The IBB, an ETF that tracks biotech's biggest players, was down more than 2 percent Wednesday, on pace for its worst day since Feb. 7, when it lost 2.5 percent. The biggest drops were Amgen, Gilead Sciences and Biogen, which were all down more than 2 percent in midmorning trading.
Salim Syed, senior biotech analyst at Mizuho Securities, told CNBC that Gottlieb represented a more "friendly FDA," adding he was "generally really liked by the biopharma investment community."
"Finding somebody better than him, that'll be hard," he added.
Gottlieb is resigning to spend more time with his family, he said in a letter to FDA staff. The physician has been commuting from his home in Westport, Connecticut, where his wife and three young daughters live. He tendered his resignation to Health and Human Services Secretary Alex Azar in a letter Tuesday.
Graham Parry, a research analyst at Merrill Lynch who covers the sector, told clients late Tuesday that Gottlieb's resignation was a "net negative for innovative biopharma companies."
Gottlieb is widely respected in the industry. In his first year as commissioner, Gottlieb approved a record number of new and generic drugs. Before his appointment, he served on the board of several drug companies and worked as an industry consultant.
"Gottlieb, in our view, as a healthcare policy expert, has been a key influence and architect, along with HHS secretary Alex Azar (former Pharma executive), of relatively innovator-friendly, evidence-based Trump administration healthcare policies and reforms laid out in its drug pricing blueprint last year," Parry said.
The FDA has not selected a replacement for Gottlieb.
— CNBC's Angelica LaVito and Gina Francolla contributed to this report.