On 2016 Jun 07, David Keller commented:

Reply to the Attack on Off-label Prescribing

The study by Eguale and colleagues ("the authors") demonstrated that off-label prescriptions backed by strong scientific evidence are just as safe as on-label prescriptions. [1] An accompanying editorial, citing their results, called for a "crackdown" against off-label prescriptions, with no exemption for those with strong scientific evidence. [2] My letter to the editor defended scientific off-label prescribing from this blanket prohibition against off-label prescribing. [3] In their reply to my letter, [4] the authors misunderstood or misrepresented my main points, which is best seen by directly comparing quotations from their reply with quotations from my letter. Below, false or misleading statements by the authors are numbered in sequence, and my rebuttals are numbered to match.

1) The authors wrote: "Unscientific prescribing constitutes 4 of 5 off-label uses, and this unscientific prescribing has resulted in a 54% increased risk of adverse drug events compared with on-label uses."

Rebuttal to #1: I never advocated unscientific prescribing. Quite the opposite, I wrote: "We need to crack down on unscientific prescribing" and we should take steps to "discourage unscientific prescribing." The authors provide no evidence or arguments here to counter my advocacy of scientific off-label prescribing.

2) The authors wrote: "To crack down on unscientific prescribing, drug regulatory bodies need to demand strong scientific evidence from pharmaceutical companies to safeguard the public."

Rebuttal to #2: We have agreed repeatedly on the need "to crack down on unscientific prescribing", which in itself implies the need for strong scientific evidence. I dispute the implication that the evidence needs to come from pharmaceutical companies, with their powerful financial biases. I am more impressed by the results of studies which are not funded by the company with so much future profit to gain or lose according to the outcome.

3) The authors wrote: " When physicians prescribe medications for unscientific, off-label uses, their patients suffer adverse drug events."

Rebuttal to #3: Actually, patients always suffer adverse drug events. They meant to say that patients suffer MORE adverse drug events from unscientific off-label prescriptions than from on-label prescriptions. The authors should have added that patients do NOT experience any increase in adverse events from off-label prescriptions backed by strong science than they do from on-label prescribing. Don't these authors recall proving this in their study? Does this constant conflation of "off-label" with "unscientific" indicate confusion on the part of the authors, or are they trying to confuse the readers?

4) The authors wrote: "The expensive and long approval process required by the US Food and Drug Administration (FDA) is exactly what produces the scientific evidence that physicians need to prescribe appropriately."

Rebuttal to #4: False. The authors repeatedly state that "4 out of 5 drugs that are prescribed off-label are prescribed for unscientific use". This means that 20% of off-label prescriptions are for scientific use, and these very authors have proved that such use is just as safe as on-label prescriptions. They are ignoring the results of their own important research.

Consider an inexpensive, generic drug, which is approved for one indication, but is also used widely for another, unapproved indication, with the support of strong scientific evidence. What is to be gained by "cracking down" on doctors who prescribe this drug for the unapproved indication? Not an increase in safety, as these authors have demonstrated in their recent study. And "strong scientific evidence" must, by definition, include evidence of efficacy.

The major effect of forcing generic drugs to be approved by the FDA for unapproved indications that have strong scientific evidence already will be a major increase in the cost of these drugs. Patients who took cheap, generic colchicine safely and effectively for gout for years got a rude shock when it was forced through the FDA approval process. The only difference noticed by patients was the tenfold increase in price they were forced to pay as cheap generic colchicine morphed overnight into an expensive branded-only version, which left many of patients unable to afford to take colchicine any longer.

References

1: Eguale T, Buckeridge DL, Verma A, Winslade NE, Benedetti A, Hanley JA, Tamblyn R. Association of Off-label Drug Use and Adverse Drug Events in an Adult Population. JAMA Intern Med. 2016 Jan;176(1):55-63. doi: 10.1001/jamainternmed.2015.6058. PubMed PMID: 26523731.

2: Good CB, Gellad WF. Off-label Drug Use and Adverse Drug Events: Turning up the Heat on Off-label Prescribing. JAMA Intern Med. 2016 Jan;176(1):63-4. doi: 10.1001/jamainternmed.2015.6068. PubMed PMID: 26524668.

3: Keller DL. In Defense of Off-label Prescribing. JAMA Intern Med.2016;176(6):861. doi:10.1001/jamainternmed.2016.1403.

4: Eguale T, Verma A, Tamblyn R. In Defense of Off-label Prescribing—Reply. JAMA Intern Med. 2016;176(6):861-862. doi:10.1001/jamainternmed.2016.1406.

