2011年9月1日木曜日

アバスチン FDAは承認取消し、薬食審は承認へ

アバスチンが再発乳がんへ適応されるようだ。
FDAは、転移性乳がんへの適応の承認取り消し勧告を出した。
薬食審は、中外製薬からの見解をもとに審議、試験結果に大きな影響を
与えないとの結論を出した。

詳細は不明だが、違いは、統計上の生存率の見方によるようだ。

FDAの諮問委員会は、製薬会社が提出したアバスチンの臨床報告が、効用
が高かった人を対象としたと判断。
アバスチンとパクリタキセルとの併用、副作用を考慮して、特定な患者
を対象とするように提案したが、承認されず、再申請となり、6年必要と
なるようだ。
アバスチンのPFS 5.5ヶ月の改善の報告が、他の同様な審査から得ること
ができず、特殊な例との印象になった。
偽薬やベバシズマブとパクリタキセル併用でも、効果に差が無かった。
副作用が重篤になるため、承認を取消しにしたようだ。

薬食審は、再発乳がんに対して、アバスチンとパクリタキセルとの併用
を承認するようだ。

対照的な審査結果なので、比較したいが、詳細な根拠が不明のため比較
できない。
このような事例もドラッグ・ラグなのだろうか。
海外の審査を基準にするなら、日本でもアバスチンは承認取消しと思う。

ワクチン禍再来か


Avastin FINAL


Local cancer fighter reacts to FDA's decision


---薬食審・第二部会 アバスチンの再発乳がん適応を再審議 承認を了承---
公開日時 2011/08/26 05:02
http://www.mixonline.jp/Article/tabid/55/artid/41294/Default.aspx

 厚生労働省の薬食審医薬品第二部会は8月25日、抗がん剤アバスチンに手術不能または再発の乳がんの適応を追加することについて、8月1日の部会に続いて審議し、承認を了承した。ほか同日は、同剤含め新薬7剤を審議し、承認してよいとの結論になった。9月にも正式承認となる運び。
 アバスチン(ベバシズマブ遺伝子組換え)の適応追加は、抗がん剤パクリタキセルと併用する形で中外製薬が09年10月に承認申請していたもの。前回の部会では、海外フェーズ3試験(E2100)で、中間解析段階で無増悪生存期間(PFS、主要評価項目)の高い改善効果が得られたために試験が早期に中止になったことに対し、中止した段階で偶然に効果が高く出たのではないかとの委員の指摘で、継続審議となっていた。
 医薬食品局審査管理課の担当官によると、25日の部会では、中外製薬から試験結果の統計上の解釈に関する見解が提出され、それなどをもとに審議。その結果、委員の指摘を踏まえたとしても、試験結果そのものに大きな影響を与えないとの結論が全員一致で得られた。米国FDAの諮問委員会が6月に同適応の承認取り消し勧告など海外の状況も含め、総合的に判断し、承認して差し支えないとの結論になった。なお、再審査期間は残余期間(平成27年4月17日)。

