Swift and Supersized FDA Enforcement

WASHINGTON WRAP-UP

Public, highly visible, and swift FDA enforcement—something skeptics say the device industry lacks—is coming under the new leadership at the agency. It was stressed by agency commissioner Margaret Hamburg at the Regulatory Affairs Professionals Society's (RAPS) annual meeting in Philadelphia in September, and simultaneously by career FDAers at a downtown Washington industry meeting the same day.
“It's a new day at FDA,” declared CDRH compliance director Timothy A. Ulatowski. “We're going to ‘crank it up' [i.e., the process of taking necessary regulatory actions]. Timelines for response to warning letters have shortened dramatically.” He warned that “industry must get up to the speed at which the agency is now working [in the compliance area], or they will be met by some real surprises.”
In Philadelphia, Hamburg was giving a discourse on why FDA enforcement is good for you. She'd been impressed by the commitment most regulated companies had made to compliance with FDA requirements, Hamburg told the RAPS audience. But she said “our goal is for all companies to make and implement such a commitment to prevent harm to the American people. We have a responsibility to clearly articulate and explain our rules and our regulations, but a key part of the strategy to support better compliance is effective enforcement.”

In addition to protecting public health, this helps companies too, Hamburg said. It helps to maintain “a level playing field for safe products, making sure that offenders are held legally accountable, and preventing companies from having to choose between doing the right thing and staying competitive.” She said that an effective enforcement strategy builds public confidence in FDA oversight, “which in turn keeps trust in the safety of FDA-regulated products from eroding.”

FDA must be vigilant through regular inspections and follow-up of signals indicating potential problems, Hamburg said. It must identify and resolve problems early, and companies should expect to be caught if they cross any lines. “And if they fail to act,” Hamburg said, “we will.”
FDA must be strategic in its enforcement, Hamburg said, and place greater emphasis on significant risks and viable solutions. Finally, FDA “must be visible and show both industry and consumers that it is on the job…We must publicize our enforcement actions and the rationale for those actions, widely and effectively.” She said that this course of action will increase public confidence in the agency.
Meanwhile, in Washington's meeting sponsored by the Parenteral Drug Association (PDA), Rick Friedman emphasized Hamburg's public health qualifications and said, “Public health implies prevention, and the longer we take to require corrective actions, the greater the public exposure to risk.” Friedman is FDA's Center for Drug Evaluation and Research director of manufacturing and product quality.
FDA managers appearing as fellow panelists at the PDA meeting unanimously agreed that a strong emphasis on regulatory compliance ranks among the most significant changes being brought to the agency by Hamburg and the Obama administration.
Deputy director of FDA drug compliance Joseph Famulare pointed out that time frames for issuing regulatory decisions addressing deviations or other out-of-compliance problems will be reduced. This will be partially achieved by allowing compliance managers to review information discovered by inspectors in real time while they are still in the field. He indicated that decisions about what action to take and whether an infraction presents a significant risk will no longer require many weeks or even months. Decisions may come immediately.
The Role of Outsourcing
There was wide agreement at the Washington PDA meeting that the effects of globalization have resulted in many challenging compliance issues, with many more challenges expected in the years ahead. Friedman noted that “outsourcing is the future of the industry,” a development that will inevitably require more international collaboration on inspections, enforcement, and compliance policy issues. “There will be much greater regulatory focus on supplier selection, qualification, and monitoring,” he said. “It is essential to know your supply chain!”
Douglas Stearn, director of compliance policy in the Office of Regulatory Affairs, said that more suppliers means that “more things are happening off-site [i.e., outside the manufacturing plant],” and many small suppliers may be unfamiliar with regulatory requirements. Of great concern, he said, is the fact that “we don't know what we don't know” about hazards that may exist in the supply chain. For this reason, he said, we must find different, creative ways to obtain safety signals.
Take More Science-Backed Risks, FDA Urges
FDA's new leadership is serious about reversing its predecessor's complacent and sometimes hostile attitude toward science. In almost every speech she gives lately, Hamburg emphasizes the importance of biomedical science and regulatory science to both the agency and the industries it regulates.
The latest manifestation of this came in September, when CDRH associate director for postmarket operations Jonathan Sackner-Bernstein told a RAPS audience that the center wants to give industry science a shot in the arm. Predecessors have been saying something similar for years and not seeming to make much of an impression, but Hamburg's enthusiasm is a new propellant.

One reason industry seems to have been holding back in the past, Sackner-Bernstein suggested, has to do with the riskiness of bold, revolutionary scientific leaps and the relative safety and comfort of much smaller evolutionary steps in product advances. But that's not a good reason to deny public health what it deserves, he said.

