PFSB/ELD/OMDE (Yakushokuki) Notification 1120 No.5
November 20, 2012

To: Directors of Prefectural Public Health Departments/Bureaux

Director, Office of Medical Devices Evaluation,Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau,
Ministry of Health, Labour and Welfare

Publication of Guidance for the Evaluation of Emerging Technology
Medical Devices/Regenerative Medical Products
The Ministry of Health, Labour and Welfare of Japan has sought to establish guidance
for the evaluation of selected emerging technology medical devices/regenerative medical
products for which there is a high demand in clinical practice, to facilitate efficient
product development and speed up the approval process of them through the advance
preparation and publication of guidance, instructing technical standards used for thereview.
Here, we present a guidance comprising the data and documents that may be required
for the evaluation of orthopedic custom-made artificial knee joint prostheses and RNA
profiling-based diagnostic equipment, and the advice for evaluation. We would like yourcooperation in promulgating this guidance among the relevant vendors and service
providers under your jurisdiction for use as a reference when filing an application for
manufacturing/marketing approval. Attention should be paid to the following points.
(For your reference, copies of this notification will also be sent to the Chief Executiveof the Pharmaceutical and Medical Devices Agency, Chairman of the Japan Federationof Medical Devices Associations, Chairman of the American Medical Devices andDiagnostics Manufacturers’ Association, the Chairman of the Medical Equipment
Committee of the Council of the European Business Community in Japan, and otherrelated associations.)

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The guidance makes recommendations regarding points that should be consideredin product evaluation (evaluation items) from the viewpoints of collecting the data
and documents for approval and accelerating the review process. The guidance is
not positioned as a legal standard but is designed to present simply currently
recognized evaluation items for emerging technology medical devices/regenerative
medical products. It has to be noted that kinds of evaluation may be needed, or there
may be some exceptions to this guidance need not be applied depending on theproduct’s characteristics.
When collecting documents and data required for submission of an approval
application of individual products, it is recommended that the issues presented in
the guidance be discussed in advance, and to use the consultation service of thePharmaceutical and Medical Devices Agency (PMDA) at as early a stage aspossible.

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(Attachment 1)
Guidance on Evaluation of Orthopedic Custom-made Artificial Knee Joint
Prosthesis
1. Introduction
In the field of orthopedics, implants (classified as “medical devices” by the
Pharmaceutical Affairs Law) have been used widely in clinical practice and contributed
to the improvement of the quality of medical care and the lives of people in Japan. There
are, however, reports of clinical cases in which approved implants cannot be usedeffectively because of a significant deviation in the bone geometry of the affected joint,
significant bone defects or deformations, and/or a re-implantation. To meet these clinicalneeds and solve the issues, so-called custom-made implants are needed.
The use of custom-made implants is expected to provide various benefits due to theirgreat compatibility for individual patients, such as realization of bone-conserving
treatment, acquisition of adequate compatibility and fixation, realization of minimallyinvasive surgery, superior functional restoration, improvements in endurance, early
initiation of rehabilitation exercise and early reentry into society, and reduction in theneed for revision surgery. In particular, the knee joint is a bodily tissue indispensable forsome base functions for human life such as the support of the trunk and the securementof ambulation; better clinical outcomes that may be achieved with custom-made artificial
knee joint prostheses may therefore be beneficial for patients and healthcare workers aswell as in terms of medical economics.
The significant advancements in the technology that allows for manufacturing custommade artificial knee joint prostheses have made it possible to produce safer implants with
better biocompatibility.
This guidance establishes the requirements regarding the quality, efficacy, and safety ofcustom-made artificial knee joint prostheses, the products highly needed in clinicalpractice, and considerations in applying for marketing approval of those products.
2. Scope
This guidance covers, among orthopedic implants, artificial knee joint prostheses
excluding unicompartmental ones. In this guidance, a custom-made artificial knee joint
prosthesis is defined as an artificial knee joint prosthesis with improved biocompatibility
and/or improved fixation achieved as a result of minimal modifications made to an
approved product according to the bone geometry of the individual patient whenincompatible regions exist in the approved product. Re-designs of the sliding surface are
not included in these modifications, except when maintaining the geometrical similarity
to the approved product.
3. Role of This Guidance
In consideration of the fact that this guidance covers orthopedic artificial knee joint
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prostheses (excluding unicompartmental ones), for which technological advancements
are being rapidly made, this guidance is not to provide a comprehensive list of issues andconsiderations but to indicate currently conceivable points. This guidance will therefore
be revised as technological innovations are made and knowledge accumulates, and it is
not to restrict, e.g., the contents of regulatory submission.
In evaluating custom-made artificial knee joint prostheses, it is required to have athorough understanding of the characteristics of individual products and with thisunderstanding, to handle the data in a flexible and scientifically rational manner.
Consultation of other relevant guidelines from Japan and overseas should also be
considered in addition to the use of this guidance.
4. Contents of Written Application for Approval of Custom-made Artificial Knee
Joint Prostheses
In the approval application of a custom-made artificial knee joint prosthesis, themanufacturer should specify the dimensional ranges in which the product can be made bymodifying a base approved product (which can be an approved product or a product undersimultaneous application).
(1) Geometry, Structure and Mechanism
The dimensional ranges in which the proposed custom-made artificial knee joint
prosthesis can be made should be specified in the section “Geometry, Structure andMechanism” of the application, separately from the description of the base approvedproduct.
(2) Purpose of Use or Indications
In the section “Purpose of Use or Indications” in the application, it should be statedthat the custom-made artificial knee joint prosthesis can be used
1) when the physician judges that incompatibilities with the approved productprevents the treatment from achieving an adequate effect, or2) when the physician judges that greater therapeutic effects such as improvements
in biocompatibility or fixation will be obtained compared with when using theapproved product.
(3) Product Specifications
With respect to the manufacturing process and product structure, technical criteria
for production that ensure that the performance of the product is equivalent or
superior to the base approved product should be described.
(4) Others
1) Data for the approved product on which the proposed custom-made artificial knee
joint prosthesis is based should be provided.
2) A draft Specification Form to be filled out by the physician should be attached.
5. Evaluation of Custom-made Artificial Knee Joint Prostheses(1) Evaluation of Manufacturing Technique4

