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FDA cracks down on labeling, initiates trial result reporting
  Nature Biotechnology 26, 1203 - 1204 (2008)
Randy Osborne1 & Emily Waltz2
1. Mill Valley, California
2. New York
Senator Ted Kennedy was instrumental in helping the FDAAA pass the two Houses.
One year after President George W. Bush signed the US Food and Drug Administration Amendments Act (FDAAA), industry watchers remain uncertain whether the new arsenal of post-market powers has added benefit or bureaucracy, but the provisions on labeling and post-marketing oversight are certainly being felt. In September, in line with the FDAAA, the US National Institutes of Health's publicly available database ( expanded to not only register human drug trials but now also track their results.
FDAAA was intended to introduce a more stringent regulatory outlook, to give agency officials more muscle to enforce label changes for pharmaceuticals and ensure better monitoring of clinical trials and approved drugs. "There's a lot here to be sorted out," says Sheldon Bradshaw, who served as chief counsel for the FDA when FDAAA became law and is now co-chair of the food and drug practice group at the law firm Hunton & Williams in Washington, DC. "I'm not sure there are too many lessons that can be learned in one year," he adds.
More time may not make matters much clearer unless the FDA gets more money. User fees went up 25%, but it's not enough, Bradshaw points out. Not only does the new law contain "400 more action items for the agency, without one additional penny" of non-user fee funding, he says, but also this is happening when the agency is "already stretched beyond the breaking point."
The new law provides the FDA with enough muscle to keep companies in line, imposing penalties on those that do not comply with agency demands, though Bradshaw believes this was never a problem. "The FDA is the 800-pound gorilla, and companies will do whatever they say-whatever is at stake in [any] particular battle is one little matter," he says. "You simply can't afford to aggravate this entity that you need to constantly go back to for approvals." One complicating factor is the disconnect between the provisions in the new law and how the agency enforces them through the legal system. Thus, although it is difficult to get companies to talk openly about FDAAA, lawyers, who end up dealing with the fallout, are much more willing to discuss the impact of the new rules.
One big change that has accompanied FDAAA is the shortening of the timeline for label changes. In the past, companies politely negotiated labeling changes with the agency for a year or two. "Literally, labeling changes are [now] completed in a month or two," Bradshaw says. The agency took its first sweeping, FDAAA-bolstered action in June, when it demanded that makers of conventional anti-psychotics add black-box warnings to alert physicians about an increased death risk in elderly patients who take the drugs for the unapproved indication of dementia-related psychosis. Another edict came the following month when the FDA told makers of fluoroquinolone antimicrobial drugs to add a black-box caution about the higher chances of tendinitis and tendon rupture. The drug family includes Leverkusen, Germany-based Bayer's Cipro (ciprofloxacin), Cipro XR and Avelox (moxifloxacin HCL); Raritan, New Jersey-based Ortho-McNeil's Levaquin (levofloxacin) and Floxin (ofloxacin); Waltham, Massachusetts-based Oscient Pharmaceuticals' Factive (gemifloxacin mesylate); Menlo Park, California-based Depomed's Proquin XR (ciprofloxacin); and Whitehouse Station, New Jersey-based Merck's Noroxin (norfloxacin).
Front-line agency staffers have been emboldened by FDAAA, and "have gotten a lot more aggressive on the labeling side," says Bradshaw, possibly to an unfair degree. The new law, however, does not change the underlying standard for adding a label warning: reasonable evidence of a causal association between an adverse event and the drug. But Bradshaw says that in letters sent out for compounds where safety may be an issue, agency officials "candidly acknowledge there isn't evidence of a causal association." He adds that "so far, companies haven't seemed to push back too hard against the FDA," though eventually drug firms may balk.
