The term "off-label" means prescribing a drug for indications not listed on the label, upping the recommended dose, prescribing a drug in combination with other medications, or using a drug with a patient population, such as children, not listed on the label.
As part of the approval process, the FDA reviews the drug's labeling, which must include the proposed claims about the drug's risks and benefits, as well as the directions for use.
If an indication is not listed, it means the drug maker has not submitted the required studies to prove the drug is safe and effective for that use. While physicians may prescribe a drug approved by the FDA for an unapproved use, it's against the law for a drug maker to influence doctors to prescribe a drug for uses outside the label.
Pfizer completed the acquisition of Warner-Lambert in June 2000, and four years later in May 2004, Pfizer pleaded guilty to illegally marketing Neurontin for unapproved uses and agreed to pay a $430 million, the second-largest settlement ever in a health care fraud prosecution, to settle charges brought by the US Department of Justice that included defrauding public health care programs.
The case specifically sought to recover the losses to public programs resulting from the off-label promotion of a drug and focused primarily on Medicaid, which spent an estimated $422 million on Neurontin between 1994 to mid-2000.
In the end, Pfizer paid $83.6 million to the federal government and $68.4 million to the 50 states and the District of Columbia. In addition, Pfizer agreed to pay the states a total of $38 million to settle liabilities under state consumer protection laws, and a $240 million criminal fine, according to the DOJ.
However, the settlement with the DOJ did not include damage awards for patients who may have been injured by Neurontin and many patients, or families representing deceased Neurontin victims, have filed lawsuits against the company.
Many of the cases are wrongful death actions based on the company's failure to warn about the risk of suicidality associated with the drug. In 2004, attorneys Derek braslow and Harris Pogust of the Pennsylvania law firm, Pogust & Braslow, began filing lawsuits on behalf of victims who became suicidal.
Pogust & Braslow represent plaintiff, Natalie Biedenbender, whose husband Mark committed suicide on July 9, 2005, at age 39, after being prescribed Neurontin off-label for back pain, in a wrongful death lawsuit.
According to the lawsuit, from July 1995 through at least August 5, 2002, the company engaged in a marketing program "to induce physicians to prescribe Neurontin, for medical conditions for which the FDA had not approved Neurontin to be used."
That program, the complaint charges, included (a) illegally promoting the sale and use of Neurontin for a variety of conditions "for which defendants had not performed the required FDA testing or established safety and efficacy;" and (b) offering and paying illegal remuneration to doctors, "either directly or through third parties, to induce them to promote and prescribe Neurontin for off-label uses."
On May 17, 2004, Andrew Finkelstein, of the New York law firm of Finkelstein & Partners, submitted a citizen's petition to the FDA requesting that a black box suicide warning be added to the label and that a Dear Doctor letter be sent out to instructing physicians to be on alert for increased depression in patients taking the drug.
Mr Finkelstein also continued to remind the FDA about the rising number of suicides. In a March 21, 2005, letter to Dr Russell Katz, he wrote in part: "Enclosed you will find two hundred fifty eight MedWatch forms ... Each represents a suicide of an American who was on Neurontin when he or she took his or her own life."
"Many of these suicides likely could have been prevented," he said, "had both the treating physician and unsuspecting families been armed with full knowledge of the risks of suicide that was known to both the FDA and the manufacturer."
But as it turns out, the FDA was fully aware of the suicidality risk when Neurontin was recommended for approval in 1992, and Dr Katz oversaw the FDA's analysis of the clinical data provided to support the New Drug Application.
According to Mr Finkelstein, the evaluation of serious adverse events during the original clinical trials showed the risk of suicide was known and a major concern. In the letter to Dr Katz, he pointed out that an FDA reviewer specifically stated in December, 1992:
Serious adverse events may limit the drug's widespread usefulness. Depression, while it may not be an infrequent occurrence in the epileptic population, may become worse and require intervention or lead to suicide, as it has resulted in some suicidal attempts during clinical trials.
In fact, in the clinical trials, Neurontin was attributed to four people actually attempting suicide, two more having depression with suicidal ideations, and 22 participants reporting depression so severe it required pharmacologic intervention. Most alarming was that 19 of the 78 participants who reported depression had no prior history of depression.
"Clearly," Mr Finkelstein told Mr Katz, "the FDA did not approve this drug with any expectation of use beyond the approved indication."
