AMSA Convention 2016 Logo

Not FDA-Approved

The New Physician May-June 2004
Your physician probably does it and you will, too—prescribe drugs for
unapproved uses. But how do you know you can trust what drug companies are saying about their products? Welcome to the nebulous world of off-label

In 1994, Neurontin, a drug clinically known as gabapentin, was approved by the U.S. Food and Drug Administration (FDA) to help control seizures in epileptics. It was developed by the pharmaceutical company Parke-Davis, a subsidiary of Warner-Lambert, and approved for a very narrow indication, only to be used in severe cases and in combination with other epileptic seizure drugs already on the market. As a result, sales for Neurontin were expected to be minimal.

Yet by 2000, the sales had ballooned to $1.7 billion per year. So how did this happen to an “add-on” drug with such narrow applications? Through the practice of off-label prescribing, when physicians recommend drugs to patients for purposes not approved by the FDA. (For a guide to the drug approval process, see “Up for Review,” p. 20.)

Over the years, physicians have prescribed Neurontin as a pain medication to treat a wide variety of conditions, including: bipolar disorder, pain syndromes, peripheral and diabetic neuropathy, reflex sympathetic dystrophy, attention deficit disorder, restless legs syndrome, trigeminal neuralgia, posthepatic neuralgia, migraine headaches, and drug and alcohol withdrawal seizures. Some physicians also began prescribing Neurontin alone to treat epilepsy. And why wouldn’t physicians use Neurontin in these ways? After all, two studies published in the Journal of the American Medical Association reported how the medication significantly reduced chronic pain, while research published in other journals praised the drug for its effectiveness in treating bipolar disorder.

Unfortunately, those studies weren’t as reliable as physicians might have believed. According to court documents from a 2001 whistleblower case filed in the U.S. District Court in Boston, Parke-Davis and Warner-Lambert, which has since been purchased by Pfizer, had hired marketing firms to write articles to endorse Neurontin’s off-label uses. As part of this “publication strategy”—as it was referred to in company documents—the firms then found physicians willing to sign their names as authors, even though they were not involved in the research. An invoice from one of the marketing firms showed that Parke-Davis agreed to pay $12,000 to the firm for each article and a $1,000 honoraria to each physician willing to serve as an “author.” Also, in order to maintain content control, the articles were reviewed by Parke-Davis and Warner-Lambert officials before being sent to medical journals for publication.

However, the whistleblower, David Franklin, who worked for Parke-Davis for five months in 1996, testified that the fraudulent studies were just a small part of the company’s efforts to promote off-label uses. Additionally, the company paid physicians—tens of thousands of dollars a year, in some cases—to speak to their peers about the benefits of Neurontin, while other physicians received payments in exchange for allowing pharmaceutical sales representatives into exam rooms to meet with patients, review medical data and even make prescription recommendations. It was all part of a marketing campaign to drive off-label sales. “If we are going to market Neurontin effectively, we have to do it for monotherapy, for epilepsy, also for pain and bipolar and other psychiatric uses,” a Parke-Davis marketing executive told sales representatives in a recorded voice-mail message submitted to the court.

And as it turns out, that marketing push worked. Pfizer reported that in 2000 nearly 80 percent of prescriptions written for Neurontin were for purposes other than treating epileptic seizures, and the drug’s profitability continues to grow, exceeding $2.3 billion in 2002. Meanwhile, Franklin’s lawsuit still lingers in federal court.


The aggressive off-label promotion of Neurontin is an extreme case of a company marketing a drug for a use not approved by the FDA. However, companies frequently push their drugs’ off-label uses.

On a daily basis, pharmaceutical sales and detail reps meet with physicians to discuss their companies’ various products. And while they’re not allowed by the FDA to promote an off-label use, they are allowed to dance on the line between promoting and providing information.

“When the sales people go out, they can’t affirmatively tell the doctor, ‘Hey doc, we got this new study just in. It’s really terrific. It shows that the drug is very safe, very effective for whatever [the off-label use] is,’ and build a following in a market for it,” says Jerome Halperin, the president and CEO of the Food and Drug Law Institute, an organization composed of more than 500 manufacturers and suppliers of medicines, medical devices, food and cosmetics subject to FDA regulation. “Now they can come very close to that, legally. Because if a physician says, ‘Do you have a reprint of the study that can be provided?’ and if the physician reads the reprint and makes a judgment that, ‘Hmm, looks like this drug will work,’” then Halperin says that’s OK.

