如何使用 Multiple Predicates 來證明 Substantial Equivalence

我還滿喜歡看 FDA 出的各種指引，雖然英文不好，但大多時候是看得懂的，寫這篇文章主要想要記錄一下使用多個 Predicates 時的重點。

我參考的 FDA Guidance 是〈The 510(k) Program〉，副標題是「Evaluating Substantial Equivalence in Premarket Notifications [510(k)]」。早在幾年前我仍在宜蘭的神祕醫材研發單位時，就已經耳聞 510(k)，當時想找個完整一點的文件來了解 510(k) 的大致概念，就找到了這篇指引，但卻一直沒有下載來看，因為當時我認為此篇指引只是在說明 510(k) 中的實質相等性比對 (Substantial Equivalence, SE)，而不是在講解 510(k) 完整的概念。後來我到了華亞園區內較有規模的醫材公司，說也奇怪，並沒有人教我關於查驗登記的知識，我卻自己領悟到原來「510(k) 最核心，或者說全部的精神就是在 Substantial Equivalence」，讀完這篇指引，其實就代表了瞭解完整 510(k) 的精神了。

在看 510(k) Summary 時常會看到廠商引用 Primary Predicate、Secondary Predicate、Reference Predicate，這些到底是什麼呀？還有，Predicate、Predicate Device 又有什麼不一樣呢？最後，Predicate (或 Predicate Device) 是什麼？

最簡單的問題先解決，Predicate = Predicate Device，結案。

第二個問題，Predicate 是什麼？在此篇指引第 10 頁， FDA 引用了 21 CFR 807.92(a)(3) 的定義，

Predicate 必須是一個合法販賣的器材，且這個器材必須符合以下三選一項目：
1) 在 1976 年 5 月 28 日之前就已經合法販售 (此類產品稱為 preamendments device)，且不需要 PMA；或
2) 已經從第三等級醫療器材重新分級為第一或第二等級；或
3) 已由 510(k) 流程證明其與 Predicate 的實質相等性 (Substantially equivalent, or SE)

a legally marketed device is a device that (i) was legally marketed prior to May 28, 1976 (preamendments device13) and for which a PMA is not required; or (ii) has been reclassified from Class III to Class II or I; or (iii) has been found SE through the 510(k) process.

The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)], Section IV.C

FDA 希望大家在證明實質相等性時盡量只使用一個 Predicate，但世界之大無奇不有，總是會遇到無法只用一個 Predicate 的情況。所以 FDA 又說，當使用多個 Predicates 時，其中 Indications for Use 和技術特徵 (Technological Characteristics) 與欲申請 510(k) 的產品最相近的那個 Predicate 需訂為「Primary Predicate」。

喔耶，最難的問題已經解決了 3 分之 2 了，Primary Predicate 外第二個 Predicate 當然就是 Secondary Predicate。

什麼時候需要多個 Predicates 來證明 SE (Substantially equivalent) 呢？來看下面 FDA 的敘述：

有三個原因可能必須引用多個 Predicates 來證明 SE：
原因一：將來自兩個或更多 Predicates 的特性放到一個產品中，且這些 Predicates 需有相同的 Intended Use；或
原因二：欲販售的產品擁有超過一個 Intended Use；或
原因三：產品希望有超過一個 Indication for Use，但這些 Indication for Use 均在同一個 Intended Use 下。

when combining features from two or more predicate devices with the same intended use into a single new device, when seeking to market a device with more than one intended use, or when seeking more than one indication for use under the same intended use.

The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)], Section IV.C

(我目前無法明確分辨出「原因一」和「原因三」的差異。)

此篇指引接下來介紹了五個範例來解釋上面這些情況。

範例一、血液透析導管

A manufacturer submits a 510(k) for a new hemodialysis catheter. This new catheter has an extension (the portion of the device outside the body) design that is similar to predicate A and a tip (the portion of the device inside the body) design similar to predicate B. Both predicates A and B have the same intended use as the new device. In this example, the manufacturer is relying on both predicate A and predicate B, which have the same intended use as the new device, to support substantial equivalence with respect to technological characteristics. The manufacturer may choose either predicate as the primary predicate in this example.

