[Federal Register Volume 84, Number 246 (Monday, December 23, 2019)]
[Proposed Rules]
[Pages 70796-70839]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-27474]
[[Page 70795]]
Vol. 84
Monday,
No. 246
December 23, 2019
Part IV
Department of Health and Human Services
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Food and Drug Administration
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21 CFR Parts 1 and 251
Importation of Prescription Drugs; Proposed Rule
Federal Register / Vol. 84, No. 246 / Monday, December 23, 2019 /
Proposed Rules
[[Page 70796]]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 1 and 251
[Docket No. FDA-2019-N-5711]
RIN 0910-AI45
Importation of Prescription Drugs
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is
proposing to amend its regulations to implement a provision of the
Federal Food, Drug, and Cosmetic Act (FD&C Act) to allow importation of
certain prescription drugs from Canada. If the rule is finalized as
proposed, States or certain other non-federal governmental entities
would be able to submit importation program proposals to FDA for review
and authorization. An importation program could be co-sponsored by a
pharmacist, a wholesaler, or another State or non-federal governmental
entity. The rule, when finalized, would contain all requirements
necessary for a State or other non-federal governmental entity and its
co-sponsors, if any, to demonstrate that their importation program will
pose no additional risk to the public's health and safety. In addition,
the proposed rule would require that the State or non-federal
governmental entity and its co-sponsors, if any, explain why their
program would be expected to result in a significant reduction in the
cost of covered products to the American consumer.
DATES: Submit either electronic or written comments on the proposed
rule by March 9, 2020. Submit comments on information collection issues
under the Paperwork Reduction Act of 1995 (PRA) by January 22, 2020.
ADDRESSES: You may submit comments as follows. Please note that late,
untimely filed comments will not be considered. Electronic comments
must be submitted on or before March 9, 2020. The https://www.regulations.gov electronic filing system will accept comments until
11:59 p.m. Eastern Time at the end of March 9, 2020. Comments received
by mail/hand delivery/courier (for written/paper submissions) will be
considered timely if they are postmarked or the delivery service
acceptance receipt is on or before that date.
Electronic Submissions
Submit electronic comments in the following way:
Federal eRulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to https://www.regulations.gov
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on https://www.regulations.gov.
If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').
Written/Paper Submissions
Submit written/paper submissions as follows:
Mail/Hand Delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
Instructions: All submissions received must include the Docket No.
FDA-2019-N-5711 for ``Importation of Prescription Drugs.'' Received
comments, those filed in a timely manner (see ADDRESSES), will be
placed in the docket and, except for those submitted as ``Confidential
Submissions,'' publicly viewable at https://www.regulations.gov or at
the Dockets Management Staff between 9 a.m. and 4 p.m., Monday through
Friday.
Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on https://www.regulations.gov.
Submit both copies to the Dockets Management Staff. If you do not wish
your name and contact information to be made publicly available, you
can provide this information on the cover sheet and not in the body of
your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852.
Submit comments on information collection issues under the PRA to
the Office of Management and Budget (OMB) in the following ways:
Fax to the Office of Information and Regulatory Affairs,
OMB, Attn: FDA Desk Officer, Fax: 202-395-7285, or email to
[email protected]. All comments should be identified with the
title, Section 804 Importation Program Proposals--21 CFR part 251.
FOR FURTHER INFORMATION CONTACT: Lyndsay Hennessey, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Silver Spring, MD 20993, 301-796-7605. With regard to
the information collection: Domini Bean, Office of Operations, Food and
Drug Administration, Three White Flint North 10A-12M, 11601 Landsdown
St., North Bethesda, MD 20852, 301-796-5733, [email protected].
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Executive Summary
A. Purpose of the Proposed Rule
B. Summary of the Major Provisions of the Proposed Rule
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C. Legal Authority
D. Costs and Benefits
II. Table of Abbreviations/Commonly Used Acronyms in This Document
III. Background
IV. Legal Authority
V. Description of the Proposed Rule
A. Scope/Applicability
B. Definitions
C. Section 804 Importation Program Proposals and Section 804
Pre-Import Requests
D. Requirements for Foreign Sellers
E. Requirements for Importers
F. Supply Chain Requirements
G. Requirements for Qualifying Laboratories
H. Laboratory Testing Requirements
I. Listing and Labeling of Eligible Prescription Drugs
J. Information and Records
K. Post-Importation Requirements
L. Severability
VI. Proposed Effective/Compliance Dates
VII. Preliminary Economic Analysis of Impacts
VIII. Analysis of Environmental Impact
IX. Paperwork Reduction Act of 1995
X. Federalism
XI. Consultation and Coordination With Indian Tribal Governments
XII. References
I. Executive Summary
A. Purpose of the Proposed Rule
FDA is proposing to amend its regulations to implement section
804(b) through (h) of the FD&C Act (21 U.S.C. 384(b) through (h)) to
allow importation of certain prescription drugs shipped from Canada.
The purpose of the proposed rule is to lower prices and reduce out of
pocket costs for American patients.
B. Summary of the Major Provisions of the Proposed Rule
Under the proposed rule, section 804 of the FD&C Act would be
implemented through time-limited Section 804 Importation Programs
(SIPs), which would be authorized by FDA and managed by States or
certain other non-federal governmental entities and by their co-
sponsors, if any (SIP Sponsors). A SIP could be co-sponsored by a
pharmacist, a wholesaler, or another State or non-federal governmental
entity.
FDA proposes that a SIP Sponsor specify the eligible prescription
drugs that would be included in the SIP. To be eligible under the
proposed rule, a drug would need to be approved by Health Canada's
Health Products and Food Branch (HPFB) and, but for the fact it bears
the HPFB-approved labeling when marketed in Canada, it would need to
otherwise meet the conditions in an FDA-approved new drug application
(NDA) or abbreviated new drug application (ANDA). Essentially, eligible
prescription drugs are those that could be sold legally on either the
Canadian market or the American market with appropriate labeling.
Under the proposed rule, the SIP Proposal would also need to
identify the foreign seller in Canada that will purchase the eligible
prescription drug directly from its manufacturer, and the importer in
the United States that will buy the drug directly from the foreign
seller. While the initial SIP Proposal would identify just one foreign
seller and one importer, once the SIP can show that it has consistently
imported eligible prescription drug(s) in accordance with section 804
and the rule, the SIP Sponsor would be able to submit a supplemental
proposal to add additional foreign sellers or importers. The supply
chain for each drug under a SIP would be limited to three entities,
i.e. one manufacturer, one foreign seller, and one importer.
FDA proposes that the foreign seller be a party that is licensed by
Health Canada as a wholesaler and registered with FDA as a foreign
seller, and that the importer be a wholesaler or pharmacist licensed to
operate in the United States. Both the foreign seller and the importer
would be subject to the supply chain security requirements proposed in
this rulemaking and under the FD&C Act. Among other things, the foreign
seller would have to ensure that a section 804 serial identifier (SSI),
which is an alphanumeric serial number unique to each package or
homogeneous case, is affixed or imprinted to each package and
homogenous case of the drugs, and the importer would have to ensure
that a product identifier meeting the requirements of section 582 of
the FD&C Act (21 U.S.C. 360eee-1) (i.e., a product identifier that
includes a National Drug Code, unique alphanumeric serial number of up
to 20 characters, lot number, and expiration date, in both human- and
machine-readable format) is affixed or imprinted to each package or
homogenous case of the drugs. The importer would also have to maintain
records linking the product identifier affixed or imprinted on a
package or homogenous case to the SSI that the foreign seller assigned.
After FDA has authorized a SIP Proposal, the importer would submit
a Pre-import Request to FDA at least 30 days prior to the scheduled
date of arrival or entry for consumption of a shipment containing an
eligible prescription drug covered by the SIP, whichever is earlier.
Entry and arrival of a shipment containing an eligible prescription
drug would be limited under the proposed rule to the U.S. Customs and
Border Protection (CBP) port of entry authorized by FDA. The importer,
or authorized customs broker, would be required to electronically file
an entry for consumption in the Automated Commercial Environment (ACE)
or other electronic data interchange system authorized by CBP for each
eligible prescription drug imported or offered for import into the
United States. These entries would be filed as formal entries. If an
eligible prescription drug is imported or offered for import that does
not comply with section 804 of the FD&C Act and the provisions of this
proposed rule, that drug would be subject to refusal under section 801
of the FD&C Act (21 U.S.C. 381).
The importer would need to arrange for statutorily prescribed
testing of the drug for authenticity, degradation, and other statutory
testing requirements by a qualifying laboratory in the United States,
if the manufacturer does not perform the testing required under section
804, and would also need to ensure that the drug complies with all
labeling requirements under the FD&C Act. Section 804 of the FD&C Act
requires that the mandatory testing either be performed by the
manufacturer of an eligible prescription drug or, if such testing is
performed by the importer, that the manufacturer supply the information
the importer needs to authenticate the drug and to confirm that its
labeling complies with all labeling requirements under the FD&C Act. In
the proposed rule, FDA specifies that this information includes, among
other things, any relevant testing protocols that the manufacturer has
developed.
Under the proposed rule, the importer can choose to admit the drug
or drugs specified in the section 804 pre-import request to an
authorized Foreign Trade Zone (FTZ) and then conduct the required
testing and relabeling, or alternatively, the importer can make an
entry for consumption and request to recondition the drug or drug(s),
which would entail the required testing and relabeling. Under the
proposed rule, the results of this testing would be reviewed and
accepted by FDA and subsequently the drug would have to be relabeled
with labeling that complies with all labeling requirements under the
FD&C Act before the drug can be distributed in the United States.
Pursuant to section 804(c)(3) of the FD&C Act, the proposed rule
also sets forth post-importation requirements. Each SIP Sponsor would
be required to provide FDA with data and information about its SIP,
including the SIP's cost savings to the American consumer. An importer
would be required to submit
[[Page 70798]]
adverse event, medication error, field alert, and other reports to a
drug's manufacturer and to FDA. If FDA or any participant in a SIP
determines that a recall is warranted, the SIP Sponsor would be
responsible for effectuating the recall. The proposed rule would
require that each SIP have a written recall plan that describes the
procedures to perform a recall of the product and specifies who will be
responsible for performing the procedures.
A SIP is eligible for extension by FDA before the end of its
approval period. A SIP may also be terminated by FDA at any time for
the reasons outlined in this proposed rule.
C. Legal Authority
Section 804(l)(1) of the FD&C Act provides that section 804 shall
become effective only if the Secretary certifies to the Congress that
the implementation of this section will pose no additional risk to the
public's health and safety, and result in a significant reduction in
the cost of covered products to the American consumer. The Secretary of
the Department of Health and Human Services (the Secretary or the
Secretary of HHS) would make this certification to Congress upon
issuance of a final rule based on this proposal. FDA is also issuing
this proposed rule under FDA's rulemaking authority regarding
importation of prescription drugs under section 804(b) through (h) of
the FD&C Act. The proposed rule is also being issued pursuant to FDA's
authorities related to adulterated and misbranded drugs under sections
501 and 502 of the FD&C Act (21 U.S.C. 351 and 352); FDA's authorities
with regard to wholesale distribution under section 503(e) of the FD&C
Act (21 U.S.C. 353(e)); FDA's authority related to new drugs under
section 505 of the FD&C Act (21 U.S.C. 355); as well as FDA's
rulemaking, inspection, and importation authorities under sections
701(a), 704, and 801(a) of the FD&C Act, respectively (21 U.S.C.
371(a), 374, and 381).
D. Costs and Benefits
The proposed rule, if finalized, would allow commercial importation
of certain prescription drugs from Canada through time-limited programs
sponsored by at least one non-federal governmental entity with possible
co-sponsorship by a wholesaler or pharmacist. As we lack information
about the expected scale or scope of such programs, we are unable to
estimate how they may affect U.S. markets for prescription drugs. In
particular, we are unable to estimate the volume or value of drugs that
may be imported under the SIPs or the savings to U.S. consumers who may
participate in such programs.
Costs of the proposed rule may accrue to the Federal Government,
SIP Sponsors, importers, and manufacturers of imported drugs. The
Federal Government would incur one-time fixed costs to implement the
rule as well as ongoing costs including those to review program
proposals and periodic reports. SIP Sponsors would face costs to
prepare SIP Proposals, implement approved SIPs, and produce SIP reports
and records. If their drugs are imported into the United States from
Canada, drug manufacturers may have to provide importers with certain
information. These costs depend on the number and type of participating
importation programs. We lack information to estimate these costs.
Finally, U.S. patients, as well as wholesale drug distributors,
pharmacies, hospitals, and third-party payers, may all experience
savings, but we lack information necessary to estimate such savings. As
drug distributors realize savings in acquiring imported drugs and pass
some of these savings to consumers and other parties in the drug supply
chain, it is possible that U.S. drug manufacturers may experience a
transfer in U.S. sales revenues to these parties.
II. Table of Abbreviations/Commonly Used Acronyms in This Document
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Abbreviation/acronym What it means
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ACE................................................. Automated Commercial Environment or any Other Electronic
Data Interchange System authorized by the U.S. Customs
and Border Protection.
ANDA................................................ Abbreviated New Drug Application.
CBP................................................. U.S. Customs and Border Protection.
CGMP................................................ Current Good Manufacturing Practice.
COA................................................. Certificate of Analysis.
DIN................................................. Drug Identification Number.
DSCSA............................................... Drug Supply Chain Security Act.
FD&C Act............................................ Federal Food, Drug, and Cosmetic Act.
FTZ................................................. Foreign Trade Zone.
HPFB................................................ Health Canada Health Products and Food Branch.
NDA................................................. New Drug Application.
OMB................................................. Office of Management and Budget.
SIP................................................. Section 804 Importation Program.
SSI................................................. Section 804 Serial Identifier.
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III. Background
Since 1938, the FD&C Act has required the submission of an
application to FDA for a new drug before it is marketed in the United
States. Under sections 301(d) and 505(a) of the FD&C Act (21 U.S.C.
331(d) and 355(a)), a new drug may not be introduced or delivered for
introduction into interstate commerce, which includes importation into
the United States, unless an application approved by FDA under section
505 is in effect for the drug. Unapproved new drugs include versions of
FDA-approved drugs that are intended for sale outside of the United
States, and which have not themselves been approved by FDA for
marketing in the United States. (United States v. Genendo
Pharmaceutical, N.V., 485 F.3d 958 (7th Cir. 2007); In Re Canadian Imp.
Antitrust Litig., 470 F.3d 785, 789-90 (8th Cir. 2006).) Under section
801(a)(3) of the FD&C Act, FDA has authority to refuse admission of a
drug that is offered for import if, among other things, it appears to
be an unapproved new drug and, therefore, in violation of section 505
of the FD&C Act. Under section 801(d)(1)(A) of the FD&C Act, a
prescription drug that is manufactured in a State and exported may only
be imported into the United States by the manufacturer, except, in
addition to another reason not relevant here, as provided in section
804. Under section 801(d)(1)(B) of the FD&C Act,\1\ a
[[Page 70799]]
prescription drug manufactured outside the United States may be
imported into the United States for commercial use only in situations
where the manufacturer has authorized the drug to be marketed in the
United States and has caused the drug to be labeled to be marketed in
the United States, except, in addition to another reason not relevant
here, as provided in section 804.
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\1\ Elsewhere in this issue of the Federal Register, FDA is
announcing the availability of a draft guidance that describes
procedures to obtain an additional National Drug Code for an FDA-
approved prescription drug that is imported into the United States
in compliance with section 801 of the FD&C Act.
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In 2000, Congress enacted legislation known as the Medicine Equity
and Drug Safety (MEDS) Act as part of the Fiscal Year 2001
appropriations bill for the Department of Agriculture and related
Agencies (Pub. L. 106-387). The MEDS Act added an earlier version of
section 804 to the FD&C Act that, if implemented, would have allowed
pharmacists or wholesalers in the United States to import certain
prescription drugs without the authorization of the manufacturer. The
MEDS Act was intended to ``empower pharmacists and wholesalers to
purchase FDA-approved medicines in Canada and pass the discounts along
to American patients[.]'' (146 Cong. Rec. S3692, 3693 (daily ed. May 9,
2000)).\2\ The law required that, prior to implementation, the
Secretary of HHS demonstrate that the importation of these drugs would
pose no additional risk to the public's health and safety and would
result in a significant reduction in the cost of covered products to
the American consumer. HHS was not able to make such demonstration
(Ref. 1).
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\2\ While this statement seems to imply that these amendments
were intended to only permit importation from Canada, the actual
amendments contained no such restriction.
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The Medicare Prescription Drug, Improvement, and Modernization Act
of 2003 (MMA) (Pub. L. 108-173) was signed into law on December 8,
2003. Section 1121 of the MMA amended section 804 of the FD&C Act to
its current version, which, among other things, authorizes the
Secretary of HHS, after consultation with the U.S. Trade Representative
and the Commissioner of Customs, to issue regulations permitting
pharmacists and wholesalers to import certain prescription drugs from
Canada under certain conditions and limitations. For section 804 of the
FD&C Act to become effective, the Secretary of HHS must certify that
its implementation will ``pose no additional risk to the public's
health and safety,'' and that it will ``result in a significant
reduction in the cost of covered products to the American consumer.''
There has been interest for many years in allowing the importation
of less expensive drugs from Canada to help American consumers benefit
from these lower prices. However, no prior HHS Secretary has made the
certification required under section 804(l) to begin implementing any
part of section 804 of the FD&C Act. Past efforts have been
unsuccessful in part because of concerns that: (1) FDA could not ensure
the safety and effectiveness of drugs imported via such a program, (2)
an importation program that opened the ``closed'' U.S. drug
distribution system for prescription drugs could increase the
opportunity for counterfeit and other substandard drugs to enter the
supply chain, and (3) an importation program would not result in a
significant reduction in costs to American consumers (Refs. 1 to 4).
In 2003, as part of the MMA, Congress directed HHS to conduct a
study on the importation of prescription drugs. The results of this
study were presented in a Task Force Report that was submitted to
Congress in December 2004 (Ref. 5). The Task Force Report identified
concerns about potential risks and challenges associated with
implementing section 804, including, but not limited to:
``The current system of drug regulation in the U.S. has
been very effective in protecting public safety, but is facing new
threats. It should be modified only with great care to ensure continued
high standards of safety and effectiveness of the U.S. drug supply.''
``Overall national savings from legalized commercial
importation will likely be a small percentage of total drug spending
and developing and implementing such a program would incur significant
costs and require significant additional authorities.''
``The public expectation that most imported drugs are less
expensive than American drugs is not generally true. Generic drugs
account for most prescription drugs used in the U.S. and are usually
less expensive in the U.S. than abroad.''
``The effects of legalized importation on intellectual
property rights are uncertain but likely to be significant. . . . These
effects could create additional disincentives to develop breakthrough
medicines and further limit any potential savings that might have been
realized.''
``Legalized importation raises liability concerns for
consumers, manufacturers, distributors, pharmacies, and other entities.
Consumers harmed by imported drugs may not have legal recourse against
foreign pharmacies, distributors, or other suppliers. Entities in the
pharmaceutical supply chain may take actions to protect themselves from
liability that could ultimately raise the cost of drugs'' (Ref. 5).
The continued rise of prescription drug prices since the issuance
of the 2004 Task Force Report has raised concerns among policymakers,
healthcare professionals, and American consumers. According to a 2017
United States Government Accountability Office (GAO) report, ``[t]he
amount of money people spend on prescription drugs has nearly doubled
since the 1990s'' (Ref. 6). Additionally, the GAO found that ``[i]n
2015, expenditures for prescription drugs sold through retail
pharmacies were estimated to account for nearly 12 percent of total
personal health care services spending in the United States, up from
approximately 7 percent of such spending through the 1990s.'' The HHS
Office of the Assistant Secretary for Planning and Evaluation (ASPE)
estimates that the United States spent about $457 billion on
prescription drugs in 2015 (Ref. 7). In 2009, by comparison,
prescription drug spending in the United States was $354 billion.
Prescription drug spending is projected to continue to rise faster than
overall health spending (Ref. 7).
FDA is committed to expanding Americans' access to high-quality,
safe and effective, affordable medicines. Congress has given FDA, as
part of the Agency's mission to promote and protect the public health,
responsibility for implementing laws intended to strike a balance
between encouraging and rewarding innovation in drug development and
facilitating robust and timely market competition. The Agency takes
seriously its responsibility to ensure that the medicines Americans use
are safe and effective. FDA also recognizes that ``[a]ccess to
affordable prescription drugs, many of which are needed to treat life-
threatening and serious conditions, is a daily concern and challenge
for many Americans.'' (Ref. 5)
Most Americans (79 percent) say the cost of prescription drugs is
``unreasonable'' (Ref. 8). Prohibitive costs can lead to medication
nonadherence, which negatively impacts health outcomes and contributes
to increased healthcare costs in the United States (Ref. 9). In a
recent national poll, almost one-third (29 percent) of U.S. adults have
reported ``not taking their medicines as prescribed'' due to the
expense, and almost 1 in 10 (8 percent) said this led to a decline in
their condition (Ref. 8). National news outlets have reported on the
dire consequences of patients rationing immunosuppressive medications
needed after organ transplants or delaying cancer
[[Page 70800]]
treatments because of costs (Refs. 10 and 11).
