With all due respect, Joshua, I have to disagree with you on several
elements.

First, you should be advised that the FDA guidance [Docket No.
FDA-2008-D-0118 "Guidance for Industry on Diabetes Mellitus:
Developing Drugs and Therapeutic Biologics for Treatment and
Prevention"] is far more detailed than the letter which was sent to
the pharmaceutical industry, so you are commenting on
less-than-complete information. The actual FDA guidance, which was
first issued in draft form back in March 2008, makes no distinction
between treatments for type 1 or type 2 diabetes mellitus. The new
guidance with regards to drugs (which incidentally, applies to
insulin, even though it is clearly a biotechnology medicine, but one
which is governed by the Federal Food Drug and Cosmetics Act and is
therefore considered to be a "drug" not a vaccine or other biotech
medicine) apply to both. Until recently, the ONLY criteria the FDA
used is what it refers to as a "surrogate endpoint", which has always
been a reduction in HbA1c, so anything other than a reduction in
tended to be viewed as irrelevant to an approval decision (adverse
effects, are a separate evaluation criteria). I need not remind
everyone that a commentary article published in the September 29, 2007
edition of The Lancet entitled "Patient-important outcomes in
diabetesâ€"time for consensus" in which the authors, largely from the
Mayo Clinic, report that a majority of diabetes clinical trials in the
U.S. ignore virtually everything EXCEPT glycemic control (as measured
by HbA1c). The authors of that article eloquently wrote:

"Unfortunately, HbA1c loses its validity as a surrogate marker when
patients have a constellation of metabolic abnormalities, when the
most common complications are macrovascular, and when the treatments
have multiple poorly understood effects."

In the FDA guidance, the FDA does provide some guidance relevant to
type 1 treatments which you SHOULD be concerned about since it does
impact type 1 patients. First, science has proven unequivocally that
that a majority of patients newly-diagnosed with type 1 diabetes are
pediatrics, and that well-managed diabetes is, in the words of Dr.
William H. Polonsky, the leading cause of nothing. In addition, we
know that many patients with type 2 diabetes are overweight which is
itself a cause of cardiovascular disease, while the same is not
typically true for most patients with type 1 diabetes. Therefore the
recommendation to work with cardiologists specifically in evaluation
of treatments for type 1 diabetes seems to be an exercise in
unnecessary bureaucracy that is unlikely to yield significant benefit
in this particular segment of the population, while simultaneously
adding unnecessary development expense and could actually discourage
the development of new therapies for type 1 diabetes as a result.

In addition, more recent evidence [e.g. S Devaraj, N Glaser, S
Griffen, J Wang-Polagruto, E Miguelino and I Jialal; "Increased
Monocytic Activity and Biomarkers of Inflammation in Patients With
Type 1 Diabetes"; Diabetes 2006 Mar 55: 774-779.] suggests that in
type 1 diabetes, cardiovascular disease has an autoimmune etiology,
thus aside from more aggressive and perhaps earlier treatment of the
known risk factors, there appears to be little the FDA can effectively
do to address the issue of cardiovascular disease in type 1 diabetes
as part of diabetes treatments beyond the general recommendations
applicable for the health of all Americans. The guidance to
demonstrate a reduction in cardiovascular disease is an added burden
on an industry that shows little interest in developing better
treatments for type 1 diabetes anyway -- while they simultaneously
lust after the enormous type 2 market.

Second, the new guidance (see Lines 277-280) overlooks the fact that
treatments could potentially emerge which serve to regenerate
pancreatic beta cells/Islets of Langerhans thus restoring endogenous
insulin production, therefore the statement that "all experimental
treatments for type 1 diabetes (and their matching placebos, as
applicable) that are not insulin analogues or other insulin receptor
ligands should be studied as add-on therapies to insulin" demonstrates
the FDA's orthodox (and foolish) adherence to approve only therapies
which aim to maintain chronic treatment of the disease, rather than
actually curing the disease. When I wrote to the FDA last March, I
suggested that they revise the language to read as follows: "all
experimental treatments for type 1 diabetes (and their matching
placebos, as applicable) that are not insulin analogues or other
insulin receptor ligands should be studied as add-on therapies to
insulin UNLESS THEY SPECIFICALLY AIM TO INDUCE BETA CELL REGENERATION
AND CAN RESULT IN SUSTAINED INSULIN INDEPENDENCE."

While no one would question the need for safer medicines, one should
question the "surrogate endpoint" as the primary evaluation criteria,
while also asking whether the incidence of cardiovascular disease
should carry the same weight for both type 1 and type 2 diabetes.
Also, they should do more to ascertain whether the diabetes is causal
of cardiovascular disease, or whether it is merely a comorbidity of
something else -- in the case of many type 2's, obesity plays a role,
whereas in the case of type 1, autoimmunity appears to be an important
factor.