The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)], Section IV.C

想像有一個新的血液透析導管，導管在身體外面的機構設計類似 Predicate A，在身體內的機構設計類似 Predicate B，無論此新血液透析導管、Predicate A 或 Predicate B 都有相同的 Intended Use，這就符合 FDA 上面說可能引用多個 Predicates 的第一個原因：「將來自兩個或更多 Predicates 的特性放到一個產品中，且這些 Predicates 需有相同的 Intended Use」。

FDA 說此新血液透析導管可利用此二擁有相同 Intended Use 的 Predicates 來證明新產品與 Predicates 在技術特徵方面為 SE (當然，這三個醫材的 Intended Use 在此範例中本來就預設是相同的)，且可選擇 Predicate A 或 Predicate B 為 Primary predicate。

範例二、新型骨板

A manufacturer submits a 510(k) for a plate indicated for fixation of both diaphyseal (the shaft of a long bone) and epiphyseal (the ends of a long bone) fractures, i.e., the plate can be used to set a long bone, such as the femur or thigh bone, that is broken in the middle or at the ends. The manufacturer cites a predicate device that is a plate indicated for middle bone fractures only and another predicate device that is indicated specifically for bone tip fractures. While the indications for use of each predicate device are different, both devices have the same intended use, namely, fracture fixation of the long bone. Thus, although the manufacturer could have used a single predicate device, in cases where a manufacturer intends to market a device for more than one indication and a different predicate exists to support each specific indication, the manufacturer may cite more than one relevant predicate device to support an SE determination. In this case, using two appropriate predicates clearly identified by the manufacturer helped to facilitate clearance of the new device, which was indicated to treat both types of fractures treated by the predicates.

The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)], Section IV.C

一個新型骨板可以用來固定 Diaphyseal 或 Epiphyseal 部位的骨折，製造商為了證明實質相等性 (Substantially equivalent, or SE)，所以引用了兩個 Predicates，一個 Predicate 可以用來固定骨頭中間骨折 (Middle Bone Fractures) 的骨頭，另一個 Predicate 則可用來固定骨頭兩端骨折 (Bone Tip Fractures) 的骨頭。

雖然兩個 Predicates 有不同的 Indication for Use，但都有相同的 Intended Use (Fracture fixation of the long bone，固定骨折的長骨)，所以符合可引用多個 Predicates 的第一 (或三) 個原因：「將來自兩個或更多 Predicates 的特性放到一個產品中，且這些 Predicates 需有相同的 Intended Use；或產品希望有超過一個 Indication for Use，但這些 Indication for Use 均在同一個 Intended Use 下。」

範例三、雷射產品

A manufacturer submits a 510(k) for a laser platform that consists of two hand pieces: an Er:YAG laser hand piece and a Q-Switch Nd:YAG laser hand piece. The manufacturer cites two predicates to support substantial equivalence for both of their requested proposed indications for use. In this case, each predicate cited does not share the same indications for use as the other predicate because each predicate consists of only one hand piece in which the indications correspond to the indications for one of the hand pieces included in the new device. However, the indications for both hand pieces fall within the scope of the general intended use of lasers, “incision, excision, ablation, vaporization of soft tissue.” The Er:YAG laser hand piece is indicated for the incision, excision, ablation, vaporization of soft tissue; and the Q-Switch Nd:YAG laser hand piece is indicated for tattoo removal. The new device is found substantially equivalent to the predicate devices because it has the same intended use and the new device’s technological characteristics are similar to the cited predicates.