Contributing to public frustration on this issue is the disparity
between prices that Americans pay for brand name medications as
compared with other developed countries. The reasons for such price
disparities are varied. Brand name prescription drugs (as distinct from
generic drugs) often are more expensive in the United States than they
are in other developed markets (Refs. 12 to 14). For instance, in 2017,
Canada's Patented Medicine Prices Review Board (PMPRB) found that
patented medicines (i.e., drug products to which patents apply) cost on
average three times more in the United States than Canada (Refs. 15 and
16). As a result of these price differentials, some American consumers
have sought to import drugs from other countries in an effort to obtain
treatments that may be otherwise inaccessible to them because of cost.
According to a national poll, millions of Americans have purchased
prescription drugs from other countries (Refs. 17 and 18).
FDA has revisited the question of whether section 804 of the FD&C
Act could be implemented so that the Secretary could make the required
certification under section 804(l)(1). Past analyses regarding the
feasibility of implementing section 804 did not consider the
possibility of implementing section 804(b) through (h) of the FD&C Act
solely through programs proposed by States or certain other non-federal
governmental entities and their co-sponsors, if any, and authorized by
FDA, as described in this proposed rule. FDA has reviewed these past
analyses and proposes that while the concerns about public health and
safety and the ability to achieve cost savings remain valid, section
804 of the FD&C Act can be implemented in a manner consistent with the
certification criteria through programs, overseen by States or certain
other non-federal governmental entities and their co-sponsors, if any,
that require authorization by and reporting to FDA. These programs
would be required to demonstrate to FDA that they could import drugs
from Canada at no additional risk to the public's health and safety
consistent with the requirements in section 804 of the FD&C Act and
this proposed rule. These include, among other requirements,
requirements relating to the types of drugs eligible for importation,
the distribution channels and methods used for product traceability,
and the testing of eligible prescription drugs for authenticity and
degradation. In addition, in accordance with section 804, the proposed
rule would require that drugs imported under section 804 meet the
specifications of an FDA-approved NDA or ANDA. These programs would
also be expected to demonstrate significant cost reductions to the
American consumer. Merely because an importation purports to be done
pursuant to section 804, that does not mean it has been authorized
under section 804 and is compliant with section 804 of the FD&C Act and
this rule, if finalized.
FDA is not proposing to implement the personal importation
provisions in section 804(j) through this rulemaking. The internet
provides consumers with instant access to information and services,
including prescription medications. Medications that are purchased
online and imported through international mail, express couriers, and
other means pose significant challenges for FDA and its ability to
adequately safeguard the quality and safety of drugs taken by U.S.
consumers. While there are pharmacy websites that operate legally and
offer convenience, privacy, and safeguards for purchasing medicines,
there are many rogue online pharmacies that sell medicines at deeply
discounted prices, often without requiring a prescription or adhering
to other safeguards followed by pharmacies licensed by a State in the
United States. These rogue online pharmacies are often run by
sophisticated criminal networks that knowingly and unlawfully cause the
importation of adulterated, counterfeit, misbranded and unapproved
drugs into the United States. These criminals frequently use
sophisticated technologies and are backed by larger enterprises intent
on profiting from illegal drugs at the expense of American patients
(Refs. 19 and 20). Consumers go to these websites believing they are
buying safe and effective medications, but often they are being
deceived and put at risk by individuals who put financial gain above
patient safety.
For example, Canada Drugs Ltd. (``Canada Drugs'') was an internet-
based pharmacy corporation located in Winnipeg, Manitoba, Canada, which
purchased drugs from questionable sources that were outside FDA's
closed supply chain (Refs. 21 and 22). Canada Drugs and its
subsidiaries put the public health at risk through widespread sales of
misbranded and unapproved drugs to U.S. consumers at discounted prices
(Ref. 23). Moreover, in two instances, Canada Drugs, through a
subsidiary, distributed counterfeit versions of the cancer drugs
Avastin and Altuzan (the Turkish version of Avastin) to healthcare
providers in the United States. The counterfeits contained no active
ingredient. After Canada Drugs became aware that they had shipped
counterfeit Avastin and Altuzan to medical clinics in the United
States, they tried to conceal the problem. Canada Drugs never notified
FDA or other U.S. authorities that it had shipped counterfeit cancer
drugs containing no active ingredient to the United States (Ref. 22).
Further, drugs promoted as being from Canada or approved by Health
Canada's HPFB that are offered to U.S. citizens in many instances are
not actually from Canada and not approved by HPFB. Instead, these drugs
are obtained from ever-evolving illicit sources of supply. A 2005 FDA
analysis of drugs imported through International Mail Facilities
revealed that while nearly half of imported drugs claimed to be
Canadian or from Canadian pharmacies, 85 percent of those drugs
originated elsewhere and were fraudulently represented as Canadian
(Refs. 24 and 25). Typically, these products are smuggled into the
United States after being transshipped to third party countries, such
as Canada, in an effort to avoid detection and create a more
trustworthy appearance (Ref. 25). Given these risks, and other concerns
discussed in the Task Force Report (Ref. 5), the proposed rule, if
finalized, would not implement personal importation provisions under
section 804(j) of the FD&C Act.
In the intervening years since the Task Force Report was issued in
2004, Canada has amended its regulations to strengthen its oversight of
both pharmaceutical manufacturing practices (Ref. 26) and
pharmaceutical supply chain participants (Ref. 27). Regulatory
harmonization between Canada and the United States has also increased
bilaterally through the U.S.-Canada Regulatory Cooperation Council and
through international organizations such as the International Council
for Harmonisation of Technical Requirements for Pharmaceuticals for
Human Use (ICH) and Pharmaceutical Inspection Co-operation Scheme
initiatives, of which both FDA and Health Canada are members. In August
2019, FDA and Health Canada announced a series of joint meetings in
advance of each bi-annual ICH face-to-face meeting to seek the public's
input on areas where harmonized ICH guidelines would be beneficial
(Ref. 28).
Additionally, since the 2004 HHS Task Force report and efforts by
Vermont and other States to implement importation programs in the early
2000s, pharmaceutical supply chains have continued to mature and
consolidate, and the ability of
[[Page 70801]]
companies engaged in the transaction of drugs to conduct business
internationally and trace their products has strengthened. This
maturation has further grown since 2013, following and due in part to
the enactment of the Drug Supply Chain Security Act (DSCSA) (Title II
of Pub. L. 113-54). Among other requirements, the DSCSA outlines steps
to build an electronic, interoperable system to identify, trace, and
verify certain prescription drugs as they are distributed among
pharmaceutical supply chain trading partners.
As wholesale drug distributors and pharmacists actively
participate, along with manufacturers and other trading partners, in
the development of an interoperable electronic system by 2023 in
accordance with standards established by FDA, as required under DSCSA,
they have developed processes and methods for complying with
requirements in place since 2015 for exchanging transaction information
and verifying products. Industry stakeholders have steadily marched
toward these goals (Ref. 29). With the implementation of the DSCSA,
supply chain security is maturing due in part to these technological
solutions adopted by manufacturers, wholesale distributors,
pharmacists, and other trading partners that serve as important links
to help protect U.S. consumers from illegitimate products. In addition,
under the DSCSA, FDA, along with the States, exercises oversight over
wholesale drug distributors and pharmacists, in addition to
manufacturers.
To address the substantial public health risks associated with
counterfeits of their prescription drugs, manufacturers around the
world now use a number of technologies to detect whether a certain drug
is legitimate or fake. These technologies include both overt and covert
security technology to enable identification of their authentic drug.
Technological advancements that support verification of these overt and
covert security features have enhanced the ability to detect
counterfeits at the border and prevent their introduction into U.S.
commerce.
Finally, FDA believes that at this time it can implement section
804(b) through (h) of the FD&C Act because it proposes to do so through
SIPs, which would be authorized by FDA and managed by States or certain
other governmental entities and their co-sponsors, if any, and which
would last for 2 years from the time a program imports its first
eligible prescription drug, with the possibility of extensions for 2-
year periods. A State or other governmental entity and its co-sponsors,
if any, would need to demonstrate to FDA that, in accordance with the
requirements proposed here, the importation would pose no additional
risk to the public's health and safety and would be expected to result
in a significant reduction in the cost of covered products to the
American consumer.
IV. Legal Authority
Section 804(l)(1) of the FD&C Act provides that section 804 shall
become effective only if the Secretary certifies to the Congress that
the implementation of this section will pose no additional risk to the
public's health and safety, and result in a significant reduction in
the cost of covered products to the American consumer. The Secretary
would make this certification to Congress upon issuance of a final rule
based on this proposal. FDA is also issuing this proposed rule under
FDA's rulemaking authority regarding importation of prescription drugs
under section 804(b) through (h) of the FD&C Act. The proposed rule is
also being issued pursuant to FDA's authorities related to adulterated
and misbranded drugs under sections 501 and 502 of the FD&C Act; FDA's
authorities with regard to wholesale distribution under section 503(e)
of the FD&C Act; FDA's authority related to new drugs under section 505
of the FD&C Act; as well as FDA's rulemaking, inspection, and
importation authorities under sections 701(a), 704, and 801(a) of the
FD&C Act.
V. Description of the Proposed Rule
FDA is proposing to establish new part 251 of Title 21 of the Code
of Federal Regulations (CFR) to implement section 804(b) through (h) of
the FD&C Act to allow importation of certain prescription drugs from
Canada. FDA proposes to implement section 804 through time-limited
SIPs, which would be authorized by FDA in 2-year increments and managed
by SIP Sponsors, with the possibility of extensions for 2-year periods.
If the rule is finalized as proposed, SIP Sponsors that want to
facilitate the importation of certain drugs from Canada would be able
to submit a SIP Proposal to FDA for review and authorization, in FDA's
discretion.
We propose that every SIP be sponsored by a State, tribal, or
territorial governmental entity. Under the proposed rule, a SIP could
be co-sponsored by a pharmacist, wholesaler, or another State or other
non-federal governmental entity. Co-sponsorship could introduce
valuable flexibility (for example, multiple States could co-sponsor a
plan with a large wholesaler) and allow SIPs to benefit from the
experience of pharmacists and wholesalers, while preserving the
advantages that accrue from sponsorship by at least one State or other
governmental entity. We seek comments on this approach. We are
specifically interested in receiving comments on what the division of
responsibility between co-sponsors should be and whether there are
certain arrangements that should not be permitted. For example, we seek
comment on whether a pharmacist or wholesaler should be able to be both
a SIP co-sponsor and an Importer within the same SIP. If yes, we seek
comment on what safeguards a SIP could include to provide for
sufficient oversight of a co-sponsor that is also acting as the
Importer of the SIP. We also seek comment on whether non-governmental
entities other than pharmacists and wholesalers, such as group
purchasing organizations, pharmacy benefit managers, or union health
and welfare benefit plans, should be permitted to co-sponsor SIPs.
This notice of proposed rulemaking (NPRM) is not intended to
address the applicability of the Medicaid drug rebate program for drugs
under a SIP, which may be addressed in further guidance or rulemaking
from HHS as appropriate.
We considered whether to allow pharmacists or wholesalers to be SIP
Sponsors without a State, tribal, or territorial governmental entity as
a co-sponsor. We believe that a State, tribal, or territorial
governmental entity should oversee each SIP because only a State,
tribal, or territorial government entity would be in a position to
demonstrate that it licenses or regulates pharmacists, wholesalers, and
others in the prescription drug supply chain. For example, States
provide the primary oversight of wholesale distributors' storage,
handling, and distribution practices to ensure the quality of drugs is
maintained. States also ensure that pharmacies and pharmacists comply
with statutes and regulations governing the practice of pharmacy, which
includes dispensing of drugs to patients. States have the authority to
inspect pharmaceutical supply chain participants and to take
disciplinary action against them if warranted. States also have tools
that they can use to respond rapidly should activities under their SIP
adversely affect the public health. We conclude that a plan that has at
least one sponsor that is a State, tribal, or territorial governmental
entity under which pharmacists or wholesalers import drugs would offer
enhanced accountability and protect the public health.
[[Page 70802]]
Although this NPRM proposes to require at least one SIP Sponsor
that is a State, tribal, or territorial government for each SIP, we
seek comment on whether it could be possible for a pharmacist or
wholesaler to be a SIP Sponsor without a State, tribal, or territorial
government co-sponsor, while posing no additional risk to the public's
health and safety. Although we cannot foresee at this time how this
approach could be adopted without posing additional risk to the
public's health and safety, if we receive information that demonstrates
how a proposal that does not include a State, tribal, or territorial
government co-sponsor would provide the same level of assurance of
safety as a proposal with such a co-sponsor, we would consider having
the final rule account for this possibility. Accordingly, we have
provided a proposed alternative codified provision for comment that
would also allow pharmacists or wholesalers to sponsor a SIP without a
co-sponsor. This alternative codified provision appears under ``Option
2'' in proposed Sec. 251.2. If we do not receive comments containing
adequate information for FDA to justify such an allowance, we intend to
omit the ``Option 2'' provision when we finalize this rule. In
addition, as with any other proposed codified provision, if we decide
to provide for additional types of Sponsors, the proposed codified
provision under ``Option 2'' may be modified when this rule is
finalized. In addition, among other potential revisions that may be
necessary, if the final rule were to permit a pharmacist or wholesaler
to be a SIP Sponsor without a State, tribal, or territorial government
co-sponsor, we would include in the final rule those additional
safeguards that would be applicable to most, and perhaps all, proposals
without a State, tribal, or territorial government co-sponsor.
A SIP Sponsor could also be defined to include additional or
different categories of sponsors and/or to exclude the possibility of
co-sponsors where the SIP Sponsor is not a State, tribal, or
territorial governmental entity. A co-sponsor could also be defined to
include additional or different categories of co-sponsors.
Additionally, we seek comment on what safeguards a SIP would need to
include to provide for sufficient oversight of a SIP Sponsor who is
also acting as the Importer for the SIP.
In its SIP Proposal, the SIP Sponsor would need to show, in
accordance with the requirements proposed in this rule, that its
proposed importation will pose no additional risk to the public's
health and safety. A SIP Proposal would also need to explain why the
Sponsor expects the proposal would result in a significant reduction in
the cost to the American consumer of the prescription drugs that the
Sponsor seeks to import. The explanation regarding the significant
reduction in the cost of covered products to the American consumer
would need to include any assumptions and uncertainty, and it would
need to be sufficiently detailed that it can be evaluated by another
component of HHS, as directed by the Secretary, which would make a
recommendation to FDA.
Where a SIP Proposal meets the requirements of section 804(b)
through (h) of the FD&C Act and this proposed rule, FDA may nonetheless
decide, in its discretion, not to authorize the SIP Proposal. Among
other reasons, FDA may decide not to authorize a SIP Proposal because
of potential safety concerns with the program, because of the relative
likelihood the program would not result in significant enough cost
savings (based on the recommendation of another HHS component as
directed by the Secretary), because FDA needs to limit the number of
authorized programs to effectively and efficiently monitor the program,
or in light of other resource demands.
In its SIP Proposal, a State or other non-federal governmental
entity and its co-sponsors, if any, would specify the eligible
prescription drugs it seeks to import. To be eligible, a drug would
need to be approved by Canada's HPFB and, but for the fact it bears the
HPFB-approved labeling, it would need to meet the conditions in an FDA-
approved NDA or ANDA. The SIP Proposal would also need to identify the
Foreign Seller in Canada that would purchase the drug directly from its
manufacturer, and the Importer in the United States that would buy the
drug directly from the Foreign Seller. FDA proposes that the Foreign
Seller be registered with FDA as a Foreign Seller and be licensed by
Health Canada as a wholesaler, and that the Importer be a wholesaler or
pharmacist licensed in the United States.
Due to resource constraints that limit FDA's ability to provide
effective safety oversight, we considered placing a limit on the number
of SIP Proposals that FDA would authorize and the number of SIPs that
FDA would oversee. We considered limiting each State, tribal, or
territorial governmental entity and its co-sponsors, if any, to
submitting one SIP Proposal for one supply chain. However, there may be
State, tribal, or territorial governmental entities and their co-
sponsors, if any, that wish to use more than one Foreign Seller or more
than one Importer. Other State, tribal, or territorial governmental
entities may not wish to submit a SIP Proposal. For this reason, we do
not propose to perpetually limit the total number of Foreign Sellers or
Importers with which a SIP Sponsor can work, although we do note that
each Foreign Seller must buy the drugs to be imported directly from the
manufacturer and sell those drugs directly to the Importer. After a
State, tribal, or territorial governmental entity and its co-sponsors,
if any, has an authorized SIP that has consistently imported eligible
prescription drugs in accordance with section 804 of the FD&C Act and
this rule, that State, tribal, or territorial governmental entity and
its co-sponsors, if any, would be able to submit a supplement to the
SIP Proposal to add a Foreign Seller or Importer. We do not expect to
be able to find that a SIP Sponsor has consistently imported drugs in
accordance with section 804 of the FD&C Act and this rule before it
submits its first quarterly report to FDA.
After FDA has authorized a SIP Proposal, the Importer would submit
a request to FDA at least 30 days prior to the scheduled date of
arrival or entry for consumption of a shipment containing an eligible
prescription drug, whichever is earlier. Entry and arrival of a
shipment containing an eligible prescription drug would be limited
under the proposed rule to the CBP port of entry authorized by FDA. The
Importer would be required to electronically file an entry for
consumption, including the data elements that FDA requires, in ACE or
other electronic data interchange system authorized by CBP for each
eligible prescription drug imported or offered for import into the
United States. These entries would be filed as formal entries. If an
eligible prescription drug is imported or offered for import that does
not comply with section 804 or the provisions of this proposed rule,
that drug would be subject to refusal under section 801 of the FD&C
Act.
In accordance with section 804(e)(1) of the FD&C Act, the proposed
rule would require the manufacturer or the Importer to conduct testing
of the drugs to be imported for authenticity, degradation, and ``to
ensure that the prescription drug is in compliance with established
specifications and standards'' (Statutory Testing). Also, in accordance
with section 804[euro](1), the proposed rule would require that the
Statutory Testing be done at a qualifying laboratory in the United
States. The Importer would also have to ensure that
[[Page 70803]]
the drug bears the required U.S. labeling.
Under section 804(e)(2) of the FD&C Act, if the manufacturer of an
eligible prescription drug does not test the drug itself, the testing
would need to be performed by the Importer using information supplied
by the manufacturer, including all the information needed to
authenticate the drug and confirm that its labeling complies with
labeling requirements under the FD&C Act. In the proposed rule, FDA
specifies that this information includes, among other things, any
testing methodologies and protocols that the manufacturer has developed
that the Importer needs to conduct the Statutory Testing.
Under the proposed rule, the Importer can choose to admit the drug
or drugs specified in the section 804 Pre-Import Request to an
authorized FTZ and then conduct the required testing and relabeling or,
alternatively, the Importer, or an authorized customs broker, can make
an entry for consumption and request to recondition the drug or drugs,
which would entail the required testing and relabeling. Under the
proposed rule, the results of the Statutory Testing would need to be
reviewed and found acceptable by FDA, and the drug would have to bear
the required U.S. labeling, before the drug is sold in the United
States.
Both the Foreign Seller and the Importer would be subject to the
supply chain security requirements proposed in this rule. Among other
things, the Foreign Seller would have to ensure that the product is
serialized at the package level and adhere to applicable DSCSA
obligations. The Importer would have to ensure that a product
identifier meeting the requirements of section 582 of the FD&C Act is
affixed or imprinted to each package and homogenous case of the drugs
and adhere to other existing DSCSA obligations, as described below.
The proposed rule also sets forth post-importation requirements.
Each SIP Sponsor would be required to provide FDA with data and
information about its SIP, including the SIP's cost savings to the
American consumer. An Importer would be required to submit adverse
event, medication error, field alert, and other reports to a drug's
manufacturer and to FDA. If FDA or any participant in a SIP determines
that a recall is warranted, the SIP Sponsor would be responsible for
effectuating the recall. The proposed rule would require that SIPs have
a written recall plan that describes the procedures to perform a recall
of the product and specifies who will be responsible for performing the
procedures.
Once effective, section 804(b) of the FD&C Act directs the
Secretary, after consultation with the U.S. Trade Representative and
the Commissioner of Customs, to promulgate regulations permitting
pharmacists and wholesalers to import prescription drugs from Canada
into the United States. Section 804(c) specifies that the regulations
shall require that safeguards be in place to ensure that each
prescription drug imported under the regulations complies with section
505 of the FD&C Act (including with respect to being safe and effective
for the intended use of the prescription drug), with section 501 of the
FD&C Act (relating to adulteration), with section 502 of the FD&C Act
(relating to labeling and misbranding) and with other applicable
requirements of the FD&C Act. The statute also provides that the
regulations require that Importers comply with section 804(d)(1) of the
FD&C Act, under which an Importer of a prescription drug under 804(b)
must submit certain information and documentation relating to the drug
to the Secretary. In addition, the regulations must require compliance
with section 804(e), which requires that importers or manufacturers
test drugs imported under section 804 at a qualifying laboratory.
Eligible prescription drugs must be in compliance with section 804
of the FD&C Act and with other applicable requirements of the FD&C Act,
including sections 505 (including with respect to being safe and
effective for the intended use of the prescription drug), 502, and 501
of the FD&C Act, in order to be imported. This proposed regulation
would create new exemptions from the statutory requirement of adequate
directions for use under section 502(f)(1) of the FD&C Ac and from
certain requirements in section 582 of the FD&C Act. Section 804(c)(3)
of the FD&C Act provides the Secretary the authority to add regulatory
requirements, as appropriate, as a safeguard to protect the public
health or to facilitate the importation of prescription drugs. Under
the authority of section 804(c) of the FD&C Act, we are proposing
additional provisions that we have determined to be appropriate as a
safeguard to protect the public health or as a means to facilitate the
importation of eligible prescription drugs.
