Did Sanofi Pay Petitioners to Help Delay Generic Lovenox?

Reed Miller

May 27, 2011

May 27, 2011 (Washington, DC) — The US Senate Finance Committee is asking the FDA to explain how it ensures the "integrity and transparency" of its citizen petition process following an investigation into Sanofi-Aventis's unsuccessful effort to delay FDA approval of generic alternatives to the company's very successful enoxaparin (Lovenox), a low-molecular-weight heparin [1].

In a report including documents acquired from Sanofi, Senate staff allege that the drugmaker "planned a coordinated strategy to delay generic alternatives to its blockbuster blood-thinner drug Lovenox" by encouraging the Society of Hospital Medicine (SHM), the North American Thrombosis Forum (NATF), and Dr Victor Tapson (Duke University, Durham, NC) to support Sanofi's petition to delay FDA approval of the drugs used for prevention and treatment of acute venous thromboembolism. SHM, NATF and Tapson all had financial relationships with the company, which made almost $3 billion from Lovenox in 2009.

The Senate committee's investigation was prompted by an article in the Wall Street Journal on June 24, 2010 about letters in support of Sanofi's citizen petition filed by the two medical groups and Tapson, arguing against approval of the generic alternatives to enoxaparin [2]. The Journal reported that Tapson, SHM, and NATF did not disclose their financial relationship with Sanofi in their letters to the FDA.

In a letter to FDA commissioner Margaret Hamburg, Finance Committee chair Sen Max Baucus (D-MT) and ranking member Sen Chuck Grassley (R-IA) state "When there are questions or concerns about the safety of a drug, they ought to be raised and resolved in a timely and thorough manner. The citizen petition process is one way that individuals and entities can express their concerns and seek appropriate government action. However, when misused or abused, the process can lead to delays in patient access to potentially affordable, safe, and effective generic alternatives" [3].

Baucus and Grassley ask whether the FDA has considered requiring organizations that submit letters under the citizen petition process to disclose their financial relationships with companies or other entities that will be affected by the FDA's decision, and to explain the steps it has taken to ensure the integrity and transparency of the citizen petition process. The senators ask the FDA to respond to their questions by June 20.

Tapson, however, refutes the Committee report's claim that he talked to the FDA because Sanofi asked him to, and he maintains that his only motivation was to protect patient safety because the generic approved was not equivalent to Lovenox, he told heartwire . However, he does concede that he could have been more transparent in his letter to the FDA.

SHM told heartwire it is now going to great lengths to disclose all of its partnerships and potential conflicts of interest, and while it could have been more transparent at the time in its dealings with FDA over Lovenox, it never tried to conceal information.

As reported by heartwire , in 2007, a US District Court in California ruled Sanofi's patents on Lovenox were unenforceable following a challenge from generics companies Teva Pharmaceuticals and Amphastar Pharmaceuticals. That ruling was later upheld on appeal and, in the summer of 2010, the FDA approved a generic version of enoxaparin made by a division of Novartis. Sanofi-Aventis then sued the FDA, alleging that it had failed to ensure that the generic version had the same active ingredient as enoxaparin, but a federal judge refused to block the sale of the generic, arguing that availability of the cheaper alternative to Lovenox was in the public interest.

Tapson Disputes Version of Events Told by WSJ, Senate Staff

The WSJ report also alleges that Sanofi paid Tapson $260 604 for "speaker/consultant services" and that he wrote a letter in 2008 to the FDA encouraging the agency to review the scientific information related to enoxaparin that had been presented at an American College of Chest Physicians (ACCP) scientific roundtable two months earlier. Sanofi paid $190 000 to sponsor this roundtable, according to the newspaper.

In an email to heartwire , Tapson says he is "disappointed" with the finance committee's report because it contains "no science and a lot of erroneous assumptions."

"The Senate report and the WSJ [article] should have included some of the key aspects of the science driving some of us to feel the obligation to contact the FDA with our thoughts instead of assuming this was for financial gain," he said. "While Sanofi was interested in delaying the approval of generic enoxaparin alternatives, and this was clear, the goal of my clinical and research colleagues interested in this issue was also clear. It was patient safety.

"Complex biologics are unlike other generics which can be synthesized or biochemically copied. The most important components in a biological such as enoxaparin are not clearly understood or characterized and cannot be copied identically in the laboratory. Potency of a biologic and the reference must be equivalent so that they will exhibit comparable pharmacokinetic properties in vivo. The only way to establish equivalence of function and safety for the biologics is through carefully conducted clinical trials," he told heartwire . But "while I disagree with the lack of any clinical trial data whatsoever, it can certainly be said that [the FDA] considered the issues with great scrutiny."

Tapson says he met with FDA officials in March 2010 on the FDA's invitation. The visit to the FDA "was neither prompted by Sanofi nor funded by [the company]. I regret that this information was not offered in the WSJ story." He says FDA officials invited him to meet with them to discuss "the appropriate diagnostic and therapeutic approach and [his] thoughts about the complex biologics, including low-molecular-weight heparins, and other forms of therapy" because of his expertise and research in venous thromboembolism.

