When the FDA approves a drug, it also approves the labeling for the drug, which explains the manner in which the medication is to be used. While physicians may prescribe approved drugs as they see fit, its against the law for drug companies to promote drugs for uses outside of the approved labeling, but they do it all the time.
Neurontin remains the most notorious example of an illegal, but highly successful, off-label marketing campaign. The drug was approved for the limited use of treating epileptic seizures but nonetheless, became an overnight blockbuster with sales that soared from $97.5 million in 1995, to more than $2.5 billion in 2003.
While Neurontin might be the most notorious, it is certainly not the only problem. A study published in the May 8, 2006, Archives of Internal Medicine, determined that more than one out of every 7 prescriptions written for 160 commonly used drugs were for off-label uses that lacked scientific support.
The study was based on information from the IMS Health National Disease and Therapeutic Index that defines drug prescribing patterns and provides market data on drug companies.
In 2001, an estimated 150 million prescriptions, or 21% of prescriptions written, were for off-label use, according to the Archives study.
To reach its results, the study first determined whether a prescription was off-label and then assessed the level of available scientific evidence supporting the use, through the Drugdex system, a comprehensive summary of evidence supporting off-label uses of prescription drugs.
The study found that 73%, or 109 million off-label prescriptions, had little or no supporting evidence. The study does not explain why doctors prescribe so many drugs off-label but one explanation may be that "both physicians and patients have misunderstood the role of the FDA," the study's lead author Randall Stafford says.
"I think there's sort of a presumption that if a drug has made it onto the market," he notes, "the FDA has vouched for its safety and efficacy for all of its potential uses."
One way drug companies have been able to increase the off-label sale of drugs is by influencing doctors in public institutions, and state policy makers, who are involved in the development of drug formularies that list which drugs will be used in state institutions and by persons covered by government health care programs like Medicaid and Medicare.
Allen Jones, a former Pennsylvania fraud investigator, explains that each state has a menu of approved drugs that doctors must prescribe to persons in state institutions. "Before a drug can be prescribed by a state physician for somebody in the state system," he says, "it has to be on the list."
According to Mr Jones, the drug companies "have bought the decision-making process from our government officials all the way down to the guy who decides what drugs get on the formulary."
Doctors who sit on the expert panels and decide which drugs will be on the lists, he says, are paid by drug companies to give positive opinions in order to circumvent the FDA approval process.
"The FDA has no control over what an individual doctor does or says," Mr Jones explains, "the pharmaceutical industry has funded a mechanism whereby they can gather favorable opinions."
"They then amplify and magnify those opinions," he says, "and put them in the form of a treatment protocol that can be implemented in any state with the approval of a few key decision-makers."
Stacking the deck with industry friendly "experts" is apparently common. An investigation by the scientific journal Nature found "extensive" financial connections between drug companies and the advisory panels, with as many as 70% of the panels affected. In one instance, Nature found every member of a panel had received payments from the company making the drug that was recommended.
In the summer of 2002, Mr Jones discovered an off-the-books account where drug companies were depositing "educational grants" from which state officials and policy makers involved in developing Pennsylvania's drug list were receiving payments.
"We had state officials accepting $2,000 honorariums," he noted, "and physicians who were taking trips, perks and gratuities."
One of the officials Mr Jones named in his investigation was the state pharmacist, Steven Fiorello. In April 2005, the State Ethics Commission fined Fiorello over $27,000 after finding that he repeatedly took money from drug makers, Pfizer and Janssen, while serving on the panel that decided which drugs could be given at 9 state mental hospitals. The commission's report cited repeated failures to disclose his income from the drug companies.
On June 10, 2005, Senators Chuck Grassley and Max Baucus announced the beginning of an investigation by the Senate Finance Committee, which has oversight responsibility for government health care programs, into the practice where drug companies give money to state governments.
"The drug companies call the awards educational grants," their press release said, "but the senators are concerned that the dollars are more focused on product promotion than education."
The Senators said their inquiry was based on reports that companies have awarded grants as inducements to prescribe medications the companies produce.
In some cases, they said, "such grants to state agencies may have prompted those agencies to develop programs leading to over-medication of patients at the expense of patient health or to unnecessary expense for taxpayers."
"We need to know how this behind-the-scenes funneling of money is influencing decision makers," Senator Grassley said. "The decisions result in the government spending billions of dollars on drugs."
