这家公司调整产品配方，却不愿分享结果数据

美国政府需要一个关键问题的答案，或许只有雷福德·布朗博士能够回答：遏制美国阿片类药物蔓延方面，新款止痛药奥施康定到底起没起作用？

布朗是肯塔基大学的疼痛治疗专家，针对重新配置成分以防止吸食和注射的阿片类药物，负责领导的外部专家小组为美国食品与药品管理局（FDA）提供咨询。

现在只有一个问题：生产奥施康定的公司和FDA都不允许专家查看数据，以确定新款奥施康定究竟能否减少滥用。

“过去四五年，为了看数据我们申请了大约40到50次，每次都被拒绝。”布朗表示，他在FDA的顾问任期已经于3月结束。

近十年前，FDA批准了新配方的奥施康定，并通知普渡制药将评估新款是否能够减少上瘾、滥用和死亡病例。由普渡提交的应答数据仍然保密。

“我们了解药品原理是为了公众利益，结果谁也看不见，认真想想真可怕。”布朗告诉美联社。

2015年，布朗和同事本应在华盛顿一场会议上审查奥施康定的后续数据，但就在会议召开的前几天，FDA宣布取消了该会议。普渡取消递交奥施康定与滥用相关的更新信息，声称希望有更多的时间来分析数据。而此类会议通常提前几个月便已计划，几乎从未取消。

总部位于康涅狄格州斯坦福德的普渡发言人表示，公司正在努力完成2016年FDA指定的四项新研究要求。公司表示，已经提交三份FDA要求的研究报告，预计10月之前提交最后一份。

“研究完成并经FDA审查后，将考虑向科学界发布相关的重要数据。”鲍勃·约瑟芬森在一份声明中表示。

但FDA内部负责阿片类药物的高层官员去年在公开会议上表示，“数年前”就希望看到相关信息。

“公司手上有数据，但很难强迫他们提交。”FDA的止痛药物部门主管莎伦·赫兹说。

不公布奥施康定数据，凸显了FDA在公共卫生机构和行业密友之间不断摇摆的身份。虽然FDA可以命令药企研究重要问题，但信息本身仍然属于公司，并被视为“商业机密”。

FDA的一位发言人通过邮件表示，在普渡制药的研究结果完全提交和审查之前就发表评论“为时过早”。FDA指出，奥施康定最终研究结果将推迟。工作人员预计，相关研究“有助于了解奥施康定调整配方后对滥用的实际影响，”林赛·梅耶表示。

过量服药死亡

即便奥施康定确实减少了过量服药导致死亡的案例，联邦统计数据中也并无体现。

奥施康定仍然是美国最畅销的阿片类药物，不过在美国阿片类药物处方中占比不到2%，可能限制了其对全国趋势的影响。（大多数阿片类药物都是廉价的仿制药。）

自从2010年批准新配方以来，涉及滥用奥施康定、扑热息痛和仿制药等处方阿片药物致死案例在2017年上升了30%以上，达到约14500人。2017年也是具有完整数据最近的一年。两周前公布的初步数据显示，去年与阿片药物滥用有关的死亡人数可能是数十年来首次下降。

一些研究人员建议重新调整奥施康定配方，加之更严格的处方和其他措施，加速了全国转向吗啡和芬太尼。2017年吗啡和芬太尼导致43000多人因服药过量死亡，几乎是处方阿片药物的三倍。

FDA已经批准了7种阿片类药物，包括奥施康定，还强调“希望”遏制滥用。

为了防止滥用，很多止痛药很难碾碎、打破，或溶解，但只要吞进肚子还是能够滥用。而且各种药都有上瘾的风险。

“从公共卫生角度来看，阿片类药物的真正问题是成瘾。”罗格斯大学急诊医学专家刘易斯·纳尔逊博士说，他也是FDA的顾问。“改变配方并不能够减少上瘾的可能性，也无法降低上瘾程度。”

普渡制药已经在同行评审的期刊上发表更改奥施康定配方的初步信息，但相关研究受潜在偏见和局限性影响。很多内容由普渡制药的科学家或研究人员撰写，资金来自于公司。多数情况下，数据来源来自于专门的网络，包括毒物控制中心、执法记录和药物康复诊所。

数据来源可以显示新款奥施康定表现良好，不少关键指标，包括紧急呼叫、执法报告，以及患者找多个医生开处方，也就是所谓的换医生比例都在下降。

但即便研究作者也承认，各项指标并不一定能够反映全美国的情况。举例来说，只有一小部分滥用阿片药物的人会接受康复治疗。

FDA的研究人员在研究中单独核查奥施康定的滥用情况，使用规模更大的数据库，也就是联邦政府的年度调查。这次他们有新发现。有滥用处方阿片病史的人当中，在药品配方调整三年内滥用奥施康定的比例相似，甚至更高。