Documents that surfaced in litigation also show that the FDA was aware of the off-label marketing scheme eight years before the DOJ settlement. In July, 1996, FDA official, Lesley Frank, wrote to Parke-Davis and said in part:
Parke-Davis may be promoting Neurontin for 'off-label' uses ... in printed promotional materials, in detail or sales presentations to physicians, and through the use of company-solicited physician participation in a series of teleconferences.
These promotions of Neurontin for off-label uses included, but were not limited to, its use in chronic pain, bipolar disorders, and other psychiatric conditions. As you are aware, Neurontin's only approved indication was for adjunctive therapy in the treatment of partial seizures with and without secondary generalization in adults with epilepsy.
The documents show that after 11 months, Parke-Davis sent a written response denying all the allegations and the FDA accepted the denials and the matter was dropped.
In reality, $430 million was chickenfeed to Pfizer, considering that at the time of the settlement, Neurontin sales were up 32% from 2003, and the 2004 sales were expected to exceed the $2.7 billion mark set in 2003. In actuality, the settlement amounted to only about 15% of the gross sales of Neurontin in 2003.
By 2002, a full 94% of Neurontin sales were for off-label use and according to the August 16, 2004, USA Today, when Pfizer settled the lawsuit, the Wall Street firm Lehman Bros estimated that 90% of the sales were still off-label.
At the time, Pfizer issued a statement that said the illegal practices took place before Pfizer acquired Warner-Lambert. However, sales figures clearly show that Pfizer was still reaping the benefits of the illegal promotion of Neurontin at the time of the settlement.
"Although Neurontin is prescribed for scores of off-label indications," Attorney Braslow reports, "since 2000 off-label use continues to be most common in the areas where the company focused its illegal marketing efforts such as bipolar disorder, peripheral neuropathy and migraine headaches."
"This increase," he points out, "is most likely a direct result of sales representatives and leading physicians, who were paid by the company recommending its use for these conditions."
According to Attorney Pogust, "there are no scientific studies that support Neurontin's use for pain disorders."
"But as a result of the company's previous promotional activities," he says, "tens of thousands of patients who could use other pain killing drugs whose effectiveness has been established, are given Neurontin."
"These prescriptions for pain," Mr Pogust notes, "are still being written, as a direct result of past illegal promotional activities."
"Likewise," he points out, "the off-label prescriptions of Neurontin for bipolar disorder, attention deficit disorder, and depression are also without any scientific evidence supporting such uses."
The off-label scheme was first revealed by whistleblower, David Franklin, a former Park-Davis employee who worked as a medical liaison, in a lawsuit against Warner-Lambert and its Parke-Davis division filed under the federal False Claims Act.
By Mr Franklin's estimates, as much as 90% of prescriptions for Neurontin were written off-label as a result of the illegal scheme which prosecutors claim dates back to1995. To back up his allegations, Mr Franklin offered a voicemail he saved from his boss that stated:
I want you out there every day selling Neurontin... holding their hand, whispering in their ear, Neurontin for pain, Neurontin for monotherapy, Neurontin for bipolar, Neurontin for everything. I don't want to see a single patient coming off Neurontin before they've been up to at least 4,800 milligrams a day.?
His boss concluded by stating: "I don't want to hear that safety crap either. It's a great drug"
As a whistleblower in a case to recover federal funds, Mr Franklin was entitled to a percentage of the settlement and received $24.6 million
The Drug Industry Document Archive (DIDA), created by the Center for Knowledge Management at the University of California San Francisco Library in collaboration with faculty members, contains roughly 1,000 documents drawn primarily from the case titled, United States ex rel David Franklin vs Parke-Davis, Division of Warner-Lambert, which describe all the specific details on the Neutontin off-label marketing scheme.
In settling the charges, Pfizer pleaded guilty only to conduct occurring before August 21, 1996, even though the DOJ determined that illegal activities had occurred much later, making it possible for Pfizer to continue to participate in federally funded health care programs despite a health care fraud law that went into effect on August 21, 1996, that would have required its exclusion from public programs.
Pfizer escaped the severe penalties, that many critics say would have sent a clear message to companies engaging in such conduct to knock it off or risk losing the most treasured customer base of all public health care programs, even though Warner-Lambert had been convicted of a felony in 1995, for failing to report failures concerning other drugs, which meant the new charges were second offenses "punishable as felonies without regard to proof of intent to defraud or mislead."