希少難病CAPS治療薬カナキヌマブ承認へ 新規HCV治療薬も同日の部会のそのほか結果は次のとおり。

【審議品目】
▽フェソロデックス筋注250mg(フルベストラント、アストラゼネカ):「閉経後乳がん」を効能・効果とする新有効成分含有医薬品。再審査期間8年。海外73カ国で承認。
▽タコシール組織接着用シート(ヒトフィブリノゲン、トロンビン画分、CSLベーリング):「肝臓外科、肺外科、心臓血管外科、産婦人科及び泌尿器外科領域における手術時の組織の接着・閉鎖」を効能・効果とする新医療用配合剤。再審査期間6年。海外49カ国で承認。
▽ムコスタ点眼液UD2%(レバミピド、大塚製薬):「ドライアイ」を効能・効果とする新投与経路医薬品。再審査期間6年。海外承認なし。
▽イトリゾール内容液1%(イトラコナゾール、ヤンセンファーマ):「真菌感染症/真菌感染が疑われる発熱性好中球減少症/好中球減少が予想される血液増悪腫瘍または造血幹細胞移植患者における深在性真菌症の予防」を効能・効果とする新効能・新用量医薬品。再審査期間は、「真菌感染症」についてはない。「発熱性好中球減少症」では残余期間(平成24年10月19日)。「深在性真菌症の予防」は4年。海外64カ国で承認。
▽テラビック錠250mg(テラプレビル、田辺三菱製薬):ジェノタイプ1aまたは2bのC型慢性肝炎の治療薬で「血中HCV RNA量が高値の未治療患者、インターフェロン製剤の単独療法、又はリバビリンとの併用で無効または再燃となった患者」を効能・効果とする新有効成分含有医薬品。再審査期間8年。米国で今年承認。
 HCV(C型肝炎ウイルス)の複製に関与するNS3-4Aセリンプロテアーゼを阻害することでHCVの増殖を抑制する新規作用の治療薬。国内治験では、標準治療のペグインターフェロンとリバビリンに併用した場合、従来のペグインターフェロンとリバビリン療法と比較して、治療効果の改善と治療期間の短縮が確認されている。過去にペグインターフェロンとリバビリンで治療したものの、再燃、無効患者でも有効性が認められた。今年1月に承認申請し、優先審査された。
▽イラリス皮下注用150mg(カナキヌマブ遺伝子組換え、ノバルティスファーマ):「クリオピリン関連周期性症候群(CAPS)」を効能・効果とする新有効成分含有医薬品。オーファンドラッグ。再審査期間10年。海外40カ国で承認。
 同剤の適応症は、国内患者数数十人といわれる希少難病で、承認されれば国内初の治療薬となる。CAPSは、炎症に関与するインターロイキン(IL)-1βが過剰に産生されることで起これるといわれ、生後すぐや幼児期から40度にも及ぶ発熱や激しい関節痛が断続的に繰り返され、さらには聴覚や視覚の障害、骨・関節の変形なども引き起こすこともある。同剤は、IL-1βと特異的に結合することで、炎症を抑える。
 日本には承認薬はなかったため「CAPS患者・家族の会」が国内で使えるよう厚生労働省に要請していた3つの治療薬の1つだった。厚労省は、開発の必要性の高い未承認薬と判断、昨年同社に開発要請。同社は要請前の09年から約20人の患者を対象に国内開発を進めていた。
【報告品目】
▽ベルケイド注射用3mg(ボルテゾミブ、ヤンセンファーマ):「多発性骨髄腫」を効能・効果とする新効能・新用量医薬品。オーファンドラッグ。再審査期間は残余期間(平成28年10月19日)。化学療法未治療の患者にも使えるようにするもの。抗がん剤メルファラン、副腎皮質ホルモン剤プレドニゾロンと併用する。
▽ブレドニン錠5mg(プレドニゾロン、塩野義製薬)、プレドニゾロン錠1mg、同5mg(同、旭化成ファーマ)、プレドニゾロン錠「タケダ」5mg、同散1%(同、武田薬品):「多発性骨髄腫」を効能・効果とする新効能医薬品。ベルケイドとの併用のための効能追加として公知申請されたもの。


---One More Plea for Avastin in Breast Cancer---
By Emily P. Walker, Washington Correspondent, MedPage Today
Published: August 08, 2011
http://www.medpagetoday.com/HematologyOncology/BreastCancer/27953

WASHINGTON -- As Genentech awaits word from the FDA on whether bevacizumab (Avastin) will lose its breast cancer indication, the company is urging the agency to consider a "middle ground" approach that would continue the drug's approval in metastatic disease.

In the company's 133-page submission to the FDA, Sandra Horning, MD, head of Genetech's oncologic clinical development program, laid out a proposal that would allow for continued marketing of bevacizumab to patients with aggressive disease -- characterized by visceral metastases, high tumor burden, and rapid disease progression -- who don't respond well to other therapies, so that the patients with the "greatest unmet need" will have access to the drug.

The FDA's Oncologic Drugs Advisory Committee voted 6-0 in June that bevacizumab should no longer be approved to treat locally recurrent or metastatic HER2-negative breast cancer. That meeting was convened at the drugmaker's request to appeal the FDA's earlier decision to remove bevacizumab's indication after the company's follow-up studies failed to show a clinical benefit of adding bevacizumab to chemotherapy.