Of course, determining the validity of that study is also an issue. That’s why the FDA, in addition to promotion restrictions, requires drug companies to provide the agency with all relevant statistical data once they become aware of unapproved uses. However, FDA officials acknowledge that because they have to rely on companies to volunteer such information, the rule is difficult to enforce.

But if a drug does successfully treat a condition, then why doesn’t the company seek approval? “When the off-label market is small, but they find out that the drug really works, it’s really a cost–benefit issue for the company,” Halperin says. “If there are enough people with this particular indication out there—even though the market may be smaller than they would like—they may still go ahead and do a study and try to get it on the label. If the population of people with this indication is so low, it just may not pay for them to do it.”

Without the submission of data, the FDA’s Division of Drug Marketing, Advertising and Communications (DDMAC)—staffed with approximately 20 people—is left to not only evaluate the flood of direct-to-consumer and physician-targeted advertising for on-label uses, but also the sources and validity of journal articles, not to mention the interactions between drug sales reps and physicians. With so much on the DDMAC’s plate, it should be no surprise the agency has cited companies approximately only 70 times for overt off-label promotion since 1998, and the agency hasn’t taken legal action against a drug company for off-label promotions since 1993, according to a November 2003 report by Knight Ridder Newspapers.


Of course, how much authority the FDA has to regulate off-label activity is debatable. In 1997, the agency issued a final guidance regulating companies’ scientific and educational activities, attempting to make a distinction between activities related to on-label and off-label uses. However, the new guidance couldn’t survive a 1998 lawsuit brought by the Washington Legal Foundation (WLF), which bills itself as a public interest law and policy center, that accused the agency of violating pharmaceutical companies’ First Amendment rights.

In Washington Legal Foundation v. Michael Friedman—the acting FDA commissioner at the time—Judge Royce Lamberth of the U.S. District Court for the District of Columbia struck down key provisions in the FDA guidance when he wrote: “In asserting that any and all scientific claims about the safety, effectiveness, contraindication, side effects and the like regarding prescription drugs are presumptively untruthful or misleading until the FDA has had the opportunity to evaluate them, [the] FDA exaggerates its overall place in the universe…. [The] conclusions reached by a laboratory scientist or university academic and presented in a peer-reviewed journal or textbook, or the findings presented by a physician at a [continuing medical education] seminar are not ‘untruthful’ or ‘inherently misleading’ merely because the FDA has not yet had the opportunity to evaluate the claim.”

And in the wake of an overwhelming legal victory, commercial free speech advocates also won a political victory when Daniel Troy, the WLF’s lead attorney in the case, was named the FDA’s chief legal counsel in August 2001. “The whole philosophy over there [now] is pretty consistent with the case. It’s pretty hard to parse the two,” says William Schultz, a former FDA deputy commissioner for policy.

However, Alexander Tabarrok, an associate professor of economics at George Mason University in Virginia and the research director for the Independent Institute, a nonprofit research organization, says it doesn’t matter who’s guiding current FDA philosophy or which party presides in the White House—the ruling alone will have long-lasting effects on the agency. “Regardless of which administration is in power, the FDA must now operate in a world in which manufacturers have well-recognized rights to commercial free speech.”


But just because it may be illegal to promote unapproved uses for a drug, it doesn’t necessarily mean that use will cause harm. Tabarrok, who is also a co-author of for the Independent Institute, says a lack of FDA citations of off-label promotions is not a reflection of agency philosophy or even authority but indicative of a lack of detriment in the practice.

