FDA regulation and non-approved use of drugs

The other day, I happened to be talking to Mark, a sales representative from one of the pharmaceutical companies.  He’s the type of rep that many doctors don’t mind seeing – someone who is careful of your time, is happy to hunt down the answers to questions that come up on the medications his company makes, and brings by useful information about new drugs that seem to be practice-appropriate.  He looked slightly drawn.  I knew that he was covering a bigger geographic area because so any of his colleagues have been laid off in the past few years.

“I’m glad to see you.” I said.  “I wanted to ask if you knew anything about the use of [drug X] in acne.  I was reading somewhere the other day that it might be useful in some tough-to-treat cases that tend to scar.”  Mark’s normally warm smile disappeared in an instant.  Something akin to terror flashed in his eyes.  He backed away just a bit.

“I can’t … I can’t tell you anything about that,” he stammered.  “It’s not an FDA-approved use of the drug.  I could lose my job if I say anything about it.”

And so he could.  Despite the fact that using his company’s treatments for this purpose is perfectly legal and, according to a number of good studies, both safe and effective.  My simple question had run afoul of one of those regulatory potholes that characterize the Road to Hellth.  This one has to do with the “off-label” use of medications.

In the real world, it’s terribly difficult, expensive and time-consuming to get a new (or old, for that matter) drug approved by the FDA.  To do so one has to submit reams of data showing that the medication is safe and effective for the treatment of a particular and specific illness.  In FDA-speak, a disease or condition and specific set of circumstances for which you’ve demonstrated the drug’s effectiveness is called an “indication”.  Once the drug is approved, the manufacturer can advertise its use to your doctor for that indication.

How difficult and expensive and time-consuming can it be?  Very.  The cost and time required to get from the initial clinical trials to simply submitting a drug for FDA approval averages about $125 million and 6-11 years.  Once the final application is submitted it then takes an additional 1-2 years for the final decision to be made.  The overall probability of success in the whole process is only about 9%.  This process has to be repeated for every separate indication that a manufacturer might wish to have approved.  All of these costs are tacked onto the price of drugs that ultimately reach you, the consumer.

Under the circumstances it should be no surprise that most drug makers would rather be attacked by alligators than submit multiple FDA applications for all of the different uses a given medication might have.  As a result, the vast majority of new drugs are just approved for the one or two major indications that seem to represent the biggest market.

In the real world, the fact that a drug is approved for one use doesn’t necessarily mean that it’s not also useful for lots of other medical problems.  For example, Botox® was first approved in 1989 for use in treating eye muscle spasms.  It wasn’t until 2002 that the FDA approved it for treating wrinkles, even though doctors started using it for this purpose in the early 1990s.  Using a drug for an indication that isn’t approved by the FDA is perfectly legal.  As one medical malpractice insurer explains on their website:

“Once approved, a drug product may be prescribed by a licensed physician for any use that, based upon the physician’s professional opinion, is deemed to be appropriate…

The FDA recognizes that off-label use of drugs by prescribers is often appropriate and may represent the standard of practice. In today’s medicine, many pediatric uses are not on a label. The reason for this off-label practice is the issue of drug or product testing experimentation in children. Many standard treatments in oncology and HIV therapy involve off-label use of medications. There are no rigorous data available on the extent or profile of off-label uses.”

This sort of thing is incredibly common, and even necessary in order to provide good care.  In the area of dermatology, about one-third of all prescriptions written are for an non-FDA approved, off-label use of the drug prescribed.

Despite the practical importance of off-label prescribing, it should be obvious that its very existence creates problems for the folks at the FDA.  If many or most drugs can be used for non-approved usage, doesn’t that undermine their regulatory authority?  If their job is to control access to medical treatments by means of the approval process, how can they allow patients to be treated without their approval?

In response, what they’ve come up with is modern American medicine’s equivalent of “don’t ask, don’t tell”, but with a twist: multi-million dollar fines for conspicuous telling, and a weird attempt to recruit every doctor in the country as an FDA informer.  Welcome to the Truthful Prescription Drug Advertising and Promotion, or the “Bad Ad” Program (BAP).

The basic policy behind the BAP is that while off-label indications exist for many drugs, drug makers can only talk about them if they’re willing to fork over the money for FDA approval first.  Otherwise the FDA will slap them with huge lawsuits and fines.  It did just this recently for drug makers Allergan and Novartis, and collected billions of dollars in the process.  And it wants every American doctor to sign on as an unpaid FDA tattletale.

No wonder Mark is paranoid.

Here’s the recruitment material from the FDA website:

“The Prescriber’s Role – Recognize and Report

FDA’s educational outreach program is designed to educate healthcare providers about the role they can play in helping the agency make sure that prescription drug advertising and promotion is truthful and not misleading.

The “Bad Ad” Program is administered by the agency’s Division of Drug Marketing, Advertising, and Communications in the Center for Drug Evaluation and Research. It will help healthcare providers recognize misleading prescription drug promotion and provide them with an easy way to report this activity to the agency.”

And here are some concrete examples of the behaviors that the FDA is looking to stamp out in the public interest:

Examples of Violations

Example of Omission of Risk

You attend a speaker program which features a slide show that presents efficacy information about Drug X, but no risk information.

This presentation would be misleading because it fails to include a fair balance of benefit and risk information for Drug X.

Example of Unapproved Use

You are in a commercial exhibit hall and a company representative tells you that a drug is effective for a use that is not in the FDA-approved product labeling.

This presentation would be illegal because it promotes an off-label use.

