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BIO letter to Rep. Michael Bilirakis, Chairman, Energy & Commerce Cmte., Subcommittee on Health, regarding the proposed approval of generic biologics
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July 26, 2001
Honorable Michael Bilirakis
Chairman
Subcommittee on Health
Committee on Energy and Commerce
U.S. House of Representatives
2125 Rayburn Building
Washington, DC 20015
Dear Mr. Chairman:
On June 13, your Subcommittee held a hearing entitled "Recent
Developments Which May Impact Consumer Access to, and Demand for, Pharmaceuticals."
During the questioning of Janet Woodcock, M.D., Director, Food and Drug Administration
(FDA), Center for Drug Evaluation and Research, Representative Pallone asked
Dr. Woodcock if "the FDA has a pathway to approve generic biologics?"
The Biotechnology Industry Organization (BIO) respectfully
requests that this letter, which responds to Representative Pallone’s question,
be included in the hearing record. For the reasons set forth below, it is BIO’s
opinion that any action establishing a pathway for "generic biologics"
would be inconsistent with current provisions of the Federal Food, Drug and
Cosmetic Act (the "FD&C Act") and the Public Health Science Act
(the "PHS Act"). Moreover, such action would clearly violate the intent
of Congress, as recently expressed during consideration of the Food and Drug
Administration Modernization Act of 1997 ("FDAMA").
Overview
A generic drug is a copy of an original, pioneer drug product.
A specific statutory mechanism exists under the FD&C Act that allows for
the premarket approval of generic drugs based on a showing that the generic
is "the same as" the pioneer drug product. No independent clinical showing of
the safety and effectiveness of the generic is required or even permitted under
the statute. Instead, FDA is required to approve the generic if it is shown
to have the same active ingredient, same dosage form, same route of administration,
and same strength as the pioneer, and if the generic becomes available inside
the body at the same rate and to the same extent as the pioneer drug. See
generally section 505(j) of the FD&C Act.
This "abbreviated" path to the market applies only to generic
versions of "new drugs" that were approved for marketing under section 505(c)
of the FD&C Act. As shown below, it does not apply to biological products
that are marketed under licenses issued under the PHS Act, including most of
the leading biotechnology products. See generally section 351 of the
PHS Act.
The Waxman-Hatch Amendments
A manufacturer seeking to market a pioneer "new drug" product
(see section 201(p) of the FD&C Act) must obtain FDA approval through
a new drug application ("NDA"). Under section 505(b) of the FD&C Act, an
NDA must include full reports of clinical studies demonstrating that the drug
is safe and effective for each proposed use. This consists of "adequate and well-controlled clinical studies" providing
"substantial evidence" to support each claim of effectiveness for the product.
21 USC 355(d); 21 CFR 314.126. The research and clinical studies needed to support
an NDA are time-intensive and costly.
In 1984, after extensive debate, Congress enacted the Drug
Price Competition and Patent Term Restoration Act of 1984 (Pub. L. 98-417) (often
referred to as "Waxman-Hatch"). The law included two principal features:
- Title I established a statutory basis for approving
generic versions of pioneer drugs. It amended the FD&C Act to authorize
premarket approval based on abbreviated new drug applications (ANDAs), which
lack an independent demonstration of safety and effectiveness. Instead of
clinical safety and effectiveness data, an ANDA need only show that the
proposed drug is the same as a "listed drug" (i.e., a drug
approved by FDA pursuant to an NDA and listed by FDA in "The Orange Book").
Among other things, the generic product must be shown to contain the same
active ingredient as the listed drug and must be bioequivalent to the listed
drug.
- Title II amended Title 35, United States Code
to authorize a limited extension of patent terms on the patents covering
approved new drugs. Title II was intended to compensate manufacturers, at
least in part, for the loss of patent term during FDA regulatory review.
Title II of Waxman-Hatch (the patent term provisions) on
its face applied both to biological products and new drugs. Title II added new
section 156 to Title 35 of the United States Code. Section 156 specifically
authorized an extension of the "term of a patent which claims a product,
a method of using a product, or a method of manufacturing a product." Title
II defined the term "product" to mean a "human drug product"
and, even further, defined the term "human drug product" as including
the active ingredient of a "human biological product." 35 U.S.C.156
(f)(1) and (f)(2).
Conversely, Title I Waxman-Hatch (the generic drug provisions)
amended only those sections of the FD&C Act relating to premarket approval
of new drugs. Title I used only the term "new drug" and not the terms
"drug" or "biological product" when referring to the filing
of an ANDA. See, e.g., section 505(j)(1) of the FD&C Act ("Any
person may file. . . an abbreviated application for a ‘new drug’.").
