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December 22, 2003

Division of Dockets Management (HFA-305)

Food and Drug Administration

5630 Fishers Ln., Room 1061

Rockville, MD 20852

**RE: {DOCKET NO. 2003D-0478} DRAFT GUIDANCE ON MARKETED UNAPPROVED
DRUGS; COMPLIANCE POLICY GUIDE; AVAILABILITY**

To Whom It May Concern:

We submit the following comments in response to the Draft Guidance dated
October 2003, entitled "Marketed Unapproved Drugs; Compliance Policy
Guide".

Adams Laboratories, Inc. (Adams) believes both that this Guidance is
important and that the principles and procedures it outlines are
generally workable. The Guidance demonstrates the agency's commitment to
regulate the marketing of unapproved drugs appropriately and to carry
out the mission of the Center for Drug Evaluation and Research to
*"Protect the public health by ensuring that human drugs are safe and
effective."* FDA's NDA review and approval, and the OTC monograph
system, ensure that human drugs are safe and effective. Adams fully
supports the goal expressed in the compliance policy \-- aggressive
protection of the integrity of this system.

In our view, one important aspect of this goal is to assure that any
period of enforcement discretion (grace period) provided to
manufacturers of unapproved drugs after a new product has obtained
approval to market is minimized. Any grace period, regardless of its
length, benefits manufacturers of illegal drugs and is damaging to
companies who have taken steps to secure approval, and thereby to market
drugs that conform to FDA laws and regulations. A grace period allows
manufacturers of illegal drugs to maintain their market share and fill
their distribution channels to maximum levels. For example, under
current industry standards for inventory control, a grace period of one
year allows a company manufacturing illegal drugs at least five to six
inventory turnovers of the unapproved product.

The situation for extended-release guaifenesin is illustrative. First,
the agency delayed taking any action for 6 months, and then implemented
an approximately 1-year grace period for manufacturers of illegal
guaifenesin. For Adams, which had secured FDA approval, this delay and
subsequent grace period had a significant negative impact. Adams was
committed and prepared to manufacture drug supplies sufficient to meet
the market demand following FDA approval of our product. To achieve that
goal, Adams built inventory based on our expectation that continued
marketing of unapproved drugs

**Page 2**

**RE: {Docket No. 2003D-0478} Draft Guidance on Marketed Unapproved
Drugs; Compliance Policy Guide; Availability**

would no longer be allowed. The extended grace period provided to the
manufacturers of unapproved products perturbed the market expectation
and forced Adams to destroy substantial quantities of the initially
manufactured product that would have exceeded its expiration date. We
urge the agency to take steps, in the final guidance, to address this
outcome through establishment of firm and more appropriate grace
periods.

Notwithstanding our concern about the length of time unapproved
guaifenesin products remained on the market, Adams endorses the
step-wise approach the agency took in this situation. However, we
strongly recommend a grace period of no longer than 6 months. This
length of time is both reasonable for current manufacturers of
unapproved products and more fair to the manufacturer of the new
approved product. We urge the agency to set, in step-wise fashion: an
absolute date when all manufacturing of illegal products must stop; an
absolute date when these products can no longer be distributed; and an
absolute date when these products can no longer be dispensed. A 6-month
grace period still will provide manufacturers of the unapproved drugs
roughly two to three inventory turns and minimal inventory losses.

The draft Guidance recognizes there are perhaps thousands of unapproved
drugs marketed illegally in the United States and that FDA cannot take
immediate enforcement action against all of these products because of
scarce agency resources. However, it is clear that manufacturers of
unapproved drugs fully understand the illegal status of these drugs and
that they also know how to conform to NDA and/or monograph requirements.
If FDA wishes to "encourage" the manufacturers of these products to
provide evidence demonstrating that their products are safe and
effective "without ... unnecessarily disrupting the market," the most
effective way to do this is to put these manufacturers on notice as to
the certainty and speed of FDA compliance action. Adams urges FDA to
firm up this notice in the final Compliance Policy Guide. Specifically,
these manufacturers are on notice, through this Guide, that once FDA has
approved a product that other companies are marketing without approval,
the agency will initiate compliance action.

The length of any grace period after FDA approval furthermore should not
be pegged to the date of submission of an NDA, which places the burden
of determining the grace period on the company submitting the
application. This is inappropriate. FDA cannot release information about
NDA submission publicly, but FDA's use of that date to calculate the
length of any grace period essentially forces a company to release the
information, whether it is in the company's interest or not. We suggest
that, instead, FDA's own action -- the publication of this Guidance --
serve as the official notification to the industry of possible FDA
enforcement action, to occur shortly after the approval of any currently
marketed unapproved drug.

Compliance with the approval provisions of the Federal Food, Drug, and
Cosmetic Act (the "Act") requires a manufacturer to develop consistent
formulation and stability testing, submit data periodically to FDA,
follow imposed manufacturing controls, and limit labeling and
promotional claims. Manufacturers who choose not to comply have
essentially unrestricted marketing and a very low risk of any disruption
by the agency.

**Page 3**

**RE: {Docket No. 2003D-0478} Draft Guidance on Marketed Unapproved
Drugs; Compliance Policy Guide; Availability**

The disparity is more troubling in a case where a manufacturer has
received approval of an NDA for an OTC product. Allowing the unapproved
prescription drug to remain on the market is truly an unprecedented
challenge to the drug approval system. Indeed there is a major benefit
to manufacturers of the non-approved prescription drug not only because
they are not required to comply with marketing limitations, formulation
performance, etc., but also because their products have a misleading
mantle of "legitimacy" through their prescription-only labeling. FDA
should deal more quickly with this type of situation because it poses a
very serious threat to the drug approval system.

In the case of single-ingredient, extended-release guaifenesin products,
for example, there were approximately 20 manufacturers and approximately
50 re-packagers and private label distributors of unapproved products.
Although Mucinex^^ (guaifenesin) Extended-Release Tablets, 600 mg and
1200 mg, were approved in July 2002 and December 2002 respectively, FDA
action against competitors was not effective until November 30, 2003.
This allowed the continued marketing of illegal products for up to 17
months. Sustained release guaifenesin continued to be marketed as a
prescription therapy for Fibromyalgia and any other indication the
manufacturer chose because it was not regulated under an NDA. Not only
did this garner sales in favor of the manufacturers of unapproved
products, but it also served to confuse prescribing physicians,
pharmacists, and consumers, who believed that the formulations were
legal, since the drugs were still available. Consumers, in particular,
were allowed continued exposure to products for uses that have never
been proven to be safe or effective. FDA enforcement action must quickly
end this type of marketing. Protecting the public against these types of
representations is a fundamental element of the drug approval system.

Adams strongly urges FDA to take a firm position that continued
marketing of unapproved drugs, especially after approval of a product,
is illegal and subject to enforcement action. To act otherwise is to
encourage non-compliance with the Act and also will lead to a larger
number of illegal products being introduced into the U.S. market.
Clearly notifying manufacturers of swift and certain enforcement action
will encourage companies to conform to the existing drug approval
system. Quickly removing unapproved drugs from the market after a
company obtains approval to market a product will provide incentives for
companies to comply appropriately with new drug requirements.

Sincerely,

D. Jeffrey Keyser

Vice President

Development and Regulatory Affairs

DJK/tc