![](media/image1.wmf){width="1.3625in" height="0.6541666666666667in"}

***Pharmaceutical Research and Manufacturers of America***

1100 15^th^ Street, NW, Washington, DC 20005 Tel: 202/835-3400

May 29, 1998

Peggy Dotzel

Senior Science Policy Advisor

Office of Policy

Food and Drug Administration (HF-13)

5600 Fishers Lane

Rockville, MD 20857

**Re: PhRMA Recommended Approach For Implementing**

> **FDAMA §401 -- Dissemination of Treatment Information**

Dear Ms. Dotzel:

We are writing on behalf of the Pharmaceutical Research and
Manufacturers of America (PhRMA), which represents the country's leading
research-based pharmaceutical and biotechnology companies, to provide
industry input on Section 401 of the FDA Modernization Act of 1997
(FDAMA).

As you know, FDAMA §401 adds a new subchapter D to the Drugs and Devices
Chapter V of the Federal Food, Drug, and Cosmetic Act to permit
manufacturers to disseminate information to health care providers on
unapproved uses of approved drugs, biological products, and devices,
under certain conditions. This provision takes effect one year after
enactment of FDAMA, November 21, 1998, or upon the issuance of
implementing regulations, whichever first occurs. Section 401 represents
a significant change from FDA's traditional prohibition on the
dissemination of any off-label information. PhRMA's Dissemination Work
Group prepared the attached comments to assist FDA in implementing this
important provision. The Work Group is available at your convenience to
discuss this recommended approach and answer any questions; we hope that
you and others at FDA, and interested members of the public, find this
input useful.

Sincerely yours,

Alexander R. Giaquinto, Matthew B. Van Hook

Sr. VP Worldwide Regulatory Affairs, Deputy General Counsel, PhRMA

Schering-Plough Corporation 202/835-3513

Chair, PhRMA Dissemination Work Group

908/298-5770

cc: Jane Axelrad, Associate Director for Policy, CDER/FDA

**May 29, 1998**

***PhRMA Recommended Approach***

***FDAMA §401 \-- Dissemination***

PhRMA'S RECOMMENDED APPROACH TO THE IMPLEMENTATION OF THE TREATMENT
INFORMATION DISSEMINATION PROVISIONS OF THE FDA MODERNIZATION ACT (§
401)

Section 401 of the Food and Drug Administration Modernization Act of
1997, Pub. L. No. 105-115, 111 Stat. 2296 (1997), adds a new subchapter
D to the Drugs and Devices Chapter V of the Federal Food, Drug &
Cosmetic Act (FFDCA) to permit manufacturers to disseminate information
on unapproved ("off-label") uses of approved drugs, biological products,
and devices under certain conditions. Section 401 facilitates the
sharing of important treatment information with health care providers to
enable better patient care in accordance with current medical knowledge.
At the same time, Section 401 places controls on the dissemination of
information on unapproved uses and establishes requirements for
manufacturers to conduct follow-up research and file supplemental
product applications with FDA to include the new use(s) in product
labeling. These provisions take effect on November 21, 1998, or upon the
FDA\'s promulgating implementing regulations, whichever is earlier.

Section 401 represents a significant change from FDA's traditional
prohibition on the dissemination of any off-label information. The
conditions Congress imposed on the dissemination of such information are
intended to protect the public health while facilitating the access of
health care providers to valuable scientific information. *See* Joint
Explanatory Statement of the Committee on Conference at 10; H. R. Rep.
No. 105-43 at 60 (1997). Those conditions should not be interpreted so
narrowly as to nullify the reforms Congress intended in enacting the FDA
Modernization Act. Indeed, Section 401 is the most detailed and lengthy
provision in the FDA Modernization Act and embodies a careful
compromise. When FDA promulgates regulations to implement Section 401,
as required by the FDA Modernization Act, it must respect that
compromise. Key issues that FDA should address in implementing Section
401 include: (1) clarifying important details of the basic requirements
for disseminating off-label information; (2) streamlining the process
for the review of reprints and adopting an appropriate definition of
qualifying reference texts; (3) clarifying the content and timing of
applicable reporting requirements; (4) ensuring that determinations
regarding proposed study protocols are timely and delineating the
obligations to submit progress reports on studies; and (5) providing for
an appeal of determinations that supplements are inadequate.

