The White House is facing pressure from prominent lawmakers over its pick to lead the Food and Drug Administration, with abortion foes urging Republican senators to reject the nominee, Dr. Robert Califf, and with key Democrats withholding support over opioid policies and his industry ties.

Nearly six years after Dr. Califf received overwhelming bipartisan support to lead the agency in the final year of the Obama administration, lawmakers and aides are struggling to lock up the votes he needs to clear an evenly divided Senate, where Vice President Kamala Harris serves as the tiebreaking vote.

Few, if any, nominees to the F.D.A. have faced as much opposition on both sides of the aisle, and the agency has been without a permanent commissioner for more than a year. The agency’s agenda includes a series of significant issues: oversight of drugs, tests and devices related to Covid-19; the pandemic-related decline in inspections of drug and device manufacturers; and the popularity of flavored e-cigarette products among teenagers.

Administration officials have been trying to rally support for Dr. Califf and say he continues to have the support of President Biden and top health officials. Senate Democratic leaders also continue to back him publicly. But a date has not been set for his confirmation vote before the full Senate. At least five Democrats are publicly opposing his nomination, so Dr. Califf needs at least five Republicans to support him.

“We are confident Dr. Califf will be confirmed with bipartisan support, and it is critical to have confirmed leadership at the F.D.A. in the midst of a pandemic,” Chris Meagher, a White House spokesman, said. Dr. Califf has declined interview requests while his nomination is pending.

This week, some senators seemed uncertain that Dr. Califf could survive the divisions over his candidacy. “I’m not sure that’s going to come to a vote, and I’ll make a final decision then,” said Senator Roy Blunt, Republican of Missouri. “I like him as a person, I think he can do the job and let’s see what else develops between now and the vote.”

Prospects for a quick vote may be further complicated by the absence of Senator Ben Ray Luján, Democrat of New Mexico, who is recovering from a stroke. A senior aide to Mr. Luján said on Wednesday that he remained in the hospital and would return in four to six weeks unless there are complications. Mr. Luján voted in favor of Dr. Califf at the committee stage.

Notable Democrats — including Senators Joe Manchin III of West Virginia, a key centrist, and Bernie Sanders of Vermont, the independent — have publicly announced that they will oppose the nominee over his ties to the pharmaceutical industry and his handling of the opioid crisis during the Obama administration.

“In terms of health care, in terms of the F.D.A., we need aggressive leadership who are prepared to take on the greed of the pharmaceutical industry,” Mr. Sanders said. “Unfortunately, I don’t think Dr. Califf is that person.”

Dr. Califf cleared a vote in the Senate Committee on Health, Education, Labor and Pensions in January with Republican support. Four senators crossed the aisle to advance the nomination: Richard Burr of North Carolina, the committee’s ranking member; Susan Collins of Maine; Lisa Murkowski of Alaska; and Mitt Romney of Utah.

Senator John Thune of South Dakota, the second-ranking Senate Republican, said on Wednesday that Dr. Califf’s experience and competence boded well for his prospects with many in his party, though concerns over his role in abortion decisions were driving others away.

“It’s hard for me to say at this point kind of where our members are going to be,” Mr. Thune said, “but I know that there are mixed views.”

Two Democrats — Mr. Sanders and Senator Maggie Hassan of New Hampshire, facing a tough re-election in a state hit hard by opioids — opposed the choice, and more Democrats are said to be leaning against his nomination. All three Democrats who voted against Dr. Califf’s first confirmation to the post in 2016, Mr. Manchin and Senators Ed Markey of Massachusetts and Richard Blumenthal of Connecticut, remain in office.

Mr. Markey’s office confirmed that he would again vote against Dr. Califf. Mr. Blumenthal said on Tuesday that if the vote were held that day, he would do the same.

“I still strongly believe that there’s a need for a new era and leadership that will separate the F.D.A. from the pharmaceutical industry in a very public and important way,” Mr. Blumenthal said, adding that he had lingering concerns after speaking with Dr. Califf. On Wednesday, he made a point of reiterating his opposition.

Dr. Califf has been making the rounds of the Senate, meeting with an estimated 45 members, among the most scheduled for any Biden nominee. Aides privately indicated that they believed they could rally the necessary support for his appointment. This week, Mr. Burr predicted: “I think Dr. Califf will be the next F.D.A. commissioner.”

Despite concerns from Mr. Manchin and other Democrats, Dr. Califf was named for the position in November. Mr. Manchin, whose state has been devastated by the opioid epidemic, has outlined numerous changes he would like to see at the F.D.A., including mandatory education for opioid prescribers similar to the education required of those prescribing addiction medication.

