Off-label prescribing vs. RCT

Incidentally, another thing that’s fascinating to me is that, there’s a very funny saying when it comes to the ethical review of science, or an anecdote, which is that if a doctor wakes up in the morning and decides that, for the next 100 patients with cancer that he or she sees that have this condition, he’s going to treat them all with this new drug because he thinks that drug works, he can do that. He doesn’t need to get anyone’s permission. He can use any drug “off-label” he wants when, in his judgment, it is helpful to the patient. He’ll talk to the patient. He needs to get the patient’s consent. He can’t administer the drug without the patient knowing. But, he can say to the patient, “I recommend that you do this,” and he can make this recommendation to every one of the next 100 patients he sees.

If, on the other hand, the doctor is more humble, and more judicious, and says “you know, I’m not sure that this drug works, I’m going to only give it to half of the next 100 patients I see,” then he needs to get IRB approval, because that’s research. So even though he’s giving it to fewer patients, now there’s more review.

That is from Nicholas A. Christakis, via Jim Olds.  The discussion is mostly about Big Data.


So, there is more review when the doctor is less sure . .

There is more review if the doctor applies scientific rigor instead of just his gut feeling.


How about, there is more review if the doctor says he is going to apply scientific rigor, because it may seem easy for one doctor to adequately design a statistically valid trial, down to details such as proper blocking, double blinding, determining the relationship between sample sizes and power, and defining end points, but most doctors aren't good at those things and so the trials they made up would not actually be scientifically rigorous, despite what they may think and despite what they tell their patients.


Not at all. The post confuses an experiment versus an essentially established protocol, just not formally authorized.

Off-label use is emphatically not "doctor wakes up in the morning and decides". Off-label use is usually an application enjoying broad consensus among the medical fraternity (and possibly strong pharmacological grounding too ), just that no body has deemed that specific application to be worth the cost and effort of a formal FDA review.

That's right. If we want to bring doctors into what passes for science we could pay them. Since we do sort of pay them we have to make sure they aren't experimenting on people without their consent.

It's actually the reverse. An experiment is usually between something they are sure will work and something they are sure won't. We could also try paying the patients being used in the experiment. We sort of do by limiting and then granting their access to clinical trials and experimental drugs.

We could also compensate people for participating in what passes for science by making it easier, but that wouldn't raise the status of the people that pass for scientists.

No, it is not between something we "are sure will work" and something we "are sure will not work".

It is between something we "believe might work" and something we "are sure will not work."

This is why proper experimental protocols and statistical analysis have the null hypothesis.

Fair enough. A lot of prescription is part of the mis-diagnosis to diagnosis process because if you knew exactly what the patient had and that they'd respond exactly by-the-book to the well-established highly documented treatment then medicine would be as easy as some people assume it is.

Often the null hypothesis isn't "the drug doesn't work." It is, "the drug doesn't work any better than the conventional pill." Then you are comparing "what we aren't sure will work" and "what we are sure will work ... but not as well as we'd like."

There is more review when the doctor is attempting to find an answer to an uncertainty than when he or she has a well-informed and educated belief about the best course of action.

Or the doctor gives it to the next x number of patients, then compares the results using the records of the same x number of previous patients to compare outcomes.

And the difference between doing it like this compared to the other described way is that latter one sounds seemingly outrageous, while the former sounds boringly prosaic.

There is more review if the doctor applies scientific rigor instead of just his gut feeling.


Isn't the doctors personal liability exposure higher for off-label use, than if he goes the IRB route? That's the downside of quick-n-dirty.

The IRB is not to review the doctor, folks.

1. Off-label prescribing does not require informed consent. And the doctor does not usually bother discussing it before prescribing.

2. There is a big difference between a doctor using a drug off-label because he is convinced there is a benefit to it and a systematic investigation where the sponsor and the participating physicians really do not know what the effect will be.

Thank Christ, Jan.

Even if a doctor doesn't know it works there is a difference between doing his best for the individual versus running an experiment.

Yup, and that is why one is regulated research and one is just treatment.

I would personally love to make doctors better adhere to actual evidence, but gut feelings and anecdote are the true drivers of innovation, right?

Okay, that's the Jan I know ;O

One is the doctor doing his fiduciary duty to his patient. The other is doing a service for the public.

Just wondering, what does "fiduciary" add to the sentence? It's stii pretty morally binding as duty.

I didn't know a better word.

A doctor trying to get his name on a publication will give people syphilis. We don't want that. That's my only point.

Insurance companies tell doctors what to prescribe by limiting reimbursement, so doctors really aren't as free to off-label prescribe as one would think. least for the lucky few rich patients that don't have to dance to the tunes of the insurer.

And if the doctor does off-label prescribe or prescribe a more expensive option, the decision must be justified to the insurance company with boatloads of paper work and hassle. It's enough to keep most doctors on the straight and narrow, for better or for worse. Physicians controlled treatment 50 years ago, but those days are long past.

And? It would be fine for a doctor to say "I think this is the best treatment, but you can't afford it." Let's think clearly about the delineations between financing, patient-doctor relationship, expertise, science, standard-of-care vs diagnostic trial-and-error, etc. rather than using how we have in the past blurred these lines as excuses to further blur them.

It depends. About 1/5 of prescriptions are for off-label uses. Most of the insurance control is via formularies, steering utilization to generics or a single preferred branded within a therapeutic class. Insurers are most concerned with whether the drug is expensive, not always whether it is for an approved use. You see the most stringent prior authorization requirements with specialty drugs, stuff than can cost tens of thousands of dollars per year.

