Maybe more than any other person alive, Richard Pazdur, the director of the Food and Drug Administration’s Office of Oncology and Hematology Products, personifies the tension between the need to get new drugs to patients fast and the competing desire to make sure they are safe and effective first.
To his critics, he is an compassionless bureaucrat who denies cancer patients lifesaving medicines using red tape and fine print. In 2007, Richard Miller, the chief executive of a company called Pharmacyclics whose drug had been rejected, wrote a series of opinion pieces in the Wall Street Journal accusing the FDA of “stifling, rather than encouraging, investments in innovation through cumbersome and over-restrictive policies.” A New York Times profile referred to him as “the man who says no.” He received threats and was called a murderer. Another drug rejection, of the prostate cancer treatment Provenge, led 200 protestors to picket the FDA chanting “Pazdur must go!”
The man himself is philosophical, and sees the need for speed. “When patients know there is an active drug, two months make a big difference, because they’re dying of a disease,” Pazdur says. “It’s like holding a glass of water in front of a person dying of thirst and saying, no, you can’t drink.”
In an interview earlier this month at the annual meeting of the American Society of Clinical Oncology, Pazdur, a greyhound-like oncologist with clear round spectacles, presented himself as anything but an obstructionist. There is a revolution on in treating tumors, he says. So far this year, seven of the 13 new drugs approved by the FDA are cancer medicines.
“I think our jobs are getting easier because the drugs are better,” Pazdur says. Frequently, he isn’t even calling together the public expert panels whose approval had become a rite of passage for new cancer drugs. There’s simply nothing to ask. “We don’t have a lot of questions on drugs because they’re slam dunks. It’s not if we’re going to approve them. It’s how fast we’re going to approve them.”
This age of fast approvals is now getting a legislative boost, thanks to a provision in the FDA Safety and Innovation Act of 2012 that compels the FDA to create a new status, known as a “breakthrough” designation, for treatments for life-threatening diseases where “preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies.”
The designation joins several other FDA prizes aimed at speeding up approvals for important medicines: Priority Review, created by Congress in 1992, cuts the targeted review time for a drug from 10 months to six; Fast Track status is designed to streamline the review process for drugs that meet an unmet medical need; and Accelerated Approval allows medicines to be approved based on preliminary data pending the completion of larger studies.
A drug can get one, two, or all of these designations at once. So given that Fast Track is already supposed to speed up the review process, Priority Review to shorten it, and Accelerated Approval to make the process start earlier, what is left for the new breakthrough designation to do?
The short answer, Pazdur says, is that it catalyzes communication between a company and the FDA. Traditionally, drug reviews take place through a series of scheduled meetings. A breakthrough designation means there are more times a company can expect to be able to pick up the phone and get an answer. The designation can lead to cleared calendars, and it also means that the senior management of the FDA division becomes involved, not just the reviewers who serve on the FDA’ s front lines.
“The true measure of success is going to be how active we are in working with the companies,” Pazdur says. “If someone gets a breakthrough therapy and it’s business as usual, than the breakthrough therapy is meaningless.”
Pharmacyclics, the company whose CEO complained about Pazdur five years ago, has received three breakthrough designations for a new cancer drug, ibrutinib, that it is developing with Johnson & Johnson. Miller, the vexed chief executive, is gone. His replacement, the investor Robert Duggan, is now a billionaire as a result of the soaring value of Pharmacyclics stock. Pazdur rarely comments on the merits of drugs his division has not approved, but at an educational session at the ASCO meeting, he called the ibrutinib data impressive. He repeated that opinion in our interview.
Merck has received a breakthrough designation for a drug that targets the immune system to fight melanoma. “It’s been a significant advantage. We have immediate access to the highest level officials in the FDA oncology division and we’ve been able to obtain guidance form them about trial design in the most rapid way,” says Gary Gilliland, Merck’s oncology research head. Hal Barron, the chief medical officer at Roche, says: “We’re confident speaking with Pazdur it will increase the frequency with which we can communicate. It’s hard to imagine it won’t increase the ease of filing. We believe it will probably reduce the time.”
Mace Rothenberg, the senior vice president in charge of oncology development of Pfizer, says so far getting the indication for a Pfizer drug is helping co-ordinate not just clinical trials but also other things that can slow down a new medicine, like manufacturing and choice brand names, which FDA also regulates. He also warns: “Just as a drug can get breakthrough designation, it can lose breakthrough designation as well.”
Pazdur advises companies who plan to file for a breakthrough designation in cancer to call his office first and schedule a conference call. One reason some applications have been denied, he says, is because companies jumped the gun. “It was too early to make a decision just based on a handful of patients.”
The fact that many approvals have sped through the review process, however, does not mean that the FDA’s standards have dropped. On May 2, the agency convened an expert panel to discuss whether it should approve tivozanib, an experimental kidney cancer treatment being developed by tiny AVEO Pharmaceuticals of Cambridge, Mass. Tivozanib’s selling point was that it was supposed to have fewer side effects than the other gene-targeted cancer drugs that have transformed the treatment of kidney cancer. But at the FDA panel the agency pointed out that patients who received tivozanib died sooner than those who had received another drug, Nexavar. And Pazdur showed why he has caused so many biotech executives nightmares over the years.
“I am extremely disappointed in the sponsor’s proposed labeling for this drug,” Pazdur said during a long aside quoted in The Cancer Letter. “There is no survival curve in the proposed labeling. There is no hazard ratio— there’s difference in the means and the explanation in one or two sentences confounding by crossover.
“But if this drug is approved, one would have to have a very careful conversation with the patient about this potential negative impact on overall survival. And how would you do this? I’ve been playing this in my mind in several scenarios, and any logical patient that I could think of would say, ‘Doc, if you are so uncertain about this most important endpoint, don’t we have any other drug to use here?’”
AVEO was done. The panel voted 13 to 1 that the company had not produced sufficient efficacy data, and the FDA rejected the drug. Pazdur says that too often, companies claiming that their products are safer are just trading one side effect for another, and that, regardless, in cancer the medicines need to be as effective as what they’re replacing. (Given the toxicities of many cancer drugs, a less-toxic but equally effective medicine might have some benefit in terms of survival.)
Pazdur thinks hard about a lot of things. He worries that his FDA reviewers couldn’t attend the ASCO meeting where data on the drugs they will review was presented because of budget cuts mandated by the sequester (he went to receive an award for his contributions to cancer care.) He is pondering deeply how the regulation of drugs that are paired with gene tests will work. He worries about how medicines will be tested in combination with each other, and hopes maybe the National Cancer Institute will step in.
One thing that doesn’t concern him: his critics. “There are people who have varying opinions of my performance,” he says. “But I have to do what I believe is the right thing for any given application.”