The fact that biological products were excluded from the
ANDA provisions was confirmed by an FDA letter issued shortly after Congress
enacted Waxman-Hatch. The letter, written in response to questions that had
been presented to FDA, provides the agency's own contemporaneous interpretation
of the law:
Q. It is clear that. . . biologicals are included in Title II. . . . [B]ut are biologicals included in Title I, the ANDA portion of the Act?
A. No. There is no specific provision
in Title I that includes. . . biologicals. . . . The Act refers to generic
versions of those drugs originally approved under Section 505(b) of
the Federal Food, Drug and Cosmetic Act. Biologicals are approved under
the Public Health Service Act. . . . Accordingly, we do not consider
these products to be covered by Title I.
Letter from Harry M. Meyer, Jr., M.D., Director, Center for Drugs and Biologics FDA, Nov. 16, 1984.
As described above, Title I of Waxman-Hatch provided
specific statutory authority for the approval of generic versions of drug products
that had been approved under NDAs. See section 505(j)(2)(A) of the FD&C
Act. No parallel provision was included or even contemplated for biological
products that are licensed under section 351 of the PHS Act. Moreover, licensed
biological products are not "approved for safety and effectiveness under [section
505(c)]" and, therefore, are neither listed in FDA's "Orange Book" nor
otherwise eligible to be referenced in a generic drug application. See section
505(j)(2)(A)(i) and 505(j)(7).
FDAMA
At the end of the debate that preceded the enactment of
FDAMA, the issue of the applicability of the ANDA provisions to biological products
was renewed, perhaps unintentionally. The conference report on FDAMA included
a provision that was not contained in either the House or Senate versions of
the 1997 legislation. The provision section 123(g) of FDAMA added a new subsection
(j) to section 351 of the PHS Act as follows:
(j) The Federal Food, Drug, and Cosmetic Act applies
to a biological product subject to regulation under this section, except
that a product for which a license has been approved under this section
shall not be required to have an approved application under section
505 of such Act.
PHS Act 351(j).
The biotechnology industry expressed concern that some may
interpret this section to allow biological products to be approved using the
"new drug" ANDA process. As a result, the House passed a technical corrections
bill (House Con. Res. 196, 105th Cong., 1st sess.) clarifying that new section
351(j) of the PHS Act did not subject biological products to Title I of Waxman-Hatch.
Although the bill was never considered by the Senate, on December 3, 1997, Senators
Jeffords and Kennedy wrote FDA's Lead Deputy Commissioner (who, at the time,
was serving as Acting Commissioner) about new section 351(j). The Senators expressed
concern that "the new provision could erroneously be read to render biological
products subject to Title I of [Waxman-Hatch]. . . . We wish to make it clear
that the provisions of section 123(g) of [FDAMA] were not intended by Congress
to change the status of biological products under the provisions of Title I
of Pub. L. 98-417."
In response, FDA’s Associate Commissioner for Legislative
Affairs sent letters to Senators Jeffords and Kennedy acknowledging the Senators'
intent "to make it clear that the provisions of the new section were not
intended to change the current status of biological products under the provisions
of Title I of Pub. L. 98-417" and assuring them that "the Food and
Drug Administration does not view the new section 351(j) as changing the current
status of the law with respect to biological products." Letters from Diane
E. Thompson, Associate Commissioner for Legislative Affairs, to Senator James
Jeffords and Senator Edward M. Kennedy, dated January 28, 1998.
Takings
Finally, some have suggested that FDA could create a regulatory
pathway for approving generic versions of biological products simply by changing
the regulatory status of a specific product or class of products from "biological
products" (requiring licensure under the PHS Act) to "new drugs" (requiring
approval under the FD&C Act). According to this argument, once a given product
is "converted" from biological product to new drug, FDA would be fully authorized
to approve generic versions of the product under section 505(j).
Putting aside the statutory issue raised above (i.e.,
that section 505(j) is available only for new drugs that were approved under
NDAs), we believe that such an approach would raise substantial constitutional
and administrative law questions, including the unlawful taking of proprietary
data and trade secrets held by the biotechnology industry. See, e.g., Ruckelshaus
v. Monsanto Co., 467 U.S. 986 (1984); Tri-Bio Laboratories Inc. v. United
States, 836 F.2d 135 (3d Cir. 1987), cert. denied 484 U.S. 818 (1988).
A change in regulatory status (from biological product to new drug) to allow
for the approval of generics would, in effect, retroactively undo the reasonable
expectations of the biotechnology industry.
The industry has made substantial investments based on the
existing structure and regulatory classifications. Were FDA to undo that structure
for licensed biological products, it would raise substantial questions under
the Administrative Procedure Act and would expose the government to financial
liability for having taken or destroyed property rights. We would welcome the
opportunity to explore this issue further, should the need arise.
Thank you for the opportunity to present BIO’s analysis
of the legal issues involved in this important public health issue. There are,
of course, important scientific issues that we would be happy to address at
a later date.
Sincerely,
Stephan E. Lawton
Vice President and General Counsel
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