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出自识林

2014-03-04 Lachman CONSULTANTS

随着John Dingell从国会去职，或许到了反思仿制药丑闻的时候

在最为成功的《药品价格竞争与专利期补偿法案》（即更加众所周知的Hatch-Waxman Act法案）立法4年多以后，天堂之所出现了麻烦。那时的仿制药部门对简化新药申请（ANDAs）的涌入做了很好的回应，并迅速将这些高质量、价廉的仿制药送入消费者手中。大家知道，哈奇•维克斯曼法案在过去十年间为美国公众节省了1.2万亿美元，仅去年一年，就节省了2.17亿美元。但在1987年晚些时候，一些公司注意到，某些申请者的ANDAs的受理审评和批准比他们的更快。

这些公司抱怨遭到不公正待遇和不公平竞争。但由于缺乏证据，FDA不愿意调查。在屡次力促这一问题引起关注未果后，最后一家公司雇佣私家侦探调查这一事件。这被戏称为“垃圾桶雀跃”，即在特定的夜晚，调查者等到目标将垃圾扔掉后，拿走垃圾仔细检查寻找证据，然后在垃圾收集之前放回原处。用这种方式收集到的证据被送至FDA，这一简单调查查处了一名FDA雇员的违法证据，继而引起了对这一行业广泛的展开调查，揭露了许多公司的大规模欺诈行为，曝光了其他FDA雇员的违法犯罪行为。

这就是仿制药丑闻的开端。这些事件揭露后不久，国会议员John Dingell和他两名最高级别的国会调查员David Nelson 和 Reid Stuntz，从头到尾检查了仿制药程序。作为仿制药办公室（OGD）与小组委员会之间的联系人，在经历过多起调查之后，我告诉您，我宁愿去看肛肠科医生，也不愿再经历一次这样的事！

究竟发现了什么？一名FDA雇员将机密的处方信息透漏并出售给其它公司。一些公司向FDA雇员们行贿，使其篡改审查排队，从而得到优先处理。数名FDA雇员收受现金、轿车、礼品以及非法酬金，一些人已身陷囹圄。

申请中的欺诈和虚报行为在违法者中猖獗，尽管如此，并未对公众健康造成明显威胁。这一行为导致了数百个ANDA最终被撤回。最终，22家公司和70名个人（制药公司和FDA雇员）受到刑事定罪，罚款超过5千万（这一数字与今天FDA违规者动辄数百万的罚款相比是如此苍白）。

这些公司存在以下行为：

• 在品牌片剂外包衣并用于对比溶出测试
• 在烧杯中制作出据称为申报批量的无菌注射产品
• 两套生产指南，一套用于实际生产产品，另一套用于提交至FDA
• 多种产品记录由同一设备同一时间产生。
• 用碳素墨水涂改稳定性数据（当待在OGD时，我们无论如何也想象不出在我们索要数据的数小时内，数据通常是怎样生成的。我猜想你们是看不到传真上的墨水变干的！
• 替换生物等效性样本 — 在对审批流程的最为恶劣的冒犯中，Bolar公司用抗高血压药物Dyazide胶囊（一种难以生产的产品）做生物等效性测试，这家公司将品牌药胶囊内容物倒入Bolar公司自己的胶囊壳内，因此在生物等效性测试中以品牌药对照品牌药。

这样的例子不胜枚举。国会通过了《仿制药实施法案》，FDA发布了《欺诈、实质事实贿赂的不实声明以及非法酬金的政策指南》（合规政策指南7150.09），之后又发布了一项申请诚信政策，概述了FDA该如何处理确认的已受到非法行为影响的申请。

这是仿制药计划的一段黑暗期，但最终却使得整个行业更为壮大。人们或许认为历史不会在这种情况下重演，但时间告诉我们，在贪婪与金钱产生的地方，一切皆有可能。问题在于，没有人针对当前的管理来吸取仿制药丑闻教训。历史容易被遗忘，随着警觉和自满在部分雇员、管理者、员工、总裁及首席执行官们心中此消彼长，需要反复重申教训，将仿制药丑闻的历史再一次讲给这一代的所有雇员、高管以及董事会成员。不幸的是，时间一定会有其方法使我们忘却昔日的一些罪过，因为即便是今天，仍然有猖獗的欺诈、篡改数据、虚报以及重要事实的虚假陈述存在和继续发生。

请保持警惕，人们啊，不要让历史的罪孽重演。就像Crosby、Stills 和 Nash所言：“教好孩子”，让他们不要重蹈覆辙。如果您有意了解更多仿制药丑闻的诡诈本性，并且希望您的员工对此问题更加清楚，请联系Lachman咨询公司的Joan Janulis（j.janulis@lachamnconsultants.com)。她能够安排一个使您保持警惕的培训计划，让您在了解到上世纪80年代晚期发生的事情后毛骨悚然，从而有望使得所有员工更加意识到并防范震撼仿制药行业的丑闻重现。

