Notice: Communications and Activities Related to Off-Label Uses of 
Marketed Products and Use of Products Not Yet Legally Marketed; Request 
for Information and Comments

Federal Register: Volume 76, Number 249 (Wednesday, December 28, 2011)
                  Pages 81508-81510

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice; request for comments.

SUMMARY: The Food and Drug Administration (FDA) is announcing the 
establishment of a docket to assist with our evaluation of our policies 
on communications and activities related to off-label uses of marketed 
products, as well as communications and activities related to use of 
products that are not yet legally marketed for any use, we would like 
to obtain comments and information related to scientific exchange. FDA 
is interested in obtaining comments and information regarding 
scientific exchange about both unapproved new uses of products already 
legally marketed (``off-label'' use) and use of products not yet 
legally marketed for any use.

DATES: Submit either electronic or written information and comments by 
March 27, 2012.

ADDRESSES: Submit electronic information and comments to http://www.regulations.gov. 
Submit written information and comments to the 
Division of Dockets Management (HFA-305), Food and Drug Administration, 
5630 Fishers Lane Rm. 1061, Rockville, MD 20852. Identify both 
electronic and written comments and any supporting documents with the 
docket number found in brackets in the heading of this document.

FOR FURTHER INFORMATION CONTACT: 

For the Center for Drug Evaluation and Research

    Nicole Mueller, Center for Drug Evaluation and Research, Food and 
Drug Administration, 10903 New Hampshire Ave. Bldg. 51, Rm. 6312, 
Silver Spring, MD 20993-0002, (301) 796-3601.

For the Center for Biologics Evaluation and Research

    Stephen Ripley, Center for Biologics Evaluation and Research (HFM-
17), Food and Drug Administration, 1401 Rockville Pike, Suite 200N, 
Rockville, MD 20852-1448, (301) 827-6210.

For the Center for Devices and Radiological Health

    Deborah Wolf, Center for Devices and Radiological Health, Food and 
Drug Administration, 10903 New Hampshire Ave. Bldg. 66, Rm. 3414, 
Silver Spring, MD 20993-0002, (301) 796-5732.

SUPPLEMENTARY INFORMATION: 

I. Background

    On July 5, 2011, a citizen petition was submitted by Ropes & Gray 
and Sidley Austin LLP on behalf of seven product manufacturers 
(Petitioners): Allergan, Inc.; Eli Lilly and Co.; Johnson & Johnson; 
Novartis Pharmaceuticals Corp.; Novo Nordisk, Inc.; Pfizer, Inc.; and 
sanofi-aventis U.S. LLC under 21 CFR 10.30. The citizen petition 
requested that FDA clarify its policies for drug products and devices 
governing certain communications and activities related to off-label 
uses of marketed products and use of products that are not yet legally 
marketed for any use.\1\ Specifically, the petition requests 
clarification in the following areas:
---------------------------------------------------------------------------

