From: David Rind <drind@caregroup.harvard.edu>
Newsgroups: sci.med
Subject: Re: Off label usage of medicine
Date: Tue, 18 Jan 2005 20:57:40 -0500
Message-ID: <cskequ$mau$1@reader2.panix.com>

zwalanga@yahoo.com wrote:
> Carey Gregory wrote:
>
>>zwalanga@yahoo.com wrote:
>>
>>
>>>neurontin and peripheral neuropathy
>
> Exactly. They are being prescribed for off-label uses, with the
> consumer (you) being used as an after market lab rat. "...many things
> they haven't been shown to be good for."

You can take the position that somehow FDA approval is the difference
between being a lab rat or not, but it doesn't make much sense. There
can be really strong evidence that a drug is of benefit without FDA
approval. Neurontin is approved by the FDA for the neuropathic pain of
postherpetic neuralgia. There are randomized trials showing it also is
of benefit for the neuropathic pain of diabetic neuropathy. Should
doctors really refuse to prescribe a beneficial drug for something just
because it hasn't been worth it to the manufacturer to apply for an
additional indication? How about for an indication that is "off label"
in the US but is an approved indication in Europe. If you're being
treated by a US doctor does that make you a "lab rat"?

It makes more sense to ask whether there is good evidence to justify
using a given medication, whether or not it is FDA approved for that
indication. Even if there is FDA approval, the drug may not be worth the
side effects or there may be some other drug that works much better.
Even if there is no FDA approval, the drug may be well proven to be the
best drug available for the problem. And sometimes, even when there is
only weak evidence and no FDA approval, it may make sense for someone to
take a drug to see if it might work, if there are no other choices
available and the benefits seem likely to outweigh the risks.

--
David Rind
drind@caregroup.harvard.edu

From: Steve Harris <sbharris@ix.netcom.com>
Newsgroups: sci.med
Subject: Re: Off label usage of medicine
Date: 18 Jan 2005 18:17:19 -0800
Message-ID: <1106101039.537245.264280@f14g2000cwb.googlegroups.com>

>>It makes more sense to ask whether there is good evidence to justify
using a given medication, whether or not it is FDA approved for that
indication. Even if there is FDA approval, the drug may not be worth the
side effects or there may be some other drug that works much better.
Even if there is no FDA approval, the drug may be well proven to be the
best drug available for the problem. And sometimes, even when there is
only weak evidence and no FDA approval, it may make sense for someone to
take a drug to see if it might work, if there are no other choices
available and the benefits seem likely to outweigh the risks.<<

COMMENT:

You've just elloquently made the case for not having an initial FDA
"approval" for any drug at all. Which I agree with. FDA should be an
advisory agency only, with no power to keep a drug off the market
entirely, just because nobody has spent the many millions needed to get
it approved for SOMETHING (anything).  The system we have is, when you
think about it, really stupid. Any use of a drug for any reason "off
label" is a big risk/benefit analysis, which would proceed
independently even if the drug had never been approved by the FDA for
anything. Some drugs available only off-shore are prescribed this way
occasionally by US doctors, legally. But it's done rarely, because
civil-suit wise, it's risky. We wouldn't need the FDA so much if we
could hamstring the tort process. If the courts were willing to let any
patient who took any drug sign the kind of stack of papers you sign
when you take up skydiving or scuba, and the courts stuck by the
contracts, you could dispense with the FDA as we know it, and
medications would be half their current price in the bargain.

SBH

From: David Rind <drind@caregroup.harvard.edu>
Newsgroups: sci.med
Subject: Re: Off label usage of medicine
Date: Wed, 19 Jan 2005 19:25:02 -0500
Message-ID: <csmtp8$n5e$1@reader2.panix.com>

zwalanga@yahoo.com wrote:
> :"And sometimes, even when there is only weak evidence and no FDA
> approval...etc..."
>
> It brings a tear to one's eye it does David. Your dedication to
> democracy. Have you thought of writing ad copy me boyo?

No, but I have had to make decisions about giving patients drugs for
potentially fatal illnesses on too little information. Sometimes later
information showed the decision to have been right and other times
wrong. I remember begging drug companies for protease inhibitors well
before they were approved by the FDA. I'm not sure why you think it's
shilling for the drug companies to recognize that such decisions have to
be made.

>
> http://www.citizen.org/eletter/articles/neurontin.htm
> Zee
>
> {and what was that David, about 27 "if's"?}

I honestly have no clue what you mean by that last sentence. As to the
prior URL, the Public Citizen letter is deceptive in that it implies
that there is no evidence that Neurontin works for any of these 11
indications. That is just untrue. As an example (sticking with diabetic
neuropathy):

------------------------------
TI - Gabapentin for the symptomatic treatment of painful neuropathy in
patients with diabetes mellitus: a randomized controlled trial.
AU - Backonja M; Beydoun A; Edwards KR; Schwartz SL; Fonseca V; Hes M;
LaMoreaux L; Garofalo E
SO - JAMA 1998 Dec 2;280(21):1831-6.

