Dec. 14, 2021 -- Robert M. Califf, MD, plans to take a close look at federal policies on opioid prescriptions in his expected second turn at the top U.S. regulator of medical products, as well as keep closer tabs on the performance of drugs cleared with accelerated approvals.

Califf on Tuesday fielded questions at a Senate hearing about his nomination by President Joe Biden to serve as FDA administrator, a role in which served in the Obama administration. He also spoke about the need to bolster the nation’s ability to maintain an adequate supply of key medical products, including drugs.

Members of the Senate Health, Education, Labor and Pensions Committee, which is handling Califf’s nomination, were largely cordial and supportive during the hearing. Sen. Patty Murray (D-WA), the committee chair, and the panel’s top Republican, Sen. Richard Burr of North Carolina addressed Califf during the hearing as if he would soon serve again as the FDA’s leader. Both were among the senators who voted 89-4 to confirm Califf in a February 2016 vote.

Califf “was previously confirmed to lead FDA in an overwhelming bipartisan vote and I look forward to working with him again to ensure FDA continues to protect families across the country, uphold the gold standard of safety and effectiveness, and put science and data first,” Murray said.

Less enthusiastic about Califf was Sen. Bernie Sanders (I-VT), who was among the seven senators who did not vote on Califf’s nomination in 2016.

Sanders objected in 2016 to Califf’s ties to the pharmaceutical industry and he did so again Tuesday. A noted leader in conducting clinical trials, Califf has worked with many drugmakers. But at the hearing, Califf said he concurs with Sanders on an idea strongly opposed by the pharmaceutical industry.

In response to Sanders’ question, Califf said he already is “on record as being in favor of Medicare negotiating with the industry on prices.”

The FDA would not take direct part in negotiations, as this work would be handled by the Centers for Medicare and Medicaid Services. Democrats want to give Medicare some negotiating authority through their sweeping Build Back Better Act.

People in the United States are dismayed over both the cost of prescription drugs and the widespread distribution of prescription painkillers that helped fuel the current opioid epidemic, Sanders told Califf. Many people will be concerned about an FDA commissioner who has benefited from close ties to the industry, Sanders said.

“How are they going to believe that you're going to be an independent and strong voice against this enormously powerful, special interest?” Sanders asked.

“I'm totally with you on the concept that the price of pharmaceuticals is way too high in this country,” Califf said in reply.

Califf was paid $2.7 million in salary and bonus by Verily Life Sciences, the biomedical research organization operated by Alphabet Inc., parent company of Google, according to his federal financial disclosure. He also reported holding board positions with pharmaceutical companies AmyriAD and Centessa Pharmaceuticals PLC.

Bloomberg Government reported that Califf has ties to about 16 other research organizations and biotech companies. Bloomberg Government also said that in his earlier FDA service, Califf kept a whiteboard in his office that listed all the activities and projects that required his recusal, citing as a source Howard Sklamberg, who was a deputy commissioner under Califf.

“He was very, very, very careful,” Sklamberg, who’s now an attorney at Arnold & Porter LLP, told Bloomberg Government.

‘Work to Do’ on Opioids

Senators looped back repeatedly to the topic of opioids during Califf’s hearing, reflecting deep concerns about the FDA’s efforts to warn of the risks of prescription painkillers.

There were an estimated 100,306 drug overdose deaths in the U.S. in the 12 months ending in April, an increase of 28.5% from the 78,056 deaths during the same period the year before, according to the CDC.

Califf said he plans to focus on what information the FDA conveys to the public about the risks of prescription painkillers, including a look at what the labels for these products say.

“I am committed to do a comprehensive review of the status of opioids, early in my tenure,” Califf said.

Califf indicated that physicians are still too quick to provide excess doses of these medicines, despite years of efforts to restrain their use. He said he knows relatives who were given 30-day prescriptions for opioids after minor surgery.

“So I know we have work to do,” Califf said.