The two-day meeting was thought to be a last-ditch effort on Genentech's part to change the FDA's mind, but that appears very unlikely after its advisory committee voted unanimously that the drug does not work and is not safe.

Now Genentech has made yet another effort at keeping the breast cancer indication -- at least for the sickest patients.

"There remains indisputable need for additional treatments for metastatic breast cancer, as was starkly demonstrated at the [advisory committee] hearing on the proposal of the Center for Drug Evaluation and Research (CDER) to withdraw the breast cancer indication for Avastin," the company wrote in latest submission.

That meeting was tense and emotional and packed with patients dubbed "super-responders," women who seem to have responded remarkably well to bevacizumab. They told the FDA advisory panel that insurance companies are unlikely to pay for the $8,000-a-month drug if the FDA strips away the breast cancer indication and pleaded with the panel and the agency to reconsider.

Genentech would like the FDA to allow bevacizumab to keep what was an accelerated approval in order to give the company time to conduct a confirmatory trial of bevacizumab with weekly paclitaxel.

The company is proposing new labeling that would direct doctors to use the drug only for the "most appropriate" metastatic breast cancer patients and would warn of "important safety considerations, including serious side effects."

At the June meeting, it was estimated that a confirmatory trial would take five or six years to complete.

Genentech actually floated the "middle ground" idea at the meeting, but the panel unanimously rejected it, saying if the drug wasn't shown to be safe and effective, then it shouldn't continue to be used in the fight against breast cancer.


---What Happened at the FDA Avastin Meeting?---
ISSUE: AUGUST 2011 | VOLUME: 06:08
http://www.clinicaloncology.com/ViewArticle.aspx?d=Solid+Tumors&d_id=148&i=August+2011&i_id=757&a_id=18820

In late June, the FDA’s Oncologic Drugs Advisory Committee (ODAC) gave a unanimous thumbs down to bevacizumab’s metastatic breast cancer (MBC) indication.

The vote followed a two-day hearing in which patients, doctors, Genentech representatives and FDA officials offered testimony as to whether the MBC indication for bevacizumab (Avastin, Genentech) should be removed or left intact.

Patients, some breaking into tears during their testimony, gave impassioned speeches as to the benefits of the drug. FDA and Genentech representatives presented copious slides discussing progression-free survival (PFS) and overall survival (OS) benefits in various trials.

At the end of the two-day hearing, the ODAC was asked to vote on several convolutedly written questions. 1) Do the AVADO and RIBBON trials fail to verify the clinical benefit of Avastin for the breast cancer indication for which it was approved? 2a) Does the available evidence on Avastin demonstrate that the drug has not been shown to be safe for the breast cancer indication for which it was approved? 2b) Does the available evidence on Avastin demonstrate that the drug has not been shown to be safe for the breast cancer indication for which it was approved, in that Avastin has not been shown to present a clinical benefit that justifies the risks associated with use of the product for this indication? The ODAC was unanimous in voting yes on all three questions.

The ODAC also voted on a fourth question: If the commissioner agrees with the grounds for withdrawal set out in issue 1, issue 2a or issue 2b, should the FDA nevertheless continue the approval of the breast cancer indication while the sponsor designs and conducts additional studies intended to verify the drug’s clinical benefit? The committee unanimously voted no.

“I think what it gets down to here is that if we don’t think it’s effective, then we can’t tolerate any toxicity from it,” said ODAC member Frank Balis, MD, director of oncology research at the Center for Childhood Cancer Research at the Children’s Hospital of Philadelphia.

To date, no trial has shown that bevacizumab improves OS in MBC. Although the committee members admitted that the 5.5-month improvement in PFS seen in the E2100 trial was impressive, they thought this result represented a “random high” because data from five well-controlled trials (seven comparisons), did not show anywhere near this magnitude of benefit (Figure). They also pointed out that there were no data showing that the drug improved quality of life, so the value of increased PFS was unclear.

