[Federal Register Volume 73, Number 185 (Tuesday, September 23, 2008)]
[Notices]
[Pages 54831-54834]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E8-22300]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2008-N-0481]


Topical Drug Products Containing Papain; Enforcement Action Dates

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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[[Page 54832]]

SUMMARY: The Food and Drug Administration (FDA) is announcing its 
intention to take enforcement action against unapproved topical drug 
products containing papain and persons\1\ who manufacture or cause the 
manufacture of such products or their shipment in interstate commerce. 
Topical drug products containing papain are marketed, without approved 
applications, to debride necrotic tissue and liquefy slough in acute 
and chronic lesions. Potentially serious adverse events have been 
reported with topical drug products containing papain. Topical drug 
products containing papain are new drugs that require approved 
applications because they are not generally recognized as safe and 
effective. Currently no firm has an approved application to market a 
topical drug product containing papain. Manufacturers who wish to 
market topical drug products containing papain must obtain FDA approval 
of a new drug application (NDA) or an abbreviated new drug application 
(ANDA).
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    \1\ A ``person'' includes individuals, partnerships, 
corporations, or associations (21 U.S.C. 321(e)).

DATES: This notice is effective September 23, 2008. For information 
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about enforcement dates, see SUPPLEMENTARY INFORMATION, section III.B.

ADDRESSES: All communications in response to this notice should be 
identified with Docket No. FDA-2008-N-0481 and directed to the 
appropriate office listed as follows:
    Regarding applications under section 505(b) of the Federal Food, 
Drug, and Cosmetic Act (the act) (21 U.S.C. 355(b)): Division of 
Dermatology and Dental Products, Office of New Drugs, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 22, Silver Spring, MD 20993-0002.
    All other communications: Jennifer Devine, Center for Drug 
Evaluation and Research (HFD-310), Food and Drug Administration, 10903 
New Hampshire Ave., Bldg. 51 (rm. 5240), Silver Spring, MD 20993-0002.

FOR FURTHER INFORMATION CONTACT: Jennifer Devine, Office of Compliance, 
Division of New Drugs and Labeling Compliance, Center for Drug 
Evaluation and Research (HFD-310), Food and Drug Administration, 10903 
New Hampshire Ave., Bldg. 51 (rm. 5240), Silver Spring, MD 20993-0002, 
301-796-3347, e-mail: [email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    Papain is a protein-cleaving enzyme derived from papaya fruit 
(Carica papaya) and certain other plants. The latex of the papaya plant 
and its green fruits contain two proteolytic enzymes, papain and 
chymopapain. The latter is most abundant, but papain is twice as 
potent. The presence and effects of proteases in papaya fruit latex 
have been well known since the 1750s, but it was not until the 1870s 
that the importance of papaya latex as a source of enzymes was 
recognized. Although the exact year is unknown, marketing of topical 
papain drug products in the United States began before 1962.
    Topical drug products containing papain are used for the 
debridement of necrotic tissue and liquefication of slough in acute and 
chronic lesions, such as diabetic ulcers, pressure ulcers, varicose 
ulcers, and miscellaneous traumatic infected wounds. These products 
generally combine papain with other active ingredients (such as urea, 
chlorophyllin copper complex, and copper sodium chlorophyllin), which 
are intended to promote healthy granulation, control local 
inflammation, reduce wound odors, and rehydrate skin. In addition, 
papain is marketed in oral formulations for a variety of indications, 
including as an aid in protein digestion.\2\ It is also used in the 
food industry as a meat tenderizer.\3\
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    \2\ Lacy, D.F., Armstrong, L.L., Goldman, M.P., Lance, L.L., 
eds., Drug Information Handbook, 2008-2009; 17th edition.
    \3\ See http://www.foodreference.com/html/fmeatttenterizer.html.
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    Papain-containing drug products in topical form historically have 
been marketed without approval, and because no firm obtained an 
application for them prior to passage of the Drug Amendments of 1962, 
they were not included in the Drug Efficacy Study Implementation (DESI) 
review.