In recent years, investigations into the prescribing patterns for people on Medicaid and Medicare has led to the discovery of a drastic increase in off-label prescribing to children and the elderly, of drugs never approved for use with children and the elderly.
One class of drugs found to be prescribed off-label most often without scientific support are psychiatric medications. In 96% of the psychiatric drugs prescribed off-label, the Archive study found support was lacking.
According to the report, Death by Medicine (2003), by Gary Null, PhD; Carolyn Dean MD, ND; Martin Feldman, MD; Debora Rasio, MD; and Dorothy Smith, PhD, a study on prescription drug use by the elderly conducted by Medco Health Solutions found that 6.3 million senior citizens received more than 160 million prescriptions and a total of 7.9 million medical alerts were triggered by off-label prescribing, with 2.2 million alerts indicating excessive dosages unsuitable for seniors, and about 2.4 million indicating clinically inappropriate drugs for the elderly.
Drug companies have promoted the off-label use of psychiatric drugs with children even after their own studies have shown the drugs to be dangerous. In 2004, New York attorney general, Eliot Spitzer, filed a lawsuit against GlaxoSmithKline for withholding studies that raised doubts about the effectiveness and safety of Paxil in treating children, and revealed that more than 2 million prescriptions for Paxil were written off-label to treat children in 2002.
In late 2004 the FDA ordered black box warnings on all SSRI antidepressants after it was discovered that drug makers had suppressed studies that showed the drugs were linked to an increased risk of suicide in children.
Documents that have surfaced during litigation reveal that drug makers knew about this risk before the SSRI antidepressants arrived on the market but continued to find ways to get doctors to prescribe the drugs to kids. A report by Express Scripts, Inc, a pharmacy benefit manager, titled "Trends in the Use of Antidepressants in a National Sample of Commercially Insured Pediatric Patients," shows that between 1998 and 2002, the overall use of antidepressants among children increased from 160 children per 10,000 in 1998, to 240 per 10,000 in 2003.
Tom Woodward's daughter Julie hung herself after being prescribed the antidepressant, Zoloft, off-label. He is angry at the Bush administration and the FDA for failing to protect the public against drug companies who hide studies that show drugs are dangerous when given to children.
"It is clear that the FDA is a political entity and its leadership has protected the economic interests of the drug industry," he says.
According to Mr Woodward, officials in leadership positions have strong ties to the industry. "FDA's chief counsel Daniel Troy has spent his career defending the drug industry," he noted, "if a study does not favor a drug, the public never hears about it."
"Under the Bush administration," Mr Woodward said, "the FDA has placed the interests of the drug industry over protecting the American public."
He points out that 86% of the millions of dollars in campaign contributions by drug companies went to Bush and Republican candidates and he wants to know, "what did Pfizer, Eli Lilly, and GlaxoSmithKline Beecham buy?"
A recent study reveals that even when the FDA does add a black box warning to a label, the highest form of drug safety alert available, doctors will continue to prescribe the drug.
The February 14, 2006 Archives of Internal Medicine featured a report on a study where researchers reviewed the records of 324,548 patients seen at several Boston area medical facilities between January 1, 2002 and December 31, 2002 and found that 33,778 patients were prescribed a drug that had a black box label, and 2,354 of those prescriptions were written contrary to the guidance set forth in black box warning.
The study found that in about 1,000 cases, patients were taking one drug at the same time as another when the warning said that taking the 2 drugs together should be avoided, and in about 90% of the cases, a drug was prescribed to treat a condition for which the drug was not approved.
According to Death by Medicine, each year approximately 2.2 million US hospital patients experience adverse drug reactions to prescribed medications and experts say many are caused by prescribing drugs for uses not approved.
The dangerous off-label prescribing practices have come under scrutiny in recent years because so many of the drugs are covered by government health care programs, and lawmakers charged with oversight of programs like Medicaid and Medicare became suspicious about the skyrocketing prescription drug costs.
In some of the largest cases involving Medicaid and Medicare fraud, former industry employees came forward with information about marketing schemes and filed lawsuits under the False Claims Act.
The Washington DC based Taxpayors Against Fraud, is a non-profit organization dedicated to combating fraud against the federal government through the promotion and use of the qui tam provisions of the False Claims Act.
