Faster Approval of New Medical Products Heightens Uncertainty Over Risks

On 11 October 1988, AIDS activists shut down the headquarters of the Food and Drug Administration, protesting that the agency was dragging its feet on approvals for promising new drugs while thousands of patients were dying. Days later, the FDA announced historic new regulations that would speed up the approval process for promising new medical products addressing unmet medical needs. 

Since then, in response to pressures from legislators, patient advocates, and pharmaceutical companies, the agency has continued to develop a variety of fast-track pathways that expedite the approval of new drugs and medical devices.

Many are concerned, however, that the FDA has overcorrected.  At a 13 June event at AAAS headquarters in Washington D.C., experts described examples of harmful drugs and devices that had reached the market and suggested that the bar to public safety has dropped below an acceptable level. The meeting was co-sponsored by AAAS, the Program on Regulation, Therapeutics, and Law within the Division of Pharmacoepidemiology and Pharmacoeconomics of Brigham and Women's Hospital/Harvard Medical School, and the National Center for Health Research.

Multiple speakers at the day-long event acknowledged that the FDA is in the challenging position of trying to both recognize groundbreaking innovation and protect the public from unsafe or ineffective medical products. Fiscal challenges further complicate matters. Keynote speaker Congresswoman Rosa DeLauro (D-Conn.) said that during her 2007-2011 tenure as chairwoman of the House Appropriations Subcommittee on Agriculture, Rural Development, Food and Drug Administration, and Related Agencies, the subcommittee increased the FDA budget by 58%. She also noted, however, that in the current fiscal climate, the relationship between the agency and pharmaceutical companies has become increasingly complex, and industry user fees are becoming "a growing source for agency support."

Science is paramount to balancing the multiple demands on the Administration, according to FDA Commissioner Margaret Hamburg: "At the end of the day we have to be guided by science in everything we do. It has to be our compass," she said in a keynote address.

How Much Evidence — and What Kind — Is Enough?

Randomized, controlled clinical trials, in which patients are randomly assigned to groups that receive either the experimental therapy or a placebo control, are the gold standard in medical research. But, this type of study is not always used when testing new medical products for FDA approval, and it is particularly rare for new devices, which are subject to different regulatory procedures from prescription drugs.

More than 90% of all new medical devices are not tested in clinical trials at all, according to Diana Zuckerman, president of the National Center for Health Research. And, when Rita Redberg, a cardiologist at the University of California, San Francisco School, investigated the approval of cardiovascular devices in the highest-risk category over an eight-year period, she found that only one third was approved on the basis of a randomized clinical trial.

Critical insights can come to light through a placebo-controlled trial, however. Gregory Curfman, executive editor of the New England Journal of Medicine, described a report he edited about an investigation of a catheter-based device for treating resistant hypertension. The device had performed well in earlier studies, but a phase III trial revealed that patients who received a sham device experienced the same reductions in blood pressure as patients who received the catheter.

"This case example shows some of the problems that can develop even with products that look very exciting and innovative at the outset," Curfman said.

The type of data that a study collects is another area of concern. The FDA's accelerated approval regulatory option, for example, is specifically designed to allow FDA validation based on studies measuring "surrogate endpoints." Certain cholesterol levels, for example, have been proven to adequately reflect a patient's risk of having a heart attack, so a drug that reduces those levels may reasonably be presumed to lower cardiovascular mortality.

Forty-nine percent of the drug approvals by the FDA from 2005 to 2012 were based on surrogate endpoints, according to a study by Joseph Ross, an assistant professor of medicine and of public health at the Yale University School of Medicine.  The numbers varied by medical specialty, with a full 80% of cancer drug approvals using these measurements. While surrogate measures may be appropriate in some cases, as more surrogates are being used in a wider variety of conditions, fewer are subject to the kind of rigorous validation of past FDA-authorized surrogates such as cholesterol levels or systolic blood pressure, speakers cautioned.

