V. 参考資料
１．ヒト（自己・同種）由来細胞・組織加工医薬品等の品質及び安全性の確保に関する指針
1-1．平成 20 年 9 月 12 日付「平成 20 年 2 月 8 日付

ヒト（自己）由来細胞や組織を加工した医薬品又は医療機器の品質及び安全性の確保についての修正後の通知」
1-2．平成 20 年 9 月 12 日付「ヒト（同種）由来細胞や組織を加工した医薬品又は医療機器の品質及び安全性の確保について」
２．Guidance for Industry Preparation of IDEs and INDs for Products Intended to Repair or Replace
Knee Cartilage (U.S. Department of Health and Human Services, Food and Drug Administration,
Center for Biologics Evaluation and Research Center for Devices and Radiological Health, 2007)
３．Draft Reflection Paper on In-Vitro Cultured Chondrocyte Containing Products for Cartilage
Repair of the Knee

(European Medicines Agency, EMEA/CAT/CPWP/288934/2009)

４ ． Assesssment Report for ChondroCelect and Annex I (European Medicines Agency,
EMEA/724428/2009)薬食発第0912006号
平成２０年９月１２日
各都道府県知事 殿

厚生労働省医薬食品局長

ヒト（同種）由来細胞や組織を加工した医薬品又は医療機器の品質及び安全性の確保について

ヒト由来の細胞・組織を加工した医薬品又は医療機器（以下「細胞・組織加工
医薬品等」という 。）の品質及び安全性を確保するための基本的な技術要件については、平成12年12月26日付け医薬発第1314号厚生省医薬安全局長通知「ヒト又は動物由来成分を原料として製造される医薬品等の品質及び安全性確保について」の別添２「ヒト由来細胞・組織加工医薬品等の品質及び安全性の確保に関する指針 」（以下「平成12年指針」という 。）を定め運用してきたが、その後の科学技術の進歩や経験の蓄積を踏まえ見直しを進めてきたところである。
ヒトの自己由来の細胞・組織加工医薬品等の品質及び安全性の確保のための基本的な技術要件については、平成20年２月８日付け薬食発第0208003号厚生労働省医薬食品局長通知「ヒト（自己）由来細胞や組織を加工した医薬品又は医療機器の品質及び安全性の確保について」により通知したところであるが、今般、ヒトの同種由来の細胞・組織加工医薬品等の品質及び安全性の確保のための基本的な技術要件についても、別添「ヒト（同種）由来細胞・組織加工医薬品等の品質及び安全性の確保に関する指針」のとおりとりまとめたので、御了知の上、貴管下関係団体、関係機関等に周知願いたい。
なお、これに伴い、平成12年指針は廃止することとする。

ヒト（同種）由来細胞・組織加工医薬品等の品質及び安全性の確保に関する指針
はじめに
１． 本指針は、ヒト由来細胞・組織のうち、同種由来細胞・組織（自己由来細胞・組織を除く。）を加工した医薬品又は医療機器（以下「細胞・組織加工医薬品等」という。）の品質及び安全性の確保のための基本的な技術要件について定めるものである。
しかしながら、細胞・組織加工医薬品等の種類や特性、臨床上の適用法は多種多様であり、また、本分野における科学的進歩や経験の蓄積は日進月歩である。本指針を一律に適用したり、本指針の内容が必要事項すべてを包含しているとみなすことが必ずしも適切でない場合もある。したがって、個々の医薬品等についての試験の実施や評価に際しては本指針の目的を踏まえ、その時点の学問の進歩を反映した
合理的根拠に基づき、ケース・バイ・ケースで柔軟に対応することが必要であること。
２． 平成11年7月30日付け医薬発第906号厚生省医薬安全局長通知「細胞・組織を利用した医療用具又は医薬品の品質及び安全性の確保について」による確認申請時点における本指針への適合性の確認の趣旨は、当該細胞・組織加工医薬品等の治験を開始するに当たって支障となる品質及び安全性上の問題が存在するか否かの確認にある。したがって、確認申請の場合、その申請に当たって添付するべき資料について
本指針に示された要件や内容をすべて充たすことを必ずしも求めている訳ではない。
製造販売承認申請時における品質及び安全性の確保のための資料は治験の進行とともに本指針に沿って充実整備されることを前提に、確認申請では、当該時点でその趣旨に適う条件を充たし、合理的に作成された適切な資料を提出すること。
また、確認に必要とされる資料の範囲及び程度については、当該製品の由来、対象疾患、対象患者、適用部位、適用方法及び加工方法等により異なり、本指針では具体的に明らかでないことも少なくないので、個別に独立行政法人医薬品医療機器総合機構に相談することが望ましい。

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目次

第１章 総則･･････････････････････････････････････････････････････････････････4
第１ 目的･･････････････････････････････････････････････････････････････････4
第２ 定義･･････････････････････････････････････････････････････････････････4
第２章 製造方法･･････････････････････････････････････････････････････････････4
第１ 原材料及び製造関連物質････････････････････････････････････････････････4
１ 目的とする細胞・組織･･････････････････････････････････････････････････4(1) 起源及び由来、選択理由･･････････････････････････････････････････････4(2) 原材料となる細胞・組織の特性と適格性････････････････････････････････ 4(3) ドナーに関する記録･･････････････････････････････････････････････････5(4) 細胞・組織の採取・保存・運搬････････････････････････････････････････5
２ 目的とする細胞・組織以外の原材料及び製造関連物質･･････････････････････6(1) 細胞の培養を行う場合････････････････････････････････････････････････6(2) 非細胞・組織成分と組み合わせる場合･･････････････････････････････････7(3) 細胞に遺伝子工学的改変を加える場合･･････････････････････････････････8
第２ 製造工程･･････････････････････････････････････････････････････････････9
１ ロット構成の有無とロットの規定････････････････････････････････････････9２ 製造方法･･････････････････････････････････････････････････････････････9(1) 受入検査････････････････････････････････････････････････････････････9(2) 細菌、真菌及びウイルス等の不活化・除去･･････････････････････････････9(3) 組織の細切、細胞の分離、特定細胞の単離等･･･････････････････････････9(4) 培養工程･･･････････････････････････････････････････････････････････9(5) 株化細胞の樹立と使用････････････････････････････････････････････････9(6) 細胞のバンク化･････････････････････････････････････････････････････10(7) 製造工程中の取り違え及びクロスコンタミネーション防止対策･･･････････10
３ 加工した細胞の特性解析･･･････････････････････････････････････････････10
４ 最終製品の形態、包装･････････････････････････････････････････････････10５ 製造方法の恒常性･････････････････････････････････････････････････････10
６ 製造方法の変更･･･････････････････････････････････････････････････････10
第３ 最終製品の品質管理･･･････････････････････････････････････････････････10
１ 総論･････････････････････････････････････････････････････････････････11
２ 最終製品の品質管理法･････････････････････････････････････････････････11(1) 細胞数並びに生存率･････････････････････････････････････････････････11(2) 確認試験･･････････････････････････････････････････････････････････11(3) 細胞の純度試験･････････････････････････････････････････････････････11(4) 細胞由来の目的外生理活性物質に関する試験･･･････････････････････････11(5) 製造工程由来不純物試験･････････････････････････････････････････････12(6) 無菌試験及びマイコプラズマ否定試験･････････････････････････････････12-2-

(7) エンドトキシン試験･････････････････････････････････････････････････12(8) ウイルス等の試験･･･････････････････････････････････････････････････12(9) 効能試験･･･････････････････････････････････････････････････････････13(10) 力価試験･･･････････････････････････････････････････････････････････13(11) 力学的適合性試験･･･････････････････････････････････････････････････13
第３章 細胞・組織加工医薬品等の安定性･･･････････････････････････････････････13
第４章 細胞・組織加工医薬品等の非臨床安全性試験･････････････････････････････13
第５章 細胞・組織加工医薬品等の効力又は性能を裏付ける試験･･･････････････････14
第６章 細胞・組織加工医薬品等の体内動態･････････････････････････････････････15
第７章 臨床試験･････････････････････････････････････････････････････････････15

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第１章
第１

総則

目的
本指針は、ヒト由来細胞・組織のうち、同種由来細胞・組織（自己由来のものを除く。）を加工した医薬品又は医療機器（以下「細胞・組織加工医薬品等」という。）の品質及び安全性の確保のための基本的な技術要件について定めるものである。

第２定義
本指針における用語の定義は以下のとおりとする。
１ 「細胞・組織の加工」とは、疾患の治療や組織の修復又は再建を目的として、細胞・組織の人為的な増殖、細胞の株化、細胞・組織の活性化等を目的とした薬剤処理、生物学的特性改変、非細胞・組織成分との組み合わせ又は遺伝子工学的改変等を施すことをいう。
組織の分離、組織の細切、細胞の分離、特定細胞の単離、抗生物質による処理、洗浄、ガンマ線等による滅菌、冷凍、解凍等は加工とみなさない。
２ 「製造」とは、加工に加え、組織の分離、組織の細切、細胞の分離、特定細胞の単離、抗生物質による処理、洗浄、ガンマ線等による滅菌、冷凍、解凍等、当該細胞・組織の本来の性質を改変しない操作を含む行為で、最終製品である細胞・組織利用製品を出荷するまでに行う行為をいう。
３ 「表現型」とは、ある一定の環境条件のもとで、ある遺伝子によって表現される
形態学的及び生理学的な性質をいう。
４ 「HLAタイピング」とは、ヒトの主要組織適合性抗原型であるHLA（ヒト白血球抗原）のタイプを特定することをいう。
５ 「ドナー」とは、細胞・組織加工医薬品等の原料となる細胞・組織を提供するヒトをいう。
６ 「遺伝子導入構成体」とは、目的遺伝子を標的細胞に導入するための運搬体、目的遺伝子及びその機能発現に必要な要素をコードする塩基配列等から構成されるも
のをいう。

第２章

製造方法

第１
原材料及び製造関連物質
１
目的とする細胞・組織(1) 起源及び由来、選択理由
原材料として用いられる細胞・組織の起源及び由来について説明し、当該細胞・組織を選択した理由を明らかにすること。
(2) 原材料となる細胞・組織の特性と適格性① 生物学的構造・機能の特徴と選択理由
原材料として用いられる細胞・組織について、その生物学的構造・機能の特徴を、例えば、形態学的特徴、増殖特性、生化学的指標、免疫学的指標、特徴的産-4-生物質、HLAタイピング、その他適切な遺伝型又は表現型の指標から適宜選択して示し、当該細胞・組織を原料として選択した理由を説明すること。
② ドナーの選択基準、適格性ドナーが倫理的に適切に選択されたことを示すこと。また、年齢、性別、民族学的特徴、病歴、健康状態、採取細胞・組織を介して感染する可能性がある各種
感染症に関する検査項目、免疫適合性等を考慮して、選択基準、適格性基準を定め、その妥当性を明らかにすること。
特にＢ型肝炎(HBV)、Ｃ型肝炎(HCV)、ヒト免疫不全ウイルス（HIV）感染症、
成人Ｔ細胞白血病(HTLV)、パルボウイルスＢ１９感染症については、問診及び検査（血清学的試験や核酸増幅法等）により否定すること。また、サイトメガロウ
イルス感染、EBウイルス感染及びウエストナイルウイルス感染については必要に応じて検査により否定すること。
この他、次に掲げるものについては既往歴、問診等の診断を行うとともに、輸血、移植医療を受けた経験の有無等からドナーとしての適格性を判断すること。
・梅毒トレポネーマ、クラミジア、淋菌、結核菌等の細菌による感染症
・敗血症及びその疑い・悪性腫瘍
・重篤な代謝及び内分泌疾患
・膠原病及び血液疾患
・肝疾患
・伝達性海綿状脳症及びその疑い並びにその他の認知症(3) ドナーに関する記録
原材料となる細胞・組織について、安全性確保上必要な情報が確認できるよう、ドナーに関する記録が整備、保管されていること。また、その具体的方策を示すこと。
(4) 細胞・組織の採取・保存・運搬① 採取者及び採取医療機関等の適格性採取者及び採取医療機関等に求めるべき技術的要件について、明らかにすること。
② 採取部位及び採取方法の妥当性
細胞の採取部位の選定基準、採取方法を示し、これらが科学的及び倫理的に適切に選択されたものであることを明らかにすること。採取方法については、用いられる器具、微生物汚染防止、取り違えやクロスコンタミネーション防止のための方策等を具体的に示すこと。
③ ドナーに対する説明及び同意
細胞・組織採取時のドナーに対する説明及び同意の内容を規定すること。
④ ドナーの個人情報の保護
ドナーの個人情報の保護方策について具体的に規定すること。
-5-

⑤ ドナーの安全性確保のための試験検査
細胞・組織採取時にドナーの安全性確保のために採取部位の状態の確認など試験検査を行わなければならない場合には、その内容、検査結果等に問題があった
場合の対処法について具体的に規定すること。
⑥ 保存方法及び取り違え防止策
採取した細胞・組織を一定期間保存する必要がある場合には、保存条件や保存期間及びその設定の妥当性について明らかにすること。また、取り違えを避けるための手段や手順等について具体的に説明すること。
⑦ 運搬方法
採取細胞・組織を運搬する必要がある場合には、運搬容器、運搬手順（温度管理等を含む。）を定め、その妥当性について明らかにすること。
⑧ 記録の作成及び保管方法①～⑦に関する事項について、実施の記録を文書で作成し、適切に保管する方法について明らかにすること。
２

目的とする細胞・組織以外の原材料及び製造関連物質
目的とする細胞・組織以外の原材料及び製造関連物質を明らかにし、その適格性を示すとともに、必要に応じて規格を設定し、適切な品質管理を行うことが必要である。
なお、生物由来製品又は特定生物由来製品を原材料として使用する場合は、その使用量を必要最小限とし、「生物由来原料基準」（平成15年厚生労働省告示第210号）
をはじめとする関連法令及び通知を遵守すること。特に、ウイルス不活化及び除去に関する情報を十分に評価する必要があるほか、遡及調査等を確保する方策についても明らかにすること。

(1) 細胞の培養を行う場合① 培地、添加成分（血清、成長因子及び抗生物質等）及び細胞の処理に用いる試薬
等のすべての成分等についてその適格性を明らかにし、必要に応じて規格を設定すること。各成分等の適格性の判定及び規格の設定に当たっては、最終製品の適用経路等を考慮すること。
② 培地成分については、以下の点に留意すること。
ア 培地に使用する成分及び水は、可能な範囲で医薬品又は医薬品原料に相当する基準で品質管理されている生物学的純度の高い品質のものを使用すること。
イ 培地に使用する成分は主成分のみでなく使用するすべての成分について明らかにし、選択理由及び必要に応じて品質管理法等を明確にすること。ただし、培地の構成成分が周知のもので、市販品等が一般的に使用されている DMEM、MCDB、HAM、RPMI のような培地は１つのものと考えてよい。
ウ すべての成分を含有した培地の最終品については、無菌性及び目的とした培養に適していることを判定するための性能試験を実施する必要がある。その他、工程管理上必要と思われる試験項目を規格として設定し、適切な品質管理を行-6-う必要がある。
③ 異種血清及び異種もしくは同種の血清に由来する成分については、細胞活性化又は増殖等の加工に必須でなければ使用しないこと。特に繰り返して使用する可能性のある製品では可能な限り使用を避けるよう検討すること。血清等の使用が避けられない場合には、以下の点を考慮し、血清等からの細菌、真菌、ウイルス及び異常プリオン等の混入・伝播を防止するとともに、最終製品から可能な限り除去するよう処理方法等を検討すること。
ア 血清等の由来を明確にすること。
イ 牛海綿状脳症発生地域からの血清を極力避ける等感染症リスクの低減に努めること。
ウ 由来動物種に特異的なウイルスやマイコプラズマに関する適切な否定試験を行い、ウイルス等に汚染されていないことを確認した上で使用すること。
エ 細胞の活性化、増殖に影響を与えない範囲で細菌、真菌及びウイルス等に対する適切な不活化処理及び除去処理を行う。例えば、潜在的なウイルス混入の危険性を避けるために、必要に応じて加熱処理、フィルター処理、放射線処理
又は紫外線処理等を組み合わせて行うこと。
オ 培養細胞でのウイルス感染のモニター、患者レベルでのウイルス性疾患の発症に対するモニター及び異種血清成分に対する抗体産生等の調査のために、使用した血清の一部を保管すること。
④ 抗生物質の使用は極力避けるべきである。ただし製造初期の工程において抗生物質の使用が不可欠と考えられる場合には、その後の工程で可能な限り漸減を図る
ほか、その科学的理由、最終製品での推定残存量、患者に及ぼす影響などの面か
ら妥当性を説明すること。また、用いる抗生物質に過敏症の既往歴のある患者の場合には、本治療を適応すべきではない。なお、抗生物質を使用する場合でも十分に除去されることが立証される場合には、その使用を妨げるものではない。
⑤ 成長因子を用いる場合には、細胞培養特性の再現性を保証するために、例えば純度及び力価に関する規格を設定する等適切な品質管理法を示すこと。
⑥ 最終製品に含有している可能性のある培地成分や操作のために用いられたその他の成分等については、生体に悪影響を及ぼさないものを選択すること。
⑦ フィーダー細胞として異種動物由来の細胞を用いる場合には、異種動物由来の感染症のリスクの観点から安全性を確保すること。
(2) 非細胞・組織成分と組み合わせる場合① 細胞・組織以外の原材料の品質及び安全性について
細胞・組織とともに最終製品の一部を構成する細胞・組織以外の原材料（マトリックス、医療材料、スキャフォールド、支持膜、ファイバー及びビーズ等）がある場合には、その品質及び安全性に関する知見について明らかにすること。
当該原材料の種類と特性、最終製品における形態・機能及び想定される臨床適応の観点から見た品質、安全性及び有効性評価との関連を勘案して、適切な情報を提供すること。生体吸収性材料を用いる場合には、分解生成物に関して必要な-7-

試験を実施すること。
なお、必要な試験等については、平成15年2月13日付け医薬審発第0213001号厚生労働省医薬食品局審査管理課長通知「医療用具の製造（輸入）承認申請に必要な生物学的試験の基本的考え方について」等を参照し、試験結果及び当該原材料を使用することの妥当性を示すこと。文献からの知見、情報を合理的に活用すること。
② 目的とする細胞・組織との相互作用について
細胞・組織との相互作用に関し、以下の事項について、確認方法及び確認結果を示すこと。
ア 非細胞・組織成分が、想定される臨床適応に必要な細胞・組織の機能、生育能力、活性及び安定性に悪影響を与えないこと。
イ 非細胞・組織成分との相互作用によって起こり得る、細胞の変異、形質転換及び脱分化等を考慮し、その影響を可能な範囲で評価すること。
ウ 細胞との相互作用によって、想定される臨床適応において非細胞・組織成分に期待される性質が損なわれないこと。
③ 細胞・組織と適用部位を隔離する目的で非細胞・組織成分を使用する場合
非細胞・組織成分を細胞・組織と適用部位を隔離する目的で使用する場合、下記の項目を参考に効果、安全性を確認すること。
ア 免疫隔離の程度
イ 細胞由来の目的生理活性物質の膜透過キネティクスと薬理効果
ウ 栄養成分及び排泄物の拡散
エ 非細胞・組織成分が適用部位周辺に及ぼす影響(3) 細胞に遺伝子工学的改変を加える場合
細胞に遺伝子を導入する場合は、次に掲げる事項に関する詳細を示すこと。
① 目的遺伝子の構造、由来、入手方法、クローニング方法並びにセル・バンクの調製方法、管理方法及び更新方法等に関する情報② 導入遺伝子の性質③ 目的遺伝子産物の構造、生物活性及び性質④ 遺伝子導入構成体を作製するために必要なすべての原材料、性質及び手順（遺伝子導入法並びに遺伝子導入用ベクターの由来、性質及び入手方法等）⑤ 遺伝子導入構成体の構造や特性⑥ ベクターや遺伝子導入構成体を作製するための細胞やウイルスのバンク化及びバンクの管理方法
遺伝子導入細胞の製造方法については、平成７年11月15日付け薬発第1062号厚生省薬務局長通知「遺伝子治療用医薬品の品質及び安全性の確保に関する指針について」（以下、「遺伝子治療用医薬品指針」という。）の別添「遺伝子治療用医薬品の品 質 及 び 安 全 性 の 確 保 に 関 す る 指 針 」 第２章等を参照すること。また、同通知の別記に準じて設定の妥当性等を明らかにすること。
なお、遺伝子組換え生物等の使用等の規制による生物の多様性の確保に関する-8-

法律(平 成 15年 法 律 第 97号 ）に基づき 、「ヒトの細胞等」若しくは「分化する能力を有する、又は分化した細胞等であって、自然条件において個体に成育しないもの」以外の細胞、「ウイルス」及び「ウイロイド」に対して遺伝子工学的改変を加える場合には、別途手続きが必要となるので留意すること。
第２製造工程
細胞・組織加工医薬品等の製造に当たっては、製造方法を明確にし、可能な範囲でその妥当性を以下の項目で検証し、品質の一定性を保持すること。
１
ロット構成の有無とロットの規定
製品がロットを構成するか否かを明らかにすること。ロットを構成する場合には、ロットの内容について規定しておくこと。
２
製造方法
原材料となる細胞・組織の受け入れから最終製品に至る製造の方法の概要を示すとともに、具体的な処理内容及び必要な工程管理、品質管理の内容を明らかにすること。
(1) 受入検査
原材料となる細胞・組織について、細胞・組織の種類や使用目的に応じて実施す
る受入のための試験検査の項目（例えば、目視検査、顕微鏡検査、採取収率、生存率、細胞・組織の特性解析及び微生物試験等）と各項目の判定基準を設定すること。
確認申請段階にあっては、それまでに得られた試験検体での実測値を提示し、これらを踏まえた暫定値を示すこと。
(2) 細菌、真菌及びウイルス等の不活化・除去
原材料となる細胞・組織について、その細胞生存率や表現型、遺伝形質及び特有の機能その他の特性及び品質に影響を及ぼさない範囲で、必要かつ可能な場合は細菌、真菌及びウイルス等を不活化又は除去する処理を行うこと。当該処理に関する方策と評価方法について明らかにすること。
(3) 組織の細切、細胞の分離、特定細胞の単離等
原材料となる細胞・組織から製品を製造する初期の過程で行われる組織の細切、細胞の分離、特定細胞の単離及びそれらの洗浄等の方法を明らかにすること。特定細胞の単離を行う場合には、その確認方法を設定すること。
(4) 培養工程
製造工程中に培養工程が含まれる場合は、培地、培養条件、培養期間及び収率等を明らかにすること。
(5) 株化細胞の樹立と使用
株化細胞の樹立に当たっては、ドナーの遺伝的背景を理解したうえで樹立すること。樹立の方法を明確にし、可能な範囲でその妥当性を明らかにすること。
株化細胞の品質の均質性および安定性を保持するため、必要な特性解析要件（細胞純度、形態学的評価、表現型特異的マーカ、核型など）を同定してその基準を設定
するとともに、安定性を維持したまま増殖が可能な継代数を示すこと。
株化細胞に関しては、適切な動物モデル等を利用し、腫瘍形成及びがん化の可能-9-性について考察し、明らかにすること。
(6) 細胞のバンク化
細胞・組織加工医薬品等の製造のいずれかの過程で、細胞をバンク化する場合には、その理由、セル・バンクの作製方法及びセル・バンクの特性解析、保存・維持・管理方法・更新方法その他の各作業工程や試験に関する手順等について詳細を明らかにし、妥当性を示すこと。平成12年7月14日付け医薬審第873号厚生省医薬安全局審査管理課長通知「生物薬品（バイオテクノロジー応用医薬品／生物起源由来医薬品）製造用細胞基剤の由来、調製及び特性解析について」等を参考とすること。
(7) 製造工程中の取り違え及びクロスコンタミネーション防止対策
細胞・組織加工医薬品等の製造にあたっては、製造工程中の取り違え及びクロス
コンタミネーションの防止が重要であり、工程管理における防止対策を明らかにすること。
３

加工した細胞の特性解析加工した細胞について、加工に伴う変化を調べるために、例えば、形態学的特徴、増殖特性、生化学的指標、免疫学的指標、特徴的産生物質、その他適切な遺伝型又は表現型の指標を解析するとともに、必要に応じて機能解析を行うこと。
また、培養期間の妥当性及び細胞の安定性を評価するために、予定の培養期間を超えて培養した細胞において目的外の変化がないことを示すこと。

４

最終製品の形態、包装
最終製品の形態、包装は、製品の品質を確保できるものでなければならない。

５

製造方法の恒常性
細胞・組織加工医薬品等の製造に当たっては、製造工程を通じて、個別に加工した製品の細胞数、細胞生存率並びに製品の使用目的及び適用方法等からみた特徴（表現型の適切な指標、遺伝型の適切な指標、機能特性及び目的とする細胞の含有率等）
が製品（ロット）間で本質的に損なわれないことを、試験的検体を用いてあらかじ
め評価しておくこと。
製造工程中の凍結保存期間や加工に伴う細胞培養の期間が長期に及ぶ場合には一定期間ごとに無菌試験を行うなど、無菌性が確保されることを確認すること。

６

製造方法の変更
開発途中に製造方法を変更した場合、変更前の製造方法による製品を用いて得た試験成績を確認申請又は承認申請に使用するときは、製造方法変更前後の製品の同等性及び同質性を示すこと。

第３１

最終製品の品質管理総論
細胞・組織加工医薬品等の品質管理全体の方策としては、最終製品の規格及び試- 10 -

験方法の設定、個別患者への適用ごとの原材料の品質管理、製造工程の妥当性の検証と一定性の維持管理のほか、中間製品の品質管理を適正に行うこと等が挙げられる。
最終製品の規格及び試験方法については、対象とする細胞・組織の種類及び性質、製造方法、各製品の使用目的や使用方法、安定性、利用可能な試験法等によって異なると考えられるため、取り扱う細胞・組織によってこれらの違いを十分に考慮して設定すること。また、製造工程の妥当性の検証と一定性の維持管理法、中間製品の品質管理等との相互補完関係を考慮に入れて、全体として品質管理の目的が達成されるとの観点から、合理的に規格及び試験方法を設定し、その根拠を示すこと。
なお、確認申請は、治験を実施する製品の品質として問題がないとみなせることを確認することを目的としている。したがって、無菌性やマイコプラズマの否定など
必須なものを除き、治験後に臨床試験成績と品質の関係を論ずるために必要な品質特性については、やむを得ない場合は少数の試験的検体の実測値をもとにその変動をしかるべき範囲内に設定する暫定的な規格及び試験方法を設定することで差し支えない。ただし、規格及び試験方法を含む品質管理法は治験の進行とともに充実・整備を図ること。
２

