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From: Rod on 25 Jul 2008 02:43
Part of an ongoing series of thyroid-related information thought to be
potentially of interest to some of our readers. :-)

IMHO this is interesting for many reasons. Not least, I have seen the
effect of changes of thyroxine brand - and some are without doubt
significant.

Also, it throws yet more dosage determination onto the TSH levels.
Without wishing to put words into anyone's mouth, Kevin might well
remind us this is is unproven for dose management.

This article is US-based - in the UK we have pharmacies which are quite
happy to substitute without any reference to anyone, prescription by
prescription (and even within a single prescription). So I will now
suggest to any UK people that they have their pharmacy records endorsed
that they will only accept one brand. At least the pharamacist will be
made aware and would not just throw any pack into the bag. Further, to
allow leaway in case of supply problems, always keep ahead of the game
with your prescriptions.


=============================


Posted on July 24, 2008


FDA urged to rethink its method of determining bioequivalence
Results of a pharmacovigilance trial have the Endocrine Society
concerned about the adverse health effects of switching L-T4 sources.

In a position statement released in June, the Endocrine Society asked
the FDA to reverse its ruling on the substitution of sodium levothyroxine.

“The FDA has been using a technique for assessing bioequivalence for
decades that not only the Endocrine Society, but also professional
endocrinology associations agree is an antiquated method that is being
inappropriately applied to the bioequivalence for thyroxine,” Leonard
Wartofsky, MD, MPH, MACP, chairman of the Department of Medicine at
Washington Hospital Center, told Endocrine Today.

The adverse health effects associated with substituting L-T4 prompted
the Endocrine Society's position statement. Currently, the FDA allows
certain manufacturer doses of L-T4 to be considered bioequivalent to
those from other makers. This allows patients to switch between sources
of L-T4 without the physician's awareness.

According to the statement, the Endocrine Society, American Association
of Clinical Endocrinologists and the American Thyroid Association
conducted a pharmacovigilance study in 2007. Researchers sent adverse
event surveys to 210 users of prescription L-T4. They reported 160
adverse events related to a change in type of L-T4; 87.6% of changes
were made by pharmacists with the knowledge of the prescribing
physician. Thirty-one percent of those surveyed reported adverse events
related to switching.

Current system is not working

The FDA's current “one size fits all” method of determining
bioequivalence cannot be applied to L-T4 for several reasons, according
to the society. Those reasons include: the natural properties of L-T4,
the delicate balance of the thyroid system and the possibility of small
changes in thyroid hormones upsetting the balance, which may not be
recognized by measurements of thyroid hormone levels.

The society is also concerned that serum TSH levels may change if
measurable changes in L-T4 levels are absent, which would cause problems
when evaluating a patient's thyroid status.

“Bioequivalence as determined by the FDA is not therapeutic equivalence
— a much more clinically important measure,” according to the statement.

Recommendations for a reversed ruling

The Endocrine Society recommends that the FDA be cautious when
determining bioequivalence due to its importance in the role of patient
safety. According to the society's position statement, other
recommendations include:

Devise and execute a system to determine therapeutic bioequivalence of
L-T4 that will consider TSH levels over time.
Retract the current methods used to determine the bioequivalence of L-T4
products and declare that the products have not been shown to be
bioequivalent.
Require the inclusion of patient warning information in L-T4 products to
emphasize the importance of consulting a prescribing physician if the
source of the product is changed.
The possible consequences of slightly altered L-T4 products must be made
clear to physicians who are not thyroid specialists. L-T4 product
information should clearly convey the potential problems with slight
alterations in dose and the need for patient reevaluation upon
substitution.
“As clinicians, we depend on the TSH yet, paradoxically, the FDA ignores
TSH and they do not, when they conduct bioequivalent studies, take into
account what affect the dosages have on TSH. So it has been the position
of these organizations that the FDA should abandon the chemical
bioequivalence technique and look instead at pharmacodynamics and
pharmacokinetics,” Wartofsky said. – by Stacey L. Adams


PERSPECTIVE


The FDA methodology is probably not optimal and likely would be improved
by using TSH concentrations over time as the measure of bioequivalence.
In fact, such a study has been done by Betty Dong et al (JAMA.
2007;277:1205-1213). They showed that two of the most widely used brands
of L-T4 were equivalent to two generics. Publication of that study was
suppressed for a time by the manufacturer of Synthroid who threatened to
sue the authors and did everything possible to prevent its publication
indefinitely. However, the paper was finally published because the
company received such bad publicity.