1.  [Basic Requirements for Disseminating Off-Label
    Information]{.underline}

Section 401 provides that a manufacturer may disseminate information
concerning the safety, effectiveness, or benefit of a product's use not
described in the approved labeling of the product to a health care
practitioner, a pharmacy benefit manager, a health insurance issuer, a
group health plan, or a Federal or State governmental agency. FFDCA §
551(a); 221 U.S.C. § 360aaa(a). In order to distribute off-label
information to these audiences, the following basic conditions must be
met:

(1) the drug, biological product, or device must be approved;

(2) the information must be in an approved form and not be false or
    misleading or pose a significant risk to the public health, as
    delineated further in a separate portion of Section 401;

(3) the information must not be derived from research conducted by
    another manufacturer, except with its permission;

(4) the manufacturer must submit the information to FDA 60 days before
    beginning distribution, together with any safety and effectiveness
    information from clinical trials and safety information from reports
    of clinical experience;

(5) the manufacturer must comply with the requirements relating to the
    submission of a supplement covering the use in question; and

(6) the manufacturer must include with the information to be
    disseminated a prominent statement that the use has not been
    approved, a copy of the approved labeling, disclosures relating to
    authorship and funding of the disseminated information, a
    bibliography of other articles published about the use of the
    product covered by the information disseminated, and a statement (if
    applicable) that other products or treatments have been approved for
    the use being discussed in the disseminated information.

FFDCA § 551(b); 21 U.S.C. § 360aaa(b). FDA may also require the
manufacturer to disseminate additional safety and effectiveness
information, if the Agency determines after giving notice and meeting
with the manufacturer that such additional information is necessary to
provide objectivity and balance. FFDCA § 551(c); 21 U.S.C. §
360aaa(c).[^1]

In order to implement these basic requirements in an efficient and
sensible manner, FDA should clarify certain important details. First,
when a manufacturer submits information to FDA as required by Section
401, it should submit the information to both the Division of Drug
Marketing, Advertising and Communication (DDMAC) and the appropriate
Reviewing Division. Second, FDA should provide that the method used to
present the disclosures and documentation required to accompany the
disseminated information may take a number of forms (*e.g.*, cover page,
reprint carrier, etc.). Nothing in Section 401 requires that the
disclosures be made in any specific manner, and FDA should provide
manufacturers flexibility, provided that the disclosures and other
information are clear and sufficiently conspicuous. Third, the
manufacturer should not be required to identify the name of any
particular product or treatment approved for the use which is the
subject of the information being disseminated, as long as the
manufacturer includes a statement that other products or treatments
exist that have been approved for such use. Nothing more is required by
Section 401, and confusion could be created if manufacturers were
required to provide detailed information about the products of other
manufacturers.

As FDA clarifies and implements these requirements, it should ensure
that it reviews the information a manufacturer submits in order to
disseminate material under Section 401 and resolves all pertinent issues
(*e.g.*, the need for additional information) within the 60-day period
prior to information dissemination. If FDA does not notify a
manufacturer of problems with the planned dissemination of information
within the 60-day review period, dissemination may proceed and the
information is considered objective and balanced under FFDCA § 551(c)
(21 U.S.C. § 360aaa(c)).

2\. [Information Authorized to be Disseminated]{.underline}

The only information that a manufacturer may distribute under Section
401 is (1) a "scientifically sound" unabridged reprint of a
peer-reviewed article published in a

scientific or medical journal[^2] about a clinical investigation, or (2)
a reference publication containing similar information. FFDCA § 552(a);
21 U.S.C. § 360aaa-1(a). To qualify, a reference publication must not
have been prepared at the manufacturer's request or significantly
influenced or distributed solely by the manufacturer, and must not focus
on a particular drug or device, or present materials that are false or
misleading. FFDCA § 552(b); 21 U.S.C. § 360aaa-1(b). None of the
information may be false or misleading or "pose a significant risk to
the public health." FFDCA § 552(a); 21 U.S.C. § 360aaa-1(a).