最終製品の品質管理法
最終製品について、以下に示す一般的な品質管理項目及び試験を参考として、必要で適切な規格及び試験方法を設定し、その根拠を明らかにすること。
ロットを構成しない製品を製造する場合は個別製品ごとに、ロットを構成する製品を製造する場合には、通常、各個別製品ではなく各ロットが品質管理の対象となるので、これを踏まえてそれぞれ適切な規格、試験方法を設定すること。
(1) 細胞数並びに生存率得られた細胞の数と生存率は、最終製品又は必要に応じて適切な製造工程の製品で測定すること。なお、確認申請時においては、少数の試験的検体での実測値を踏まえた暫定的な規格を設定することでも良い。
(2) 確認試験目的とする細胞・組織の形態学的特徴、生化学的指標、免疫学的指標、特徴的産
生物質その他適切な遺伝型あるいは表現型の指標を選択して、目的とする細胞・組織であることを確認すること。
(3) 細胞の純度試験
目的細胞以外の異常増殖細胞、形質転換細胞の有無や混入細胞の有無等の細胞の純度について、目的とする細胞・組織の由来、培養条件等の製造工程等を勘案し、必要に応じて試験項目、試験方法及び判定基準を示すこと。なお、確認申請時においては、少数の試験的検体での実測値を踏まえた暫定的な規格を設定することでも良い。
(4) 細胞由来の目的外生理活性物質に関する試験
細胞由来の各種目的外生理活性物質のうち、製品中での存在量如何で患者に安全性上の重大な影響を及ぼす可能性が明らかに想定される場合には、適切な許容量限- 11 -

度試験を設定すること。なお、確認申請時においては、少数の試験的検体での実測値を踏まえた暫定的な規格を設定することでも良い。
(5) 製造工程由来不純物試験
原材料に存在するか又は製造過程で非細胞・組織成分、培地成分、資材、試薬等に由来し、製品中に混入物、残留物、又は新たな生成物、分解物等として存在する可能性があるもので、かつ、品質及び安全性の面からみて望ましくない物質等（例
えば、ウシ胎児血清由来のアルブミン、抗生物質等）については、当該物質の除去に関するプロセス評価や当該物質に対する工程内管理試験の結果を考慮してその存在を否定するか、又は適切な試験を設定して存在許容量を規定すること。試験対象物質の選定及び規格値の設定に当たっては、設定の妥当性について明らかにすること。
なお、確認申請時においては、少数の試験的検体での実測値を踏まえた暫定的な規格を設定することでも良い。
(6) 無菌試験及びマイコプラズマ否定試験
最終製品の無菌性については、あらかじめモデル検体を用いて全製造工程を通じて無菌性を確保できることを十分に評価しておく必要がある。最終製品について、患者に適用する前に無菌性（一般細菌及び真菌否定）を試験により示すこと。また、
適切なマイコプラズマ否定試験を実施すること｡最終製品の無菌試験等の結果が、患者への投与後にしか得られない場合には、投与後に無菌性等が否定された場合の対処方法をあらかじめ設定しておくこと。また、この場合、中間製品で無菌性を試
験により示し、最終製品に至る工程の無菌性を厳密に管理する必要がある。また、同一施設・同一工程で以前に他の患者への適用例がある場合には、全例において試験により無菌性が確認されていること。ロットを構成する製品で密封性が保証されている場合には、代表例による試験でよい。適用ごとに試験を実施する必要がある場合で、無菌試験等の結果が、患者への投与後にしか得られない場合には、適用の可否は直近のデータを参考にすることになるが、この場合でも最終製品の無菌試験等は必ず行うこと。
抗生物質は細胞培養系で極力使用しないことが望まれるが、使用した場合には、無菌試験に影響を及ぼさないよう処置すること。
(7) エンドトキシン試験
試料中の夾雑物の影響を考慮して試験を実施すること。規格値は必ずしも実測値によらず、日本薬局方等で示されている最終製品の１回投与量を基にした安全域を考慮して設定すればよい。また、工程内管理試験として設定することも考えられるが、その場合には、バリデーションの結果を含めて基準等を設定し、その妥当性を説明すること。
(8) ウイルス等の試験
バンク化されておらず、ウインドウピリオドが否定できず、HBV、HCV、HIV等を製造工程中に増殖させる可能性のある細胞を用いる際には、中間製品、最終製品等についてもウイルス等の存在を否定する適切な試験を実施すること。また、製造工程中で生物由来成分を使用する場合には、最終製品で当該成分由来のウイルスにつ- 12 -

いての否定試験の実施を考慮すべき場合もあるかも知れない。しかし可能な限り、もとの成分段階での試験やプロセス評価で迷入が否定されていることが望ましい。
(9) 効能試験
幹細胞、リンパ球、遺伝子改変細胞その他の細胞等、臨床使用目的又は特性に応じた適切な効能試験の実施を考慮すべき場合もある。なお、確認申請においては、
少数の試験的検体による実測値を踏まえた暫定的な規格を設定することでも良い。
(10) 力価試験
細胞・組織から分泌される特定の生理活性物質の分泌が当該細胞・組織加工医薬品等の効能又は効果の本質である場合には、その目的としている必要な効果を発揮することを示すために、当該生理活性物質に関する検査項目及び規格を設定すること。遺伝子を導入した場合の発現産物又は細胞から分泌される目的の生成物等について、力価、産生量等の規格を設定すること。なお、確認申請時においては、少数の試験的検体による実測値を踏まえた暫定的な規格を設定することでも良い。
(11) 力学的適合性試験
一定の力学的強度を必要とする製品については、適用部位を考慮した力学的適合性及び耐久性を確認するための規格を設定すること。なお、確認申請時においては、
少数の試験的検体による実測値を踏まえた暫定的な規格を設定することでも良い。
第３章 細胞・組織加工医薬品等の安定性製品化した細胞・組織加工医薬品等又は重要なそれらの中間製品について、保存・流通期間及び保存形態を十分考慮して、細胞の生存率及び力価等に基づく適切な安定性試験を実施し、貯法及び有効期限を設定し、その妥当性を明らかにすること。特に凍結保管及び解凍を行う場合には、凍結及び解凍操作による製品の安定性や規格への影響がないかを確認すること。また、必要に応じて標準的な製造期間を超える場合や標準的な保存期間を超える長期保存についても検討し、安定性の限界を可能な範囲で確認すること。ただし、製品化後直ちに使用するような場合はこの限りではない。
また、製品化した細胞・組織加工医薬品等を運搬する場合には、運搬容器及び運搬
手順（温度管理等を含む）等を定め、その妥当性について明らかにすること。
第４章 細胞・組織加工医薬品等の非臨床安全性試験
製品の特性及び適用法から評価が必要と考えられる安全性関連事項について、技術的に可能であれば、科学的合理性のある範囲で、適切な動物を用いた試験又はin vitroでの試験を実施すること。なお、非細胞・組織成分及び製造工程由来の不純物等については、可能な限り、動物を用いた試験ではなく理化学的分析法により評価すること。
ヒト由来の試験用検体は貴重であり、また、ヒト由来の製品を実験動物等で試験して必ずしも意義ある結果が得られるとは限らない。このため、動物由来の製品モデルを作成し適切な実験動物に適用する試験系により試験を行うことで、より有用な知見が得られると考えられる場合には、むしろ、このような試験系を用いることに科学的合理性がある場合がある。場合によっては細胞を用いる試験系も考慮し、このようなアプローチにより試験を行なった際には、その試験系の妥当性について明らかにする- 13 -

こと。
以下に、必要に応じて非臨床的に安全性を確認する際の参考にすべき事項及び留意点の例を示す。これらは例示であって、合理性のない試験の実施を求める趣旨ではな
く、製品の特性等を考慮して適切な試験を検討すること。
１ 培養期間を超えて培養した細胞について、目的外の形質転換を起こしていない
ことを明らかにすること。
２ 必要に応じて細胞・組織が産生する各種サイトカイン、成長因子等の生理活性物質の定量を行い、生体内へ適用したときの影響に関して考察を行うこと。
３ 製品の適用が患者等の正常な細胞又は組織に影響を与える可能性について検討、考察すること。
４ 製品及び導入遺伝子の発現産物等による望ましくない免疫反応が生じる可能性について検討、考察すること。
５ 株化細胞を用いた場合には、適切な動物モデル等を利用し、腫瘍形成及びがん化の可能性について考察し、明らかにすること。
６ 製造工程で外来遺伝子の導入が行われている場合には、遺伝子治療用医薬品指針に定めるところに準じて試験を行うこと。特に、ウイルスベクターを使用した
場合には増殖性ウイルスがどの程度存在するかを検査するとともに、検査方法が適切であることについても明らかにすること。
また、導入遺伝子及びその産物の性状について調査し、安全性について明らかにすること。細胞については、増殖性の変化、腫瘍形成及びがん化の可能性について考察し、明らかにすること。
７ 動物由来のモデル製品を含めて製品の入手が容易であり、かつ臨床上の適用に関連する有用な安全性情報が得られる可能性がある場合には、合理的に設計された一般毒性試験の実施を考慮すること。
なお、一般毒性試験の実施に当たっては、平成元年9月11日付け薬審1第24号厚生省薬務局新医薬品課長・審査課長連名通知「医薬品の製造（輸入）承認申請に必要な毒性試験のガイドラインについて」の別添「医薬品毒性試験法ガイドライン」等を参照すること。
第５章 細胞・組織加工医薬品等の効力又は性能を裏付ける試験
１ 技術的に可能かつ科学的に合理性のある範囲で、実験動物又は細胞等を用い、適切に設計された試験により、細胞・組織加工医薬品等の機能発現、作用持続性及び医薬品・医療機器として期待される効果を検討すること。
２ 遺伝子導入細胞にあっては、導入遺伝子からの目的産物の発現効率及び発現の持続性、導入遺伝子の発現産物の生物活性並びに医薬品等として期待される効果等を検討すること。
３ 適当な動物由来細胞・組織製品モデル又は疾患モデル動物がある場合には、それを用いて治療効果を検討すること。
４ 確認申請段階では、当該製品の効力又は性能による治療が他の治療法と比較した
ときはるかに優れて期待できることが国内外の文献又は知見等により合理的に明ら- 14 -

かにされている場合には、必ずしも詳細な実験的検討は必要とされない。
第６章 細胞・組織加工医薬品等の体内動態
１ 製品を構成する細胞・組織及び導入遺伝子の発現産物について、技術的に可能で、かつ、科学的合理性がある範囲で、実験動物での吸収及び分布等の体内動態に関する試験等により、患者等に適用された製品中の細胞・組織の生存期間、効果持続期間を推測し、目的とする効果が十分得られることを明らかにすること。
２ 当該細胞・組織が特定の部位（組織等）に到達して作用する場合には、その局在性を明らかにすること。
第７章 臨床試験
確認申請の段階における安全性については、臨床上の有用性を勘案して評価されるものであり、細胞・組織加工医薬品等について予定されている国内の治験計画について以下の項目を踏まえて評価すること。
１ 対象疾患２ 対象とする被験者及び被験者から除外すべき患者の考え方
３ 細胞・組織加工医薬品等の適用を含め、被験者に対して行われる治療内容
４ 既存の治療法との比較を踏まえた臨床試験実施の妥当性
５ 現在得られている情報から想定されるリスク及びベネフィットを含め、被験者への説明事項の案
なお、臨床試験は、適切な試験デザイン及びエンドポイントを設定して実施する必要があり、目的とする細胞・組織の由来、対象疾患及び適用方法等を踏まえて適切に計画すること。

- 15 -

Guidance for Industry
Preparation of IDEs and INDs for
Products Intended to Repair or
Replace Knee Cartilage
DRAFT GUIDANCEThis guidance document is for comment purposes only.

Submit comments on this draft guidance by the date provided in the Federal Register noticeannouncing the availability of the draft guidance. Submit written comments to the Division ofDockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061,
Rockville, MD 20852. Submit electronic comments to http://www.fda.gov/dockets/ecomments.
You should identify all comments with the docket number listed in the notice of availability thatpublishes in the Federal Register.
For questions on the content of this guidance, contact Dr. Richard McFarland, Office of Cellular,
Tissue and Gene Therapies, Center for Biologics Evaluation and Research, at 301-827-5102 or
Mr. Aric Kaiser, Office of Device Evaluation, Center for Devices and Radiological Health, at
240-276-3676.

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and ResearchCenter for Devices and Radiological HealthJuly 2007

Contains Nonbinding Recommendations
Draft – Not for Implementation

Guidance for Industry
Preparation of IDEs and INDs for Products Intended toRepair or Replace Knee Cartilage
Additional copies of this guidance are available from:
Office of Communication, Training and Manufacturers Assistance, HFM-40
Center for Biologics Evaluation and Research
Food and Drug Administration
1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448
Phone: 800-835-4709 or 301-827-1800
Internet: http://www.fda.gov/cber/guidelines.htm
orOffice of Communication, Education, and Radiation Programs
Division of Small Manufacturers, International, and Consumer Assistance (DSMICA),
HFZ-220
Center for Devices and Radiological Health
Food and Drug Administration
1350 Piccard Drive, Rockville, MD 20850
Phone: 800-638-2041 or 240-276-3150
Internet: http://www.fda.gov/cdrh/guidance.html
Email: dsmica@fda.hhs.gov
Fax: 240-276-3151

Contains Nonbinding Recommendations
Draft – Not for Implementation

Table of Contents
I.

INTRODUCTION............................................................................................................. 1II.

BACKGROUND ............................................................................................................... 2

III.

PRODUCT DESCRIPTION ............................................................................................ 2IV.

MANUFACTURING AND CMC INFORMATION..................................................... 3
A.
B.

V.

Device Component ................................................................................................ 3
Cellular or Gene Therapy Product or Cellular Component of Combination
Product................................................................................................................... 3

NONCLINICAL DATA AND TESTING....................................................................... 4A.

B.

Animal Data and Testing...................................................................................... 4
1.
Suitability of animal model(s) .................................................................... 5
2.
Animal report(s) to be submitted ................................................................ 6
Mechanical Data and Testing .............................................................................. 6VI.

BIOCOMPATIBILITY.................................................................................................... 8VII.

CLINICAL STUDY PROTOCOLS................................................................................ 8
A.

B.
C.
D.
E.
F.
G.

Design ..................................................................................................................... 8
1.
Exploratory Clinical Studies ....................................................................... 82.
Confirmatory Clinical Studies .................................................................... 9Control Group..................................................................................................... 10
Patient Population............................................................................................... 11
Study Endpoints .................................................................................................. 12
Investigational Product Administration ........................................................... 14
Follow-Up............................................................................................................. 14
Adverse Event (Risk) Reporting........................................................................ 15

VIII. REFERENCES................................................................................................................ 16i

Contains Nonbinding Recommendations
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Guidance for Industry
Preparation of IDEs and INDs for Products Intended to Repair or
Replace Knee Cartilage
This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s)
current thinking on this topic. It does not create or confer any rights for or on any person anddoes not operate to bind FDA or the public. You can use an alternative approach if theapproach satisfies the requirements of the applicable statutes and regulations. If you want todiscuss an alternative approach, contact the appropriate FDA staff. If you cannot identify theappropriate FDA staff, call the appropriate number listed on the title page of this guidance.

I.

INTRODUCTION

This guidance document provides to you, sponsors, recommendations about certain informationthat should be included in an investigational device exemption (IDE) or investigational new drug
application (IND) for a product intended to repair or replace knee cartilage. For the purposes ofthis document, a product intended to repair or replace knee cartilage, as with other articularcartilage repair or replacement products, 1 may include a biologic, device, or combination
product 2 whose components would be individually regulated by the Center for Devices andRadiological Health (CDRH) and the Center for Biologics Evaluation and Research (CBER). 3,4This guidance supplements recommendations regarding IDE and IND submissions contained inother FDA publications (e.g., “Guidance on Applications for Products Comprised of Living
Autologous Cells Manipulated ex vivo and Intended for Structural Repair or Reconstruction”(Ref. 1)). For general information on IDEs and INDs, see
http://www.fda.gov/cdrh/devadvice/ide/index.shtml and http://www.fda.gov/cber/ind/ind.htm,
respectively.
1

Prostheses such as unicondylar or total knee implants are beyond the scope of this guidance. Meniscus
replacement products—which are being studied for use in preventing cartilage damage—are also beyond the scopeof this guidance unless manufacturers propose new indications related to cartilage repair, replacement, orpreservation.
2
A combination product is comprised of two or more different types of regulated constituents (i.e., drug-device,drug-biologic, device-biologic, or drug-device-biologic). See Title 21 Code of Federal Regulations (CFR) 3.2(e) for
further information on how combination products are defined by FDA.
3
Forward specific questions regarding the jurisdiction over a combination product to the Office of Combination
Products (OCP) at 301-427-1934 or combination@fda.gov. Information about the Request for Designation (RFD)
program and guidance related to the regulation of combination products are available at the OCP website(http://www.fda.gov/oc/combination). Forward questions regarding the applicability of specific regulations forarticular cartilage repair or replacement products, for which jurisdiction has already been determined, to the Centerwith jurisdiction.
4
Human cells, tissues, and cellular and tissue-based products (HCT/P’s) regulated solely under section 361 of the
Public Health Service Act (42 U.S.C. 264) and 21 CFR Part 1271 are beyond the scope of this guidance.

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We, FDA, typically regard investigational devices for articular cartilage repair or replacement tobe significant risk devices (see 21 CFR 812.3(m)(1)). Therefore, if you intend to conductclinical studies of these devices in the United States, you will likely need to submit to FDA an
IDE (21 CFR 812.20(a)). All investigational studies for cellular therapy products, except for
HCT/Ps that meet the criteria specified in 21 CFR 1271.10(a), including products for articularcartilage repair or replacement, require submission of an IND (21 CFR 312.20). When an INDor IDE is required, you must comply with FDA's IND regulations (21 CFR Part 312) or IDE
regulations (21 CFR Part 812), as appropriate, to proceed with clinical investigations of theseproducts. Institutional review board (IRB) approval alone is generally not sufficient tocommence a clinical study in human subjects involving articular cartilage repair or replacement
products (21 CFR 56.103).
FDA’s guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the FDA’s current thinking on a topic and should beviewed only as recommendations, unless specific regulatory or statutory requirements are cited.
The use of the word should in FDA’s guidances means that something is suggested orrecommended, but not required.
II.

BACKGROUND

We prepared this guidance to address issues that may arise in the development of articularcartilage repair or replacement products. This guidance also reflects input received from thepublic and the Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) at the
March 3 to 4, 2005, CTGAC meeting (Ref. 2).
In addition, we carefully considered the relevant statutory criteria for FDA decision-making andany possible burden you may incur in your attempt to address the issues and follow ourrecommendations in the guidance. We believe that we have considered the least burdensome
approach to resolving the issues presented in this guidance document. If, however, you believethat there is a less burdensome approach, we recommend that you follow the procedures outlinedin the “Guidance for Industry: A Suggested Approach to Resolving Least Burdensome Issues”(Ref. 3).
III.

PRODUCT DESCRIPTION

For products subject to the IDE submission requirement in 21 CFR Part 812, you should, and insome cases are required to, provide in an IDE the following information to describe theinvestigational device. Depending on the particular design of the product, additional information
may be appropriate:2

Contains Nonbinding Recommendations
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A complete written description of the individual components and how any components
interact. See 21 CFR 812.25(d) and 812.20(b)(2).
A description of the material(s) and any voluntary material standard(s) to which thematerial(s) conform. See 21 CFR 812.25(d) and 812.20(b)(2). Depending on thematerial, we may recommend biocompatibility testing, as described in section VI.
A description of anticipated changes to the system. See 21 CFR 812.25(d) and
812.20(b)(2).
A list of all instruments unique to the implantation of the product, the material andvoluntary material standard to which they conform, and supporting magnified sketches orphotographs of them. See 21 CFR 812.25(d) and 812.20(b)(2).

For any concurrent control product or treatment, we recommend that you provide a written
description, any available drawings and photographs, and information regarding materials fromwhich the control product is manufactured.
For products regulated under an IND, we recommend that you incorporate a description of the
product into the Chemistry, Manufacturing, and Controls (CMC) section of the IND submission
as described in the final guidance listed below in section IV.B. and, when finalized, the two draft
guidances listed in section IV.B.
IV.

MANUFACTURING AND CMC INFORMATIONA.

Device Component

Under 21 CFR 812.20(b)(3), you must provide a description of the methods, facilities,
and controls used for the manufacture, processing, packing, storage, and, whereappropriate, installation of the device, in sufficient detail so that a person generallyfamiliar with good manufacturing practices can make a knowledgeable judgment about
the quality control used in the manufacture of the device.
As part of that information, you should provide the following:••B.

basic manufacturing information regarding product design issues; andsterilization information for the finished device, as described in the guidance
entitled, “Updated 510(k) Sterility Review Guidance K90-1; Final Guidance forIndustry and FDA” (Ref. 4).
Cellular or Gene Therapy Product or Cellular Component of Combination
Product

For a cellular or gene therapy product or cellular constituents of a combination product,
we recommend that you refer to “Guidance for Industry: Guidance for Human Somatic
Cell Therapy and Gene Therapy” (Ref. 5). When finalized, we also recommend that you
refer to the following draft guidances:3

Contains Nonbinding Recommendations
Draft – Not for Implementation••

V.

Draft “Guidance for Reviewers: Instructions and Template for Chemistry,
Manufacturing, and Control (CMC) Reviewers of Human Somatic Cell Therapy
Investigational New Drug Applications (INDs)” (Ref. 6); andDraft “Guidance for FDA Review Staff and Sponsors: Content and Review ofChemistry, Manufacturing, and Control (CMC) Information for Human Gene
Therapy Investigational New Drug Applications (INDs)” (Ref. 7).

NONCLINICAL DATA AND TESTING

You should provide nonclinical data sufficient to establish a scientific rationale for clinicalinvestigation of your product, and to demonstrate an acceptable safety profile of your productprior to initiating a human clinical study (see 21 CFR 312.23(a)(8) for IND-specific requirements
relating to the submission of pharmacology and toxicology information). These data can bederived from animal studies, mechanical testing, or a combination of both. You should choose
the most appropriate testing to demonstrate the activities and address the safety issues raised byyour product. We encourage you to design testing strategies that combine animal andmechanical testing in single studies if such a strategy does not compromise the validity of themeasurements, or the usefulness of the data.
A.

Animal Data and Testing

Generally, animal studies are used to assess the following issues:
•

•

•

•

Biological response to products (e.g., biological activity [proof of concept andsafety data] of each component of a combination product). You can use animalstudies to demonstrate that a product's components have the potential tocontribute to the clinical efficacy of the final product.
Durability of the response (e.g., length of time needed to assess repair of the
cartilage lesion and durability of the repair). You can assess durability of the
response in large animal studies. Generally studies of one year in length arerecommended to provide an adequate period for completion of healing andassessment of durability.
Toxicology (e.g., potential for local and systemic toxicities due to component of
the product). Local toxicities may be due to interactions of the product with thecomponents of the joint, or degradation of the product in the joint. Systemic
toxicities may be due to cell migration outside of the articular space. Potential fortumorigenicity or inappropriate differentiation of cellular products exist within or
outside of the articular space.
Dose response (e.g., effect of variation in cell number or size of lesion). Dose
response can be assessed in large animal studies.

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1. Suitability of animal model(s)We recognize that choosing and determining the suitability of an animal model(s)for evaluation of any specific product is difficult because there is no perfectanimal model of articular cartilage injury. As discussed at the March 2005
CTGTAC meeting (Ref. 2):•••

the scientific literature contains descriptions of numerous methods forevaluating the nonclinical behavior of native cartilage and, consequently,
articular cartilage repair or replacement products;
not all of these methods may apply to a specific articular cartilage repair
or replacement product; andgoats, sheep, and horses are the most frequently used large animal models
for cartilage repair.

Any of these animal species may be appropriate in studies designed to support theactivity and safety of your cartilage repair or replacement product. However, werecommend that you choose the species after carefully considering the model’sability to reflect the intended clinical use.
In the case of a product containing human cells, studies performed in animals
often require the use of either immunosuppressive agents to avoid rejection of the
product, or the use of analogous cellular products in animals. Analogous cellular
products are cellular products derived from the animal species used for testingthat are analogs of the ultimate clinical product in phenotype and biologic
activity. You should characterize the level of analogy with the human product inpreliminary studies prior to conducting a pivotal toxicology study with theanalogous cellular product.
We recommend the use of pilot studies designed to confirm the suitability of
testing a particular product in a specific animal species. Several different animalstudies and/or species may be necessary to adequately model functional aspects
and potential toxicities of a single product. However, the number of studies
needed should be determined by relevant structural and biological characteristicsof the product, not by the number of components of the product. We recommendthat you design nonclinical testing of cartilage repair and replacement productsthat contain a cellular or gene therapy component, following the principles
provided in section VIII of the “Guidance for Industry: Guidance for Human
Somatic Cell Therapy and Gene Therapy” (Ref. 5).
Because a recommendation for a set of specific evaluations is not possible without
detailed description of the articular cartilage repair or replacement product,reference is made to the American Society for Testing and Materials (ASTM)
F2451-05, “Standard Guide for in vivo Assessment of Implantable Devices

5

Contains Nonbinding Recommendations
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Intended to Repair or Regenerate Articular Cartilage,” approved April 1, 2005. 5
This standard provides guidelines related to the development of animal models
and mechanical testing, and we recommend that you consult this standard or theapplicable scientific literature when designing animal studies. Specifically, thestandard contains a:••••comparison of animal models, articular cartilage defect types, and articularcartilage defect locations;discussion of articular cartilage defect preparation;
description of gross and histological assessments; anddescription of various mechanical evaluations and their applicability.

2. Animal report(s) to be submitted
You should provide complete reports of any animal studies conducted using theinvestigational product, whether adverse or supportive, relevant to the evaluationof the safety or effectiveness of the investigational product. For INDs, you must
provide a full tabulation of data suitable for detailed review for each toxicology
study that is intended primarily to support the safety of the proposed clinicalinvestigation (21 CFR 312.23(a)(8)(ii)(b)). For each nonclinical laboratory study
subject to the good laboratory practice (GLP) regulations under 21 CFR Part 58,
you must include a statement that the study was conducted in compliance with the
GLP regulations, or, if the study was not conducted in compliance with thoseregulations, a brief statement of the reason for the noncompliance(21 CFR 312.23(a)(8)(iii) for INDs and 21 CFR 812.27(b)(3) for IDEs). You
should specify in the animal report the purpose of the study and provide a detailed
methods section, to include the creation and location of the cartilage defect, andsupporting pathological, histological, and radiological evaluations. In addition,
you should describe any differences between the product used in the animalstudies and the product proposed for clinical use in the IDE or IND.
B.