Section 804(l)(1) of the FD&C Act provides that section 804 shall
become effective only if the Secretary certifies to the Congress that
the implementation of this section will pose no additional risk to the
public's health and safety, and result in a significant reduction in
the cost of covered products to the American consumer. After
consideration of comments received on this NPRM, if warranted, the
Secretary will make this certification to Congress concurrent with
finalization of this rule. The Secretary's certification will be
conditioned on each authorized SIP meeting the relevant requirements of
section 804 of the FD&C Act and this rule, including the use of time-
limited importation programs as described in this document. If one or
more of the provisions in this rule becomes invalid, in addition to the
entire rule becoming invalid, the certification would become null and
void because the certification is based on a finding that
implementation of section 804 will pose no additional risk to the
public's health and safety, and that finding would no longer be
accurate because it would have been based on a final rule that contains
all the requirements that were included when published. We are not
implementing section 804(j) of the FD&C Act relating to importation by
individuals at this time.
A. Scope/Applicability
These proposed amendments to the regulations at part 251 would
apply to eligible prescription drugs that are imported from Canada into
the United States pursuant to an importation program authorized by FDA
under section 804 of the FD&C Act.
B. Definitions
The proposed rule contains a number of definitions for terms used
in the rule. Some of these definitions are provided in section 804 of
the FD&C Act or cross-reference definitions elsewhere in part 251. We
seek comment on our proposed definitions.
Subject to certain exclusions, section 804(a)(3) defines a
``prescription drug'' as a drug subject to section 503(b) of the FD&C
Act, which is the provision requiring a prescription for drugs that are
not safe for use except under the supervision of a healthcare
practitioner. For purposes of this regulation, we propose to define
``eligible prescription drug'' to mean a drug subject to section 503(b)
of the FD&C Act that has a marketing authorization from HPFB and, but
for the fact it bears the HPFB-approved labeling, also meets the
conditions in an FDA-approved NDA or ANDA, including those relating to
the drug substance, drug product, production process, quality controls,
equipment, and facilities. Essentially, eligible prescription drugs are
those that could be sold legally on either the Canadian market or the
American market with appropriate labeling. An eligible prescription
drug would need to
[[Page 70804]]
be relabeled with the required U.S. labeling, including the carton and
container labels, prescribing information, and any patient labeling,
before it can be sold in the United States.
In addition, to be eligible for importation under section 804 of
the FD&C Act, the proposed rule would require that a prescription drug
be marketed in the United States currently. We believe that FDA will be
better able to determine if there is a safety issue with an imported
HPFB-approved drug if the FDA-approved drug is currently marketed,
because that will make it more likely that there will be current
adverse event reports, medication error reports, and product quality
complaints about the FDA-approved drug. In addition, a comparison
between the cost of the HPFB-approved drug sold in Canada and the cost
of the FDA-approved drug sold in the United States may be necessary to
establish that importation has resulted in a significant reduction in
the cost of covered products to the American consumer.
Section 804(a)(3) of the FD&C Act excludes several categories from
the definition of prescription drug, including controlled substances,
biological products, infused drugs (including a peritoneal dialysis
solution), intravenously injected drugs, and drugs that are inhaled
during surgery. The proposed regulation excludes these categories from
the definition of ``eligible prescription drug.'' In addition, we
propose to exclude drugs that are subject to risk evaluation and
mitigation strategies (REMS). Section 505-1 of the FD&C Act, which
authorizes FDA to require REMS, was passed after section 804 of the
FD&C Act. REMS drugs are high-risk products with known safety issues.
REMS programs are mandated by FDA but implemented by manufacturers. In
order to implement and assess a REMS, a manufacturer needs to have
control over the drug that is the subject of the REMS. For example, a
REMS could require that a medication's labeling include a Medication
Guide for patients. The manufacturer would not be able to ensure that
this is done for drugs imported under section 804 of the FD&C Act
because these drugs are relabeled by the Importer. Similarly, if it is
a requirement of a REMS that a manufacturer provide certain information
about a drug to prescribers, this could be complicated by the presence
in the supply chain of versions of that drug that are imported by SIPs
and so have different NDC numbers. Finally, for REMS that require tight
controls on distribution of the drug in order to mitigate risks, use of
Foreign Sellers will make it much more difficult to maintain those
restrictions and could introduce gaps that have a significant impact on
the safety of the drug.
The proposed regulation also excludes drugs that do not meet the
definition of a ``product'' for purposes of section 582 of the FD&C
Act. The DSCSA, which added section 582, was passed after section 804
of the FD&C Act. As explained earlier, one reason that FDA believes
that at this time it can implement section 804(b) through (h) of the
FD&C Act is the DSCSA's electronic, interoperable system to identify,
trace, and verify certain prescription drugs as they are distributed
among pharmaceutical supply chain trading partners. Drugs that are
imported under section 804 of the FD&C Act must meet the definition of
a DSCSA ``product'' so that they are subject to all DSCSA
identification, tracing, and verification requirements.
Under the proposed rule, a SIP Sponsor would need to explain in its
SIP Proposal how it will address any concerns arising from the
manufacture, storage, and transport of each eligible prescription drug,
including concerns related to controlling contamination, preserving
sterility, and ensuring stability. We considered excluding other
categories of products from eligibility for importation, including: (1)
Drug-device combination products that are approved under section 505 of
the FD&C Act, whether all such products or certain specific ones, such
as dry powder inhalers, metered-dose inhalers, and transdermal patch
products; (2) inhaled drugs; (3) modified-release drugs; (4) sterile
drugs; (5) ophthalmic drugs; (6) narrow therapeutic index drugs; (7)
drugs with boxed warnings; and (8) drugs requiring special storage
conditions. While each of these categories of products could pose
potentially heightened safety concerns, we did not exclude these
categories of products from eligibility in this proposed rule. Instead,
we propose that FDA will determine whether a product that falls into
one of these categories can be imported safely in the context of a
specific SIP Proposal on a product-by-product basis. If the product to
be imported is a combination product, this would include whether
requirements specific to combination products would be met. We request
comments on this approach.
The definition of ``prescription drug'' in section 804(a)(3) of the
FD&C Act also excludes ``a drug which is a parenteral drug, the
importation of which . . . is determined by the Secretary to pose a
threat to the public health.'' We note that several categories of
parenteral drugs--infused drugs, intravenously injected drugs, and
drugs that are inhaled during surgery--are specifically excluded from
importation under section 804 of the FD&C Act. We propose to exclude
two other categories of parenteral drugs, intrathecally injected drugs
and intraocularly injected drugs, from the definition of eligible
prescription drug. Intrathecal and intraocular injection pose
potentially significant risks because these routes of administration
bypass some of the body's natural defenses. In fact, they pose more
risks than intravenous injection, which is excluded by statute from
importation under section 804 of the FD&C Act. We propose that other
parenteral drugs that are not excluded from importation under section
804 of the FD&C Act or this proposed rule be evaluated in the same way
as drugs with other routes of administration. An importation program
that seeks to import any eligible prescription drug would have to
demonstrate that it can do so without posing additional risk to the
public's health and safety.
Consistent with section 804(f) of the FD&C Act, we propose to
define ``Foreign Seller'' to mean an establishment within Canada
engaged in the distribution of an eligible prescription drug that is
imported or offered for importation into the United States. As
discussed later in this document, under the proposed rule, Foreign
Sellers would be required to be licensed by Health Canada as drug
wholesalers and be registered with a provincial pharmacy regulatory
authority to distribute HPFB-approved drugs. Under the proposed rule, a
Foreign Seller could not be licensed to distribute drugs that are
approved by countries other than Canada and that are not HPFB-approved
for distribution in Canada. A Foreign Seller also must be registered
with FDA as required by section 804 of the FD&C Act.
We propose to define ``Importer'' to mean a U.S. distributor that
is a State- or FDA-licensed wholesale drug distributor or a State-
licensed pharmacist and that is the U.S. owner of an eligible
prescription drug at the time of importation of the drug into the
United States.
We propose to define ``manufacturer'' to include an applicant, as
defined in 21 CFR 314.3, who owns an approved NDA or ANDA for an
eligible prescription drug, or a person who owns or operates an
establishment that manufactures an eligible prescription drug.
Manufacturer also means a holder of a drug master file containing
information necessary to authenticate an eligible prescription
[[Page 70805]]
drug. These entities are those that would have the necessary
information required of manufacturers in section 804 and the
requirements proposed in this rule.
C. Section 804 Importation Program Proposals and Section 804 Pre-Import
Requests
Subpart B of the proposed rule provides the procedures for the
submission and evaluation of SIP Proposals for time-limited SIPs.
Subpart B also covers the submission of Pre-Import Requests by the
Importer, which would seek FDA's permission to begin importation of a
particular eligible prescription drug(s). In addition, Subpart B
outlines the procedures FDA proposes to use to authorize, revise,
revoke, and extend SIPs.
Under the proposed rule, once a SIP receives FDA authorization, the
SIP's Foreign Seller can purchase eligible prescription drugs with the
intent to sell them to the SIP's Importer for importation under section
804 of the FD&C Act, and the SIP's Importer can seek FDA's permission
to start importation of the drugs by submitting a section 804 Pre-
Import Request, as described later in this document. The Pre-Import
Request would include, among other things, a detailed description of
the plan for conducting the testing required under section 804 of the
FD&C Act and an attestation from the manufacturer that, but for the
fact that it bears the HPFB-approved labeling, the HPFB-approved drug
meets the conditions in the FDA-approved drug's NDA or ANDA.
Once FDA grants the section 804 Pre-Import Request, the Importer
may start the process for the importation of an eligible prescription
drug identified in the Pre-Import Request. The Agency's grant of the
section 804 Pre-Import Request by itself does not confer any type of
right to import. To be imported notwithstanding section 801(d)(1) of
the FD&C Act, a particular importation would need to meet the
requirements of section 804 and this regulation, including that the
prescription drug comply with sections 501, 502, and 505 of the FD&C
Act.
The Importer can choose to admit the drug(s) specified in the
Section 804 Pre-Import Request to an authorized FTZ and then conduct
the required testing and relabeling before offering the drug for entry.
Alternatively, the Importer can make an entry and request, under
section 801(b) of the FD&C Act and Sec. 1.95 (21 CFR. 1.95), to
recondition the drug(s), which would entail the required testing and
relabeling. The results of the Statutory Testing would need to be
reviewed and found acceptable by FDA before the drugs are relabeled and
sold in the United States. We believe this is necessary to prevent
having relabeled drugs refused entry and exported back to Canada where
they may subsequently be sold illegally back into the United States or
elsewhere.
1. The Section 804 Importation Program Proposal
The proposed regulations provide that a SIP Sponsor that seeks to
implement a SIP to import prescription drugs from Canada would need to
submit a proposal to FDA in electronic form to FDA's Electronic
Submissions Gateway (ESG) or to an alternative transmission point
identified by the Agency.
The proposal would need to include the following:
A cover sheet with the name or names of the SIP Sponsor
and co-sponsors, if any, and the name and contact information for the
point of contact with FDA during its review of the proposal;
A table of contents;
An introductory statement that includes an overview of the
SIP Sponsor's SIP Proposal; and
The SIP Sponsor's importation plan.
The overview in the introductory statement would need to identify
the State or a tribal or territorial governmental entity that is going
to sponsor the SIP, along with any co-sponsors. The overview would also
list each of the eligible prescription drugs that the SIP Sponsor seeks
to import and provide the name and address of the manufacturer of the
finished dosage form for each drug, as well as the name and address of
the manufacturer of the active pharmaceutical ingredient (API), if that
information is available to the SIP Sponsor. If the API information is
not available to the SIP Sponsor at the time their proposal is
submitted, the Importer would need to provide it later in the process,
when it submits a Pre-Import Request.
The overview in the introductory statement would also need to
provide the name and address of the Foreign Seller who will export the
drug from Canada to the United States, as well as the name and address
of the Importer in the United States. The overview would need to
summarize how the SIP Sponsor will ensure (1) that the imported
eligible prescription drugs meet the Statutory Testing requirements,
(2) that the labeling requirements of the FD&C Act and this rule are
met, (3) that the supply chain is secure, and (4) that the post-
importation pharmacovigilance and other requirements of the FD&C Act
and this rule are met. Finally, the overview would need to summarize
the proposer's reasons for expecting that the significant reduction in
cost from the importation accrues to the American consumer.
Under the proposed rule, the content of a SIP Proposal would
include the following. The SIP Proposal would need to identify the
State or tribal or territorial governmental entity that is going to
sponsor the SIP, along with its co-sponsors, if any. The SIP Proposal
would also need to identify the licensed wholesale drug distributor or
licensed pharmacist that will act as the Importer and explain its legal
relationship to the SIP Sponsor. Only a pharmacist or wholesaler could
import drugs under section 804 of the FD&C Act and this rule. The SIP
Proposal would need to identify each of the other entities in the
supply chain and explain their legal relationship to the SIP Sponsor,
if any, including the finished dosage form manufacturer and the Foreign
Seller. The SIP Proposal would need to state and provide supporting
evidence to establish that the Importer and the Foreign Seller meet all
the requirements in section 804 and this proposed regulation.
FDA proposes to require that a SIP Proposal include the Health
Canada inspectional history for the previous 5 years, or if the Foreign
Seller has been licensed for less than 5 years, for the duration of its
period of licensure, and the State and Federal inspectional history for
the Importer for the previous 5 years, or if the Foreign Seller has
been licensed for less than 5 years, for the duration of its period of
licensure. The SIP Sponsor would also need to provide an attestation
containing a complete disclosure of any past or pending civil penalties
or violation, or criminal convictions or violations, of applicable
State, Federal, or Canadian laws regarding drugs or devices against the
Foreign Seller or Importer or an affirmation and attestation that the
Foreign Seller or Importer has not been involved in, or convicted of,
any such criminal or prohibited acts. Such attestation would need to
include principals, any shareholder who owns 10 percent or more of
outstanding stock in any non-publicly held corporation, directors,
officers, and any facility manager or designated representative of such
manager. We also propose that the SIP Proposal include a list of all
disciplinary actions, along with the date of and parties to any action,
imposed against the Foreign Seller or the Importer by State, Federal,
or Canadian regulatory bodies, including any such actions against the
principals, owners,
[[Page 70806]]
directors, officers, or any facility manager or designated
representative of such manager over the previous 7 years. We seek
comment on whether the rule should require additional or alternative
background information and on whether the background information
requirement should cover additional or alternative individuals or
entities.
As part of demonstrating that the proposed importation will pose no
additional risk to the public's health and safety, the SIP Proposal
would need to set forth all the steps the SIP Sponsor would need to
take to ensure that the supply chain is secure, including ensuring that
the Foreign Seller is able to serialize the drugs to be imported with
an SSI. The SIP Proposal would need to include the steps that the SIP
Sponsor will take to ensure that the storage, handling, and
distribution practices of supply chain participants, including
transportation providers, maintain and ensure the quality and security
of the drugs. The storage and handling conditions and practices must
meet the minimum requirements of 21 CFR part 205. The SIP Proposal
would also need to set forth the Importer's responsibility for
screening the drug(s) that it imports for issues or problems, including
whether they are adulterated, counterfeit, damaged, tampered with, or
expired, and the Foreign Seller's and the Importer's responsibilities
for adverse event, medication error, field alert reports, or other
reporting, in addition to a detailed plan for effectuating any recalls.
The SIP Sponsor would have to explain how it will obtain recall or
market withdrawal information and how it will ensure that recall or
market withdrawal information is shared among the SIP Sponsor, the
Foreign Seller, the Importer, and FDA and provided to the manufacturer.
The SIP Proposal would also need to identify the FDA-registered
repackager or relabeler in the United States that will relabel the
imported drugs with the required U.S. labeling, including the carton
and container labels, prescribing information, and any patient
labeling, such as medication guides, instruction for use documents, and
patient package inserts. The proposed rule would also require that the
SIP Proposal describe the ways in which the SIP Sponsor will educate
pharmacists, healthcare providers, and patients about its SIP. We seek
comment on whether a SIP Proposal should also be required to describe
the SIP Sponsor's plan for ensuring that the FDA-approved patient
labeling is dispensed to patients with the drug imported under section
804 of the FD&C Act. In its proposal, the SIP would need to provide
supporting evidence to establish that the repackager or relabeler is
registered with FDA, as required by section 510(b) of the FD&C Act (21
U.S.C. 360(b)) and in accordance with part 207 (21 CFR part 207), and
that any objectionable conditions or practices identified during its
most recent FDA inspection have been addressed satisfactorily. While an
imported drug would need to be relabeled, it would need to remain in
the manufacturer's original container-closure system and not be
repackaged, except to the limited extent necessary to relabel it, as
described in this proposed rule.
Under the proposed rule, the SIP Proposal would be required to
identify each HPFB-approved prescription drug that the SIP Sponsor
seeks to import. The SIP Proposal would also be required to include the
proprietary and established names of the HPFB-approved product and of
its FDA-approved counterpart and confirm that the FDA-approved drug is
currently marketed. It would need to provide a description of all the
information that is available about the HPFB-approved product and its
FDA-approved counterpart and would be required to include the name and
quantity of the active pharmaceutical ingredient(s) of the two drug
products, the inactive ingredients of the two products, and the dosage
form of the two drug products. The proposal would also need to include
the HPFB-approved product's drug identification number (DIN), and the
FDA-approved product's National Drug Code (NDC) and NDA or ANDA
numbers. The proposal would also need to include the HPFB-approved
drug's labeling. Under the proposed rule, the proposal would be
required to include the FDA-approved drug's labeling and the FDA-
approved labeling with the revisions necessary for the HPFB-approved
drug to meet the requirements of this rule, as well as a side-by-side
analysis of the FDA-approved drug's labeling and the proposed labeling
to help demonstrate that the applicable FDA labeling requirements and
the requirements of this rule are met.
The proposed rule would also require that the proposal identify the
establishment where the active ingredient for each drug is
manufactured, if this information is available, and the establishment
where the finished dosage form for each drug is manufactured, if this
information is available. This information is important for FDA to
adequately assess whether the eligible prescription drug meets the
conditions in an approved NDA or ANDA. If this information is not
available to the SIP Sponsor at the time that the proposal is
submitted, it would need to be provided later by the Importer in the
Pre-Import Request.
The Statutory Testing that would be done under the proposed rule
should be described in as much detail as possible in the SIP Proposal.
The proposal would also need to explain how the SIP Sponsor will ensure
that any information that the manufacturer provides to the Importer to
allow the Importer to conduct the Statutory Testing would be kept in
strict confidence and used only for purposes of testing or otherwise
complying with the FD&C Act, as required by section 804(e)(2)(B). The
information that the manufacturer provides must not be disseminated
except to the qualified laboratory that will test the drug and to FDA,
and the SIP Sponsor would need to explain how it will ensure that the
information is not disseminated to any person by the qualified
laboratory. If confidential manufacturer information is disclosed
beyond the parameters described above, FDA will terminate the SIP.
Moreover, a violation of any of these regulations, including this
provision, is a prohibited act under section 301(aa) of the FD&C Act.
An Importer that fails to comply with the requirement that the
manufacturer's information be kept in strict confidence and be used
only for testing or otherwise complying with the FD&C Act can be
imprisoned for not more than 10 years under section 303(b)(6) of the
FD&C Act (21 U.S.C. 333(b)(6)), fined under 18 U.S.C. 3571, or both. We
seek comments on this approach.
The proposal would also need to indicate which laboratory in the
United States will conduct the testing described in section
804(d)(1)(J) and (L) of the FD&C Act, which is discussed later in this
document, and it would need to establish that the laboratory is located
in the United States and is qualified to conduct the tests. As
discussed later in this document, we propose that when FDA authorizes a
SIP Proposal, FDA would thereby approve the laboratory identified in
the proposal as a ``qualifying laboratory'' for purposes of section
804, as required by section 804(a)(4) of the FD&C Act. To be approved
as a qualifying laboratory, a laboratory would need to have ISO 17025
accreditation and comply with the applicable elements of the
pharmaceutical current good manufacturing practice (CGMP) requirements
in parts 210 and 211 (21 CFR parts 210 and 211). It would need to have
an FDA inspection history and satisfactorily addressed any
objectionable conditions or practices
[[Page 70807]]
identified during its most recent FDA inspection.
We recognize that not all data and information needed to show that
a HPFB-approved drug meets the conditions in an FDA-approved NDA or
ANDA may be available to a SIP Sponsor at the time that it submits its
SIP Proposal. For example, testing results would not be available until
the Importer receives a shipment of an eligible prescription drug and
conducts the Statutory Testing. FDA may authorize a SIP based on the
available information about a drug. An Importer will not be able to
sell a drug imported under section 804 of the FD&C Act in the United
States until the testing described in section 804(d) is completed
satisfactorily, and the Importer has secured the information from the
manufacturer described in section 804(e) that is needed to show that
the drug meets the conditions of an approved NDA or ANDA and poses no
additional risks to the public's health and safety.
Finally, the SIP Proposal would need to explain how the SIP Sponsor
expects that the SIP would result in a significant reduction in the
cost to the American consumer of the prescription drugs that the SIP
Sponsor seeks to import. The explanation would need to include any
assumptions and uncertainty, and it would need to be sufficiently
detailed to allow for a meaningful evaluation. We propose that whether
a reduction in cost is significant be determined in the context of
considering a specific proposal. We seek comment on the factors that
should be considered in determining whether a reduction in the cost of
covered products is significant.
