Tuesday, July 11, 2006

Off-Label Prescriptions

My readers have asked me to write about off-label prescriptions and to explain what that is all about.

So here's the deal.

An “off-label drug” is simply a drug used for a condition or in a manner not appearing on the FDA approved label.

The American Medical Association reported in 1995 that approximately half of all prescriptions were written for off-label uses and its hardly less today. Moreover, the General Accounting Office (GAO) has testified that 90 percent of cancer drug use, 80 percent of pediatric use, and 80-90 percent of drugs used to treat rare diseases are prescribed off-label.

Perhaps the best known example is aspirin.

For years, physicians prescribed aspirin to reduce the risk of heart attacks. However, the FDA did not approve such usage until 1998.

A less celebrated example is Fen-Phen. Both fenfluramine (“Fen”) and phentermine (“Phen”) were approved by the FDA for weight loss. However, doctors ignored fenfluramine’s labeling by having some patients use the medicine for more than a year when it was only labeled for duration of a “few weeks,” and by combining the two drugs even though neither label discussed using the drugs in tandem. Many patients suffered heart valve damage as a result.

We can identify three kinds of off-label activities – off-label use, off-label prescription, and off-label marketing.

Off-label use occurs when a consumer uses a drug in a manner inconsistent with its label. This entails changing the dosage amount or frequency, combining the drug with others, using the medicine to treat an unapproved condition, or giving the medicine to someone for whom it was not prescribed. It is nearly impossible to monitor for off-label use and congress has never attempted to outlaw its practice.

Off-label prescription, in contrast, occurs when a doctor prescribes a drug in a manner inconsistent with its FDA approved label. For example, a physician may prescribe a drug for a disease other than the ones listed on the label, in an unapproved dosage, for unapproved duration or in an unapproved combination with other medicines. The doctor may also prescribe the drug to groups, such as children or pregnant women, for whom the FDA has not approved the drugs usage. Congress has long deferred to a physician’s medical judgment to prescribe medicine as they wish..

The final category, off-label promotion, is regulated by the FDA. Manufacturers cannot market their products “for purposes, to users, in dosages, or in combinations other than FDA-approved ones." While recent legislation has created certain exceptions to this blanket prohibition, the promotion of drugs for off-label uses remains highly regulated and has resulted in the drug indusry paying billions of dollars in fines.

It must be stressed that there is no doubt as to the legality of off-label use or prescription for most drugs. (There are a few exceptions to this rule, such as growth hormone, where distribution for off-label use is a criminal offense.) The illegality concerns the appropriateness of prescription drug manufacturers promoting off-label aspects of their product.

The GAO reports that off-label use often represents “state-of-the-art” treatment, and the FDA asserts that “good medical practice and patient interests require that physicians use commercially available drugs, devices, and biologics, according to their best knowledge and judgment.”

Furthermore, one should be careful not to interpret the phrase “unapproved use” to mean “disapproved use.” The FDA does not take a position on the safety of an off-label use; rather, the agency leaves that determination to the individual doctor as part of his or her practice of medicine.

This position has been stated repeatedly.

For example, in a 1972 pronouncement, the FDA declared that once a drug has left a manufacturer’s warehouse a “physician may, as part of the practice of medicine lawfully prescribe a different dosage for his patient, or may otherwise vary the conditions of use from those approved in the package insert. Ten years later, the FDA again stressed that off-label use is accepted medical practice, and FDA approved labeling should be used for informational purposes only. Physicians have embraced this freedom and off-label drug use has become an accepted method of treatment for many diseases.

1. Beck, James M. and Azari, Elizabeth D. 1998. FDA, Off-Label Drug Use, and Informed Consent: Debunking Myths and Misconceptions. 53 Food, Drug, Cosmetic Law Journal 71.

2. Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration 2003. Oncology Tools: A Short Tour. www.fda.gov (accessed June 15, 2004). www.wada-ama.org

3. Harris, Gardener. 2004. Pfizer to Pay $430 Million Over Promoting Drug to Doctors. New York Times, May 14, at C5.

4. O'Reilly, James O. and Dalal, Amy 2003. Off-Label or Out of Bounds? Prescriber and Marketer Liability for Unapproved Uses of FDA-Approved Drugs. 12 Ann. Health L. 295-324.

