treatment method;
4) Regimen of treatment: anatomical model generation of patients, dose optimization and calculation method, biological dose model, RBE value determination; Note: models of biological dosimetry differ by therapy system. Attention to the basis for their identification is needed.
5) Respiratory gating and / or other management of human organ movements;
6) Image guidance (specific imaging method) and patient location verification measures
7) Special treatment techniques such as eye treatment
Summary of Approvals from Other Countries
Time of approval, cumulative sales, total number of patients treated, tumor site treated, tumor type, efficacy, adverse events (especially adverse events related to product technology / failure / malfunction) of the products shall be listed.
Scope of Application and Clinical Use
Applicants shall clearly declare the specific function, intended use, applicable population, applicable site, etc. in the scope of application, and clearly define absolute contraindications, relative contraindications and related restrictions. Following aspects shall be noted:
1) Where the performance and function of the device (such as image guidance, positioning accuracy, etc.) meet the requirements of Less-split high-dose therapy or single-high-dose therapy.
2) Whether equipped with mobilized management system
3) Intended use: Malignant tumor, benign tumor, functional diseases, arteriovenous malformation, etc.
4) Applicable sites (head, neck, chest, abdomen, spine, pelvis, limbs, etc.) and special sites such as eyes;
5) If used in the treatment of children, it should be stated in the instructions for use: Health care providers shall comply with the requirements regarding the qualification of pediatric use.
Comparative Analysis with Same Type Products
1) General Principle
Determine the same type of products to be compared by their manufacturer, product name, model, installation location, time for approval, etc. Either one or multiple products within the same type can be chosen, to conduct comparative analysis with the product to be declared, demonstrating the substantial equivalence between them.
The aspects should include, but not limited to, those listed in Appendix 2 of the Guidance for Clinical Evaluation of Medical Devices, including the qualitative and quantitative data, and verification and confirmation results. And the detailed information of the similarity and difference shall be given; Whether the difference(s) have impact on the safety and effectiveness of the product shall be verified and/or confirmed by declaring non-clinical data, literature review and clinical data carried out in China pertaining the the differences between those products.
Non-inferiority test shall be conducted for their safety and effectiveness in the comparative analysis. These differences, by their nature, shall not increase the potential harm, create new safety issues and increase the likelihood of ineffective treatment.
If there is significant difference in scope of application, working principle, structure design, production technology, main functions, performance, main functions of software, etc. comparative analysis shall not be conducted. Following aspects are included but not limited:
- Different scope of application (systemic therapy system and localized therapy system);
- Different particle type (proton therapy systems and carbon ion therapy systems);
- Different beam delivery method (scanning beam and scattering beam);
- Different Rotation / fixing method of the gantry (fixed gantry and rotating gantry);
- Significant difference in Performance (particle beam energy);
- Significant differences in software core functions in terms of clinical algorithms (effects on dose calculation, biological models, exercise management, etc.)
Clinical trial shall be conducted if:
- In the past, no proton / carbon ion therapy system was registered in China.
- New working principle or design are adopted which are different from any product approved in China.
- The scope of application has been enlarged;
- The device incorporates a novel component with new technical features that have a significant impact on the clinical application and operation of the device, and this component does not have sufficient clinical validation.
- New method of operation is adopted, and engineering design documents to demonstrate the usability are incomplete;
- Laboratory testing fails to confirm the safety and effectiveness.
2)Content of Comparative analysis
a. Comparative Analysis of Technical Characteristics
Refer to Table 1, Comparison of Technical Characteristics, of “Guidance for Technical Review of Proton / Carbon Ion Therapy System”. In addition, comparative analysis of treatment methods, such as point scanning, uniform scanning, single scattering, double scattering, single large dose, less-split large-dose, exercise management methods and patient location verification methods should be conducted to test safety and effectiveness.
b. Comparative Analysis of Treatment Plan
The main issues to consider are: Differences between the calculated value and measured values of the treatment plan, the dose calculation models, the bio-dose models (bioequivalence dose models and the RBE values in carbon ions therapy system) and the limitations of the model (mobilized target management, etc.).
