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Coming soon: off-label marketing

Changes at FDA mean faster new drug approvals—and more promotion

From the December 1997 ACP Observer, copyright 1997 by the American College of Physicians.

By Deborah Gesensway

Maybe you have seen them in newspapers and on the Internet. They are ads from medical malpractice lawyers looking for patients who were prescribed Fen-Phen—the unapproved combination of fenfluramine and phentermine—to help them lose weight, but who instead developed heart valve problems or other serious side effects.

Doctors have the right to prescribe approved drugs any way they want, even for conditions and diseases the drugs were never intended for. Only the threat of malpractice suits—like those currently brewing over Fen-Phen—have made doctors think twice before helping patients through experimental uses of drugs.

But the perils of off-label drug prescribing are about to get more complicated. Under bipartisan legislation passed this fall by Congress to overhaul the FDA, drug companies will be allowed to promote off-label uses of their approved drugs. Doctors will have more reasons to prescribe drugs off-label, which many say will increase the chance that they might wind up in court.

The new legislation also promises to change the way the FDA does business, establishing new procedures for how the agency approves new drugs and reviews medical devices. As a result, physicians can expect the law will alter the way they relate to the FDA, as well as change how they practice.

With off-label drug use, drug companies will not be allowed to buy ads promoting off-label uses of their drugs, but they will be allowed to distribute reprints of articles from peer-reviewed journals or medical textbooks discussing successful uses of a product that have not been subject to full-scale FDA review and approval. In exchange, the drug companies will have to promise to ask the FDA to expand the approval to cover these new applications within three to five years.

As a result, more doctors will likely prescribe more drugs off-label. This will heighten the chance physicians will someday face a malpractice suit that hinged on a decision to write an off-label prescription. If the use is off-label, then by definition it is unapproved by the FDA, which is charged with protecting the public from unsafe drugs, medical devices and foods.

"We know already that a substantial number of people have been seriously harmed by Fen-Phen" without promotional efforts from the pharmaceutical companies, said Arnold S. Relman, MACP, the former editor of the New England Journal of Medicine and professor emeritus at Harvard Medical School. "Can you imagine how many more would have been involved if the companies had been able to mount a huge marketing campaign to use Fen-Phen?"

Out of control?

The law's provisions permitting off-label promotion are causing some physicians to question whether off-label prescribing is a necessary and worthwhile part of practice. "Off-label use has serendipitously led to some very valuable findings about other uses of drugs," said Paul D. Stolley, FACP, a professor and chair of epidemiology and preventive medicine at the University of Maryland School of Medicine. "But this is a very uncontrolled part of medical practice. Doctors are doing uncontrolled experimentation in their own practices, and the American people are being experimented on because the drugs aren't being tested adequately."

Arthur Ammann, MD, president of the American Foundation for AIDS Research and a pediatric infectious diseases specialist, said he understands the value of using drugs off-label but has concerns about the new law. "If off-label promotion is allowed, who is going to review all of this material?" he asked. "A lot of us feel that this now will overwhelm the FDA. It will take resources away from the system that is now providing drugs to patients the fastest we ever had."

But proponents of the new law say it will improve the practice of medicine by allowing easier distribution of information about possible uses of drugs. By speeding up the time it takes to get new drugs and devices on the market, they say, it will help doctors do their jobs and improve patients' health. In addition, the new law may increase the number of clinical trials done because companies will eventually have to submit data to the agency if they want to keep promoting off-label uses.

The new law, partly as a result, has support from the Clinton administration and medical organizations like the AMA. (ACP didn't weigh in during the debate.) The Pharmaceutical Research and Manufacturers Association (PhRMA) claims that off-label prescribing will be safer due to the legislation because physicians will receive more peer-reviewed, scientifically validated information about how new treatments can help their patients.

Critics, however, say that some provisions—particularly those that allow off-label promotion, privatize some medical device reviews and lower the minimum standard accepted by the FDA to establish safety and efficacy of a new drug or device—are dangerous and negate the good parts of the new law. Nearly everyone supports the core of the legislation—reauthorizing fees that drug companies pay when they submit a new drug application.

"There are some valuable things in the bill that I can support, but if the price is having this, then I'd much rather see the bill go down," said the University of Maryland's Dr. Stolley. "I don't think you can encourage the haphazard, uncontrolled use of drugs and not expect that there are going to be a lot of problems. ... Here, with Fen-Phen, we have a wonderful example of the dangers of off-label use happening at exactly the time the legislation appears and nobody seems to be putting it together."