On 2016 Jun 07, David Keller commented:

Reply to the Attack on Off-label Prescribing

The study by Eguale and colleagues ("the authors") demonstrated that off-label prescriptions backed by strong scientific evidence are just as safe as on-label prescriptions. [1] An accompanying editorial, citing their results, called for a "crackdown" against off-label prescriptions, with no exemption for those with strong scientific evidence. [2] My letter to the editor defended scientific off-label prescribing from this blanket prohibition against off-label prescribing. [3] In their reply to my letter, [4] the authors misunderstood or misrepresented my main points, which is best seen by directly comparing quotations from their reply with quotations from my letter. Below, false or misleading statements by the authors are numbered in sequence, and my rebuttals are numbered to match.

1) The authors wrote: "Unscientific prescribing constitutes 4 of 5 off-label uses, and this unscientific prescribing has resulted in a 54% increased risk of adverse drug events compared with on-label uses."

Rebuttal to #1: I never advocated unscientific prescribing. Quite the opposite, I wrote: "We need to crack down on unscientific prescribing" and we should take steps to "discourage unscientific prescribing." The authors provide no evidence or arguments here to counter my advocacy of scientific off-label prescribing.

2) The authors wrote: "To crack down on unscientific prescribing, drug regulatory bodies need to demand strong scientific evidence from pharmaceutical companies to safeguard the public."

Rebuttal to #2: We have agreed repeatedly on the need "to crack down on unscientific prescribing", which in itself implies the need for strong scientific evidence. I dispute the implication that the evidence needs to come from pharmaceutical companies, with their powerful financial biases. I am more impressed by the results of studies which are not funded by the company with so much future profit to gain or lose according to the outcome.

3) The authors wrote: " When physicians prescribe medications for unscientific, off-label uses, their patients suffer adverse drug events."

Rebuttal to #3: Actually, patients always suffer adverse drug events. They meant to say that patients suffer MORE adverse drug events from unscientific off-label prescriptions than from on-label prescriptions. The authors should have added that patients do NOT experience any increase in adverse events from off-label prescriptions backed by strong science than they do from on-label prescribing. Don't these authors recall proving this in their study? Does this constant conflation of "off-label" with "unscientific" indicate confusion on the part of the authors, or are they trying to confuse the readers?

4) The authors wrote: "The expensive and long approval process required by the US Food and Drug Administration (FDA) is exactly what produces the scientific evidence that physicians need to prescribe appropriately."

Rebuttal to #4: False. The authors repeatedly state that "4 out of 5 drugs that are prescribed off-label are prescribed for unscientific use". This means that 20% of off-label prescriptions are for scientific use, and these very authors have proved that such use is just as safe as on-label prescriptions. They are ignoring the results of their own important research.

Consider an inexpensive, generic drug, which is approved for one indication, but is also used widely for another, unapproved indication, with the support of strong scientific evidence. What is to be gained by "cracking down" on doctors who prescribe this drug for the unapproved indication? Not an increase in safety, as these authors have demonstrated in their recent study. And "strong scientific evidence" must, by definition, include evidence of efficacy.

The major effect of forcing generic drugs to be approved by the FDA for unapproved indications that have strong scientific evidence already will be a major increase in the cost of these drugs. Patients who took cheap, generic colchicine safely and effectively for gout for years got a rude shock when it was forced through the FDA approval process. The only difference noticed by patients was the tenfold increase in price they were forced to pay as cheap generic colchicine morphed overnight into an expensive branded-only version, which left many of patients unable to afford to take colchicine any longer.

References

1: Eguale T, Buckeridge DL, Verma A, Winslade NE, Benedetti A, Hanley JA, Tamblyn R. Association of Off-label Drug Use and Adverse Drug Events in an Adult Population. JAMA Intern Med. 2016 Jan;176(1):55-63. doi: 10.1001/jamainternmed.2015.6058. PubMed PMID: 26523731.

2: Good CB, Gellad WF. Off-label Drug Use and Adverse Drug Events: Turning up the Heat on Off-label Prescribing. JAMA Intern Med. 2016 Jan;176(1):63-4. doi: 10.1001/jamainternmed.2015.6068. PubMed PMID: 26524668.

3: Keller DL. In Defense of Off-label Prescribing. JAMA Intern Med.2016;176(6):861. doi:10.1001/jamainternmed.2016.1403.

4: Eguale T, Verma A, Tamblyn R. In Defense of Off-label Prescribing—Reply. JAMA Intern Med. 2016;176(6):861-862. doi:10.1001/jamainternmed.2016.1406.