It should be shown that the manufacturing technique for the proposed custom-madeproduct is the same as that of the base approved product, or equivalent or superior tothat of another approved product for which the applicant holds marketing
authorization.
(2) Evaluation of Physical and Chemical Characteristics and Biological Safety
It should be shown that the materials used for the production of the custom-madeartificial knee joint prosthesis are equivalent or superior to those of the approved
product in terms of their biological safety and other relevant characteristics. The needfor the studies to evaluate the biological safety may be obviated by showing data of
the approved product with a scientific rationale for the use of them. If it is consideredthat high functionality and/or durability are clinically needed, data of the same kindof biomaterial approved for the use in artificial knee joint prosthesis products should
be shown with a scientific rationale.
(3) Evaluation of Mechanical Safety
The need for the studies to evaluate the mechanical safety may be obviated byshowing that the dimensions of the proposed custom-made artificial knee joint
prosthesis are within the range of the base approved product or that the mechanicalstrength of the custom-made product is non-inferior to the base approved product.
There may be two approaches to show that the mechanical strength of the custommade product is non-inferior to the approved product:1) If the custom-made artificial knee joint prosthesis is made by modifying thegeometry of the base approved product toward a direction that makes the custommade product mechanically safer than the approved product, the need for themechanical safety studies may be obviated by describing it in reference to theAppendix (use of test data of an approved product for which the applicant holds
marketing authorization may also be possible).
2) If, in the custom-made artificial knee joint prosthesis, improvements are requiredin some parts that can be structurally stressed, the applicant should show that it ispossible to ensure adequate mechanical strength for the product by conducting
appropriate studies such as mechanical tests according to relevant guidelines andother references (use of test data of an approved product for which the applicant
holds marketing authorization may also be possible).

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Appendix. Items to be Customized
Fixed-bearing, cruciate retaining (CR)-type and posterior stabilized (PS)-type are adapted
to cementless direct and cemented indirect fixation techniques.
This guidance does not cover mobile-type knee prostheses.
This guidance does not cover the hinge part of hinge-type knee prostheses.
Re-designs of the sliding surface are not included in the customizations considered.
1. Femoral component
Addition of a particular geometry to the femoral component (i.e., addition of a partial
structure for a bone defect or another bone irregularity to improve the compatibility
with the bone geometry)
Addition of a particular geometry to the bone-implant interface
i. Optimization of the design of the bone-implant interface (front, front flange,back, and/or proximal designs)
ii. Optimization of the stem (length, thickness, shape)iii. Optimization of pegs (length, thickness, number, shape, position)
iv. In cementless direct fixation, optimization of the surface treatment area ofthe back2. Tibial component
Re-design of the bone-implant interface
i. Optimization of the design of the bone-implant interface (front, back, inside,outside, and/or distal designs)
ii. Optimization of the stem (length, thickness, shape)iii. Optimization of pegs/fins (length, thickness, number, shape, position)
iv. Optimization of screw holes (number, position)v. In cementless direct fixation, optimization of the surface treatment area ofthe backvi. Optimization of the polyethylene inserts
3. Patellar component
Optimization of the design of the bone-implant interface (thickness, number of pegs,peg position)
4. Parts for filling with a metallic material
These are customizations to add a particular shape by filling a bone deficit with ametallic material.
i. Optimization of the design of the bone-implant interface
ii. In cementless direct fixation, optimization of the surface treatment area ofthe back6