Example of Overstating the Effectiveness

‘Doctor Smith, Drug X delivers rapid results in as little as 3 days.’

This presentation is misleading because the majority of patients studied in the clinical trials for Drug X showed results at 12 weeks, with only very few showing results in 3 days.

Finally, there’s the pitch to be a snitch:

What You Can Do: Recognize & Report

The prescriber can play an important role in ensuring that prescription drug advertising and promotion is truthful by recognizing and reporting misleading drug advertising and promotion.

Recognize –

Be aware of the many advertisements and promotions that you see every day.

Report –

Help FDA stop violations by reporting activities and messages that you consider false or misleading.

Frankly, I find the whole thing to be somewhat bizarre.

Let’s say you’re a doctor.  Presumably you’re grown up, and can read and evaluate information as well as the next person.  You have patients who are failing all of the “approved” therapies, and would like a drug company to share with you whatever information that they might have about a promising off-label use.  If they answer your question it’s a crime and you’re supposed to squeal on them to the FDA.  But if you ask the same question of anyone else in the world, it’s not?

Now let’s look at the patient’s perspective.  You have a medical problem that’s not responding well to conventional therapy.  Wouldn’t you want your doctor to know that there are off-label alternatives?  Would you really care who told him/her about them?

Of course the FDA does have a responsibility to the public to ensure that medications are safe and effective, but isn’t the most important barrier here the incredibly high cost and time involved with securing approval?  Isn’t it perhaps worth an investigation to see whether something can be done to address this root cause of the problem?

Personally, I’m going to hold out for a bounty for each drug rep I turn in.  If they make it high enough, it might be more profitable than actually providing those stuffy old healthcare services.

Doug Perednia is an internal medicine physician and dermatologist who blogs at Road to Hellth.

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  • http://www.stevebalt.com SteveBMD

    I agree the whole situation is ridiculous. Here’s a radical solution:

    1. Change the FDA approval process so they approve drugs on the basis of safety ONLY, not efficacy or indication. This would be far less costly for the drug companies and would emphasize the FDA’s role in the protection of patient health.

    2. Require drug companies to publish or distribute ALL data regarding the effects of their new drugs on animals and humans. (And since they’re not “going for an indication” anymore– see #1– they will have the resources to do a wider range of tests on each new agent.)

    3. Give the doctor the ultimate authority & responsibility to review the data and make a treatment decision. I agree a doctor should be “grown up” and able to read, but he/she should also be able to critically evaluate data. Today, we abdicate that responsibility to drug companies’ marketing departments, legal teams, and sales reps. None of them went to med school, and they lack the clinical experience of MDs, so why do we trust them to make decisions about our patients?

    Sure, this process may result in more drugs being approved, all of questionable efficacy. And I don’t know how prescription drug plans would deal with the lack of “FDA-approved” indications. But I would predict that it would result in doctors making more effective treatment decisions, and drug companies devoting resources only to drugs that they felt would be advantageous in real-world patients, not just to those for which they can get a specific “indication.”

    • pj

      The FDA used to approve based on safety only, with the result being huge $$$ spent by desparate pts on meds w/at best, questionable efficacy. Dr. kene below notes this as well. Never underestimate profit motive.

  • Oncology Pharmacist

    You’ve presented a maddening situation, but it’s inaccurate. Mark can respond to your unsolicited question about an off-label use. That is not promotion. He has always been able to do that and still is able to that. (Of course, one issue is whether or not his company has provided him any training on that use or not, but that’s another matter.)

    You say he’s always been able to seek information for you, and he still can. In fact, there is an entire department at his company called Medical Affairs or Professional Services that can and will provide you with off-label information; this group usually consists of pharmacists, nurses, or even other doctors. They are then to respond to unsolicited requests for medical information.

    In the Bad Ad example, the rep is in *trouble* because he approaches the doctor with the off-label information; that is promotion. The key to all of this is who initiates the conversation.

    Of course, I suppose some reps could be fearful that a doctor will turn on them. I suppose a doctor could ask an off-label question, receive the information, then contact the authorities at Bad Ad! But I don’t think that is what you or Mark had in mind in this situation.

  • Dr. Kene Mezue

    @Steve…if we stop the FDA from ensuring efficacy (ie. only dealing with safety), then Big Pharma will start ripping the public off big time…they’ll tout a lot of ineffective medication which may be safe (remember oral glucosamine for osteoarthritis? the FDA saved us from that rip off) just to make money…and take patients money…analogous to what the guys in alternative medicine and homeopathy do most of the time.

  • http://www.roadtohellth.com Douglas Perednia

    Oncology Pharmacist…I assure you that the story is accurate with respect to Mark’s reaction. Whether he could technically give me the information that I requested or not, he’s been told that he’d darned well better not give out ANY information about non-label uses at the risk of losing his job. The reality is that the aggressive “rat out a rep” campaign by the FDA has had a chilling affect on the dispersal of knowledge. Also, the line between what is allowed and not allowed is not always a bright one. Sure, I might ask “Has product X ever been used successfully for condition Y?” But I’d have to know to ask. However, if I were to say “I’ve tried X, Y and Z on this patient without response, do you have anything that would help?”, can the rep volunteer the information about an off-label use? He/she is not going to want to find out the hard way. All of which means that the information is not going to the clinician who is actually taking care of the patient.

  • http://www.somebodyhealme.com Diana Lee

    Good article. As someone with a highly treatment resistant chronic condition this issue is very important to me. We have to find a way to balance safety concerns with the needs of patients like me who need a wide range of options.

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