Qui tam is a mechanism that allows persons with evidence of fraud to bring suit on behalf of the government. TAF educates the public about the FCA and its qui tam provisions and provides assistance to whistleblowers and their attorneys and sometimes files amicus curiae briefs on important issues.
TAF also has a staff of lawyers and other professionals who are available to assist anyone interested in the FCA and publishes the False Claims Act and Qui Tam Quarterly Review.
Whistleblower lawsuits are proving to be highly effective in exposing fraud. Of the 10 top FCA Medicaid fraud recoveries to date, the top 5 are whistleblower cases against drug companies.
According to TAF, during FY 2004, between October 1, 2003 and September 30, 2004, the US Department of Justice settled 3 whistleblower cases against drug companies for a total of over $800 million, raising the total recoveries in such cases by nearly 50% to $2.46 billion.
Two of the settlements involved both criminal fines and civil penalties. The recoveries included $290 million in criminal fines, $275 million in civil penalties and damages to the federal government, and nearly $235 million to state governments. All three settlements involved allegations of fraud against Medicaid.
Two of the cases began as lawsuits filed under the FCA by whistleblowers and the third began as a case under the Texas Medicaid Fraud Prevention Act.
The defendant in one case was the nation's largest drug maker, Pfizer, with annual sales of $30 billion. The conduct at issue concerned a Pfizer subsidiary, the Parke-Davis Division of Warner-Lambert, acquired by Pfizer in 2000.
Drug maker Schering-Plough was the defendant in the other 2 cases.
Government recoveries from Pfizer totaled $430 million, and the two Schering settlements were $345 million and $27 million.
This is the second FCA whistleblower settlement entered into by Pfizer, and the second largest drug maker settlement ever when measured by the combined civil recovery of $430 million and the criminal fine of $240 million.
The Pfizer case broke new legal ground by recovering losses to Medicaid resulting from the illegal off-label promotion of a drug for uses other than those approved as safe and effective.
At the time of the settlement in May 2004, Pfizer's drug, Neurontin, ranked 9th among all drugs sold in the US, with annual sales of $2.7 billion, according to IMS Health, "Leading 20 Products by U.S. Sales, Moving Annual Total, June 2004," [imshealth.com].
The whistleblower, David Franklin, a former medical liaison for Parke-Davis, who filed the FCA lawsuit, received a $24.6 million settlement, when Warner-Lambert agreed to plead guilty to two felonies to settle charges that it fraudulently promoted Neurontin for a wide variety of unapproved uses.
Among the tactics the DOJ found the company using to achieve its goal of increasing off-label use of Neurontin were the following:
- Encouraging sales reps to provide one-on-one sales pitches, or "details," to physicians about off-label uses of Neurontin;
- Utilizing medical liaisons, who represented themselves, often falsely, as neutral scientific experts on Neurontin, to promote off-label uses, working in tandem with the sales reps to directly sell Neurontin to physicians for off-label uses;
- Paying doctors to allow a sales reps to see patients with the doctor and to participate in discussing the treatment plan;
- Paying physicians, through both direct payments, and trips, hotel rooms, dinners and other benefits, to attend meetings termed "consultant" or "advisory" meetings or "speaker bureau trainings" in which doctors listened to presentations about off-label uses;
- Implementing frequent teleconferences in which doctors were paid to speak about Neurontin on off-label topics to other doctors; and
- Sponsoring independent "medical education" events on off-label uses where there was actually extensive input from the company on topics, speakers, content, and participants.
In the settlement agreement, the company admitted that it aggressively marketed the drug by illicit means for unapproved uses including pain, bipolar disorder, migraines, and drug and alcohol withdrawal.
The prosecutors described the harm that resulted from the off-label scheme as:
- health care reimbursement programs such as Medicaid paid more in reimbursement;
- consumers paid for ineffective, experimental use and may have been improperly medicated;
- improper medication could have resulted where Neurontin was not as effective as another approved drug; and
- unnecessary exposure of patients to adverse side effects of Neurontin.
According to court documents filed in the case, doctors were paid honoraria to listen to presentations that took place at: "Bus to Yankee Stadium," "World Yacht Cruise" and "Braves Stadium."