Other provisions

In addition to the provisions regulating the promotion of off-label drug uses, there are several other controversial components of the FDA reform legislation. Here is how they are expected to affect physicians:

Faster approval times. First, the FDA will be allowed to approve drugs for use in the United States based on a lower level of evidence than had previously been allowed. In all but the most important breakthrough drugs (for instance, a number of drugs for people with HIV and AIDS), the FDA has had the discretion to require a drug company to submit data from two or more clinical trials that show the efficacy and safety of the proposed therapy. The new law states instead that "one or more clinical investigations" would be acceptable. The FDA won't have the authority to demand more studies if it doesn't think there is enough information, although it will still be able to reject a drug's application.

While many say that a streamlined drug approval process will benefit patients, the provision has some fierce critics. According to Sidney M. Wolfe, MD, an internist and director of Public Citizen's Health Research Group, a watchdog of the FDA that campaigned ardently against the legislation, known as the "FDA Modernization and Accountability Act of 1997," changing the default from two studies to one means that the country will be seeing more drug recalls down the line.

"One of the reasons why a large number of drugs that we keep off the market here get on the market in Europe is that they have lower standards there for drug approval," he said. "After a drug turns out to be more dangerous and less effective, it is taken off the market." In a recent study, Dr. Wolfe said he found there were 45 drugs taken off the market because of safety problems in Great Britain, France and Germany between 1970 and 1992 that were never approved for sale in the United States.

"That happens over and over again to drugs that never get on the market here," Dr. Wolfe said. "That protective gap that Americans enjoy may have been seriously narrowed by passing this law."

According to PhRMA, the time it takes to bring a new drug to market has been increasing steadily-from 8.1 years in the 1960s to 14.8 years for drugs approved in the first part of the 1990s-in part because of complex FDA rules and regulations. It took the FDA an average of 30.3 months to review a drug application before 1991, when the user fees paid by drug companies seeking new drug approvals were instituted. Since those fees took effect, the mean approval time has dropped to 19.2 months, according to the organization. Federal law requires reviews be done in six months, however, so the drug companies and many patient-advocacy groups say the FDA needs all reforms that will help speed the process further.

Dr. Ammann from the American Foundation for AIDS Research, which also opposed the FDA reform bills, however, said that even some AIDS activists, who five years ago were calling most vociferously for reforms to speed up the agency's review process and have supported the fee program, are now wondering if the FDA is "going too fast to ensure the safety of new drugs."

New review system for medical devices. The new law also sets up a parallel private system of reviewing some new medical devices. Instead of having FDA staff experts review applications for new devices, drug companies will be able to choose and directly pay an approved, private, for-profit firm to do the review in many cases.

"It's absurd," Harvard's Dr. Relman said about this provision. "Anybody with any common sense knows that if a company makes its living by providing a review of your device, then they're not inclined to reject it. It's a gross and obvious conflict of interest."

More consumer ads. The increase in the number of new drugs hitting the market will mean more advertising, particularly more direct-to-consumer advertising. Because rules for drug ads targeting consumers were loosened this summer (see ACP Observer, September 1997), doctors should brace themselves for an onslaught of patients who come in to the office asking about the latest drug they read about in People or saw during a commercial break in "ER."

"I can tell you from my practice that everybody who was eight pounds or more overweight wanted to be put on Redux (dexfenfluramine)," said Michael Wilkes, an internist and professor at University of California, Los Angeles, and author of several journal articles on the accuracy of drug advertisements. "I spent hours collectively talking to patients and convincing them not to go on this drug during the 14 months it was on the market." At the FDA's request, Wyeth-Ayerst announced in September it was withdrawing Redux and fenfluramine from the market.

The increase in television direct-to-consumer drug advertising, he said, is particularly worrisome because of the high costs of these ads. "This isn't going to be coming out of the corporate profits of the drug companies," Dr. Wilkes said. "They are going to add it to the cost of drugs. And the last thing that the consumer needs is to pay for more marketing aimed at scaring people into asking their doctor for this or that."

New claims about cost effectiveness. Doctors who sit on formulary committees of their HMOs, hospitals or groups can expect their jobs to become more complex as a result of the legislation. They will have more drugs and medical devices to consider, but they also will be forced to deal with more claims about drugs' cost effectiveness.

The new law changes the FDA's authority to limit how companies are allowed to market their drugs' cost effectiveness. In the past, the companies had to have "adequate and well-controlled studies" that showed a drug's cost effectiveness. Now, drug companies will just have to submit "competent and reliable" evidence. For instance, a company will not need to carry out a randomized control trial to say that a drug is cheaper (easy to prove) and is equally effective as a competitor (harder to prove).

"It's not clear what [the pharmacoeconomics clause of the bill] means, but it does set up a different standard, and it is a standard that would include a considering of expert opinion in the field, which is very different than 'adequate and well-controlled,'" said Laurie Burke, RPh, MPH, senior regulatory research office in the FDA's Division of Drug Marketing, Advertising and Communications.

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