Additionally, data from a recent Phase II study did not bolster Genentech’s case. In this trial, 282 patients with untreated HER2-negative MBC were randomly assigned in a 1:1:1 ratio to paclitaxel plus either motesanib (Amgen), placebo or bevacizumab. The overall response rate (ORR) in the bevacizumab group was similar to that in the motesanib group, which did not differ significantly from the placebo group (Lancet Oncol 2011;12:360-376, PMID: 21429799).

“I think the label should reflect the current understanding of the benefit-risk profile and that benefit-risk profile is not favorable right now,” said ODAC member Brent Logan, PhD, associate professor of biostatistics at the Medical College of Wisconsin, in Milwaukee. Although ODAC members agreed that the drug’s safety profile has not changed, they argued that the risks were acceptable in cancers such as colon cancer because the benefits outweighed the risks, but this wasn’t the case with MBC. In MBC, the limited effects on PFS and ORR do not outweigh the serious and potentially fatal risks, such as hemorrhage or gastrointestinal perforation, or ongoing risks for new or worsening hypertension or for glomerular injury manifesting as proteinuria, argued the members.

Among the many arguments that Genentech put forth in favor of keeping the breast cancer indication was that AVADO and RIBBON-1 merely suggest that bevacizumab’s therapeutic impact may vary depending on its chemotherapy partner. Genentech representatives proposed launching a double-blind, randomized trial that incorporates a biomarker component to identify patients more likely to derive benefit from the bevacizumab-paclitaxel combination. Enrollment for this Phase III trial would begin in 2012, they said, with an interim analysis at 3.5 years to determine futility, and a final analysis at roughly 4.5 years. They asked that the breast cancer indication be maintained in the meantime.

The company argued that drugs that have been approved for MBC do not meet the standard that the FDA is using for bevacizumab. The agency has accepted PFS and time-to-progression (TTP) end points as the basis for drug approvals in MBC without requiring a demonstration of OS benefit. Gemcitabine, argued Genentech, in particular does not meet the criteria that the FDA is now setting forth. Gemcitabine was approved based on TTP data, and mature data showed that the drug’s effect on OS was not statistically significant. The company also argued that detecting improvements in OS in the first-line setting of MBC is difficult, because subsequent lines of therapy may obscure the effect of a treatment tested in a clinical trial.

At the meeting, Lee Pai-Scherf, MD, medical officer, Office of Oncology Drug Products, FDA’s Center for Drug Evaluation and Research, shared several concerns that the E2100 study had shortcomings and inconsistencies such as missing scans and data. Genentech pointed out that in the FDA’s 2007 medical review of lapatinib (Tykerb, GlaxoSmithKline), the missing rate of scans was 10%, exactly the same as in the E2100 trial.

Patricia Keegan, MD, director of the Division of Biologic Oncology Products at FDA’s Office of Oncology Drug Products, said that Genentech had not supplied any evidence that Avastin’s efficacy depends on the chemotherapy partner or duration of therapy. They had not provided data on the synergism between bevacizumab and paclitaxel, pharmacokinetic interactions between bevacizumab and other chemotherapies, or antagonism between bevacizumab and other chemotherapies.

Most of the patients and doctors who presented public testimony spoke in favor of keeping the drug available for patients with MBC, but a handful spoke in support of the indication’s withdrawal. “[The drug] does not extend life,” testified Christine Brunswick of the National Breast Cancer Coalition. “The drug does raise false expectations and does detract from focusing on other research that may produce effective and lifesaving drugs.” At times, emotions ran high. Kimberly Jewitt, a breast cancer survivor who testified after Ms. Brunswick, stepped to the podium enraged. “I am completely disgusted to have to follow something like that,” said Ms. Jewitt, and then went on to testify as to how the drug benefited her.

Joyce O’Shaughnessy, MD, Celebrating Women Chair in Breast Cancer Research, Baylor Sammons Cancer Center, and co-chair, Breast Cancer Research, US Oncology, both in Dallas, testified in favor of keeping the indication. “I call on the FDA to work with the sponsor to keep Avastin/paclitaxel available as an approved option, even by limiting the indication to patients with metastatic triple-negative and aggressive ER [estrogen receptor]-positive breast cancer whom their oncologists believe need combination therapy, while the confirmatory trial is being done,” she said. Dr. O’Shaughnessy, a paid consultant for Genentech, pointed out that triple-negative MBC is highly symptomatic with a median survival of 12 to 18 months and has few known effective treatment options. A pooled analysis of first-line MBC trials showed a median PFS difference of 2.7 months with a hazard ratio of 0.63.