On one weekend in April 1996, the DOJ discovered that Warner-Lambert had arranged 2 weekend "consultant" meetings, one at the Jupiter Beach Resort in Palm Beach, Florida, and the other at the Ritz-Carlton in Aspen, Colorado. Both were 3 day affairs, for which each attendee received a $250 cash payment, plus airfare, and all other expenses paid at the resort, and the doctors who acted as faculty were also paid between $1,500 and $2,000.
According to the DOJ, the total cost for the Jupiter Beach weekend was approximately $361,000 for about 100 doctors, meaning the price per doctor was about $3,000, and the cost of the Aspen weekend ran about the same.
Documents showed that both meetings included presentations on off-label topics such as "Neurontin: Use as Monotherapy," and "Reduction of Pain Symptoms During Treatment with Gabapentin," that were designed to present information to the attendees, rather than to receive information from consultants.
One advisory board was treated to an extravaganza at the 1996 summer Olympics in Atlanta, Georgia. Along with free Olympics tickets valued at $650 each, the company staged an Epilepsy Advisory Meeting, at the Chateau Elan Winery and Resort, in Atlanta.
The brochure for the event describes the resort as: "Chateau Elan has made a name for itself as a fine winery. It is now earning a reputation as a one-of-a-kind resort... Here, you'll enjoy all the comforts and amenities you'd expect of a fine resort, mellowed by the warm ambiance of a French country inn."
"During your meeting breaks," the brochure says, "you will have the opportunity to play a round at one of three accessible golf courses, swim, play tennis, explore the Georgia hill country by foot or by horseback, or escape to Chateau's European style spa for a pampering body treatment...."
For this event, records show the company paid all expenses for 18 advisers and their spouses, and each adviser was given $750 in cash for spending. In planning the Olympics advisory board meeting, a company document obtained by the DOJ, referred to the cost of the event as a "$3 million investment."
Another example of the lavish meetings doctors attended for free, was the Western Advisory Board Meeting, held at the Grand Wailea Resort, Hotel & Spa in Maui, Hawaii in April 2000.
Only one of the attendees resided in Hawaii and the company paid for all of the others to fly to Hawaii for a two night stay at the resort to attend only 3 hours of meetings, all on off-label uses of Neurontin, according to the DOJ.
In planning this meeting, the company targeted doctors whose uses for Neurontin were only off-label and "evidence shows this event was promotional, not an independent, scientific meeting," according to the DOJ's sentencing memorandum.
The DOJ said Parke-Davis held hundreds of meetings where doctors were paid to attend, and paid even more to speak, and that Parke-Davis was especially interested in two types of physicians: (1) those who prescribed large amounts of anti-convulsants; and (2) those who had a prominent reputation.
These doctors were often referred to as the "movers and shakers" or "thought leaders" because of their influence, and were recruited as spokespersons on behalf of Neurontin.
Parke-Davis paid key "thought leaders" who could be counted on to deliver a strongly favorable message on off-label use. At least 20 of these doctors, the DOJ said, were paid more than $50,000 over time for speaking on the company's behalf. In fact, some received in excess of $250,000.
Corporate documents show, the DOJ says, that the company focused its attention on recruiting doctors from major teaching hospitals to serve as "Neurontin champions."
For example, documents show that Dr Steven Schachter, a professor at Harvard Medical School and a physician at Beth Israel Deaconess Medical Center in Boston received $71,477 between May 1994 and September 1997, and a Dr B.J. Wilder, a former professor of neurology at the University of Florida, was paid more than $300,000 for speeches given between 1994 and 1997. Six other doctors, including some from top medical schools, the DOJ said, received more than $100, 000 each.
The most common forums for speakers were consultant and advisory board meetings, where doctors were gathered to listen to a presentation. Parke-Davis justified holding these meetings, because it entered into pro forma consultant agreements with the physician attendees and doctors were paid anywhere from $250-$2,500 to serve as consultants or advisers.
In one 6-month period alone, the DOJ said, Park-Davis held over 50 meetings and despite being called "consultant" meetings, the actual objective was to provide off-label information to the doctors rather than to receive information from the consultants.
During its investigation, the DOJ discovered that doctors were misled into believing that educational programs they attended were independent programs when they were actually led by the drug maker. For example, prosecutors found a Ward-Lambert relationship with a company known as Physicians World where Warner-Lambert employees transferred to Physicians World to run the company's speakers bureau.