The medical device industry's need for innovation might be seen in the example of infusion pumps, he suggested. There have been multiple recalls over the years, two of the most recent examples being Baxter's Colleague pumps and Cardinal's Alaris, both with 300,000 units recalled. Each of those recalled units could be a new technology's sales opportunity, he said.
Infusion pumps are in every hospital. They have power cord problems, battery problems, software problems, free-flow problems—so many problems it would take him a whole afternoon just to describe them. “If any of you are looking for a market opportunity, here is one from FDA—just go look at the recalls!”
He found a picture on Google of an intubated patient hooked up to five different infusion pumps with pressure transducers and other attachments—“a very common scenario,” Sackner-Bernstein said, because there's not always someone at the bedside to respond quickly to a problem.
Typically, nurses have to monitor two such entangled patients in the ICU at the same time. “The systems have to be unbelievably reliable, and right now they're not. That's why we have the recalls,” Sackner-Bernstein said. “Where are the innovations?”
“We need device interfaces that would make Apple jealous,” he said. But the riskiness of the revolutionary science frightens many away, and the breakthroughs may come from other disciplines. “It's not only the things we create de novo, but it's also the ideas and experience we can bridge from other industries to the medical industry. The best example may be with the paint industry, which has applied nanotechnology to make sure that the colors stay true.”
Sackner-Bernstein said that there are five new science platforms that apply to the medical device industry: nanotechnology, synthetic biology, tissue engineering, stem cells, and robotics. Overall, the medical device industry is not where it could be or where other industries have gone. Nanotechnology is not well defined, he acknowledged. Many look to smallness as the best definition, but he thinks the molecule's properties or behavior would be better indicators. Nanotechnology applied to carbon fiber can produce artificial muscle that is 100 times stronger than natural muscle, Sackner-Bernstein said.
In the field of robotics, he said, much of the device industry is still using late-1940s technology. “It's a little embarrassing,” he said. “Come on guys, isn't there one company here that makes robotics not based on 1940s technology?” He showed a slide of a Deka robotic arm developed at a VA hospital that can use an electric drill. He speculated about a prosthetic combining robotics with nanotechnology. “That's a miracle. That's what we need to shoot for.”
FDA isn't spearheading these innovations, Sackner-Bernstein admitted, because it lacks the in-house capacity to do so. The agency needs to work with industry to help bring innovation
forward—not for the benefit of industry or itself, but for patients.
The new leadership at CDRH and the agency recognizes this, and “I expect that in the coming months, you'll hear some more about this,” he said.
The key that's going to drive it all is recognizing the importance of asking questions, Bernstein told his audience. For example, he said, we should be embarrassed that we haven't done more about Parkinson's disease. Although the work that has been done is “truly amazing,” so much more could be done. He showed a slide of a large craniotomy cut made to implant deep-brain stimulator leads. Is the next innovative step from this the evolutionary one of a smaller hole cut in the skull? Or is it a revolutionary externally mounted stimulator? One such stimulator was shown in a recent Science article that discussed stimulators for the spinal cord currently being tested on rodents. It suggested that these devices could eventually be applied to Parkinson's.

Companion Diagnostics ‘Worry' FDA
What happens when a new diagnostic test is developed that affects—without its sponsor's collaboration—a drug that's already on the market?
That can be a thorny issue, CDRH Office of In Vitro Devices biologist Elizabeth Mansfield told the audience of a RAPS annual meeting session in September. She updated the meeting on current “worries” FDA has about labeled sole-test manufacturers of companion diagnostics for approved drugs biologics. She focused on the unresolved issues with after-market developers of such tests. The agency hasn't published any guidances yet for these situations, she said.
Informally, Mansfield defined a companion diagnostic device or test as one that is intended to ensure that a certain biologic or drug is used in accordance with its label to achieve the approved safety and effectiveness. The informal definition also includes tests that the makers claim benefit selected populations that have not been recognized by the drug's maker in the approved label and have not been approved for that use by FDA. The agency considers companion diagnostics critical to the safe use of the subject drug or biologic, so they are classified as Class III PMAs.
After-market tests developed for drugs that are already on the market may introduce new limits or warnings, Mansfield said, but “we have a problem when there is nonconcurrence between the drug sponsor and the diagnostic sponsor” concerning the new knowledge. Approving the new diagnostic against the wishes of the approved drug or biologic manufacturer “would be promoting an off-label [use]. We're not sure how to handle it—it comes down to what's in the best interest of the patient. It's a thorny area.”
Examples of sole-test companion diagnostics include Genentech's Herceptin (trastuzumab) with its required HER2 test as well as Bristol-Myers Squibb's and Eli Lilly's Erbitux (cetuximab) and their EGFR test. In July, FDA approved labeling changes for Erbitux and Amgen's comparable Vectibix (panitumumab) contraindicating their use in colorectal cancer patients with a certain KRAS genetic mutation. But Mansfield told me that no companion diagnostic to detect this condition has yet been approved.
The current situation is unsettled, Mansfield said, because there are several questions that need to be answered, such as

If you put the name of the test in the label, what happens when something new comes along? Do you keep expanding the drug label? We're worried about sole-test labeling. If only one manufacturer is named in the labeling, what happens if that company goes out of business? What happens if that manufacturer does something that causes FDA to make them stop selling the test? What if there's a better test that comes along, that can select more definitively, or is cheaper?

Then there may be ethical issues in conducting clinical trials of a new companion diagnostic that may be better than one that is already approved, Mansfield said.
Sounds to me like a good case for a new guidance from FDA.
FDA Clarifies 510(k) and PMA User Fees
FDA has released User Fees and Refunds for Premarket Notification Submissions (510(k)s), a guidance for industry and agency staff to describe the user fees and refunds associated with the 510(k) program under the Medical Device User Fee and Modernization Act of 2002. The guidance says that the user fees associated with reviewing certain 510(k) submissions will enable FDA, with industry cooperation, to improve the device review process to meet performance goals set in letters from the HHS secretary to Congress.
The guidance includes 10 frequently asked questions about user fees and refunds and four tables. It can be accessed at www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/
GuidanceDocuments/ucm089753.htm.
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