Mechanical Data and Testing

You should provide mechanical data for all articular cartilage repair products or arationale addressing why mechanical testing is not necessary to establish an acceptablesafety profile of the investigational product.
The mechanical testing appropriate for your product may depend on the design, material,
method of attachment to the subchondral bone and/or surrounding intact cartilage, andpatient indication. However, you should generally provide mechanical testing results toaddress the ability of the implant to withstand expected in vivo static and dynamic
loading (e.g., compression, shear, propensity to generate wear debris, analysis of fixation
5

The referenced document is an American Society for Testing and Materials Standard. The standard is available at
http://www.astm.org, or contact ASTM Customer Service at service@astm.org.

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method). We recommend that you compare the properties of the repaired or regenerated
cartilage to those of normal articular cartilage. You should determine the aggregate
modulus (HA), Poisson’s ratio (ν) and permeability (κ) of the solid phase. Permeability
and aggregate modulus can be determined by confined compression creep testing, while
all three of these properties can be determined from creep indentation tests using porous
indentors (ASTM Standard F2451-05 contains information regarding suggested test
methods). You should also include an assessment of the degree of cartilage breakdown.
This may be done visually after staining with India ink or indentation probe “stiffness”
evaluations.
We realize that some types of products are not capable of fully withstanding applied
loads at the time of implantation (e.g., a cellular product held in place by a periosteal flap
or a flexible scaffold that will eventually be populated by cells that ultimately form aload-bearing tissue). For these products, it would be appropriate to characterize various
properties at discrete timepoints. You should initially assess the product’s ability tomaintain its location within the loaded joint, and subsequently continue to assess thischaracteristic while adding assessments of the newly-formed tissue and its ability to bear
applied loads.
When there are differences between the proposed clinical product and the product tested,
you should explain how or why the results are relevant in establishing the relative safetyof the proposed product. Regardless of the evaluations which are performed, you should
compare the properties of the repaired or regenerated tissue to control tissue (e.g., thecartilage collected from an unoperated control joint). While it is understood that the
repair tissue might have properties that differ from those of normal cartilage, you should
describe why these differences might not be relevant to the in vivo and clinical behaviorof the product.
You should provide complete reports of any mechanical testing conducted on theinvestigational product, whether adverse or supportive, that are relevant to the evaluationof the safety or effectiveness of the investigational product. Each test report should
include, but need not be limited to, the following elements:
•
•
•
•
•
•
•

identification of the components that comprised the product tested;
the set-up;
the procedures;
rationale supporting the testing environment as being a worst case condition
rationale for the loading modes chosen;
the results; anda discussion of the results in terms of the expected in vivo and clinicalperformance of the system.

You should also provide a comprehensive summary of all mechanical testing in addition
to complete reports for each test.

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BIOCOMPATIBILITY

Depending on the material(s) used in the product, we may recommend biocompatibility testing.
FDA's guidance entitled, “Use of International Standard ISO-10993, ‘Biological Evaluation of
Medical Devices Part-1: Evaluation and Testing’” (Ref. 8) and/or ASTM F748-04, “Standard
Practice for Selecting Generic Biological Test Methods for Materials and Devices” 6 may berecommended as acceptable approaches for conducting biocompatibility testing. You should
include in the IND or IDE a complete test report describing the tests performed, the specificmethods utilized, and the results.
In addition, for any biological or drug component (e.g., bone morphogenic protein, bovine
protein), we recommend that you follow any applicable FDA guidances.
VII.

CLINICAL STUDY PROTOCOLSClinical studies of articular cartilage repair or replacement products must be conducted incompliance with IDE regulations (21 CFR Part 812) or IND regulations (21 CFR Part 312), alongwith Informed Consent (21 CFR Part 50) and IRB regulations (21 CFR Part 56) and otherapplicable regulatory requirements.
A.

DesignIn general, the clinical development program for an investigational knee cartilage repair
or replacement product should proceed through an orderly series of exploratory andconfirmatory clinical studies. The number of clinical studies as well as the specificdesign requirements for each of these studies is contingent upon multiple factors,
including the characteristics of the investigational product, the route of productadministration, the characteristics of the target patient population and the proposed
product indication. Consequently, this guidance provides only a broad outline of the
major features to consider in designing a clinical study.
1. Exploratory Clinical Studies
You should design exploratory clinical studies that are conducted early in clinicaldevelopment to obtain, in addition to any other features, the following
information:••

6

safety data;
data assessing the ability to properly administer the product, including
identification of any study procedures that should be modified to optimize
product administration;

Id.

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bioactivity data, such as assessments of cartilage integrity based upon
imaging results and biopsy findings;
data assessing the appropriateness of the target patient population; anddata providing information concerning the activity of the product in vivo
or other information related to product activity that may be informative for
future development such as:
o product dose-response relationships
o product design-response characteristics

You should comprehensively evaluate exploratory clinical study data to facilitate
the design of confirmatory studies. At the conclusion of exploratory clinicalstudies, you should be able to provide clinical data explaining the important
aspects of the proposed confirmatory clinical studies that apply to theinvestigational product, such as:
•
•
•
•
•
•
•

data that support the product dose and design characteristics;
route of administration, including surgical technique in the use of the
product;
extent and nature of follow-up evaluations;study subject sample size;
eligibility and ineligibility criteria;
choice of the major study endpoints; andstatistical assessments of the major study endpoints.

An important consideration for an exploratory clinical study of knee cartilage
repair or replacement products is the use of a control group(s) to optimize theinterpretability of the exploratory findings. In general, the most important clinicaloutcomes associated with use of these products are relief of pain and restorationof knee function, outcomes we believe are highly susceptible to bias due toassessment subjectivity. The use of control groups may greatly facilitate theinterpretation of the clinical study findings, even if–because of the nature of thestudies–the statistical assessments lack the robustness or power expected ofconfirmatory clinical studies.
2. Confirmatory Clinical Studies
Confirmatory clinical studies are designed to obtain hypothesis-testing data (i.e.,
to test a primary efficacy hypothesis and provide sufficient supportive data forthat hypothesis as well as corresponding safety data). Depending upon thecharacteristics of the investigational product, safety concerns may render a larger
sample size appropriate than one might estimate based solely upon the size of the
projected primary efficacy endpoint treatment effect. Consequently, we
recommend that you consider both efficacy and safety considerations in designingconfirmatory clinical studies.
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Typically, confirmatory clinical studies utilize a randomized, controlled design.
Whenever possible, we recommend that you utilize a randomized, controlled
study design with endpoints ascertained in a blinded manner (e.g., primary
endpoints should be performed in either a completely blinded manner or with theuse of major endpoint evaluators who are blinded to the study treatment
assignments). However, alternative confirmatory study designs may beconsidered; as described, for example, in existing FDA guidance for products
regulated under IND. 7 You should provide us with data (from your studies andapplicable literature) and a rationale to support your confirmatory study designprior to initiation of a confirmatory study for any cartilage repair product.
Listed below in section VII.B through G are important considerations for the design ofboth exploratory and confirmatory clinical studies.
B.

Control GroupMultiple options exist for the choice of a study’s control groups, and we recommend thatyou review the “Guidance for Industry: E10 Choice of Control Group and Related Issues
in Clinical Trials” (Ref. 9). This guidance, while intended for biological products anddrugs, contains concepts which, we believe, may also be relevant to the clinical study ofan investigational device-biologic combination product.
In general, control groups may be broadly divided into either concurrent or historicalcontrols. Rapid advances in surgical techniques and the medical care of damaged knees
over the past several years suggest that you should generally use a concurrent control
group to obtain the most informative clinical data. We believe historical controls are
rarely sufficient for confirmatory clinical studies of knee cartilage repair or replacement
products.
The most common types of concurrent control groups include placebo controls, shamsurgery controls, active-comparator controls, or standard care controls. If you choose an
active comparator control, we recommend that you use one that is well accepted as
standard treatment for the indication. For example, this comparator may be an approved
or licensed product or a well-accepted surgical procedure for the indicated condition.
Comparator procedures may include the following: microfracture, debridement,
osteochondral autograft transplantation (e.g., mosaicplasty), autologous chondrocyte
implantation, autogenous perichondral or periosteal grafts, and osteochondral allografts,
depending on the standard treatment for the indication.

7

For cell, gene therapy, and combination products regulated under section 351 of the Public Health Service Act (42USC 264), please refer to the discussion of surrogate endpoints in FDA's “Guidance for Industry on Fast Track
Drug Development Programs: Designation, Development, and Application Review” dated January 2006
(http://www.fda.gov/cber/gdlns/fsttrk.pdf).

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You should provide a rationale for the selected comparator(s). This rationale should
include the comparability of the experimental and control treatments with respect to theextent of the surgical procedures involved as well as the duration and extent of
rehabilitation.
A study could also include more than one comparator study arm. For example, acontrolled study could compare treatment effects across a range of investigational
product dosages or compare treatment effects among a group of alternative
procedures/products.
“Sham controlled studies” represent one study design and choice of control group which
may allow for discrimination of patient outcomes caused by the test treatment fromoutcomes caused by other factors such as patient or observer expectations. This type ofstudy design could be considered in studies with subjective endpoints such as reduction
in patient-reported symptoms. Sham surgical procedures/treatments involve more risk
than the placebo control arm in drug trials and should be used in limited circumstances.
This study design should only be considered when it is methodologically necessary, i.e.
when designs that are unblinded are methodologically unacceptable (e.g., because
endpoints are subjective) and when a “no treatment” control is methodologicallyrequired. Furthermore, the withholding of treatment should not lead to serious harm,such as death or irreversible morbidity. FDA recognizes that it may be difficult forsponsors to develop a clinical study design with a sham control arm that investigators,
institutional review boards, and patients believe is ethical; for this reason, studies
involving a sham control arm should be carefully considered and planned. Additionally,
if a sham procedure/treatment is being considered in a clinical investigation involving
children, the requirements of 21 CFR Part 50 Subpart D (Subpart D) also apply.
We recommend that, for most studies, randomized controls be used such that the control
group populations have lesions that are similar to the experimental group in terms of
depth, size, and extent of cartilage/bone damage.
C.

Patient Population

We recommend you prespecify the following patient selection characteristics within astudy protocol’s eligibility criteria:
•
•
•
•
•
•
•
•

degree of pain;
presence or absence of osteoarthritis and method of diagnosis of osteoarthritis;
minimum and/or maximum degree of physical function;
location of articular lesion (e.g., medial femoral condyle, lateral femoral condyle);
depth of lesion;
size area of lesion (i.e., in cm2);
concomitant joint pathology (e.g., meniscal tear, ligament tear); andwhether there has been prior treatment for the lesion.

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In defining each of these characteristics, you should select unambiguous definitions,preferably based upon well-accepted evaluation techniques. One acceptable way for
determining subject eligibility by size and extent of the cartilage lesion is through use of
the International Cartilage Rating System (ICRS), as described in the International Knee
Documentation Committee (IKDC) Knee Examination Form-2000. 8 You should provide
a scientific rationale in your study protocol or supportive documents for selecting
minimum values, maximal values, lesion depth, and lesion size. To determine subject
eligibility by clinical parameters such as pain and clinical function we recommend thatyou use an established clinical measurement instrument such as those described in section
VII.D.
D.

Study Endpoints

We recommend that clinical studies assess the endpoints described in this section.
However, the applicability of these endpoints depends on the characteristics of theinvestigational product and its method of administration.
We believe that clinically meaningful endpoints, such as improvement in pain andphysical function, provide the most persuasive evidence of efficacy. Consequently, you
should identify changes in pain and/or physical functioning as the primary endpoint for
confirmatory clinical studies. Examples of measures that may be used to assess these
endpoints include the:
•
•
•
•
•

Knee injury and Osteoarthritis Outcome Score (KOOS);IKDC Subjective Knee Evaluation Form-2000;
Cincinnati Knee Rating System;
Symptom Rating Form; andWestern Ontario and McMaster Universities Osteoarthritis Index (WOMAC).

Depending on the primary abnormality in the target population and other study design
characteristics, we recommend that you use change in knee pain and/or physicalfunctioning as the single primary endpoint in confirmatory studies. If you use a coprimary approach, then statistical success should be met in both endpoints in a mannerthat preserves the overall type 1 error.
Secondary endpoints that may be studied include:•

arthroscopic assessments of changes in the size, location, and grade of cartilage
lesions both before and after debridement, if debridement is intended. One
acceptable method for assessing these endpoints is through use of the ICRS, as
described previously in section VII.C above.

8

This form is contained in the ICRS Cartilage Injury Evaluation Package, available at
http://www.cartilage.org/_files/contentmanagement/ICRS_evaluation.pdf.

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Contains Nonbinding Recommendations
Draft – Not for Implementation•assessment of the physical findings from examination of the knee joint, including:
o
o
o
o
o
o
o

•

both passive and active range of motion
quadriceps muscle strength
presence of patellar subluxation
presence and degree of effusionalignment
presence and degree of crepitus
presence and degree of ligament laxity

arthroscopic evaluation to assess:o the integrity of repaired tissue
o the binding of implanted investigational product to adjacent tissue, including
assessments of stiffness/firmness based upon tissue probing•

histologic evaluation at both short (e.g., six months) and long term (e.g., twoyears) follow-up in a subset of subjects to assess:
o
o
o
o
o
o
o
o

•
•
•

matrix zonal organization
cell density
cell morphology (i.e., chondrocytic vs. fibroblastic)
type I or type II collagen concentration
Aggrecan concentration, size, and composition
Dermatan sulfate proteoglycan concentration
noncollagenous protein concentrations (fibronectin, tenascin)
inflammatory response

serological assessments for antibody formation and evidence of inflammation.
assessment of synovial fluid samples for cell count, sterility and, as applicable,markers of inflammation and antibody formation.
joint/cartilage structure as assessed by magnetic resonance imaging (MRI), for:
o
o
o
o
o

articular surface integrity
thickness and volume of chondral surface
subchondral bone plate contour
thickness and volume of synovial membranevolume of synovial fluid

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We recommend that the protocol specify which MRI techniques and views will be taken,
and that the images be interpreted by at least two independent (blinded) readers. The
protocol or study supportive documents should include a clear, prospectively stated,
description of the plan for review of these images, and plans for resolving conflicting
readings.
E.

Investigational Product Administration

The clinical protocol and supportive documents must provide a detailed description of theprocedures to be used in administration of the investigational product. See
21 CFR 312.23(a)(6) and 812.25(b). This description is especially critical in multi-centerstudies. We acknowledge that many surgical procedures use techniques common to
standard surgical practice and these procedures can be briefly summarized in thedescription of the investigational product administration procedures. Any uniqueprocedures for administration of the investigational product should be described in detail.
For plans related to any surgical procedures, the clinical protocol should identify andprovide details on the:
•

•

F.

Surgical technique for both the investigational and control treatments, including
the type of anesthesia, the size of the incision, and the use of antibiotics and pain
medications, as applicable. We recommend that the surgical procedures becomparable, as much as possible, between treatment groups.
Plans for post-operative care. Supportive documents should address the use ofcontinuous passive motion; the duration, method, and frequency of weightbearing; the type, dose, and frequency of pain medication used; and the type andfrequency of rehabilitation. These factors should be standardized between/among
treatment groups when possible.
Follow-Up

You should include sufficient follow-up information for all investigational products
within a premarket approval application (PMA) or BLA. For investigational products
which are resorbed, degraded, or remodeled, the study subject follow-up duration should
be based on information gathered from in vivo and in vitro nonclinical studies, as well asfrom information based upon the natural history of the underlying, target clinicalcondition. However, even in this situation, we recommend that the PMA or BLA include
two-year follow-up safety information on a subset of study subjects (this subset of
subjects could be from initial, exploratory clinical studies). Data from an extended
follow-up period provides an important component of the information to be contained
within product labeling. Therefore, the subjects enrolled in initial or exploratory studies
should continue to be followed during the period of confirmatory studies so that you
ultimately provide some long-term follow-up information from these initial studies. For
reference, guidance on the length of follow-up for gene therapy products is available in14

Contains Nonbinding Recommendations
Draft – Not for Implementation
the “Guidance for Industry: Gene Therapy Clinical Trials - Observing Participantsfor Delayed Adverse Events” (Ref. 10).
For investigational products which are not reabsorbed or degraded, a longer duration ofpatient follow-up is recommended to document safety outcomes. In this situation,
generally five years of patient follow-up is recommended. This may be initiated during
the pre-market phase and continued post-market.
Adverse Event (Risk) Reporting

G.

This section concerns adverse event (AE) reporting by the investigator(s) to you. See
21 CFR 312.64 and 812.150(a)(1). 9 When an investigator reports AEs to you, theinvestigator should stratify the AEs by those general to any surgery, those related to knee
surgeries (open vs. arthroscopic), and those specific to the investigational product. We
recommend that you incorporate definitions or descriptions of known or anticipated AEs
into the case report forms (CRFs) to ensure uniform reporting. You should also state in the
protocol and CRFs that all subsequent surgical interventions, investigational productrelated or not, should be reported and recorded.
We define subsequent surgical interventions as follows:•••

Revision - a procedure that adjusts or in any way modifies or removes part of theoriginal investigational product, with or without replacement of a component; it
may include adjusting the position of the original investigational product. If theinvestigational product is used/implanted in conjunction with an FDA approved
product/component, a revision to any component, even to the approved
component, should be reported as a revision.
Removal - a procedure where all or part of the original investigational product isremoved with or without replacement.
Reoperation - any subsequent surgical procedure at the involved surgery site that
does not involve removal, modification, or addition of any component(s) to the
product.

9

For requirements regarding adverse event reporting by the sponsors to FDA, see 21 CFR 312.32 and812.150(b)(1).

15

Contains Nonbinding Recommendations
Draft – Not for Implementation
VIII. REFERENCES
1. Guidance on Applications for Products Comprised of Living Autologous Cells Manipulated ex vivo
and Intended for Structural Repair or Reconstruction, May 1996(http://www.fda.gov/cber/gdlns/gdexv.pdf).
2. Cellular, Tissue, and Gene Therapies Advisory Committee meeting, March 3, 2005
(http://www.fda.gov/ohrms/dockets/ac/05/transcripts/2005-4093T1.htm); March 4, 2005
(http://www.fda.gov/ohrms/dockets/ac/05/transcripts/2005-4093T2_01.htm).
3. Guidance for Industry: A Suggested Approach to Resolving Least Burdensome Issues, September
2000 (http://www.fda.gov/cdrh/ode/guidance/1188.html).
4. Updated 510(k) Sterility Review Guidance K90-1; Final Guidance for Industry and FDA, August
2002 (http://www.fda.gov/cdrh/ode/guidance/361.html).
5. Guidance for Industry: Guidance for Human Somatic Cell Therapy and Gene Therapy, March 1998
(http://www.fda.gov/cber/gdlns/somgene.pdf).
6. Draft Guidance for Reviewers: Instructions and Template for Chemistry, Manufacturing, andControl (CMC) Reviewers of Human Somatic Cell Therapy Investigational New Drug Applications(INDs), August 2003 (http://www.fda.gov/cber/gdlns/cmcsomcell.pdf).*
7. Draft Guidance for FDA Review Staff and Sponsors: Content and Review of Chemistry,
Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New
Drug Applications (INDs), November 2004 (http://www.fda.gov/cber/gdlns/gtindcmc.pdf).*
8. Guidance on Use of International Standard ISO-10993, “Biological Evaluation of Medical Devices
Part 1: Evaluation and Testing,” May 1995 (http://www.fda.gov/cdrh/g951.html).
9. Guidance for Industry: E10 Choice of Control Group and Related Issues in Clinical Trials, May
2001 (http://www.fda.gov/cber/gdlns/clincontr0501.htm).**10. Guidance for Industry: Gene Therapy Clinical Trials – Observing Participants for Delayed
Adverse Events, November 2006 (http://www.fda.gov/cber/gdlns/gtclin.pdf).
*These draft guidances, when finalized, will represent FDA’s current thinking on their respective topics.
**International Conference on Harmonization document.

16

European Medicines Agency

London, 17th September 2009
Doc. Ref. EMEA/CAT/CPWP/288934/2009

1
2
3
4
5

COMMITTEE FOR ADVANCED THERAPIES
(CAT)

6

DRAFT for External Consultation

7

8

REFLECTION PAPER ON

910

IN-VITRO CULTURED CHONDROCYTE CONTAINING PRODUCTS FOR CARTILAGE
REPAIR OF THE KNEEDRAFT AGREED BY CPWP

July – September 2009

DRAFT AGREED BY CAT

July - September 2009

DRAFT DISCUSSED BY BWP, EWP, SWP, SAWP

September 2009

ADOPTION BY CAT FOR RELEASE FOR CONSULTATION

11 September 2009

END OF CONSULTATION (DEADLINE FOR COMMENTS)

31 December 20091

AGREED BY <WORKING PARTY>2
ADOPTION BY CAT<month year><day month year> 3

11
Comments should be provided using this template to AdvancedTherapies@emea.europa.eu
12
KEYWORDS

Chondrocytes, Cell therapy, autologous, Advanced Therapies, Cartilage repair,
Quality, Nonclinical, Clinical13

1

Last day of the month concerned
If other WPs have been involved in discussions this needs to be specified
3
Last day of relevant Committee meeting2

7 Westferry Circus, Canary Wharf, London, E14 4HB, UK
Tel. (44-20) 74 18 84 00 Fax (44-20) 75 23 70 51
E-mail: mail@emea.europa.eu http://www.emea.europa.eu© European Medicines Agency, 2009. Reproduction is authorised provided the source is acknowledged

13

14

REFLECTION PAPER ON

15
16

IN-VITRO CULTURED CHONDROCYTE CONTAINING PRODUCTS FOR CARTILAGE
REPAIR OF THE KNEE17

TABLE OF CONTENTS

18

1.

INTRODUCTION ......................................................................................................................... 3

19

2.

DISCUSSION................................................................................................................................. 3

20

3.

CONCLUSION.............................................................................................................................. 821

4.

REFERENCES .............................................................................................................................. 822
23©EMEA 2009

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23
24

1.

INTRODUCTION (background)

25
26
27
28

This reflection paper addresses specific points related to products containing autologous chondrocytes
intended for the repair of lesion of cartilage of the knee not discussed in the ‘Guideline on human cellbased medicinal products’ (EMEA/CHMP/410869/2006) and therefore it should be read in
conjunction with the guideline.

29
30

2.

DISCUSSION

31
32

CONSIDERATIONS ON QUALITY DATA

33
34
35

For novel products as well as for products with clinical experience gathered before entry into force ofReg. No. (EC) 1394/2007 the same level of quality is expected for a central marketing authorisation
application.

36
37

Starting material

38
39
40
41
42
43

The active substance is based on chondrocytes obtained from a cartilage biopsy. Due todedifferentiation tendency of the chondrocytes when cultured in monolayer, the yield in cell number islimited by the size of the biopsy and will limit the size of the defect that can be treated with theresulting product. Therefore specific consideration should be given to the amount and quality of thestarting material to ensure that sufficient cell numbers can be produced for the presented defect to betreated.

44
45
46
47

The collection of the cartilage biopsy should be standardised in order to minimise possible
contaminants (fibroblasts) arising from fragments of the synovial membrane. The presence / absenceof fibroblasts should be controlled through appropriate in-process testing. Acceptance criteria in
relation to cellular impurities should be set through process validation.

48

Manufacturing process

49
50
51
52

The total number of cells to return to differentiated state depends on the number of duplication inmonolayer culture, thereby limiting the overall expansion of the biopsy. Therefore adequate limits topopulation doubling / passage number should be set considering appropriate functional markers
related to the differentiation stage and the resulting cartilage forming capacity of the cells.

53
54
55

In cases where a 3-dimensional cell culture process in combination with a structural component isused, attention should be paid to the functionality and number of cells in the combination product, andnot only of the cell suspension.

56
57
58

Process validation is a prerequisite to ensure consistent manufacture. Given the limitations related tothe cellular material available (especially for autologous products) for process validation, alternative
material with comparable characteristics could be used e.g. collected from joint replacement surgery.

59

Potency

60
61
62
63
64

Two main aspects for the biological characterisation and control of chondrocytes containing products
are the cartilage forming capacity and stage of differentiation of the cells. Potency can be expressed
through (a) functional assay(s) established for characterisation of the product and for processvalidation. The functional assay is expected to be suitable to detect changes in the product in relation
to the aspects described above which may be clinically meaningful.

©EMEA 2009

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65
66
67

Due to time constraints, for batch release, an assay based on surrogate marker(s) could be envisaged.
In case mRNA based assays or other surrogate markers are used, their correlation with a functional
assay is expected.

68

Quality controls

69
70
71

Biocompatibility of all materials coming into contact with the cells should be demonstrated. This
includes not only materials used during the manufacturing process, but also those used as part of theapplication (e.g. membranes for local containment, fibrin glues).

72
73

CONSIDERATIONS ON NON-CLINICAL DATA

74
75
76
77
78
79
80
81

Clinical experience gathered prior to entry into force of Reg. No. (EC) 1394/2007 can be consideredon a case-by-case basis. Clinical experience might substitute for some parts of the non-clinicaldevelopment. However, the acceptability of such approach will clearly depend on the quality of thedata that have been collected. Such approaches have to be justified by the Applicant and are at the
Applicant’s risk. Of high importance are, as part of such justification, what changes have been made to
the manufacturing process over time, and what impact these had, i.e. it needs to be justified that thedata submitted to substitute for non-clinical data are indeed relevant to the product which is appliedfor. In any case, justification for the omission of any non-clinical analyses has to be provided[0].

8283Pharmacology

84
85
86
87
88

Initial proof of principle studies could be initiated with the use of in vitro cell culture methods such as
3-dimensional cell culture models (i.e. Pellet culture model, 3-dimensional alginate cell culture).
Attention should be paid to use of the final product in the proof of principle animal studies. This
includes the use of the proposed cell-device combination and other non-cellular components (e.g.
membranes, fibrin glues), where appropriate.

89
90
91
92
93

First in vivo proof of principle studies can be conducted in small animal models where, usually, data
can be generated relatively quickly with a larger sample size. An example could be the ECFA model,
in which human chondrocytes are implanted ectopically in immuno-compromised animals. However,such models have limitations, e.g. the different anatomical structure of the knee joint, or difficulties ofmanipulation and mimicking the clinical use.

94
95
96
97
98

As immuno-compromised large animal models are not available it is recommended to use autologous
animal cells. The pivotal non-clinical study should be conducted in a large animal model to mimic asmuch as possible the situation in humans and to allow for more invasive testing than possible inhumans. Currently the best available large animal models are goat, horse or sheep. Mouse models will
normally not be sufficient as a proof of concept. Deviation from these principles should be justified.

99
100
101
102

The pivotal non-clinical studies should be long enough to show regeneration and repair and to obtainenough evidence for a long term clinical use in humans. These studies could include testing forbiomechanical properties and tissue integrity (morphological characteristics of the cartilage). The
number of animals in these studies should allow robust analysis of the data.