Post-market approval is important, and we should be asking why the FDA
currently has NO SYSTEM in place to gather post-marketing analysis for
approved drugs; most of the data is derived from other sources, such
as the Department of Veterans Affairs (using the VA database), but
anyone who has seen the data gathering ability for the FDA --
especially post-market analysis -- is saddened by its pathetic state.

In an effort to better protect U.S. consumers, on September 27, 2007,
President George W. Bush signed into law the Food and Drug
Administration Amendments Act of 2007 (FDAAA), which aims to deliver
expanded authority to the U.S. Food and Drug Administration (FDA) to
govern the safety of the U.S. food and drug supply. A key element of
that legislation is that it requires more comprehensive, objective
post-market safety and risk-mitigation activities from pharmaceutical,
biotech, and medical device companies than has historically been required.

The collection of information relating to Adverse Events (AEs) is an
integral part of understanding the safety of a product throughout its
marketed life cycle. The FDA has stated its commitment to maximizing
the public health benefit of collecting and reporting serious and
non-serious AEs. Central to addressing this question is determining
the number and type of safety concerns discovered by AE collection,
the age of products at the time safety concerns are detected by AE
collection and the types of actions that are subsequently taken to
protect patient safety. As part of this effort, the FDA held a public
workshop on January 29, 2008 and also solicitedpublic comments to be
included in the docket.

Again, last January, when the FDA solicited public comments on
post-market analysis, I offered my own comments to the FDA, among them
were the following:

Because most patients with type 2 diabetes mellitus typically suffer
from a relative rather than an absolute deficiency of insulin, and
because a majority of patients with type 2 diabetes who use insulin
will use it for a significantly shorter duration, although the
evaluation of safety in this particular patient group should be
considered, it should not necessarily carry the same weight or
consideration in post-market safety and risk-mitigation activities
relative to patients with type 1 diabetes, especially with regards to
AEs. This is particularly true when evaluating novel insulin
formulations, including variations by species, method of manufacture,
and genetic alterations when conducting post-market analysis. A
majority of clinical trials sponsored by insulin manufacturers have
recruited patients with type 1 and type 2 diabetes more or less
equally, in part, because of the significant market potential that
type 2 diabetes patients represent to industry.

However, the adverse event profile is profoundly different in each of
these groups (for example, the incidence of severe hypoglycemia is
almost 25 times higher in patients with type 1 vs. insulin-using type
2's); therefore, I believe the FDA's study design methodology has
effectively marginalized the collection of and the examination of AEs
in patients with type 1 diabetes mellitus, giving the appearance that
the overall risk of AEs for that particular patient group is smaller
than it is in reality.

Note that biosynthetic insulin has NEVER been subject to post-market
analysis for adverse events, even though a number of studies have
suggested it carries a higher rate of hypoglycemia without symptoms
than highly-purified animal-sourced insulin (pork, beef or combination
of pork and beef). Ironically, synthetic insulin relies almost
exclusively on animal-sources for the agar that is used to culture the
hormone.

The bottom line is that while you are entitled to disagree on the
petition, I think you were a bit quick to condemn it before knowing
what the guidance actually says. It is for these reasons (and more)
that I am supporting the petition.

Regards,
Scott Strumello





--- In nathanfaustmantrials@yahoogroups.com, Joshua Levy
<joshua2levy@...> wrote:
>
>
> I don't agree with your petition at all!
>
> First, the letter only applies to medicines that treat type-2
diabetes, so it will not slow down a cure for type-1 at all.
>
> Second, there have been a couple of drugs which actually got
approved for type-2 diabetics which had bad side effects in terms of
raising the chance of heart attacks. The FDA reacted to these
problems by fixing their process: by requiring the drug companies to
do testing focused specifically at heart risks. That is the right
thing to do!
>
> Prior to these new regulations, type-2 diabetic drugs could be
approved after clinical trials lasting only 3-6 months. That's nuts!
Those drugs are typically taken for years (maybe even decades).
Requiring them to be tested for a year is long over due. The extra
time is required to get a statistically valid sample of heart risk.
>
> If we want a safe drug supply in this country, the FDA should go
farther, and require post-approval (called "postmarket") safety
testing lasting as long a the expected use of the drug. That is basic
common sense. That would shake out a lot of safety issues before
people got hurt, without slowing down drug approvals. But in the mean
time, the FDA's rule change is a good step in the right direction. In
my opinion.
>
> Joshua Levy
>
>
>
>
> ________________________________
> From: Bernard Farrell <bernard.farrell@...>
> To: nathanfaustmantrials@yahoogroups.com
> Sent: Monday, January 5, 2009 8:15:01 PM
> Subject: [nathanfaustmantrials] Ask FDA to better serve the needs of
diabetes patients
>
>
> A large group of us has started an online petition to the FDA.
>
> We're asking them to remove new requirements they recently placed on
> diabetes drugs.
>
> Please sign. The petition is at: http://HealTheFDA. com/
>
> If you want more details, I've posted them on my blog at
> http://is.gd/ eEMB.
>