Concerns about the FDA’s previous work in managing opioids has led to protests from a few Democratic senators about the prospect of Biden nominating the acting FDA commissioner, Janet Woodcock, MD, for the permanent post.

At the hearing, Sen. Ben Ray Luján (D-NM) raised the case of the FDA’s approval of the powerful Zohydro painkiller. The agency approved that drug despite an 11-2 vote against it by the FDA’s Anesthetic and Analgesic Drug Advisory Committee.

Luján asked Califf what he would do if an FDA advisory committee voted “overwhelmingly” against recommending approval of a medicine, as happened in the Zohydro case.

While not mentioned by Luján in this exchange during the hearing with Califf, the FDA staff’s rejection of recommendations of advisory committees has been a growing concern among researchers.

The agency last year approved aducanumab (Aduhelm, Biogen), a drug for Alzheimer’s disease, dismissing the advice of its Peripheral and Central Nervous System Drugs Advisory Committee. That decision triggered the resignation of several members of the panel. The FDA staff also earlier rejected the conclusion the majority of members of the same advisory committee offered in 2016 on eteplirsen (Exondys 51), a drug for Duchenne muscular dystrophy.

Califf told Luján he had done recent research into how often the FDA staff does not concur with the recommendations of an advisory committee. He said the FDA takes a different course of action in about 25% of cases. In about three-quarters of those cases, the FDA staff opts for a “more stringent” approach regarding allowing the public access to the drug, as opposed to a more generous one as seen in the Zohydro, Aduhelm and Exondys 51 cases.

Still, Califf said that when there's an 11-2 advisory committee vote against recommendation of a product, “the leaders at FDA really need to take a close look” at what’s happening.

Question on Accelerated Approvals

The FDA’s approval of aducanumab drew attention to a debate already underway about conditional clearances known as accelerated approvals.

The FDA has used this path since the 1990s to speed access to drugs for serious conditions. The trade-off for early access is that the agency sometimes makes the wrong call based on initial findings, and clears a medicine later found not to benefit patients as expected.

The FDA’s cancer division is in the midst of public efforts to address cases where drugmakers have not been able to deliver studies that support accelerated approvals of their oncology drugs. In addition, the Office of the Inspector General of the Department of Health and Human Services announced in August that it is reviewing the FDA’s handling of the accelerated approval process.

At Tuesday’s hearing, Burr grilled Califf about how he would respond to calls to change how the FDA handles the accelerated-approval process.

“Can you commit to me and to patients who may rely on cutting-edge treatments that you will not support efforts to narrow this pathway or raise the bar for drugs to be approved under those pathways?” Burr asked Califf.

Califf responded by saying he was “a fan of accelerated approval -- for the right conditions.”

Earlier, in his opening statement, Califf had said his mother benefited directly from the accelerated approval of new drugs for multiple myeloma. Califf told Burr that he had spent “countless hours with patient groups” and understands the need to speed the approval of medicines for serious diseases.

But the FDA also has to make sure it holds up its end of the bargain struck with accelerated approvals. This involves checking on how these medicines work once they are marketed.

“We're accepting that there's more uncertainty,” Califf said. “That means we've got to have a better system to evaluate these products as they're used on the market. And I think there are ways that we can do that now. Technology is making this possible in ways that it just was not possible before.”

Worries about the Medical Supply Chain

Sen. Susan Collins (R-ME) asked Califf about the vulnerability of the U.S. medical system to disruptions of the supply chain. She raised concerns about China’s dominance in antibiotic manufacturing as an example. She asked if Congress could do more to encourage domestic manufacturing of medical supplies, such as by offering tax incentives.

Califf told Collins he shared her concern about the US manufacturing of ingredients used in both branded and generic drugs. He said he recently has served on a committee of the National Academy of Medicine that is examining supply chain issues.

This committee will soon release a report with specific recommendations, Califf said.

“We don't have enough competitive entities in what's become sort of a commodity business” of drug manufacturing, Califf said. “So we need a number of steps to make the system more resilient.”