Despite what the Endocrine Society, the American Thyroid Association and
the Association of Clinical Endocrinologists state, there is, as yet, no
published evidence that indicates a serious problem at this time. The
professional organizations mention only anecdotal data and results of a
survey to conclude that more people are out of range with generic
switching and suffer adverse health issues. That is no solid data from a
controlled study that is peer reviewed and published.

Cross-sectional studies have repeatedly shown that when groups of
patients are treated mostly with major branded products, about 20% are
over-treated and 20% are undertreated; only 60% are within the target
reference range for serum TSH. To my knowledge, there are no similar
observations for those on generics and for those who are switched from
brand to generic. What is needed is a prospective controlled study in
this area.

My own experience in a middle class community in Bronx, N.Y., which is
not a controlled study, is that most patients are switched from brand to
generic products by the pharmacist. My assessment is that the percentage
of patients who are out of range on annual checkups is around 15%, not
that different from when brand name products dominated the market. Also,
I have not seen any drug related adverse health issues in these
patients, as mentioned by the Society's document.

– Martin I. Surks, MD, MACP

Program Director for the Division of Endocrinology and Metabolism,

Montefiore Medical Center, Bronx, N.Y.

<http://www.endocrinetoday.com/view.aspx?rid=29873>

--
Rod

Hypothyroidism is a seriously debilitating condition with an insidious
onset.
Although common it frequently goes undiagnosed.
<www.thyromind.info> <www.thyroiduk.org> <www.altsupportthyroid.org>
From: kgrhoads on 29 Jul 2008 16:37
So in the commentary we find the following:
"Cross-sectional studies have repeatedly shown that when groups of
patients are treated mostly with major branded products, about 20% are
over-treated and 20% are undertreated; only 60% are within the target
reference range for serum TSH. "

Once again, the untested assumption that TSH can be used to
determine adequacy of dose is presumed, without any question.

So long as adequacy of thyroid hormone replacement is judged
on the basis of TSH I do not believe the problems discussed
in this article can be avoided.

Still, using TSH remains unquestioned, in spite of this approach
having never been tested, let alone proven useful.

I still have to comment with "Bah, Humbug!" This is not
science, nor is this scientific medicine. Using untested
approaches may sometimes be necessary, but making
an untested hypothesis part of the "gold standard" of
treatment -- for over three decades -- Bah, Humbug.
From: Rod on 29 Jul 2008 17:10
kgrhoads(a)alum.mit.edu wrote:
> So in the commentary we find the following:
> "Cross-sectional studies have repeatedly shown that when groups of
> patients are treated mostly with major branded products, about 20% are
> over-treated and 20% are undertreated; only 60% are within the target
> reference range for serum TSH. "
>
> Once again, the untested assumption that TSH can be used to
> determine adequacy of dose is presumed, without any question.
>
> So long as adequacy of thyroid hormone replacement is judged
> on the basis of TSH I do not believe the problems discussed
> in this article can be avoided.
>
> Still, using TSH remains unquestioned, in spite of this approach
> having never been tested, let alone proven useful.
>
> I still have to comment with "Bah, Humbug!" This is not
> science, nor is this scientific medicine. Using untested
> approaches may sometimes be necessary, but making
> an untested hypothesis part of the "gold standard" of
> treatment -- for over three decades -- Bah, Humbug.

Even if you/we completely believed this wonderful, exquisitely sensitive
TSH test - they *still* manage to get 40% wrongly dosed. So are the
doctors under and over dosing by adjusting to treat patient symptoms [1]
- or, umm, what?

Today I have been pondering the possibilities of mixed/concurrent
primary and secondary hypothyroidism. Seems ever so likely that in
primary hypoT both the pituitary and the hypothalamus will not be
working right. What effect this has before treatment (especially if the
hypoT is long standing and severe) and thereafter (while being treated)
is entirely open to speculation - but to suggest, as the establishment
effectively does, that it is "none" is about as unlikely as it gets.