At the same time, a division of Physicians World, known as Professional Post-Graduate Services, purported to be an independent education provider for a program on anticonvulsants for pain, when in fact, Ward-Lambert staff planned and developed the program and thousands of US doctors took the classes.
This program was provided to thousands of doctors all around the country and in each instance, the materials stated that they were created in compliance with ACCME guidelines, which prohibited content control by Parke-Davis as a condition of accreditation, and required disclosure of all financial affiliations.
The materials did not disclose the relationship between Physicians World and Parke-Davis, and did not disclose the financial links between Parke-Davis and each of the faculty members, all of whom were paid consultants, the DOJ said.
For instance, one physician was a regular Neurontin speaker who had received payments of more than $10,000 and yet by the listing of each faculty member, there was an asterisk indicating "no significant financial or other affiliation reported."
"This evidence," the US attorney said, "demonstrates that Parke-Davis knew that these events were unlawful promotional activities."
Another method of promoting face-to-face was the preceptorship, or "shadowing." This involved paying a doctor to allow a sales rep to follow the doctor through the course of a day seeing patients. In one example, a sales rep did a preceptorship with a neurologist and after they saw a teenage patient, the doctor and the sales rep discussed treatment options.
The sales rep advised the doctor to increase the Neurontin dose and at the same time, taper the patient off other epilepsy medication to reduce side effects, thus resulting in Neurontin being used for monotherapy. According to the sales rep, as recorded in a voice mail sent in to the company obtained by the DOJ: "I really felt I made a difference. I saw the actual prescription generated in front of me... and I certainly felt that by me being there, I had some influence on that medical decision."
Another patient seen was a 65 year old veteran who suffered neuralgia with pain in his limbs. The patient developed blurred vision while on Neurontin; and the sales rep told the doctor that such side effects are mild and transient and so the doctor kept the patient on the drug. In the sales rep's own words: "I felt like I influenced that particular situation. So again, another prescription was generated for us. Overall, the day went, you know, very well. And we had the immediate impact of two prescriptions written."
The DOJ said the drug maker decided not to seek an expanded use for Neurontin with the FDA because it would have required solid proof from clinical trials so instead, the company boosted sales through promotional strategies, even for conditions where studies had indicated that Neurontin was not effective.
In his sentencing Memorandum the US Attorney noted: "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."
Moreover, the DOJ found the company paid no attention even when the FDA did refuse to approve an additional use. For instance, Parke-Davis sought approval for use as a monotherapy on September 16, 1996, but because one of 2 clinical trials submitted with the application showed no demonstrable monotherapy efficacy, on August 26, 1997, the FDA rejected the application.
Nonetheless, the DOJ found that Parke-Davis had actively promoted the drug for monotherapy before it applied for approval, and after the FDA rejected its application right through at least 2000, when slides, lecture summaries and audiotapes obtained by the DOJ demonstrate that Parke-Davis continued to promote Neurontin for monotherapy without ever mentioning the fact that the FDA had rejected its application.
Documented examples listed by the DOJ, of statements made after the FDA's non-approval include a marketing event in 1998, where Parke-Davis went so far as to state that Neurontin was "now approved as monotherapy for seizures."
In his whistleblower lawsuit, Mr Franklin explained how Warner-Lambert had hired two marketing firms to write favorable articles about the unapproved uses of Neurontin and to find doctors willing to sign their names as the authors. The marketing firms, he said, were paid $12,000 for the articles and the doctors were paid $1,000 for signing off as authors.
The off-label scheme proved to be highly successful. By government estimates, citing company documents and independent market research, by 2002 94% of Neurontin's sales were for off-label use, up from 40% in 1995.
At the time of the settlement in 2004, Vermont Attorney General, William Sorrell, noted that a 30-day supply of Neurontin at a common dose sold for $205.
