The FDA, for most of the past 10 years, was the regulatory agency that many people in biotech and pharma loved to hate. Critics have long complained about bureaucratic foot-dragging, byzantine organization, poor communication, excessive aversion to risk, and arbitrary decisions around whether to approve new drugs for sale in the U.S.
But FDA bashers, at least in the pharmaceutical world, haven’t had much to complain about in 2012. Suddenly the FDA and the pharma industry it regulates look like best pals. The FDA, under commissioner Margaret Hamburg, has been making noise for some time about its desire to not just ensure the safety and effectiveness of the U.S. drug supply, but to also help promote the development of innovative new medicines. This year, the agency has absolutely done everything it can to back up its rhetoric with actions that prove it isn’t an adversary but more of a partner in the development of new medicines.
You can’t expect the FDA to say it is becoming more permissive in its reviews of new drug applications, or more industry friendly than it has been in the past. The official line is that it reviews applications on the scientific merits, in order for the public to maintain confidence in its decisions. But scientific results can be interpreted many different ways. I’ve previously said I was skeptical the FDA would really change its waysand become an industry partner. But after reviewing the FDA’s actions from 2012, I can see there’s a clear pattern that the FDA is becoming more friendly toward drugmakers.
People often try to use data to see which way the FDA is leaning, by adding up the number of new chemical entities the FDA approves for sale in the U.S. each year, and concluding that when the numbers go up, the FDA is more friend than foe. CenterWatch does a nice job of putting together a running tally of FDA drug approvals, which had 81 drugs on it when I checked on Friday. The FDA even crowed itself last November about its increasing number of approvals. But simply adding up those approvals and comparing the number to past years can be misleading, because the FDA might get more applications some years, and those applications might vary in quality from year to year. And not all of the molecules on the CenterWatch list are new, some of the approvals are for additional uses of existing meds.
I don’t have any moles inside FDA headquarters confirming any change of direction at the agency, but I do cover the news and attempt to read the tea leaves about what’s going on there just like others in the media, at companies, and on Wall Street. To get a handle on this elusive question, I’ve tried to put together a list below of the more important FDA actions on innovative new medicines this year, and compare—in a tongue-in-cheek way—what could have happened under a cautious FDA, and what actually did happen. Consider:
|Company||Drug||A Cautious FDA Could Have Said…||FDA Decision||FDA Comment|
|Vertex Pharmaceuticals||Kalydeco||Clinical trial looks outstanding. We’ll approve this drug for sale by the Apr. 18 legal deadline||Approved Jan. 31||“Kalydeco is an excellent example of the promise of personalized medicine – targeted drugs that treat patients with a specific genetic makeup.”–FDA commissioner Margaret Hamburg|
|Onyx Pharmaceuticals||Kyprolis||Data look intriguing from your single, non-randomized Phase II clinical trial. Yet our reviewers are concerned about deaths in your trial, and unsure what caused them. We already have two excellent drugs for multiple myeloma, so what’s the rush? We’ll say no now, and take another look when you have results from your ongoing, more rigorous Phase III trial.||Approved July 20||“The approval of Kyprolis provides a treatment option to patients with multiple myeloma whose disease has progressed despite use of available therapies. We are encouraged by the continued progress.”–FDA’s Richard Pazdur.|
|Medivation||Xtandi||Your clinical trial data looks great, and safety profile is clean. We’ll approve this drug by Nov. 22, under our faster-than-usual 6-month priority review system for groundbreaking new medicines||Approved Aug. 31||“The need for additional treatment options for advanced prostate cancer continues to be important for patients. Xtandi is the latest treatment for this disease to demonstrate its ability to extend a patient’s life.”—Pazdur|
|Vivus||Qsymia||Good grief, another obesity drug? Your clinical trial data is so-so. The safety profile is OK, but there’s a history that says when pregnant women take one of the components in this drug for migraine, there’s increased risk of cleft palates among their newborns. An obesity drug is likely to be taken by millions of people—including many pregnant women—and this is a risk we can’t take. While you’re proving to us this won’t happen, how about you run a 5-year study assessing whether your drug raises the risk of heart attack and stroke?||Approved July 17||“Obesity threatens the overall well being of patients and is a major public health concern. Qsymia, used responsibly in combination with a healthy lifestyle that includes a reduced-calorie diet and exercise, provides another treatment option.”—FDA’s Janet Woodcook|
|Arena Pharmaceuticals||Belviq||Geez, another obesity drug. You don’t appear to have any issue with cleft palates, but we saw an increase in breast tumors in female rats who got excessive doses of your drug. And even though your data says you aren’t damaging heart valves like a previous generation drug that worked through a similar biological pathway, we’re still worried about it. How about you run another 5-year study assessing whether your drug raises the risk of heart attack and stroke. Pass that one, and we’ll talk again.||Approved June 27||“Obesity threatens the overall well being of patients and is a major public health concern. The approval of this drug, used responsibly in combination with a healthy diet and lifestyle, provides a treatment option for Americans who are obese or are overweight.”—FDA’s Woodcock.|
|Ironwood Pharmaceuticals||Linzess||You hit the main goal of all four clinical trials in your application for approval, which is impressive. But this is a drug with a totally new way of working that we’re unfamiliar with. And it isn’t a magic bullet for chronic constipation and irritable bowel syndrome with chronic constipation. Doctors might prescribe this drug “off-label” to children, and we don’t have any data to suggest it’s safe and effective for them. How about you run another study in children and call us back in a couple years?||Approved Aug. 30||“No one medication works for all patients suffering from these gastrointestinal disorders. With the availability of new therapies, patients and their doctors can select the most appropriate treatment.”—FDA’s Victoria Kusiak.|
|Talon Therapeutics||Marqibo||Another chemotherapy drug with some nanoparticle delivery system? Exactly how much better is this than the typical chemo combos? Yawn.||Approved Aug.9||“Marqibo’s approval demonstrates the FDA’s commitment to the development and approval of drugs that address serious, unmet medical needs,”—FDA’s Pazdur.|
Those actions look quite favorable and surprising to me. They look especially favorable when compared with a couple of the most newsworthy FDA actions of the past couple years. Recall it was just two short years ago that Genentech/Roche sought U.S. approval for the breast cancer antibody T-DM1 on the basis of a single mid-stage clinical trial and was told to fuhggetaboutit, and call back in a couple years when it had more rigorous evidence from a Phase III clinical trial (which it now has). Less than one year ago, this same FDA took another tough stance, antagonizing Genentech/Roche again, by revoking its earlier approval ofbevacizumab (Avastin) for breast cancer, after long-term follow up data showed it wasn’t able to extend lives of patients.