“Getting FDA approval for a new use of an old drug can be expensive and time-consuming. As a result, the best, most advanced treatment for a disease is often an off-label treatment,” he says. “Off-label prescribing is common, for example, in AIDS, cancer and psychiatric treatment, and most hospital patients will be prescribed at least one drug off-label. Disseminating information about off-label uses is thus a vital aspect of good medicine. Physicians have many sources of information about off-label drug uses, including pharmaceutical compendia, medical journals and HMO formularies. Manufacturers are another important resource, because manufacturers have both the incentive and the ability to provide the information to physicians in a timely and efficient manner”

In fact, off-label scripting is a popular medical practice, and it is widely accepted that it benefits more patients than it harms. (For advice on off-label prescribing, see “Going Off-Label,” p. 15.) According to an analysis by Knight Ridder Newspapers, more than 100 million off-label prescriptions were written in 2002, which is nearly double the number written five years ago. And according to a 1991 study by the U.S. General Accounting Office, 56 percent of cancer patients have been given off-label prescriptions, and 33 percent of total cancer treatment prescriptions were for unapproved uses. Other studies have estimated that 81 percent of AIDS patients received at least one drug off-label and that 40 percent of all reported AIDS medication use was off-label. Even in general medicine, off-label prescribing is common. Physicians were recommending aspirin to heart attack victims years before the FDA officially sanctioned such an indication.

“One of the most important things to know is that the FDA label is very much behind science,” says Dr. Raymond Woosley, the vice president of the University of Arizona Health Sciences Center and a former chair of Georgetown University’s department of pharmacology. “It is also limited by what the industry applies for. There may be unapproved indications that are clearly beneficial effects of drugs in certain uses, but if the industry doesn’t apply for that use, the FDA won’t have that data or even the stimulus to act on it and even include it in labeling.”

And nowhere is this more apparent than in pediatric medicine. In congressional testimony, Dr. Sumner Yaffe of the American Academy of Pediatrics said 80 percent to 90 percent of pediatric patients are prescribed off-label drugs. “This does not imply that 80 percent of our drugs are contraindicated, unsafe or disapproved for use in infants and children. Rather, it means that necessary testing has not been done to produce the data that would enable the Food and Drug Administration to grant approval status for specific clinical indications and uses in pediatric populations,” he said.

The reason for this is the absence of research, industry-sponsored or otherwise, on medications’ effects on children. “There are tons of children that can be benefited by drugs, but it will be off-label most of the time, because even right now we don’t have a law that says companies should evaluate their drugs in children,” Woosley says. “So the industry very often doesn’t do the work, or they do it very late after the drugs are on [the] market.”

And without the research submitted, the FDA isn’t able to make judgments on such uses, so physicians are left to extrapolate a dosage to treat the child and see if it is effective. “Any physician can administer any drug to any patient, as long as the physician understands he or she is at risk if that administration causes some adverse reaction or toxicity in the child…,” Halperin says. “But when a kid is really sick, somebody is going to take what is possibly a very prudent risk. And in most cases it is probably going to turn out fine, but in some cases it’s not going to turn out fine, and a child is injured or a child dies. And that is what everyone worries about.”


Measuring risk is part of the off-label equation. For physicians, they have to comprehend the health risks to patients, as well as the legal risks to themselves. “The truth is we are not bound to practice by the label,” Woosley says. “Physicians are bound to practice by what they can defend in court, and if there is an adequate science base, the label is irrelevant…. If a physician has some scientific basis, usually a report in literature, which often has not been substantiated, that can be a sound enough basis for most physicians to go ahead and use a drug off-label.”

For pharmaceutical companies, there may be greater risk in going on-label with certain treatments. Woosley says that a drug company may not be interested in applying for approval for high-risk uses because it would make them more vulnerable to liability issues. And if manufacturers can make the same sales without exposing themselves legally, then even the better for them.

Of course, whether or not a pharmaceutical company crosses the line into illegal behavior is often debatable, because it’s unclear where the line is. “It’s something that I don’t think is very clear in the law,” says Larry Sasich, a pharmacist and researcher for Public Citizen’s Health Research Group. “If you ask the company, I’m sure that they will tell you that their study in the Journal of the American Dental Association (JADA) was a scientific communication. You ask me, I’d say it was commercial speech and subject to regulation by the government as commercial speech and not as academic speech or political speech or anything like that.”