Communicating Risk

The thorny issues don't end with clinical research. Individual patients may have a very different appetite for risk than an agency that is tasked with acting in the whole population's best interest. These patients' individual stories, as told via the media or testimony on Capitol Hill, may be more compelling than arguments based on data and may thus contribute to the rising pressure to accelerate FDA approvals, according to bioethicist Bernard Lo, who is president of the Greenwall Foundation. Michael Rosenblatt, executive vice president and chief medical officer at Merck, called this an "intrinsic tension" that "isn't ever going to go away."

Public understanding of how the FDA approves new products is also limited, suggests research by Steven Woloshin and Lisa Schwartz, who are both professors of medicine and of community and family medicine at Dartmouth Medical School and co-directors of the Dartmouth Institute for Health Policy and Clinical Practice's Center for Medicine and the Media. About 40% of Americans believe that FDA only approves and permits the advertising of extremely effective drugs or devices without serious side effects, according to Woloshin. In fact, FDA approval means only that the FDA reviewers have concluded based on the data they have that a new medical product's benefits outweigh its harms.

The language in warning labels and press releases can also be misunderstood. Woloshin and Schwartz conducted an Internet-based randomized trial of about 3,000 U.S. adults and asked them to choose between two equivalent drugs whose only difference was that one had been approved eight years earlier than the other. When no additional information about safety was provided, 66% chose the newer drug, even though the older drug would have been the safer choice because more data on side effects would be available. When a disclaimer explaining this was provided in another arm of the survey, the portion of people choosing the newer drug declined to 47%.

Press releases and advertisements can also contribute to a common misperception that drugs that have received accelerated approval have shown extra promise, according to Schwartz. In fact, because these drugs are approved on the basis of preliminary evidence, they offer greater uncertainty.

For example, Zykadia, a drug for metastatic lung cancer, received a "breakthrough therapy" designation that allows expedited approval based on preliminary evidence for certain drugs that treat serious conditions. The clinical evidence shows that it shrinks tumors, but whether it actually saves lives has not yet been shown. Nonetheless, an FDA press release described Zykadia as "a breakthrough therapy drug approved four months ahead of review completion goal date," a message that was reflected in reporting by the Washington Post. 

"I think it's very easy to read into that that 'breakthrough therapy' means a proven benefit — there's no uncertainty about how it works," Schwartz said.

The Search for Solutions

Many speakers argued that more research is needed on tools like surrogate endpoints that promise to expedite the FDA review process: "We need to do better studies to validate whether these surrogates are as good as we think, and not just assume things about them," said Avorn.

Research on drugs and devices after they have entered the marketplace should also be more rigorous, several experts said. An NIH trial that revealed the dangers of a previously approved device called the Wingspan stent was able to enroll patients quickly and gather data effectively because it required anyone using the device to be enrolled in the trial, according to Redberg. She suggested that this SAMPRISS trial, as it was called, would be a good model for future post-market studies, though she also argued that the FDA should have more authority to recall unsafe and ineffective devices after approval.

To motivate drug manufacturers to complete these labor-intensive trials, Lo suggested, approval regulations could contain sunset clauses requiring the trials to be completed within a reasonable timeframe.

Several speakers argued that the FDA should provide better access to the data on which it bases its decisions. To that end, Hamburg described a newly launched, online initiative, OpenFDA, which is intended to make it easier for researchers, developers, and the public to access and use the FDA's publicly available datasets.

Policy-makers and their constituents should also get involved, argued DeLauro and others. Gregg Gonsalves, an audience member who had been part of the ACT UP movement in the 1980s and 1990s and is now co-director of Yale's Global Health Justice Partnership, earned a round of applause when he argued that the safety of medical products was a public policy issue that should not be dominated by lobbying from the pharmaceutical industry. "We have to do our jobs as citizens, not just as physicians, doctors and researchers," he said.