To demonstrate expected cost savings, a SIP Sponsor could compare
anticipated acquisition costs or consumer prices per unit of each drug
that the SIP Sponsor is seeking to import. For example, a SIP Sponsor
could compare the anticipated acquisition cost per unit of the HPFB-
approved drug to the acquisition cost per unit of the FDA-approved
drug. A SIP Sponsor could also compare the current retail cash price of
the drugs. We seek comment on these and other relevant measures that
may be available to SIP Sponsors during proposal development.
We also seek comments on what mechanisms SIPs could use to ensure
that there is a significant reduction in the cost of covered products
to the American consumer and comments on what, if any, additional
showing SIP Sponsors would need to make if the cost savings do not go
directly to consumers. If the cost savings do not go directly to
consumers directly because, for example, they accrue to a healthcare
provider or payor, the SIP Proposal would need to show that there is a
significant reduction in the cost of covered products to the American
consumer.
We anticipate that some SIP Sponsors may seek to import drugs to be
used by patients in State-run programs in which participants do not
directly pay the cost of drugs. In such cases, a SIP Sponsor could
submit information about whether cost-sharing expenses are reduced for
the participants, or whether the program will result in cost savings
that are passed on to consumers in other ways, such as increasing the
number of people who can be covered by a State program, or increasing
the availability of drugs covered by the program. We seek comment on
this and on what other cost-related information SIP Sponsors could
provide where drugs would be imported for use by patients in State-run
programs.
The SIP Sponsor would be responsible for ensuring that the SIP and
each entity that participates in the SIP complies with section 804,
with other applicable sections of the FD&C Act, and with this and other
applicable regulations for the entire length of the approval period.
The SIP Sponsor should explain in detail how it will do so in the SIP
Proposal.
2. Review and Authorization of Section 804 Importation Program
Proposals
FDA will review and approve or deny SIP Proposals. We solicit
comments on what the timeline for such review should be, and on what
type and frequency of communication between FDA and SIP Sponsors would
be helpful and efficient. We also seek comment on whether SIP Proposals
should be addressed on a first-come, first-served basis, or whether
they should be prioritized. If they should be prioritized, we seek
comment on what the basis for prioritization should be.
As noted previously, we recognize that at the time of submission,
the SIP Sponsor may not know whether a drug meets the conditions in an
FDA-approved NDA or ANDA. FDA will review, among other things, the
information that the SIP Sponsor is able to provide about each of the
drugs that the SIP Sponsor seeks to import to confirm that each is
approved by both HPFB and FDA, that each FDA-approved drug is currently
marketed in the United States, and that none of the drugs fall into any
of the exclusions from the definition of eligible prescription drug.
FDA will also review the proposal to ensure that the requirements of
the FD&C Act and this rule are met, and specifically that the proposed
supply chain, the proposed plan to relabel the eligible prescription
drugs, and the proposed pharmacovigilance measures meet the
requirements of the FD&C Act and this rule. FDA intends to call on
other divisions of HHS, such as ASPE, to assist with the review and
evaluation of the components of the proposal, and to refer questions to
such divisions as appropriate, that relate to the price of the drugs to
be imported and to the steps that will be taken to ensure that there is
a significant reduction in the cost of drugs to consumers. FDA and/or
HHS may issue guidance on this topic as appropriate.
Where a SIP Proposal meets the requirements of section 804(b)
through (h) of the FD&C Act and the requirements in the proposed rule,
FDA may nonetheless decide, in its discretion, not to authorize the SIP
Proposal. Among other reasons, FDA may decide not to authorize a SIP
Proposal because of potential safety concerns with the SIP, because of
the relative likelihood the SIP would not result in significant enough
cost savings, or because FDA needs to limit the number of authorized
SIPs to effectively and efficiently run the program or in light of
other resource demands.
3. The Section 804 Pre-Import Request
After FDA authorizes a SIP, the Foreign Seller can proceed to
purchase one or more of the eligible prescription drugs included in the
SIP Proposal directly from the manufacturer with the intent to sell
them to the Importer. The Importer can then request that the
manufacturer agree to conduct the testing set forth in section
804(d)(1)(J) and (L) of the FD&C Act. If the manufacturer declines to
do so, the manufacturer must provide the information needed to conduct
the testing, as required by section 804(e)(2) of the FD&C Act. The
Importer can then submit a section 804 Pre-Import Request to the ESG or
other transmission point identified by the Agency.
The Importer would need to submit a section 804 Pre-Import Request
at least 30 days prior to the scheduled date of arrival of a shipment
containing an eligible prescription drug(s) at the CBP port of entry
authorized by FDA, or entry for consumption in ACE of one or more
batches of an eligible prescription drug(s) covered by a SIP, whichever
occurs first. FDA believes at least 30 days will be needed for FDA to
sufficiently review the information provided. Under the proposed
process, the Importer would not be permitted to
[[Page 70808]]
ship an eligible prescription drug into the United States until a
section 804 Pre-Import Request that includes that specific drug was
granted by FDA.
Under the proposed rule (Sec. 251.5), a complete Pre-Import
Request would include, at a minimum: Identification of the Importer,
including Importer name, business type (wholesale distributor or
pharmacist), U.S. license number or numbers and State or States of
license, business address, unique facility identifier if required to
register with FDA as an establishment under section 510 of the FD&C Act
or FDA establishment identification number if not required to register
as an establishment, and name of a contact person with their email and
phone number; identification of the FDA-authorized SIP Proposal
including the name of the SIP, the name or names of the SIP Sponsor and
co-sponsors, if any, business address, and name of a contact person,
with their email and phone number; identification of the Foreign
Seller, including the name of the Foreign Seller, business address,
unique facility identifier, any license numbers issued by Health Canada
or a provincial pharmacy regulatory body, and the name of a contact
person with their email and phone number; and identification and
description of the eligible prescription drug or drugs covered by the
Pre-Import Request including the following information: Name of the
HPFB-approved drug or drugs (established and/or trade), DIN, and
complete product description including strength, description of dosage
form, and route of administration; API information, including name of
API, manufacturer of API and its unique facility identifier, and amount
of API and unit measure in each eligible prescription drug; name
(established and/or trade) of the FDA-approved counterpart drug or
drugs and their NDA or ANDA number or numbers; manufacturer of the
eligible prescription drug with the business address and unique
facility identifier; copies of the invoice and any other documents
related to the manufacturer's sale of the drugs to the Foreign Seller
provided by the manufacturer to the Importer and copies of the same
documents provided by the Foreign Seller to the Importer; quantity,
listed separately by dosage form, strength, batch and lot or control
number assigned by the manufacturer to each eligible prescription drug
intended to be imported under this Pre-Import Request compared to the
quantity of each batch and lot or control number originally received by
the Foreign Seller from the manufacturer and the date of such receipt;
expiration date of each HPFB-approved drug, listed by lot or control
number; expiration date to be assigned to each eligible prescription
drug when relabeled by the Importer with a complete description of how
that expiration date was calculated to comply with the FDA-approved
drug's NDA or ANDA; NDC proposed for assignment by the Importer for
each eligible prescription drug to be imported; and FDA product code
for each eligible prescription drugs to be imported.
A Statutory Testing plan would also be part of the request,
including: A description of how the samples will be selected from a
shipment for the Statutory Testing; the name and location of the
qualifying laboratory in the United States that will conduct the
Statutory Testing; and if the importer will be conducting the Statutory
Testing, or a description of the testing method(s) that will be used to
conduct the Statutory Testing. If the manufacturer will be conducting
the Statutory Testing, the description of the testing methods can be
submitted by the manufacturer to FDA directly, as discussed later in
this document. An attestation from the manufacturer, which is described
in more detail later in this document, that, but for the fact that it
bears the HPFB-approved labeling, the eligible prescription drug meets
the conditions in the FDA-approved drug's NDA or ANDA, would also be
included. If the manufacturer conducts the Statutory Testing, the
manufacturer would need to provide the attestation to FDA. If the
Importer conducts the Statutory Testing, the manufacturer would need to
provide the attestation to the Importer.
Information related to the Importation would be provided, including
the location of the eligible prescription drugs in Canada and
anticipated date of shipment (date eligible prescription drug or drugs
will leave their location in Canada); name, address, email, and
telephone number of the foreign shipper; anticipated date of export
from Canada and Canadian port of exportation; anticipated date of
arrival at port(s) authorized by FDA to import eligible prescription
drugs under section 804; the name, address, FDA establishment
identification number, and telephone number of the warehouse, location
within a specific FTZ, or other secure distribution facility controlled
by or under contract with the Importer where the eligible prescription
drug(s) will be stored pending testing, relabeling, and FDA
determination of admissibility; and information regarding the facility
where the relabeling and any limited repackaging activities will occur
for all eligible prescription drug(s) covered by this Pre-Import
Request, including: (1) The facility's unique facility identifier; (2)
the facility's name, address, and FDA establishment identification
number; (3) the anticipated date the relabeling and any limited
repackaging will be completed; and (4) information about where the
relabeled drug will be stored pending distribution, including the FDA
establishment identification number of the storage facility, if
available.
FDA's grant of a section 804 Pre-Import Request does not constitute
an admissibility determination by the Agency of any of the drugs
covered by the Request. When a Pre-Import Request is granted by FDA,
that Pre-import Request would cover subsequent shipments of the
eligible prescription drug(s) identified in the Agency's grant of that
Request provided that the rest of the information contained in the Pre-
Import Request, with the exception of the anticipated dates of shipment
and export, is the same. We seek comment on this approach.
When the Agency grants a section 804 Pre-Import Request, it will
specify an FDA field laboratory to which the Importer would need to
submit three sets of the samples that the Importer sends to the
qualifying laboratory to enable FDA to conduct the Statutory Testing as
FDA deems warranted.
4. Importation
When goods are imported into the United States, they must be
entered at one of the CBP ports of entry (sea, land, rail, and air).
The term entry generally refers to the information or documentation
that an importer of record, or an authorized customs broker, must file
with CBP for importing merchandise into the United States. A SIP
Importer will be, and must qualify as, the importer of record for
eligible prescription drugs imported under section 804.
The proposed rule would require that an entry for consumption of an
eligible prescription drug under an authorized SIP be filed
electronically in ACE, or any other Electronic Data Interchange (EDI)
system authorized by CBP. Currently, ACE is the sole EDI system
authorized by CBP for electronic entry of FDA-regulated products. ACE
serves as the ``single window'' through which an import filer submits
the data elements required for an import entry, including data elements
designated by a Partner Government Agency (PGA). As a PGA, FDA has
designated a PGA Message Set in ACE for FDA-regulated
[[Page 70809]]
products. This message set contains both required and optional data
elements to assist us in our admissibility review of FDA-regulated
articles. In the Federal Register of November 29, 2016 (81 FR 85854),
FDA published a final rule, effective December 29, 2016, entitled
``Submission of Food and Drug Administration Import Data in the
Automated Commercial Environment,'' which requires certain data
elements that are material to our import admissibility review be
submitted in ACE or any other EDI system authorized by CBP, at the time
of entry. The rule was intended to facilitate automated ``May Proceed''
determinations by the Agency for low-risk FDA-regulated products which,
in turn, allows the Agency to focus our limited resources on products
that may be associated with a greater public health risk. The final
rule is codified in subpart D, 21 CFR part 1.
All shipments containing eligible prescription drugs to be imported
under an authorized SIP would need to arrive and be entered at the CBP
port of entry that is authorized by FDA. When an entry for consumption
containing an FDA-regulated product is processed by CBP, CBP relays the
data in the PGA Message Set to FDA using an electronic interface with
FDA's import processing system, currently the Operational and
Administrative System for Import Support (OASIS). The import filer need
only submit this entry information once in the ACE system, provided
that the information submitted in ACE is accurate. ACE entries are
electronically screened in OASIS against criteria developed by FDA.
FDA's Predictive Risk-based Evaluation for Dynamic Import Compliance
Targeting (PREDICT) is a risk-based electronic screening tool for OASIS
that performs this initial electronic screening to assist FDA entry
reviewers by evaluating the potential risks associated with each
article and identifying those articles that may present a higher public
health risk for further examination by FDA.
As discussed, the drugs covered by a SIP can be imported using two
proposed pathways: Admission to an FTZ with later entry for consumption
and filing in ACE when compliant, or filing an entry for consumption in
ACE with a request to bring the eligible prescription drugs into
compliance with the FD&C Act under section 801(b) of the FD&C Act and
Sec. 1.95. The plan submitted under Sec. Sec. 1.95 and 1.96 for the
drugs would need to include the testing and relabeling required under
this proposed rule.
FDA proposes that the testing and relabeling of a shipment, as
described in the Section 804 Pre-Import Request, take place after the
shipment has arrived in the United States, but before it can be
distributed in the United States. This will enable the Importer to
inspect the Canadian labeling and packaging as part of its screening
obligations. It will also place the responsibility on the Importer to
ensure that the samples submitted for testing are representative of the
actual shipment. The Importer will also be responsible for ensuring
that the relabeling and the product identifier are compliant with U.S.
laws and regulations after FDA has determined that the testing results
are acceptable and before an eligible prescription drug is sold in the
United States. Placing these responsibilities on Importers will aid FDA
in its efforts to monitor compliance with and enforce the requirements
of the FD&C Act and this proposed rule when it is finalized.
As discussed earlier, under the proposed rule, an Importer could
admit an eligible prescription drug to an FTZ in the United States for
the purpose of completing the required testing and relabeling. An FTZ
is a secure area under the supervision of CBP. FTZs were established in
the United States under the Foreign Trade Zones Act of 1934 (19 U.S.C.
81a-81u) for importers to hold or otherwise manipulate goods without
being subject to certain CBP requirements including customs entry
(articles are ``admitted'' to an FTZ and not entered), payment of duty,
tax, or bond. Since these FTZ Act exclusions only affect the
application of certain CBP laws, FDA-regulated articles that are
brought into an FTZ remain subject to other U.S. laws and regulations
affecting imported goods. Therefore, placement of eligible prescription
drugs in an FTZ does not affect FDA's jurisdiction and inspectional
authority over them. Samples of the eligible prescription drug or drugs
can be removed from the FTZ for the purpose of the required testing by
a qualifying laboratory and for providing samples to FDA as proposed in
this rule.\3\
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\3\ Any such samples removed from the FTZ for testing in the
customs territory of the United States will have to be entered using
normal Customs procedures.
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If the Importer pursues the second pathway, filing an entry for
consumption in ACE and requesting to bring the drugs into compliance,
under section 801(b) of the FD&C Act, the Importer would submit Form
FDA 766, to the relevant FDA Imports Division Director. After review,
the Director would notify the Importer of FDA's approval or disapproval
of the plan to bring the drugs into compliance. If approved, the FDA
notice of approval will specify the conditions to be fulfilled and the
time limit for fulfilling them (see Sec. 1.96). Under the proposed
rule, the Importer would need to keep the product at a designated
secured warehouse, and under appropriate environmental conditions to
maintain the integrity of the products, until FDA issues an
admissibility decision. The secured warehouse would need to be within
30 miles of the authorized Port of Entry to facilitate FDA oversight,
including the collection and examination of samples.
After the authorized plan has been completed, the Importer will
complete the section entitled ``Importer's Certificate'' on Form FDA
766 and provide that certification to the relevant FDA Imports Division
Director. At this point, FDA may choose to conduct a followup
inspection and/or sampling to determine compliance with the terms of
the authorized plan. If FDA determines that the conditions of the
authorized plan have been fulfilled, the Agency will notify the
Importer through a Notice of Release indicating that the admissible
portion of the shipment is no longer subject to detention or refusal of
admission. This Notice is usually identified as ``Originally Detained
and Now Released.'' A copy of the Notice is sent to the owner or
consignee; CBP would then be notified electronically of FDA's ``May
Proceed'' determination. If there is a non-admissible portion of the
shipment, that portion can be destroyed, or re-exported by the Importer
under FDA or CBP supervision (21 U.S.C. 381(a)). A Notice of Refusal of
Admission will be issued to the Importer for the rejected portion.
Under the proposed rule, FDA would intend to refuse admission into
the United States under section 801(a)(3) of the FD&C Act if: (1) 6
Months have passed since the entry date of the shipment; (2) the
conditions of the SIP or the section 804 Pre-Import Request are not
met; or (3) the drug otherwise appears to be adulterated, misbranded or
unapproved in violation of section 505 of the FD&C Act. If FDA refuses
admission into the United States under section 801(a)(3) of the FD&C
Act, the drug should be exported or destroyed by the Importer within 90
days of the refusal.
The proposed rule would require that an entry for consumption be
made electronically in ACE for any shipment containing an eligible
prescription drug. The port of arrival and port of entry would be
limited to a CBP port that is authorized by FDA, so that FDA can
[[Page 70810]]
ensure that it has adequate resources at the port to process the
arrival and entry of shipments that contain an eligible prescription
drug and to perform sampling of any such shipment, if necessary. The
following data elements would be required to be submitted in ACE at the
time of entry:
a. The unique facility identifier of the Foreign Seller;
b. The Importer's NDC for each eligible prescription drug;
c. The NDA or ANDA number of each eligible prescription drug's FDA-
approved counterpart;
d. The lot or control number assigned by the manufacturer for each
eligible prescription drug;
e. The FDA Quantity, which is the quantity of the eligible
prescription drug or drugs in an import line delineated by packaging
level, including the type of package from the largest packaging unit to
the smallest packaging unit; the quantity of each packaging unit; and
the volume and/or weight of each of the smallest of the packaging
units; and
f. The Pre-Import Request number.
FDA would require submission of these data elements in ACE at the
time of entry to facilitate the importation of eligible prescription
drugs as part of a SIP. The proposed rule would clarify that for
eligible prescription drugs the unique facility identifier of the
registered Foreign Seller and the NDC proposed for assignment by the
Importer be submitted in ACE at the time of entry. The application
number of the NDA or ANDA for the FDA-approved drug that is the
counterpart of the eligible prescription drug would also be submitted
in ACE. This information will help FDA to verify that an entry for
consumption contains eligible prescription drugs. The lot or control
number of each eligible prescription drug would be required to be
submitted by the Importer to FDA under this proposed rule, in
accordance with section 804(d)(1)(H) of the FD&C Act.
In accordance with section 804(d)(1)(D) of the FD&C Act, we propose
to require the Importer submit information on the quantity of the
eligible prescription drug that is shipped in ACE at the time of entry.
FDA is proposing to require that quantity include the quantity of each
layer/level of packaging of the eligible prescription drug(s); the unit
of measure, which is the description of each type of package; and the
volume and/or weight of each of the smallest of the packaging units.
The quantity would be required to be submitted in decreasing size of
packing unit (starting with the outermost/largest package and ending
with the innermost/smallest package).
Information on the quantity of each layer or level of packaging
will help the Agency identify an article being imported or offered for
import as an eligible prescription drug. Although CBP and FDA utilize
Harmonized Tariff Schedule codes to generally identify which imports
are subject to an FDA admissibility review, these codes are often not
sufficient to specifically identify a product for FDA decision making.
There may be instances in which a drug's packaging does not meet the
conditions of the approved NDA or ANDA. Packaging can affect the safety
of an FDA-regulated product, for example, where an article is
represented as ``sterile.'' Submission of the quantity, including of
each layer or level of packaging, in ACE at the time of entry would
assist the Agency should it need to perform field examinations, label
examinations, sample collections, detentions, or refusals.
Finally, the Pre-Import Request number, which FDA would provide to
the Importer when we grant the Pre-Import Request, would allow FDA's
review staff to verify that a Pre-import Request covering the eligible
prescription drugs in the shipment has been approved by FDA.
5. Submission and Review of Testing Results
Once the testing described in section 804(d)(1)(J) and (L) of the
FD&C Act is complete, the results would be submitted to FDA, along with
a Certificate of Analysis (COA), selection method for the samples, the
testing methods used, laboratory records required by the proposed rule
in accordance with section 804(d)(1)(L), and any other documentation
demonstrating that the testing was conducted at a qualifying laboratory
and otherwise meets the requirements in section 804(e)(1) of the FD&C
Act. If the Importer performs the Statutory Testing after the shipment
has been admitted to an FTZ but before filing entry for consumption,
the Importer would be required to submit the required testing results
and records to FDA in electronic form to the ESG or to an alternative
transmission point identified by FDA, prior to relabeling the drugs. If
the Importer performs the testing at a qualifying laboratory as part of
an FDA-approved plan under Sec. Sec. 1.95 and 1.96, the Importer would
be required to submit the required testing results and records as part
of the Importer's plan prior to relabeling of the drugs. If a
manufacturer performs the Statutory Testing, the manufacturer would
submit the test results and records to FDA directly in electronic form
to the ESG or to an alternative transmission point identified by FDA.
FDA would review the test results and records and notify the Importer
whether the test results are acceptable to the Agency and then the
Importer would cause the drugs to be relabeled in accordance with the
proposed rule. Under the proposed rule, if the data and information
that the manufacturer or Importer submits do not establish that the
drug the SIP Sponsor seeks to import is authentic, not degraded, and
meets the conditions of an FDA-approved NDA or ANDA, the drug cannot be
relabeled, and FDA would refuse admission of the drug. FDA proposes to
require that the relabeling only take place after the Agency has
accepted the test results to avoid potential diversion that could occur
if eligible prescription drugs are relabeled for the U.S. market and
then fail the testing requirements, which could happen before or after
export of the refused drugs to Canada.
6. Period of Authorization of Section 804 Importation Programs
Under the proposed rule, SIPs would initially be authorized for a
2-year period, with the possibility of extensions for additional 2-year
periods. Each 2-year period would begin when the Importer files an
electronic import entry for consumption for its first shipment of
drugs. If the Importer does not file an electronic import entry for
consumption for a shipment of eligible prescription drugs within 1 year
of the date the SIP is authorized by FDA, the SIP Sponsor would have to
submit, and FDA would have to authorize, a new SIP Proposal before it
could begin the importation process.