    \1\ See Docket No. FDA-2011-P-0512 at http://www.regulations.gov 
for a copy of the citizen petition.
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    1. Manufacturer responses to unsolicited requests;
    2. Scientific exchange;
    3. Interactions with formulary committees, payors, and similar 
entities; and
    4. Dissemination of third-party clinical practice guidelines.
    For some time, FDA has been considering these issues and is 
currently evaluating our policies on sponsor or investigator 
communications and activities related to off-label uses of marketed 
products and use of products that are not yet legally marketed for any 
use. We have been considering what actions to take in the areas 
specified by the petitioners with respect to manufacturer responses to 
unsolicited requests; interactions with formulary committees, payors, 
and similar entities; and the dissemination of third-party clinical 
practice guidelines. To assist with our evaluation of our policies on 
communications and activities related to off-label uses of marketed 
products, as well as communications and activities related to use of 
products that are not yet legally marketed for any use, we would like 
to obtain comments and information related to scientific exchange.
    Under the Federal Food, Drug, and Cosmetic Act (the FD&C Act) and 
the Public Health Service Act (PHS Act), any person who wishes to 
introduce or deliver for introduction into interstate commerce any new 
drug (including a biological drug product) must demonstrate that the 
product is safe and effective for its intended uses (see sections 
505(a) and 512(a) of the FD&C Act (21 U.S.C. 355(a) and 360b(a)) and 
section 351 of the PHS Act (42 U.S.C. 262)). Any person who wishes to 
introduce or deliver for introduction into interstate commerce a new 
medical device (including a biological device product) must either 
demonstrate that the device has a reasonable assurance of safety and 
effectiveness for its intended uses or that it is substantially 
equivalent to a legally marketed predicate device (see sections 510(k), 
513(f), and 515(a) of the FD&C Act (21 U.S.C. 360(k), 360c(f), 360e(a)) 
and section 351 of the PHS Act (42 U.S.C. 262)).
    The demonstrations of product safety and efficacy usually consist 
of data and information derived from clinical investigations and 
presented as part of a marketing application. The marketing application 
also contains information regarding the product's intended uses, the 
patient population (including any special conditions, restrictions, or 
limitations for segments of the population, such as children, pregnant 
women, or the elderly), potential adverse events associated with the 
product's use, and technical information about the product (see, e.g., 
21 CFR 314.50, 514.1, 601.25, and 814.20). If FDA agrees that a product 
is safe and effective for its intended uses, as reflected in the 
marketing application, it approves the application and certain required 
product labeling. For devices subject to clearance through the 510(k) 
process, the clearance establishes the intended use(s) for which it is 
legal to market the product. The uses that are approved or cleared by 
the Agency are sometimes referred to as ``labeled'' uses because they 
appear in the product's required labeling. Uses that do not appear in 
the labeling and are not approved or cleared by the Agency are referred 
to as ``unapproved,'' ``unlabeled,'' ``off-label,'' or ``extra-label'' 
uses.
    As explained previously in this document, under section 505 of the 
FD&C Act, a new drug (which includes a marketed drug intended for a new 
use) may not be introduced or delivered for introduction into 
interstate commerce without approval by FDA, but FDA is authorized to 
create regulations

[[Page 81509]]

exempting from this requirement drugs intended for use in 
investigations to examine their safety or effectiveness (21 U.S.C. 
355(i)). Under this authority, current FDA regulations in part 312 (21 
CFR part 312) require submission of an investigational new drug 
application (IND) to FDA and set the other requirements for exemption. 
Regulations at Sec. Sec.  312.22 and 312.23 contain the general 
principles underlying the IND submission and the general requirements 
for an IND's content and format. Drugs under investigation are subject 
to certain requirements in order to meet the terms of the exemption 
from approval prior to introduction into interstate commerce. One such 
requirement is a limitation on promotional activity, set forth in Sec.  
312.7. However, this regulation expressly states that it is not 
intended to restrict the full exchange of scientific information 
concerning the drug, including dissemination of scientific findings in 
scientific or lay media. Rather, its intent is to restrict promotional 
claims of safety or effectiveness of the drug for a use for which it is 
under investigation and to preclude commercialization of the drug 
before it is approved for commercial distribution.
    There is a similar statutory and regulatory framework for 
investigational devices. Section 520(g) of the FD&C Act (21 U.S.C. 
360j(g)) establishes the program by which sponsors may apply for 
investigational device exemptions (IDE), which allow for the 
investigational use of devices by experts qualified by scientific 
training and experience to investigate the safety and effectiveness of 
those devices and exempt the devices subject to approved IDEs from the 
statutory requirement that devices not otherwise exempt from premarket 
notification under section 510(k) of the FD&C Act be approved or 
cleared via premarket approval or premarket notification submissions. 
Regulations at 21 CFR 812.7 provide in relevant part that: ``A sponsor, 
investigator, or any person acting for or on behalf of a sponsor or 
investigator shall not:'' (1) ``Promote or test market an 
investigational device, until after FDA has approved the device for 
commercial distribution'' or (2) ``Represent that an investigational 
device is safe or effective for the purposes for which it is being 
investigated.''
    FDA has made prior statements regarding scientific exchange about 
investigational products. For example, in the Federal Register of May 
22, 1987 (52 FR 19466), the Agency published a final rule entitled 
``Investigational New Drug, Antibiotic, and Biological Drug Product 
Regulations; Treatment Use and Sale'' that provided for ways in which 
investigational new drugs could be made available to desperately ill 
patients prior to general marketing and that addressed charging for 
investigational drugs. In the preamble to that rule, FDA stated: 
``FDA's understanding of commercial promotion does not place limits on 
the free exchange of scientific information [regarding investigational 
drugs] (e.g., publishing results of scientific studies, letters to the 
editor in defense of public challenges, investigator conferences). 
However, responses by sponsors or investigators to unsolicited media 
inquiries or statements made in the exchange of scientific information 
should (1) Make clear that a drug is investigational; (2) make no 
claims that a drug has been proven to be safe or effective; and (3) be 
truthful and non-misleading when measured against available information 
on the drug--and fairly represent available information-- as set forth 
in materials such as investigators' brochures and patients' informed 
consent sheets.'' (52 FR 19466 at 19475).