CONTEXT: Pain is the most disturbing symptom of diabetic peripheral
neuropathy. As many as 45% of patients with diabetes mellitus develop
peripheral neuropathies. OBJECTIVE: To evaluate the effect of gabapentin
monotherapy on pain associated with diabetic peripheral neuropathy.
DESIGN: Randomized, double-blind, placebo-controlled, 8-week trial
conducted between July 1996 and March 1997. SETTING: Outpatient clinics
at 20 sites. PATIENTS: The 165 patients enrolled had a 1- to 5-year
history of pain attributed to diabetic neuropathy and a minimum 40-mm
pain score on the Short-Form McGill Pain Questionnaire visual analogue
scale. INTERVENTION: Gabapentin (titrated from 900 to 3600 mg/d or
maximum tolerated dosage) or placebo. MAIN OUTCOME MEASURES: The primary
efficacy measure was daily pain severity as measured on an 11-point
Likert scale (0, no pain; 10, worst possible pain). Secondary measures
included sleep interference scores, the Short-Form McGill Pain
Questionnaire scores, Patient Global Impression of Change and Clinical
Global Impression of Change, the Short Form-36 Quality of Life
Questionnaire scores, and the Profile of Mood States results. RESULTS:
Eighty-four patients received gabapentin and 70 (83%) completed the
study; 81 received placebo and 65 (80%) completed the study. By
intent-to-treat analysis, gabapentin-treated patients' mean daily pain
score at the study end point (baseline, 6.4; end point, 3.9; n = 82) was
significantly lower (P<.001) compared with the placebo-treated patients'
end-point score (baseline, 6.5; end point, 5.1; n = 80). All secondary
outcome measures of pain were significantly better in the gabapentin
group than in the placebo group. Additional statistically significant
differences favoring gabapentin treatment were observed in measures of
quality of life (Short Form-36 Quality of Life Questionnaire and Profile
of Mood States). Adverse events experienced significantly more
frequently in the gabapentin group were dizziness (20 [24%] in the
gabapentin group vs 4 [4.9%] in the control group; P<.001) and
somnolence (19 [23%] in the gabapentin group vs 5 [6%] in the control
group; P = .003). Confusion was also more frequent in the gabapentin
group (7 [8%] vs 1 [1.2%]; P = .06). CONCLUSION: Gabapentin monotherapy
appears to be efficacious for the treatment of pain and sleep
interference associated with diabetic peripheral neuropathy and exhibits
positive effects on mood and quality of life.
----------------------

Pretending that data like these don't exist just because it wasn't
worthwhile for the manufacturer to apply to the FDA for an added
indication is just silly. Neurontin may not be worth its side effects
when used for diabetic neuropathy, but there is good evidence that it
relieves pain.

--
David Rind
drind@caregroup.harvard.edu

From: Steve Harris <sbharris@ix.netcom.com>
Newsgroups: sci.med
Subject: Re: Off label usage of medicine
Date: 20 Jan 2005 17:06:26 -0800
Message-ID: <1106269586.624213.317420@z14g2000cwz.googlegroups.com>

Here's one: Lithium. It was discovered to be an anti-mania drug in
1949, but cardiac risk concerns delayed its use through the 50's, and
in the US though the 60's (while the Europeans used it). The FDA didn't
approve it till 1970 for mania, and for prevention of bipolar disorder
not till 1974. Before that, doctors had to use it off label. This
sometimes involved having psych students make up capsules from lithium
carbonate powder bought from chemical supply companies.

Similar problems beset newer treatments. Lithium has nasty side effects
in many, but the second line drug valproate, wasn't approved for
treating bipolar disorder because nobody wanted to pay for the studies.
It was instead used for seizures from 1983, and was used off label for
mania until 1995 when one form of it (the newly patented divalproex, a
partial sodium salt) got approved to treat mania. But even this one
missed being studied as a preventive for bipolar cycling, and the first
drug to get THAT FDA approval was lamotrigine, in 2003, almost 30 years
after lithium. And even lamotrigine had been used off label for bipolar
disorder for much of the 9 years between first getting approved for
epilepsy in 1994 (doctors by then knew that many antiepileptics were
effective at preventing bipolar cycling). Sensing a pattern?

For children, amplify all these problems and add years to approval for
each of them.

SBH

From: Steve Harris <sbharris@ix.netcom.com>
Newsgroups: sci.med
Subject: Re: Off label usage of medicine
Date: 20 Jan 2005 16:22:32 -0800
Message-ID: <1106266952.018951.129400@z14g2000cwz.googlegroups.com>

>>What do you mean "may not be worth its side effects" but relieves pain?
Why would Neurontin be worth anything to me, if to relieve pain I risk
something else, and no one knows why or what, until several thousand of
us are injured trying to find out why or what?<<

COMMENT:

People who are actually in a lot of pain never ask "Why should [x pain
reliever] be worth anything to me?"  If you're in pain, it's bloody
obvious why it might be worth a lot to you. People risk their lives to
relieve pain all the time. Hell, people risk their lives to releave
boredom. Or for cosmetic reasons. Or even just for the thrill or the
hell of it.  Doing it to stop hurting ought to be particularly easy for
anybody to understand. Unless you're not hurting and have no
imagination.

The problem with having *the government* (some government agency)
balance unknown risks of a treatment against known benefits to those in
pain or those dying, is that the government itself is never in pain,
and is never dying. And isn't known for it's great empathy or
imagination, either.  So it tends to make judgements that individual
patients and doctors wouldn't.

As I've said before, everybody seems to think drugs can be developed
and sold without any "bias." But that is sort of like the idea that the
government could produce movies or cars for you without any "bias".
Based, of course, on what kind of movies and cars you NEED, not upon
any kind of biased notion, like what you want or like. The idea that
"science" can completely inform government decision- making is
particular nonsense. Science tells you only what you CAN do. Beyond
that, it's no help at all in deciding what you SHOULD do.

SBH