We believe that SIPs should be given a 2-year period before re-
authorization is required to continue in the program because we believe
that this will provide sufficient time for SIP Sponsors to demonstrate
that they can in fact import drugs from Canada with no additional risk
to the public's health and safety and that such importation in fact
results in a significant reduction in the cost of covered products to
the American consumer. We believe that SIPs should terminate after 2
years unless re-authorized because importation under section 804 is
novel. After 2 years, we will have the data necessary to evaluate a
SIP's success. We will be able to determine if the safeguards in
section 804 of the FD&C Act and in this rule, should it be finalized,
are working and, if they are, if there are requirements that could be
amended or streamlined. We will be
[[Page 70811]]
able to compare and contrast the approaches taken by different SIP
Sponsors. FDA will also take the opportunity to assess any changes in
the marketplace that result from section 804 importation. For example,
we will be able to determine whether section 804 importation resulted
in changes in the price or supply of drugs in Canada or the United
States, whether there are newly erected or existing barriers to section
804 importation, and whether and how bad actors respond to section 804
importation. FDA seeks comment on this approach, including whether 2
years is the appropriate initial period of time for a SIP, whether 2-
year re-authorization periods are appropriate, and whether there should
be a limit on the number of re-authorization periods.
7. Modification or Extension of Section 804 Importation Programs
Under the proposed rule, if a SIP Sponsor wishes to make a change
to an authorized SIP (for example, to amend the list of eligible drugs
it seeks to import or to work with a different Foreign Seller,
Importer, or qualifying laboratory), the SIP Sponsor would be required
to submit a supplemental proposal for FDA's consideration. As noted
earlier, if a SIP Sponsor wishes to work with more than one Foreign
Seller or Importer, it must first demonstrate that it has consistently
imported eligible prescription drug(s) in accordance with section 804
and this rule. We generally expect that a SIP Sponsor would have
submitted its first quarterly report to FDA before it submits a
supplement to the SIP Proposal seeking to add an additional Foreign
Seller or Importer.
If FDA authorizes the supplemental proposal, a new Pre-Import
Request would be required for the next shipment. Under the proposed
rule, a SIP Sponsor would not be permitted to make any changes or
permit any changes to be made to the SIP without first securing FDA's
authorization.
Under the proposed rule, an authorized SIP Sponsor would be able to
submit a proposal asking for authorization to extend the SIP for
additional 2-year-long periods beyond the initial 2-year long
implementation period. To be eligible for extension, a SIP would need
to be up to date on all the information and records-related
requirements of section 804 and this rule. A request for authorization
to extend a SIP should be submitted at least 3 months before the SIP's
2-year-long authorization period expires.
8. Denial, Suspension, or Revocation of Authorization of Section 804
Importation Programs
If at any point in the course of its review of a SIP Proposal, FDA
finds minor, correctable deficiencies, the Agency intends to make a
reasonable effort to promptly communicate them to the SIP Sponsor so
that they can be corrected in a timely way. However, FDA may deny a
request for authorization, modification, or extension of a SIP in its
discretion, as described elsewhere in this proposed rule, including if
a proposed SIP does not meet the standard for authorizing a SIP under
this proposed rule.
Under the proposed rule, FDA can revoke the authorization of a SIP
in whole or in part, including with respect to one or more drugs in the
SIP, at any time for any reason in FDA's discretion, including if, for
example: (1) FDA finds that the SIP Proposal contained an untrue
statement of material fact or omitted material information required by
this part; (2) the SIP no longer meets the requirements of section 804
of the FD&C Act or the standard for authorizing a program under this
proposed rule; (3) continued implementation of the SIP will pose
additional risk to the public's health and safety; (4) continued
implementation of the SIP will not result in a significant reduction in
the cost of covered products to the American consumer; or (5) continued
monitoring of the SIP imposes too much of a drain on Agency resources
or is inconsistent with the Agency's prioritization of resources.
Under the proposed rule, if at any point a SIP Sponsor has reason
to suspect that a drug, manufacturer, Foreign Seller, Importer,
qualifying laboratory, or other participant in or element of the supply
chain that FDA initially authorized does not in fact meet the
requirements of section 804 or any other applicable requirements of the
FD&C Act, or of any applicable regulation, including this rule, the SIP
Sponsor would be required to stop importation immediately, notify FDA,
and demonstrate to FDA that importation has in fact been stopped
pending an investigation. In addition, FDA may also suspend a SIP under
such circumstances, or under other circumstances in FDA's discretion,
which would prevent further importation of drugs under it. Under
certain circumstances set forth in section 804(g) of the FD&C Act, FDA
is required to suspend importation. Section 804(g) provides that the
Secretary shall require that importations of a specific prescription
drug or importations by a specific importer under subsection (b) be
immediately suspended on discovery of a pattern of importation of that
specific prescription drug or by that specific importer of drugs that
are counterfeit or in violation of any requirement under this section,
until an investigation is completed and the Secretary determines that
the public is adequately protected from counterfeit and violative
prescription drugs being imported under subsection (b).
In addition, under the proposed rule, where a SIP Sponsor fails to
timely extend its authorized SIP, the SIP would be considered expired.
The sponsor of an expired SIP would need to submit a new SIP Proposal
because FDA may be unable to confirm that the SIP Sponsor continues to
meet all the necessary requirements. FDA is also proposing to terminate
a SIP upon request from the SIP Sponsor when the request includes a
notice of the SIP Sponsor's intent to discontinue its activities. The
sponsor of an expired SIP would be required to submit a new SIP
Proposal should it decide to resume section 804 importation activities.
9. Monitoring and Compliance
SIP Sponsors will be responsible for ensuring that all the
participants in a SIP comply with the requirements of section 804 of
the FD&C Act and this rule. As noted earlier, a SIP Sponsor would need
to develop a compliance plan and describe it in detail in their SIP
Proposal for FDA's review and authorization. We ask for comment on what
elements should be included in a SIP's compliance plan. Among other
things, such a plan could require: (1) A description of the division of
responsibilities between co-sponsors, if any, (2) the creation of
written compliance policies, procedures, and protocols; (3) the
provision of education and training to ensure that Foreign Sellers,
Importers, qualifying laboratories, and their employees understand
their compliance-related obligations; (4) the creation and maintenance
of effective lines of communication, including a process to protect the
anonymity of complainants and to protect whistleblowers; and/or (5) the
adoption of processes and procedures for uncovering and addressing
noncompliance or misconduct. We seek comment on what alternate or
additional requirements might be appropriate if a SIP is co-sponsored.
FDA's usual compliance and enforcement tools apply to SIP
participants. We will retain our usual rights to conduct pre-
authorization,
[[Page 70812]]
surveillance, and risk-based inspections under section 704 of the FD&C
Act. In addition, the proposed rule would require that SIP Sponsors and
other SIP participants agree to submit to audits of their books and
records and inspections of their facilities as a condition of
participation in a SIP. If a SIP Sponsor, manufacturer, Foreign Seller,
Importer, qualifying laboratory, or other participant in or element of
the supply chain delays, denies, or limits an inspection, or refuses to
permit entry or inspection of their facility or their records, any drug
that they have held would be deemed to be adulterated (FDA, 2014.
``Guidance for Industry: Circumstances that Constitute Delaying,
Denying, Limiting, or Refusing a Drug Inspection.'' (Available at
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/circumstances-constitute-delaying-denying-limiting-or-refusing-drug-inspection). FDA could also suspend the SIP, in whole or
in part, immediately in that circumstance.
FDA can take action through, e.g., warning letters, seizure, and
detention, to address failure to abide by applicable requirements,
including requirements in this rule, when finalized, and requirements
concerning product quality. FDA would also retain the authority under
section 801 of the FD&C Act to refuse admission to a drug that does not
comply with the FD&C Act or the rule, including, under section
801(a)(3) of the FD&C Act, the authority to refuse entries of drugs
that appear to be adulterated, misbranded, including if it does not
comply with the product identifier requirement of section 582 of the
FD&C Act, or in violation of section 505 of the FD&C Act.
D. Requirements for Foreign Sellers
A ``Foreign Seller'' under section 804 and this proposed rule is an
establishment within Canada engaged in the distribution of an eligible
prescription drug that is imported into the United States. Under the
proposed rule, the Foreign Seller would buy eligible prescription drugs
directly from the manufacturers and then sell them directly to the
Importer. The Foreign Seller would also be responsible for relabeling
the drug product solely to affix or imprint the SSI on each package and
homogenous case of the eligible prescription drug(s).
The SIP Sponsor would be required to ensure that the Foreign Seller
meets all the licensing and registration requirements set forth in the
statute and this proposed rule. We propose to require that Foreign
Sellers have an active drug establishment license as a wholesaler from
Health Canada. We also propose to require that they be registered with
provincial pharmacy regulatory authority to distribute HPFB-approved
drugs. In addition, we propose that a Foreign Seller could not be
licensed to distribute drugs that are approved by countries other than
Canada and that are not HPFB-approved for distribution in Canada. We
believe that this is an important safeguard that will help ensure that
only HPFB-approved drugs are imported to the United States under SIPs.
We seek comment on what additional standards should be imposed or
qualifications required of Foreign Sellers.
The proposed rule would also require Foreign Sellers to register
with FDA. Section 804(f) of the FD&C Act requires that any
establishment within Canada engaged in the distribution of a
prescription drug that is imported or offered for importation into the
United States shall register with the Secretary the name and place of
business of the establishment and the name of the U.S. agent for the
establishment. This proposed rule implements that provision and largely
tracks the registration requirements for foreign establishments set
forth in 21 CFR 207.21, 207.25, and 207.29.
Facilities that register with FDA as Foreign Sellers should do so
using the existing structured product labeling (SPL) format used by
establishments required to register under section 510 of the FD&C Act.
FDA intends to create a new business operation code for Foreign
Sellers, ``Section 804 Foreign Seller.'' After the initial
registration, a facility registered with FDA as a Foreign Seller would
also be required to register annually for each year thereafter in which
it wishes to remain a Foreign Seller, during the registration period
between October 1 and December 31. We propose to require in this rule
that a Foreign Seller's registration include its name, place of
business, unique facility identifier, Health Canada Drug Establishment
License number, point of contact email address and telephone number,
the name of its U.S. agent, the name of each SIP with which it works,
and any other information that FDA may decide is necessary.
U.S. agents of Foreign Sellers would be subject to the same
requirements as agents of foreign registrants are under 21 CFR
207.69(b). Their responsibilities would include responding to
communications and questions from FDA and helping FDA to schedule
inspections. Under the proposed rule, in certain circumstances, FDA may
provide information and/or documents to the U.S. agent, which would be
considered equivalent to providing the same information and/or
documents to the Foreign Seller.
We note that as an entity that holds drugs, the Foreign Seller
would be subject to FDA inspection under section 704 of the FD&C Act.
E. Requirements for Importers
Under section 804, an Importer is defined as a pharmacist or a
wholesaler. Under the proposed rule, if finalized, to be part of a SIP,
an Importer would need to be duly licensed as a pharmacist by the State
in which the Importer is located and in which it does business, or duly
licensed as a wholesaler. In addition, the Importer's pharmacist or
wholesaler licenses would need to be in effect (i.e., not expired), and
the Importer must be in good standing with the licensor. Furthermore,
the Importer would need to be the U.S. owner of an eligible
prescription drug at the time of entry or arrival of the drug into the
United States.
We note that the Importer has a number of responsibilities under
section 804 and this rule, including screening eligible prescription
drugs for evidence regarding whether or not they are adulterated,
counterfeit, damaged, tampered with, or expired; arranging for each
shipment of eligible prescription drugs to be tested by a qualifying
laboratory; and arranging for them to be relabeled with the FDA-
approved labeling, including the carton and container labels,
prescribing information, and any patient labeling, such as medication
guides, instruction for use documents, and patient package inserts. The
Importer is also responsible for facilitating the affixation or
imprinting of a product identifier at the same time that the eligible
prescription drugs are relabeled with the FDA-approved labeling.
We propose that the screening conducted by the Importer would
include examination of the Canadian labeling of a sample of each
shipment of section 804 drugs to verify that the labeling is consistent
with that of an HPFB-approved drug and that the drugs have been
serialized as prescribed in the proposed rule, when finalized. The
screening could also include a visual comparison of a sample of the
section 804 drug to a sample of the HPFB-approved drug. We seek comment
on the feasibility and sufficiency of this screening, as well as on
what additional or alternative screenings that the Importer could do to
ensure that imported eligible prescription drugs are not adulterated,
counterfeit, damaged, tampered with, or expired.
[[Page 70813]]
If an Importer will be relabeling the drug itself, the Importer
must also be registered with FDA under section 510(b) of the FD&C Act
and obtain a labeler code from FDA under Sec. 207.33(c) (21 CFR
207.33(c)). If the Importer chooses to contract with a separate entity
(e.g., a repackager or relabeler) to relabel the drug on its behalf,
the Importer will be a private label distributor, as that term is
defined in Sec. 207.1 (21 CFR 207.1), because it will be commercially
distributing under its own label drugs that it did not itself
manufacture, repackage, or relabel. As noted elsewhere in this proposed
rule, a repackager or relabeler acting on an Importer's behalf would
only repackage to the extent it is required to label the drug. As a
private label distributor, the Importer will not be required to
register with FDA, but it must obtain its own labeler code from FDA,
under Sec. 207.33(c). Under the proposed rule, the NDCs for the
section 804 drugs that are relabeled by an entity other than the
Importer would nonetheless incorporate the Importer's labeler code.
Among other requirements, before an eligible prescription drug can be
released into interstate commerce it will need a new NDC and will need
to be listed. We note that a drug imported under section 804 of the
FD&C Act will have a different NDC than its FDA-approved counterpart.
Under the requirements proposed in this rule, if the Importer is also a
repackager or relabeler, it will be the Importer's responsibility to
propose an NDC for assignment for each eligible prescription drug under
Sec. 207.33. Under these circumstances, the Importer will also be
responsible for listing each eligible prescription drug under Sec.
207.53 (21 CFR 207.53). If the Importer is a private label distributor,
it would be the Importer's responsibility to ensure that the entity
relabeling an eligible prescription drug on its behalf proposes an NDC
under Sec. 207.33 and lists each eligible prescription drug under
Sec. 207.53.
The Importer, or authorized customs broker, would also be
responsible for filing an entry for consumption in ACE for the drugs to
be imported through a CBP port of entry designated in a SIP Proposal
authorized by FDA. In addition, Importers would be required to collect
and submit to FDA the information and documentation about the imported
drug that is set forth in section 804(d) of the FD&C Act as discussed
later. Importers also would have responsibilities related to adverse
event, medication error, field alert reports, and other reports, and
related to drug recalls.
We seek comment on whether there are qualifications Importers
should be required to have, beyond being licensed as a pharmacist or
wholesaler, given their responsibilities.
F. Supply Chain Requirements
When Congress enacted section 804 of the FD&C Act in 2003, FDA's
authority with respect to drug supply chain security was more limited
than it is today. In 2013, Congress enacted the DSCSA, which
strengthened FDA's authority to protect the security and integrity of
the drug supply chain. Specifically, section 582 of the FD&C Act, as
added by the DSCSA, establishes the product identification,
verification, and tracing requirements that manufacturers, wholesale
distributors, pharmacists, and other trading partners must adhere to
for covered transactions involving certain prescription drugs. Because
the DSCSA did not include an exemption for drugs imported under section
804 of the FD&C Act, such drugs are subject to the requirements in
section 582 of the FD&C Act. We recognize, however, that certain
requirements in section 582 may be difficult or impossible for such
drugs to meet. Accordingly, under the authority provided by section
582(a)(3)(A)(iii) of the FD&C Act, FDA proposes to exempt from section
582 certain transactions for drugs imported under section 804 of the
FD&C Act.
Under section 804(c)(3), this proposed rule may contain ``any
additional provisions determined by the Secretary to be appropriate as
a safeguard to protect the public health or as a means to facilitate
the importation of prescription drugs.'' To ensure the proposed
exemptions from section 582 of the FD&C Act do not compromise the
security of the supply chain for drugs imported under section 804 of
the FD&C Act, this rule also proposes additional provisions to
safeguard the public health. These additional safeguards are necessary
for the Secretary to certify that implementation of section 804 of the
FD&C Act would pose no additional risk to the public's health and
safety.
First, if an eligible prescription drug is manufactured outside of
Canada, it would need to be exported commercially into Canada by the
manufacturer and labeled for the Canadian market. It could not be
transshipped through Canada for sale in another country because this
could create opportunities for counterfeiting or other forms of fraud.
Second, an eligible prescription drug would need to be sold by the
manufacturer directly to a Foreign Seller in Canada. FDA has determined
that this requirement is critical because FDA would generally not
possess information needed to trace drug products labeled for the
Canadian market back to the original manufacturer. As discussed further
in the ``Supply Chain Security Requirements'' section below, for
products and transactions that are subject to the DSCSA, supply chain
protections are in place to allow for tracing products up to the
manufacturer at the package and homogenous case level.
Under FDA's general proposed approach, a Foreign Seller would then
ship the drug directly to the Importer in the United States. We
considered whether to propose allowing more than one Foreign Seller in
the Canadian supply chain but decided against this approach because we
do not believe it would be possible for a SIP Sponsor to demonstrate
that the same level of safety would be assured. For a SIP to pose no
additional risk, it would have to match the protections of the DSCSA
through other means. The short supply chain, coupled with this proposed
rule's other provisions like serialization and testing, would permit
control over and transparency into the supply chain to help ensure
comparable safety. Therefore, we propose to require that each Foreign
Seller buy the drug directly from the manufacturer and then sell it
directly to the Importer in the United States because this would
minimize supply chain security risks, including the risks posed by
increased opportunities for counterfeiting and other forms of fraud
that obscure the origin of drugs imported under section 804 of the FD&C
Act. As the number of entities outside the United States that handle
the drugs increases, the supply chain becomes progressively less
transparent and more vulnerable to risk. The proposed short supply
chains would also allow FDA and States to supervise the supply chain
participants more closely. This rule proposes additional safeguards on
tracing products through the pre-U.S. supply chain, which we believe
will result in a level of supply chain security that poses no
additional risk to the public's health and safety, but these proposed
provisions are premised on the presence of just one Foreign Seller per
supply chain. Allowing for additional Foreign Sellers in a supply chain
would undermine our ability to ensure that our proposed approach poses
no additional risk.
Although we cannot foresee at this time how a longer supply chain
would not pose additional risk to the public's health and safety, we
seek comment on whether there actually are safeguards
[[Page 70814]]
that could be put in place that would enable FDA to authorize a SIP
with multiple Foreign Sellers in a single supply chain in Canada. Such
comments should provide specific details regarding the additional
safeguards and how they would provide the same level of protection to
the supply chain. If, in response to comments, we determine that FDA
could authorize a SIP with more than one Foreign Seller in a single
supply chain because we are able to adopt additional safeguards such
that the SIP would pose no additional risk to the public's health and
safety, we would consider having the final rule account for this
possibility. For example, we could revise Sec. Sec. 251.3,
251.14(a)(4), 251.19(c), and 251.19(d)(2), as follows.
Section 251.3 could be revised to state that, in its
initial proposal, a SIP Sponsor must only designate one Foreign Seller
and one Importer that may engage in the distribution of any drug
specified in the proposal, unless the SIP Sponsor demonstrates that the
SIP will meet additional safeguards, which would be detailed in the
final rule, necessary to ensure that the inclusion of subsequent
specified Foreign Sellers would pose no additional risk to the public's
health and safety.
Section 251.14(a)(4) could be revised to state: ``For each
drug imported under the SIP, the drug is only shipped by the entities
that are specified in the SIP.''
Section 251.19(c) could be revised to state: ``The
Importer must also confirm that the eligible prescription drug was
bought directly from the manufacturer by a Foreign Seller, and that all
subsequent sales of that eligible prescription drug, up to and
including the sale to the Importer, were made only among Foreign
Sellers described in the SIP.''
Section 251.19(d)(2) could be revised to state:
``documentation demonstrating that the eligible prescription drug was
only handled by the manufacturer and Foreign Seller(s) described in the
SIP before the Importer received the drug;''.
In addition, among other potential revisions that may be necessary,
if the final rule were to permit longer supply chains, we would include
in the final rule those additional safeguards--submitted in comments
justifying an allowance for multiple Foreign Sellers in a single supply
chain--that would be applicable to most, and perhaps all, proposals
that include multiple Foreign Sellers. We note that other requirements
would apply as well that would need to be specified in the final rule,
including the testing requirements described in section
804(d)(1)(J)(ii).
Under the proposed rule, following the shipment into the United
States, the Importer would be responsible for: (1) Sending FDA
information about the drug, including information it receives from the
Foreign Seller and the test results from the qualifying laboratory and
also for (2) ensuring that the drug is relabeled with the required U.S.
labeling and DSCSA product identifier. The Importer would then sell the
product to either another entity in the United States (if it is a
wholesaler) or dispense the product itself to patients (if it is a
pharmacist).
We acknowledge that there are certain assurances regarding
authenticity and quality when a manufacturer manufactures drugs
intended for sale in the United States. We seek comment on the approach
in this proposed rule and whether it contains sufficient safeguards to
ensure that the proposed importation poses no additional risk to health
or safety.
