TRIAL magazine

David Franklin’s four-month stint at pharmaceutical maker Parke-Davis provided him an unexpected education. Hired as a medical liaison in 1996, Franklin was told that the job entailed giving doctors scientific information about the company’s drugs. Instead, he was encouraged to promote the drug Neurontin for off-label uses, despite a dearth of legitimate studies showing its efficacy.

Today, at least 90 percent of Neurontin prescriptions are for off-label uses such as treatment for bipolar disorder and a wide variety of pain syndromes. The drug is FDA-approved only for use with other drugs to treat epilepsy and as a treatment for nerve pain resulting from shingles. (Although it is illegal for pharmaceutical companies to promote drugs for off-label uses, doctors are allowed to prescribe drugs for any use they deem necessary.)

The whistleblower lawsuit that Franklin brought under the False Claims Act was settled in May. Neurontin’s maker, Pfizer (which had acquired Parke-Davis’s parent company, Warner-Lambert, in 2000), agreed to pay the federal and state governments a penalty of $430 million for its role in illegally marketing the drug for nonapproved uses and to reimburse Medicaid for its costs. (Franklin v. Parke-Davis, No. 96-CV-11651-PBS, Criminal No. 04-10150 (D. Mass. May 13, 2004).)

Now, a spate of new lawsuits promises to keep the popular drug in the news. Many current cases are class actions for consumer fraud, in which plaintiffs are seeking reimbursement for a drug they say the company knew could not help them, but a growing number focus on an alleged side effect of Neurontin: suicides.

Harris Pogust, cochair of ATLA’s new Neurontin Litigation Group, said his firm in Pennsauken, New Jersey, has filed two such cases and sees potential clients daily. The harm done by Neurontin’s off-label use, he noted, extends well beyond suicide. The drug company conducted two clinical trials on Neurontin’s use as a treatment for bipolar disorder, he said. One showed that a placebo was as good as Neurontin; the other showed that the placebo worked better than the drug. But the company continued to promote Neurontin as an off-label treatment for bipolar disorder.

Pogust compared Parke-Davis’s conduct to “coming into the house of a bipolar patient on lithium,” removing the lithium from his or her medicine cabinet, “and saying, ‘You’re not going to be medicated. See what happens.’”

The complaint and sentencing memorandum from Franklin’s lawsuit help explain why a drug the FDA approved for only two relatively obscure uses now accounts for almost $3 billion of its maker’s approximately $50 billion annual revenues.

According to both of the documents, Parke-Davis promoted the drug for off-label uses to get as much revenue as possible while the drug was still under patent and to make sure that any competing generics would have limited use—instead of spending critical time and money to conduct studies and obtain FDA approval for those uses.

Using tape-recorded messages and other evidence that Franklin had accumulated, the suit detailed how Parke-Davis instructed its medical liaisons to ask doctors leading questions so the liaisons could talk about off-label uses. The company also provided grants and all-expenses-paid junkets to doctors who promoted the drug or prescribed it often. And, the lawsuit claimed, Parke-Davis hired a third party to ghostwrite scientific articles boosting Neurontin, then paid doctors to attach their names as bylines to the articles, which were published in medical literature.

‘Smoking gun’ suit

“This [lawsuit] was the smoking gun,” said Larry Sasich, a pharmacist and research analyst for Public Citizen’s Health Research Group located in Washington, D.C.

“We suspected that companies were manipulating the scientific literature, essentially using it as another promotional platform. All we had was circumstantial evidence. [Franklin] was the first time we had documentation [of] a conscious decision to bypass the FDA’s drug-approval process and to use the peer-reviewed medical literature as another form of advertising.”

Such promotion falls into a regulatory gray area that drug companies can easily exploit, critics say.

“If they wanted to, the FDA could [tell drug companies], ‘You are not allowed to mention at all—in any way, shape, or form—off-label uses of your drugs [to doctors].’ But that’s not what they do,” said Arnold Relman, a former editor of the New England Journal of Medicine and a frequent critic of pharmaceutical companies.

“A few years ago, after some hearings, the FDA decided that companies couldn’t promote off-label uses, but if doctors ask [pharmaceutical salespeople] about off-label uses or want to see any articles in the literature about off-label uses, it’s OK for drug companies to make those articles available and to allow their representatives to talk about those off-label uses.” Relman called that “a pretty slippery slope.”

He noted that the problem is compounded by paid-for bylines. “There is no hard, accurate information” about the extent of the practice, he said. “I know of many such instances myself and have been told of many others.”

The consequences are far-reaching, he said: “Prescription drugs are not like ordinary items of commerce; human health and safety are involved, and the consumer doesn’t have the power to protect himself against the ill effects of prescription drugs. The consumer must rely on what he or she learns from doctors. If the doctors are going to rely on what they’re told by the drug companies, and the drug companies are going to use unethical means to spread the information, it’s a very unfortunate situation.”