II. FDA Is Seeking Comments on Communications and Activities Related to 
Off-Label Uses of Marketed Products and Use of Products Not Yet Legally 
Marketed

    Interested persons are invited to provide detailed comment on all 
aspects of scientific exchange communications and activities related to 
off-label uses of marketed drugs, biologics, and devices and use of 
products that are not yet legally marketed. FDA is particularly 
interested in responses to the following questions.
     How should FDA define scientific exchange?
     What types of activities fall under scientific exchange?
     What types of activities do not fall under scientific 
exchange?
     Are there particular types and quality of data that may 
indicate that an activity is, or is not, scientific exchange?
     In what types of forums does scientific exchange typically 
occur? Should the use of certain forums be given particular 
significance in determining whether an activity is scientific exchange 
or an activity that promotes the drug or device? If so, which forums?
     What are the distinctions between scientific exchange and 
promotion? What are the boundaries between scientific exchange and 
promotion?
     Generally, who are the speakers involved in scientific 
exchange, and who is the audience for their communications?
     Should the identity of the participants (either speakers 
or audience) be given particular significance in determining whether an 
activity is scientific exchange or an activity that promotes the drug 
or device? If so, which participants would be indicative of scientific 
exchange and which would be indicative of promotion?
     How do companies generally separate scientific roles and 
promotional roles within their corporate structures?
     How should the Agency treat scientific exchange concerning 
off-label uses of already approved drugs and new uses of legally 
marketed devices? Please address whether there should be any 
distinctions between communications regarding uses under FDA-regulated 
investigation (to support potential approval) and communications 
regarding uses that are not under express FDA-regulated investigation.
     How should the Agency treat scientific exchange concerning 
use of products that are not yet legally marketed (that is, products 
that cannot be legally distributed for any use outside of an FDA- or 
institutional review board (IRB)-approved clinical trial)?
     Should investigational new drugs and investigational 
devices be treated the same with respect to scientific exchange? Why or 
why not?
     Under 21 CFR 812.7(b), an investigational device is 
considered to be ``commercialized'' if the price charged for it is more 
than is necessary to recover the costs of manufacture, research, 
development, and handling. Similarly, FDA considers charging a price 
for an investigational drug that exceeds that permitted under its 
regulations (generally limited to cost recovery) to constitute 
``commercialization'' of the drug (see 74 FR 40872 at 40890, August 13, 
2009; 52 FR 19466 at 19467). What other actions indicate the 
commercialization of drug and/or device products? If there are 
differences in the steps taken to commercialize drug products and the 
steps taken to commercialize device products, either before or after 
approval, please explain these differences.

III. Submission of Information and Comments

    Interested persons may submit information and comments to the 
Division of Dockets Management (see ADDRESSES) in electronic or written 
form. It is only necessary to send one set of comments. Identify 
comments with

[[Page 81510]]

the docket number found in brackets in the heading of this document. 
Except for data and information prohibited from public disclosure under 
21 U.S.C. 331(j) or 18 U.S.C. 1905, submissions may be seen in the 
Division of Dockets Management between 9 a.m. and 4 p.m., Monday 
through Friday.

    Dated: December 21, 2011.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2011-33188 Filed 12-27-11; 8:45 am]
BILLING CODE 4160-01-P