経過
1996-6-11

国立保険研究所がRezulinの糖尿病臨床試験に1億5千万ドルの予算をつける。研究は政府ので糖尿病の権威Richard Eastman博士を長に行われた。同氏は、製造元のワーナー･ランバート社に、Rezulinの発売開始に関し、コンサルタントとして雇われていた。この研究の後、ワーナー･ランバート社はEastman博士が糖尿病に特効性がある旨、プレス発表。

1996-7-31

ワーナー･ランバート社がRezulinのファーストトラックでの認可をFDAに申請。

1996-10-9

FDAの科学者たちは、Rezulinが、動物実験で肝臓や心臓に障害をもたらす兆候に懸念を持った。最初にRezulin担当になったFDA医師は同薬の認可に否定的だったJohn Gueriguian博士。

1996-11-4

ワーナー･ランバート社が、言葉がわかりにくいという理由でGueriguian博士をRezulinの評価チームから外すことに成功。これにより、FDAの記録から同氏の意見も抹消される。

1996-12-11

ワーナー･ランバート社がRezulinをFDAの委員会に対して発表。同薬が心臓肥大や心機能の障害をもたらすことはないと証言。

1997-1

ファーストトラック認可システムにより、Rezulin が FDAの認可を受ける。通常は数年かかる新薬の認可が、今回は半年で終わった。肝臓に対する実際の試験は行われなかった。

1997-2-24

FDA は、ワーナー･ランバート社がプレス発表の中で「間違いで誤解を招く」表現を行ったと発表。同様の表現を使用したものも含めて、同発表を中止するよう伝えた。

1997-5-1

ワーナー･ランバート社の実験ではRezulinを使用すると placebo使用時に比べて肝機能障害を起こす可能性が3.6倍になると結果が出ているにもかかわらず、4色刷りの広告で、Rezulinによる副作用が placebo と同程度であると発表。Placebo は比較実験でよく使用される試薬。

1997-5-5

ワーナー･ランバート社の最高経営責任者が投資家に Rezulin が大ヒットして巨額の利益をもたらす可能性があると説明。

1997-9-30

FDAの糖尿病グループリーダー、Alexander Fleming博士が心臓、肝臓、腎臓に疾患がある患者が同薬によって悪い影響を受けないとは考えにくい、と発表。

1997-10-10

Rezulinに起因する肝臓の機能停止2例がFDAに報告される。

1997-11-3

FDAが、Rezulinのラベルに以下の表示を義務付ける。

･ Rezulinの治療を受ける際には最初の1，2ヶ月の間に肝臓酵素の試験を受け、最初の1年間は3ヶ月ごとに、その後も定期的に続けること。
･ Rezulinの服用による肝機能低下の症状として、吐き気、嘔吐、腹痛、疲労、食欲不振、尿の変色があり、このような症状が現れた人は肝臓試験を受けること。
･ Rezulinの服用者は肝臓障害が現れたら直ちに服用を中止すること。
･ 臨床試験の結果、Rezulin服用者のおよそ2%は服用をやめなければならない結果が出ている。
1997-11-12

FDAの糖尿病専門医Robert I.

Misbin博士がFDAの上層部に内部告発報告を提出。それによると、FDAの認可以前よりRezulinを使用していた, an FDA diabetes specialist that supported the Rezulin approval, sent an internal report to FDA supervisors stating that 21 patients treated with Rezulin prior to FDA approval had to discontinue the drug due to Rezulin liver injury, 13 patients had markers of Rezulin liver injury 10 to 30 times above normal which can threaten the lives of patients, and an estimated 2% or 12,350 of the 650,000 patients using Rezulin would experience some degree of liver injury.

12-1-97
England prohibits sales of Rezulin due to concerns about liver damage to patients in the U.S. The FDA announces a label change to require more frequent Rezulin liver testing. The new label recommends liver enzyme tests before starting Rezulin, monthly for the first six months of treatment, every other month for the next six months, and periodically thereafter.

5-17-98
A 55 tear old woman in good health dies of Rezulin liver failure while participating in the National Institutes of Health diabetes study. The panel of specialists hired by NIH concluded that her liver failure was probably due to the use of Rezulin diabetes drug.

6-4-98
The NIH study drops Rezulin due to the risk of liver damage in the remaining participants.

6-5-98
A press release by Warner-Lambert denies Rezulin killed the woman and instead claimed her death was the result of complications unrelated to the study or the diabetes medication. The FDA had then received 21 reports of Rezulin liver failures resulting in death and three Rezulin liver transplant patients.

7-27-98
The consumer group Public Citizen filed a petition for the immediate ban of Rezulin. At this point the FDA had received 26 reports of Rezulin liver failure deaths.

7-28-98
The FDA required another Rezulin label change to increase the frequency of liver testing. The recommendation then stated a Rezulin patient be tested before using Rezulin, monthly for the following 8 months and every two months for the rest of the year and periodically after that.

1-99
The FDA Commissioner orders a reevaluation of Rezulin after the series of articles by the Los Angeles Times investigated the "fast track" drug Rezulin tied to 33 Rezulin liver failure deaths.

3-26-99
After two months of FDA research the findings are present to an FDA advisory panel. The report found that an estimated 430 or more Rezulin patients have suffered a liver failure, Rezulin patients incur 1,200 times more risk of liver failure, one out of every 1,800 Rezulin patients can expect t suffer a liver failure, and liver function tests do not provide enough protection due to the rapid and unpredictable way Rezulin can affect the liver. In addition, Rezulin patients did not follow the recommended liver function tests after more than 4 months on the drug.

3-29-99
A Rezulin patient undergoing monthly monitoring in a Warner-Lambert clinical trial dies of liver failure.

6-16-99
The FDA requires the Rezulin label be changed for the fourth time now, increasing the frequency once again for liver tests. The new label recommended Rezulin patients get monthly liver monitoring for the first year on the diabetes drug.

12-15-99
The Los Angeles Times reports 21 Rezulin patients have died of liver failure since the March 26, 1999 report by Dr. Graham to the FDA Advisory Panel. Graham begins a new analysis of Rezulin despite his supervisors having no knowledge of his actions.

3-3-00
Dr. Graham sends an email to 14 FDA officials with the opinion that Rezulin is unsafe and should be stopped due to the liver failure problems occurring. Graham stated there was no existing data to support the idea that monitoring can prevent the Rezulin liver failures from occurring.

3-00
The FDA diabetes specialist who had analyzed the first cases of liver failure in October to November 1997 sends eight members of Congress internal FDA emails discussing Rezulin liver toxicity. Included in the email was the correspondence he had received from Dr. Janet B. McGill who had conducted early research on Rezulin for Warner-Lambert saying the company "deliberately omitted reports of liver toxicity and misrepresented serious adverse events experienced by Rezulin patients in their clinical studies." The FDA opens an internal-affairs investigation after Warner-Lambert complains about the leaks.

3-21-00
The FDA withdraws Rezulin from the U.S. market after finding the benefits of other diabetes drugs offer the same benefits Rezulin did without the same risks. Up to this point Warner-Lambert had grossed $2.1 billion in Rezulin sales. The FDA had reports of 63 Rezulin liver failure deaths.

8-16-00
The L.A. Times reports about the Federal prosecutors examining the FDA's quick approval method and the delayed withdrawal of Rezulin. It was reported that both the FDA and Warner-Lambert's actions were being examined.

Serious, life-threatening Rezulin side effects have been directly linked to the use of the diabetes drug. Warner-Lambert has been blamed in dozens of deaths from life failure and thousands of other liver damage cases from 1997-2000.