如何用 Reference Devices 證明 510(k) 的實質相等性 (SE)？

前言

在〈如何使用 MULTIPLE PREDICATES 來證明 SUBSTANTIAL EQUIVALENCE〉中已說明該什麼情況下可以使用一個以上的 Predicate devices 去證明產品的實質相等性 (Substantial Equivalence, SE)。

這篇文章同樣參考〈The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)]〉，進一步說明在實質相等性 (SE) 比較過程中，什麼情況下可以使用「Reference device」？

Reference Device 定義

Reference Device – A legally marketed device that is intended to provide scientific and/or technical information (e.g., test methodology) to help address the safety and effectiveness of a new technological characteristic. Reference devices are not predicate devices and may only be used after Decision Point 4 on the 510(k) Decision-Making Flowchart.

– The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)] | Appendix D. Glossary of Significant Terminology

Reference device 有以下三個特點：

1. 須為美國合法上市醫材 (Legally marketed device)；
2. 目的是用來證明有新技術特徵 (Technological characteristic) 的產品的安全與功效；
3. 在 SE 流程中，只可用於 Decision Point 4 (不同的技術特徵是否引起不同的安全與功效問題) 之後。

深入了解 Reference Device

在上一篇文章中已討論了如何使用多個 Predicates devices 來證明產品的 SE，但有時會看到 510(k) summary 內除了 Predicate device，還會和 Reference device 比對。例如，K181310、K200629、K192684 就用到一個 Predicate device、一個 Reference device。

何時可出動 Reference device 呢？在〈The 510(k) Program〉這篇 FDA 指引的 Appendix A. 510(k) Decision-Making Flowchart，將 SE 流程 (510(k) Decision-Making Flowchart) 拆分成五個步驟 (Decision 1 ~ 5)，分別探討以下問題：

前二個 Decision 的答案須為「Yes」，才可繼續往下討論，否則及判定為 Not Substantially Equivalent (NSE)；Decision 3 若仍是「Yes」，恭喜，直接判定為 SE，結束這趟漫長的 SE 比對旅程 (510(k) Decision-Making Flowchart)！

但若 Decision 3 的結果是「No」呢？

則廠商須在 Decision 4 回答「Do the different technological characteristics of the devices raise different questions of safety and effectiveness?」只有答案是「No」時，才可繼續 SE 比對旅程 (若答案是「Yes」，則為 NSE)。

「Decision 4」是個分水嶺，只有在 Decision 4 判定為「No」後，才可繼續往下討論，也只有在此階段，才可開始動用 Reference device。

換句話說，只有「Decision 5a」和「Decision 5b」此二階段可和 Reference device 比對。

「技術特徵不同，但沒不同的安全與功效問題」是什麼意思？

若此時流程已到 Decision 5a，代表了此產品與其 Predicate device 的技術特徵有不同之處，但沒有引起不同的安全與功效問題。

例如，雖然表層塗料不同，但無論用何種塗料，須考慮的安全與功效問題都是生物相容性 (biocompatibility)、耐磨性 (abrasion) 等問題，如此即為「The different technological characteristics of the device do not raise different questions of safety and effectiveness」。

Reference Device 的限制

Reference device 目的是在 Decision 5a 階段用來支持「Scientific methodology」和「Standard reference values」。Reference device 不是 Predicate device，因此

1. 不可用於 SE 流程 (510(k) Decision-Making Flowchart) 的 Decison 1 到 Decison 4。
2. 若 Reference device 的「Anatomical location (應用在人體上的位置)」或「Physiological purpose (生理目的)」與新產品不同時，則 Reference device 的適用性可能會被審查員質疑。

以下是此篇指引的兩個範例。

Reference Device 範例

範例一、用 Reference Device 來支持 Scientific Methodology

Decision 1：Yes，代表 P 已合法上市，是個適當的 Predicate device；

Decision 2：Yes，代表 P 和 N 有相同的 Intended use；

Decision 3：No，P 和 N 的技術特徵 (Technological characteristic) 不同，因為此二產品的 Coating 不同。

Decision 4：No，Coating 不同並沒有引起不同的安全與功效 (Safety and effectiveness) 疑慮，因為無論 Coating X 或 Coating A，安全與功效的問題都是 (1) 生物相容性以及 (2) Coating 的特性 (例如，耐磨性)。

上面四階段，只可用 Predicate device；下面開始，才可動用 Reference device。

在 Decision 5a，可提出足夠的科學依據 (Scientific rationale) 來說明，用於證明 H 的 Coating 生物相容性與耐磨性的方法 (Scientific methodology) 同樣適用於證明 N 的 Coating。

雖然新產品 (N) 和 Reference device (H) 的 Intended use 不同，但 FDA 認可在此階段使用 Reference device 來證明新產品的 Coating X 是安全有效的。