Although a couple of ODAC members appeared to be possibly leaning toward an affirmative answer to the last question-keeping the indication intact until a new trial was completed-in the end they voted unanimously to pull the indication. “It’s very difficult in the absence of clear information that indicates that a subset of patients is benefiting. Intuitively, one might think patients with bulky disease and symptoms would be most likely to benefit, [but] maybe they would do worse because they would have the disease plus the serious adverse events to deal with,” said ODAC member Ralph Freedman, MD, PhD, clinical professor in the Department of Gynecologic Oncology at the University of Texas, Houston. “The agency has to look at protecting a larger number of patients. Sometimes they have to make a decision that doesn’t favor individual patients, but is on the basis of a whole.”

ODAC member Michael Skeres, MD, seemed a bit more pessimistic about finding a subgroup in which the drug worked. “We tried to slice this pie in lot of different ways, to try to find some kind of benefit for this drug in combination with chemotherapy for a desperate breast cancer population,” he said. “No matter which way we look at it … looking for data about subgroups, all we are left with are crumbs. There is nothing we can hang our hat on in these studies that would make me feel comfortable continuing to expose a lot of patients to risk without a clear benefit.” Dr. Skeres is associate professor of medicine in the Department of Hematologic Oncology and Blood Disorders at the Cleveland Clinic Taussig Cancer Institute, in Ohio.

Executive vice president of Genentech, Hal Barron, MD, said the company will proceed with the Phase III trial they planned whether or not the FDA follows the advice of ODAC and withdraws the breast cancer indication. ODAC member Wyndham Wilson, MD, PhD, chief of the Lymphoma Therapeutics Section at the National Cancer Institute, encouraged the company “to do this follow-up trial as quickly as possible.”

At press time, the FDA had not announced whether it would follow ODAC’s advice.

-Kate O’Rourke


---臨床試験---
監修:畠清彦 癌研有明病院化学療法科・血液腫瘍科部長
取材・文:町口充 (2006年12月号)
http://www.gsic.jp/examination/ex_03/02.html

臨床試験データの見方・読み方
受ける臨床試験の目的、意味を理解することが重要
★★★だれでもわかる臨床試験データの見方・読み方

何例以上なら信用できるか?
 「ただし、今、述べたことは、よく効いたかどうかどうかであり、治療の片側を見ていることになります。一方で毒性、有害事象をチェックしないといけません。つまり、いくらよく効いても患者さんが亡くなってしまったのでは何にもなりません。1回目の治療で効果があっても、薬が強すぎて2回目がとてもやれないぐらいになってしまったのではいけない。したがって、副作用のチェックが必要になってきます」
 副作用の評価としては、血液学的有害事象と、非血液学的有害事象が問題となる。血液学的有害事象とは、白血球が減ったり血小板が減ったりした場合で、輸血が必要になったり、副作用を抑える薬の投与が必要になるので、試験を続けていくことができなくなってしまう。また、非血液学的有害事象とは、神経のしびれやだるさ、吐き気などがあげられ、これも投与の中止につながる。
 副作用は前述したようにゼロから5までのグレードでチェックする。5は死亡で、ゼロなら何もなし。1~2はとくに処置を要さないもの、3~4は点滴をしたりの処置が必要。どのパーセンテージが多いかで、強い治療か、軽い治療かを判定する。

[治療法の評価に関する用語]
無イベント生存  events free survival    EFS 再発、増悪、合併症などがなく生存
無病生存     disease free survival   DFS ほかの病気が発生することなく生存
無増悪進行生存  progression free survival PFS 病気が進行することなく生存
全生存      overall survival      OS  すべてを含めた生存
無再発生存    relapse free survival   RFS 病気が再発しないで生存している
治療奏効維持生存 failure free survival   FFS 治療効果が持続している期間
無進行期間    time to progression    TTP 進行するまでの期間

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