103
104

The quality of animal cells should be comparable to the medicinal product for clinical use. The impact
of deviations in the manufacturing process used for the animal cells on quality should be justified.

105

Biodistribution

106
107
108
109
110

Biodistribution studies in a relevant animal model are considered necessary in cases where the productmight not be sufficiently physically retained, e.g. by a membrane and/or when a scaffold is not applied
together with a physical barrier. In any case, potential biodistribution can be of clinical concern, andthus the Applicant should justify their approach to show absence or lack of clinical significance of any
untoward safety issue related to biodistribution.

111

Toxicology

112
113

The necessity of conventional toxicity studies depends on the nature of the product and should follow
a risk-based approach.
©EMEA 2009

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114
115

Conventional toxicity studies may not be required for autologous chondrocyte products; safety
endpoints may be incorporated into proof of concept studies in justified cases.

116
117

CONSIDERATIONS ON CLINICAL DATA

118

Potential claims.

119
120
121
122
123
124
125
126

The principal aim for autologous chondrocytes containing product is to repair cartilaginous defects
either from traumatic damage or degenerative disease. The indication could be further defined byrelevant components, particularly, number of defects treated (multiple or single defect), size of defect,
localisation of the defect (such as femoral condyle or trochlea), symptomatic or asymptomatic defect,
grading of the defect (such as ICRS score), and previous failed therapies (such as after failed previous
therapeutic or surgical intervention). Due to different aetiologies of the lesions, separate safety andefficacy studies would be appropriate. For claims of the product as second line treatment, special
attention should be paid to the characteristics of the previously treated lesion.

127

Subject characteristics and selection of subjects.

128
129
130
131
132

The patient population included in the studies should be selected by relevant criteria like symptoms,
functionality, localisation, size and depth of the knee defect(s), concomitant joint pathology(ies), andprevious treatments of the defect. Restriction of target population may increase precision of study(such as excluding patients with previous mosaicplasty, advanced osteoarthritis etc.) but also could
diminish generalisation or benefit of the results (such as limiting the defect size).

133

Strategy and design of clinical trials.

134

A. Clinical Pharmacology.

135
136
137
138
139

Pharmacokinetics. As there is no clear common agreement for conventional clinical kinetic dataneeded to be analysed in clinical setting, the majority of the issues regarding clinical pharmacology
are expected to be addressed during the non-clinical phase. If non-cellular component are present,
their combination with cells is expected to be assessed clinically for compatibility, degradation rate
and functionality.

140
141
142
143
144
145

Pharmacodynamics. Macroscopic, histological and MRI assessment of the repair tissue areconsidered adequate tools for pharmacodynamic assessment of autologous chondrocytes containing
products. MRI is to date, considered clinically relevant and could be included in trial protocols,
although it is acknowledged that it is not validated as such in the follow up of the repair tissue.
Validation of MRI in a large animal (such as horse or sheep) with histopathological investigations
might yield supportive data to surmount the clinical database (see non-clinical section).

146

B. Exploratory trials.

147
148
149
150
151
152
153

The dose definition should be carefully chosen reflecting both actual numbers of the cells engrafted
and adjustments for particular defect sizes (e.g. expressed in minimal number of cells/cm2). Parallelgroup, randomised, controlled studies are recommended, where comparative agent could be similar tothe one used for confirmatory study and concomitant therapy could be a perisurgical, therapeutic,
rehabilitation together with a follow up regimen acceptable from clinical perspective. The study
duration is expected to be not less than 2 years for clinical endpoints and not less than 1 year for
structural endpoints.

154
155

The published data from other relevant studies could be supportive for dose definition, provided thatthe quality of the product is comparable.

156
157

Dose definition could be justified also by unequivocally observed effect size (e.g. more the 10 pointchange in a KOOS subscale) and sufficient safety database.
©EMEA 2009

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158
159
160
161

Depending on the amount and quality of clinical data gathered before entry into force of Reg No. (EC)1394/2007 exploratory studies might not be required. Justification for the omission of exploratory
studies should be provided, including evidence that in case of changes in the manufacturing process
over time these do not affect the clinical development program.

162
163

The clinical data should be sufficient to justify the administration procedure and the design of theconfirmatory studies.

164

Exploratory clinical trial endpoints should be suitable to address pharmacodynamics, dose and safety.
C. Confirmatory trials.

165
166

Methods to assess efficacy.

167
168
169
170
171
172

Definition of the primary endpoints. Patient-based outcome data is acceptable as primary endpoint in
the pivotal study, given the current lack of other outcome measures that are both sensitive andobjective. For patient-based outcomes, validated methods to assess improvement of function and pain
should be used (e.g. knee injury and Osteoarthritis Outcome Score (KOOS) or other validated
outcome measures). Other primary endpoints, including either treatment failure or total joint
replacement can be used, however these should be validated methods.

173
174
175
176
177
178

Definition of secondary endpoints. The structural improvement is the main secondary endpoints. The
suitable structural endpoints could be chosen from blinded standardised MRI with/or without
histological evaluations. Until validated methods are available, it is the Applicant’s responsibility todemonstrate that the method is qualified for its intended use. Structural endpoint could also serve as arelevant supportive surrogate marker for benefit risk assessment in case of need for long-term efficacy
that could be performed post-marketing.

179
180
181
182

Other specific secondary endpoints could be used e.g. the ones representing clinical / functional
assessments (such as IKDC subjective scale, Lysholm score, ICRS objective scale, physical findings
for the knee) or the ones representing structural assessments (such as arthroscopic and X-ray
assessments).

183

Trial design

184
185
186

For patients with lesions of less than 4 cm2 clinical non-inferiority/superiority with supporting
structural superiority against currently employed reasonable surgical comparative therapy (such as
microfracture) is the reasonable option.

187
188
189

For patients with lesions of more than 4 cm2, no standard therapy has shown unequivocal efficacy,
therefore superiority against best standard of care is the reasonable option. Medicinal product without
centralised authorisation would not be a valid comparator.

190
191
192

For the confirmatory trials and due to the nature of the product, blinding of the trial design may bedifficult to be maintained. For these trials prospective randomised, open label, blinded evaluation isrecommended.

193

Various options can be considered for the design of confirmatory trials, e.g.

194
195
196

-

A randomized controlled trial including microfracture as comparator. In this case theappropriateness of the microfracture procedure with respect to the lesion size to be treated needs
to be addressed, since microfracture is only recommended in smaller lesions.

197
198
199

-

A randomized controlled trial including an active comparator. If a licensed chondrocytecontaining product that has been validated in a randomized controlled trial is used as comparator,
a non-inferiority design may be considered.

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200
201
202
203

-

A randomized controlled trial including a standardized exercise program as control arm. The
standardized exercise program should be suitable to stabilize muscle function and could beviewed as an active placebo control. The design should consider a switch of patients from active
placebo to the verum arm according to predefined criteria.

204-

Any other clinical trial design, when appropriately justified.

205
206
207
208

For larger lesions, where there is no established treatment available, a dose response assessment isdesirable. This could be done by including the assessment of the dose-response relationship in theconfirmatory study, whereby the dose (of chondrocytes) per size (cm2) of the defect would be added
as a covariate.

209
210
211
212
213

Study duration. A 3 year follow-up for clinical efficacy evaluation is normally necessary. However,for registration purposes, structural repair by histological / MRI analysis could be acceptable at earlier
evaluation timepoints, where appropriately justified. The follow-up period for clinical efficacy could
be envisaged post-authorisation (Efficacy follow-up within Art. 14 of Reg. (EC) 1394/2007) provided
positive benefit risk profile is obtained.

214

D. Methodological considerations

215
216
217
218
219
220
221
222
223

Numerous procedures and treatment related risk factors are emerging and include: (1) Patient factors,
especially size of the defect. Other reasonable patient factors to be considered are BMI, gender, age,sports activity, and defect localisation; (2) Variability due to other therapies, such as variability ofsurgical procedures among different centres and surgeons (standardised surgical protocols should bedone); symptomatic treatment allowed (both as pre-procedurally or peri-procedurally prior the
implantation), peri-surgical procedures (such as arthroscopy or open surgery procedures prior the
implantation), rehabilitation protocols and the follow-up programs are reasonable to be considered.
These considerations demonstrate that a standardized approach might be valuable in order to reduce
variability between study arms that could render interpretation of data difficult.

224
225
226

At best the most important factors should be identified beforehand and be taken into consideration byproper stratification of the randomisation and/or inclusion of these factors into the analysis model byprospectively planned subgroup analyses.

227

Clinical safety evaluation

228
229
230
231

General safety issues. The autologous chondrocytes-containing products have been used for more then
15 years in clinical practice and the experience for this class of products is relevant and has to beconsidered. For the safety assessment, the clinical program could consider results of quality and nonclinical investigations as well as unresolved issues that could not have been assessed non-clinically.

232
233
234

For products for which clinical data has been gathered before entry into force of Reg No. (EC)1394/2007, the acceptability of safety data will depend on the quality of the data and their collection
over the years.

235
236
237
238
239

Specific safety issues. Special attention has to be paid on long-term structural changes, such as local
histological or MRI detectable changes, rates of treatment failures, as defined through relevant
investigation techniques, including re-operation for revision purposes. In cases of treatment failure, aroot-cause analysis should be performed in order to identify the factors, which gave rise to treatment
failure (i.e. quality of the product, surgical procedure, patient characteristics).

240©EMEA 2009

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240
241

3.

CONCLUSION

242

4.

REFERENCES

243

Guideline on human cell-based medicinal products (EMEA/CHMP/410869/2006).

244
245
246

Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007
on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No
726/2004 (OJ L 324 of 10.12.2007, p 121)

©EMEA 2009

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ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS

1

1.

NAME OF THE MEDICINAL PRODUCTChondroCelect 10,000 cells/microlitre implantation suspension

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

2.1

General description

Characterised viable autologous cartilage cells expanded ex vivo expressing specific marker proteins.
2.2

Qualitative and quantitative composition

Each vial of product contains 4 million autologous human cartilage cells in 0.4 ml cell suspension,corresponding to a concentration of 10,000 cells/microlitre.
For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Implantation suspension
Before re-suspension the cells are settled to the bottom of the container forming an off-white layer andthe excipient is a clear colourless liquid.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Repair of single symptomatic cartilage defects of the femoral condyle of the knee (International
Cartilage Repair Society [ICRS] grade III or IV) in adults. Concomitant asymptomatic cartilage
lesions (ICRS grade I or II) might be present. Demonstration of efficacy is based on a randomised
controlled trial evaluating the efficacy of Chondrocelect in patients with lesions between 1-5cm².
4.2

Posology and method of administration

ChondroCelect must be administered by an appropriately qualified surgeon and is restricted to hospitaluse only. ChondroCelect is solely intended for autologous use and should be administered inconjunction with debridement (preparation of the defect bed), a physical seal of the lesion (placementof a biological membrane, preferentially a collagen membrane) and rehabilitation.
Posology
The amount of cells to be administered is dependent on the size (surface in cm²) of the cartilage defect.
Each product contains an individual treatment dose with sufficient number of cells to treat the predefined lesion size, as measured at biopsy procurement. The recommended dose of ChondroCelect is
0.8 to 1 million cells/cm², corresponding with 80 to 100 microlitre of product/cm² of defect.
Elderly
Limited data are available on adult patients older than 50 years.
Paediatric population
The safety and efficacy in children and adolescents (aged less than 18) have not been established.
ChondroCelect is therefore not recommended for use in children and adolescents below 18 years.

2

Method of administration
ChondroCelect is intended solely for use in autologous cartilage repair and is administered to patientsin an Autologous Chondrocyte Implantation procedure (ACI).
Implantation of ChondroCelect is to be performed during arthrotomy under sterile conditions andrequires both preparation of the defect bed and a seal (biological membrane) to secure the implant.
Complete joint haemostasis must be achieved prior to membrane fixation and cell implantation. In
clinical studies with ChondroCelect a periosteal flap was used as a biological membrane. Scientificpublications have shown that commercially available collagen membranes can be used as analternative to the periost in ACI procedures. However, ChondroCelect has not been evaluated in
combination with collagen membranes in clinical studies, although a commercially available collagenmembrane has been used in patients treated with ChondroCelect under compassionate use. The safety
data obtained in these patients do not indicate a particular safety concern, and confirm a lower
incidence of hypertrophy as suggested by scientific literature on the use of collagen membranes versus
periost.
The implantation should be followed by an appropriate rehabilitation schedule for approximately one
year, as recommended by the physician (see section 4.4).
Full technical details on the procedures associated with this implantation technique are provided in the
ChondroCelect user manual.
For information on preparation and handling of ChondroCelect, please refer to section 6.6.
4.3

Contraindications

Hypersensitivity to any of the excipients or to bovine serum.
ChondroCelect must not be used in case of advanced osteoarthritis of the knee.
4.4

Special warnings and precautions for use

GeneralChondroCelect is an autologous product and should under no circumstances be administered to other
patients.
Patients with acute or recent history of bone or joint infections should be temporary deferred until
documented recovery.
Precautions for use
Concomitant knee problems like early osteoarthritis, osteochondritis dissecans (OCD), instability of
the knee, cartilage lesions at other locations than the femoral condyle, lesions of knee ligaments or of
the meniscus, varus or valgus malalignment (abnormal weight distribution in the knee), andinflammatory joint disease are potential complicating factors. In the pivotal study of ChondroCelect,patients with these comorbidities of the knee were excluded from treatment. Where possible,
concomitant knee problems should be corrected prior to or at the latest at the time of ChondroCelectimplantation.
In the pivotal study there was no influence of Body Mass Index (BMI) on outcome but bibliographic
data shows that a BMI over 30 may also adversely affect the success of the procedure.
Rehabilitation
Upon implantation, the patient should follow an appropriate rehabilitation schedule and physicalactivity should be resumed as recommended by the physician. Depending on the location, the size ofthe lesion and the patient’s profile, appropriate rehabilitation instructions have been developed. Too
early and vigorous activity may compromise the grafting and the durability of clinical benefit from
ChondroCelect. Therefore the treated knee should be protected according to the recommendations as
outlined in the appropriate rehabilitation schedule, to avoid early damage which might lead to graft
failure.
Details and information on the appropriate rehabilitation schedule is provided in the ChondroCelectuser manual.
3Cases in which ChondroCelect cannot be supplied
In some cases it can be possible that the source chondrocytes of the patient are not expandable or thatthe release criteria are not met, due to poor biopsy quality, patient characteristics, or manufacturing
failure. Therefore it can occur that ChondroCelect cannot be delivered. The surgeon will be informed
as early in the process as possible, and should hence select an alternative treatment for the patientconcerned.
4.5Interaction with other medicinal products and other forms of interaction

Fibrin glues are routinely used in ACI procedures to seal the outside margins and to improve thewater-tightness of the compartment of the biological membrane used to cover the defect. Fibrin sealantproducts differ significantly in their quantitative and qualitative composition. In vitro interaction
studies were performed with a commercially available fibrin glue containing aprotinin (a fibrinolysis
inhibitor of bovine origin). . These studies have demonstrated that this type of fibrin sealant can besafely used with ChondroCelect. No interaction studies with any other type of fibrin glues were
performed. However, the concomitant use of another type of fibrin glue with a synthetic fibrinolysis
inhibitor (tranexamic acid) in the pivotal clinical trial did not reveal any safety signal.
Pain medicinal products should be used according to the recommendations of the responsible surgeon.
4.6

Pregnancy and lactation

For autologous cartilage cells no clinical data on exposed pregnancies are available.
Conventional reproductive and developmental toxicity studies are not considered relevant, given thenature and the intended clinical use of the autologous cell therapy product.
As ChondroCelect is used to repair a cartilage defect of the knee and is implanted with the ACI
procedure using open-knee surgery, it is not recommended for pregnant or breast-feeding women.
4.7

Effects on ability to drive and use machines

Due to the surgical nature of the underlying procedure, implantation with ChondroCelect has a major
influence on the ability to drive and use machines. During the rehabilitation period that follows
treatment with ChondroCelect, patients should refer to their treating physician and follow their advice
strictly.
Driving cars and using machines may be limited during the rehabilitation period.
4.8

Undesirable effects

In a randomized, controlled study in the target population, 51 patients were treated with
ChondroCelect. In these patients, a periosteal flap was used to secure the implant.
Adverse reactions occurred in 78.4% of the patients over a 36-months postoperative follow-up period.
The most common adverse reactions were arthralgia (47.1%), cartilage hypertrophy (27.4%), joint
crepitation (17.6%) and joint swelling (13.7%). Adverse reactions collected from 370 patients
included in a Compassionate Use Program are similar to those reported in the target population.
Most of the reported adverse reactions were expected as related to the open-knee surgical procedure.
The most frequently occurring reactions reported immediately after surgery include joint swelling,arthralgia and pyrexia. These were generally mild and disappeared in the weeks following surgery.
Adverse reactions reported in patients implanted with ChondroCelect are provided in the table below.
The following categories are used to rank the undesirable effects by frequency of occurrence: very
common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100). Within eachfrequency grouping, adverse reactions are presented in order of decreasing seriousness.

4System organ class

Very common

CommonUncommon≥1/10≥1/100 to <1/10≥1/1,000 to <1/100

Psychiatric disorders
Nervous systemdisordersAutonomic neuropathy,
Complex regional pain
syndrome,
Pain in extremity,
Peripheral neuropathy,
Syncope,
Trendelenburg’s
symptom
Deep vein thrombosis,
Haematoma,
Superficial phlebitis
ApnoeaVascular disorders

Respiratory, thoracic
and mediastinal
disorders
Gastrointestinal
disordersSkin andsubcutaneous tissue
disorders

Musculoskeletal andconnective tissue
disordersAnxiety
Hyperesthesia,
Migraine,
Photophobia,
Transient ischaemic
attackFat embolism,
Thrombophlebitis
Lung embolism

NauseaWound infection,
Erysipelas,
Erythema,Hypertrophic scar,
Postoperative woundcomplication,
Pruritus,
Scar pain,
Wound dehiscence,
Wound secretion
Arthrofibrosis,
Joint range of motion
decreased,
Joint effusion,
Joint lock,
Arthritis,
Arthropathy,
Bone cyst,
Bone swelling,
Bursitis,
Chondropathy,
Exostosis,
Haemarthrosis,
Joint instability,
Joint stiffness,
Loose body in joint,
Mobility decreased,
Muscle atrophy,
Osteoarthritis,
Synovial cyst,
Synovitis,
Tendon disorder,
Tendonitis

Arthralgia,
Cartilage hypertrophy,
Joint crepitation,
Joint swelling5

Itching scar

Chondromalacia,
Gonarthrosis

System organ class

Very common

CommonUncommon≥1/10≥1/100 to <1/10≥1/1,000 to <1/100

Ineffective therapeutic
product,
Gait disturbance,
Impaired healing,
Implant site
hypersensitivity,
Peripheral edema,
Pyrexia
Arthroscopy
Graft complication,
Graft delamination,
Cartilage injury,
Injury,Joint injury,
Procedural site reaction

Atrophy,
Discomfort,
Granulomatous lesion

General disorders andadministration site
conditions

Investigations
Injury, poisoning andprocedural
complications

Adverse reactions of special interest
Arthrofibrosis
In the compassionate use patients, a higher incidence of arthrofibrosis and decreased joint range of
motion was observed in a subgroup of patients with a patellar lesion (8.2% and 13.1% respectively)
compared to non-patellar lesions (0.6% and 2.6% respectively).
Cartilage hypertrophy
In the majority of the 370 patients included in the Compassionate Use Program, a collagen membrane
instead of a periosteal flap was used to seal the defect. According to current literature the incidence of
cartilage hypertrophy can be reduced by using a collagen membrane to cover the lesion site instead ofusing a periosteal flap (Gooding et al., 2006; Niemeyer et al., 2008). When a collagen membrane wasused to seal the lesion site after application of ChondroCelect, the incidence of cartilage hypertrophy
was reported to be 1.8% compared to 25% in the randomized, controlled trial alone.
4.9

Overdose

No case of overdose has been reported.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: {group}, ATC code: {code} <not yet assigned>
Conventional pharmacodynamic studies for ChondroCelect have not been performed.
Clinical efficacy
The efficacy of ChondroCelect was studied in a phase III, multicenter, randomized, controlled trial(TIG/ACT/01/2000) and the first two years of its 4-years extension phase (TIG/ACT/01/2000EXT).
ChondroCelect was compared to the procedure of microfracture in the repair of symptomatic single
cartilage lesions of the femoral condyles of the knee. 51 patients were treated with ChondroCelect, 61
patients were treated with microfracture. Patients aged between 18 and 50 years, who had a single
symptomatic cartilage lesion between 1 and 5 cm2 of the femoral condyles met the inclusion criteria.
Patients could be treatment-naïve or might have undergone previous arthroscopic or other surgicalrepair procedure(s). Patients with patellofemoral cartilage lesion, OCD, depth of lesion >0.5 cm, priormeniscal transplant, prior mosaicplasty and prior microfracture within the last 12 month were6

excluded. Patients had to agree to actively participate in a strict rehabilitation protocol and follow-up
program.
The median time since onset of knee injury was slightly longer in the ChondroCelect group than in the
microfracture group (2.0 years versus 1.6 years). More patients in the ChondroCelect treatment group,compared to patients in the microfracture group, had undergone previous knee surgery (88% versus77%). In the ChondroCelect group 77% of patients had a medial and 23% a lateral condyle defect.
Histological examination of the repair biopsy at 12 months showed superior structural repair in the
ChondroCelect arm compared to the microfracture arm. There was continuous improvement up to 36
months in the clinical outcome measure KOOS (the Knee Injury and Osteoarthritis Outcome Score) inboth treatment arms. The estimated benefit was larger in the ChondroCelect group but the results did
not reach statistical significance. At this time point 41 patients were evaluated in the ChondroCelectarm and 49 were evaluated in the microfracture arm. Patients with less than 3 years since onset ofsymptoms (n=27 in the ChondroCelect arm and n=32 in the microfracture arm) benefited most from
ChondroCelect. For the group with a longer time since onset of symptoms there were no apparent
differences between the 2 groups. Re-intervention on the treated lesion for graft delamination or
periost loosening occurred in 2 of 51 patients within 36 months after ChondroCelect implantation,compared to 7 of 61 patients treated with microfracture having generally insufficient or inadequate
cartilage repair.
Patients with lesions larger than 5 cm² have been treated under compassionate use only. The safety
data obtained in these patients do not indicate a particular safety concern. Further clinical data inpatients with larger lesions are foreseen to be collected in the future.
Sixteen patients below 18 years have been treated with ChondroCelect under compassionate use. No
specific safety signal was detected in these patients. If, based on the benefit/risk assessment of the
responsible surgeon treatment of patients below 18 years is considered, special attention should begiven to ensure that the growth plate is completely closed.
5.2

Pharmacokinetic properties

The product is implanted locally.
The nature and intended clinical use of ChondroCelect are such that conventional studies on
pharmacokinetics, absorption, distribution, metabolism and elimination are not applicable.
5.3

Preclinical safety dataNon-clinical data based on implantation of expanded cartilage cells in goats and mice did not reveal
special hazard for humans.
In studies in goats, mild signs of synovitis were observed in the majority of the animals, including
controls at 10 weeks post surgery. Inflammation resolved with time and parameters returned tobaseline levels with only some very mild and local signs of synovitis remaining in a few animals.
Although it is thought that these reactions are mostly surgery-related, a potential influence of the
expanded chondrocytes can not be completely excluded.
In a study in sheep, the majority of animals showed penetration of the transplanted cells insubchondral bone; in two of these cases complete penetration of underlying bone marrow wasobserved. This finding might be related to the inability to perform a progressive loading under nonweight bearing conditions post-surgery in these models and therefore cannot be fully extrapolated assuch to the human situation.

7

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Dulbecco’s Modified Eagles Medium (DMEM) (containing amino acids, vitamins, salts andcarbohydrates).
6.2

Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal
products.
6.3

Shelf life

48 hours.
6.4

Special precautions for storage

Store between 15°C – 25°C.
Do not refrigerate or freeze.
Keep the product vial(s) within the falcon tube in the outer plastic screw top container in order toprotect from light and bacterial/fungal contamination.
Do not irradiate.
6.5

Nature and contents of container and special equipment for use, administration or
implantation

ChondroCelect is supplied as one individual treatment dose (falcon tube) contained in 1 to 3 Type I
glass vials of 1 ml. Each vial contains 0.4 ml of autologous human cartilage cells suspension and isclosed with a chlorobutyl stopper and aluminium seal.
The vials are placed in a sterile falcon tube with a plastic screw top.
The falcon tube is placed in a plastic screw top container together with surgery materials (one sterile
syringe of 1 ml, one 18G intravenous catheter and two pieces of Vicryl 6.0) and a temperaturemonitor.
6.6

Special precautions for disposal and other handling

ChondroCelect is intended solely for autologous use. Prior to implantation match the patient name tothe patient/donor identification on the shipment documentation and product vial.
Before administration, ChondroCelect should be resuspended by gently tapping the vial to bring thecells back into suspension.
ChondroCelect should not be sterilised. If the ChondroCelect vial is damaged or its sterility has been
compromised, the product must not be used and must be shipped back to TiGenix.
Any unused product or waste material should be disposed of in accordance with local requirements.

7.

MARKETING AUTHORISATION HOLDER

TiGenix NV
Romeinse straat 12/2
B-3001 LEUVEN
Belgium8

8.

MARKETING AUTHORISATION NUMBER(S)9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10.

DATE OF REVISION OF THE TEXT

Detailed information on this product is available on the website of the European Medicines Agency(EMEA) http://www.emea.europa.eu

9ANNEX IIA.

MANUFACTURER OF THE BIOLOGICAL ACTIVE
SUBSTANCE AND MANUFACTURING AUTHORISATIONHOLDER RESPONSIBLE FOR BATCH RELEASE

B.

CONDITIONS OF THE MARKETING AUTHORISATION

10

A.

MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE

Name and address of the manufacturer(s) of the biological active substance(s)TiGenix NV
c/o U.Z. Gasthuisberg
Centraal Dienstengebouw, level 2. Herestraat 49
BE-3000 Leuven
Belgium
Name and address of the manufacturer(s) responsible for batch release
TiGenix NV
c/o U.Z. Gasthuisberg
Centraal Dienstengebouw, level 2. Herestraat 49
BE-3000 Leuven
Belgium

B.
•

CONDITIONS OF THE MARKETING AUTHORISATIONCONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON
THE MARKETING AUTHORISATION HOLDER

Medicinal product subject to restricted medical prescription (See Annex I: Summary of ProductCharacteristics, section 4.2).
The Marketing Authorisation Holder (MAH) shall ensure that the medicinal product will be distributed
only to Healthcare Establishments that meet criteria described in the Risk Management Plan.
•

CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCTThe Marketing Authorisation Holder (MAH) shall ensure, prior to the distribution of the product to aparticular Healthcare Establishment, that all surgeons and other healthcare professionals involved in
the handling and administration of ChondroCelect or its components, as well as those involved infollow-up of patients treated with ChondroCelect in the Healthcare Establishment, receive training as
per the educational programme described in the Risk Management Plan.
The educational programme for healthcare professionals contains the following components:• Training material for Surgeons• Training material for other Healthcare Professionals• Informed consent for the patients to be signed prior to the treatment with ChondroCelectThe training materials for Surgeons shall include the following key messages and components:• Summary of Product Characteristics• The biopsy harvest procedure• The surgical checklist to be completed at the operating theatre immediately prior to the firstincision confirming the right patient, the right product, the right side of the implantation, andthe type of biological membrane and fibrin sealant to be used in the procedure.
• The implantation procedure by knee-joint arthrotomy• The follow-up protocol

11

The training material for other Healthcare Professionals shall include the following key messages andcomponents:• Summary of Product Characteristics• The need for screening of donors using patient questionnaire and laboratory tests for hepatitis C,
hepatitis B, HIV, and Syphilis• The handling of the biopsy harvest• The handling of ChondroCelect and its preparation for the implantation• The schedule of follow-up of patients• The recommended physiotherapy•

OTHER CONDITIONS

Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 1 dated(03/05/2007) presented in Module 1.8.1. of the Marketing Authorisation Application, is in place andfunctioning before and whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional activities detailed in the
Pharmacovigilance Plan and in the Efficacy Follow-up plan, as agreed in version 4 (dated 22/06/2009)of the Risk Management Plan (RMP) presented in Module 1.8.2. of the Marketing Authorisation
Application and any subsequent updates of the RMP agreed by the CAT and the CHMP.
As per the Volume 9A of the Rules Governing Medicinal Products in the EU, the updated RMP should
be submitted at the same time as Periodic Safety Update Reports (PSURs).
In addition, an updated RMP should be submitted• When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan, Efficacy Follow-up Plan or risk minimisation activities• Within 60 days of an important (pharmacovigilance, efficacy, or risk minimisation) milestone
being reached• At the request of the EMEA

12

ANNEX III
LABELLING AND PACKAGE LEAFLET

13

A. LABELLING

14

PARTICULARS TO APPEAR ON THE OUTER PACKAGINGWhite screw top container
1.

NAME OF THE MEDICINAL PRODUCTChondroCelect 10,000 cells/microlitre implantation suspension.
Characterised viable autologous cartilage cells expanded ex vivo expressing specific marker proteins.

2.

STATEMENT OF ACTIVE SUBSTANCE(S)Each vial contains 4 million autologous human cartilage cells in 0.4 ml, corresponding to aconcentration of 10,000 cells/microlitre.

3.

LIST OF EXCIPIENTS

Dulbecco’s Modified Eagles Medium (DMEM).

4.

PHARMACEUTICAL FORM AND CONTENTS

Implantation suspension.
1 falcon tube with 1, 2 or 3 vials (x 0.4 ml)
Vials are supplied with surgery materials (one sterile syringe of 1 ml, one 18G IV catheter and twopieces of Vicryl 6.0 sutures)

5.

METHOD AND ROUTE(S) OF ADMINISTRATION

For implantation.
Read the package leaflet before use.

6.

SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN

Keep out of the reach and sight of children.

7.

OTHER SPECIAL WARNING(S), IF NECESSARY

For autologous use only.
8.

EXPIRY DATE

EXP {DD month YYYY} at {hours} CET

15

9.

SPECIAL STORAGE CONDITIONSStore between 15°C – 25°C.
Do not refrigerate or freeze.
Keep the product vial(s) within the falcon tube in the outer plastic screw top container in order toprotect from light and bacterial/fungal contamination.
Do not expose to radioactive irradiation (X-rays).

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Dispose of in accordance with local requirements.

11.

NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

TiGenix nv, Romeinse straat 12/2, B-3001 Leuven, Belgium
Tel: +32-(0)16 39 60 60
Fax: +32-(0)16 39 60 70
info@tigenix.com

12.

MARKETING AUTHORISATION NUMBER(S)EU/0/00/000/000

13.

BATCH NUMBER, DONATION AND PRODUCT CODES

Lot {lot number}
Patient number (Pt N°) {patient number}
Patient Initials (Pt initials) {patient intitials}

14.

GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15.

INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE
Justification for not including Braille accepted

16

MINIMUM PARTICULARS TO APPEAR ON SMALL INTERMEDIATE PACKAGING
UNITS
Falcon tube

1.

NAME OF THE MEDICINAL PRODUCTChondroCelect 10,000 cells/microlitre implantation suspension.

2.

METHOD OF ADMINISTRATION

3.

EXPIRY DATE

EXP {DD month YYYY} at {hours} CET

4.

BATCH NUMBER, DONATION AND PRODUCT CODES

Lot {lot number}
Pt N° {patient number}
Pt Initials {patient intitials}

5.

CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

1, 2 or 3 vials x 0.4 ml

6.

OTHER

For autologous use only.

17

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
Vial

1.

NAME OF THE MEDICINAL PRODUCTChondroCelect2.

METHOD OF ADMINISTRATION

3.

EXPIRY DATE

EXP {DD month YYYY} at {hours} CET

4.

BATCH NUMBER, DONATION AND PRODUCT CODES

Lot {lot number}
Pt N° {patient number}
Pt Initials {patient intitials}

5.

CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

0.4 ml5.

OTHER

For autologous use only.

18

B. PACKAGE LEAFLET

19

PACKAGE LEAFLET: INFORMATION FOR THE USER

ChondroCelect 10,000 cells/microlitre implantation suspension
Characterised viable autologous cartilage cells expanded ex vivo expressing specific marker proteins

Read all of this leaflet carefully before you start using this medicine.
Keep this leaflet. You may need to read it again.
If you have any further questions, ask your doctor, surgeon or physical therapist.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,please tell your doctor, surgeon or physical therapist.

In this leaflet:
1.
2.
3.
4.
5.
6.

What ChondroCelect is and what it is used for
Before you use ChondroCelectHow to use ChondroCelectPossible side effects
How to store ChondroCelectFurther information

1.

WHAT CHONDROCELECT IS AND WHAT IT IS USED FOR

ChondroCelect consists of autologous cultured cartilage cells. The product is made from a small
sample of cartilage cells (a biopsy) taken from your knee.
• Autologous means that your own cells are used to make ChondroCelect.
• Cartilage is a tissue that is present in every joint. It protects the ends of our bones and allows our
joints to function smoothly.
ChondroCelect is used to repair single symptomatic cartilage defects in the femoral condyle of theknee in adults. A defect can be caused by acute trauma, such as a fall. It can also be caused byrepetitive trauma, such as long-term incorrect weight-bearing on the knee.
•
2.

The femoral condyle is the end of the thigh bone, which forms part of your knee.
BEFORE YOU USE CHONDROCELECT

Do not use ChondroCelectIf you are allergic (hypersensitive) to any of the ingredients of ChondroCelect or to bovine serum
If you suffer from advanced osteoarthritis (degenerative joint disease) in your knee.
Take special care with ChondroCelectIf you have an acute or recent history of bone or joint infections, you should be temporary deferred
until documented recovery.
The use of ChondroCelect is not recommended when you have overweight (i.e. a Body Mass Index
over 30). Your surgeon will give you more information.
ChondroCelect is not recommended for the repair of cartilage defects in other locations than thefemoral condyle.
20

The use of ChondroCelect is not recommended in children and adolescents below 18 years.
Limited data are available on adult patients older than 50 years.
ChondroCelect should be implanted in an otherwise healthy knee. This means that other knee
problems such as lesions of the knee ligament or of the meniscus should be corrected before or during
ChondroCelect implantation.
You should resume physical activity according to the rehabilitation plan recommended by the physicaltherapist. Too early and vigorous activity may compromise the implant and the durability of clinicalbenefit from ChondroCelect.
Your surgeon will give you more information on any special considerations for your particular case.
Other cases in which ChondroCelect cannot be supplied
Even if the surgeon has already taken a small sample of cartilage cells (a biopsy) needed to produce
the product, it is possible that you will not be eligible for treatment with ChondroCelect. This is thecase if the biopsy is of insufficient quality to make ChondroCelect, or in some instances, it may be thecells cannot be grown in the laboratory or that the expanded cells do not meet all the quality
requirements Your surgeon will be informed and might have to select an alternative treatment for you.
Using other medicines
The safe use of ChondroCelect with other medicines has not been studied.
Ask your doctor for more information as to which pain medication you can safely use.
Please tell your doctor or physical therapist if you are taking or have recently taken any othermedicines, including medicines obtained without a prescription.
Pregnancy and breast-feeding
The safe use of ChondroCelect has not been demonstrated during pregnancy or breast-feeding.
ChondroCelect is not recommended for pregnant and breast-feeding women.
Please inform your doctor if you are pregnant or think you may be pregnant.
Driving and using machines
The surgical procedure will have a major influence on your ability to drive and use machines. Drivingcars and using machines may be limited during the rehabilitation period, and the advice of your doctor,
surgeon or physical therapist should be strictly followed during this period.

3.

HOW TO USE CHONDROCELECT

ChondroCelect can only be prescribed and implanted by an orthopaedic surgeon in a hospital.
Treatment with ChondroCelect: a two-step procedure
Visit 1: evaluation of the cartilage defect and biopsy
On the first visit, the surgeon will evaluate your cartilage defect during an exploratory operation(arthroscopy). An arthroscopy is performed through very small incisions in the skin, using a narrow
telescope (arthroscope) to look at the inside of the knee. If the surgeon decides that treatment with
ChondroCelect is appropriate for you, he/she will take a small sample of cartilage cells (a biopsy) fromyour knee. This cartilage sample will be used to make ChondroCelect.
It will take at least four weeks to select and culture the cells to make ChondroCelect.

21

Visit 2: ChondroCelect implantation
During open-knee surgery, the cartilage cells are implanted into the cartilage defect. This is called‘autologous chondrocyte implantation’ (ACI). The purpose is to repair the defect with healthy andfunctional cartilage over time.
To keep the cartilage cells in place, a biological membrane is sewn over the defect.
Rehabilitation
After surgery, you will have to follow a rehabilitation program for approximately one year, to allow
your knee to heal well. Your doctor or physical therapist will give you more details on yourrehabilitation.
It is very important to carefully observe the recommendations of your doctor and/or physicaltherapist. If you do not follow your rehabilitation schedule, the risk of treatment failure may
increase.
You should be very cautious when bending and putting weight on your treated knee. During therehabilitation period, the level of weight-bearing will increase gradually, depending on your weight
and the size of the cartilage defect. To protect your knee, you will have to wear a brace.
Ask your doctor or physical therapist if you have any further questions about the treatment with
ChondroCelect.

4.

POSSIBLE SIDE EFFECTS

Like all medicines, ChondroCelect can cause side effects, although not everybody gets them.
Most side effects of ChondroCelect implantation are side effects related to open-knee surgery. In
general, these side effects are quite mild and disappear in the weeks following surgery.
You can recognize most of the joint- related side effects if you have symptoms like pain, snapping,
grinding, locking, swelling, bending limitations and stiffness in the knee. Tell your doctor immediately
if you notice any of these symptoms.
The frequency of possible side effects listed below is defined using the following convention:very common (affects more than 1 user in 10)
common (affects 1 to 10 users in 100)
uncommon (affects 1 to 10 users in 1,000)
rare (affects 1 to 10 users in 10,000)
very rare (affects less than 1 user in 10,000)
not known (frequency cannot be estimated from the available data)
Very common side effects (likely to occur in more than 1 in 10 patients) include: joint pain
(arthralgia), overgrowth of cartilage cells (cartilage hypertrophy), crackling or clicking sensation whenarticulating the knee (joint crepitation), and joint swelling.
Common side effects (likely to occur in 1 to 10 patients in 100) include: restriction of knee montion(arthrofibrosis, decreased joint range of motion, decreased mobility), excessive amount of joint fluid in
the joint (joint effusion), joint lock, joint inflammation (arthritis, bursitis, synovitis), cavity filled withfluid in the knee (bone cyst, synovial cyst), bone swelling, cartilage disorder (chondropathy), benign
bony growth (exostosis), blood in a joint (haemarthrosis), joint instability, joint stiffness, loose body injoint, weakening of muscle (muscle atrophy, Trendelenburg’s sign), degenerative joint disorder(osteoarthritis), tendon disorder, inflammation of the tendon (tendonitis), impaired healing, treatment
failure, gait disturbance, implant site hypersensitivity, peripheral edema, fever (pyrexia), postoperative
wound complication (wound site reaction), loosening of the graft or membrane (graft complication,
graft delamination), injury (cartilage injury, joint injury), blood cloth in the deep vein of the leg (deep22vein thrombosis), large bruise (haematoma), superficial vein inflammation (phlebitis), nausea, pain or
nerve disorder (peripheral neuropathy, complex regional pain syndrome, autonomic neuropathy),
syncope, apnea, arthroscopy.
Uncommon side effects (likely to occur in 1 to 10 patients in 1,000) include: anxiety, hypersensitivity(hyperesthesia, photophobia), migraine, mini stroke (transient ischaemic attack), fat entering thecirculatory system (fat embolism), vein inflammation (thrombophlebitis), blockage in a lung artery(lung embolism), itching scar, pain at the front of the knee (chondromalacia), breakdown of tissue(gonartrhosis, atrophy), discomfort, chronic inflammation (granulomatous lesion).
Long-term experience with the implantation of cartilage cells is limited. Therefore, it is possible thatcomplications or side effects as yet unknown may occur.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,please contact your doctor or physical therapist.

5.

HOW TO STORE CHONDROCELECT

Keep out of the reach and sight of children.
Do not use ChondroCelect after the expiry date which is stated on the container and vial after EXP.
Store between 15°C – 25°C.
Do not refrigerate or freeze.
Keep the product vial(s) within the falcon tube in the plastic screw top container in order to protectfrom light and bacterial/fungal contamination.
Do not irradiate.
Since this product will be used during your knee surgery, the hospital staff is responsible for thecorrect storage of the product both before and during its use, as well as for the correct disposal
6.

FURTHER INFORMATION

What ChondroCelect contains
The active substance of ChondroCelect consists of a treatment dose of viable autologous humancartilage cells in vials containing 4 million cells in 0.4 ml, corresponding to a concentration of
10,000 cells/microlitre.
The other ingredient is sterile, buffered Dulbecco’s Modified Eagles Medium (DMEM), a liquidcontaining amino acids, vitamins, salts and carbohydrates to store the cells in the vial.
What ChondroCelect looks like and contents of the pack
ChondroCelect is a cell suspension (a fluid) for implantation. The cells are kept alive in a small sterilevial. The product is packaged in several layers of packaging materials which guarantee sterility andstable temperature conditions for 48 hours if stored at room temperature.
Each packaging contains an individual treatment dose consisting of 1 to 3 vials, depending on thenumber of cells needed to treat the specific lesion size.
Marketing Authorisation Holder and Manufacturer
TiGenix nv
Romeinse straat 12/2, 3001 LEUVEN
Belgium+32 16 39 60 60+32 16 39 60 70
info@tigenix.com
23

The leaflet was approved in
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web
site: http://www.emea.europa.eu.

24

European Medicines Agency
Evaluation of Medicines for Human Use

EMEA/724428/2009

ASSESSMENT REPORTFORChondroCelectCommon name: characterised viable autologous cartilage cells expanded ex vivo expressing specificmarker proteins
Procedure No. EMEA/H/C/000878

Assessment Report as adopted by the CHMP withall information of a commercially confidential nature deleted.

7 Westferry Circus, Canary Wharf, London E14 4HB, UK
Tel. (44-20) 74 18 84 00 Fax (44-20) 74 18 84 16
E-mail: mail@emea.europa.eu http://www.emea.europa.eu© European Medicines Agency, 2009. Reproduction is authorised provided the source is acknowledged.

TABLE OF CONTENTS

1.

BACKGROUND INFORMATION ON THE PROCEDURE ........................................... 3

1.1

Submission of the dossier ........................................................................................................ 3

1.2

Steps taken for the assessment of the product.......................................................................... 3

2.

SCIENTIFIC DISCUSSION................................................................................................. 5

2.1

Introduction.............................................................................................................................. 5

2.2

Quality aspects ......................................................................................................................... 6

2.3

Non-clinical aspects ............................................................................................................... 10

2.4

Clinical aspects ...................................................................................................................... 13

2.5

Pharmacovigilance................................................................................................................. 31

2.6

Overall conclusions, risk/benefit assessment and recommendation ...................................... 35

Page 2 of 38

1.

BACKGROUND INFORMATION ON THE PROCEDURE

1.1

Submission of the dossier

The Applicant TiGenix NV submitted on 01 June 2007 an application for Marketing Authorisation to
the European Medicines Agency (EMEA) for ChondroCelect, through the centralised procedurefalling within the Article 3(1) and point 1 of Annex of Regulation (EC) No 726/2004. The eligibility to
the centralised procedure was agreed upon by the EMEA/CHMP on 26 September 2006.
The legal basis for this application refers to:
A - Centralised / Article 8(3) / New active substance.
Scientific Advice:
The Applicant received Scientific Advice from the CHMP on 28 April 2008 (EMEA/151996/2206).
The Scientific Advice pertained to quality, non-clinical and clinical aspects of the dossier.
Licensing status:
The product was not licensed in any country at the time of submission of the application.
The Rapporteur and Co-Rapporteur appointed by the CHMP and the evaluation teams were:
Rapporteur: Christian K. Schneider
Co-Rapporteur: Jaana Kallio
As ChondroCelect is an Advanced Therapy medicinal product, the advanced therapy regulation wasapplicable to this procedure. Therefore, during the CHMP meeting of 12 – 13 February 2009, a CAT
Rapporteur, a CAT Co-Rapporteur and a CHMP Co-ordinator were appointed.
Rapporteur: Egbert Flory

Co-Rapporteur: Paula Salmikangas

1.2

Steps taken for the assessment of the product•••

The application was received by the EMEA on 01 June 2007.
The procedure started on 20 June 2007.
The Rapporteur's first Assessment Report was circulated to all CHMP members on 03
September 2007. The Co-Rapporteur's first Assessment Report was circulated to all CHMP
members on 03 September 2007. In accordance with Article 6(3) of Regulation (RC) No
726/2004, the Rapporteur and Co-Rapporteur declared that they had completed their assessment
report in less than 80 days.
During the meeting on 18 October 2007, the CHMP agreed on the consolidated List of
Questions to be sent to the Applicant. The final consolidated List of Questions was sent to theApplicant on 18 October 2007.
The Applicant submitted the responses to the CHMP consolidated List of Questions on 28 April
2008.
The final report of inspections carried out at the manufacturing site in Belgium on 13-14
December 2007 and 20-21 May 2008 was issued on 17 June 2008.
The Rapporteurs circulated the Joint Assessment Report on the Applicant’s responses to the Listof Questions to all CHMP members on 09 June 2008.
During the CHMP meeting on 26 June 2008, the CHMP agreed on a list of outstanding issues tobe addressed in writing and in an oral explanation by the Applicant.
The Applicant submitted the responses to the CHMP consolidated List of Outstanding Issues on
03 September 2008.
The Rapporteurs circulated the Joint Assessment Report on the Applicant’s responses to the Listof Outstanding Issues to all CHMP members on 11 September 2008.

•
•
•
•
•
•
•

Page 3 of 38

•
•
•
•
•
•
•
•
•
•
•

•

During a meeting of an Ad Hoc Expert group / Biologics Working Party on 13 October 2008,
experts were convened to address questions raised by the CHMP.
During the CHMP meeting on 23 October 2008, outstanding issues were addressed by the
Applicant during an oral explanation before the CHMP. The CHMP agreed on a second list of
outstanding issues to be addressed in writing and in an oral explanation by the Applicant.
During the CHMP meeting of 12 – 13 February 2009 Dr. Egbert Flory was appointed as CAT
Rapporteur and Dr Paula Salmikangas was appointed as CAT CoRapporteur.
The Applicant submitted the responses to the CHMP consolidated second List of Outstanding
Issues on 24 April 2009.
The Rapporteurs circulated the Joint Assessment Report on the Applicant’s responses to the 2nd
List of Outstanding Issues to all CHMP and CAT members on 11 May 2009.
During the CAT meeting on 14 May 2009, outstanding issues were addressed by the Applicant
during an oral explanation before the CAT.
During the CAT meeting on 14 May 2009, a 3rd List of Outstanding Issues was adopted byCAT. The CHMP endorsed the 3rd LoOI on 29 May 2009.
The Applicant submitted the responses to the third List of Outstanding Issues on 03 June 2009.
The Rapporteurs circulated the Joint Assessment Report on the Applicant’s responses to the 3rd
List of Outstanding Issues to all CHMP and CAT members on 12 June 2009.
The Applicant provided the letter of undertaking on follow-up measures to be fulfilled postauthorisation on 23 June 2009.
On 24 June 2009, the CAT, in the light of the overall data submitted and the scientificdiscussion within the Committee, issued a positive draft opinion for granting a Marketing
Authorisation to ChondroCelect by written procedure including the recommendation under
Article 14(2) of Regulation (EC) No 1394/2007 that the Marketing Authorisation Holder
performs the studies and additional activities detailed in the Pharmacovigilance Plan and in the
Efficacy Follow-up plan, as agreed in version 4 (dated 22/06/2009) of the Risk Management
Plan (RMP) presented in Module 1.8.2. of the Marketing Authorisation Application and any
subsequent updates of the RMP agreed by the CAT.
During the meeting on 25 June 2009, the CHMP, in the light of the overall data submitted andthe scientific discussion within the Committee, issued a positive opinion for granting aMarketing Authorisation to ChondroCelect including the recommendation under Article 14(2)of Regulation (EC) No 1394/2007 that the Marketing Authorisation Holder performs the studies
and additional activities detailed in the Pharmacovigilance Plan and in the Efficacy Follow-up
plan, as agreed in version 4 (dated 22/06/2009) of the Risk Management Plan (RMP) presented
in Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the
RMP agreed by the CHMP.

Page 4 of 38

2.

SCIENTIFIC DISCUSSION

2.1

Introduction

Joint surface defects can originate after trauma, after osteochondritis dissecans or can be caused by anunderlying genetic predisposition. The healing capacity of articular cartilage is poor and damaged
articular cartilage is thought to be a precursor to the development of osteoarthritis. Damaged articularcartilage can result in pain, loss of joint function and disability. An early intervention on symptomatic
cartilage lesions may prevent or delay irreversible changes in the joint surface.
Currently, there is no uniform approach to managing significant knee cartilage defects. Interventions
that aim to provide symptomatic relief include debridement, lavage and rehabilitation. Interventions
intended to re-establish the cartilage surface include marrow stimulation techniques (i.e. microfracture(MF), abrasion arthroplasty or drilling), mosaicplasty and autologous chondrocyte implantation (ACI).
Microfracture is frequently used as treatment for patients with smaller articular cartilage defects of theknee (for lesions < 4cm2). It induces cartilage repair by penetrating the subchondral bone andstimulating bleeding and thus the formation of a fibrin clot, which is considered to stimulate fibro
cartilage formation, and has been shown to result in functional improvements within the first 2 years
following treatment. For larger lesions particularly those exceeding 4cm2, however, this procedure is
not recommended.
Mosaicplasty takes advantage of the limited self-renewal capacity of the joint surface by fitting one orseveral osteochondral plugs, obtained from a low weight bearing area of the joint into a mosaic. It
transforms large defects into several small defects that can be repaired spontaneously by thesurrounding tissue and by the invading bone marrow derived skeletal precursors/mesenchymal stem
cells.
The ACI procedure was first developed in 1994 described by Brittberg et al. (1994) using a first
generation autologous chondrocyte product. In the following years many groups could demonstrate thebenefit and formation of ‘cartilage repair tissue’ with long-lasting stability and symptomatic relief
between two and nine years after ACI treatment. For larger lesion sizes exceeding 4cm², ACI is also
considered a suitable treatment option.
ChondroCelect by Tigenix nv is a medicinal product for use in ACI treatment. ChondroCelect is asuspension of approximately 10,000 cartilage cells per microliter of medium for autologous use. The
cells have been obtained by ex vivo expansion of chondrocytes isolated from a biopsy of the articularcartilage from the patient’s knee.
Treatment with ChondroCelect comprises a two-step surgical procedure. In the first step a cartilage
biopsy is obtained arthroscopically from healthy articular cartilage from a lesser weight bearing areaof the patient’s knee, approximately 4 weeks prior to implantation. Chondrocytes are isolated from thebiopsy by enzymatic digestion, expanded in vitro, characterised and delivered as a suspension of 1 x
104 cells/μl for implantation in the same patient. During the second step of the procedure the expandedchondrocyte suspension is implanted in an open-knee surgery. In the pivotal study a periosteal flap
was harvested from the medial tibia, sutured into the defect, with the cambium layer facing thesubchondral bone, and sealed with fibrin glue. In future applications the defect will be covered withthe help of a biodegradable membrane. The dosage of the cell suspension is defined as 0.8 to 1 million
cells per cm² defect size. Hence, depending on the defect size measured at biopsy procurement, 4 or 8
or 12 million cells are formulated into 1 or 2 or 3 vial(s) of 4 million cells/ 0.4 ml excipient.
The claimed indication for ChondroCelect is repair of single symptomatic cartilaginous defects of thefemoral condyle of the knee (ICRS grade III or IV) in adults.