But there haven’t been many examples lately of tough regulatory decisions that cost companies billions of dollars. Most of the examples are like the ones in the table above, in which the FDA is opening the door for companies to pursue their multi-million and billion-dollar product opportunities.
“I don’t know exactly what it is down there in the water, but there is clearly something going on at the FDA,” says David Miller, the president of Biotech Stock Research, and a veteran observer of FDA decisions regarding new drugs over the past decade.
One example of pro-industry leanings that stands out for Miller is the recent approval of Talon Therapeutics’ vincristine sulfate (Marqibo). A few years ago, the FDA essentially said that drug wasn’t ready for the market. But even though the drug represents a marginal innovation as
a reformulated chemotherapy drug, it was approved by the FDA in the summer of 2012. And the agency was quick to take credit for its role in bringing forward a new medicine for leukemia patients. “Marqibo’s approval demonstrates the FDA’s commitment to the development and approval of drugs that address serious, unmet medical needs,” said Richard Pazdur, the head of the FDA’s cancer office, in a statement. For me, an equally big eye-opener came in June when FDA staff said in a briefing document about Onyx Pharmaceuticals’ carfilzomib (Kyprolis) that the “FDA is very concerned with the severe toxicities, including deaths that are associated with the use of this agent. The pathogenesis of these toxicities is not understood. Considering these factors, the risks of carfilzomib may not outweigh its benefits.” A couple days later, an FDA advisory committee voted 11-0 to recommend the drug be approved, and the FDA cleared it a month later.
In addition to those surprising approvals, Miller adds that he’s seen no recent examples of “forehead slapping” decisions, which he defines as good drug applications being stalled or rejected because of some unreasonable FDA demand.
Given that we are in an election year, and the FDA is a government body, it would be naïve to think that politics has no role whatsoever in the overall FDA attitude. For the past couple years, venture capitalists and industry trade groups have mounted a dedicated lobbying campaign to get the FDA to become more industry friendly.The VCs and trade groups have grabbed the attention of Congress and the White House, arguing that the FDA’s past intransigence and impossible demands have made it almost impossible for them to invest in new companies with innovative new medicines in development. These arguments gained a lot of currency when the VCs started that contending the FDA was essentially undercutting one of the few industries in which the U.S. is still No. 1. Many good-paying jobs are being sent overseas, and many more are bound to go there, right at a time of worrisome high unemployment in the U.S., they argued.
While those points were falling on sympathetic ears in Congress and at the White House, the industry and the FDA were also working together behind the scenes on the Prescription Drug User Fee Act, the critical governing document on industry/FDA relations. Not everybody got everything they wanted in the renewal of the PDUFA legislation, but just about everybody claimed victory in the end, as the FDA got more resources to do its job, and the industry got some accelerated approval language for reviews of innovative new medicines.
FDA commissioner Margaret Hamburg, speaking on a panel with industry leaders in June at the Biotechnology Industry Organization convention, was positively beaming about how her agency fared in those behind-the-scenes talks. She went so far as to suggest that the agency is being empowered to take a more balanced view of drug risks and benefits, because the public is becoming more sophisticated. To paraphrase, she said the public no longer expects new FDA approved drugs to be absolutely safe in all cases, and that people now understand that an FDA approval means the agency thinks a drug’s benefits outweigh the risks. Presumably, if the public believes that, then it ought to be more understanding when the next Vioxxcomes along and causes dangerous side effects, because prescription drugs aren’t Cheerios. If a drug harms you and helps 1 million other people, you can’t really break out the pitchforks and march on FDA headquarters, because the agency warned you that drugs aren’t absolutely safe—they just offer more benefit than risk.
I’ve been saying for a long time to anyone who will listen that the FDA has an incredibly tough job, making decisions with incomplete information, and with millions of dollars and many lives on the line. It has often done a poor job explaining its work, and not surprisingly, it has been frequently misunderstood.
Even though the agency appears to be leaning in favor of industry this year, it would be wrong to conclude that the FDA has turned into an industry lacky that shouldn’t be trusted. I don’t see any decisions here that look like drugs were recklessly approved on half-baked datasets. Many of its cautious decisions of the past must be considered in the broader context of an agency that made a few mistakes and swung too far in the direction of excessive risk-aversion, partly to satisfy an ill-informed public and Congress. Now the pendulum is swinging the other way, in favor of industry, and in favor of patient advocacy groups that argue the FDA should allow patients in need to get access to groundbreaking medicines. That’s just this writer’s view. If you know of examples that either buttress this argument or poke holes in it, please leave a comment in the space below. I could be wrong about change at the FDA, but at least from reviewing the agency’s actions in 2012, it looks like a pretty good time to be in the business of developing new medicines for patients.