3) Documents demonstrating differences do not affect the safety and efficacy of the product shall include both non-clinical and clinical data.
a. Non-clinical data: Radiation safety test, verification data of performance test (verification data of functional module test), dose distribution data, collimator performance test, biocompatibility data, bioequivalence data, etc.
b. Clinical data: Clinical trial data, literature review, complaints and adverse events data, corrective actions related to clinical risks, etc. Note: In accordance with the requirements of Article 6 of the Notice of the State Food and Drug Administration on the Administration of Registration of Medical Devices and In Vitro Diagnostic Reagents (CFDA  No. 247), if the same type of manufacturing technology and clinical data are adopted, the applicant shall submit the authorization certificate for the manufacturing technology and clinical data.
Collection of Clinical Data
Data obtained from clinical trials or clinical use of products might be derived from published literature in China and / or abroad and legally obtained corresponding data, including clinical research data, literature review, clinical experience data, complaints and Adverse event data (with a focus on adverse events related to product technology / failure / malfunction) and corrective action data related to clinical risk. Applicants shall select the appropriate data sources and collection methods.
1) Information on clinical trials prior to and after its approval in the country of origin shall be submitted to Ethics Committee with INDs
2) Complaints and Adverse Events
The applicant shall establish the database of complaints and adverse events and collect data from the database established by foreign regulatory agencies such as the “Medical Device Adverse Events Information Bulletin” and “Medical Devices Alerts” issued by China Food and Drug Administration, MAUDE in US and MDA in UK.
The applicant shall provide a summary of the related situation of the medical device complaints and adverse events of the declared products and the same variety of products. The analysis of reasons, frequency, severity, treatment measures and the treatment results shall be given in detail.
3)Corrective Action (Recalls, Announcement, Warning)
Applicants shall collect and provide detailed information on the corrective measures such as recalls, announcements, warnings, etc. The description of recall should include the reasons for the recall, the level, treatment measures and treatment results.
Literature review shall be accurate and complete. For search and key words requirement, see Attachment 5 of “Guidance for Clinical Evaluation of Medical Devices”. For content and format, see Attachment 6 and 7. The search and key words can be reproducible. Personnel should possess professional knowledge and practical experience.
1) Selection of Database
choose a database that contains only peer-reviewed publications such as Pubmed, Cochrane Library, MEDLINE, EMBASE and others.
2) Search Period
Time of approval in other countries and time of approval of same type products
3) Selection Criteria and Exclusion Criteria
The following lists the standards that should be met for literature review:
- Publications with clinical data (non-laboratory data);
- Meta-analysis with higher level of data should be prioritized;
- Human clinical research data (non-animal data).
4) Classification of Data
Methods of clinical evidence grading shall be described, such as the grading of recommendations assessment、development and evaluation working group, GRADE, and Evidence Level Evaluation Criteria established by Oxford Evidence-Based Medicine Center, etc.
Clinical data collected shall be fully evaluated as some literature reviews may not be suitable for demonstrating the effectiveness, while the data for safety existed; and vice versa.
The rationality of the research methods shall be evaluated to prevent potential data bias. The reasons for the adverse outcomes stated in the literature should be analyzed as to whether the outcome of the product is a result of the product or the combination of drugs.
Examples of classification include anatomical site, age group of patients, treatment method, tumor radio-sensitivity and toxicity.
1) Safety Considerations
The factors of total dose of treatment, dose distribution outside the target area, positioning accuracy, exercise management have impact on the safety.
2) Efficacy Considerations
The main considerations include tumor type and tumor biology. The efficacy is mainly related to the radiation tolerance of the tumor, depending on the dose administered.
The clinical evaluation report should conclude that the device evaluated meets the applicant’s expected needs and that its benefit overweighs the risk and the associated risks and side effects are acceptable. If the clinical evidence is not sufficient, applicants shall get more clinical data or expand the scope of the literature search. In this case, clinical evaluation is shown as a continuous cycle and iterative process.