不過，FDA 在此篇指引註解 17 提到，Reference device 的適用性是要 Case by case 討論的。

例如，範例一要考量的點可能是，Coating 接觸人體的時間等。雖說 Reference device 的 Intended use 可和新產品不同，但有時 Intended use 不同會影響到支持 Scientific methodology 的效力，像是說，同樣是植入物，同樣 Coating X，但心血管支架就不適合作為上述例子的 Reference device。

以下引述註解原文：

The applicability of the scientific methodology used to characterize certain aspects of a legally marketed device will depend upon the specific scenario. In this example, it is determined that the duration of contact, which affects the biocompatibility testing, and the mechanical testing conducted to fully characterize the coating on the hip implant are directly relevant and informative for the same coating applied to the knee implant. However, if the manufacturer wanted to rely on the scientific methodology for a coating used in a different type of implant (e.g., cardiovascular), it may not be appropriate to exercise this approach.

The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)] | Footnote 17

範例二、用 Reference Device 來支持 Standard Reference Values

Decision 1：Yes，代表 P 已合法上市，是個適當的 Predicate device；

Decision 2：Yes，代表 P 和 N 有相同的 Intended use；

Decision 3：No，因為 P 和 N 的技術特徵 (Technological characteristic) 不同。

Decision 4：No，技術特徵不同並沒有引起不同的安全與功效 (Safety and effectiveness) 疑慮。

上面四階段，只可用 Predicate device；下面開始，才可動用 Reference device。

因為傳統的非處方用血糖機總體固有誤差 (Inherent total error) 滿大的，量測出來的血糖值不適合給新產品 (N) 用來證明其安全與功效 (例如，Predicate device 自己的血糖量測精準度、再現性都不好，新產品要怎麼跟它比對呢)。

為了在 Decision 5a「Are the methods acceptable?」回答「Yes」，勢必要找一個更準的機器來比對血糖值。在此範例中，Reference device 是一台精準度經過充分確效 (well-validated)、且其量測數值可向上追溯至更高等級標準 (例如，國際公認標準) 的 Laboratory-based glucose measurement device，如果新產品 (N) 與 Predicate device 比對出來的結果可以證明安全與功效相等 (包含與 Reference device 比對的血糖值精準度等規格) ，則 Decision 5b「Do the data demonstrate substantial equivalence?」可回答「Yes」，證明新產品 (N) 與 Predicate device 有實質相等性 (SE)。

網路參考資料

以下摘錄一些搜尋到的網路討論可當作 Reference device 的重點整理：

第一篇 – Predicate Device 和 Reference Device 的差異

A predicate device is a legally U.S marketed medical device that is most similar to the device under review in terms of indications of use and technological characteristics.

Reference devices are other legally marketed devices that may be used to support scientific methodology and/or provide technical information to help address the safety and effectiveness of a new technological characteristic. They may be useful in comparing technologies used within devices, instead of the devices as a whole. If a selected reference device is used in an anatomical location or for a physiological purpose that is considerably different than that of the new device, its utility as a reference device may be limited.

What is the difference between a Predicate device and a reference device found in some 510k summary? | Neenu Jacob

Reference devices may be included to support scientific methodology or standard reference values in 510(k) submission. … These devices do not assist as predicate devices because of differences in intended use but they are significant on other hand as they have same technological similarities to the new device.

What is the difference between a Predicate device and a reference device found in some 510k summary? | Kalyani sachin

A predicate device is a medical device that is legally marketed in the US which is used for to demonstrate substantial equivalence with a new device for the approval of 510(K).

A reference device allows its experience with other devices. Reference devices do not act as predicate devices because of differences in intended use or technological characteristics, but they are useful because of the technological similarities to the new device. Using reference devices in the 510(k) can able to fill the gap between a subject and a predicate device.

What is the difference between a Predicate device and a reference device found in some 510k summary? | Neethu

第二篇 – Reference Device 的使用時機

The Final Guidance also addresses the concept of a “reference device” which was first raised in the 2011 draft guidance. A reference device is not a predicate device and it cannot be used to address Decision Points 1-4 on the Flowchart. FDA explains that it will rely on a “reference device” only in assessing the acceptability of the scientific methods or standard reference values at Decision Point 5a on the Flowchart.

FDA Issues Final Guidance on Evaluating Substantial Equivalence in 510(k) Submissions | William H. Kitchens

第三篇 – Reference Device 使用限制

Unlike a predicate device, which is required to possess the same intended use as the subject device, a reference device can be used to validate the safety of technological characteristics without possessing the same intended use as the new device. However, a reference device can only be used in addition to a valid predicate device and cannot on its own serve as sufficient validation for device approval.

The Use of Predicates in FDA Regulation of Medical Devices: A Case Study of Robotic Surgical Devices | Charlotte Lefkovich