The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)], Section IV.C

有一個廠商做出一台可射出鉺雅鉻雷射「和」Q-SWITCH 釹雅克雷射的雷射產品，引用了兩個 Predicates 去證明新產品的 SE。因為兩個 Predicates 分別只能射出一種雷射，所以兩個 Predicates 的 Indication for Use 不同。鉺雅鉻雷射可用來切開、切除、燒灼、蒸發軟組織，而 Q-SWITCH 釹雅克雷射可用來移除紋身。不過此兩種不同的 Indication for Use 都落在相同的 Intended Use 範圍內 ─ incision, excision, ablation, vaporization of soft tissue。這台新雷射產品因為和 Predicates 有相同的 Intended Use，技術特徵也和 Predicates 相似，所以可以證明和 Predicates 有實質相等性。

上述範例符合前文提到的可能引用多個 Predicates 的第三個原因：「產品希望有超過一個 Indication for Use，但這些 Indication for Use 均在同一個 Intended Use 下」。(但應該也符合第一個原因吧？)

範例四、多參數監控器

A manufacturer submits a 510(k) for a multi-parameter monitor. The monitor includes different technologies that can stand alone independently, but can also be used together for the general intended use of measuring patient vital information. If there is a predicate device for each of the parameters, then the combination of these parameters, assuming that monitoring of each individual parameter does not interfere with the others, can be found substantially equivalent.

The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)], Section IV.C

有一家醫材製造廠想要為「將多個可獨立運作的生理參數監控技術合併在一個設備中成為多參數的監控器」申請 510(k)，且每一個監控參數技術皆可以找到一個對應的 Predicate。假設監控多種參數的技術之間不會互相干擾，則此多參數監控器可利用多個擁有不同 Intended Use 的 Predicates 來證明實質相等性 (Substantially equivalent, or SE)。此範例應該屬於使用多個 Predicates 來證明 SE 的「第二個原因：欲販售的產品擁有超過一個 Intended Use 」

在上述 2 ~ 4 個範例中，雖然可能需要做一些測試來證明產品效能，但因為新產品的 Intended Use 與 Predicates 的 Intended Use 相同，或新產品涵蓋 Predicates 的 Intended Use (範例四)，所以還是可以說明與 Predicates 的實質相等性。

不過有時候一些 Indication for Use 會修改到 Intended Use，如何判斷 Indication for Use 會不會修改到 Intended Use 又是另一個議題了，之後再去看看〈General/Specific Intended Use〉這篇指引好了。

有時候廠商為了增加使用便利性或功能性，將一項新功能加進產品中，就算此新功能是屬於不同的分類規範 ( classification regulation )，只要不改變與 Predicate 相同的 Intended Use 的風險概況 (Risk Profile)，仍可以送交 510(k) 審查。請看最後一個範例。

範例五、導管+溫度計

A manufacturer submits a 510(k) for a urinary catheter with a thermometer. The thermometer/temperature-measuring feature is not affecting the intended use or risks of using the catheter (assuming it is integrated appropriately), nor is the catheter affecting the performance or risk profile of the thermometer. The temperature-measuring feature is a convenience component that is added to the catheter, with the intended use of the device still being that of the catheter to pass fluids to or from the urinary tract, so it is appropriate to have a legally marketed catheter serving as the primary predicate.

The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)], Section IV.C

導管和溫度計之間沒有影響到對方的風險概況 (Risk Profile)，溫度計當作一個便利的工具放進導管裡，導管仍然有引流尿道液體的功能，在此情況下，可以將合法販售的導管當作 Primary Predicate。

最後的範例說明了，如果加入的特徵或零件修改到 Intended Use 或風險概況，則不能和 Predicate 比較，在這個情況下就不能申請 510(k) 了。指引這部分最後說，「新儀器必須至少和一個 Predicate 有相同的分類規範 (classification regulation) 才符合 SE 標準」。

A new device with a new design feature or added component must meet the SE standard with at least a single predicate from the same classification regulation.

The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)], Section IV.C

雖然此篇指引還有非常非常多的資訊，至少已經討論完「使用多個 Predicates 去證明實質相等性的情況」了。

好累。