1. Foreign Seller's Supply Chain Security Obligations
Once the Foreign Seller receives product from a foreign
manufacturer, which would be entirely intended and labeled for sale in
the Canadian market, the Foreign Seller would need to separate the
portion of product it intends to sell to the Importer in the United
States under section 804, and maintain that portion in a separate area
in its facility from the portion intended for the Canadian market. We
anticipate that the volume of drug included in the portion intended for
the U.S. market will be agreed upon between the Foreign Seller and the
Importer to whom it will sell the drug, and that such volume will be
identified in a contract agreement and in records that the Importer is
obligated to send to FDA under section 804(d) of the FD&C Act.
Under the proposed rule, for the portion of drug that will be
transacted between the Foreign Seller and the Importer under section
804, the Foreign Seller would need to assign an SSI to each package and
homogenous case of drug in that portion. The rule proposes that
``package'' means the smallest individual salable unit of product for
distribution that is intended by the Foreign Seller for sale to the
Importer located in the United States, and that ``individual saleable
unit'' means the smallest container of product sold by the Foreign
Seller to the Importer. The rule proposes that an ``SSI'' consists of a
unique alphanumeric serial number of up to 20 characters. Using a stamp
or adhesive sticker, the Foreign Seller would be required to place the
SSI on each package and homogenous case, but would not otherwise
repackage or relabel the drug. If the product already contained a
manufacturer-affixed DSCSA-compliant product identifier at the time the
Foreign Seller receives it, the Foreign Seller would not be required to
assign an SSI to the product before further engaging in a transaction
with the Importer.
Under the proposed rule, the Foreign Seller would need to maintain
records identifying its process for serializing and affixing the SSI
onto each package and homogenous case, including an explanation of the
controls in place to ensure the stamp or adhesive sticker is properly
affixed. The Foreign Seller would also be required to adhere to all
applicable good manufacturing practice requirements in accordance with
section 501(a)(2)(B) of the FD&C Act and part 211. The SSI would need
to occupy blank space on the package and homogenous case, and not
obscure any other labeling information, including the manufacturer-
labeled Canadian DIN that was on the package and homogenous case at the
time the Foreign Seller received the product from the manufacturer.
Therefore, a drug without a DIN would not be an eligible prescription
drug that could be imported into the United States. Finally, the
Foreign Seller would need to maintain records associating the SSI with
the DIN and all the records it received from the manufacturer upon
receipt of the original shipment intended for the Canadian market.
The rule also proposes that various verification requirements on a
Foreign Seller, that correspond, where applicable, with those
provisions pertaining to a ``manufacturer'' under the DSCSA in section
582(b)(4)(A) through (C) of the FD&C Act. Specifically, the Foreign
Seller would need to verify that a drug was not a suspect or
illegitimate foreign product and would need to send information to the
Importer about the purchase of the drug. ``Suspect foreign product''
and ``illegitimate foreign product'' are proposed in the rule as
defined terms relating to the product that the foreign seller purchases
from the manufacturer and align with the definitions of ``suspect
product'' and ``illegitimate product'' in DSCSA. In addition, the
Foreign Seller would need to be able to respond to requests for
verification from FDA or others within 24 hours or in other such
reasonable time as determined by FDA based on the circumstances of the
request. We seek comment on the scope of the foreign seller's proposed
verification
[[Page 70815]]
responsibilities, and the extent to which Foreign Sellers currently or
in the future may have systems or processes in place to meet such
requirements.
Under the proposed rule, the Foreign Seller would not be engaged in
repackaging, only relabeling, and it would be receiving a product from
the original manufacturer that is not DSCSA-compliant, since that
product would have been intended and labeled entirely for the Canadian
market. To address potential risks, this rule proposes to impose
several requirements on Foreign Sellers. For example, as noted above,
the Foreign Seller would need to be registered with FDA under section
804 of the FD&C Act. Additionally, the rule proposes that, prior to or
at the time of each transaction with the Importer in which the Foreign
Seller transfers ownership of the product to the Importer, the Foreign
Seller would need to provide the Importer with a statement and
information that is comparable with transaction information and
transaction statement as defined in section 581(26) and (27) of the
FD&C Act, respectively. Specifically, the Foreign Seller would be
required to provide to the Importer:
The proprietary or established name of the product;
Strength and dosage form of the product;
The container size;
The number of containers;
The lot number of the product;
The date of the transaction;
The date of the shipment, if more than 24 hours after the
date of the transaction;
The business name and address of the person associated
with the Foreign Seller from whom ownership is being transferred;
The business name and address of the person associated
with the Importer to whom ownership is being transferred;
The SSI for each package and homogenous case of product;
and
The Canadian DIN for each product transferred.
These requirements would be in addition to the statutory
requirement under section 804(d)(1)(G) of the FD&C Act that the
Importer obtain from the Foreign Seller, and submit to FDA,
documentation specifying the original source of the prescription drug
(i.e., identifying the original foreign manufacturer) and the quantity
of each lot of the drug the Foreign Seller originally received from the
manufacturer. The rule also proposes that the Foreign Seller would be
required to send information to FDA and other officials as appropriate
and upon request. For example, upon a request by FDA, or other
appropriate Federal or State official, in the event of a recall or for
purpose of investigating a suspect product or an illegitimate product,
the Foreign Seller would need to promptly provide the official with the
information about the transaction with the Importer. This is comparable
to the requirement for repackagers under section 582(e)(1)(C) of the
FD&C Act; other DSCSA trading partners currently have similar
obligations.
The required activities of the Foreign Seller proposed in this
rule, as described above, presume a single Foreign Seller between the
manufacturer and Importer in a particular supply chain. However, as
noted above, if in response to comments, we determine that additional
safeguards exist such that a SIP with a subsequent Foreign Seller or
Foreign Sellers in a supply chain could be proposed to ensure that the
longer supply chain would not pose additional risk to the public's
health and safety, we would consider having the final rule account for
this possibility. Our analysis of comments received will include a
consideration of how the requirements described above on the single
Foreign Seller (e.g., to place an SSI on products, send transaction
information to the Importer, verify products, and maintain records)
would be applied to subsequent Foreign Sellers in a supply chain.
In sum, we have determined that a Foreign Seller would need to be
capable not only of registering with FDA per section 804(f) of the FD&C
Act and sharing relevant information and records with the Importer per
section 804(d)(1)(G) of the FD&C Act, but also of preserving supply
chain security and sending package-level information about the product
they are selling to the Importer in a format that enables
interoperability. This is consistent with section 804(c) of the FD&C
Act, which permits the Secretary to include any additional requirements
determined to be appropriate as a safeguard to protect the public
health. Without these requirements, the Secretary would not be able to
make the certification required under 804(l) that importation poses
``no additional risk to the public's health and safety.''
2. Importer's Supply Chain Security Obligations
Under the proposed rule, when the Foreign Seller sends a shipment
of the product to the Importer, the product would need to include the
Foreign Seller-affixed SSI, and, as noted earlier, contain the original
Canadian labeling that the manufacturer had applied to the drug. The
Importer would be responsible for relabeling the product with the
required U.S. labeling.
If the Importer intends to place the product into further
transactions in commerce, that relabeling would also need to include
placing or affixing a product identifier that is associated with the
SSI that the Foreign Seller assigned to the product prior to sending it
to the Importer. Therefore, as part of the relabeling, this rule
proposes that the Importer is responsible for affixing or placing a
product identifier, as that term is defined in section 581(14) of the
FD&C Act, on each package and homogenous case of product that it
receives from the Foreign Seller. If, however, the Importer intends to
directly administer the product to patients, as may be the case if the
Importer intends to dispense the drug as a pharmacist, a product
identifier would not be required to be affixed or imprinted on each
package and homogenous case of the eligible prescription drug.
To avoid unnecessary steps in the supply chain, the product
identifier would need to be affixed or imprinted at the same time at
which the drug is being relabeled with the required U.S. labeling. As
proposed, the Importer may relabel the product itself, or may choose to
contract with a separate entity to relabel on its behalf. In either
case, the entity that relabels the product must be registered with FDA
as a relabeler, or a repackager if limited repackaging will occur as
permitted in this proposed rule, under section 510(b) of the FD&C Act,
in accordance with part 207, and also list the drug as required. We
note that an entity that is a ``repackager'' as defined in the DSCSA
under section 581(16) of the FD&C Act is likely to already have
facilities and capabilities in place to affix or imprint a product
identifier based on existing DSCSA requirements. A relabeler who
contracts with the Importer to affix a product identifier on the
Importer's behalf must, even if not engaged in a repackaging operation
with respect to the eligible prescription drug, have systems and
processes in place to meet applicable requirements of a ``repackager''
under section 582(e) of the FD&C Act for any transaction involving the
eligible prescription drug.
Per section 581(14) of the FD&C Act, the product identifier must
include a standardized numerical identifier (SNI), as that term is
defined in section 581(20) of the FD&C Act, the lot number, and
expiration date of the product and be in human and machine-readable
form encoded in a 2-dimensional barcode. An SNI consists of an
alphanumeric serial number and
[[Page 70816]]
NDC under section 581(20). For a product imported under section 804 of
the FD&C Act, the Importer is responsible for obtaining an NDC for the
product (as described elsewhere in this proposed rule). With regard to
the serial number component of the SNI, the Importer may elect to use
the same serial number (i.e., the SSI) that the Foreign Seller had
previously assigned to the product, or it may elect to assign a new
serial number. Under the proposed rule, the Importer would need to
maintain records, for no less than 6 years, that allow the Importer to
associate the product identifier it affixed on each package and
homogenous case of product it received from the Foreign Seller, with
the SSI that had been assigned by the Foreign Seller, and the Canadian
DIN that was on the package when the Foreign Seller received the
product from the original manufacturer. This is analogous to the record
retention requirement in section 582(e)(2)(A)(iv) of the FD&C Act for a
repackager that associates a product identifier with a manufacturer-
affixed product identifier.
In addition to the requirements proposed in the rule, the Importer
is required to comply with any applicable existing requirement of the
DSCSA for subsequent transactions to trading partners in the supply
chain once the product has been relabeled with the required U.S.
labeling (including the product identifier). For example, any Importer
of eligible drugs under a SIP who is a ``pharmacist'' as defined in
section 804(a)(2) of the FD&C Act (i.e., a person licensed by a State
to practice pharmacy, including the dispensing and selling of
prescription drugs), is also considered to be a ``dispenser'' under the
DSCSA, as defined in section 581(3) of the FD&C Act. Such dispenser
must be ``authorized'' under the DSCSA, i.e., have a valid license
under State law (as defined in section 581(2)(D) of the FD&C Act). Such
dispenser must also comply with all applicable requirements pertaining
to a dispenser under section 582(d) of the FD&C Act. Furthermore, any
Importer of eligible drugs under section 804 who is a ``wholesaler'' as
defined in section 804(a)(5)(A) of the FD&C Act, is also considered to
be a ``wholesale distributor'' under the DSCSA, as defined in section
581(29) of the FD&C Act. Such wholesale distributor must be
``authorized'' under the DSCSA, i.e., have a valid license under State
law or section 583, in accordance with section 582(a)(6) of the FD&C
Act, and otherwise meet the definition in section 581(2)(C) of the FD&C
Act. Such wholesale distributor must also comply with all applicable
requirements pertaining to a wholesale distributor under section 582(c)
of the FD&C Act.
3. Exemptions From Certain DSCSA Requirements
We propose to exempt certain transactions from DSCSA requirements
in section 582 of the FD&C Act, as permitted by section 582(a)(3)(iii),
because they would be difficult or impossible for section 804 imported
drugs to meet, and the proposed rule includes other safeguards to
maintain supply chain security:
Section 582(c)(1)(A) and (d)(1)(A): For an Importer that
is a wholesale distributor receiving the product from a Foreign Seller
in Canada, the proposed rule would exempt the Importer from the
requirement not to accept ownership unless the previous owner provides
the transaction history, transaction information, and a transaction
statement for the product. Similarly, if the Importer is a pharmacist
receiving the product from a Foreign Seller in Canada, the proposed
rule would exempt the Importer from the requirement on dispensers to
not accept ownership unless the previous owner provides the transaction
history, transaction information, and a transaction statement for the
product. Instead, as previously described, this rule proposes to
require the Foreign Seller to provide certain transaction-related
information to the Importer that is adequate to ensure no additional
risk to supply chain security.
Section 582(c)(2) and (d)(2): The proposed rule would
exempt Importers that are wholesale distributors and dispensers from
the prohibition on receiving products that are not encoded with a
product identifier. Instead, as previously described, products received
from the Foreign Seller would be required to have an SSI. Wholesale
distributors and dispensers would otherwise be required to engage only
in transactions of products encoded with a product identifier, as
defined in DSCSA.
Section 582(c)(3) and (d)(3): Importers that are wholesale
distributors and dispensers would be permitted to conduct transactions
with Foreign Sellers even though they are not ``authorized trading
partners'' under section 581. Wholesale distributors and dispensers
would otherwise be required to transact only with authorized trading
partners, as defined in the DSCSA.
Section 582(c)(4)(A)(i)(II) and (d)(4)(A)(ii)(II): For
section 804 imported products, the proposed rule would exempt an
Importer from the requirement to verify that a product in the
Importer's possession or control contains a ``standardized numerical
identifier.'' Instead, the Importer would be required to verify that
the section 804 imported product at the package level includes the SSI
that the Foreign Seller had previously assigned to the product.
Note that FDA would not consider a drug imported under section 804
to have been diverted solely as a result of being imported under a SIP.
A drug imported under section 804 may meet the definition of suspect or
illegitimate product for other reasons, however (e.g., counterfeit or
stolen products), and entities that are obligated to identify such
products under the DSCSA would be obligated to do so for drugs imported
under section 804 in the same manner as they would for any other drugs
subject to the same requirement.
We welcome comments on whether FDA should include exemptions from
additional DSCSA requirements. We also note that manufacturers,
repackagers, wholesale distributors, or dispensers may request waivers
or exceptions at any time, under section 582(a)(3)(i) and (ii) of the
FD&C Act.
4. Manufacturer's Supply Chain Security Obligations
Pursuant to section 804(d)(1) of the FD&C Act, this regulation,
once finalized, would require the Importer to submit to FDA certain
information and records about the imported drug. Under section
804(d)(1)(J) of the FD&C Act, such information would include the
results of testing for authenticity and degradation, to be done per
section 804(e) by either the Importer or the manufacturer. In the case
of testing that is done by the Importer, other parts of this regulation
specify information that the manufacturer is required to share in
confidence with the Importer in order for the testing to occur, but in
this section we further propose that the manufacturer would also need
to provide to the Importer information it has about the transaction of
the drug to the Foreign Seller located in Canada. Such information is
necessary, along with other testing and laboratory record information
specified elsewhere in this proposed rule, to ensure that the imported
drug is authentic, as required in section 804(d)(1)(J) of the FD&C Act.
Furthermore, under section 804(d)(1)(N) of the FD&C Act, we consider
such information pertaining to drug's transactions in the pre-U.S.
supply chain to be necessary to ensure the protection of public health.
Manufacturers would also need to be able to provide sufficient
information to the Importer about the imported drug's movements in the
pre-U.S. supply chain. To this end, this rule proposes to
[[Page 70817]]
require, under section 804(e) of the FD&C Act, that the manufacturer
provide to the Importer all relevant documentation about the
transaction that it provided to the Foreign Seller, upon its transfer
of ownership of the product for the Canadian market. The rule does not
propose to require any additional information about this transaction
that is otherwise not maintained or submitted in accordance with
Canadian law, or in the normal course of business for products the
manufacturer intends to introduce to the Canadian market. The Importer
would be required to use this information obtained from manufacturers
under section 804(e) of the FD&C Act to help determine whether the
supply chain was intact, by comparing the information about the
transaction between the manufacturer and Foreign Seller to that
received by the Importer from the Foreign Seller, as required under
this rule.
We seek comments on this approach, including whether different or
additional safeguards are necessary to ensure the integrity of the
supply chain with respect to drugs imported under section 804 of the
FD&C Act.
G. Requirements for Qualifying Laboratories
Section 804 of the FD&C Act requires that imported drugs be tested
by a ``qualifying laboratory,'' which is defined as ``a laboratory in
the United States that has been approved by the Secretary for the
purposes of this section.'' As indicated earlier in this document, a
SIP Proposal would need to indicate which laboratory the SIP will use
to test the drugs it imports. The SIP Proposal would also need to
explain why that laboratory is qualified to do the testing and so
should be approved by FDA for use by a SIP.
To be considered qualified, we propose that a laboratory would need
to comply with the applicable elements of the CGMP requirements,
including provisions regarding laboratory controls in 21 CFR 211.160
and regarding laboratory records in 21 CFR 211.194. In addition, a
laboratory would need to have ISO 17025 accreditation. Finally, we
propose that it also would need to have an FDA inspection history and
it would need to have satisfactorily addressed any objectionable
conditions or practices identified during its most recent FDA
inspection.
We seek comment on whether there are other requirements that all
laboratories should meet before FDA approves them for use by a SIP. For
example, we seek comment on whether we should require accreditation
different from or in addition to ISO 17025.
If the rule is finalized as proposed, FDA would approve qualifying
laboratories for use by a SIP on a case-by-case basis as part of its
review and authorization of a SIP Proposal. FDA would also consider
publishing a list of approved qualifying laboratories for the benefit
of States or other non-federal governmental entities and their co-
sponsors, if any, that may be developing a SIP Proposal.
H. Laboratory Testing Requirements
Section 804(d)(1)(J)(i) of the FD&C Act sets forth testing
requirements for shipments of imported drugs that are shipped directly
to the Importer from the first foreign recipient of the prescription
drug from the manufacturer and section 804(d)(1)(J)(ii) sets forth
testing requirements for shipments that are not shipped directly to the
Importer from the first foreign recipient of the prescription drug from
the manufacturer. Because we are proposing to require that all
shipments under a SIP be shipped directly from the Foreign Seller,
which is the first foreign recipient of the prescription drug from the
manufacturer, to the Importer, this rule focuses on the testing
requirements in section 804(d)(1)(J)(i) and does not address the
requirements in section 804(d)(1)(J)(ii) of the FD&C Act. In addition,
section 804(d)(1)(L) of the FD&C Act requires that the Importer provide
laboratory records to FDA that include ``complete data derived from all
tests necessary to ensure that the prescription drug is in compliance
with established specifications and standards.''
Section 804(d)(1)(J)(i) of the FD&C Act provides that, in the case
of an initial imported shipment, an Importer must provide documentation
to FDA demonstrating that the drug ``was received by the recipient from
the manufacturer and subsequently shipped by the first foreign
recipient to the importer,'' that ``the quantity being imported into
the United States is not more than the quantity that was received by
the first foreign recipient,'' and that ``each batch of the
prescription drug in the shipment was statistically sampled and tested
for authenticity and degradation.'' For any subsequent shipments from
the same batch of a drug, section 804(d)(1)(J)(i)(III)(bb) of the FD&C
Act allows for more limited testing, of ``a statistically valid sample
of the shipment.'' For an initial imported shipment, the testing would
have to be done on a statistical sample of ``each batch of the
prescription drug in the shipment.'' For example, if a shipment
contained drugs from two batches, Batch A and Batch B, the testing
would have to be done on a statistical sample of all of the drugs that
came from Batch A and on a separate statistical sample of all the drugs
that came from Batch B. For a subsequent shipment, the testing could be
done on a statistical sample of the shipment as a whole, unless, for
example, there are drugs from a third batch, Batch C, in the shipment.
In that case, the testing would need to be done on a statistical sample
of all the drugs that came from Batch A and Batch B, as a whole, and on
a separate statistical sample of all the drugs that came from Batch C.
We propose to require that a statistical sample of a batch or
shipment of section 804 drugs be randomly selected from the batch or
shipment being tested or, in the alternative, that the sample be
representative of the batch or shipment. We seek comment on whether we
should specify a sampling method. We also seek comment on whether we
should require that sampling be done according to an established
standard such as those issued by the American National Standards
Institute (ANSI) or by ASTM International.
Regarding the size of the sample, the number of packaged units in
the sample would need to be large enough to enable a statistically
valid statement to be made regarding the authenticity and stability of
the entire batch or entire shipment. We seek comment on whether we
should require that the sample size be determined using an established
standard such as ASTM International's E122-17 ``Standard Practice for
Calculating Sample Size to Estimate, With Specified Precision, the
Average for a Characteristic of a Lot or Process'' (Ref. 30).
As noted previously, we propose that the testing done on the sample
of the batch or shipment be sufficiently thorough to establish, in
conjunction with data and information from the manufacturer, that the
batch or shipment is eligible for importation under a SIP. The proposed
rule would require the sample of the HPFB-approved drug to be tested to
confirm that the HPFB-approved drug meets the FDA-approved drug's
specifications, including the analytical procedures and methods and the
acceptance criteria. In addition, to meet the statutory requirement
that shipments be tested for degradation, a stability-indicating assay
provided by the manufacturer would be required to be conducted on the
sample of the drug that is proposed for import. Pursuant to section
804, the proposed rule would require all testing to be done
[[Page 70818]]
in a qualifying laboratory in the United States.
The testing required under section 804(d)(1)(J) of the FD&C Act can
be conducted ``by the importer or by the manufacturer.'' If the
Importer conducts the testing, section 804(e)(2)(A) of the FD&C Act
requires the manufacturer to provide the Importer with the information
needed to authenticate the prescription drug. Under the proposed rule,
specifically, the manufacturer would be required to provide the
Importer with formulation information about the HPFB-approved drug and
the FDA-approved drug and any testing methodologies and protocols that
the manufacturer has developed that the Importer needs to conduct the
Statutory Testing.
