Steven Nissen, Conflicts Of Interest, And The New Cholesterol Drugs 6

(Updated)

Does Steve Nissen, an outspoken critic of inappropriate industry influence in medicine, have his own conflict of interest problem?

This week Nissen, the chief of cardiology at the Cleveland Clinic, was widely quoted in news reports about the FDA advisory panels evaluating two new highly promising cholesterol drugs from Amgen and Sanofi/Regeneron.

Nissen was broadly supportive of the drugs. Although he has been one of the leading voices against approving and using drugs based solely on their effect on surrogate outcomes, he was much more liberal about these drugs than some other experts and many of the panel members. Here’s what he told CNBC:

“I am somebody who generally is opposed to approving drugs on the basis of surrogate endpoints without the outcome data,” Nissen said by telephone Wednesday, referring to lowering of LDL cholesterol already shown by the medicine. “However, in this case, I actually support approval and I actually think the concerns of the committee are not on target.”

On the NBC Nightly News program he was even more effusive:

“These drugs are breakthrough drugs, they are blockbuster drugs that are very likely going to have a big impact.”

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Takeda Disagrees With Orexigen Over Data Disclosure Reply

(Updated)

On Tuesday Orexigen sparked a firestorm by disclosing the interim results of an ongoing clinical trial of its weight loss drug Contrave. Takeda, which markets the drug in the US, has released a statement in which it states that it does not support the release of the interim data.

Here is the Takeda statement:

“Pursuant to the Collaboration Agreement between Takeda and Orexigen, Orexigen has the sole right and responsibility for the drafting, prosecution and issuance of Orexigen patent filings.  Takeda respects the need to vigorously protect intellectual property relating to pharmaceutical products; however, Takeda does not support the issuance of patents that contain and disclose interim data results of an ongoing clinical trial.  Takeda is working with the academic leadership of the Light trial (Data Monitoring Committee, Executive Steering Committee) and the FDA to determine the most appropriate next steps for the LIGHT trial.”

Update:

And here is Orexigen’s mildly updated statement about the events:

Orexigen conducted a large cardiovascular outcomes trial in order to file for approval, with the study planned to continue after approval to serve a postmarketing regulatory requirement for additional risk exclusion. We observed an unexpected result in the interim analysis. We filed patent applications based on the results in order to preserve the potential for additional intellectual property. Prior to approval in September 2014, the FDA informed us it had determined that the Light Study would not serve as the postmarketing requirement for Contrave; an entirely new trial would be required. At that point, the company decided to continue with the patent prosecution. The second cardiovascular outcomes trial is expected to start later this year. We are confident that this trial can be enrolled and conducted successfully and we look forward to the results, which are expected by 2022.

On March 3 2015 the USPTO published an issued patent and supporting documentation, and we believed it was appropriate and necessary to make sure this information was equally available to all investors.
Orexigen proactively discussed the challenges inherent in using interim data from ongoing trials for regulatory approvals, and has been, and continues to be, committed to working with FDA and others to support its regulatory obligations to thoroughly explore Contrave’s therapeutic profile. Just as important, Orexigen is committed to its obligation to patients to fully explore the drug’s profile.
Orexigen is also committed to simultaneously meeting its obligations to other regulatory authorities in the U.S., such as the SEC, and abroad, such as the EMA, which are relevant to, and have authority over, its business. The Company is similarly committed to meeting its fiduciary duties to shareholders.

I will have much more to report about this story soon.

 

 

Orexigen Released Interim Data Without Approval Of Trial Leaders Reply

Earlier today Orexigen Therapeutics disclosed positive results from a clinical trial of Contrave, its weight loss pill (a combination of naltrexone and bupropion) that it markets with Takeda. (You can read a good summary of the findings by Adam Feuerstein on TheStreet.)

The surprising thing about the Orexigen disclosure, which was contained in a Form 8-K filed with the SEC, is that it consisted of data derived from an interim analysis of the company’s ongoing Light trial. Normally, interim results are performed by an independent data monitoring committee and the results are known only to the members of the DMC. Occasionally, when important regulatory issues are at stake, the FDA may also be involved. But the detailed results of the analysis are never made public until the trial is stopped.

In this case neither the DMC nor the trial Executive Committee, headed by the Cleveland Clinic’s Steve Nissen, knew about or approved the release of the data. Here’s a statement Nissen sent me:

Click here to read the full post on Forbes.

 

Independent Re-Adjudication Of RECORD Confirms Safety Of Rosiglitazone Reply

An independent re-adjudication of the RECORD trial has confirmed the original findings of the trial, that rosiglitazone d0es not increase cardiovascular risk. But critics of the trial and the drug are unlikely to be appeased by the new result.

The re-adjudication of RECORD will be the subject of an extraordinary two-day FDA advisory committee meeting next week on June 5 and 6. GlaxoSmithKline posted a summary of the results (PDF) on its website last October, but its presence was not generally known until the publication of an article in BioCentury on Tuesday.

The FDA also required GSK to commission the independent re-adjudication of RECORD that has now resides on the GSK website. The re-adjudciation was performed by the Duke Clinical Research Institute. According to BioCentury, “GSK said it does not typically publicize data put on its clinical trial registry and added that the Duke researchers are planning to submit the data for publication.”