“如果想看影响，从这里应该就可以看出来。但我们什么也没有看到。”克里斯托弗·琼斯博士说，他与人合著了2017年的报告，如今在疾病控制和预防中心工作。

报告的发现与调查结果一致，显示在配方调整后，放弃奥施康定的长期滥用者不到5%。

洛杉矶的加勒特·哈德说，之前阿片药物上瘾时，他只需要在厨房里花上几分钟就可以准备好奥施康定，然后注射。

“最后变成‘日常注射没关系，反正奥施康定可以防滥用。’”32岁正在康复中的哈德说。

奥施康定的持续成本

奥施康定最早于1996年推出，后来掀起了滥用浪潮，因为有些人很快学会了将长效缓释的药片弄碎，获得大量阿片成分。在监管机构、政界人士和执法部门压力下，2010年普渡制药采取了新设计。

两周前公布的政府数据显示，2006年至2012年期间，普渡和其他药企在美国出售了超过760亿片阿片药物。销量最多的地区滥用率也最高。

如今，普渡面临着2000多起地方和州一级诉讼，指控其淡化奥施康定成瘾风险，积极市场推广，并称之适用于普通的疼痛管理，最终导致阿片药物蔓延。面临多重诉讼，公司还公开讨论过破产问题。

调整药品配方提振了业务。

最初版奥施康定的专利在2013年到期，价格低廉的仿制药就能够抢走普渡的市场份额。通过调整配方，普渡将专利延长到2030年。

药品跟踪服务公司IQVIA称，2010年以来奥施康定在美国的销售额已经超过210亿美元。

推广材料显示，普渡认为新配方的防滥用功效是“关键推动力”，向医生推销时也不断强调。面临越发严格的审查，去年普渡已经停止直接向医生推销奥施康定。

与此同时，数据公司Elsevier的数据显示，普渡已经将奥施康定的价格稳步提高了超过95%，服用最高剂量的话达到每片22美元。

至于该药的防滥用特性值不值得付出更高成本，一直在争论中。

非营利组织临床和经济评论研究所发现，奥施康定防滥用方面其实并无定论。

FDA的前高级官员彼得·卢里博士与他人合著了2017年的报告，发现长期使用奥施康定的人滥用行为基本上没有变化。

如今担任非营利组织公益科学中心主席的卢里指出，奥施康定是迄今为止处方量最大、被研究最多的防滥用阿片药物。

“如果无法证明奥施康定能够防止滥用，如何证明其他药有此作用？”他问道。（财富中文网）

译者：冯丰

审校：夏林

Dr. Raeford Brown was uniquely positioned to help the U.S. government answer a critical question: Is a new version of the painkiller OxyContin helping fight the national opioid epidemic?

An expert in pain treatment at the University of Kentucky, Brown led a panel of outside experts advising the Food and Drug Administration on opioids that have been reformulated to deter snorting and injecting.

There's just one problem: Neither the company that makes OxyContin nor the FDA has allowed the experts to see data on whether it reduces abuse.

“We asked for that data probably 40 or 50 times in last four or five years and were denied every time,” said Brown, whose term as an FDA adviser ended in March.

Nearly a decade ago, the FDA approved reformulated OxyContin and told the company, Purdue Pharma, that it would be evaluated on whether the new version decreased cases of addiction, overdose and death. The data submitted by Purdue to answer that question remains secret.

“It's in the public interest that we all know what these drugs are doing and yet none of us can see it, which is really terrifying when you think about it,” Brown told The Associated Press.

In 2015, Brown and his colleagues were supposed to review follow-up data on OxyContin at a meeting in Washington, but the FDA canceled it only days before. Purdue had pulled its application to update OxyContin's label with new information on abuse, saying it wanted more time to analyze the data. Such meetings are typically planned months in advance and are almost never canceled.

A Purdue spokesman said the Stamford, Conn.-based company has been working to complete four updated study requirements assigned by the FDA in 2016. The company said it has submitted three of the FDA-mandated studies and expects to submit the final one by October.

“Once all of the studies are completed and FDA has had the opportunity to review the results, we will evaluate options to disseminate this important data to the scientific community,” said Bob Josephson, in a statement.

But the FDA's top staffer for opioids said at a public meeting last year that the agency expected the information to become available “years ago.”

“They have it, but it's hard for us to force them to submit it,” said Sharon Hertz, FDA's division director for pain medications.

The unreleased OxyContin data highlights the FDA's precarious role as both a public health agency and close confidante of industry. While the agency can order a drugmaker to research important questions, the information itself still belongs to the company and is deemed “confidential commercial information.”

An FDA spokeswoman said in an email that it would be “premature” to comment on Purdue's results before they have been fully submitted and reviewed. The agency noted that the company's final OxyContin study has been delayed. FDA staffers expect the studies “will help us understand the real-world impact of OxyContin's reformulation on abuse,” said Lyndsay Meyer.

