Several Democrats objected to Dr. Califf's nomination, mainly due to his pharmaceutical industry ties, but six former FDA commissioners endorsed him as an experienced leader who will be able to guide the agency and the country out of the COVID-19 pandemic. Vermont Senator Bernie Sanders was one of the objectors, as well as West Virginia Senator Joe Manchin, who criticized how FDA handled the opiod crisis under Dr. Califf's guidance. Dr. Califf was confirmed by a narrow margin, with 50 votes in favor and 46 against. One senator voted "present." During Dr. Califf's first time in the role, 89 senators voted to confirm him. 

Califf takes over from longtime FDA veteran Janet Woodcock, who had been serving as acting commissioner. Although the White House considered Woodcock for the permanent role, she ran into opposition on Capitol Hill. She originally led FDA's Center for Drug Evaluation and Research when prescription opiods such as OxyContin were approved in the 1990s.

In a December 2021 letter to the Senate health committee, six former FDA chiefs endorsed Dr. Califf as someone who has enough experience to effectively lead FDA in a time of crisis. The letter also said that the year-long absence of a confirmed commissioner had compromised FDA's ability to fulfill its mandate.

“Confirming Dr. Califf is critical not only for moving beyond the COVID-19 emergency, but also to help meet FDA’s many other major regulatory responsibilities where Senate confirmed leadership is essential for the nation’s wellbeing,” wrote Drs. Scott Gottlieb, Stephen Hahn, and four other former commissioners.