In applying these requirements, FDA should accept for review final
manuscripts or pre-prints of articles that have cleared the peer-review
process (*i.e.*, have been accepted for publication or are to be
published during the 60-day review period). This will prevent the
dissemination of qualifying articles from being delayed by having to
wait for actual publication before beginning the 60-day review period.

In addition, FDA should exercise prudence in construing the prohibition
that a reference publication cannot focus primarily on new uses of a
particular product. Provided that the discussion of the product is
objective, a reference publication with a significant focus on a
particular product provides valuable new clinical information in
accordance with the purposes underlying Section 401.

3\. [Recordkeeping and Reporting]{.underline}

A manufacturer must submit to FDA biannually a list of articles and
reference publications distributed under Section 401 and a list
identifying the categories of persons that received them. FFDCA §
553(a); 21 U.S.C. § 360aaa-2(a). A manufacturer must also maintain
records to facilitate any corrective action that FDA might require.
FFDCA § 553(b); 21 U.S.C. § 360aaa-2(b). In implementing these
requirements, FDA should not require that a manufacturer maintain
records of individual recipients of information disseminated under
Section 401. Maintaining records of the categories of recipients of
information is adequate to facilitate appropriate corrective action and
avoids the heavy administrative burden of individual records. The
required timing for the submission of reports to FDA should be
determined by the date of the first dissemination of any information by
the manufacturer.

4\. [Requirement of Submitting a Supplemental Application]{.underline}

In order to disseminate off-label information concerning a new use under
Section 401, a manufacturer must have submitted to FDA a supplemental
application covering the new use, certify that it will submit a
supplement, or obtain an exemption from the

supplement requirement. FFDCA § 554(a); 21 U.S.C. § 360aaa-3(a).[^3]

When a manufacturer certifies that it will submit a supplemental
application within 36 months of disseminating information under Section
401 and submits a proposed protocol and schedule, FDA should determine
the adequacy of the proposed protocol and schedule pursuant to FFDCA
§ 554(c)(1)(B) (21 U.S.C. § 360aaa-3(c)(1)(B)) and resolve any issues
with the manufacturer within the 60-day time period prior to the start
of information dissemination activities. If FDA does not notify the
manufacturer otherwise during the 60-day period before dissemination,
the proposed protocol and schedule should be deemed adequate. If FDA has
any objection to the proposed protocol and schedule during the 60-day
period before dissemination, it should immediately notify the
manufacturer and provide the manufacturer an opportunity to meet and
resolve the issue.

Progress reports on studies required under this section should be
submitted in accordance with the standard IND/NDA reporting
requirements.

When a manufacturer applies for an exemption from the supplement
requirement, the 60-day period within which FDA must approve or deny the
application should run from the date FDA receives the application. FDA
should provide timely notice to the applicant of the date it received
the application. As specified in Section 401, an exemption request will
be deemed to be approved if FDA does not act on it within 60 days of
receipt, although FDA can thereafter terminate the approval. FFDCA §
554(d)(3); 21 U.S.C. § 360aaa-3(c)(3).

5\. [Corrective Actions]{.underline}

If FDA receives new information following the dissemination of
information under Section 401 that indicates that the new use may not be
effective or may present a "significant risk to public health," the
Agency may, after consulting with the manufacturer, take appropriate
action, including ordering the manufacturer to cease dissemination of
information concerning the new use. FFDCA § 555(a); 21 U.S.C.
§ 360aaa-4(a). Manufacturers are required to report new safety and
effectiveness information to FDA. FFDCA § 555(a)(2); 21 U.S.C. §
360aaa-4(a)(2).[^4]

Before FDA takes any corrective actions based on a determination that a
supplement is inadequate for approval, the Agency should afford a
manufacturer the opportunity (informally, or through available appeals
procedures) to resolve outstanding issues to avoid unnecessary and
burdensome corrective action. The manufacturer should be permitted to
continue to disseminate the information related to such an application
pending the outcome of any resolution or appeals process. FDA should
only order corrective action when the dissemination of information
concerning a new use presents a significant risk. Corrective action will
not be warranted in all cases where FDA does not approve a supplement,
and FDA should use its authority under this provision judiciously.