5. Salbu, Steven R. 1999. The FDA and Public Access to New Drugs: Appropriate Levels of Scrutiny in the Wake of HIV, AIDS, and the Diet Drug Debacle. 79 Boston Univ. L. Rev. 93 (1999).

6. Tabarrok, Alexander T. 2000. Assessing the FDA Via the Anomaly of Off-Label Drug Prescribing. The Independent Review V(1):25-53.

7. U.S. Food and Drug Administration 2000. Decision in Washington Legal Foundation v. Henney. 65 Fed. Reg. 14286 (March 16).

8. 1972: Legal Status of Approved Labeling for Prescription Drugs; Prescribing for Uses Unapproved by the Food and Drug Administration, 37 Fed. Reg. 16503, 16504 (July 30).


Anonymous said...

So basicly, the practice of off-label prescription isn't really illegal itself unless certain complication does occur??

I don't know about others, but it feels a bit wierd to hear this.

Anonymous said...

My experience as teacher and patient, and friend of two pharma salesmen, leads me to believe that folks tend to trust doctors entirely too much when it comes to drugs. They don't say "ask your pharmacist" for nothing. Choosing your pharmacist is at least as important as choosing your family doctor. Find one you can trust.

Too many doctors have been influenced by drug pushers or not kept up with the lastest on the drugs they prescribe. In defense of doctors, there's a lot to know.

On the other hand, although not a very scientific study, I found pre-pharma students to be much more humanitarian than pre-meds in general. Most of the pre-meds I dealt with were obsessed with money and/or grades. Kinda scary.

Anonymous said...

Here is a short-list of some off-label prescription drugs. Click the drug name to see what the FDA-approved uses are.

Anonymous said...

Fascinating discussion. So I wonder about how this off labeling begins anyway.

IF a product is designed for one thing and another use is found, then why not simply get the permission for that usage?

I won't pretend to understand the legalities involved but it seems as though it can't be that difficult to do. IF a medicine can be shown to be effective in another use, it would appear to be in the best interests both of the pharma company and in the patient's.

Sorry but my thinking isn't it's best sometimes in areas I have no idea of or expertise in.

shooter said...

Hello, everyone. If I may, let me give you my take on this discussion.
1. I have tried for many years, to no avail, to find a reference guide in finding a "good" doctor, dentist, lawyer, etc. There is no "consumers guide" for the professions, as far as I know. The only people who "know" who they are are other doctors, dentists, lawyer, etc, and they're not talking.
2. Having grown up in a home with a doctor, my father, I can tell the ladies out there, don't marry one. Unless, you're willing to make an appointment weeks in advance to see him. The study necessary to keep your life and death skills current never stops. When my father died, the books and medical literature was stacked to the ceiling in his study, and like the rabbit in "Alice in Wonderland" he always had to hurry, hurry, hurry to read them as soon as possible.
3. Most pharmacists today work for the large chains (turnover is incredible) where they're overworked, underpaid, and under constant pressure to keep the lines moving.
4. All corporations, including pharma, do not work for you and me. They are responsible to their owners, the shareholders, who rightly expect them to maximize profits, hopefully legally and ethically.
5. The real villains in this story are the Government and the HMO's. The Governments goal is elections and re-elections and the the HMO's is hoping you die early.
6. My apologies for #2 above. I, of course should have said spouses, as there are greater and greater numbers of women joining these groups.
7. Finally, all of these groups have different agendas. As our founding fathers knew so profoundly, nature shows that all people will strive to gain advantage over others. That's why they spent so much time and energy on putting safeguards into the Constitution. Competition is the lifeblood of advancement, but you need a referee, with a whistle to keep it fair.

And that's why our country is in such mortal peril today.

Peter Rost said...

Shooter, I think you nailed it!

shooter said...

Thanks, Sir. And Beeta, I wouldn't be so hard on "we the people." The more I read about the formation of our country, the more I'm convinced that, like the formation of the universe, it was a coming together of factors unparalled in recorded history. The agony, the fights, the debates were just fabulous. Every experience each of them brought to the new world was different. Religous freedom here, Debtor's prison there. Strong central government, strong states rights, slaves, women, representation, armies, militias, morality, personal freedom, and on and on. When they finally were ready to sign the document, more out of fatigue than anything else, nobody could say that their interests were not considered and debated. It was about as good a document that man had conceived up until that time.