6. Preparation and Actions by Marketing Authorization Holder
The MAH must follow the requirements (1)-(4) below:(1) Design of the custom-made artificial knee joint prosthesis
The MAH is required to design the custom-made artificial knee joint prosthesis
within the approved range according to the specifications determined by thephysician.
(2) Records to be retained by MAH
In producing a custom-made artificial knee joint prosthesis and selling andproviding it to the physician who determines its specifications, the MAH is required
to retain the following records based on the Ministerial Ordinance on Quality
Management System (QMS) for Medical Devices and In vitro Diagnostics (MHLW
Ministerial Ordinance No.169 of 2004), the Ministerial Ordinance on Good Quality
Practice (GQP) for Drugs, Quasi-drugs, Cosmetics, and Medical Devices (MHLW
Ministerial Ordinance No.136 of 2004), the Ministerial Ordinance on Good Vigilance
Practice (GVP) for Drugs, Quasi-drugs, Cosmetics, and Medical Devices (MHLW
Ministerial Ordinance No.135 of 2004), or the Ministerial Ordinance on Good PostMarketing Study Practice (GPSP) for Medical Devices (MHLW Ministerial
Ordinance No.38 of 2005):
1) Name of the physician who determines the specifications of the prosthesis
2) The Specification Form filled out by the physician (including data for the patient'sbone geometry)3) Documents ensuring that the prosthesis’ design conforms to the bone geometry
data4) Documents showing that the physician confirmed that the geometry of the productmeets its specifications when the final product was made or during the design ofit.
(3) Efficacy Assessment
In applying the custom-made artificial knee joint prosthesis based on specifications
determined by a physician to a clinical case, the MAH is required to assess theclinical effectiveness of the customized prosthesis by, in cooperation with thephysician, comparing it with the patient’s bone geometry before and afterimplantation.
(4) Post-marketing Survey
After implantation of each customized knee prosthesis, the MAH is required tocollect information on its clinical outcomes and malfunctions in cooperation with thephysician. The MAH should submit a partial change application and/or implement
safety measures, as necessary.
7. Precautions for Use
The MAH should provide the following information in the “Precautions for Use” section(or another appropriate section) of the product’s instruction document.
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(1)The custom-made artificial knee joint prosthesis can be used only when the physician
judges that any approved prosthesis will not provide an adequate therapeutic effectbecause of some incompatibilities or that the custom-made artificial knee joint
prosthesis will provide a significantly better therapeutic effect (improved compatibility
or fixation) compared with approved prostheses.
(2)The patient must be informed about the need for and clinical effect of the custom-madeartificial knee joint prosthesis and give written consent beforehand.
(3)The treating physician must determine specifications for the custom-made artificial
knee joint prosthesis prior to its use.
(4)The physician should provide the MAH with the specifications that clearly define theitems requiring customization.
(5)The physician must confirm that the custom-made artificial knee joint prosthesis meets
its specifications when the final product is made or during the design of it, prior to itsuse.
(6)The physician is required to prepare appropriate measures such as preparing a surgery
plan with an approved knee joint prosthesis beforehand in case of a situation in which
the custom-made artificial knee joint prosthesis cannot be used because of a difficultysuch as a malfunction or an intraoperative clinical problem.
(7)For the custom-made artificial knee joint prosthesis used, the physician is required toevaluate its clinical effectiveness, collect information about malfunctions, andpromptly inform the MAH about the information about the evaluation results and themalfunctions.
(8)An unused custom-made artificial knee joint prosthesis made for a particular patient
should not be used for another patient because custom-made artificial knee joint
prostheses are made so that they are compatible with individual patients.
(9)The physician must retain a copy of the Specification Form of each custom-madeartificial knee joint prosthesis together with patient records including the medical
record of the patient.

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