The senator’s concerns about the crisis have hampered negotiations over Mr. Biden’s marquee $2.2 trillion domestic policy bill, as Mr. Manchin rejected plans to extend the child tax credit over concerns that those monthly payments to families with children were being used to purchase opioids.

“I strongly opposed his nomination, which is an insult to those who have been impacted by the drug epidemic,” Mr. Manchin said on Twitter on the day of the panel’s vote, adding: “It’s time the F.D.A. had leadership willing to step forward to protect Americans from the drug epidemic that continues to ravage our nation. Dr. Califf is not that leader.”

Several senators, pressed this week on their support for Dr. Califf, said they had not yet made a decision.

Senator Shelley Moore Capito, Republican of West Virginia, said she was still undecided: “I know there’s some issues that have come up, but he has been to West Virginia — he has seen firsthand some of the issues that we have. That’s important to me.”

The F.D.A. commissioner role has been subject to Senate confirmation since 1988, unlike the director of the Centers for Disease Control and Prevention, who is a presidential appointee. The nominee tends to be subject to sharp questioning, but observers say the decision has never been so wrapped up in national politics unrelated to the nominee’s qualifications.

With no confirmed leader, Dr. Janet Woodcock, the interim commissioner, can serve while the nomination is pending. If Dr. Califf’s nomination is voted down, she could lead the agency for 210 more days, according to Charles Young, a spokesman for the Government Accountability Office.

Dr. Califf spent much of his career running cardiology trials at Duke University medical school, where he earned a reputation as an evenhanded expert. In 2017, he joined Verily, the life sciences arm of Alphabet, the parent company of Google.

As head of clinical policy and strategy there, he earned $2.7 million in income and between $1 million and $5 million in stock, according to his ethics disclosure. He also held lucrative leadership roles at pharmaceutical and biotech companies developing drugs for patients with hemophilia and impaired muscle function. In an effort to shore up more support, he committed to Senator Elizabeth Warren, Democrat of Massachusetts, that he would adhere to additional restrictions to separate any administration decisions from his prior work.

“The F.D.A. nominee has agreed to go beyond the current legal requirement to cut himself off from participating in the revolving door after his government service and insulate himself from interactions with former employers during his time in office,” Ms. Warren said. “Because he was willing to make a public commitment to stop the revolving door, I will support him.”

Some critics of Dr. Califf cite his track record at the F.D.A., where he was deputy commissioner for medical products and tobacco starting in 2015 and the Senate-confirmed agency commissioner in 2016 and 2017.

The anti-abortion group Susan B. Anthony List is leading a coalition that is pressuring Republican senators to vote against Dr. Califf. The group criticized changes to medication abortion policies, which became less restrictive in 2016 when Dr. Califf was leading the agency. “In 2016, he was a nominee without a record; now he is a nominee with a track record of disregarding life,” the group wrote.

The group also is opposing Dr. Califf over his responses to questions during the Dec. 14 committee hearing on the agency’s imminent decision about the medical abortion drug mifepristone. Dr. Califf said he trusted the agency to make the right decision with the evidence at hand.

Two days later, the F.D.A. announced that it would permanently allow telehealth providers to prescribe at-home abortion medications.

Tommy Tuberville of Alabama, Mike Braun of Indiana and Roger Marshall of Kansas, all Republicans, voted against Dr. Califf in committee partly over abortion-related issues, staff members confirmed.

The advocacy group is also pressing Mr. Romney, who was one of the four Republicans on the Senate Committee on Health, Education, Labor and Pensions who voted in favor of Dr. Califf on Jan. 13.

Some of the lawmakers’ concern over opioid policy is also based on Dr. Califf’s brief tenure as commissioner in 2016. Three months into his term, the Centers for Disease Control and Prevention issued new guidelines and a searing commentary decrying the often-fatal risks of opioid medications amid “unproven and transient benefits.”

Instead of following up with policy changes, Dr. Califf commissioned another study, said Dr. Andrew Kolodny, a critic of the F.D.A.’s opioid policies who has advised Mr. Manchin, Mr. Markey and Ms. Hassan.

If Dr. Califf is confirmed, “there’s a chance he could do something and then maybe we’d finally get somewhere,” said Dr. Kolodny, who is medical director of the Opioid Policy Research Collaborative at Brandeis University. “But I wouldn’t hold my breath. Because I think at the end of the day, he’s an industry guy.”

Nearly 100,000 Americans died of overdoses in 2020, the C.D.C. has reported, though many of the deaths were related to illicit fentanyl.

Sheryl Gay Stolberg contributed reporting.