I am willing to accept that it just might work, if you knew the person's
'healhty' TSH level, in those in whom mild hypoT is detected and treated
promptly. But please, as you also ask, prove it. And prove that it works
over the many decades for which patients might well need to be treated.

[1] Are they? Bollocks.

--
Rod

Hypothyroidism is a seriously debilitating condition with an insidious
onset.
Although common it frequently goes undiagnosed.
<www.thyromind.info> <www.thyroiduk.org> <www.altsupportthyroid.org>
From: kgrhoads on 31 Jul 2008 12:04
On Jul 29, 9:10 pm, Rod <polygo...(a)ntlworld.com> wrote:
> kgrho...(a)alum.mit.edu wrote:....
> > Once again, the untested assumption that TSH can be used to
> > determine adequacy of dose is presumed, without any question.
> .....
> > Still, using TSH remains unquestioned, in spite of this approach
> > having never been tested, let alone proven useful.
>
> Even if you/we completely believed this wonderful, exquisitely sensitive
> TSH test - they *still* manage to get 40% wrongly dosed. So are the
> doctors under and over dosing by adjusting to treat patient symptoms [1]
> - or, umm, what?
>
> Today I have been pondering the possibilities of mixed/concurrent
> primary and secondary hypothyroidism. Seems ever so likely that in
> primary hypoT both the pituitary and the hypothalamus will not be
> working right. What effect this has before treatment (especially if the
> hypoT is long standing and severe) and thereafter (while being treated)
> is entirely open to speculation - but to suggest, as the establishment
> effectively does, that it is "none" is about as unlikely as it gets.
>
> I am willing to accept that it just might work, if you knew the person's
> 'healhty' TSH level, in those in whom mild hypoT is detected and treated
> promptly. But please, as you also ask, prove it. And prove that it works
> over the many decades for which patients might well need to be treated.
>
> [1] Are they? Bollocks.
>
> --
> Rod
>
> Hypothyroidism is a seriously debilitating condition with an insidious
> onset.
> Although common it frequently goes undiagnosed.
> <www.thyromind.info> <www.thyroiduk.org> <www.altsupportthyroid.org>

Well one of the things that I've been wondering about is anti-thyroid
antibodies.
THere are several flavours of these, and for TED (thyroid eye disease,
a.k.a.,
GED) there is evidence that the antibodies attack eye tissue.
Furthermore,
there is strong suspicion that Grave's/hyper- results from antibody
attacks
which "fool" the TSH receptors on the thyroid gland into making more
hormones.

So, if the antibodies can attack other kinds of tissue and are known
to
cause problems with TSH receptors on the thyroid gland, why do we
assume that TSH receptors in the pituitary are still working
perfectly?
You need that assumption to put any faith in the pituitary's take on
the thyroid status, which is what the TSH level is.

ANd, with the known problems with adrenal function impairment
under long standing hypo- conditions, why assume any other
endocrine gland is UN-impaired?

Then there is the assumption that the pituitary responds to
one large dose once a day the same way it responds to a
continuous gradual release of hormones over 24 hours.
REALLY? No other biological system does that!

I could go on, but the assumptions necessary to believing that
TSH for hypo- sufferers, including ex-hypers after gland ablation,
mean anything but purely random noise are just unbelieveable.

Do the MDs also believe in the tooth fairy, the Easter Bunny and
Santa Claus/Father Christmas? I could arguably suggest that
believing in TSH meaningfulness in the presence of autoimmune
antithyroid antibodies is just as fanciful as belief in the tooth
fairy.
Both requrie equal amounts suspension of critical faculties and
disbelief.

Believing in something that has not only never been proven
but assumes things that we know are highly unlikely, at best,
and probably totally untrue -- that is NOT science.

That's why I keep calling the "set dose by TSH" approach
"voodoo". To put any creedence in "set dose by TSH" one
must swallow assumptions that are so preposterous, so
unreasonable and so totally discredited that it is clear that
one has turned their back on reality.

Trouble is most MDs never "look under the hood" at what they
are taught. So they have no idea how unreasonble the
assumptions underneath "set dose by TSH" truly are.

SO, once again, we get to "Bah, Humbug!" as the summary
comment on "set dose by TSH".

But why should they listen to me, I'm only a Ph.D.
in electrical engineering, specializing in measurement
and in avoiding mismeasuring things because of
wrong assumptions. What has that to do with
medicine?
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