Accurate and fair dissemination of medical information has long concerned the medical and legal communities. New York Attorney General Eliot Spitzer recently brought a lawsuit against GlaxoSmithKline, alleging that the company withheld negative studies about the antidepressant Paxil and its use in children. As part of the settlement, the company agreed to post results of all its clinical trials online. (New York v. GlaxoSmithKline, No. 04-CV-5304 MGC (S.D.N.Y. Aug. 26, 2004).) Another pharmaceutical company, Forest Laboratories, agreed to do the same after Spitzer investigated its practices.

In addition, several editors of prominent medical journals recently agreed to require that any clinical trials related to articles under consideration for publication first be registered on a free, public Web site (www.clinicaltrials.gov). And Reps. Henry Waxman (D-Cal.) and Edward Markey (D-Mass.) have proposed federal legislation to require public registration of all drug trials on the same Web site.

Anecdotes and suicides

Although evidence of a trend linking suicides and Neurontin is anecdotal, the FDA admitted in March that a problem exists, said lawyer Andrew Finkelstein of Newburgh, New York, who represents several plaintiffs. He said FDA officials used the term “imminent health hazard” before holding a conference call with him about data his law firm had accumulated on a link between Neurontin and suicide.

The officials said his law firm, not the agency or Pfizer, should undertake a comprehensive analysis because his data was far more extensive than the agency’s. Finkelstein countered that the FDA should issue a public health advisory similar to the one it had issued a few days earlier regarding the risk of suicide associated with antidepressants taken by children.

After the FDA did nothing, Finkelstein’s office petitioned the agency to require a warning label for Neurontin noting the suicide risk. The petition cited the FDA’s own adverse event data, which showed an increase in suicides among Neurontin users during the first six months of 2003.

The agency again did nothing. Finkelstein wrote to Rep. Maurice Hinchey (D-N.Y.), noting that Pfizer had admitted in its settlement of the Franklin lawsuit that it promoted what was essentially a placebo, but “what has been ignored by both Pfizer and the FDA is that Neurontin causes adverse events, while a placebo does not.” Hinchey asked the FDA for a response to Finkelstein’s data and at press time had not received a reply. When contacted for this story, FDA spokesman Jason Brodsky said the agency was working on a response to the petition to change Neurontin’s labeling but had no comment on the conference call.

Fraud claims

Fraud is a linchpin of many Neurontin lawsuits. Several public interest groups are suing Pfizer in California, claiming that the company violated the state’s unfair-competition and false-advertising statutes. (Congress of California Seniors v. Pfizer, No. BC289643 (Cal., L.A. County Super. Ct. filed Mar. 19, 2004).)

In addition, two women have filed a proposed class action in Florida regarding the drug’s illegal marketing there; the plaintiffs are fighting removal to federal court. (Medero v. Pfizer, No. 04-222-228 CIV (S.D. Fla. filed Sept. 7, 2004).) And a multidistrict litigation hearing in Philadelphia held at press time will consolidate Neurontin consumer fraud cases in either Boston, New York, or New Jersey.

One of the biggest monetary losers in Neurontin fraud has been Medicaid, which ordinarily does not cover off-label drug use.

However, Medicaid has paid for many prescriptions for off-label use of Neurontin because a provision in the law allows coverage for an unapproved use that a provider deems a medical necessity and that is mentioned in one of several drug compendia.

One of them, Drugdex, lists many unapproved uses for the drug, said Public Citizen’s Sasich. “[Drugdex] will look for everything in the world of medical literature that mentions [a] use for a drug and they’ll put it into the compendium,” he said. “I suppose that covers the intent of the law. So medical necessity is no standard at all.”

Although doctors often cite the advantages of off-label drug use, consumer advocates like Sasich say any off-label use threatens health.

“Some of the worst drug disasters in the United States are the result of off-label use,” he said. He cited drugs used off-label to treat heart rhythm disturbances and extensive off-label use of hormones to prevent heart disease and reduce the risk of Alzheimer’s in women before a major study refuted those benefits.

“The tragic part is that with off-label drug use, the patient is participating as an unwitting subject in an uncontrolled clinical trial where nobody is keeping track of the data,” Sasich said.

Some critics say the pharmaceutical industry’s pursuit of profits also affects safety.

“Good drugs and mediocre and useless ones are available and are being promoted on a scale never seen before, because they can be sold under patent protection,” Relman said. “Companies [charge] as much as the traffic will bear. The consumer who has to pay the price is in no position to evaluate the need for the drug or decide whether the drug is worth the money. They have to take what the doctor tells them, and the doctors take what the company tells them. It’s a cozy system, which has ensured huge profits for the drug companies.”

Sasich echoed that concern. “There are drug companies that try to get around the approval standard, and physicians who think they are smart enough to know when a drug is helpful and when it’s harmful,” he said.

But there’s always a catch: “We can’t tell how many people were hurt [by off-label drug use], because we don’t have a very good system for capturing adverse events outside clinical trials. And we don’t know how many people are helped,” Sasich said.
“We are relying on the belief of the individual who makes the diagnosis, prescribes the drug, and evaluates the treatment, which I would submit is not an advised view.”

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