Under the terms of the settlement agreement, Pfizer agreed to:
- plead guilty to inadequately labeling of Neurontin and to introducing Neurontin into interstate commerce for unapproved purposes, which, by virtue of its prior violation of the Food, Drug & Cosmetic Act, constitute felony violations of the Act, and to pay a $240,000,000 criminal fine;
- settle its False Claims Act and other civil liabilities and to pay the Government $83,600,000, plus interest, in civil damages for losses suffered by the federally funded portion of the Medicaid program as a result of off-label promotion of Neurontin;
- settle its civil liabilities to the 50 states and the District of Columbia in an amount of $68,400,000, plus interest, in civil damages for losses suffered by the state-funded portion of the Medicaid program as a result of off-label promotion of Neurontin;
- settle its civil liabilities to the Consumer Protection divisions of 50 states and the District of Columbia state attorney general's offices in an amount of $38,000,000, plus interest, in civil damages for losses suffered by consumers and to fund a remediation program designed to offset the impact of the improper marketing of Neurontin; and
- comply with the terms of an amendment to the corporate compliance program of its parent, Pfizer, which, among other things, prescribes off-label marketing and requires training of employees and audits of its marketing practices.
For instance, on August 19, 2004, USA Today noted that: "Pfizer's confession that the success of one of its top drugs was built partly on fraud may have been humbling, but it isn't hurting the bottom line. Neurontin sales last quarter rose 32% from a year ago, and 2004 sales should pass last year's $2.7 billion."
"With few exceptions," USA said, "state Medicaid programs pay for Neurontin just as before and so do major insurers."
Pfizer's denials also rang hollow at the time due to the fact that the company's regulatory filings showed the DOJ was also scrutinizing its off-label marketing of the Genotropin growth hormone and a federal grand jury in Maryland was taking testimony from former Pfizer employees about the diabetes drug, Rezulin, that was pulled off the market in 2000 after it was linked to over 60 liver-related deaths.
But as far as fearing the FDA, the drug companies had no fear and apparently for good reason. documents unearthed in litigation reveal that the FDA was well aware of the company's off-label marketing scheme eight years before the 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.Documents show that after 11 months, Parke-Davis responded and denied all allegations and the FDA simply accepted the company's denial and the issue was dropped.
"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."
As part of the settlement with the DOJ, Warner-Lambert pleaded guilty only to conduct that occurred before August 21, 1996, even though illegal conduct is documented as occurring much later than 1996.
This part of the agreement made it possible for Pfizer to continue to participate in government health care programs despite an August 21, 1996, health care fraud law that would have led to its exclusion.
In addition to financial fraud, the company pleaded guilty to criminal misbranding of the drug in promotional and advertising material claiming that "the drug is safe and effective for uses which have not been approved by the FDA."
Pfizer's settlement with the DOJ did not cover damages for any patients who may have been harmed by Neurontin and those patients are entitled to file personal injury lawsuits.
Pfizer is currently engaged in multi-district litigation (MDL). On October 26, 2004, the Judicial Panel on Multidistrict Litigation consolidated nearly all Neurontin off-label cases in the US District Court for the District of Massachusetts.
The JPML is a panel of seven federal judges chosen by the Chief Justice of the US Supreme Court that decides on the appropriateness of establishing an MDL, and where the MDL should reside. The MDL brings together lawsuits with common claims to determine pretrial matters.
The MDL primarily involves cases of consumers who purchased Neurontin for off-label uses that Pfizer knew showed no efficacy but more lawsuits have been filed on behalf of persons who suffered adverse effects when Neurontin was prescribed for off-label uses. The first Neurontin trial is expected to take place later this year or early 2007.
In 2004, the New York law firm of Finkelstein & Partners filed several lawsuits and announced plans to file many more. At the time, the firm's senior partner, Andrew Finkelstein, said he had gathered the names of 160 people who committed suicide and 2000 more who attempted suicide while taking Neurontin.
In addition to handling lawsuits, for more than 2 years Mr Finkelstein's law firm has been warning the FDA about patients committing suicide while taking Neurontin and asked the FDA numerous times to add a black box warning to Neurontin's label about the risk of suicide in patients taking the drug. As of October 2005, Mr Finkelstein has been contacted by the relatives of 425 people who committed suicide while on Neurontin.
After a year of inaction by the FDA, on March 21, 2005, Mr Finkelstein wrote a letter to the FDA's Dr Russell Katz and said 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."
Mr Franelstein told Dr Katz the "complete inaction by the FDA to warn an unknowing population that was relying upon the FDA to require warnings for potential adverse events from off-label usage, is deplorable."
"Since our conversation of March 31, 2004," he wrote, "my firm has learned of seventy four additional suicides that occurred after that date."