Lachman CONSULTANTS - Bob Pollock先生 2014-02-25
校译：识林-Kapok 2014-03-03

With John Dingell's Departure from Congress, Maybe it is Time to Reflect on the Generic Drugs Scandal
Written by Bob Pollock • February 25, 2014

Some 4+ years after the most successful piece of legislation, the Drug Price Competition and Patent Term Restoration Act (more commonly known as the Hatch-Waxman Act), there was trouble in paradise. The-then Division of Generic Drugs responded well to the influx of new ANDAs and acted rapidly to get these new high quality, low cost generic products into the hands of consumers. We know the Hatch-Waxman has saved the American people $1.2 trillion dollars in the last 10 years and $217 million last year alone. But in late 1987, some firms noticed that certain applicants began receiving reviews and approvals of their ANDAs faster than they did.

These firms complained of unfair treatment and an uneven playing field. But without proof, FDA was not willing to investigate. After repeated attempts to gain traction on this issue, one company finally hired a private investigator to look into the matter. Lovingly referred to as the “Garbage Can Caper”, the investigator would wait until the target placed his garbage out on the designated collection night, took it, went through it looking for evidence, and then placed it back before collection time. The evidence gathered in this manner was taken to FDA and this simple investigation lead to evidence of wrongdoing by an FDA employee and lead to a widespread and expanded investigation into the industry, and uncovered wholesale fraud at a number of companies and exposed other FDA employees guilty of wrongful acts.

This was the beginning of the Generic Drug scandal. Soon after these revelations, Congressman John Dingell and his two top congressional investigators, David Nelson and Reid Stuntz, examined the generics program from head to toe. Having lived through the investigations as the OGD contact for the sub-committee, I can tell you that I would rather visit a proctologist than go through that again!

So what was found? Confidential formulation information was revealed and sold to other firms by an FDA employee. There was manipulation of the review queue to give preferential treatment to firms that paid bribes to some FDA employees. There was acceptance of cash, cars, gifts and illegal gratuities by several FDA employees and some went to jail.

Fraud and misrepresentation in applications was found to be rampant among the wrong doers and, despite this, there was no apparent threat to public health. This resulted in the ultimate withdrawal of hundreds of ANDA applications. Ultimately, there were 22 drug companies that received criminal convictions, 70 criminal convictions of individuals (drug company and FDA personnel) and over $50 million in fines (which pales in comparison to the hundreds of millions in fines we see today for FDA violations).

Firms were found to have:

• Over-coated brand tablets and used them in comparative dissolution tests,
• Manufactured what were claimed to be exhibit size batches of sterile injectable products in beakers
• Two sets of manufacturing instructions, one for how they actually made the product and another set for submission to FDA
• Records of multiple products being made on the same piece of equipment at the same time.
• Graphite stability data (when at OGD, we never could figure out how data always came on the fax machine within hours of us asking for it. I guess you can't see the ink drying on a fax!)
• Switched bioequivalence samples – in the greatest affront to the approval process, Bolar performed bioequivalence testing on Dyazide Capsules( a difficult to manufacture product) and it was found that the firm emptied brand capsules into Bolar capsule shells, and thus, tested the brand against the brand in bioequivalence tests.
• False walls found in manufacturing facilities, which hid secret manufacturing rooms.

And the list goes on. Congress passed the Generic Drug Enforcement Act, the FDA issued a policy guide entitled, Fraud, Untrue Statements of Material Facts Bribery and Illegal Gratuities (CPG 7150.09) and then issued the Application Integrity Policy that outlined how the Agency would treat applications found to be impacted by illegal activities identified.

This was a dark period for the Generic Drugs Program, but made it stronger in the end. One would think that history would not repeat itself in this instance, but time has shown us that, where there is greed and money to be made, anything is possible. The problem is that no one teaches the history of the generic drug scandal to current management. The past is easy to forget and as vigilance and complacency wane on the part of employees, managers, staff, presidents and CEOs alike, the message needs to be reiterated and the story of the generic drug scandal needs to be retold to all this generation of employees, senior managers, and board members. Unfortunately, time must have a way to make us forget of some of the transgressions of the past because there are still incidents of rampant fraud, data manipulation, misrepresentation and misstatements of material facts that have and continue to occur even today.

Keep vigilant, people, and don't let the sins of the past repeat themselves. As Crosby, Stills and Nash say “teach your children well” so they do not repeat the same mistakes. If you are interested in learning more about the insidious nature of the Generic Drug Scandal and would like your employees made more aware of the issues, please contact Joan Janulis of Lachman Consultants (j.janulis@lachamnconsultants.com) and she can arrange for a training program that will make your hair stand up on the back of your necks and give you goosebumps learning about what happened in the late 80’s to hopefully make all employees more aware and to prevent a reoccurrence of the scandal that rocked the generic industry.