Initially, Neurontin was approved only to treat epilepsy in combination with another drug, and at a maximum 1800 mg daily dose. But the DOJ found the drug was being promoted for a multitude of pain uses, psychiatric conditions such as bipolar disorder and anxiety, social phobia, and general mood stabilization, as well as certain unapproved uses within epilepsy treatment. According to the DOJ, the list of unapproved uses became so long that company employees called it the "snake oil" list.
Over all, the DOJ listed the potential harm caused by the illegal scheme as: (1) public health care programs paid more in reimbursement; (2) consumers paid for ineffective, experimental use and may have been improperly medicated; (3) patient's unnecessary exposure to adverse side effects; and (4) improper medication may have resulted where Neurontin was not as effective as another approved drug.
The DOJ listed six tactics involved in carrying out the off-label scheme as: (1) Detailing by sales representatives; (2) Use of Medical Liaisons; (3) Preceptorships; (4) Consultant meetings, speakers bureaus and advisory boards; (5) Series of teleconferences to disseminate off-label uses; and (6) Control of Purportedly Independent Medical Education.
Another element of the overall scheme to increase profits was to convince doctors to prescribe Neurontin at substantially higher doses than the maximum approved dose.
The DOJ produced evidence to show that Parke-Davis had arranged hundreds of teleconferences, meetings, and educational seminars, in addition to the detailing of individual doctors by sales representatives, to promote the off-label use of Neurontin.
In 1996, a Parke-Davis sales representative created a document that said sales representatives could ask doctors if they ever used other antiepileptic drugs for painful neuropathies and then mention that approximately 35% of all Neurontin use is non-seizure. This same document, entitled "Neurontin Can Do/Can't Do," also stated that sales representatives could present lunch programs on Neurontin and pain.
According to Mr Franklin, the company gave financial incentives to hundreds of doctors by inviting them to dinners, sports outings, and weekend trips to resorts where fellow-physicians were paid to speak about the use of Neurontin for unapproved indications.
The company founded a speakers' bureau, as a method of making large payments to physicians who gave presentations and court documents show doctors were paid to listen to speeches that took place on a "Bus to Yankee Stadium," a "World Yacht Cruise," and the "Braves Stadium."
During one trip in 1996, Parke-Davis paid for 18 doctors and their spouses to stay in Atlanta for 5 days to attend the Summer Olympics. The company paid for their meals, use of a resort, and travel to the games while the agenda for the seminar listed only 10.5 hours of business meetings, including one devoted to off-label uses for Neurontin. ?
The DOJ determined that the company kept track of how well these marketing efforts paid off. For instance, in a memo dated June 26, 1995, a marketing executive reported that doctors who attended dinners and listened to speeches from other physicians, wrote 70% more off-label prescriptions than doctors who did not attend.
Documents show that the company intentionally hired influential doctors from major teaching hospitals to speak at these events. For instance, Dr Steven Schachter, a professor at Harvard Medical School, received $71,477 between May 1994 and September 1997, and Dr B J Wilder, a former professor at the University of Florida, was paid more than $300,000, and other doctors received more than $100,000 each.
The company also paid to disseminate papers and articles on off-label uses throughout the medical literature so that doctors would find themselves bombarded with information about the many uses for Neurontin, made to look like independent scientific papers.
For some uses, like monotherapy, the research was used to support an attempt to obtain FDA approval. But in other cases, the company's goal was to disseminate the information as widely as possible to increase off-label prescribing for conditions like pain and bipolar disorder, without ever trying to obtain approval.
To carry out this part of the scheme, Warner-Lambert hired two marketing firms to write the articles and then found doctors willing to sign on as authors. According to Mr Franklin, the PR firms were paid $12,000 per article and the doctors were paid $1,000.
The DOJ found more than twenty 20 articles published in various medical journals that were fully paid for by Parke-Davis. Critics say this tactic still affects off-label prescribing today. According to Mr Braslow, "since 1999, the types of off-label are most likely weighted in the precise areas where the drug maker focused its illegal marketing efforts: bipolar disorder, peripheral neuropathy, migraine, depression, etc."
"Because physicians were inundated with false information for years," Mr. Pogust says, "they continue to prescribe it for off-label uses for which there is no reliable scientific support."
Parke-Davis also infiltrated the continuing education arena where doctors were misled into believing that seminars on the off-label uses for Neurontin were independent educational programs, when they actually were marketing events set up by Park-Davis.