"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."
Neurontin was recommended for approval by the Neuropharmacolgical Drug Products Division of the FDA in 1992, and according to Mr Finkelstein, at that time, Mr Katz oversaw the FDA's analysis of the clinical data supplied by the sponsor seeking approval to sell Neurontin.
Mr Finkelstein obtained the FDA's 1992 analysis of the New Drug Application for Neurontin, and in reviewing the data, he told Dr Katz he found "shocking information."
"During your evaluation of serious adverse events that occurred during original clinical trials," he advised Dr Katz in the letter, "the risk of Neurontin causing suicide was both known and a major concern."
The FDA reviewer from your Division, Mr Finkelstein pointed out, "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"Clearly," Mr Finkelstein wrote, "the FDA did not approve this drug with any expectation of use beyond the approved indication."
"In fact, during the clinical trials... Neurontin was attributable to four people actually attempting suicide, two more having depression with suicidal ideations and twenty-two participants reporting depression so severe it required pharmacologic intervention.
"Additionally," he said, "nineteen of the seventy-eight participants who reported depression during the clinical trials had no prior history of depression."
"Even though the FDA knew Neurontin caused depression that may lead to suicide and that Neurontin's effects were never fully tested on people who suffered from chronic pain, bipolar disorder or other psychiatric conditions," he told Dr Katz, "the FDA acted with no urgency."
Mr Finkelstein reminded Dr Katz of the company's 2004 conviction for fraud in the DOJ case and said: "The complicity by the FDA in Parke-Davis's scheme to defraud physicians and consumers is more egregious than the underlying fraud itself."
"The governmental body charged with the responsibility of protecting the health and safety of Americans has done absolutely nothing to prevent entirely preventable deaths," he continued. "Such complicity borders on criminality," he added.
On October 14, 2005, Mr Finkelstein wrote another letter to Dr Katz and summarized the efforts by his law firm to get the FDA to warn people about the risk of suicide over 2 years and began by saying: "Due to the continued public danger facing a substantial class of prescription drug users, I am compelled to write to you regarding the FDA's ineffective oversight related to appropriate warnings for Neurontin."
"On March 31, 2004," he reminded Mr Katz, "you were advised of thousands of serious psychiatric adverse events that occurred while Americans were taking Neurontin."
"At that time," he said, "the FDA recognized a potential imminent health crisis existed, yet nothing was done to require enhanced warning labels."
"Due to the FDA's inaction," Mr Finkelstein continued, "my firm filed a citizen's petition on May 17, 2004 with the hope that the FDA would investigate the potential for Neurontin contributing to self-injurious behavior."
In addition to the black box warning, the Petition asked that a Dear Doctor letter be sent to health care providers cautioning them to be on alert for increased depression in patients taking Neurontin.
"The FDA took six (6) months to respond," Mr Finkelstein told Dr Katz, "and stated no decision had been reached and more time was needed to investigate."
"All investigations, if any," he wrote, "have been couched in secrecy and not open to public scrutiny while the same serious health crisis continues."
"Regrettably," the letter concluded, "this is an example of why the American people have lost faith in the FDA's ability to protect them from unsafe drugs."
"While your real motivations are not known at this time," he advised, "it is clear your interest is not in discovering the truth or protecting the health and safety of the American people."
Author, Dr Marcia Angell, also recognizes the massive influence that drug companies exert over the FDA, Congress, and doctors, and how this influence is harming Americans.
After she resigned as interim editor-in-chief of the New England Journal of Medicine in 2000, Dr Angell decided to write a book about the biases in clinical trials but in doing her research, says she discovered that "all roads led back to drug companies."
Her book, "The Truth about Drug Companies: How They Deceive Us and What to Do About It," provides an indepth account of the entanglements between Big Pharma and every area of the health care field including government agencies, doctors, medical journals, Congress, and universities, as well as how these relationships harm the public.
During an August 18, 2004 interview with Business Week Online, Dr Angell told reporter Amy Tsao, that she saves her harshest criticism for her fellow physicians and the medical profession as a whole. "After all," she said, "the industry is in business to make money, but that isn't what doctors and medical schools should be doing."
"They don't have to be in bed with the drug companies," she said. "But they are."