In addition, under the proposed rule, the manufacturer would be
required to provide an attestation to the Importer, or alternatively to
FDA if the manufacturer conducts the testing itself, to establish that,
but for the fact that it bore the HPFB-approved labeling, the drug that
the manufacturer sold to the Foreign Seller in fact met the conditions
in the FDA-approved NDA or ANDA. This would include any process-related
or other requirements for which compliance cannot be established
through laboratory testing. If the manufacturer does the testing, the
manufacturer would be required to provide the attestation to FDA under
the proposed rule. We propose that the attestation would need to
include confirmation that the HPFB-approved drug has the active
ingredient(s), active ingredient source(s) (including manufacturing
facility or facilities), inactive ingredient(s), dosage form,
strength(s), route(s) of administration, etc., described in the FDA-
approved drug's NDA or ANDA. The attestation would also need to confirm
that the HPFB-approved drug conforms to the specifications in the FDA-
approved drug's NDA or ANDA regarding the quality of the drug
substance(s), drug product, intermediates, raw materials, reagents,
components, in-process materials, container closure systems, and other
materials used in the production of the drug. In addition, the
attestation would need to confirm that the HPFB-approved drug was
manufactured in accordance with the specifications described in the
FDA-approved drug's NDA or ANDA, including with regard to the
facilities and manufacturing lines that are used, and in compliance
with CGMP requirements set forth in section 501(a)(2)(B) of the FD&C
Act and 21 CFR parts 4 (if a combination product), 210, and 211. The
attestation would also need to include the original date of manufacture
or whatever date was used in calculating the labeled expiration date
based on the HPFB-approved or scientifically validated expiration
period, the expiration period set forth in the FDA-approved drug's NDA
or ANDA, and any other information needed to label the drug with an
expiration date that meets the specifications of the FDA-approved
drug's NDA or ANDA.
The attestation would also need to include information needed to
confirm that the labeling of the prescription drug complies with
labeling requirements of the FD&C Act. Finally, as discussed elsewhere
in this proposed rule, the attestation would need to include
information about the transaction of the eligible prescription drug to
the Foreign Seller.
In addition to the attestation, the manufacturer would need to
provide the Importer with the executed batch record, including the
executed COA, for at least one recently manufactured, commercial-scale
batch of the HPFB-approved drug and for at least one recently
manufactured commercial-scale batch of the FDA-approved drug that was
produced for and released for distribution to the U.S. market under an
NDA or ANDA. The manufacturer would need to provide these analyses for
each manufacturing line that the manufacturer used to produce either or
both of the drugs.
As discussed earlier in this document, section 804(e)(2)(B) of the
FD&C Act states that the information that a manufacturer provides to an
Importer under section 804(e)(2)(A) must be kept in strict confidence
and used only for purposes of testing or otherwise complying with this
Act.'' The statute goes on to state that the regulations implementing
section 804 of the FD&C Act can include provisions to provide for the
protection of trade secrets and commercial or financial information
that is privileged or confidential. We have proposed in Sec. 251.15(g)
and (h) additional provisions regarding the protection of information
that may be supplied by a manufacturer to an Importer under this rule.
We seek comment on whether any other provisions are needed to protect
the information that manufacturers would need to provide to Importers
under this rule. We note that instead of providing its proprietary test
methods to an Importer, a manufacturer can do the testing itself in a
qualifying laboratory in the United States.
As discussed above, for subsequent shipments of drugs from a batch,
drugs from which have already been imported under a SIP, section
804(d)(1)(J)(i)(III)(bb) of the FD&C Act allows Importers to test a
statistically valid sample of each shipment, as opposed to a
statistically valid sample of each batch within a shipment. We seek
comment on whether a different approach to testing subsequent shipments
should be permitted. For example, it may be appropriate to use
vibrational spectroscopic tests to test drugs in subsequent shipments.
We note, however, that formulation-related physical stability and other
quality issues cannot be tested by using spectroscopy. For that reason,
a stability-indicating assay developed by USP or the manufacturer would
have to be conducted as well. We seek comment on what testing would be
appropriate at this stage.
The obligations on manufacturers under section 804(e) of the FD&C
Act are enforceable under section 301(aa) of the FD&C Act, which
provides that, among other things, a violation of the regulations
implementing section 804 is a prohibited act. Furthermore, section
303(b)(6) of the FD&C Act sets forth penalties for manufacturers or
Importers that knowingly fail to comply with a requirement of section
804(e) of the FD&C Act. These requirements include that: (1) The
manufacturer or Importer conduct the Statutory Testing at a qualifying
laboratory; (2) if the Importer conducts the testing, the manufacturer
supply the information needed to authenticate the drug being tested and
to confirm that the labeling is in compliance with the FD&C Act in a
timely fashion, and (3) if the manufacturer supplies information to the
Importer, the Importer keep it in strict confidence and only use it for
testing and complying with the FD&C Act. A manufacturer or Importer
that fails to comply with these requirements can be imprisoned for not
more than 10 years under section 303(b)(6) of the FD&C Act, fined under
18 U.S.C.3571, or both.
In the event that a manufacturer fails to provide information
required by this proposed rule in a timely fashion, including
information necessary for the Importer to conduct the Statutory
Testing, authenticate the drug being tested, or confirm that the
labeling is in compliance with the FD&C Act, FDA may provide such
information to an Importer if the information is contained in the
manufacturer's approved NDA or ANDA. We seek comment on what would be
considered a timely fashion that would provide the manufacturer
adequate time to provide the necessary information and that would not
create excessive difficulty for the Importer
[[Page 70819]]
who needs that information to import the drugs.
I. Listing and Labeling of Eligible Prescription Drugs
Section 804(d)(1)(K)(ii) of the FD&C Act requires that a drug
covered by section 804 meets all labeling requirements of the FD&C Act.
Additionally, section 804(c) of the FD&C Act requires that each
prescription drug imported under this importation program comply with
sections 501, 502, and 505 of the FD&C Act. Under section 804(h) of the
FD&C Act, the manufacturer of a prescription drug is required to
provide the Importer with written authorization to use the drug's
approved labeling at no cost. If the manufacturer fails to do so in a
timely fashion, FDA will deem this authorization to have been given. In
addition, under the proposed rule, as required by section
804(e)(2)(A)(ii) of the FD&C Act, the manufacturer would need to supply
the Importer, in a timely fashion, with information needed to confirm
that the labeling of the prescription drug complies with the labeling
requirements of the FD&C Act. Furthermore, under the requirements
proposed by this rule, before a drug can be introduced into interstate
commerce under section 804 of the FD&C Act, it would be required to be
listed in accordance with part 207, and it would be relabeled so that
it bears certain information that is unique to the eligible
prescription drug. Specifically, the labeling will need to display an
NDC that is unique to the eligible prescription drug, and it will need
to provide information about the Importer. This section describes the
proposed requirements for obtaining an NDC, listing, and relabeling an
eligible prescription drug.
The rule proposes that before an eligible prescription drug can be
sold it would need to bear a new NDC and be listed. We note that drugs
imported under section 804 will have the same name but will have a
different NDC than do their FDA-approved counterparts. As stated above,
the Importer of an eligible prescription drug would need to either: (1)
Propose an NDC for the drug, following the procedures in Sec. 207.33,
and it would need to list the drug, following the procedures in Sec.
207.53 or (2) if the Importer is a private label distributor, take
responsibility to ensure that the entity performing relabeling on its
behalf proposes an NDC and lists each eligible prescription drug in
accordance with the applicable requirements of part 207.
Additionally, we propose to make the Importer responsible for
relabeling the drug, or arranging for it to be relabeled, to meet the
requirements of this proposed rule. The relabeling and associated
limited repackaging activities must meet applicable requirements,
including applicable CGMP requirements under parts 210 and 211. At the
time that an eligible prescription drug is sold or dispensed it would
need to have been relabeled to be consistent with the FDA-approved the
carton and container labels, prescribing information, and any patient
labeling, such as medication guides, instruction for use documents, and
patient package inserts. In addition, the eligible prescription drug
would need to have been assigned a product identifier in compliance
with section 582 of the FD&C Act. The relabeled eligible prescription
drug will be considered consistent if it varies from the FDA-approved
carton and container labels, prescribing information, and patient
labeling solely to the extent described in this rule.
Except for repackaging that is necessary to perform the relabeling
described in this proposed rule, the proposed rule would not allow
further repackaging of drugs imported pursuant to a SIP. ``Repack'' or
``repackage'' is defined in Sec. 207.1 as ``the act of taking a
finished drug product or unfinished drug from the container in which it
was placed in commercial distribution and placing it into a different
container without manipulating, changing, or affecting the composition
or formulation of the drug.'' We believe that allowing repackaging that
breaches the immediate container closure system introduces unnecessary
risk of adulteration, degradation, and fraud for drugs subject to a
SIP. We also note that some container closure systems include a tamper-
evident seal, which would be disturbed if repackaging were allowed. In
addition, if a drug is repackaged from its immediate container closure,
the expiration period set forth in the NDA or ANDA may no longer be
valid because the expiration period in an approved NDA or ANDA is based
on stability studies involving the particular container closure system
into which a drug is placed without opening it to expose the contents
to the outside environment. Additional stability studies would
generally be required to establish a new expiration period.
The proposed rule would require that the prescribing information of
an eligible prescription drug would need to include that drug's NDC in
the HOW SUPPLIED/STORAGE AND HANDLING section for products with
Physician Labeling Rule (PLR) labeling (see Sec. 201.57(c)(17)(iii)
(21 CFR 201.57(c)(17)(iii))) or the HOW SUPPLIED section for products
with ``old'' (non-PLR) format labeling (see Sec. 201.80(k)(3) (21 CFR
201.80(k)(3))) in place of any NDCs assigned to the FDA-approved U.S.
versions of the drug. The proposed rule would also require that the
eligible drug's new NDC be added to the container label and the carton
labeling. If applicable, the new NDC would replace any NDC otherwise
appearing on the label and carton labeling of the FDA-approved version
of the drug. We seek comment on whether having multiple otherwise
identical drugs in the marketplace with different NDCs will create any
issues, such as with pharmacy dispensing or otherwise, and, if so, if
there are steps that can be taken to mitigate such issues.
In addition to the names and places of businesses of entities that
appear on the FDA-approved labeling, in this rule we propose to require
that the label and labeling of an eligible prescription drug also bear
conspicuously the name and place of business of the Importer. If the
FDA-approved labeling does not include the name and place of business
of the manufacturer, the name and place of business of the manufacturer
should be added as well.
We also propose to require that the labeling on or within the
package from which the drug is dispensed include the following
statement: ``This drug was imported from Canada under the [Name of
State or Other Governmental Entity and of Its Co-Sponsors, If Any]
Section 804 Importation Program to reduce its cost to the American
consumer.'' If the SIP maintains a website, the statement could also
include the website address. To help avoid potential confusion between
products with the same name, we propose that this statement would be
included after the PATIENT COUNSELING INFORMATION section for products
subject to Sec. 201.56(d) (21 CFR 201.56(d)) and Sec. 201.57, or
after the HOW SUPPLIED section (or after the last section of labeling)
for products subject to Sec. Sec. 201.56(e) and 201.80. The statement
also would be included on the immediate container and outside package
to help pharmacists distinguish a section 804 product when selecting
the product on the pharmacy shelf. The statement would be sufficiently
prominent to help a pharmacist readily distinguish the eligible
prescription drug without obscuring required or recommended information
(e.g., information that will reduce the risk of medication errors and
ensure safe administration of the drug) (see FDA, 2013, ``Draft
Guidance for Industry: Safety Considerations for Container Labels and
Carton Labeling Design to
[[Page 70820]]
Minimize Medication Errors.'' Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/safety-considerations-container-labels-and-carton-labeling-design-minimize-medication-errors). The statement may also aid in pharmacovigilance by
increasing the likelihood that adverse event, medication error, field
alert, and other reports include the fact that the drug was imported
under a SIP. We seek comments on the content of the disclosure
statement, in particular whether such a statement is necessary, whether
it will be understandable and meaningful to prescribers, pharmacists,
and patients, and whether more or less information is needed. We seek
comment on whether it is necessary to provide the name of the SIP or
whether it would be sufficient to state that the drug was imported
under a SIP.
If an eligible prescription drug's container is too small to fit
the additional information required by this proposed rule, FDA would
consider a proposal for supplementary labeling from the SIP Sponsor.
The container label would need to include at minimum the product's
proprietary and established name (if any); product strength; lot
number; and the name of the manufacturer and the Importer (see FDA,
2013, ``Draft Guidance for Industry: Safety Considerations for
Container Labels and Carton Labeling Design to Minimize Medication
Errors.'' Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/safety-considerations-container-labels-and-carton-labeling-design-minimize-medication-errors).
In addition to the required statement on the labeling, the proposed
regulation also would require the SIP Sponsor to describe in the SIP
Proposal how it will educate pharmacists, healthcare providers, and
patients about its SIP. If pharmacists, healthcare providers, and
patients know that a drug was originally intended for sale in Canada,
they will have the ability to include this information if they
subsequently report any adverse events or quality concerns. It may also
help ensure that a recall is effective if healthcare providers and
patients have this knowledge.
Among other things, a SIP could create and maintain a website that
would set forth the name and NDC number of each drug that it imports.
This would allow pharmacists, healthcare providers, and patients to use
the NDC number to determine at any time whether a drug was originally
intended for sale in Canada. The website could also include any
relevant adverse event, medication error, field alert reports, or other
reports or recall information. As stated earlier, the website address
could be included along with the disclosure statement in the labeling
of an eligible prescription drug.
A SIP could also distribute a Dear Healthcare Provider letter to
physicians and pharmacists by United States mail, by email, by posting
the letter on the Importer's website, or by other effective means,
explaining that the drugs will have a different NDC because they were
originally intended for sale in Canada. The letter could recommend that
patients be counseled that the drugs were originally intended for sale
in Canada, that they have different NDCs than their FDA-approved
counterparts, and that they can use the NDCs to find out pertinent new
information regarding the HPFB-approved drug or its FDA-approved
counterpart, including information about recalls. A SIP could also
propose to distribute a Dear Consumer letter (similar to a Dear
Healthcare Provider letter) that pharmacists could dispense along with
eligible prescription drugs and that consumers could access on the
SIP's website.
J. Information and Records
Section 804(d) of the FD&C Act lists information and documentation,
to be required in the regulations under section 804(b), that Importers
of eligible prescription drugs must submit to the Secretary. The rule
proposes that section 804(d) information would be submitted to FDA each
quarter by SIP Sponsors. SIP Sponsors would be required to submit a
report to FDA each quarter containing the information set forth in
section 804(d) of the FD&C Act, beginning after the SIP Sponsor files
an electronic import entry for consumption for its first shipment of
drugs.
Consistent with the statute, the proposed rule would require that
Importers collect and submit to FDA the information listed here, but
also clarifies that the Importer's submission obligations are met if
the SIP sponsor submits a report to FDA as described above: (1) The
name, address, telephone number, and professional license number (if
any) of the Importer; (2) the name and quantity of the active
ingredient of the prescription drug; (3) a description of the dosage
form of the prescription drug; (4) the date on which the prescription
drug is shipped; (5) the quantity of the prescription drug that is
shipped; (6) the lot or control number assigned to the prescription
drug by the manufacturer of the prescription drug; (7) the point of
origin and destination of the prescription drug; and (8) the per unit
price paid by the Importer for the prescription drug in U.S. dollars,
as well as any other information that FDA determines is necessary to
ensure the protection of the public health. We propose to require that
Importers submit to FDA, in addition to the point of origin (i.e., the
manufacturer of the finished dosage form) and the destination (i.e.,
the wholesaler, pharmacy, or patient to whom the Importer sells or
dispenses the drug), information regarding the rest of the supply
chain, which this rule proposes would consist solely of the Foreign
Seller in Canada.
Section 804(d) of the FD&C Act also requires the Importer to
collect and submit to FDA certain documentation, including: (1)
Documentation from the Foreign Seller specifying the original source of
the prescription drug (which under this rule would be the manufacturer
of the eligible prescription drug) and the quantity of each lot of the
prescription drug originally received by the seller from that source
and (2) in the case of a prescription drug that is shipped directly
from the first foreign recipient of the prescription drug from the
manufacturer (which, under this rule, would be the Foreign Seller),
documentation demonstrating that the prescription drug was received by
the first foreign recipient from the manufacturer and subsequently
shipped by the first foreign recipient to the Importer. The Importer
must also collect and submit documentation of the quantity of each lot
of the prescription drug received by the first foreign recipient
demonstrating that the quantity being imported into the United States
is not more than the quantity that was received by the first foreign
recipient. While the Importer does not need to submit records
associating the eligible prescription drugs' SSIs with their U.S.
product identifiers, the Importer would need to maintain such records
and make them available to FDA upon request. In the case of an initial
imported shipment, Importers would also need to submit documentation
demonstrating that each batch of the prescription drug in the shipment
was statistically sampled and tested for authenticity and degradation,
and in the case of any subsequent shipment, they would need to submit
documentation demonstrating that a statistically valid sample of the
shipment was tested for authenticity and degradation.
Importers also would need to submit a certification from the
Importer or the manufacturer of an imported drug that the drug is
approved for marketing in the United States and is not adulterated or
misbranded, and meets all labeling
[[Page 70821]]
requirements under the FD&C Act. In this rule, we propose to require
that the certification include: (1) That there is an approved SIP; (2)
that the drug is covered by the SIP; (3) that the drug is an eligible
prescription drug as defined in this rule; (4) that the FDA-approved
counterpart of the drug is currently commercially marketed in the
United States; (5) that the drug is approved for marketing in Canada;
and (6) that the drug is not adulterated or misbranded and meets all
labeling requirements under the FD&C Act. Importers would need to
collect and submit laboratory records, including complete data derived
from all tests necessary to ensure that the prescription drug is in
compliance with established specifications and standards, and
documentation demonstrating that the Statutory Testing was conducted at
a qualifying laboratory, unless the manufacturer conducted the
Statutory Testing and submitted the relevant information directly to
FDA.
In addition, SIP Sponsors would be required to provide FDA with
data and information on the SIP's cost savings to the American
consumer. We recognize a SIP's scope will influence the appropriate
cost savings calculation methodology. SIPs should, therefore, report
their total cost savings to consumers as well as the methodology used
to calculate this measure. Cost savings calculations should be based on
savings to the American consumer. Calculations should therefore rely,
to the greatest extent possible, on prices paid by the intended
consumer population. Average price measures by drug may be appropriate
if drugs are dispensed through multiple channels or if the imported
drugs' prices fluctuate throughout the reporting period. Calculation
methods should also account for factors that may influence cost savings
over time, such as changes in drug utilization, the price of domestic
drugs, and exchange rates. As mentioned above, we anticipate that some
SIP Sponsors may seek to import drugs to be used by patients in State-
run programs. In such cases, a SIP Sponsor could submit information
about whether cost-sharing expenses are reduced for the participants,
or whether the program will result in cost savings that are passed on
to consumers in other ways, such as increasing the number of people who
can be covered by a State program, or increasing the availability of
drugs covered by the program. We seek comments on these and other
factors relevant to the reporting of cost savings.
K. Post-Importation Requirements
Under proposed Sec. 251.18, SIP Sponsors and Importers would be
required to take certain actions regarding eligible prescription drugs
if they are violative of an applicable requirement. Under the proposed
rule, the SIP Sponsor would be required to immediately stop importation
of eligible prescription drugs under a SIP if it determines that a drug
or entity in the supply chain does not meet all applicable requirements
of the FD&C Act, FDA regulations, and the authorized SIP. The Importer
must establish and maintain records and submit reports to FDA and to
the manufacturer of all domestic adverse events and medication errors
associated with the use of their imported eligible prescription drugs
about which they obtain or otherwise receive information. These reports
would be required to help inform whether there are safety concerns with
imported eligible prescription drugs, generally, and also specifically
in relation to the handling of these drugs. The Importer must also
develop written procedures for the surveillance, receipt, evaluation,
and reporting of adverse events and medication errors to FDA and to the
relevant manufacturer.
The Importer must submit expedited reports on adverse events that
are both serious and unexpected to FDA and the manufacturer as soon as
possible but no later than 15 calendar days from initial receipt of the
information by the Importer. The Importer must also submit expedited
reports on medication errors to FDA and the manufacturer within the
same timeframe.
The Importer must promptly investigate all adverse events and
medication errors that are the subject of these expedited reports and
must submit follow-up reports within 15 calendar days of receipt of new
information or as requested by FDA. If additional information is not
obtainable, the Importer should maintain records of the unsuccessful
steps taken to seek additional information. Furthermore, the Importer
must submit reports on adverse events that are both serious and
expected or that are nonserious, whether expected or unexpected, to FDA
and the manufacturer within a 90-calendar day timeline.
FDA may require the Importer to submit certain adverse events
within 15 calendar days, even though the events do not meet the
criteria for expedited reporting. FDA will specify these adverse events
in advance and will provide the reason for requiring that they be
reported to the Agency on an expedited basis.
While Sec. 314.80(c)(1)(iii) (21 CFR 314.80(c)(1)(iii)) gives
distributors of approved drugs the choice of submitting reports to
either FDA or the applicant, we propose to require that Importers of
section 804 drugs be required to submit reports to both FDA and the
manufacturer. This will aid the manufacturer in its pharmacovigilance
efforts, and it will provide FDA with information that may be relevant
to its review of SIP Proposals and Pre-Import Requests as well as to
its oversight of drugs imported under section 804 of the FD&C Act and
section 804 in general.
