At his confirmation hearing last month to lead the Food and Drug Administration, Robert Califf was pressed by U.S. senators for his views on the opioid crisis, on tobacco and e-cigarette regulation, and on his relationship with pharmaceutical and tech companies.
Califf came prepared and, by all accounts, sailed through.
But the hearing did little to address a fundamental question: Who is Robert Califf, and what can we expect him to do?
advertisement As a reporter who has watched his career for more than 15 years and interviewed him countless times, I know of Califf as more than a vessel for one policy or another. He’s a pioneer when it comes to large-scale clinical trials. He’s a passionate believer in evidence-based medicine. And, when confronted with controversy, he looks for a systemic problem lurking beneath it. In Washington, as with his first go-round as FDA commissioner, this tendency could be either a strength or a weakness. It could help him steady an agency that is shaking from the weight of the pandemic and struggling with internal tensions about the nature of its mission. But it could also make it hard for Califf to accomplish his own goals, to deal with problems like opioids or tobacco precisely because he is so driven by building consensus. The stakes are high.
advertisement To understand Califf, start by looking back to 1993. That was the year that he served as the clinical director of a study chaired by the cardiologist Eric Topol that showed that a clot-busting drug made by Genentech could save the lives of 1 in 100 heart attack patients compared to an older treatment. It was not the first major clinical trial to change the way doctors practiced, but it was set apart by its scale: It enrolled 41,000 heart attack patients around the globe, a number that was virtually unheard of at the time.
The idea was that clinical trials needed vast amounts of data to produce reliable results.
The effort led Califf to found the Duke Clinical Research Institute in 1996, building on the existing Duke Database for Cardiovascular Disease. The Cleveland Clinic, where Topol worked, also became an epicenter for clinical research.
‘We worked together for almost 20 years,’ Topol, now the director of the Scripps Research Translational Institute, told STAT in an interview. The work, he pointed out, paid dividends beyond the results of the Genentech trials. It set a standard for how large studies could be done. Over the next decades, that led to proof that medicines to lower blood pressure and cholesterol can save lives. It’s in the creation of this ecosystem that Califf became a giant. It also meant that both he and Topol were among the experts who found themselves in a delicate dance with the pharmaceutical industry, which funds most large clinical trials. The scientists needed to be viewed as independent enough to be reputable but not so critical of pharmaceutical firms that they would go elsewhere — including outside academia, to companies like Quintiles, now known as IQVIA — for partners.
Doing industry-funded trials did not mean kowtowing to industry interests. In endorsing him to be FDA commissioner in 2016, the New England Journal of Medicine noted that Califf had reported the outcomes of seven clinical trials sponsored solely by industry. Of those, four were negative and one had mixed results. Only two actually made the drug studied look good. ‘Given this performance, it is impossible to argue that Califf has a pro-industry bias,’ the journal’s editor, Jeffrey Drazen, wrote.
But Califf’s evenhandedness could often cushion criticism in a way that others might view as overly soft. Take the case of Vioxx, a Merck arthritis drug that was withdrawn in 2004 because it caused heart attacks and strokes. Topol became a fierce critic of Merck, and remembers arguing with his old friend on TV.
A PBS appearance from that time shows Califf’s more nuanced approach. ‘I would say that Merck played by the rules from everything that I’ve seen,’ he said. But he also said the company didn’t follow his advice. Vioxx’s heart risk, which some experts had been warning about for years, showed up in a study of heart patients. Merck could have gotten an answer faster, Califf said, if it had done a study in heart patients with arthritis. The problem was not one of malfeasance, but of inadequate data. Certainly, Califf had a point: Often both sides in heated arguments about new medicines ended up being wrong. Take Natrecor, a heart failure medicine from Johnson & Johnson that critics argued might cause kidney problems. Califf was enlisted to run a large study of the medicine, which found that it was neither dangerous nor very effective.
‘Once again, small studies give us the wrong answers,’ Califf told the New York Times in 2010. ‘There was no safety issue at all.’ But it’s also true that the next year, J&J pleaded guilty to marketing Natrecor to patients for whom it was not approved.
In 2008, Califf defended Zetia, a Merck cholesterol drug, against criticism that it might be, in the words of one cardiologist, ‘an expensive placebo.’ A 2014 study he ran showed that the medicine was effective at preventing heart attacks, but that the effect was small.
‘The questions were legitimate, but I think some of the grandstanding that happened was probably not ideal,’ Califf told me then about some of the medicine’s critics. He said he had proposed an entirely different study, in which the drug, which is not that potent but is very safe, would be taken by people with high cholesterol in the early stages of heart disease for many years; the drug maker balked.
He also did not always fall on the pro-industry side. Califf was instrumental in the FDA’s embrace of a proposal that established that diabetes medicines have to prove their safety to the heart. The proposal was initially accompanied by fears that it would prevent the development of new medicines. Instead, it led to the discovery that some newer diabetes medicines could prevent heart attacks, something researchers did not expect.Califf notably confronted controversy during his last go-round as FDA commissioner. A drug for muscular dystrophy, made by the biotechnology firm Sarepta, was up for approval based on data about levels of a key protein, dystrophin, that is missing in the muscles of boys with the disease. FDA officials were at odds: Some did not want to approve the medicine, but Janet Woodcock, now the FDA’s acting commissioner and then a top official, decided to approve it. When other officials appealed the ruling, Califf let it stand on the grounds that Woodcock had not done anything improper and that he did not want, as a political appointee, to overrule a staff decision. Topol said the decision was ‘compromising reasonable approval standards.’
‘I said, what about the data?’ Topol said recently. ‘What about the evidence? That was a big surprise to me because he does support data.’
Califf had, essentially, been asked to choose between his desire for data and his desire for maintaining proper processes, and process had won out.
That matters because most of the concerns facing the FDA boil down to whether the agency’s processes are doing enough to generate the right amount of data and to make correct decisions. On opioids, the FDA followed its processes, but they were the wrong ones — even when this meant approving new, potent opioids when the pandemic was in full swing. Controversies around the FDA’s decisions don’t really revolve around whether the FDA followed protocol, but whether it made the right call. Look, for instance, at the controversial decision to approve Aduhelm, the Alzheimer’s drug from Biogen. Other global regulators, including those in Europe and Japan, have decided not to approve the medicine. The right question is not whether the FDA followed its protocols, but whether the data back its decisions.
Topol said he was sure that Califf was taking the new job for the right reasons. Califf, he said, was having a fine time working in tech and playing golf. He is likely taking the job because of a sense of duty. ‘I give him credit,’ Topol said, ‘for responding to the call.’
Some ambition and ego, however, would probably be well-placed. If he wants to serve the agency, he should serve himself and make sure he has a clear and unwavering idea of what it should do and how it should act. At his confirmation hearing, many senators seemed unsure how to even pronounce his name. He’d serve the FDA best by making sure that he’s making a firm enough mark that that doesn’t ever happen again.
https://www.statnews.com/2022/01/05/robert-califf-fervent-believer-data-fda/