A manufacturer should be able to satisfy its obligations to report new
safety and effectiveness information to FDA by complying with the
existing postmarketing reporting requirements related to adverse drug
experiences (21 C.F.R. § 314.80) and annual reports (21 C.F.R.
§ 314.81). All significant information on safety and effectiveness is
reported through these established mechanisms, and there should be no
need to create an additional administrative obligation.

\* \* \*

Section 401 of the FDA Modernization Act provides an important new
mechanism to share valuable medical information with health care
providers. The detailed requirements already specified in Section 401
ensure that such information must be disseminated in an appropriate
manner and that incentives exist to file supplemental product
applications. When implementing Section 401, FDA should clarify certain
important additional details related to the requirements of Section 401.
At the same time, FDA should take care to preserve the compromises and
balance already embodied in this significant statutory provision. FDA
should not impede implementation of Section 401 by promulgating
restrictive regulations where the statutory provisions themselves
already provide adequate controls and specific restrictions on the
dissemination of off-label information.

[^1]: Information disseminated in accordance with these and the other
    requirements of Section 401 will not be considered product labeling
    and will not cause a product to be adulterated or misbranded, or be
    considered as evidence of a new intended use. FFDCA § 557(b); 21
    U.S.C. § 360aaa-6(b). Disseminating information in violation of
    Section 401 is a prohibited act under the FFDCA. FFDCA § 301(z); 21
    U.S.C. § 331(z). Manufacturers remain free to respond to unsolicited
    requests for information. FFDCA § 557(a); 21 U.S.C. § 360aaa-6(a).

[^2]: A scientific or medical journal under Section 401 is a journal
    that has an expert editorial board and policy requiring full
    disclosure by authors of conflicts of interest, requires that
    articles be peer-reviewed in accordance with regular procedures, is
    "generally recognized to be of national scope and reputation," is
    indexed in the Index Medicus, and is not in the form of a "special
    supplement" funded wholly or partly by one or more manufacturers.
    FFDCA § 556(5); 21 U.S.C. § 360aaa-5(5).

[^3]: When a manufacturer certifies that it will submit a supplement, it
    must either certify that it has completed the necessary studies and
    will submit the supplement within six months of the initial
    dissemination of off-label information (FFDCA § 554(b); 21 U.S.C. §
    360aaa-3(b)), or submit a proposed protocol and schedule for the
    studies to FDA and commit to filing the supplement within 36 months
    (FFDCA § 554(c)(1); 21 U.S.C. § 360aaa-3(c)(1)). For proposed
    studies, FDA must make a determination that the proposed protocol is
    adequate and that the planned schedule is reasonable. FFDCA
    § 554(c)(1); 21 U.S.C. § 360aaa-3(c)(1). The manufacturer must also
    make periodic progress reports to FDA. FFDCA § 554(c)(2); 21 U.S.C.
    § 360aaa-3(c)(2). FDA can extend the 36-month period for up to 24
    additional months if the manufacturer has acted with "due
    diligence." FFDCA § 554(c)(3); 21 U.S.C. § 360aaa-3(c)(3).

    A manufacturer can request an exemption from the supplement
    requirement if it would be "economically prohibitive" or "unethical"
    to conduct the studies and submit the supplement. FFDCA § 554(d); 21
    U.S.C. § 360aaa-3(d).

[^4]: FDA may also order a manufacturer to cease dissemination of
    information under Section 401 if FDA determines that the information
    being disseminated does not comply with the requirements of Section
    401, the manufacturer has not submitted a supplement within six
    months as promised or has not acted with due diligence in the
    completion of studies and submission of a supplement, or FDA
    terminates a "deemed approved" exemption from the supplement
    requirement. FFDCA § 555(b); 21 U.S.C. § 360aaa-4(b). When FDA
    orders a manufacturer to cease disseminating information, the Agency
    may also require the manufacturer to take action to correct
    information that has been disseminated. FFDCA § 555(d); 21 U.S.C. §
    360aaa-4(d).