Page 5 of 38

2.2

Quality aspects

Introduction
ChondroCelect is an autologous cell-based medicinal product consisting of chondrocytes that wereexpanded ex vivo after sourcing from a small biopsy of healthy cartilage from a lesser weight bearing
area of the same patient's damaged knee.
The active substance consists of autologous cartilage forming (chondrogenic) cells which arecharacterised by specific marker proteins.
For details on the composition of ChondroCelect please refer to Table 1.
Table 1. Composition of ChondroCelectSubstance

Function

Pellet of washed cells

Active Substance

Dulbecco’s Modified Eagle Medium
with glucose, without phenol red

ExcipientContent
4 Mio Cells/ 0,4 ml
0,4 mlActive Substance
The Active Substance is a centrifuged pellet of 4 to 12 million cells that were expanded ex vivo,
harvested and washed. The expansion process is designed to preserve the integrity and function of thecells and particularly to maintain the cells' ability to produce hyaline cartilage. This method has beendeveloped and validated in order to limit the usually observed dedifferentiation of chondrocytes inculture. Lineage marker analysis are performed in order to demonstrate that the culture conditions do
not enrich for other cell lineage populations for example fibroblasts and provide reassurance of thehomogeneity of the ChondroCelect cell population.
•

Manufacture

Biopsy procurement
The starting material consists of an autologous articular cartilage biopsy procured arthroscopicallyfrom a non weight-bearing area of the femoral condyle of the patient’s knee. The Applicant provides
hospitals with biopsy procurement kits, which are stored at the orthopaedic unit. Each kit is labelledwith a unique lot number on the outer box and the containers within.
Eligible patients for ChondroCelect treatment are screened for HIV type 1 and 2, HCV, HBV, andsyphilis. Only tissue from donors who test negative will be released from quarantine and allowed into
the tissue/cell processing area.
The orthopaedic surgeon will plan an arthroscopy to assess the cartilage lesion and procure a cartilage
tissue biopsy. The cartilage tissue biopsy is aseptically transferred into sterile biopsy medium.
The biopsy kit is conditioned prior to shipment and is transported under strict monitoring of thetemperature during transport. Upon receipt of the biopsy kit, the biopsy is quarantined until successful
donor screening results are available.
Each biopsy kit is identified with a unique lot number which is composed of the following elements:
the date on which the biopsy kit is assembled, the product type and the batch sequence number. At thetime of arthroscopy the surgeon records two patient identifiers, i.e. donor initials and the patient’s
administration number in the hospital (hospital identifier) on the patient form and thus links the patient
Page 6 of 38

identifiers to the lot number of the biopsy kit. These three codes are designed to form a unique
combination, and the biopsy lot number is used throughout the entire process to identify the donor’s
tissue and all lot related materials and documentation.
Manufacturing process
The manufacturing process of the Active Substance consists of the following steps:•••

Biopsy digestion
Expansion culture
Cell culture harvest and wash

Biopsy digestion
Before further processing, the appearance of the biopsy medium is verified with respect to clarity andcolour. The tissue is minced under aseptic conditions and bone fragments are removed. The cartilage
fragments are then transferred to allow for dissociation of the cartilage tissue fragments and to release
the chondrocytes from the tissue matrix. Chondrocytes are isolated, washed, counted and seeded intissue culture flasks in culture medium.
Expansion culture
The isolated cells are transferred to an incubator with humidified atmosphere and replenished withfresh culture medium in regular intervals. The flasks are regularly inspected. When the cultures reachconfluence the cells are dissociated from the flask surface and subcultured in fresh tissue culture flasks
until the appropriate number of expanded cells has been reached.
The spent medium is pooled from every flask and sampled for microbiological testing
The total number of passage numbers should remain lower or equal than 3
Cell culture harvest and wash
At the end of culture the cells are trypsinized and collected, centrifuged and washed thoroughly. Cell
viability is verified and a gram stain is performed on the collected wash solution. The cells obtained asa pellet at this stage are considered the Active Substance (i.e. living human autologous cartilage
forming cells).
In-process controls and specifications
The in-process controls of the manufacturing process have been clearly specified.
Critical parameters have been included as in process controls to routinely confirm the quality of theMedicinal product by testing the biopsy and cell culture for aspects like e.g. medium appearance, pH,
microbiology, cell morphology, purity, cell viability and cell yield. Appropriate operating ranges havebeen defined. As the manufacturing process is a continuous process and the active substance is notstored in between, no formal Active Substance specifications have been set.
Process validation and characterisation of Active Substance
The Applicant used a series of functional tests capable to characterise the cells and suitable to validate
the manufacturing process. These functional assays include a cell culture (3D cell culture assay), an invitro assay in animal models and cellular expression patterns of genes relevant for cartilage andchondrocyte biology.
The validation of the manufacturing process has been adequately performed. Some minor issues on theacceptance criteria for some parameters followed during the validation are still outstanding. The
Applicant has committed to explore further the specification limits for the functional assay and to
Page 7 of 38

further define the acceptance criteria for process validation. On basis of the validation approach, thedata collected and the commitment on further exploration of the specification limits, the comparability
and consistency of lots produced by the proposed manufacturing process have been demonstrated.

Medicinal product
The manufacturing process from the Active Substance to the Medicinal product is a continuous
process without intermediate holding steps. The cell pellet is immediately resuspended in the excipient
nutrient medium and packaged for shipment. The dosage is defined as 0.8 to 1 million cells per cm2
defect size. Hence, depending on the defect size measured at biopsy procurement, 4 or 8 or 12 million
cells are formulated into 1 or 2 or 3 vial(s) of 4 million cells/ 0.4 ml excipient/ vial. Concentration of
the Medicinal product is 10,000 cells formulated per microliter excipient.
•

Pharmaceutical development

The Manufacture of ChondroCelect Medicinal product involves the formulation of the cell pellet in the
excipient medium and subsequent filling into glass vials. The Applicant has conducted studies todemonstrate the suitability of the transport medium to serve as the excipient of the Medicinal product.
The Medicinal product is composed of the Active Substance (a pellet of washed cells) and an aqueous
nutrient medium (Dulbecco’s Modified Eagle Medium with glucose).
•

Manufacture of the product

The Medicinal product is manufactured, routinely controlled and batch released by Tigenix (Leuven,
Belgium). Operations are in compliance with Good Manufacturing Practice (GMP).
The re-suspension of the Active Substance, the cell pellet in medium, without any intermediateholding steps yields the Medicinal product. The product is filled into a 1 ml clear, V-shaped, type 1borosilicate glass vial, which is closed with a grey chlorobutyl /45 stopper. Vial and cap are manuallycrimp sealed with an aluminium tear-off seal. The glass vial complies with Ph.Eur. requirements. The
chlorobutyl stopper is made of material that has “low extractables” characteristics and is certified by
the manufacturer to be compliant with all applicable procedures and specifications.
Based on the cell counts from the final harvest, the Medicinal product is formulated to contain 10,000
cells /µl and 0.4 ml of the cell suspension is filled per vial. Each vial thus contains a total of 4 million
cells. Depending on the total amount of cells needed to treat a specific lesion, up to three vials arefilled and provided within the falcon flask. Since the dosage is 0.8 to 1 million cells per cm2, thedefective area, which may be treated with ChondroCelect, is limited to 15 cm2.
•

Adventitious agentsThe raw materials of biological origin used in the production of ChondroCelect include collagenase,fetal bovine serum and porcine trypsin. All raw materials, which are sourced directly or indirectlyfrom animal material, are subjected to a risk analysis procedure and a compliance check with theappropriate legislative requirements. Certificate of suitability from the European Directorate for
Quality of Medicinal Products (EDQM) have been provided.
A valid EDQM Certificate of Suitability for foetal bovine serum (FBS) has been provided. Absencefrom bovine viruses according to Ph. Eur. 01/2008/2262, monograph Serum bovinum and EMEA
Guideline (CPMP/BWP/1793/02) has been demonstrated. In addition, test methods have been
described in details and virus inactivation results using gamma irradiation have been provided.
Overall, sufficient data is provided to exclude a risk of TSE transmission through ChondroCelect. The
risk of transmitting TSE by ChondroCelect is thus considered very remote.

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•

Product specification

The quality control program performed on the Medicinal product for ChondroCelect includes a test forsterility by Ph. Eur., testing for absence of Mycoplasma by Ph. Eur., testing for absence of endotoxin
by Ph. Eur. and gram staining. Dosage and cell viability are confirmed prior to release. Visual tests forabsence of particles and vial integrity are performed.
All analytical methods are performed according to Ph. Eur. where applicable and are validated
according to ICH guidelines.
Compliance with the product specifications has been demonstrated, and the provided data is
considered acceptable. The Company has committed to provide additional data in support of the
product specification post-marketing.
•Stability of the productStability was addressed by analyzing various lots at time point 0 and time point 48 h. The data reveal
no major changes. Hence, a shelf life of 48h is justified for ChondroCelect.
•

GMO

ChondroCelect is composed of non-modified human autologous cells. The cells administered to thepatient are likely to remain in the implantation site and are not released to the environment.
Furthermore, incidental cell leakage is expected to result in metabolism, as is the case for natural
release of cells within the body. Therefore the use of ChondroCelect is unlikely to result in any risk to
the environment, due to its nature and also because the product is not released into the environment.
Discussion on chemical, pharmaceutical and biological aspects
Information on development, manufacture and control of ChondroCelect Active Substance andFinished product have been presented in a satisfactory manner. The results of the tests carried out
indicate satisfactory consistency and uniformity of the manufacturing process and finished product,
and these in turn lead to the conclusion that the product should have a satisfactory and uniform
performance in the clinic.
At the time of CAT opinion, there were a number of minor unresolved quality issues related to thespecification limits, biodegradable membrane and storage conditions (see above). These shortcomings,
however, have no impact on the Risk-benefit balance of the product. The Applicant provided a Letterof Undertaking and committed to resolve these as follow-up measures after the opinion, within anagreed timeframe.

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2.3

Non-clinical aspects

Introduction
Non-clinical studies were performed as combined pharmacodynamic / pharmacokinetic (distribution) /toxicological studies in the ectopic mouse (nu/nu model) and in orthotopic models in sheep and goats.
These studies were non-GLP which is not in conformity with the pharmaceutical standards. However,these deficiencies were considered by CHMP to be tolerable in view of the specificity of thedevelopment programme for this particular product. In addition human data were supported byadequate clinical studies and did not raise any safety concerns.
Pharmacology•

Primary pharmacodynamics

Nude mouse model
Nude mice received an intramuscular injection of human articular chondrocytes expanded according to
the ChondroCelect culture process. Implants retrieved from nude mice at 2 weeks post injection were
subjected to histological staining. Based on these characteristics, the cartilage implants wereconsidered of hyaline-like nature. Compared to normal adult human articular cartilage, the cartilage
implants were hypercellular and lacked the typical columnar organisation.
A further mouse study was performed using early or late passage expanded human articularchondrocytes. When injected intramuscularly into nude mice, late passage expanded cells did not form
any cartilage tissue. In contrast, early passage expanded human articular chondrocytes formed a
cartilage implant.
Studies in a large animal species
The importance of phenotypic stability for inducing in vivo hyaline-like cartilage formation wasinvestigated by comparing goat or human articular chondrocytes of different passages. The
histological score of implants indicated a loss of stable cartilage-forming potential at higher passages.
In goats ChondroCelect-like chondrocytes showed a more stable cartilage forming potential thandedifferentiated chondrocytes. Implantation of ChondroCelect-like autologous chondrocytes resulted
in an improved repair efficacy compared to dedifferentiated chondrocytes or dermal fibroblasts asobserved in an improved repair in the defect centre, and improved repair tissue integration.
Dedifferentiated autologous chondrocytes induced moderate defect filling with poor repair tissue andno or minimal basal and/or lateral integration. In all animals, partial or complete delamination of
periosteal flap and fissures in the grafted area and surrounding cartilage was observed.
The repair of the cartilage defect was evaluated by the Modified O’Driscoll (MOD) scores that
represent a scoring system to assess late-stage cartilage regeneration. The number of data points wasvery limited and the MOD score obtained in goats have shown a non-valid correlation with thehistology score obtained for the same cell preparations in nude mice.
As observed for goat chondrocytes, the in vivo cartilage-forming capacity of human articularchondrocytes in nude mice was progressively lost during in vitro cell culture from passage 2-3
onwards. Chondrocytes expanded to higher passage numbers did not form an implant when injected
into the thigh of nude mice. In another study in goats comparing passage 1 versus passage 5 expanded
human articular chondrocytes according to ChondroCelect culture process all animals showed poor
repair, possibly due to an immunological reaction to the human cells.
In a goat study ChondroCelect-like autologous chondrocytes controls were performed with or without
periosteal flap. Goats sacrificed up to 53 weeks post-implantation of ChondroCelect-like autologous
chondrocytes showed normal mobility, almost complete filling of the cartilage lesion with hyaline-likecartilage or hyaline-like cartilage/fibrocartilage. However, goats sacrificed at various weeks postimplantation showed some degree of bone front ingrowths into the defect. The degree of bone front
ingrowths into the defect at 52 weeks was most prominent in animals implanted with ChondroCelectlike cells.
Page 10 of 38

•Secondary pharmacodynamics

The potential formation of other tissue types as a consequence of the loss of phenotypic stability
during the in vitro expansion process was investigated. Further secondary pharmacodynamic studies
were not performed.
•

Safety pharmacology programme

ChondroCelect is administered locally. No direct effect of the cells or an effect of secreted
pharmacologically active substances on CNS, cardiac or respiratory system is considered for this celltherapy medicinal product, thus the omission of safety pharmacological studies is in line with theguideline on human cell based medicinal products (EMEA/CHMP/410869/2006).
•

Pharmacodynamic drug interactions

No formal pharmacodynamic drug interaction studies have been performed, since the Applicant
justified that the intended clinical use and the applied surgical procedures are not associated withpotential concerns regarding pharmacodynamic interactions with pre-, peri- or post-operatively
administered medicinal products.
Fibrin sealants are broadly employed in orthopaedic surgery as an adjunct to haemostasis during total
knee prosthesis replacement or as mechanical seal of the outside margins of the membrane used tocover the defect in ACI. Fibrin sealant products differ significantly in their quantitative and qualitative
composition, of the active substance and the excipients, thus it cannot be excluded that certain fibrin
glues have, due to their composition, a negative effect on the viable cells and/or membrane.
Compatibility data for the fibrin glue TissuCol (Tisseel) have demonstrated the safe and effective useof this sealant with ChondroCelect in non-clinical studies. No interaction studies with any other typeof fibrin glues were performed. However the concomitant use of Quixil in the pivotal clinical trial did
not reveal any safety signal so far.
Pharmacokinetics
Two studies were performed in goats to evaluate the persistence of cells in the inflicted cartilage
defect as well as the potential migration of cells outside the implantation site. These studies withfluorescently-tagged ChondroCelect-like autologous chondrocytes demonstrated that implanted cells
become a structural part of newly formed cartilage.
No pharmacokinetic drug interaction studies were performed. This is in line with the draft guidelineon human cell based medicinal products (EMEA/CHMP/410869/2006).
Toxicology•

Single dose toxicity

Female NMRI nu/nu mice received intramuscular or subcutaneous injections of human articularchondrocytes (freshly isolated or expanded according to the ChondroCelect culture process), goatarticular chondrocytes, pig articular or epiphysial chondrocytes, a combination of pig articularchondrocytes and human periosteal cells, goat dermal fibroblasts, immortalized cell lines withchondrocyte characteristics or human synovial membrane-derived mesenchymal stem cells. Twodeaths unlikely to be caused by ChondroCelect were observed, all other animals treated were normal
and healthy during the course of the experiment, regardless of the number and type of cells
administered.
In a sheep study, 70% if the animals receiving an implantation of either autologous articularchondrocytes expanded according to the ChondroCelect culture process, freshly isolated allogeneic
articular chondrocytes, freshly isolated human articular chondrocytes or freshly isolated human stem
cells showed penetration of cells in subchondral bone, partly with granulomatous reaction. Two ofthese animals also showed complete penetration of underlying bone marrow.
In goats either autologous cells or human articular chondrocytes, expanded according to theChondroCelect culture process were implancted via an ACI procedure. In one study an extensive set ofsafety parameters was monitored. Clinical and laboratory signs observed occurred with low incidence,
Page 11 of 38

were of short duration and are considered related to the surgical procedure including anaesthesia
and/or post-surgery immobilization. Animals treated with autologous cells showed no majordifferences concerning macroscopic and microscopic findings of the femoral condyle as compared tocontrol animals.
As part of the goat study, the macroscopic, histological and biochemical composition of the synovium
and synovial fluid was investigated 10 and 52 weeks post-implantation with particular attention to
inflammation and ectopic cartilage or bone formation. At 10 weeks, ca. 70 % of all animals showedvarious degrees of synovitis.
In a feasibility study in sheep the majority of the animals showed penetration of the transplanted cells
in subchondral bone. In two cases complete penetration of underlying bone marrow was observed.
Similar findings were observed in long-term studies in goats. In addition these animals showed
complete penetration of underlying bone marrow.
The observed synovitis and the reported penetration of the transplanted cells in the subchondral bone
have been identified in the RMP as potential safety concerns related to the use of the product thatwarrant a specific statement under section 5.3 ‘Preclinical safety data’ of the SmPC.
None of these potential concerns are found to have an impact on the safe clinical application ofChondroCelect. Further risk minimization actions or additional non-clinical data are not considerednecessary.
No effects on body systems or systemic toxicity was seen in the mice, sheep or goats as expected forthis kind of autologous cell therapy medicinal product applied locally in this compartment.
•

Repeat dose toxicity (with toxicokinetics)

As the observation period of the single dose studies described above were up to 12 weeks in mice, 14
weeks in sheep and 53 weeks in goats, these studies are considered to be sufficient to assess the longterm effects of ChondroCelect. Therefore the omission of repeat-dose toxicity studies is in line with
the EMEA guideline EMEA/CHMP/410869/2006.
•

Genotoxicity

The omission of genotoxicity studies in the development program for ChondroCelect is in line with
EMEA/CHMP/410869/2006.
•

Carcinogenicity

In order to address the carcinogenic potential of ChondroCelect, the Applicant performed an in vitro
study to evaluate senescence of human articular chondrocytes after serial passaging, using
ChondroCelect culture conditions. Cells were kept beyond the routine cell culturing as suggested in
EMEA/CHMP/410869/2006.
The results provide sufficient evidence that immortalisation of human chondrocytes during limited
time in in vitro culture conditions would not occur, and that the risk of tumorigenic growth isnegligible.
In view of these results, the absence of standard carcinogenicity studies was considered to be
acceptable.
•

Reproduction Toxicity

Taking into account the nature of the product and its intended clinical use the risk for reproductive anddevelopmental toxicity is considered to be negligible.
Therefore, the omission of reproductive and developmental toxicity studies in the development
program for ChondroCelect is acceptable and in line with the EMEA guideline
EMEA/CHMP/410869/2006.
•

Local tolerance

Local tolerance was an integral part of the toxicological studies. Therefore, no dedicated local
tolerance studies with ChondroCelect. were deemed necessary. Pharmaco-toxicological studies in the
Page 12 of 38

orthotropic animal model showed that implantation of human or allogeneic chondrocytes causes animmune response to the CBMP, resulting in poor repair.
•

Other toxicity studies

Ecotoxicity/environmental risk assessment
ChondroCelect is composed of non-modified human autologous cells. The cells administered to thepatient are likely to remain in the implantation site and are not released to the environment. Therefore
the use of ChondroCelect is unlikely to result in any risk to the environment, due to its nature and also
because the product is not released into the environment.
Consequently, the absence of environmental studies is in line with the EMEA guideline
EMEA/CHMP/SWP/4447/00.

2.4

Clinical aspects

Introduction
GCP
The GCP inspection highlighted the amount of missing data on the structural endpoint and the change
to the ICRSII read-out in the pivotal study as major concerns.
Most of the concerns related to the ICRSII were resolved during the procedure. The generation of newslides from the original repair biopsy has increased the ICRSII data base from 73% to 93%. It was,however, acknowledged that the a priori determined primary efficacy end point, the MODs score (onthe basis of which the for example a priori sample size calculations and power analysis were
performed), was post hoc disregarded as invalid and a new primary end point, the ICRSII wasdeveloped within the course of the study, the conclusion being that this GCP non compliance cannot,
as such, be post hoc rectified.
Pharmacokinetics
Studies on absorption, distribution, metabolism and excretion have not been performed Conventional
ADME studies are usually not relevant for a cell based medicinal product. The body
distribution/migration studies are part of the non-clinical development program. This is acceptableconsidering the nature and origin (autologous) of the product.
Pharmacodynamics
Conventional pharmacodynamic studies for ChondroCelect have not been performed. The
pharmacodynamic parameter “histological evaluation” was part of the efficacy assessment in the phase
III trial. The ChondroCelect score is a functional test which suggests a correlation between the gene
expression profile of chondrocytes and hyaline cartilage formation in vivo in animal models and wasused also in the phase III study (see Overview on quality and non-clinical development as regards thediscussion on validity of this score). In the pivotal study a periosteal flap was used to seal the defectand maintain the chondrocyte suspension in situ.
Clinical efficacy•

Dose response study(ies)

No dose-response studies have been performed. The dose selection was based on a combination ofanimal studies conducted by TiGenix, published literature and experience in humans with ACI. On thebasis of this information the dose of between 0.8 and 1 × 106 cells/cm2 was used.

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•Main study(ies)Study TIG/ACT/01/2000 is a phase III, multicentre, randomized, controlled trial to compare
ChondroCelect to the procedure of microfracture in the repair of symptomatic single cartilaginous
lesions of the femoral condyles of the knee. This study TIG/ACT/01/2000 and its ongoing 4-year
extension phase (TIG/ACT/O1/2000EXT) (both referred to as TIG/ACT/OI&EXT') were initiallyseparate studies which were merged late in the development.
Methods
Study Participants
Patients aged between 18 and 50 years, who had a single symptomatic cartilage lesion between 1 and 5
cm2 of the femoral condyles met the inclusion criteria.
Patients with patellofemoral cartilage lesion, osteochondritis dissecans (OCD), depth of lesion >0.5cm, prior meniscal transplant, prior mosaicplasty and prior microfracture within last 12 month were
excluded.
Patients had to agree to actively participate in a strict rehabilitation protocol and follow-up program.
Treatments
Microfracture is considered an effective standard treatment for smaller femoral cartilage lesions
according to currently available literature data, and is an acceptable control therapy.
Objectives / Outcomes / Endpoints
The primary objectives of this study were changed in August 2006, after end of the initial study
period. The primary objective of the original protocol was to show superiority in structural repair at 12
months compared to the control group. However, CHMP Scientific Advice suggested that a clinicallymeaningful primary endpoint should be used. Therefore, the Applicant decided to follow CHMP
Scientific Advice and to select overall KOOS (The Knee Injury and Osteoarthritis Outcome Score,1998) for the second primary efficacy endpoint. This questionnaire-based endpoint has five separately
scored subscales: 1) pain; 2) other symptoms such as swelling, restricted range of motion andmechanical restrictions; 3) function in daily living; 4) function in sport and recreation; 5) knee-related
Quality of Life. At the ad-hoc expert group that was convened on 13th of October 2008, the experts
confirmed that patient-reported outcomes should be the primary outcome measure in studies inorthopaedics and sports medicine, and that the KOOS is one of the most meaningful clinical endpoints
to date.
The modified primary objectives of the study included the following structural and clinicalobjectives: To show an advantage of ChondroCelect compared with microfracture in the treatment ofsymptomatic cartilaginous defects of the femoral condyle of the knee by demonstrating superiority on
the structural repair (histology) endpoint at 12 months and non-inferiority on the clinical endpoint(change from baseline in KOOS) for the average of the 12- to 18-months follow-up data. Due, firstly,
to the more complex nature of ACI compared with microfracture and associated safety issues,secondly, due to the fact that very limited data exists on the efficacy of MF, in particular in the longterm setting, and thirdly, due to the fact that the relevance, both short term and long term, of thestructural findings has not been established, CHMP Scientific advice (EMEA/151996/2006)
recommended that it is of importance to establish the superiority of ACI.
Secondary objectives were to assess the difference between ChondroCelect and microfracture at 12
months in terms of the following structural outcome parameters: ICRS II sub-scales, MRI
measurements and ICRS Visual Histological Assessment Score.
Primary efficacy parameters were•
The sum of histomorphometric scores on safranin-O and collagen II staining (sum of two ratios)
and the mean Overall Histology Assessment score at 12 months.
Page 14 of 38

•

The change from baseline in Overall KOOS score averaged over 12 and 18 months.

Sample size and Randomisation
Sample size calculation was based on the score component of the MODS (primary endpoint according
protocol). Due to a lack on information on the expected variability, the sample size was determinedusing only the categorization (success/failure) element of the MODS. Anticipating a 30% success rate
for the microfracture group and a 60% success rate for the ChondroCelect procedure, it was calculated
that with 112 (56 per group) a one-sided test at the 2.5% level would have 90% power to detect such a
difference. However, this primary endpoint was disregarded as invalid and a new histological end
point was developed during the conduct of the study.
Randomisation was performed via a central IVRS.
Blinding (masking)All clinical assessments were performed by independent evaluators at each site. Two central
histopathologists who were blinded to the treatment allocation completed the histopathological andhistomorphometric assessments of the biopsies. The scoring of the MRI scans was also performed
centrally by two independent musculoskeletal radiologists, who were blinded to the treatment
allocation. The randomisation was performed using the “minimisation” method, in order to balancegroups for the most important prognostic factors.
Statistical methods
All analyses were performed for the FAS population (i.e. all patients randomized who underwent thesurgical procedure). For the primary efficacy parameter additional (secondary) analyses were to be
performed for the ITT and PP population respectively.
RESULTS
Participant flow

Page 15 of 38

Recruitment
The study was performed in 13 centres in 4 countries.
Conduct of the study
The initial 12-months trial protocol was dated 22 October 2001. Seven protocol amendments were
subsequently implemented. The first two amendments were implemented prior to inclusion of any
patient.

Page 16 of 38

Baseline data
The randomisation to ChondroCelect and microfracturing groups was successful for age (mean age
33.9 years and 33.9 years, respectively, gender (61% and 67% males), and weight (mean 78.1 kg and80.6 kg). There was a higher proportion of patients with a BMI >30 kg/m2 in the microfracture groupthan in the ChondroCelect group (9.8% versus 5.3%) and a slightly higher proportion of patients in the
microfracture group whose onset of symptoms was acute compared to the ChondroCelect group. The
median duration of time since onset of knee injury was slightly longer in the ChondroCelect groupthan in the microfracture group (2.0 years versus 1.6 years). The presence of concomitant cartilage
lesions was comparable in both groups (30% versus 25%). More patients in the ChondroCelecttreatment group, compared to patients in the microfracture group, had undergone previous knee
surgery (88% versus 77%).
The lesions of the femoral condyle that were treated with ChondroCelect or microfracture were ICRS
grade III or IV, except for one patient with a grade II lesion in the ChondroCelect group. Thirty percent (17/57) of patients in the ChondroCelect group and 25% (15/61) of patients in the microfracturegroup had additional concomitant cartilage lesions (data from Clinical Overview). The mean surface
area of cartilage defect post-debridement was similar in both treatment groups (mean 2.64 and 2. 44,
respectively).
Numbers analysed
The patient disposition is seen in the Table below.

The full analysis set (FAS) was used for the main efficacy analysis. Six patients in the ChondroCelectgroup were excluded from FAS because acceptable products could not be prepared from the biopsies.
All patients were included in the safety analysis. Seven patients in both groups were lost for follow up
between months 12 and 18.