The words, they had down on paper. That was the easy part. Every precaution, every experience, every fear, they considered. More than anything else, they feared the inevitable human urge to accumulate power. Thus the incredibable system of checks and balances was put into place. In almost every word, starting with the first words, "We the people," you can feel the reverence for personal liberty, they wanted to protect for all time.

Since all power was to be vested in "the people," it was imperative that "the people" were smart enough and educated so that they could make informed decisions. Thus, only landowners were given the right to vote inasmuch as they had the wherewithal to hire teachers and form schools for their children.

So what happened? The founders had considered every possible contingency known at that time. And for about 100 years they were proven right. Millions of people, free to pursue their dreams, piloted this country to heights never before even dreamed of. But, and there's the stick in the eye, they didn't think of "The Corporation." Once formed, they quickly metastized, exponentially in wealth and inevitably, power. The rest is history. They bought our representatives, our media, and more recently, our Executive and Court.

Any psychiatrist will tell you, that with enough money, you can convince people that dogshit is filet mignon and that an uneducated, uncurious, unread, untraveled, conflicted failure and ne-er do well should lead the greatest democracy in history.

Anonymous said...

Corporations don’t have to be evil they choose to be. Then again, WE don't have to consume so damn much either; they exist because we pay them to exist. We put our money into them, sometimes voluntary, sometimes involuntarily, but it's all the same because there is only one thing they can really tax us on, our labor since most of us don't really own anything because we buy everything on credit. Here's the kicker, corporations can't exist without labor, so they trick us into believing that we need their service. The dilemma arises when the corporation must produce its service. The way you can tell between a good corp. and bad corp. depends on the workers ability to afford the product he/she produces. Globally, workers are getting screwed.
People can't always fight if they are starving. The idea of making Profits is truly underrated, we don't talk enough about profits and who gets what. People get real testy about their money don't they? I do. I get even testier about my labor. It is out of sheer greed that these companies complain about providing healthcare and adequate pay as if having healthy workers was a loss not an advantage. Labor is so cheapened that it's like these corporation s don't have shame any more. I’m tired of being a "slave on this global plantation." The thing with slaves is that they can be bought, hence, our politicians and judges.
So glad our constitution keeps us free.

Anonymous said...

1. The "average" US citizen is a scary animal, indeed. I find them extremely hard to educate. I, for one, simply don't have the time nor the patients (really, there was no pun intended there, I swear).

2. Capitalism is not working for the masses, nor was it ever probably intended to work for anyone other than the "haves".

3. Many very good people (one of my Pharma sales friends for one) will sell you out to make their living in this system. I once asked him how he liked his career. He said he really enjoyed it, except when he was pitching one of his company's drugs, knowing all the while there was a much better choice available from another company. Personal financial secrurity will win out over the "good of the people" almost every time. Many of those who maintain their integrity very likely end up unemployed.

4. Waiting for the masses to save us is going to take a lot of patients (see #1).

5. Go back and read "1984" again". I think that sums it up rather well.

shooter said...

Beeta, I hope you didn't misconstrue what I was saying. I agree with just about everything you said. You're absolutely right that the founders didn't trust anyone, certainly not the President, the Legislators, nor the Courts. While the engine of our form of government, the three co-equal branches, worked pretty well, they absolutely knew they inevitably would become corrupted over time. That's why they bet the ranch on oversight vested in "WELL EDUCATED and INFORMED VOTERS," AND, a "FREE, FEERLESS PRESS."

I think our downturn leading to today's catastrophe happened something like this:
A. Their fears were realized pretty quickly vis-a-vis the President and Congress, just through human nature.
B. The second to go bye-bye was an educated population. In the 1950's and 60's, we had the best educated kids in the world, statistically certifiable. Then came the tumult of the Viet Nam War, the rise of Liberalism, and then in 1980, the Conservative backlash. "The Reagan Revolution," gave us de-regulation and the beginning of the "dumbing down" of our schools. Since the Conservative goal has always been to organize wealth and power into the hands of a select few, an educated citizenry was anathema to their plans.
C. As luck would have it, in 2004 the good voters of Ohio made a wonderful "Christian" choice and decided that preventing two gays from kissing in San Fransisco trumped their children's health care, and we got a swaggering chimp to lead us.
D.De-regulation ran amuck, all the safeguards meant to protect our way of life, were fed into the shredder. The inmates were allowed to purchase their guards, and the last bastion of protection forged by our fore fathers, a free and feerless press, said "asta-la-vista" "see ya in Aruba."