OMNITROPE
[Somatropin] Side Effects and Warnings
Omnitrope (somatropin [rDNA origin])

What is Omnitrope?
Omnitrope (somatropin [rDNA origin]), is a recombinant human growth
hormone product indicated for long-term treatment of pediatric patients who
have growth failure due to an inadequate secretion of endogenous growth
hormone, and for long-term replacement therapy in adults with GHD of
either childhood- or adult onset.

Is Omnitrope a generic biologic?
No. Omnitrope is not rated as therapeutically equivalent to (and therefore
substitutable for) any of the other approved human growth hormone
products.   Omnitrope is more appropriately characterized as a "follow-on
protein product."

What is a follow-on protein product?
The term follow-on protein products generally refers to protein and peptide
products that are intended to be sufficiently similar to a product already
approved or licensed to permit the applicant to rely for approval on certain
existing scientific knowledge about the safety and effectiveness of the
approved protein product.  Follow-on protein products may be produced
through biotechnology or derived from natural sources.

Is this FDA's first approval of a follow-on protein product?
No.  FDA has approved other follow-on protein products under section 505
of the Food, Drug, and Cosmetic Act.  These include GlucaGen (glucagon
recombinant for injection), Hylenex (hyaluronidase recombinant human),
Hydase and Amphadase (hyaluronidase), and Fortical (calcitonin salmon
recombinant) Nasal Spray.

Does todayÂ’s approval of Omnitrope create a new pathway for follow-on
versions of all protein products?
No.  The approval of Omnitrope in a 505(b)(2) application does not establish
a pathway for approval of follow-on products for biological products licensed
under section 351 of the Public Heath Service Act, nor does it mean that
more complex and/or less well understood proteins approved as drugs
under the Food, Drug, and Cosmetic Act could be approved as follow-on
products.

The majority of protein products are licensed as biological products under
the Public Health Service Act, not approved as drugs under the Food, Drug,
and Cosmetic Act.  There is no abbreviated approval pathway analogous to
505(b)(2) or 505(j) of the Act for protein products licensed under section 351
of the Public Health Service Act.  Such a pathway for the approval or
licensure of follow-on protein products under the Public Health Service Act
would require new legislation.

Why could FDA approve Omnitrope as a follow-on product?
Among other things, human growth hormone (hGH) has several
characteristics that enable one rhGH product to be adequately compared to
another for purposes of approval under section 505(b)(2) of the Act.  For
example:

* hGH is well characterized and non-glycosylated (in other words, sugar
molecules are not added to the protein, which would increase the complexity
of a protein and make it more difficult to compare the structures from one
version of the protein to another using standard tools such as mass
spectrometry)
* The primary structure of hGH is known, and physicochemical tests exist for
the determination of an hGH productÂ’s secondary and tertiary structures
(how the protein folds upon itself)
* Clinically relevant bioassays and qualified biomarkers are available for hGH
* hGH has a long and well documented history of clinical use as a
replacement for endogenous growth hormone deficiency
* hGHÂ’s mechanism of drug action is known, and its human toxicity profile is
well understood

Has FDA's authority to approve follow-on protein products been questioned?
FDA  has received citizen petitions raising regulatory, legal, and scientific
issues associated with these approvals and requesting that the Agency use
a public process to obtain input from industry. FDA has used a public process
to gather additional information. This process consisted of convening two
public meetings (September 2004 and February 2005) and establishing a
related public docket for the submission of written comments (docket #
2004N-0355)

In conjunction with today's approval, FDA issued a response to the
questions raised in the citizen petitions and in the public process that apply
to the approval of this recombinant human growth hormone product.

Approval of Omnitrope does not involve the regulatory and legal questions
that may be associated with approval of follow-on products licensed under
the Public Health Service Act.  It also does not raise the scientific issues, of
the type identified during the public meetings and in the public comments,
that are associated with protein products that have unknown or multiple
active ingredients (rhGH products have one known active ingredient,
somatropin); protein products that have an unknown mechanism of action
(rhGHÂ’s mechanism of action related to hGH's efficacy for pediatric and adult
GHD is well understood); protein products that are difficult to characterize
(currently available technologies allow rhGH to be extensively
characterized); or protein products that are glycosylated (rhGH is not
glycosylated).

Why has it taken so long to take an action on Omnitrope?
Sandoz submitted its new drug application for Omnitrope in July 2003.  In
August 2004, the FDA notified Sandoz in a letter that it had completed its
review of the Omnitrope application but was unable to reach a final decision
because of uncertainty about scientific and legal issues relating to follow-on
protein products raised in the citizen petitions and expected to be
addressed through a public process.

FDA has now completed its analysis of the issues pertaining to the
Omnitrope approval that were raised in the citizen petitions and in the public
meetings and docket. The Agency has also reviewed additional data
submitted recently to the Omnitrope NDA.  FDA has determined that the
Sandoz application provides the evidence of safety and effectiveness
necessary for approval under the Act.

Was there a court case involved with this application?
Yes, Sandoz, Inc. filed a lawsuit against the FDA in September 2005.  On
April 10, 2006, a federal judge in Washington, D.C. ruled that the FDA must
make a decision on the Omnitrope application.

What is a 505(b)(2) application?
Section 505(b)(2) of the Food, Drug, and Cosmetic Act permits an applicant
to rely for approval of a drug on information from published scientific
literature or on the fact that the agency has already found a similar drug to
be safe and effective.  A 505(b)(2) application, like an application under 505
(j) for approval of a generic drug, can only be approved when the applicable
patent and marketing exclusivity protections for the innovator drug have
expired.

What is section 351 of the Public Health Service Act?
Biological products such as vaccines, blood products, allergenic products,
and certain other products such as monoclonal antibodies are licensed by
FDA under section 351 of the Public Health Service Act.  There is no
abbreviated approval pathway similar to 505(b)(2) or 505(j) for products
licensed under the Public Health Service Act.

Does FDA believe it has the authority to develop an abbreviated pathway for
licensed biological products?
For products approved under section 505 of the Food, Drug, and Cosmetic
Act, FDA believes there is existing authority to allow applications for follow-
on protein products to be approved under section 505(b)(2) of the Act
through a process that relies on the earlier approval of the innovator
product.  In contrast, there is no abbreviated approval pathway analogous
to 505(b)(2) or 505(j) of the Act for protein products licensed under section
351 of the Public Health Service Act.
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