Outcomes and estimation
Primary endpoints
The results of the analysis of structural repair and of the clinical endpoint are presented in the Table
below:
Parameter

Treatment

N

Difference (95% CI)

p-value

47
54

Adjusted
Mean (SE)1.01 (0.08)
0.75 (0.08)

Histomorphometric
endpoint

ChondroCelectMicrofracture

0.26 (0.09, 0.44)

0.003

ICRS II at 12

ChondroCelect49

55.11 (3.98)

10.92 (2.63, 19.21)

0.0103

Page 17 of 38

months

Microfracture

55

44.20
(3.74))

Change in KOOS at
12 and 18 months

ChondroCelectMicrofracture

51
58

16.18 (2.42)
14.37 (2.35)

1.81 (-3.28, 6.90)-

All estimates from ANCOVA models; adjusted for age, associated lesion & location of lesion (histomorphometric & histological endpoints);
adjusted for baseline Overall KOOS score, age, associated lesion(s) & location of lesion (KOOS)

In line with the testing strategy as provided with the statistical analysis plan, superiority of
ChondroCelect compared to microfracture could be shown for both endpoints describing structural
repair, the histomorphometric and the histological endpoint.
The average change from baseline (at month 12 and 18) total KOOS scores for the FAS population arepresented in the Table below:

Mean change in Overall KOOS from baseline to the average of 12 and 18 months
The mean change in Overall KOOS from baseline to the average of 12 to 18 months was slightly
higher for patients in the ChondroCelect group than for patients in the microfracture group. The results
fulfil the predefined criteria for non-inferiority in this co-primary clinical endpoint and both changes
are clinically relevant (≥10 points on a scale of 0-100). No significant differences between the groups
were detected in the KOOS subdomains pain and activities in daily living. No significant difference in
the improvement of pain as measured by VAS was seen between the groups.
Secondary endpoints
A “responder” analysis (20% improvement) showed comparable results in the groups for total KOOS
and for its subdomains.
The clinical data have also been analysed when all patients reached at least 36 months follow-up. Twomain analyses have been documented: analysis according to mixed linear models and further analysisof the non-inferiority over time.
During the procedure the Applicant completed and submitted statistical analysis of up to 60 monthfollow-up data including graphical illustrations of a mixed model with time as a continuous and as acategorical variable. However, the mean structure of the KOOS (overall as well as for each of the
subdomains) is not linear over time. As a result, models anticipating a linear mean structure
overestimate the effect in the CC group beyond month 24. Therefore, the time wise comparisons oftreatment effects were based on a mixed model with time as a categorical variable.
The results of the different analyses are shown below. The results from 36 months on could only beconsidered as descriptive, because of the small number of patients already reaching later follow-up
time points.

Page 18 of 38

Mixed model with time as a categorical variable – all data up to month 36

p-value for the time by treatment interaction:
Treatment effect at month 36 (CC – MI):7.655,

0.070
p-value: 0.0481

Mixed model with time as a categorical variable – all data up to month 60

p-value for the time by treatment interaction:
Treatment effect at month 36 (CC – MI):
7.148
Treatment effect at month 48 (CC – MI):
6.893
Treatment effect at month 60 (CC – MI):
5.771

0.1192p-value: 0.0514
p-value: 0.1493
p-value: 0.4616

The additional analyses indicate that Change (increase) from baseline in KOOS in the ChondroCelectgroup (CC) is numerically more pronounced when compared to the Microfracture group (MI). Thisobservation is true not only for the overall KOOS but also for the subdomains. The additional mixed
model analysis with time as a categorical variable does not give statistically significant differences atmonths 36, 48 and 60 (when considering multiplicity).
The second analysis which was performed was the further analysis of the non-inferiority over time.
The Applicant has calculated the 95% CI for the treatment difference for each consecutive visit (i.e.
Page 19 of 38

months 2, 3, 6, 9, 12, 18, 24, 30, 36, 48, and 60) in order to assess a possible non-inferiority of CC(compared to MF). For data missing as a result of treatment failure, a last observation carried forward(LOCF) approach was applied.
The results for the change from baseline over time in Overall KOOS are presented in the table below.
Table 1 Overall KOOS – change from baseline till 36 months
Time point
2 months
3 months
6 months
9 months
12 months
18 months
24 months
30 months
36 months

Treatment
group
CC
MF
CC
MF
CC
MF
CC
MF
CC
MF
CC
MF
CC
MF
CC
MF
CC

N

Mean

Difference

51
59
51
59
51
59
51
56
51
57
44
51
45
52
43
51
41

6.66
6.42
12.51
10.44
14.27
13.18
17.63
13.83
16.96
13.54
18.45
15.50
19.38
13.09
20.71
15.16
22.14

0.24

MF

50

14.69

2.07
1.09
3.80
3.42
2.95
6.29
5.55
7.45

LS
mean
4.71
6.81
11.65
11.66
13.29
14.18
15.74
13.78
14.64
13.09
19.19
18.47
19.65
15.19
18.49
15.22
21.25

SE

Difference

95% CI

2.43
2.35
2.30
2.23
2.40
2.32
2.51
2.48
2.55
2.48
2.79
2.87
3.28
3.29
3.47
3.39
3.60

-2.10

-7.19, 2.98

-0.02

-4.84, 4.81

-0.89

-5.91, 4.14

1.96

-3.33, 7.25

1.55

-3.83, 6.93

0.72

-5.33, 6.78

4.46

-2.63, 11.55

3.27-3.92, 10.46

5.42-2.09, 12.94

15.83

3.48

Source data: TIGACT01&EXT, efficacy tables – analysis of month 36 data, 11 May 2009

The data show that the (unadjusted) mean change from baseline is higher for patients in the
ChondroCelect group than for patients in the microfracture group at all time points and with a gradualincrease over time (which is also found in the adjusted means).
Non-inferiority of ChondroCelect compared to microfracture is confirmed at all time points as thelower limit of the 95% CI for the difference between the adjusted means is above the pre-defined deltaof -9% points for all time points.
Neither BMI nor Gender have a significant influence on the overall KOOS.

Page 20 of 38

Treatment failures
Treatment failure is defined as “the decision by the participating orthopaedic surgeon to proceed witha re-intervention (i.e. new procedure) on the same defect (index lesion) based on persistence orrecurrence of symptoms as reported by the patient”. In the context of this definition, any operation on
the involved knee that involves the index lesion to a clinically relevant extent (i.e. 20% or more of its
surface), or is intended as a result of clinical treatment failure is considered a re-intervention.
Generally, the surgeon relies on MRI and/or arthroscopic assessment to confirm the patient’s
complaints are caused by failure of the therapeutic intervention on the index lesions and to exclude
possible other causes (e.g. a new lesion).
After 36 months post-surgery follow-up, the total number of treatment failures is 2 for the
ChondroCelect group and 7 for the microfracture group (p=0.178). However, as the inefficacy of thetherapeutic procedure is considered a serious AE, since requiring a surgical re-intervention withhospitalisation, it was felt important to include all known treatment failures up to the 36 month time
point and not only those that effectively occurred within a 36-months post-surgery timeframe. As aresult, the cumulative number of treatment failures becomes 5 for the ChondroCelect group (9.8%)
and 9 for the microfracture group (15%) (p=0.569), as outlined in the table below. These failure rates
are concurring with failure rates reported in published literature on ACI and microfracture (Peterson etal., 2000; Peterson et al., 2002; Peterson et al., 2003; Micheli et al., 2006; Wood et al., 2006; Minas etal., 2009; Mithoefer et al., 2009).
Table 2 TIG/ACT/01&EXT – treatment failures
AEs reported over a 36 month
post-operative period
Total number of treated patients
Treatment failures after 36 months
follow-up
Treatment failures - all cases
known at time of 36 months
database cut-off

P-value*

ChondroCelectMicrofracture

N
51
2

%
100%
3.9%

N
61
7

%
100%
11%

0.178

5

9.8%

9

15%

0.569

As is shown in table 2, fewer re-interventions for inefficacy were reported in patients treated with
ChondroCelect compared to microfracture (i.e. 5 out of 51 patients [9.8%] versus 9 out of 61 patients[15%], respectively). Treatment failures in the ChondroCelect treated patients were all associated withsome degree of periost loosening or graft delamination whereas in the microfracture group the
majority of re-interventions were reported to be associated with insufficient or inadequate repair tissue
formation. As the use of a biological membrane is expected to result in less friction at the graft surface(i.e. less hypertrophy and less crepitations), the use of a biological membrane instead of periost may
possibly reduce the frequency of treatment failures upon treatment with ChondroCelect.

Ancillary analyses•

Analysis performed across trials (pooled analyses and meta-analysis)

N/A•

Clinical studies in special populations

N/A•

Supportive study(ies)Page 21 of 38

Prospective, long-term follow-up study of patients in the Belgian Armed Forces treated with
ChondroCelect (TIG/ACT/02)
Methodology and baseline data
This study is a prospective, non-comparative, open-label study of 2 to 5 years’ duration in 20 patientswith single and multiple symptomatic cartilage defects, in any location of the knee, who underwent
CCI using ChondroCelect. Patients satisfying the inclusion and exclusion criteria were administered
ChondroCelect during an arthrotomy which occurred approximately 4 weeks after the arthroscopic
procurement of cartilage. Approximately 1 week following arthrotomy, they were discharged from thehospital and invited for regular follow-up visits for up to 5 years after CCI. Clinical outcome, knee
pain and activity levels are assessed before (pre-operatively) and after CCI by the KOOS, visual
analogue scale (VAS) for pain, Activity Rating Scale (ARS) and military tests for physical fitness(MTLG). Data on pre-defect activity levels were available for the ARS and were expected to beavailable for MTLG.
Secondary objectives of this study included to assess the extent to which the ARS and MTLG scores
return to their pre-defect levels within a 5-year post-operative follow-up period. An additional efficacy
endpoint listed in the SAP is to assess the change from preoperative baseline in MRI measurements. A
final objective is to assess the safety of CCI with ChondroCelect in this specific patient population
with single or multiple symptomatic cartilage defects in the knee of any location.
Patients with symptomatic cartilage defects in the knee of any location were eligible for inclusion if
they, were between 18-50 years of age, had a total cumulative cartilage defect between 1 and 21 cm2and agreed to adhere to the rehabilitation regimen and the restrictions with regard to concomitant
medication.
The study population enrolled was characterized by a male predominance (80%), a relatively high age(65% ≥40 years), relatively high body mass index (BMI) (60% >25 kg/m2), and a relatively recent
onset of symptoms (mean: 0.9 years; median 0.5 years, range: 0 - 4 years). A femoral cartilage lesion
was reported in 95% (19/20) of patients, a patellar lesion in 40% (8/20) and a tibial lesion in 15%(3/20). A total of 35 lesions were reported in 20 patients. The majority of patients had only one lesion(60%;12/20), whilst the remaining patients had two (10%; 2/20), three (25%; 5/20) or four (5%; 1/20)
lesions. One of the patients with three lesions and the patient with four lesions each had three lesions
treated with CCI. All other patients (18/20; 90%) had only single lesions treated with CCI. Of the 7patients with multiple lesions who did not have all their lesions treated with CCI, four had their otherlesions treated with either shaving (4 lesions in 3 patients) or microfracture (1 lesion in 1 patient) andthree had untreated lesions.
Of all reported lesions, 80% were reported to be of ICRS Grade III or IV. Of 24 femoral lesions
reported in 19 patients, 21 were treated with CCI. All femoral lesions were ICRS grade III-IV. Two of
the femoral lesions not treated with CCI were ICRS Grade IV and were located on the trochlea, one ofthese had been treated with microfracture at arthroscopy; the third untreated femoral lesion was also
located on the trochlea and was shaved at arthroscopy (lesion grade unknown). Of 8 patellar lesions
reported in 8 patients, three were treated with CCI (one ICRS grade II, one ICRS grade III and one
ICRS grade IV). Of the five untreated patella lesions, three were ICRS Grade I and two were ICRS
Grade III. One of the grade I patella lesions not treated with CCI and one of the grade III patellalesions not treated with CCI had been shaved at arthroscopy. Three tibial lesions were reported in 3
patients, none of which were treated with CCI. Two of the tibial lesions were ICRS grade II and one
was ICRS grade II to III. One of the grade II tibial lesions had been shaved at arthroscopy. Of allenrolled patients, 60% (12/20) had undergone previous cartilage repair surgery at least once (45%
[9/20] debridement, 10% [2/20]) microfracture, 5% [1/20]) abrasion arthroplasty, and 5% [1/20])
multiple osteochondral autologous grafts), 60% had a previous meniscus operation, and 20% had
previous ligament surgery at baseline. Two patients (9%) had an ACL repair and five patients (23%)
had meniscus surgery during the arthroscopy performed for the harvest biopsy. The lesion size treatedwith ChondroCelect was 2.33 cm² (SD 1.16; range, 0.8 - 9.2 cm2).

Page 22 of 38

Results

At 24 months following CCI, the patients’ clinical status was improved compared to baseline: meanchange in Overall KOOS 28.3 [95% CI 11.28, 45.1; n=9]); VAS (mean change -37.3 [95% CI -63.2, 11.5; n=9]); ARS total score at 24 months was 1.0 (95% CI: -0.2 to 2.2; n=7) indicating a trend
towards improved.

The percentage of patients with asymptomatic knees (patient categorization derived from KOOS
scores) was increased from none at baseline (0/19 patients) to 38% at Month 18 (5/13 patients) and
56% at Month 24 (5/9 patients).

There was a trend towards an improvement in the patients’ activity level at 18 and 24 months
compared to pre-operative baseline, although their activity level remained below their pre-defectlevels. The data on MTLG were insufficient to draw any conclusion.

Overall discussion on Efficacy
The efficacy evaluation of ChondroCelect is based on one pivotal study. At 12 months post-surgery,structural assessments (histology and MRI) were performed, and at 12 to 18 months post-surgery theclinical outcome was assessed. In line with the testing strategy as provided with the statistical analysis

Page 23 of 38

plan, superiority of ChondroCelect compared to microfracture could be shown for both endpoints
describing structural repair
The ICRSII had been developed within the trial, and the validity of this new tool had not beenassessed prior to starting the trial. This finding could not be corrected post-hoc. However, the need todevelop a suitable assessment method for structural repair was acknowledged, as well as the fact thatthe new ICRSII score was developed in a blinded manner.
A further issue was that many of the tissue sections could not be assessed which lead to 20% of
missing data. In the course of the procedure the missing data were provided, which strengthened thesuperiority claim of structural repair.
With respect to the clinical component (change in overall KOOS) non-inferiority was proven. The
clinical non-inferiority in the KOOS at 12-18 months was explained by the fact that cartilage requires
a longer time to be repaired, given the bradytrophic nature of human joint cartilage and the long timerequired for differentiation and functional repair. However, statistically significant superiority overmicrofracture at later time points could not be shown, although the formal requirements todemonstrate non-inferiority at 36 months are fulfilled.
In the supportive study TIG/ACT/02 the results of the informal interim analysis show a trend towards
clinical benefit. However, only 9/20 patients reached the 24 month time point by the time of theanalysis and were assessed for efficacy. The contribution of this study to the benefit/risk analysis of
the product is small.

Clinical safety• Patient exposure
A total of 463 patients have been exposed to ChondroCelect. In the two clinical studies 71 patients w
were treated with ChondroCelect, and 61 underwent microfracture treatment. Twenty-two (22)patients were included in the expanded access program and 370 patients were included in thecompassionate use program. Safety data from 334 patients are available from the compassionate use
program. In both the clinical studies and programs, the absolute dose of ChondroCelect received wasdetermined by the size of the lesion(s) treated.
•

Adverse eventsFirst, the overall frequencies of adverse events (AEs) between the two groups are summarised. Then,
those AEs that occurred more frequently in the ChondroCelect group as compared to the microfracturegroup are discussed.
Comparative AE frequencies (TIG/ACT/01&EXT – ChondroCelect vs microfracture)
Table 3 provides an overview of the frequencies of treatment-emergent adverse events (TEAEs) inboth treatment groups in the pivotal clinical trial (ChondroCelect and microfracture). Overall, patientstreated with either ChondroCelect or microfracture show a similar frequency pattern of TEAEs. A
slightly larger proportion of the patients in the ChondroCelect group experienced at least one TEAE
when compared to microfracture (98% versus 82%); a similar pattern is also observed when only the
related TEAEs are considered (78% versus 62%). The number of patients that experienced a severe
TEAE, however, is very similar in both treatment groups. In contrast, the number of serious adverse
events (SAEs) or the number of patients with an adverse event (AE) leading to discontinuation, washigher in the microfracture group (respectively 9.8% versus 18%, and 0% versus 4.9%). The totality ofthese data suggests that, despite the observed excess of TEAEs in the ChondroCelect group, thepatient’s functionality was not mayoral impacted. There is thus no indication that patients treated with
ChondroCelect in the 2-step ACI procedure are significantly more impaired by AEs than patientstreated by a 1-step microfracture technique.

Page 24 of 38

Table 3 TIG/ACT/01&EXT - Overall comparative AE frequencies

ChondroCelectAEs reported over a 36 month
post-operative period°
Total number of treated patients
Patients with at least one TEAE
Patients with at least one severe
TEAE
Patients with at least one related
TEAE
Patients with at least one
treatment-emergent SAE
Patients with at least one AE
leading to discontinuation

Microfracture

N
51
50

%
100%
98%

N
61
50

%
100%
82%

14

27%

15

25%

40

78%

38

62%

5

9.8%

11

18%

0

0.0%

3

4.9%

Reference: Database cut-off TIG/ACT/01&EXT (13-Feb-2008)° AEs are presented as number of patients experiencing at least one AE

A similar pattern in frequencies of TEAEs between both treatment groups is further confirmed whenthe AEs are summarised by body system (Table 4). Up to the 36 months time point, the highest
incidence of TEAEs in both treatment groups were observed in the following four body systems: i)
Musculoskeletal&
Connective
TissueDisorders,ii) Infections and Infestations, iii) Injury, Poisoning & Procedural Complications,and iv) General Disorders & Administration Site Disorders. The incidence in the Musculoskeletal &Connective Disorders as well as in the Injury, Poisoning & Procedural Complications body system
was higher in the ChondroCelect group as compared to the microfracture group (respectively 92%
versus 77%, p=0.038; and 41% versus 25%, p=0.070). These observed differences relate to somespecific AEs in the ChondroCelect group, and will be further discussed here below. For all other bodysystems, the frequency in AEs was quite similar between both treatment groups and no statisticaldifferences could be found.
Table 4 TIG/ACT/01&EXT – Summary of treatment-emergent AEs by body system
ChondroCelectMicrofracture

N
51
47

%
100%
92%

N
61
47

%
100%
77%

0.038

30

59%

33

54%

0.703

Injury, Poisoning & Procedural
Complications
General Disorders &Administration Site Disorders
Gastrointestinal Disorders

21

41%

15

25%

0.070

18

35%

15

25%

0.298

13

25%

11

18%

0.364

Nervous System Disorders

9

18%

18

30%

0.185

Psychiatric Disorders

9

18%

9

15%

0.798

Skin & Subcutaneous Tissue
Disorders

6

12%

4

6.6%

0.508

AEs reported over a 36 month
post-operative period°
Total number of treated patients
Musculoskeletal & Connective
Tissue Disorders
Infections & Infestations

Page 25 of 38

P-value*Surgical & Medical Procedures

5

9.8%

3

4.9%

0.465

Investigations

4

7.8%

6

9.8%

0.753

Vascular Disorders

4

7.8%

5

8.2%

1.000

Cardiac Disorders

3

5.9%

1

1.6%

0.329

Immune System Disorders

2

3.9%

3

4.9%

1.000

Respiratory, Thoracic &Mediastinal Disorders

1

2.0%

5

8.2%

0.217

Reference: Database cut-off TIG/ACT/01&EXT (13-Feb-2008)° AEs are presented as number of patients; an AE is counted only once per patient* Comparison of treatment groups by Fisher’s exact test

When applying a conservative statistical significance of p<0.1, a selection of those AEs that are more
frequently observed in the ChondroCelect group as compared to the microfracture group up to the 36
months time point is obtained. These are summarised in Table 5. As could be expected, four of theseselected AEs categorised in the Musculoskeletal & Connective Tissue Disorders group (i.e. cartilage
hypertrophy, joint swelling, joint crepitation, and joint effusion), whereas influenza-like illness iscategorised in the General Disorders & Administration Site Disorders group (of note: this body system
also includes the treatment failures, which will be discussed in a later section). Graft complication iscategorised in the Injury, Poisoning & Procedural Complications group.
The vast majority of the ChondroCelect specific AEs all occurred during the first 18 months postsurgery, with the exception of joint effusion (Table 5). Each of these events will be discussed infurther detail in the paragraphs below.
Table 5 TIG/ACT/01&EXT – ChondroCelect specific AEs
AEs reported post-operatively°

Cartilage hypertrophy

Period between
0-18 months
CC
MF(N=51)(N=61)
14
8

Joint swelling

11

3

Joint crepitation

7

3

Joint effusion

4

5

Influenza-like illness

40Graft Complication

30Period between 0-36 months
CC(N=51)
14
(27%)
11
(22%)
9
(18%)
12
(24%)
4
(7.8%)
3(5.9%)

MF(N=61)
8(13%)
4(6.6%)
4(6.6%)
6(9.8%)
0(0.0%)
0(0.0%)

P-value*
0.093
0.026
0.082
0.070
0.040
0.091

Reference: Database cut-off TIG/ACT/01&EXT (13-Feb-2008)° Selected based on p<0.1, AEs are presented as number of patients; an AE is counted only once per patient* Comparison of treatment groups by Fisher’s exact test

Page 26 of 38

Symptomatic cartilage hypertrophy
Symptomatic cartilage hypertrophy is an undesirable AE that may result in physical impairment
requiring surgical arthroscopic intervention. Symptomatic cartilage hypertrophy is generally resolved
after arthroscopic shaving during day-care arthroscopy.
The events of cartilage hypertrophy included both those events that were symptomatic and those thatwere asymptomatic. The reporting of the latter type of (asymptomatic) hypertrophy occurred mostly at
1 year, as it was observed at the 12-month arthroscopic endpoint biopsy procedure related to theclinical protocol.
Of the 14 ChondroCelect-treated patients who had AEs of cartilage hypertrophy recorded, 7 had
symptomatic AEs (7/51 [14%]). The other 7 patients had AEs that were asymptomatic. In the
microfracture group, 7 of the 8 patients had asymptomatic AEs of cartilage hypertrophy and one was
symptomatic (1/61 [2%]). The difference between the two treatment groups of the clinically relevant
symptomatic hypertrophy is statistically significant (p = 0.022). It is worth noting that the majority ofthese events occurred in the first 18 months post-surgery, indicating that this event is related to theregenerative phase of the repair tissue. All reported AEs of cartilage hypertrophy were mild or
moderate in severity in both treatment groups. None was recorded as severe and none was reported asserious.
In the pivotal clinical trial, a periosteal flap was used to cover the ChondroCelect implant as this wasat that time the standard surgical procedure. However, the use of a periosteal flap to cover the cultured
chondrocytes is also generally considered to involve a risk of cartilage hypertrophy. Indeed, literature
data indicate that tissue hypertrophy can be related to the periosteal flap that is used to cover the defectbefore injection of the cells (Gooding et al., 2006). In recent publications, the potential risk ofhypertrophy was reported to be reduced with the use of biological membranes without periosteal cells(Haddo et al, 2004; Gooding et al., 2006; Steinwachs and Kreuz, 2007). In current clinical practice,
the use of a periosteal cover has decreased over the last years in favour of the use of biologicalmembranes. The preference for collagen membranes was also confirmed by the experts in the ad-hoc
scientific advisory group organised by EMEA on October 13, 2008. It is anticipated that the frequency
of hypertrophy as observed in the clinical trial can be reduced when a biological membrane is used.,This is supported by a comparison of the symptomatic hypertrophy frequency observed in the pivotal
trial population (7/51 patients, i.e. 14%) and the patients treated under compassionate use (6/334
patients, i.e. 1.8%).
Joint swelling
The reported frequency of joint swelling is higher after ChondroCelect than after microfracture and ismainly explained by the arthrotomy performed for the ChondroCelect implantation. Knee swellingsuggests the accumulation of fluid in and/or around the knee. It is a well-described symptom after
arthrotomy as a result of the inflammatory synovial reaction due to incision (Muckle, 1984). This isfurther confirmed by analysing the temporal relationship of the reported joint swelling events withsurgery, showing a high frequency and a significant difference with microfracture in the first weeks
after the intervention. 7 of the 11 patients reported with joint swelling after ChondroCelectexperienced the AE in the first 4 weeks after intervention, compared to none after microfracture(p=0.003). This earlier onset in the ChondroCelect group is linked to the arthrotomy procedure. After
this initial 4-week post-operative period, no significant differences between the 2 groups were reported(i.e. 3 patients in the ChondroCelect group versus 4 patients in the microfracture group). Postoperative swelling is not associated with a significant risk and is temporary. No events of jointswelling were recorded as severe during the study, and none was reported as serious.
Compassionate use program
Comparison of TIG/ACT/01&EXT and compassionate use AEs
In Table 6, a comparison is made between the safety results of the pivotal trial population and thepatients treated under compassionate use, this latter population being considered to be more
representative for the real-life situation. In this table, only those AEs that are considered related toPage 27 of 38

ChondroCelect or to the surgical intervention are reported. Overall, the frequencies of AEs are
consistently lower in the compassionate use population as compared to the TIG/ACT/01&EXT
population. This is likely explained by a relative underreporting of AEs in the real-life situation,
outside the controlled environment of a clinical trial. Assuming a 50% underreporting rate, the overallfrequency for most of the reported AEs becomes similar to the frequencies observed in the clinical
trial.
Table 6 TIG/ACT/01&EXT and CUP – comparison of most frequent related† AEs
AEs reported post-operatively°

Total number of patients
Patients with at least one related
AE
Arthralgia (knee pain)

TIG/ACT/01&EXT

CUP

N
51
40

%
100%
78%

N
334*
155

%
100%
45%

24

47%

67

20%

6

1.8%

Cartilage hypertrophy symptomatic(Total)

7

14%

(14)

(27%)

Joint crepitation

9

18%

17

5.1%

Joint swelling

7

14%

23

6.9%

Joint effusion

5

9.8%

24

7.2%

Treatment failure

5‡

9.8%

9

2.7%

Reference: TIG/ACT/01&EXT database cut-off 13 February 2008 (36 months), CUP database cut-off 7 January
2009° AEs are presented as number of patients; an AE is counted only once per patient* Number of patients contributing to the safety population at time of database cut-off (7 January 2009)†
Related to ChondroCelect or surgical intervention‡
All cases known at the time of the 36 months database cut-off