Here is the conclusion of the DCRI re-adjudciation:

Click here to read the full post on Forbes.

 

 

Spinning RECORD: Battle Over Rosiglitazone Heats Up Two Weeks Before Crucial FDA Meeting 1

Battle lines are being drawn two weeks before a highly unusual two-day FDA advisory committee meeting to discuss the contentious diabetes drug rosiglitazone (Avandia, GlaxoSmithKline). This will be the second time an FDA panel has wrestled with the fate of the drug and expectations have been that the discussion will once again be heated.

But at least one source of fierce criticism won’t be participating in the panel. Steve Nissen, who originally raised concerns about the drug and who has remained the most consistent critic of the drug, will not participate in the deliberations or present to the committee. Early on Thursday Nissen contributed a blog post on Forbes accusing the FDA of stacking the committee in favor of rosiglitazone. The FDA leadership, he says, is trying to use the meeting to “whitewash” its reputation:

GlaxoSmithKline said that “many inaccuracies exist in Dr. Nissen’s commentary and need to be addressed.” The company specifically denied the multitude of reports over the years that it had suppressed negative data about rosiglitazone over the years. The GSK response offers one potentially very important piece of news. The main focus of the June 5-6 hearing will be the re-adjudication of the RECORD trial performed by the Duke Clinical Research Institute. No public disclosure of the results of the re-adjudication have been made, and in the normal course of events the details of the re-adjudication, along with the rest of the committee’s briefing documents, would appear two days before the start of the hearing on the FDA website. But FDA staff, advisory panel members, and the drug sponsor (GSK) have almost certainly already seen the re-adjudication. In its statement, GSK flatly states that the re-adjudication confirms the safety of rosiglitazone:

The RECORD study is the largest clinical trial designed to evaluate the cardiovascular safety of Avandia. The study conclusions have now been confirmed through a re-examination by one of the leading independent institutions in the country (Duke Clinical Research Institute). In the accepted hierarchy of evidence generation, the results of a randomized, controlled clinical trial usually take precedence over other forms of evidence such as meta-analysis and observational studies. Despite some limitations of trial design, including the open label nature of the study, RECORD remains the only randomized trial of cardiovascular outcomes for Avandia at this time. The confirmation of the RECORD results by the independent re-examination support a positive risk/benefit profile for Avandia for the treatment of type 2 diabetes in appropriate patients.

It remains to be seen whether this is more RECORD spinning or an accurate summary of the Duke re-adjudication.

Click here to read the full story on Forbes.

 

Deutsch: Tonabnehmer eines Plattenspielers

 

Controversial NIH Chelation Trial Published In JAMA Reply

Final results of the troubled NIH-sponsored TACT trial testing chelation therapy for coronary disease have now been published in JAMA. Last November, when the preliminary results were presented at the American Heart Association meeting, the positive finding in favor of chelation therapy surprised many observers, though the investigators and senior AHA representatives expressed considerable caution  about the proper interpretation of the results. Full publication of the main results should now allow for a more thorough consideration of the trial.

The Trial to Assess Chelation Therapy (TACT) was initially funded by the NIH more than a decade ago to test chelation therapy with EDTA, an alternative medicine therapy received by more than 100,000 people every year but with no evidence base for support. The highly controversial trial was temporarily suspended in 2008 in response to ethical concerns but was then allowed to resume. The trial was also hampered by slow enrollment, eventually resulting in a downsizing of the trial population. To maintain the trial’s power to achieve a meaningful result the follow-up time was increased. (Because of this change, and because the data and safety monitoring board reviewed the data multiple times over the course of the study, the threshold for statistical significance was lowered to 0.036.)

TACT was a double-blind study testing active or placebo infusions of chelation in 1,708 stable patients with a history of MI.  The primary endpoint of the trial– the composite of death, MI, stroke, coronary revascularization, or hospitalization for angina– was significantly lowered in the chelation group:

  • 26% in the chelation group versus 30% in the placebo group (HR 0.82, 0.69-0.99, p=0.035)

Nissen

Steve Nissen

The editorial by the JAMA editors is itself evidence of the extraordinary sensitivity of the TACT trial. The JAMA editors, in a highly unusual situation, discuss their detailed review of TACT and explain their decision to publish the trial. Although they acknowledge multiple limitations of the trial, they defend its value: “reports of rigorous investigations should not be censored because of preexisting ideological positions,” they write.

In his editorial, Steve Nissen agrees with the JAMA editors decision to publish the trial but issues a fierce indictment of the trial and its conduct. The TACT paper, Nissen writes, “represents a situation in which many important limitations in the design and execution of a clinical trial compromise the reliability of the study and render the results difficult to interpret. Unfortunately, the efforts of these investigators fell short of the minimum level of quality necessary to adequately answer the question they sought to investigate.”

Daniel Mark

Daniel Mark

TACT investigator Daniel Mark provided CardioBrief with the following detailed response to Nissen’s criticism. (Nissen declined to respond to Mark.)

In his editorial, Dr. Nissen asserts that the “logical” explanation for the greater withdrawals in the placebo group is that patients were unblinded. He further implies that the CAM sites were more likely to be responsible for such unmasking.

His editorial is written from the perspective of someone who is absolutely sure that the trial results are wrong and his mission is to identify where the flaws originate.

Click here to read the full story on Forbes.