Because of a lack of authority within the FDA, drug companies’ marketing practices are being scrutinized by outside agencies and organizations more and more frequently. In the wake of the revelations of the Neurontin whistleblower case, the U.S. Attorney’s office in Boston, as well as attorneys from 47 states and the District of Columbia, have begun investigating whether Parke-Davis officials violated federal and state marketing regulations with their promotion of Neurontin.

A lawsuit regarding Neurontin was also filed against Pfizer in February 2003 by Community Catalyst’s Prescription Access Litigation project, the California Public Interest Research Group, the Congress of California Seniors and USAction. “We intend to show that Parke-Davis intentionally manipulated FDA exemptions intended to promote professional dialogue regarding pharmaceutical science to illegally promote off-label use,” Steve Berman, the plaintiffs’ lead attorney, said in a press release. The suit is being filed in California state courts, citing violations of the state’s unfair competition laws and advertising code.

In the meantime, the Congress of California Seniors has also filed suit against Pharmacia in December 2002 for illegally promoting the off-label use of Bextra, which is approved for treating osteoarthritis, rheumatoid arthritis and menstrual pain. Specifically, the suit claims that the company hired a clinical testing firm owned by a large advertising conglomerate to study the medication. The result was an article in the JADA, trumpeted by press releases from Pharmacia, which declared the drug could provide relief for acute pain caused by impacted molars. What the article failed to note was that the FDA had rejected that conclusion only six months before.

“I can’t ever remember getting a press release about an article that is going to be published in a dental journal about something as mundane as dental pain after somebody’s impacted wisdom tooth is removed,” Sasich says. But once again, the drug company’s efforts seemed to have worked as Bextra sales jumped 60 percent in the three months following the article, according to the New York Times.

Drug companies aren’t the only ones under attack, though. Public Citizen has filed a suit against the FDA over Bextra, contending that the agency omitted public information from Bextra’s approval application. “By regulation, once a drug is approved, the FDA’s analysis of data submitted by manufacturers goes into the public domain. We looked it up, and we found that everything that had to do with acute pain in the FDA reviews was redacted—it was removed from the file,” Sasich says. “What we did…was to file suit to get an unredacted copy of the FDA reviews placed into the public domain to see what was submitted by the company for acute pain and what the FDA thought of the data that was submitted, and then to put that into the public domain so that patients and prescribers can use it.” Sasich and Public Citizen are unsure why the FDA would omit such information. As of presstime, the FDA has not responded to the lawsuit.


One of the benefits to these lawsuits—besides discouraging pharmaceutical companies from zealously promoting off-label uses—is an increase in the amount of information provided to physicians and patients.

Sasich says the agency must play a bigger role in sharing data about off-label drug uses. “I think the FDA really needs to change some policy that I don’t think they would need to go back to Congress to get laws changed. So we wouldn’t have to sit around and file suit to get all of the information we want about Bextra. The agency can be much more transparent with this kind of information, and we could do a much better job communicating it to the public and to professionals. I think that’s absolutely necessary, because I don’t think you’ll ever find a business that’s not going to try to push the envelope as much as possible, depending on the competitive environment they find themselves in.”

Woosley says, however, not to expect too much from the FDA. “It’s very limited what they can do, and I think that’s generally what the public and physicians need to recognize…that [the FDA’s] resources and even their legislative mandate are very limited.”

Sasich also notes the need for more skepticism from both medical journals and mass media outlets. “Journalists have to be a lot more critical. I think the news media—some elements of the news media—has turned into an additional advertising platform for the pharmaceutical industry. Every time a story runs about a new drug that is based on a company’s press package, they are not serving the public at all.”

The bottom line, in regard to off-label scripting, is that physicians and patients must rely on the ancient doctrine of caveat emptor—Latin for buyer beware. “As every consumer knows, manufacturers have an incentive to provide information that puts their product in a good light but not information that suggests problems,” Tabarrok says. “To deal with this problem, consumers supplement advertising with information from their own previous experiences, from friends and from disinterested, reputable organizations such as [Consumers Union]. In the same way, physicians [must] supplement information from manufacturers with information from other sources.”
Scott T. Shepherd is an associate editor with The New Physician. Direct comments and questions about this article to