Path to Top FDA Post Gets a Bit Rockier for Califf

Robert Califf, MD, has faced mostly smooth sailing as President Obama’s nominee for commissioner of the US FDA but questions about the integrity of data in the ROCKET AF trial are creating some chop.

The current acting director at the FDA, Califf served as co-chairman of the ROCKET AF executive committee and is founder and former director of Duke Clinical Research Institute (DCRI), the group that led the study.

The ROCKET AF study compared rivaroxaban (Xarelto, Bayer/Johnson & Johnson) against warfarin in patients with nonvalvular A-fib and showed the new factor Xa inhibitor was noninferior to the older agent.

Study investigators and the sponsor are under fire, however, following revelations that the device used to monitor and calibrate warfarin use in ROCKET AF has been the subject of 2 FDA warning letters and a class I recall. The criticism is relevant as the effectiveness of warfarin as a comparator is dependent on attaining a therapeutic window measured by the international normalized ratio (INR).

In 2014, which was 4 years after ROCKET AF ended, the FDA recall stated the INRatio and INRatio2 PT/INR Monitor System (Alere), both of which were used in the trial, saying they “may provide an INR result that is lower than [the] expected result obtained using a laboratory INR method.” They also warned that incorrect results may occur if a patient has certain medical conditions, such as anemia or other bruising or bleeding conditions.

In response to the criticisms, the DCRI initiated an independent secondary review of the data that confirmed the noninferiority of rivaroxaban.

“The findings from the analysis are consistent with the results from the original trial and do not alter the conclusions of ROCKET AF,” a DCRI statement reads. “Rivaroxaban is a reasonable alternative to warfarin and is noninferior for the prevention of stroke and systemic embolism with less intracranial hemorrhage and fatal bleeding.”

The DCRI plans to publish the analysis and the results soon.

The Project for Government Oversight (POGO), an independent government watchdog, first raised the issue about the malfunctioning INR-measurement devices and their potential impact on the study’s results.

In addition to the completed DCRI review, the FDA is currently reviewing “relevant data” and the European Medicines Agency (EMA) is investigating whether the data from the INRatio device could have influenced the ROCKET AF results. The FDA said they have no timeline for their review, while the EMA said they expect results to be known in early 2016.

Rivaroxaban is also approved for stroke prevention in A-fib patients in Europe.

Senators Also Livid About ‘Frankenfish’

In addition to the ROCKET AF concerns, Califf’s path to the commissioner job also faces challenges by politicians in Alaska upset over the recent FDA decision to allow genetically-engineered salmon to come to market. In November, under Califf’s watch as Deputy Commissioner, the FDA approved the first genetically modified animal intended for human consumption and did not require the company to label the fish as genetically altered.

Sen. Lisa Murkowski (R-Alaska) is quoted in the Alaska Journal of Commerce, saying she is furious with the FDA decision and will vote against Califf’s nomination as FDA commissioner unless the agency changes its decision and requires the mandatory labelling of such “Frankenfish.”

Democratic presidential nominee Sen. Bernie Sanders (I-VT) previously stated he plans to vote against Califf because of his former ties to the pharmaceutical industry and his alleged lack of commitment toward lowering the cost of medications for Americans.

The US Senate has the final say on the FDA’s top job, and a vote is expected soon. On November 17, the US Senate Committee on Health, Education, Labor, and Pension (HELP), which oversees the FDA, held a nomination hearing. 

1. Duke Clinical Research Institute. ROCKET AF clinical trial executive committee releases secondary analysis. Published on: December 7, 2015. Accessed on: December 10, 2015.
2. Project for Government Oversight. European regulator investigating trial led by FDA nominee. Published on: November 30, 2015. Accessed on: December 10, 2015.

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Michael O’Riordan is the Managing Editor for TCTMD. He completed his undergraduate degrees at Queen’s University in Kingston, ON, and…

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