For example, prosecutors found an undisclosed relationship with a firm known as Physicians World where Parke-Davis employees transferred to the firm to run the company's speakers bureau. ??At the same time, the DOJ discovered that in a division of Physicians World, known as Professional Post-Graduate Services, which purported to be an independent education provider presenting programs on anticonvulsants for pain to thousands of US doctors, Parke-Davis employees actually planned and developed the programs. ?
According to the DOJ, in late 1995, the company took the position that medical liaisons could discuss off-label issues with doctors, so long as the doctor asked a question about the topic first. Because physicians believed medical liaisons were persons with a scientific background and not employed to sell Neurontin, they were often able to gain access to doctors that the sales representatives could not.
For example, Mr Franklin was trained to increase the rate of prescriptions of Neurontin as monotherapy, and one of the ways he was able to gain access to doctors was by fraudulently presenting himself as a neurology specialist conducting research on epilepsy and the actions of anticonvulsant drugs.
Company records reveal an extensive pattern of misuse of medical liaisons. A January 31, 1996, memo describes a goal to "utilize the medical liaison group to target the Neurontin, Pain & Psychiatric market."
"Objective to conduct twice weekly Pain Teleconferences moderated by key Neuro Consultants," the memo states. "Goals 250 Physician participants quarterly."
One of the most alarming sales tactics identified during the DOJ's investigation was that sales representatives were allowed to review patient records, suggest an increase in Neurontin dosage, and "shadow" doctors while they examined patients, in exchange for paying the doctor a few hundred dollars a day.
According to the DOJ, at various times Parke-Davis made a conscious decision to not seek approval for a new use because it would have required solid proof from clinical trials that could not be provided.
Documents show that Parke-Davis even went to the trouble of determining how much could be made off Neurontin for a new approved use, compared to sales from marketing the drug off-label for the same use.
For example, a May 19, 1995, Marketing Assessment forecast potential revenue from Neurontin for bipolar without approval at $6 million in 1997, rising to $36 million in 1999. On the other hand, with approval, forecasted sales were almost $12 million in 1997, to over $80 million in 2002, but the company still decided not to seek approval for bipolar.
The DOJ found that similar projections were made for other uses including various types of pain but again, after evaluating the potential sales with and without approval, Parke-Davis decided to market Neurontin off-label instead of seeking approval.
The company also kept track of doctor's prescribing habits for Neurontin's competitors. In October of 1995, Parke-Davis determined that two competing epilepsy drugs, Tegretol and Depakote, had total sales of 18-27% for bipolar disorder, and up to 9% for pain, while at the time, only 1-2% of sales for Neurontin were for pain and bipolar.
The company continued to market the drug for bipolar even after studies showed it was ineffective for that use. The DOJ's sentencing Memorandum states: "One of the psychiatric uses for which Neurontin was promoted ... bipolar disorder, was particularly troubling because the Company had very weak evidence of Neurontin's efficacy in treating this condition."
"Indeed," the prosecutor wrote, "in one study ... the placebo was as effective or more effective than was Neurontin."
Yet with full knowledge of this study, medical liaisons told psychiatrists that early results from clinical trials indicated a 90% response rate for bipolar. Likewise, they told pediatricians that Neurontin was effective for children with attention deficit disorder, when no data other than occasional anecdotal evidence supported that claim.
And although no studies existed to prove that Neurontin was even as effective as inexpensive pain killers already on the market, medical liaisons told doctors that clinical trials demonstrated that Neurontin was highly effective in treating various pain syndromes and reported once again that a 90% response rate was found in the treatment of pain.
The DOJ also reports that the company continued to promote Neurontin for monotherapy even after the FDA refused to approve it. Parke-Davis sought approval in September 1996, but because one of the 2 clinical trials submitted with the application showed no demonstrable monotherapy efficacy, the application was denied.
Nonetheless, the DOJ produced evidence showing that Parke-Davis continued to promote Neurontin for monotherapy through at least 2000, without ever mentioning the rejected application, and that at one 1998 event, Parke-Davis went so far as to state that Neurontin is "now approved as monotherapy for seizures."
When caught red-handed promoting drugs for unapproved uses, drug makers always feign ignorance of the high rate of off-label prescribing. However in this instance, company documents show that Warner-Lambert regularly obtained detailed information on the number of prescriptions written for Neurontin and what indication they were written for.
Neurontin sales did finally drop to $182 million in the first quarter of 2005, but as a result of new generic competition on the market, according to USA Today on April 20, 2005.