He also denies the committee report's insinuation that he concealed his relationship to the company from the FDA. Tapson says he disclosed his relationship with Sanofi during his meeting with FDA officials. Specifically, he told them that he had conducted research funded by the company, served on international steering committees for Sanofi-funded clinical trials, and received consulting fees and honoraria from Sanofi. Tapson then sent a letter to the FDA describing his concerns about approving generic alternatives to enoxaparin. "Transparent disclosure is crucial. In retrospect, it should have been included not only as it was during the visit, but also in the letter I sent," he said. "And while I was not paid or prompted to visit the FDA, full disclosure of any physician/researcher's financial relationship with the FDA and pharmaceutical industry is essential."

Tapson said he does not understand how the finance committee concluded that Sanofi has given him over $260 000. "[That figure] does not match my 1099 forms, which I carefully reviewed and which totaled less than half of that amount. I am continuing to research the source of the disparity, which perhaps includes funds allotted for research," he says.

Report Says Sanofi Marshaled Support From Professional Societies

The documents in the Senate committee report include a 2009 Sanofi slide presentation stating that generic versions of enoxaparin posed an "imminent threat to [Sanofi's] Lovenox franchise," since the courts ruled Sanofi's patents on the drug were unenforceable. Emails between PR firm Makovsky to senior Sanofi staff show that the company wanted to encourage "independent communication with [the] FDA by professional organizations and prominent [key opinion leaders]" regarding Lovenox, according to the report.

Sanofi gave the gave Society of Hospital Medicine (SHM) $2 675 850 from 2007 through 2010 for conference exhibits, sponsorship, and grants, accounting for 8% of SHM's total revenue from 2007 to 2009, according to the Senate report.

The SHM wrote a letter to the FDA in August 2008 arguing that an "untested" generic substitute for low-molecular-weight heparin was not in patients' best interest. Documents in the report show that Sanofi's public-relations team regarded the SHM's letter to the FDA as one of their own "key accomplishment[s]." Internal Sanofi communications show that SHM consulted with ACCP and Tapson about sending a letter to the FDA following "a very positive meeting."

A few weeks before the SHM sent that letter to the FDA, SHM CEO Dr Larry Wellikson sent an email to Sanofi's director of external affairs Rachel Couchenour explaining that the "SHM has no history of making similar comments to the FDA or any government agency of this kind. While the [executive committee] might be supportive, they may feel this is not something that SHM has the expertise or knowledge to say much about. . . . That being said, when something is important to any of our partners (like Sanofi) that we have a long-term relationship with, we want to give any issue that is important to our partner careful consideration." The Senate committee report highlights this quote from Wellikson's letter as evidence that SHM staff may have felt compelled to support Sanofi's position because Sanofi was financially supporting some of the organization's activities.

However, Wellikson told heartwire : "It's like any other relationship. The fact that we'd been dealing with them made it so that they had a contact point to talk to us about it." Although the SHM may not have previously written a letter to the FDA on a generic drug issue, the organization often writes letters to politicians, the Centers for Medicare & Medicaid Services, MedPAC, and other government agencies about issues facing its members, he said. "We also get asked to do a lot of things that we decide not to do," he said.

Wellikson said that his organization is now going to great lengths to be transparent. The organization's disclosure policies were not as zealous at the time of its letter to the FDA about enoxaparin alternatives, but it never tried to hide those relationships, he asserts. "We believe that there should be disclosure when people are petitioning the FDA or other places. In our initial letter, that was an oversight. At that time, we were showing all of our relationships on our website, and it was on our [IRS form] 990 filing. If there was an oversight, it was unintentional to not include that in that letter. . . We felt at that time we were transparent, but obviously facts have shown that it doesn't appear that we were as transparent as we could be.

"But since about a year and a half ago, we made sure there'd be no slippage," Wellikson said. For example, the SHM now puts the web address for a list of its disclosures on its letterhead. "We decided to drive people and not leave it to chance that we'd ever write a letter to anyone again [without disclosing industry relationships.]" SHM also follows the Council on Medical Specialty Societies code for interaction with industry, he said.

Sanofi gave the North American Thrombosis Forum (NATF) over $2 million between 2007 and 2010, accounting for 81% of the NATF's total revenue during that period, according to the Senate report. Email correspondence acquired by the Senate committee show that "Sanofi officials coordinated their media strategy with NATF and were sensitive to how Sanofi's close relationship with NATF was perceived by the FDA and in the press," the report states. NATF has not yet responded to heartwire's request for comment.

Sanofi-Aventis Says Petitioners' Comments Were Independent

In an email to heartwire, Emmy Tsui, a spokesperson for Sanofi-Aventis, wrote "The citizen's petition on Lovenox and the comments of some of the outside experts brought legitimate and important patient safety facts and considerations to the attention of the FDA. The NATF, SHM and Dr Tapson each made their own, independent decisions to submit comments to the FDA."

Tsui said that the company's collaboration with the NATH, SHM, and Tapson on this issue was not unusual. "Sanofi-Aventis US works with professional medical societies, patient advocacy organizations, and healthcare professionals on issues of common interest, such as patient safety. Where there is an appropriate forum for public discourse, we may encourage experts in the field to express their own opinions.

"Sanofi-Aventis US conducted itself in compliance with existing FDA regulations governing citizen's petitions. We have [complied] and will continue to comply with any and all disclosure requirements," Tsui said. "Sanofi-Aventis US cooperated with the Senate finance committee's inquiry relating to the citizen's petition to the FDA on Lovenox."

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