Health
Part 1 of 3 parts; Off-label prescribing of prescription drugs: Profits for big pharma and risk to patients
By Evelyn Pringle
Online Journal Contributing Writer


May 30, 2006, 00:54

The off-label prescribing of drugs has become a serious problem over the past decade. Doctors are adjusting dosage levels and prescribing drugs for medical indications and treatment durations for which the drugs were never approved or intended.

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 seven 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 percent 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 percent, 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 percent 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 have led to the discovery of a drastic increase in off-label prescribing to children and the elderly of drugs never approved for use in children and the elderly.

One class of drugs found to be prescribed off-label most often without scientific support are psychiatric medications. In 96 percent 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 between1998 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 hanged 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 percent of the millions of dollars in campaign contributions by drug companies went to Bush and Republican candidates and 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 drug when the warning said that taking the two drugs together should be avoided, and in about 90 percent 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 the10 top FCA Medicaid fraud recoveries to date, the top five 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 percent 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 two 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.

Part 2: Tactics Pfizer used in promoting off-label use of Neurontin