II. Safety and Efficacy Issues in the Use of Topical Papain Drug 
Products

    Adverse events associated with the use of topical papain products 
reported to FDA raise serious safety concerns regarding these products. 
Through January 2008,\4\ FDA has received 37 reports of adverse events 
associated with topical papain products. In addition to several 
complaints that the products were ineffective, the reports include 
cases of potentially life-threatening hypersensitivity reactions. 
Reactions described include serious cases of anaphylaxis and 
anaphylactic shock that started within 15 minutes of topical papain use 
and resulted in hospitalizations, including admissions to the intensive 
care unit. Published literature also describes incidents of 
hypersensitivity to other papain-containing products, including meat 
tenderizer, contact lens solution, and adhesive removers in the beauty 
industry. Another concern exists regarding patients with latex 
sensitivity. Cross-reactivity between latex and papaya has been 
documented in medical literature, and one of the cases reported to FDA 
involved anaphylactic shock in a patient with a history of allergy to 
latex. It is notable that labeling for currently marketed topical 
papain products does not provide any warnings regarding 
hypersensitivity reactions and latex cross-reactivity.
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    \4\ Data in the current system date back to 1969, when FDA first 
implemented an adverse event reporting system.
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    FDA is particularly concerned about adverse events associated with 
the use of papain-containing topical drug products in light of the 
dearth of published well-controlled studies demonstrating the 
effectiveness of those products. Given the absence of the kinds of 
scientific studies routinely conducted by sponsors and submitted for 
agency review as part of the FDA approval process, it is impossible for 
the agency to assess either the amount of risk associated with these 
products or the extent to which their benefits might justify their 
risks, including severe, systemic, potentially life-threatening 
hypersensitivity reactions.

III. Legal Status

A. Topical Papain Products Are New Drugs Requiring Approved 
Applications

    Based both on the safety considerations previously described and 
the absence of published literature documenting that topical drugs 
containing papain are safe and effective, such drugs are not generally 
recognized as safe and effective under section 201(p) of the act (21 
U.S.C. 321(p)) for any indication, including for the debridement of 
necrotic tissue and liquefication of slough in acute and chronic 
lesions. Therefore, a topical drug product containing papain, alone or 
in combination with other drugs, is regarded as a new drug as defined 
in section 201(p) of the act and is subject to the requirements of 
section 505 of the act. As set forth in this notice, approval of an NDA 
or an ANDA under section 505 of the act is required as a condition for 
manufacturing or marketing all topical drug products containing papain. 
After the dates identified in this notice, FDA intends to take 
enforcement action as described in this notice against unapproved 
topical drug products containing papain and persons who

[[Page 54833]]

cause the manufacture or interstate shipment of such products. Any 
person who submits an NDA or an ANDA for a topical product containing 
papain but has not received approval must comply with this notice.
    This notice does not affect drugs containing papain in oral dosage 
forms, which FDA intends to address at a later date.