Another attorney, Joseph Price, who oversees pharmaceutical and medical-device litigation in the Minneapolis office of Faegre & Benson, believes lawsuits will almost certainly ensue. "It's a natural result," he says, even if the lawsuits take a couple of years to crop up. At the same time, however, Price likes the new law's emphasis on post-market surveillance and the requirements for phase 4 studies once a drug is approved. "You're dealing with products that inherently have side effects and adverse reactions, and it's incredibly difficult to pick those up pre-marketing," he says. Also, under FDAAA rules, regulators can mandate risk evaluation and mitigation strategies (REMS), which are programs to ensure drugs with known or potential risks are managed carefully. "People are hard pressed to say anything bad about that," Price notes.
But plenty of analyst nail-biting and commentary surrounded the summertime FDAAA decree that forced Thousand Oaks, California-based Amgen and Horsham, Pennsylvania-based Ortho Biotech, a unit of Johnson & Johnson, to add warnings to labels of their erythropoiesis-stimulating agents. Regulators ordered a label warning that patients should not start the anemia therapies if their hemoglobin levels are greater than or equal to 10 g/dl. Another label crackdown came in September, when the FDA told makers of tumor necrosis factor blockers to strengthen existing black-box warnings to highlight the risk of histoplasmosis. The drugs include Thousand Oaks, California-based Amgen's Enbrel (etanercept); Abbott Park, Illinois-based Abbott's Humira (adalimumab); Horsham, Pennsylvania-based Centocor's Remicade (infliximab); and Brussels-based UCB's Cimzia (certolizumab pegol).
FDAAA also expanded the existing clinical-trials database run online by the National Institutes of Health in Bethesda to ramp up the number and types of trials it includes. Drug makers or principal investigators must register trials of drugs and biologics subject to FDA regulation within three weeks after the first patient starts testing a therapy. What's more, inclusion of clinical trial results in the database that can be perused by patients and doctors was also part of the measure, though this was not implemented until late September ( David Shearer, chief medical officer of Integrated Clinical Trial Services in Raleigh, North Carolina, calls the wider database "a step in the right direction. For the public, it couldn't be better."
Bradshaw, however, is less upbeat, pointing out that FDA continues to send conflicting messages to the public and drug firms, and the FDAAA does nothing to fix this. One example he cites is the decision of the agency in October 2007 to ask makers of all phosphodiesterase type 5 inhibitors for erectile dysfunction and pulmonary arterial hypertension to put label warnings on their products about possible hearing loss, even though the FDA admitted no causal relationship had been shown.
The same happened with Chantix (varenicline), the smoking cessation drug from Pfizer that the FDA said might lead to suicide and thoughts of depression. In another example, Basel-based Roche and GlaxoSmithKline of London agreed in March 2008 at the FDA's urging to revise labels of the influenza drugs Tamiflu (oseltamivir) and Relenza (zanamivir), cautioning prescribers about unproven but potentially fatal neuropsychiatric events. In early September, under the FDAAA's adverse-event reporting system, the FDA published a list of 20 drugs pegged as having "potential safety issues" (Table 1). The FDA assembled the list based on its review of adverse event reports, though a drug's appearance on the list does not mean that the drug is unsafe, the agency said, only that closer examination is warranted and they are looking into it.
A year after it passed into law, perceptions over the FDAAA's main impact have shifted somewhat. At the outset, phase 4 clinical trials and REMS were viewed as the key elements of the new legislation. Bradshaw argues, however, that the FDA's new labeling authority could have the largest impact. "I have great confidence in the current chief counsel," he says. "The problem is that 99% of these labeling requests the chief counsel will never hear about," since word will go up the ladder "only in the rare cases where the company objects." One probable outcome is that more companies will object, says attorney Price. Bradshaw agrees, though he is overall optimistic about FDAAA because it gives the FDA "breathing room to approve much-needed drugs, and gives folks the comfort of knowing" that REMS and phase 4 trials (along with label changes) can protect patients. Shearer agrees, adding that the somewhat more involved and time-consuming drug application process entailed by FDAAA should help. "Do the job right up front, and you don't have to pay the piper later," he says.
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