As can be seen from the table, knee pain (Arthralgia) is the most frequently reported treatment-related
AE in both the pivotal study (24/51 patients, i.e. 47%) and the CUP(67/334 patients, i.e. 20%). In the pivotal study, a similar frequency of Arthralgia was observed in the
ChondroCelect (47%) and microfracture (43%) groups up to the 36 months cut-off. This AE was notdiscussed in the overall analysis of the TIG/ACT/01&EXT data as the difference between the twotreatment groups was not significant (p=0.704).
The incidence of symptomatic cartilage hypertrophy was reduced to 1.8% in the CUP patientscompared to 14% in the pivotal study. It can be assumed that the 6 reported AEs in the CUP patientsare all symptomatic AEs, as these patients did not undergo an endpoint biopsy. In the patients treatedunder compassionate use, ChondroCelect has been covered with a biological membrane(ChondroGide®) in the majority of the patients in contrast to the use of a periosteal flap in the pivotal
trial. The lower incidence of cartilage hypertrophy observed in the CUP is in line with other reports
published in the literature on low hypertrophy rates with a biological membrane (Haddo et al, 2004;
Gooding et al., 2006; Steinwachs and Kreuz, 2007), and illustrates that a similar benefit of using a
biological membrane can also be obtained for ChondroCelect.
The relatively high incidence of joint effusion in the compassionate use patients (7.2% of patients in
the CUP as compared to 9.8% in the pivotal trial) is considered to result from the fact that in thispopulation more salvage cases with more complex concomitant knee pathology have been treated. A
detailed assessment of these cases reveals that in all patients but 2, the effusion was considered to be
Page 28 of 38

of mild (14) or moderate (8) intensity. None of the 24 cases was reported to be serious. In 15 cases, thejoint effusion was considered to be related to the surgical procedure (3 unknown, 6 not related tosurgery), and in 7 patients the event was considered to be related to ChondroCelect.
For all other AEs, similar or slightly lower frequencies are observed when considering a 50%
underreporting in the CUP (i.e. joint crepitation [18% versus 5.1%], joint swelling [14% versus 6.9%],and treatment failures [9.8% versus 2.7%]).
•

Serious adverse event/deaths/other significant events

Twenty four serious adverse events (SAEs) were reported in 16 patients (8 SAEs in 7 patients in the
TIG/ACT/01&EXT study and 16 SAEs in 9 patients in the TIG/ACT/02 study). Only one of the 24
cases was considered to be related (possibly) to ChondroCelect. In this case, the ChondroCelecttransplant was considered to have failed possibly because of loosening of the periosteal flap, and wasremoved; microfracture was subsequently performed. The majority of cases (14/24; 58%) wereconsidered to be unrelated to the study procedure. In the pivotal TIG/ACT/01&EXT there were 10
SAEs in 8 patients recorded in the microfracture group. All cases recorded for microfracture-treatedpatients were considered either unrelated or unlikely to be related to the surgical procedure.
From additional safety information gathered from the EAP and compassionate use program, there havebeen 26 SAEs reported for 18 patients (17 SAEs in 10 of the 22 patients in the EAP, 9 SAEs in 8 of
the 163 patients in the compassionate use program for whom safety data are available). Of these, only
one case was considered by the surgeon to be related (possibly) to ChondroCelect. In this case thepatient experienced a deficit in knee mobilisation of moderate severity, approximately 2 months after
the implantation of ChondroCelect (secured with ChondroGide). The patient underwent a procedure tomobilize the knee under anaesthesia.
There were no patient deaths recorded during the study. No patients are recorded as being
discontinued from the study due to SAEs.
•

Laboratory findings

No laboratory findings related to the ChondroCelect treatment were reported.
•

Safety in special populations

Twelve paediatric patients were treated in the compassionate use program with ChondroCelect.
Five of the 11 (45%) paediatric patients had no reported AE. The remaining 6 paediatric patients
reported a total of 11 AEs. None of the AEs reported was considered serious. None of the AEs wasconsidered to be related to ChondroCelect; most were considered to be related to surgery (7/11 events;64%). Most AEs (8/11; 73%) were of mild or moderate intensity and did not require any intervention
or medical therapy. Three events were recorded as being of severe intensity, one event of muscle
atrophy (n=2) and arthralgia (n=1).
There was one pregnancy during ChondroCelect therapy. The mother developed pre.eclampsia, had apremature birth of a normal child. The use of ChondroCelect is not recommended during pregnancy,
mainly because of the surgical procedures.
•

Safety related to drug-drug interactions and other interactions

No investigations have been performed•

Discontinuation due to adverse events

See efficacy part for discontinuation due to treatment failure.

Page 29 of 38

•

Post marketing experience

N/A•

Other relevant safety information

A clinically meaningful event that is not reported in the classical AE capturing relates to the impact ofthe procedures on the subchondral bone. Detailed assessment of the MRI data of the pivotal clinical
trial revealed that treatment with ChondroCelect resulted in less subchondral bone reaction ascompared to microfracture. A difference of 0.45 on the 0-3 global scale was observed in favour of
ChondroCelect (p=0.0559). In addition, the incidence of subchondral bone plate elevation was shown
to be higher in the microfracture group when compared to the ChondroCelect group (51.5% compared
to 25%, respectively).
The difference in subchondral bone reactions relates to the difference in surgical intervention. In
microfracture, chondral defects are treated by recruiting blood and cell populations including
mesenchymal stem cells from the underlying bone marrow. By physically disturbing the osteochondraljunction (upon puncturing the subchondral bone), an osteochondral defect is de facto created, and thebiology of the cartilage defect significantly altered. In contrast, in ACI cells are re-implanted into thedefect without damaging the subchondral bone. The consequences of the injury and its increased
subchondral bone reaction and moving up of the bone front might lead to poorer repair tissue,
decreased durability of the repair tissue, and consequently increased risk of treatment failure(Mithoefer et al., 2009). The moving of the bone front (ultimately leading to intra-lesional
osteophytes) might also have consequences for future re-interventions. Indeed, Minas et al., 2009
published that prior treatment affecting the subchondral bone such as microfracture increases thefailure rate of subsequent regenerative procedures. Finally, the biological stability of the osteochondraljunction can be of importance in the development of osteoarthritis, instability of the subchondral boneand progressive bone damage being important factors in progression to the disease (Dieppe andLohmander, 2005; McQueen, 2007). It is also anticipated that in genetically predisposed patients,
disturbing the osteochondral junction presents an additional risk for a fast progression to osteoarthritis(Luyten et al., 2009).
Discussion on Safety
Microfracture is performed in one arthroscopic procedure with either local (spinal) or generalanaesthesia, while ACI requires 2 interventions: an arthroscopy to inspect the defect and to obtain thebiopsy specimen, and open knee surgery (arthrotomy) in general anaesthesia for chondrocyte implant
four weeks later. In the case of patients included in the ChondroCelect arm of the pivotal trial a second
incision was made over the medial tibia to harvest the periosteal flap which was needed to cover thechondrocyte suspension.
The most likely AEs observed when treating with ChondroCelect are arthralgia, symptomatic cartilage
hypertrophy, joint crepitations, joint swelling, and joint effusion. Arthralgia is an expected andcommon consequence of knee surgery and occurs in both treatment arms. The data provided on the
CUP program as well as data from published literature suggest that it may be possible to reduce
ChondroCelect-related cartilage hypertrophy by the use of a collagen membrane. This modification
will reduce the potential for morbidity associated with the harvest of the periosteal flap. Joint
crepitation is a mild complication and occurs also in the normal population. Joint swelling is anothercomplication observed at a higher rate in the ChondroCelect group. It is a consequence of thearthrotomy surgical intervention and can as such not be avoided. However, it is a mild and transientcomplication. The incidence of joint effusion was higher after 18 months post-intervention than in the
period after the surgery, and the reason for this is not completely clear. Analysis of the individual
cases indicate that the underlying knee disease status as well as potentially higher physical activity rate
might be related to this occurrence. The cases were not severe or serious, and do therefore notrepresent a major safety signal.
Overall, the safety profile of ChondroCelect is considered acceptable. Considering that cartilage
hypertrophy may be reduced by use of a physical seal the main difference is related to arthrotomy andthe implantation procedure. No complications were seen in relation to the arthroscopic harvest biopsy
procedure.
Page 30 of 38

Considering the higher treatment failures after microfracture which require more surgical reinterventions microfracture and ChondroCelect implantation have a balanced safety profile.
The CHMP was of the opinion that the indications (section 4.1 of the SPC) should be reworded asfollows:
Repair of single symptomatic cartilage defects of the femoral condyle of the knee (International
Cartilage Repair Society [ICRS] grade III or IV) from 2 cm² onwards in adults. Concomitant
asymptomatic cartilage lesions (ICRS grade I or II) might be present
Demonstration of efficacy is based on a randomised controlled trial evaluating the efficacy of
ChondroCelect in patients with lesions between 1-5cm2.
The scientific reasons for this change are described below:
CHMP considered that putting a precise lower boundary would prevent physicians from treating
patients on-label who have lesions in sizes formally below 2cm2, for whom, however, ChondroCelecttreatment might nevertheless be medically indicated by the individual decision of the treating
physician. Likewise, CHMP recognised the greater need for the treatment of larger lesions, but wasconcerned about the amount of data available for larger lesions. Therefore, in line with previous
similar scenarios, the CHMP has taken the approach to put an indication that is permissive, but topoint out the limitations of the data and to clearly inform the prescribing physician in section 4.1. A
wording like this is usually perceived as stronger as compared to a wording in section 5.1, thus being
more in line with the overall principles of the CAT draft opinion. This allows the physician to take an
informed decision for a particular patient’s situation based on the knowledge of the availability ofevidence from the pivotal study.

2.5

Pharmacovigilance

Detailed description of the Pharmacovigilance system as agreed at CAT
The CAT considered that the Pharmacovigilance system as described by the Applicant fulfils thelegislative requirements.
Risk Management Plan as agreed at CAT
The MAA submitted a risk management plan, which included a risk minimisation plan and efficacy
follow-up plan.
Table Summary of the risk management plan
Important potential risks
Safety concern

Partial or complete delaminationof the periost flap, synovitis,
subchondral bone injuries

Proposed pharmacovigilance
Activities

Proposed risk minimisation
activities(routine and additional)(routine and additional)








Routine pharmacovigilance
Proactive training oforthopaedic surgeons andtheir staff on the use of the
product and the associatedprocedures
Solicited adverse reaction
Page 31 of 38



Information in section 5.3of the SPC on the findingsof synovitis andsubchondral bone injuries.
Pro-active training in theframework of a controlled
distribution system.

Safety concern

Proposed pharmacovigilance
Activities

Proposed risk minimisation
activities(routine and additional)(routine and additional)

reporting and interaction
with the surgeon based on
the medical dossier
Medical information andfeedback to the surgeon

Important identified risks
Safety concern

Symptomatic cartilage
hypertrophy

Proposed pharmacovigilance
Activities

Proposed risk minimisation
activities(routine and additional)(routine and additional)

Routine pharmacovigilance
Proactive training oforthopaedic surgeons andtheir staff on the use of the
product and the associatedprocedures
Solicited adverse reaction
reporting and interaction
with the surgeon based on
the medical dossier
Medical information andfeedback to the surgeon

Routine pharmacovigilance
Proactive training oforthopaedic surgeons andtheir staff on the use of the
product and the associatedprocedures
Solicited adverse reaction
reporting and interaction
with the surgeon based on
the medical dossier
Medical information andfeedback to the surgeon
Routine pharmacovigilance
Proactive training oforthopaedic surgeons andtheir staff on the use of the
product and the associatedprocedures
Solicited adverse reaction
reporting and interaction
with the surgeon based on
the medical dossier
Medical information andfeedback to the surgeon
Routine pharmacovigilance
Proactive training oforthopaedic surgeons andtheir staff on the use of the
product and the associatedprocedures
Solicited adverse reaction







Knee joint swelling







Knee joint crepitation







Joint effusionPage 32 of 38















Information in section 4.8of the SPC that the event ofcartilage hypertrophy canbe associated with the useof a periosteal flap insteadof a biological membrane.
Information in section 4.8of the SPC on the observed
incidence of this adverse
event.
Pro-active training in theframework of a controlled
distribution system.
Information in section 4.8of the SPC on the observed
incidence of this adverse
event.
Pro-active training in theframework of a controlled
distribution system.

Information in section 4.8of the SPC on the observed
incidence of this adverse
event.
Pro-active training in theframework of a controlled
distribution system.

Information in section 4.8of the SPC on the observed
incidence of this adverse
event.
Pro-active training in theframework of a controlled
distribution system.

Safety concern

Proposed pharmacovigilance
Activities

Proposed risk minimisation
activities(routine and additional)(routine and additional)
Arthrofibrosis








Ineffectiveness (treatment
failure)









reporting and interaction
with the surgeon based on
the medical dossier
Medical information andfeedback to the surgeon
Routine pharmacovigilance
Proactive training oforthopaedic surgeons andtheir staff on the use of the
product and the associatedprocedures
Solicited adverse reaction
reporting and interaction
with the surgeon based on
the medical dossier
Medical information andfeedback to the surgeon
Routine pharmacovigilance
Proactive training oforthopaedic surgeons andtheir staff on the use of the
product and the associatedprocedures
Solicited adverse reaction
reporting and interaction
with the surgeon based on
the medical dossier
Medical information andfeedback to the surgeon
Non-interventional Postmarketing safety andefficacy study.












Information in section 4.4of the SPC on risks
associated withconcomitant knee
pathologies or use outside
the target population.
Information in section 4.8of the SPC on the observed
incidence of this adverse
event.
Pro-active training in theframework of a controlled
distribution system.
Information in section 4.4of the SPC on risks
associated withconcomitant knee
pathologies or use outside
the target population.
Information in section 4.8of the SPC on the observed
incidence of this adverse
event.
Pro-active training in theframework of a controlled
distribution system.

Important missing information
Safety concern

Proposed pharmacovigilance
Activities(routine and additional)

Proposed risk minimisation
activities(routine and additional)

Long term durability of repair
and clinical data in patients withlarger lesions (from 4 cm²
onwards), and confirmatory
clinical data in patients withsmaller lesions














Routine pharmacovigilance
Proactive training oforthopaedic surgeons andtheir staff on the use of the
product and the associatedprocedures
Solicited adverse reaction
reporting and interaction
with the surgeon based on
the medical dossier
Medical information andfeedback to the surgeon
Continued follow-up ofpatients of the pivotal
clinical study(TIG/ACT/01&EXT).
.
Post-marketing safety andPage 33 of 38Post-marketing safety andefficacy study.
Further efficacy dataobtained in patients in aconfirmatory clinical study.

efficacy study.

The CAT, having considered the data submitted, was of the opinion that the risk management systemshould be requested according to the Article 14 (2) of the Regulation (EC) 1394/2007. There are thefollowing particular causes for concern:• There were deficiencies in the conduct of the pre-authorisation studies and uncertainties
related to the result of the submitted single pivotal trial.
• There is unknown long-term durability of the product efficacy.
• Benefit/risk of the product is significantly influenced by the level of compliance with thedefined procedures throughout the treatment with ChondroCelect, from the biopsy harvest till
the correct physiotherapy.
The CAT, having considered the data submitted in the application is of the opinion that the following
risk minimisation activities are necessary for the safe and effective use of the medicinal product:
The Marketing Authorisation Holder (MAH) shall ensure that the medicinal product will be distributed
only to Healthcare Establishments that meet criteria described in the Risk Management Plan.
The Marketing Authorisation Holder (MAH) shall ensure, prior to the distribution of the product to aparticular Healthcare Establishment, that all surgeons and other healthcare professionals involved in
the handling and administration of ChondroCelect or its components, as well as those involved infollow-up of patients treated with ChondroCelect in the Healthcare Establishment, receive training as
per the educational programme described in the Risk Management Plan.
The educational programme for healthcare professionals contains the following components:• Training material for Surgeons• Training material for other Healthcare Professionals• Informed consent for the patients to be signed prior to the treatment with ChondroCelectThe training materials for Surgeons shall include the following key messages and components:• Summary of Product Characteristics• The biopsy harvest procedure• The surgical checklist to be completed at the operating theatre immediately prior to the firstincision confirming the right patient, the right product, the right side of the implantation, andthe type of biological membrane and fibrin sealant to be used in the procedure.
• The implantation procedure by knee-joint arthrotomy• The follow-up protocol
The training material for other Healthcare Professionals shall include the following key messages andcomponents:• Summary of Product Characteristics• The need for screening of donors using patient questionnaire and laboratory tests for hepatitis C,
hepatitis B, HIV, and Syphilis• The handling of the biopsy harvest• The handling of ChondroCelect and its preparation for the implantation• The schedule of follow-up of patients• The recommended physiotherapy
The CAT also considered that performing of post-authorisation studies will need to be a part of thePharmacovigilance plan and Efficacy follow-up plan presented in the Risk Management Plan.

Page 34 of 38

In the Risk Management Plan, the MAH commits to confirm and extend the pivotal clinical study datawith an appropriately designed trial. The design should be subject to EMEA Scientific Advice, andagreed with the CAT.
In the Risk Management Plan, the MAH also commits to further study efficacy and safety of
ChondroCelect in large lesions. The design of such a study should be subject to EMEA Scientific
Advice, and agreed with the CAT.
The timetable for the conduct of the studies was agreed with the Applicant. The MAH commits tosubmit, within two weeks after the CHMP opinion, an update to the Risk Management Plan (RMP) to
include the following points:
a. Studies, and their protocol outlines as requested by CAT and CHMP to be reflected in the
Pharmacovigilance plan and Efficacy Follow-up plan.
b. Timetables of the actions in the Pharmacovigilance plan and in the Efficacy Follow-up plan:- Submission of application for Scientific Advice to EMEA regarding all interventional studies
planned in the RMP – Date of CHMP opinion + 2 month- Start of the studies in a way recommended by the Scientific Advice – within 1 year after adoption of
the requested EMEA Scientific Advice- Annual reporting providing interim analysis of safety and efficacy from the studies.
The CHMP agreed with the above

2.6

Overall conclusions, risk/benefit assessment and recommendation

Quality
The Applicant has made considerable progress towards the improvement of critical quality aspects inthe manufacture and control of ChondroCelect. The outstanding major concerns raised during theprocedure could be resolved and are now considered adequately addressed with data and/or follow-up
commitments. A number of control measures as well as adequate tools to monitor functionality of thecells and to perform a robust process validation have been successfully implemented. Some activities
related to the specification limits are still under development and await their final implementation. The
Applicant has committed to address these minor outstanding issues through follow-up measures.
In conclusion, information on development, manufacture and control of ChondroCelect Active
Substance and finished product have been presented in a satisfactory manner. The results of the tests
carried out indicate satisfactory consistency and uniformity of the manufacturing process and finishedproduct, and these in turn lead to the conclusion that the product should have a satisfactory anduniform performance in the clinic.
Non-clinical pharmacology and toxicology
Primary pharmacodynamic studies were performed in two animal models, an ectopic model in nu/nu
mice and an orthotopic model in goats. These pharmacodynamic studies were conducted non-GLP.
The implications of this deficiency to the validity and significance of the safety data collected in thepivotal goat study are considered tolerable.
The mouse ECFA assay was originally central on the one hand in validating the potency assay, and on
the other hand in correlating the potency data with the cartilage repair in clinically relevant setting, i.e.
implantation to knee. Since a direct correlation between the potency and the cartilage repair in patients
could not be demonstrated, the animal data would have been invaluable in providing evidence for thisPage 35 of 38

interrelationship. Since the Applicant has later developed a new functional assay to follow potency of
the Medicinal product during characterisation and process validation studies, the problems related to
the validity of the ECFA assay in bridging the potency and clinical efficacy data is no more an issue.
The studies in goats are adequate to demonstrate proof of principle in a clinically relevant setting.
However, the set of data is very limited and the Applicant did not demonstrate a valid correlation
between the ECFA histology score and cartilage repair in the orthotopic goat model. In addition,although the orthotopic goat model demonstrates the proof of concept of ChondroCelect-likechondrocytes, this model is not fully representing the human situation (such as using membrane/ fibrin
sealant) and is limited for cartilage repair in long-term.
Since data in humans are available, it is agreed that further data to obtain a real correlation between
the ECFA histology score and cartilage repair in the goat model is not appropriate.
Regarding the fibrin sealants used together with ChondroCelect compatibility data for the fibrin glue
TissuCol (Tisseel) have demonstrated the safe and effective use of this sealant with ChondroCelect in
non-clinical studies. The concomitant use of Quixil in the pivotal clinical trial did not reveal any safety
signal so far. The concomitant use of fibrin glue has been addressed in the SPC.
Efficacy
In one pivotal, multicentre, randomized, controlled phase III study ACI was compared to
Microfracture with regards to structural repair and KOOS. Results of the histological analysis of
structural repair at 12 months favour ChondroCelect and the difference is statistically significant for
both qualitative and quantitative analysis. It was, however, acknowledged that this end point was notin compliance with GCP as it was developed during the conduct of the study as the original a priori
determined primary efficacy point was considered as invalid.
The mean change in overall KOOS from baseline to the average of 12 to 18 months was slightly
higher for patients in the ChondroCelect group than for patients in the microfracture group. The results
fulfil the predefined criteria for non-inferiority and changes are clinically relevant.
The clinical data have also been analysed when all patients reached at least 36 months follow-up.
During the procedure the Applicant provided data for the pivotal clinical trial including graphicalillustrations of a mixed model with time as a categorical variable. The additional mixed model analysis
indicates that change (increase) from baseline in KOOS in the ChondroCelect group (CC) isnumerically more pronounced when compared to the Microfracture group (MI), but does not give astatistically significant difference at months 36, 48 and 60 (when considering multiplicity) in favor of
ChondroCelect. However, it does fulfill the formal requirement for non-inferiority. Neither BMI nor
Gender has a significant influence on the overall KOOS. The results of time points beyond 36 months
were to be taken only as descriptive, because of the small number of patients already reaching later
follow-up time points (i.e. 48 and 60 months).
SafetyThe overall safety summary shows that the main difference in treatment related adverse events
compared to microfracture is related to the open knee surgery (arthrotomy) which causes an increasein joint swelling and possible joint effusion. Cartilage hypertrophy can be reduced by using abiomembrane to cover the lesion, and will therefore not pose a major safety concern in futureapplications of ChondroCelect. However, a higher number of patients in the microfracture arm have atreatment failure and require a subsequent surgical intervention. Therefore the short and long termcomplication rate is not higher for ChondroCelect compared to microfracture.
The Applicant has presented an acceptable RMP including a proposal for a confirmatory randomized
controlled trial and an observational follow-up study.
From the safety database all the adverse reactions reported in clinical trials have been included in theSummary of Product Characteristics

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•User consultation

The user/readability testing is considered acceptable. The information on user testing provided by the
Applicant was found to be satisfactory.
Risk-benefit assessment
The CAT, having considered the data submitted, was of the opinion that the risk management systemshould be requested according to the Article 14 (2) of the Regulation (EC) 1394/2007. There are thefollowing particular causes for concern:• There were deficiencies in the conduct of the pre-authorisation studies and uncertainties
related to the result of the submitted single pivotal trial.
• There is unknown long-term durability of the product efficacy.
• Benefit/risk of the product is significantly influenced by the level of compliance with thedefined procedures throughout the treatment with ChondroCelect, from the biopsy harvest till
the correct physiotherapy.
Therefore, fully produced Risk Management Plan, including Pharmacovigilance plan, Risk
Minimisation plan and Efficacy Follow-up plan was required. The details are described above in the
Chapter 3.5 – Pharmacovigilance.
Benefits
The benefits of the ACI technique using ChondroCelect for smaller lesions (up to 5 cm2) are based on
the demonstration of superiority for structural repair and non-inferiority in the clinical analysis(KOOS) compared to the standard treatment microfracture.
ACI techniques would particularly be suitable for larger defects (≥4 cm2), for which other suitable
treatment does not exist. While limited data are available with ChondroCelect the literature data
provided confirm this observation. The repair of full size chondrocyte defects and the restoration offunctional cartilage need special consideration with the aim to reduce the risk of developing knee
osteoarthritis on the long term.
Risks
The combination of current conservative and invasive therapies for cartilage injuries is associated withreasonably good control of symptoms and physical function in the short term. However, it is less clear
whether these therapies provide a good long term outcome or whether the injury will have long term
consequences, such as secondary arthrosis.
BalanceGiven that microfracture is considered an effective standard treatment for femoral cartilage lesions
below 3-4cm² size, and given the proven statistical non-inferiority of ACI with ChondroCelect tomicrofracture as well as the balanced overall safety profile the final overall B/R is considered positive.
However, considering the limited data as efficacy is only based on one single pivotal trial, follow upof the clinical efficacy is required.
Recommendation
Based on the CAT/CHMP review of data on quality, safety and efficacy, the CAT considered bymajority that the risk-benefit balance of ChondroCelect in the treatment of repair of single
symptomatic cartilaginous defects of the femoral condyles of the knee (ICRS grade III or IV) in adults(Concomitant asymptomatic cartilage lesions (ICRS grade I or II) might be present) was favourable
and therefore recommended the granting of the marketing authorisation.
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The CAT, having considered the data submitted, was of the opinion that the risk management systemshould be requested according to the Article 14 (2) of the Regulation (EC) 1394/2007. There are thefollowing particular causes for concern:• There were deficiencies in the conduct of the pre-authorisation studies and uncertainties
related to the result of the submitted single pivotal trial.
• There is unknown long-term durability of the product efficacy.
• Benefit/risk of the product is significantly influenced by the level of compliance with thedefined procedures throughout the treatment with ChondroCelect, from the biopsy harvest till
the correct physiotherapy.
The CHMP agreed with the Benefit-Risk assessment and recommendation for approval of theMarketing Authorisation for ChondroCelect as expressed by the CAT.
The CHMP had a comment to amend the wording of the indication (section 4.1 of the SPC) as
follows:
Repair of single symptomatic cartilage defects of the femoral condyle of the knee (International
Cartilage Repair Society [ICRS] grade III or IV) from 2 cm² onwards in adults. Concomitant
asymptomatic cartilage lesions (ICRS grade I or II) might be present
Demonstration of efficacy is based on a randomised controlled trial evaluating the efficacy of
ChondroCelect in patients with lesions between 1-5cm2.
The scientific reasons for this change are described below:
CHMP considered that putting a precise lower boundary would prevent physicians from treating
patients on-label who have lesions in sizes formally below 2cm2, for whom, however, ChondroCelecttreatment might nevertheless be medically indicated by the individual decision of the treating
physician. Likewise, CHMP recognised the greater need for the treatment of larger lesions, but wasconcerned about the limited amount of data available for larger lesions. Therefore, in line withprevious similar scenarios, the CHMP has taken the approach to put an indication that is permissive,
but to point out the limitations of the data and to clearly inform the prescribing physician in section
4.1. A wording like this is usually perceived as stronger as compared to a wording in section 5.1, thus
being more in line with the overall outcome of the CAT draft opinion. This allows the physician totake an informed decision for a particular patient’s situation based on the knowledge of the availabilityof evidence from the pivotal study.

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