B. Notice of Enforcement Action

    Although not required to do so by the Administrative Procedure Act, 
the act, or any rules issued under its authority, or for any other 
legal reason, FDA is providing this notice to persons who are marketing 
unapproved topical drug products containing papain that the agency 
intends to take enforcement action against such products and those who 
manufacture them or cause them to be manufactured or shipped in 
interstate commerce. Manufacturing or shipping unapproved topical 
products containing papain can result in enforcement action, including 
seizure, injunction, or other judicial or administrative proceeding. 
Consistent with policies described in the agency's guidance entitled 
``Marketed Unapproved Drugs--Compliance Policy Guide'' (the Marketed 
Unapproved Drugs CPG), the agency does not expect to issue a warning 
letter or any other further warning to firms prior to taking 
enforcement action relating to unapproved papain-containing topical 
drug products. The agency also reminds firms and individuals that, as 
stated in the Marketed Unapproved Drugs CPG, any unapproved drug 
marketed without a required approved drug application is subject to 
agency enforcement action at any time. The issuance of this notice does 
not in any way obligate the agency to issue similar notices or any 
notice in the future regarding marketed unapproved drugs.\5\
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    \5\ The agency's general approach in dealing with these products 
in an orderly manner is spelled out in the Marketed Unapproved Drugs 
CPG. That CPG, however, provides notice that any product that is 
being marketed illegally, and the persons responsible for causing 
the illegal marketing of the product, are subject to FDA enforcement 
action at any time.
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    As described in the Marketed Unapproved Drugs CPG, the agency may, 
at its discretion, identify a period of time during which the agency 
does not intend to initiate an enforcement action against a currently 
marketed unapproved drug on the ground that it lacks an approved 
application under section 505 of the act in order to, for example, 
preserve access to medically necessary drugs or ease disruption to 
affected parties. With respect to unapproved topical drug products 
containing papain, the agency intends to exercise its enforcement 
discretion for only a limited period of time because these are drugs 
with potential safety risks that lack scientific evidence of 
effectiveness. Therefore, the agency intends to implement this notice 
as follows.
    For the effective date of this notice, see the DATES section of 
this document. FDA intends to take action to enforce section 505(a) of 
the act against any unapproved topical drug product containing papain 
that is not listed with FDA in full compliance with section 510 of the 
act (21 U.S.C. 360) before September 22, 2008, and that is 
manufactured, shipped, or otherwise introduced or delivered for 
introduction into interstate commerce by any person on or after 
September 23, 2008. FDA also intends to take action to enforce section 
505(a) of the act against any unapproved topical drug containing papain 
that has a National Drug Code (NDC) number listed with FDA in full 
compliance with section 510 of the act but is not being commercially 
used or sold\6\ in the United States on September 22, 2008, and that is 
manufactured, shipped, or otherwise introduced or delivered for 
introduction into interstate commerce by any person on or after 
September 23, 2008.
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    \6\ For the purposes of this notice, the term ``commercially 
used or sold'' means that the product has been used in a business or 
activity involving retail or wholesale marketing and/or sale.
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    However, for unapproved topical drug products containing papain 
that are commercially used or sold in the United States, have a NDC 
number listed with FDA, and are in full compliance with section 510 of 
the act before September 22, 2008 (``currently marketed and listed''), 
the agency intends to exercise its enforcement discretion as follows. 
FDA intends to initiate enforcement action against any currently 
marketed and listed unapproved topical product containing papain that 
is manufactured on or after November 24, 2008 or that is shipped on or 
after January 21, 2009.\7\ Further, FDA intends to take enforcement 
action against any person who manufactures or ships such products after 
the dates set forth above. Any person who submits a new drug 
application for a topical drug product containing papain but has not 
received approval must comply with this notice.
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    \7\ If FDA finds it necessary to take enforcement action against 
a product covered by this notice, the agency may take action 
relating to all of the defendant's other violations of the act at 
the same time. For example, if a firm continues to manufacture or 
market a product covered by this notice after the applicable 
enforcement date has passed, to preserve limited agency resources, 
FDA may take enforcement action relating to all of the firm's 
unapproved drugs that require applications at the same time (see, 
e.g., United States v. Sage Pharmaceuticals, 210 F. 3d 475, 479-480 
(5th Cir. 2000) (permitting the agency to combine all violations of 
the act in one proceeding, rather than taking action against 
multiple violations of the act in ``piecemeal fashion'')).
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    The agency, however, does not intend to exercise its enforcement 
discretion as outlined previously if the following apply: (1) A 
manufacturer or distributor of an unapproved topical drug product 
containing papain covered by this notice is violating other provisions 
of the act (including but not limited to, violations related to FDA's 
current good manufacturing practices, adverse drug event reporting, or 
labeling requirements) or (2) it appears that a firm, in response to 
this notice, increases its manufacture or interstate shipment of 
unapproved topical drug products containing papain above its usual 
volume.
    Nothing in this notice, including FDA's intent to exercise its 
enforcement discretion, alters any person's liability or obligations in 
any other enforcement action or litigation, or precludes the agency 
from initiating or proceeding with enforcement action in connection 
with any other alleged violation of the act, whether or not related to 
an unapproved drug product covered by this notice. Similarly, a person 
who is or becomes enjoined from marketing unapproved drugs may not 
resume marketing of unapproved topical drug products containing papain 
based on FDA's exercise of enforcement discretion as set forth in this 
notice.
    Drug manufacturers and distributors should be aware that the agency 
is exercising its enforcement discretion as described previously only 
in regard to topical papain drug products that are marketed under an 
NDC number listed with the agency in full compliance with section 510 
of the act before September 22, 2008. As previously stated, unapproved 
topical drug products containing papain that are not currently 
marketed, or that are currently marketed but not listed with the agency 
on the date of this notice must have approved applications prior to 
their shipment in interstate commerce. Moreover, any person or firm 
that submits an NDA or an ANDA but has yet to receive approval for such 
products is still responsible for full compliance with this notice.

C. Discontinued Products

    Some firms may have previously discontinued the manufacturing or 
distribution of products covered by this notice without removing them 
from the listing of their products under section

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510(j) of the act. Other firms may discontinue manufacturing or 
marketing listed products in response to this notice. Firms that wish 
to notify the agency of product discontinuation should send a letter, 
signed by the firm's chief executive officer, fully identifying the 
discontinued product(s), including the product NDC number(s), and 
stating that the product(s) has (have) been discontinued. The letter 
should be sent to Jennifer Devine (see ADDRESSES). Firms should also 
update the listing of their products under section 510(j) of the act to 
reflect discontinuation of unapproved topical papain drug products. 
Updating of listing information may be advantageous for a firm because 
FDA plans to rely on its existing records, the results of a subsequent 
inspection, or other available information when we evaluate whether to 
initiate enforcement action.
    This notice is issued under sections 502 and 505 of the act (21 
U.S.C. 352) and under authority delegated to the Deputy Commissioner 
for Policy under section 1410.10 of the FDA Staff Manual Guide.

    Dated: September 8, 2008.
Jeffrey Shuren,
Associate Commissioner for Policy and Planning.
[FR Doc. E8-22300 Filed 9-22-08; 8:45 am]
BILLING CODE 4160-01-S