Private insurers are happy to cover cheaper off-label prescriptions. Unfortunately some medicaid programs etc. will instruct docs to prescribe more expensive meds rather than cover a cheaper one off-label. Off-label uses fairly often have stronger scientific support than many FDA approved uses.

If insurers are consistently denying payment for off label uses and there is more evidence for the off label uses than on (not sure I believe this), then I think drug makers would return to FDA to add an indication to the label. It would give them the ability to legally market it for that indication.

You have a drug that is off patent and now made by 3 competitors. Are you going to spend 150 million dollars to get FDA approval for a new indication that might increase sales by 100,000 prescriptions per year? Oh and the generics are probably sold at Walmart, Target etc for four dollars.

Private insurere do not consistently deny payment for cheap drugs prescribed off label! They will however often use a drug being off-label as a reason to deny payment for an expensive drug even when there is copious data to support its effectiveness and safety. For instance Savella....FDA approved for treating pain....not FDA approved for depression...but effective and approved for depression in many nations.

That makes sense about the lack of market exclusivity for off-patent drugs. So if insurers (I read "medicaid programs etc." as insurers generally, but let's just say it is Medicaid only) are denying prescriptions for off-label uses of off-patent drugs, then you would hope they have a very good efficacy reason to do so, as it would not cost them much to cover those products. I have not heard of this and don't know for what specific drugs it is a problem, but it would be good to know why this happens in Medicaid and not private insurance.

On your statement re private insurers, I'd have to go back to my original point. If there is copious data supporting the efficacy of an expensive drug for off-label uses, you have to wonder why the company hasn't gone back to the FDA to expand the labeling indication. In this case I do see insurers using off-label as an excuse to not cover, but if the drug is on-patent and expensive why isn't the company leaving money on the table?

If you have four years left on patent, and expect it to take three years to get a new FDA approved indication you probably will not bother even for a costly drug. Now if you have ten years left on patent you very well might. It depends on the number of potential new customers for the new FDA indication and the time left on patent.

I thas to be a complicated calcualtion also factoring in how many, if any other drugs may already have an indication for the new use you want the FDA to aprove your drug for and how widely is the drug already being used off-label.

I'm looking forward to reading the article, but my initial response:

The review is because in an RCT the patient doesn't actually know which treatment she's getting.

Conflating an RCT with a doctor's private practice is a straw man.

I can't understand off label use.
For Type 1 diabetes, there is a device that measures glucose levels continuously, if less accurately than a blood test (which you do in addition to using the device). It is approved only for groups of older kids and adults, but since Type 1 is harder to manage in young kids it is widely used off label in that population. I don't even understand why a prescription is needed for this device, since you don't need a prescription to buy other measuring devices like thermometers and blood pressure cuffs.

Conversely, there's a line of research for Type 1 that uses the TB vaccine, a very old pharmaceutical used worldwide today. There's some indication that the TB vaccine can mitigate the immune system attack. The research is out of Harvard, but it is $10 million dollars and 10 years in and there's still no say one way or the other, nothing anywhere near production, just barely out of human trials and now they say they need 10/10 more.

I don't understand why there aren't some doctors out there just giving some of their Type 1 adult patients, on request, a TB vaccine.

Is this why? Because it would look like research? Is the down side that the prescribing doctor would get strung up, or is it that the research would then be compromised by folks playing around with the vaccine out in the field? Or is it that if one patient has a reaction to the TB vaccine, that doctor is not covered by malpractice because he shouldn't have had it in the first place?

You need a prescription for the glucose monitor and some other items basically because manufacturers have often worked hard to make it need a prescription. If a prescription is needed insurance will more likely cover the cost. If insurance covers the cost the price goes way up. Can I profit more by selling fewere at much higher cost, or by selling more at much lower cost?

There is a single hurdle for everything no matter how cheap or how well-tolerated, for marketing it to a medical use. That's all.

Just to agree with Andrew...

Off label use often concerns giving a drug which has been fully tested on one group of people to another group. For example, as mentioned above, giving a drug which has only been tested on adults to a child. Even if there haven't been a round of RCTs on children, the doctor has a pretty good idea of the drug's effects and side effects. Similarly, doctors may give a drug tested for condition Y to a patient with very similar condition X. Again, the doctor knows what the likley effects of the drug are.

Off label is necessary and widespread because, as mentioned, its too expensive to fully test every drug for every possible condition and type of person. Moreover, for obvious reasons its very hard to do any research at all on some types of people - eg children and pregnant women.

That's very different from research, in which the patient may receive a placebo instead of an actual drug (and doesn't know), and the effects of the drug in question may well not be fully understood (if they were why would anyone go to the huge expense of conducting research).

Finally, if a doctor simply divided 100 patients into two groups and gave one group drug A and another drug B that really wouldn't cut it as good research. There are good reasons why drug trials employ all that bothersome randomisation and double blinding.

In theory, a doctor should make a good faith effort to inform patients about the risks and benefits of a given treatment and how solid the evidence is. If your doctor wants you to be part of an RCT, that involves deliberately keeping information from you: you won't know whether you are receiving a drug that may help you or else receiving a placebo. IRB exists to ensure there is a legitimate gap in the literature to be filled by doing an RCT and that the research is worth the potential risk to some patients.

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