Dr Angell explained how drug companies finance most of the continuing education seminars for doctors, as well as meetings of professional societies, and how they lavish all kinds of gifts on doctors including dinners in fancy restaurants and trips to exotic resorts.
"And they provide speakers and meals for interns and residents in teaching hospitals," she told Business Week.
All of which, she says, adds to the high cost of prescription drugs. "The profession should acknowledge that this is all a form of marketing," she said, "which adds to the prices of prescription drugs."
"Doctors should take responsibility for their own education and buy their own meals," Dr Angell said.
The most perverse examples of off-label marketing involve drugging children. In 2001, Dr Stefan Kruszewski, a Harvard-trained psychiatrist working for the Pennsylvania Department of Public Welfare, began investigating the widespread off-label use of psychotropic drugs and found cases of what he calls "horrendous polypharmacy."
The first disturbing pattern he noticed was that an overwhelming number of patients were being prescribed Neurontin to treat conditions like anxiety, depression, psychosis and impotence. "The FDA had not approved using that drug for mental illnesses," he noted.
Dr Kruszewski found patients on as many as 5 medications at the same time, something he says is "hard to justify."
One of the most disturbing cases he found was a mentally retarded 15-year-old girl who was supposedly being treated for defiance and sexual promiscuity.
Dr Kruszewski discovered that the girl was on 11 different drugs, including five anti-psychotics, even though she had no diagnosis of a psychiatric disorder. "She was so overmedicated," he said, "that she had trouble getting out of bed or standing up by herself."
"Although physicians can choose to prescribe virtually any medication for any condition," he explains, "the promotion of Neurontin remains the subject of intense scrutiny since Pfizer's off-label promotion was previously the subject of civil and criminal penalties by the US Department of Justice."
"In my opinion as a clinical and academic psychiatrist," Dr Kruszewski says, "Neurontin's link to severe emotional and cognitive disturbances, including mania, depression, suicide and memory loss, continues to be the most egregious aspect of Neurontin's promotion."
"It causes suffering, morbidity and death," he noted, "problems that Pfizer and the current generic makers of Neurontin have failed to make known to consumers and potential victims," he said.
Attorney, Zena Crenshaw, Executive Director for National Judicial Conduct and Disability Law Project, agrees that off-label prescribing is a major problem and says any drug manufacturer even suspected of such "market expansion" should be called to the carpet.
"The idea of salesmen hyping drugs to doctors," she says, "for conditions beyond those for which the products were approved, is unnerving."
"Considering that even dire prescription drug warnings probably reflect a minimum level of adequate care," she warns, "prescribing drugs off-label should seem universally hazardous."
When Dr Kruszewski warned his superiors that off-label use of the drugs was not only harmful to patients but could also expose the state to liability from lawsuits by injured patients, he was told "it's none of your business."
When Dr Kruszewski continued to voice his concerns he was told to quit digging up dirt, and when he refused to let go, he was fired. He has since filed a whistleblower lawsuit against state officials and 6 drug companies including Pfizer, alleging, among other things, that the defendants: "through the use of political friendships, money and other emoluments, effectively achieved a level of influence with Pennsylvania's state government that allowed them to abuse state finances and state citizens with impunity."
The Government Accountability Project (GAP) is a nonprofit public interest group that promotes government and corporate accountability by advancing occupational free speech, defending whistleblowers, and empowering citizen activists.
The GAP is assisting Dr Kruszewski with his lawsuit against the drug giants. Mark Cohen, an attorney with the GAP, describes whistleblowers like Dr Kruszewski as "regular people who have been pushed beyond the limits their consciences can bear."
"They feel a moral duty to set the situation right," he says.
"They can no longer "go along to get along" in the face of wrongdoing," he explains. "And they can't simply opt out - take another job and keep their lips sealed - and ignore the wrongdoing," he says.
"But if "right" and "wrong" mean anything," Mr Cohen says, "they feel they don't really have a choice but to blow the whistle."
"Of course, they do so at great personal risk," he says. "Speaking up puts their current job in jeopardy and it threatens to brand them as trouble-makers with other employers."
In fact, people who do expose the highly profitable Medicaid fraud or off-label practices often find themselves fired, like Dr Kruszewski. However, the False Claims Act now provides a cause of action for whistleblowers with remedies that include reinstatement to their job, 3 times the wages lost, compensatory damages, and attorney's fees.