Overdose deaths

If OxyContin has reduced overdose deaths, federal statistics don't show it.

OxyContin remains the best-selling opioid brand in the country, but it accounts for less than 2% of U.S. opioid prescriptions, potentially limiting its impact on national trends. (Most opioids prescribed are low-priced generic pills.)

Since the new formulation was approved in 2010, fatal overdoses involving prescription opioids including OxyContin, Percocet, and generic pills have risen more than 30% to about 14,500 in 2017, the most recent year for which complete data is available. Preliminary figures released two weeks ago suggest drug-related deaths likely fell last year for the first time in decades.

Some researchers have suggested reformulated OxyContin, combined with tighter prescribing and other measures, accelerated the nationwide shift toward heroin and fentanyl. Those drugs were involved in more than 43,000 overdose deaths in 2017, nearly three times the number as prescription opioids.

The FDA has now approved seven opioids, including OxyContin, with labeling that they are “expected” to discourage abuse.

Those pills are intended to be difficult to crush, break, or dissolve, but they can still be misused when simply swallowed. And the drugs carry the same addiction risks.

“The real problem with opioids from the public health perspective is addiction,” said Dr. Lewis Nelson, a Rutgers University emergency medical specialist who also serves as an FDA adviser. “These pills in the reformulated version don't do anything to reduce the likelihood or magnitude of addiction.”

Purdue has published preliminary information on reformulated OxyContin in peer-reviewed journals, but the studies are clouded by potential biases and limitations. Many are written by Purdue scientists or researchers whose work is funded by the company. In most cases, the data comes from a network of specialized sources, including poison control centers, law enforcement records and drug rehabilitation clinics.

Those sources show a positive picture for OxyContin's performance, with key indicators like emergency calls, law enforcement reports, and rates of patients seeking prescriptions from multiple prescribers—known as doctor shopping—dropping.

But even the study authors acknowledge that those measures don't necessarily reflect what's happening across the country. Only a small segment of people misusing opioids ever enter rehabilitation, for instance.

When FDA researchers decided to independently examine OxyContin abuse in a study using a much larger dataset—a federal government annual survey—they found a different picture. Among people with a history of misusing prescription opioids, rates of OxyContin abuse were similar or higher three years after the drug was reformulated.

“If you were going to see an impact, this is the population where you should see it. And we didn't see anything,” said Dr. Christopher Jones, who co-authored the 2017 paper and now works at the Centers for Disease Control and Prevention.

The paper's findings square with survey results suggesting less than 5% of long-term abusers gave up OxyContin after it was reformulated.

Garrett Hade of Los Angeles said that when he was addicted to opioids it would take him only a few minutes in his kitchen to prepare OxyContin for injecting.

“It just became a matter of 'this is what you have to do today because you have abuse-deterrent OxyContin,'” said Hade, 32, who is in recovery.

The continuing cost of OxyContin

First launched in 1996, the original OxyContin helped spark a wave of abuse as some people quickly learned to crush the long-acting pills to release a massive opioid dose. Under pressure from regulators, politicians and law enforcement, Purdue reformulated the painkiller in 2010.

Government data unveiled two weeks ago showed Purdue and other drugmakers flooded the U.S. with more than 76 billion opioid pills between 2006 and 2012. Areas that received the most pills also had the highest overdose rates.

Today, Purdue faces some 2,000 local and state lawsuits alleging its aggressive marketing contributed to the opioid epidemic by downplaying OxyContin's addiction risks and promoting the drug for common pain ailments. The lawsuits have pushed the company to publicly discuss bankruptcy.

The reformulation has been good for business.

The patent on original OxyContin would have expired in 2013, allowing lower-priced generics to gobble up Purdue's market share. By reformulating the drug, Purdue was able to extend its patent until 2030.

Since 2010, OxyContin has generated more than $21 billion in U.S. sales, according to pharmaceutical tracking service IQVIA.

Purdue viewed the anti-abuse reformulation as a “key driver” of new prescriptions and stressed the features in promotions to doctors, according to its marketing materials. Purdue stopped promoting OxyContin directly to doctors last year amid mounting scrutiny.

Meanwhile Purdue has steadily increased OxyContin's price more than 95 percent, to $22 per pill for the drug's highest dose, according to data firm Elsevier.

Whether the drug's anti-abuse features warrant those costs has been debated.

The nonprofit group Institute for Clinical and Economic Review has found mixed evidence for OxyContin's ability to fight abuse.

Dr. Peter Lurie, a former FDA senior official, co-authored the 2017 paper that found OxyContin misuse was essentially unchanged among long-term users.

Now president of the nonprofit Center for Science in the Public Interest, Lurie notes that OxyContin is by far the most prescribed and most studied abuse-deterrent opioid.

“If we can't prove it for OxyContin, how are we going to show it for anything else?” he asked.