Off-label prescribing of medications is a huge problem.  On January 15, Eli Lilly agreed to a settlement that required the company pay $1.4 billion to settle criminal and civil charges that it illegally marketed the antipsychotic drug Zyprexa for off-label uses in patients at high risk to experience harmful and devastating side effects. Among the charges, Lilly has been accused of a scheme stretching for years to persuade doctors to prescribe Zyprexa to pediatric and geriatric patients – two patient groups for whom the drug was not federally approved.  In one marketing effort, the company urged geriatricians to use Zyprexa to sedate unruly nursing home patients and in another charge the company pressured pediatricians and family practitioners to prescribe the drug to manage disruptive children, even though there was a confirmed tendency of the drug to cause severe weight gain and metabolic disorders that is particularly pronounced in children.

But thanks to the Bush administration and an 11th hour rule change, the problem of off-label prescribing is likely to get much worse.  

As the sun was setting on the Bush administration, new guidelines to make it easier for pharmaceutical companies to promote off-label uses of prescription drugs were finalized  in spite of objections and warnings from other agencies.  The most notable criticism came from the Department of Veterans Affairs, which said the change “favors business interests over public safety” and warned that the new rule could lead to a “decline in drug safety.”   The rules were devised and adopted over the objections of state and federal law-enforcement experts that want the FDA to crack down on off-label marketing of drugs.  

As the Obama administration reviews all the midnight rules that the departing Bush administration issued, it will have to decide whether to try to modify or reverse this last-minute change in the FDA’s oversight of off-label drug marketing.

Congressional leaders from both parties criticized the guideline when it was proposed last year. Sen. Charles Grassley, an Iowa Republican who’s repeatedly investigated the FDA, said he had serious concerns about the proposal, which he said would deem appropriate something that “the FDA once considered evidence of unlawful marketing.”

“A legislative fix may be in order,” Grassley said Thursday.

In the House of Representatives, Rep. Henry Waxman, a California Democrat, called the guideline a “long-coveted parting gift” for the pharmaceutical industry that “fundamentally undermines” the FDA’s authority.

The use of drugs “off-label” – for reasons the FDA hasn’t approved – has long been tolerated, and sometimes encouraged. For certain ailments, it can be helpful.

The practice also can be dangerous, however. Nearly every drug has side effects, some of them serious. Those risks can be worth the potential benefit that comes with an FDA-approved, on-label use. With an off-label use, however, the risks remain but the benefits are far less certain.

Off-label prescribing is perfectly legal for physicians, who have extensive training and access to the latest medical research.  However, it is illegal is for pharmaceutical companies to market off-label uses.  Yet over the last five years, federal prosecutors and state attorneys general have brought over a dozen cases against the manufacturers of prescription drugs for marketing their drugs off-label.  Those prosecutions have yielded over six billion dollars in criminal and civil penalties.  “The FDA has been abysmal policing this area,” said Connecticut Attorney General Richard Blumenthal. “One reason the states have been more and more active is that the federal government has been asleep at the switch.”  

The problem is, the system has become corrupted and drug companies do their own “research,” get it published, and then promote the off-label uses that their “research” showed was effective.  A really common one is to prescribe antidepressants for pain management.  I refused to take Cymbalta along with my anti-inflammatory and pain management meds because I can not see where changing my neurochemistry would have any effect on my degraded and damaged knees.  He got pissy when I questioned the wisdom of the drug makers – and I got a new doctor.  Within the first five minutes of meeting him, I told him to make sure to put on my chart in big letters that I refuse off-label uses, and in fact, given that my only health problems are annoyances more than illnesses, I prefer to stick with drugs that have been around long enough to have generics available.  When he found out I did some of the peer review on Rezulin, Vioxx and Baycol, he realized exactly where I was coming from.

The FDA – the agency that prevented the tragedy of thalidomide back when it was empowered – has become a tool of the companies they are supposed to regulate.  

Blumenthal, mentioned above, was one of the prosecutors who brought the case against Cephalon Inc., and the Cephalon case is not merely illustrative, it is infuriating.

 At the start of the decade, Cephalon was a relatively small drug maker, and its three main drugs had limited audiences: for epilepsy, for the sleep disorder narcolepsy and for cancer pain.

So the company launched a “highly organized” and “concerted plan to maximize revenue by the off-label marketing” of the drugs, Gabitril, Provigil and Actiq, according to the government’s trial memorandum. The off-label marketing “was no accident . . . . The very top levels of the company knew and approved of these efforts,” the memorandum says.

Cephalon sales representatives were trained to encourage off-label marketing, sweet-talking doctors at lavish resort gatherings and rewarding them with consulting contracts, prosecutors said. Their income was dependent on high off-label sales.

Actiq, for example, was designed for cancer patients with extreme pain. Cephalon told its sales staff to pitch the powerful drug to general practitioners, not just to cancer specialists.

“Any patients suffering from moderate to severe episodic pain due to migraine headaches, sickle-cell pain crises, etc., are potential candidates for Actiq,” a 2002 sales strategy said.

It paid off. “The sales of Actiq doubled, tripled, quadrupled. As much as 80 percent of the sales of Actiq were off label,” said Laurie Magid, the acting U.S. attorney in Philadelphia.

Actique is the brand name for the drug generically known as fentanyl, and fentanyl is one of those drugs that healthcare workers view as a necessary evil.  It does a good job of controlling severe pain – but it is highly addictive, and an opiate, it is a strong CNS depressant, and it is easy to achieve a fatal overdose.  Fentanyl overdoses kill hundreds every year.  

The Bush FDA issued the new guidance over the objections of Bush’s Department of Veterans Affairs, which pays for drugs taken by its health-system patients.

“We urge the FDA to withdraw” the proposal, the VA wrote the FDA last year. “It will not improve drug safety and could very well result in a decline in drug safety.” Among other things, the VA said, “second-rate ‘studies’ published in journals with questionable peer-review processes will be used to convince physicians to use drugs for an ever-increasing number of unapproved uses.”

Two researchers writing in the Journal of the American Medical Association echoed those comments, saying that medical literature is often the victim of manipulation.

Beyond that, the attorneys general of Illinois and Oregon complained of a “disturbing pattern”
of drug companies “aggressively building market share based largely on off-label marketing campaigns that rely on widespread distribution of selected articles.” The FDA, they argued, should boost oversight, not lessen it.

So of course, the Bush administration, on their way out the door, did just the opposite.  

Every day I am more and more relieved that those terrible, horrible, craven thugs are gone.

Next time you go to your doctors office, look around.  Count the items you see in the lobby, the nurses station and the exam room that advertise drugs and pharmaceutical companies.  Five will get you ten that you are offered a prescription for the most prevalent drug or a drug from the company with the most prevalent advertising in the practice.  And every time your doctor offers you a prescription, ask the following questions…

  1. What is this prescription for, specifically?
  2. Is there a generic equivalent, and if not, is there a medication that will work just as well that has a generic equivalent?
  3. Are you prescribing this medication for off-label use?
  4. If so, why this drug, and who funded the research that promoted the off-label use?

Me personally?  If I don’t get satisfactory answers to those questions, I refuse the prescription.