FDA proposes to require submission of individual case safety
reports (ICSRs) and ICSR attachments in electronic format, as described
in Sec. 314.80(g)(1). Importers may request in writing a temporary
waiver of the electronic reporting requirements as described in Sec.
314.80(g)(2). Such waivers will be granted on a limited basis and for
good cause.
The Importer would also be required to submit to the manufacturer
and to FDA field alert reports about the products it distributes. These
reports would need to be made when the Importer becomes aware of
information concerning any incident that causes the drug product or its
labeling to be mistaken for, or applied to, another article, or
information concerning any bacteriological contamination, or any
significant chemical, physical, or other change or deterioration in the
distributed drug product, or any failure of one or more distributed
batches of the drug product to meet the specification established for
it in the FDA-approved NDA or ANDA. If a SIP imports a drug-device
combination product, the Importer would also need to submit to the
manufacturer and to FDA the reports described in 21 CFR 4.102(c)(1) for
combination products containing a device constituent part, in the
manner and by the deadlines provided in part 4. The Importer would also
need to maintain the records described in 21 CFR 4.102(c)(1) and
4.105(b).
An Importer should notify the Foreign Seller and the SIP Sponsor
any time it makes an adverse event, medication error, field alert
report, or other report to FDA and the manufacturer. Notification to
Health Canada would be done by the Foreign Seller in accordance with
Health Canada requirements. FDA would share adverse event, medication
error, field alert report, or other report information it receives with
Health Canada as appropriate.
[[Page 70822]]
The SIP Sponsor would be required to establish a procedure to track
the public announcements of the manufacturer of each of the drugs that
they import and they must also monitor FDA's recall website at https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts, and Health
Canada's recall website at https://healthycanadians.gc.ca/recall-alert-rappel-avis/index-eng.php?cat=3, for any recall or market withdrawal
information relevant to the drugs that they import under section 804 of
the FD&C Act. The SIP Sponsor would have to explain in its SIP Proposal
how it will ensure that information about recalls or market withdrawals
will be shared among the SIP Sponsor, the Foreign Seller, the Importer,
and FDA and provided to the manufacturer.
If FDA or a SIP Sponsor determines that a recall is necessary, the
SIP Sponsor must ensure that the recall is carried out effectively
based on the classification and depth determined by FDA or the SIP
Sponsor. A SIP must have a written recall plan that describes the
procedures to perform a recall of the product and specifies who will be
responsible for performing the procedures. The recall plan must cover
recalls initiated by FDA and recalls initiated by the SIP Sponsor, as
well as recalls in Canada or the United States initiated by a drug's
manufacturer that implicate a drug imported under a SIP, with which the
Foreign Seller and/or Importer must cooperate. The recall plan must
include sufficient procedures for the SIP Sponsor, Foreign Seller and/
or Importer to:
Immediately cease distribution of the drugs affected by
the recall;
directly notify consignees of the drug or drugs included
in the recall, including how to return or dispose of the recalled
drugs;
specify the depth to which the recall will extend (e.g.,
wholesale, intermediate wholesale, retail, or consumer level);
notify the public about any hazard or hazards presented by
the recalled drug when appropriate to protect the public health;
conduct effectiveness checks to verify that all consignees
at the specified recall depth have received notification about the
recall and have taken appropriate action;
appropriately dispose of recalled product; and
notify FDA of the recall.
In addition, in the event of a recall, Importers and Foreign
Sellers would be required, upon request by FDA, to provide the
transaction history, information, and statement, as those terms are
defined in sections 581(25), 581(26), and 581(27) of the FD&C Act,
respectively, of the FD&C Act. We seek comment on how a SIP Sponsor and
co-sponsor, if any, Foreign Seller, or Importer would effectuate a
recall in the United States, given that this will be a new
responsibility for these entities.
L. Severability
Proposed Sec. 251.20 contains a severability provision clarifying
the Agency's intent regarding whether the provisions of part 251 are
severable from the rest of the regulation if one or more of the
provisions are stayed or determined to be invalid by a court. The
provisions of part 251 contain requirements that are either expressly
mandated by section 804 of the FD&C Act, or are otherwise necessary
pursuant to section 804(c)(3) because they have been determined by the
Secretary to be appropriate as a safeguard to protect the public health
or as a means to facilitate the importation of prescriptions drugs
under section 804. Each of the requirements that will be included in
the final rule will address significant potential safety concerns
associated with drugs imported under section 804 and would be necessary
to protect public health. If one or more of these provisions becomes
invalid, the rule, as a whole, would no longer adequately protect
public health and therefore should be invalid in its entirety.
In addition, section 804 of the FD&C Act, and by extension, this
regulation, which is promulgated in part pursuant to that authority,
only becomes effective if the Secretary certifies to Congress that
implementation of section 804 will pose no additional risk to the
public's health and safety. This certification is contingent upon this
rule becoming effective with all the requirements that are included
when finalized. If one or more of the provisions in this rule becomes
invalid, in addition to the entire rule becoming invalid, the
certification would become null and void because the certification is
based on a finding that implementation of section 804 will pose no
additional risk to the public's health and safety, and that finding
would no longer be accurate because it would have been based on a final
rule that contains all the requirements that were included when
published.
VI. Proposed Effective and/or Compliance Dates
FDA proposes that any final rule that issues based on this proposal
become effective 30 days after the final rule publishes in the Federal
Register.
VII. Preliminary Economic Analysis of Impacts
We have examined the impacts of the proposed rule under Executive
Order 12866, Executive Order 13563, Executive Order 13771, the
Regulatory Flexibility Act (5 U.S.C. 601-612), and the Unfunded
Mandates Reform Act of 1995 (Pub. L. 104-4). Executive Orders 12866 and
13563 direct us to assess all costs and benefits of available
regulatory alternatives and, when regulation is necessary, to select
regulatory approaches that maximize net benefits (including potential
economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). Executive Order 13771
requires that the costs associated with significant new regulations
``shall, to the extent permitted by law, be offset by the elimination
of existing costs associated with at least two prior regulations.'' We
believe that this proposed rule is a significant regulatory action as
defined by Executive Order 12866.
The Regulatory Flexibility Act requires us to analyze regulatory
options that would minimize any significant impact of a rule on small
entities. We cannot anticipate if sponsors will contract with small
entities to implement their authorized SIP proposals and request
comment on the impact the proposed rule may have on small entities. We
also lack information to quantify the total impacts of the proposed
rule. Therefore, we propose to certify that the proposed rule will not
have a significant economic impact on a substantial number of small
entities.
The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires
us to prepare a written statement, which includes an assessment of
anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $154 million, using the most current (2018) Implicit
Price Deflator for the Gross Domestic Product. This proposed rule would
not result in an expenditure in any year that meets or exceeds this
amount.
1. Summary of Costs and Benefits
The proposed rule, if finalized, would allow commercial importation
of certain prescription drugs from Canada through time-limited
programs, SIPs, sponsored by at least one non-federal governmental
entity with possible co-sponsorship by a
[[Page 70823]]
wholesaler or pharmacist. If such programs allow Importers to leverage
drug price differences between the United States and Canada, they will
result in cost savings for U.S. consumers.
Expected costs of the proposed rule accrue to the Federal
Government, SIP Sponsors, Importers, and manufacturers of imported
drugs. The Federal Government would incur one-time fixed costs as well
as ongoing costs to implement the rule, if finalized, and to review SIP
Proposals and reports. SIP Sponsors would face costs to prepare
proposals, implement approved SIPs, and produce SIP reports and
records. SIPs may offer cost savings to consumers, as well as other
parties in the drug supply chain including participating wholesale drug
distributors, pharmacies, hospitals, and third-party payers. If their
drugs are imported into the United States from Canada, drug
manufacturers will have to provide importers with certain information.
As drug distributors realize savings in acquiring imported drugs and
pass some of these savings to consumers, it is possible that U.S. drug
manufacturers may experience a transfer in U.S. sales revenues to these
parties.
We are unable to estimate the cost savings from this proposed rule,
as we lack information about the likely size and scope of SIP programs
and about the specific drug products that may become eligible for
importation, the degree to which imported drugs would be less expensive
than non-imported drugs available in the United States, and which SIP
eligible products are produced by U.S. drug manufacturers.
Table 1 summarizes the benefits and costs of the proposed rule.
Table 1--Summary of Benefits, Costs and Distributional Effects of Proposed Rule
--------------------------------------------------------------------------------------------------------------------------------------------------------
Units
------------------------------------
Category Primary Low High Period Notes
estimate estimate estimate Year Discount covered
dollars rate (%) (years)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits:
Annualized Monetized $millions/ .......... .......... .......... 2019 7 10 ........................................
year. 2019 3 10
Annualized Quantified............. .......... .......... .......... 2019 7 10 ........................................
2019 3 10
-----------------------------------------------------------------------------------------------------------------
Qualitative....................... Potential cost savings to .......... .......... 10 ........................................
consumers and third-party payers
or entities
--------------------------------------------------------------------------------------------------------------------------------------------------------
Costs:
Annualized Monetized $millions/ .......... .......... .......... 2019 7 10
year. 2019 3 10
Annualized Quantified............. .......... .......... .......... 2019 7 10 ........................................
2019 3 10
-----------------------------------------------------------------------------------------------------------------
Qualitative....................... Potential costs to Federal .......... .......... 10 ........................................
Government, SIP sponsors,
importers, and manufacturers of
imported drugs
--------------------------------------------------------------------------------------------------------------------------------------------------------
Transfers:
Federal Annualized Monetized .......... .......... .......... 2019 7 10 ........................................
$millions/year. 2019 3 10
-----------------------------------------------------------------------------------------------------------------
From/To........................... .......... From:
To:
--------------------------------------------------------------------------------------------------------------------------------------------------------
Other Annualized Monetized .......... .......... .......... 2019 7 10 ........................................
$millions/year. 2019 3 10
-----------------------------------------------------------------------------------------------------------------
From/To........................... From: U.S. drug manufacturers
To: Importers and U.S. consumers Not
Quantified
.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Effects:
State, Local or Tribal Government: Potential costs and cost savings to State, tribal, and territorial government entities from sponsoring SIPs......
Small Business:.....................................................................................................................................
Wages:..............................................................................................................................................
Growth:.............................................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
We lack information about the likely size and scope of SIP
programs, the specific drug products that may become eligible for
importation, the degree to which drugs imported under section 804 would
be less expensive than drugs not imported under section 804, and which
SIP eligible products are produced by U.S. drug manufacturers to
estimate the present and annualized values of the costs and cost
savings of the proposed rule over an infinite time horizon. The
designation under Executive Order 13771 of any final rule resulting
from this proposal will be informed by comments received and subsequent
analysis at the final rule stage. Thus, we exclude the Executive Order
13771 summary table from this analysis.
We have developed a comprehensive Preliminary Economic Analysis of
Impacts that assesses the impacts of the proposed rule. The full
preliminary analysis of economic impacts is available in the docket for
this proposed rule (Ref. 31) and at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.
VIII. Analysis of Environmental Impact
We have determined under 21 CFR 25.30(h) and 25.31(a) that this
action is of a type that does not individually or cumulatively have a
significant effect on the human environment. Therefore, neither an
environmental assessment nor an environmental impact statement is
required.
IX. Paperwork Reduction Act of 1995
This proposed rule contains information collection provisions that
are subject to review by the Office of Management and Budget (OMB)
under the Paperwork Reduction Act of 1995
[[Page 70824]]
(44 U.S.C. 3501-3521). A description of these provisions is given below
under the Description heading with an estimate of the annual reporting,
recordkeeping, and third-party disclosure burden. Included in the
estimate is the time for reviewing instructions, searching existing
data sources, gathering and maintaining the data needed, and completing
and reviewing each collection of information.
FDA invites comments on these topics: (1) Whether the proposed
collection of information is necessary for the proper performance of
FDA's functions, including whether the information will have practical
utility; (2) the accuracy of FDA's estimate of the burden of the
proposed collection of information, including the validity of the
methodology and assumptions used; (3) ways to enhance the quality,
utility, and clarity of the information to be collected; and (4) ways
to minimize the burden of the collection of information on respondents,
including through the use of automated collection techniques, when
appropriate, and other forms of information technology.
Title: Section 804 Importation Program Proposals--21 CFR part 251.
Description: The proposed regulations provide that a SIP Sponsor
that seeks to implement a SIP to import prescription drugs from Canada
must submit a proposal that includes, among other things, information
about the SIP Sponsor and the SIP Sponsor's importation plan. In
addition, SIP Sponsors must provide FDA with data and information on
the drugs the SIP imports and on the SIP's cost savings to the American
consumer. Importers would have a number of responsibilities related to
submitting a Pre-Import Request, screening eligible prescription drugs
and arranging for importation, testing, and relabeling. Manufacturers
would provide information needed to authenticate eligible prescription
drugs.
Description of Respondents: Respondents would include SIP Sponsors
(State, tribal, or territorial governmental entities), Importers
(pharmacists or wholesalers), and manufacturers of eligible
prescription drugs.
FDA anticipates submissions will be made through the Electronic
Submissions Gateway.
FDA estimates that there will be 10 SIP Sponsors requiring 360
hours each to research, prepare, and administer requirements annually;
10 Pre-Import Requests requiring 24 hours each annually; and 20
manufacturers also requiring 24 hours each annually to participate in
the program. In addition, FDA estimates that a recordkeeping burden of
52 hours will be imposed annually on the 10 SIP Sponsors; and a
recordkeeping burden of 24 hours will be imposed annually on each of
the 10 Importers and the 20 manufacturers. The 20 manufacturers
anticipated to participate in the program will also incur an estimated
burden of 24 hours each for copying and providing records to SIP
Sponsors and Importers of foreign transactions.
FDA estimates the burden of this collection of information as
follows:
Table 2--Estimated Annual Reporting Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Number of
Type of information collection activity/respondent Number of responses per Total annual Average burden Total hours
respondents respondent responses per response
--------------------------------------------------------------------------------------------------------------------------------------------------------
SIP Sponsor 251.3; 251.8; 251.14--SIP Proposal Submission 10 1 10 360 3,600
Requirements; 251.18--Post-Importation Requirements; 251.19--
Reports to FDA....................................................
Importer 251.5; 251.12; 251.13; 251.17--Pre-Import Request and 10 1 10 24 240
Importation Requirements..........................................
Manufacturer 251.16 Lab Testing Requirements....................... 20 1 20 24 480
------------------------------------------------------------------------------------
Total.......................................................... ............... ............... ............... ............... 4,320
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.
Table 3--Estimated Annual Recordkeeping Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Number of Average burden
Type of information collection activity/respondent Number of records per Total annual per Total hours
recordkeepers recordkeeper records recordkeeping
--------------------------------------------------------------------------------------------------------------------------------------------------------
SIP sponsor 251.8--Modification or Extension of Authorized 10 1 10 52 520
Importation Programs..............................................
Importer 251.14(d)--Supply Chain Security Requirements; 251.17-- 10 1 10 24 240
Importation Requirements; 251.18 Post-Importation Requirements....
Manufacturer 251.14(b)--Supply Chain Security Requirements......... 20 1 20 24 480
------------------------------------------------------------------------------------
Total.......................................................... ............... ............... ............... ............... 1,240
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.
Table 4--Estimated Annual Third-Party Disclosure Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Number of
Type of information collection activity/respondent Number of disclosures per Total annual Average burden per Total hours
respondents respondent disclosures disclosure
--------------------------------------------------------------------------------------------------------------------------------------------------------
Manufacturer 251.14(b)--Supply Chain Security 20 1 20 24 480
Requirements.......................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.
[[Page 70825]]
To ensure that comments on information collection are received, OMB
recommends that written comments be faxed to the Office of Information
and Regulatory Affairs, OMB (see ADDRESSES). All comments should be
identified with the title of the information collection.
In compliance with the Paperwork Reduction Act of 1995 (44 U.S.C.
3407(d)), we have submitted the information collection provisions of
this proposed rule to OMB for review. These information collection
requirements will not be effective until FDA publishes a final rule,
OMB approves the information collection requirements, and the rule goes
into effect. FDA will announce OMB approval of these requirements in
the Federal Register.
X. Federalism
We have analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. We have determined that
this proposed rule does not contain policies that have substantial
direct effects on the States, on the relationship between the National
Government and the States, or on the distribution of power and
responsibilities among the various levels of government. Accordingly,
we conclude that the rule does not contain policies that have
federalism implications as defined in the Executive Order and,
consequently, a federalism summary impact statement is not required.
XI. Consultation and Coordination With Indian Tribal Governments
We have analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13175. We have tentatively
determined that the rule does not contain policies that would have a
substantial direct effect on one or more Indian Tribes, on the
relationship between the Federal Government and Indian Tribes, or on
the distribution of power and responsibilities between the Federal
Government and Indian Tribes. The Agency solicits comments from tribal
officials on any potential impact on Indian Tribes from this proposed
action.
XII. References
The following references marked with an asterisk (*) are on display
at the Dockets Management Staff (see ADDRESSES) and are available for
viewing by interested persons between 9 a.m. and 4 p.m., Monday through
Friday; they also are available electronically at https://www.regulations.gov. References without asterisks are not on public
display at https://www.regulations.gov because they have copyright
restriction. Some may be available at the website address, if listed.
References without asterisks are available for viewing only at the
Dockets Management Staff. FDA has verified the website addresses, as of
the date this document publishes in the Federal Register, but websites
are subject to change over time.
*1. Donna Shalala, Secretary of Health and Human Services, 2000,
Letter to President Clinton, accessed September 27, 2019, https://www.congress.gov/congressional-record/2002/7/17/senate-section/article/s6906-2?q={%22search%22:[%22Shalala+\%22flaws+and+loopholes\%22%22]{time} &
s=1&r=3.
*2. Mark B. McClellan, FDA Commissioner, 2003, Letter to Senator
Thad Cochran, accessed September 27, 2019, https://www.congress.gov/congressional-record/2003/6/19/senate-section/article/s8202-2?r=73.
*3. Randall W. Lutter, Acting Associate Commissioner for Policy and
Planning, 2005, Letter to Theodore R. Kulongoski, Governor of
Oregon, Requested Waiver for Certification of Oregon's Pioneer
Prescription Drug Program, accessed September 27, 2019, https://wayback.archive-it.org/7993/20170112030500/http:/www.fda.gov/Drugs/DrugSafety/ucm179372.htm.
*4. Nomination of Robert Califf to Serve as FDA Commissioner, 2015,
Hearing Before the Committee on Health, Education, Labor and
Pensions, S Hrg 114-717 at 47, accessed September 27, 2019, https://www.govinfo.gov/content/pkg/CHRG-114shrg97694/pdf/CHRG-114shrg97694.pdf.
*5. HHS Task Force on Drug Importation, 2004, Report on Prescription
Drug Importation, accessed September 27, 2019, http://www.safemedicines.org/wp-content/uploads/2018/03/HHS-Report1220.pdf.
*6. United States Government Accountability Office (GAO), 2017,
``Fast Facts--Drug Industry: Profits, Research and Development
Spending, and Merger and Acquisition Deals,'' GAO-18-40, accessed
July 31, 2019, https://www.gao.gov/assets/690/688472.pdf.
*7. HHS, 2016, Office of The Assistant Secretary for Planning and
Evaluation (ASPE) Issue Brief: Observations on Trends in
Prescription Drug Spending, accessed July 31, 2019, https://aspe.hhs.gov/system/files/pdf/187586/Drugspending.pdf.
*8. Kaiser Family Foundation, 2019, Kaiser Family Foundation (KFF)
Health Tracking Poll--February 2019: Prescription Drugs, accessed
September 26, 2019, https://www.kff.org/health-costs/poll-finding/kff-health-tracking-poll-february-2019-prescription-drugs/view/footnotes/.
*9. Iuga, A.O. and M.J. McGuire, 2014, ``Adherence and Health Care
Costs,'' Risk Management and Healthcare Policy, 7:35-44, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3934668/pdf/rmhp-7-035.pdf.
*10. Jonel Aleccia, 2019, ``Lawmakers, Advocates Push To Extend
Medicare's Coverage of Kidney Transplant Drugs,'' National Public
Radio, accessed October 15, 2019, https://www.npr.org/sections/health-shots/2019/07/17/742349066/lawmakers-advocates-push-to-extend-medicares-coverage-of-kidney-transplant-drugs.
*11. Liz Szabo, 2017, ``As Drug Costs Soar, People Delay or Skip
Cancer Treatments,'' National Public Radio, accessed July 31, 2019,
https://www.npr.org/sections/health-shots/2017/03/15/520110742/as-drug-costs-soar-people-delay-or-skip-cancer-treatments.
*12. John R. Thomas, 2016, Congressional Research Service, ``Patents
and Prescription Drug Importation,'' accessed September 27, 2019,
https://fas.org/sgp/crs/misc/R44640.pdf.
*13. Ben Hirschler, 2015, ``How the U.S. Pays 3 Times More for
Drugs,'' Scientific American, accessed July 31, 2019, https://www.scientificamerican.com/article/how-the-u-s-pays-3-times-more-for-drugs/.
*14. Gagnon, M.-A. and S. Wolfe, 2015, ``Mirror, Mirror on the Wall:
Medicare Part D Pays Needlessly High Brand-Name Drug Prices Compared
with Other OECD Countries and with U.S. Government Programs,''
Carleton University, School of Public Policy and Administration,
accessed July 31, 2019, https://carleton.ca/sppa/wp-content/uploads/Mirror-Mirror-Medicare-Part-D-Released.pdf.
*15. Patented Medicine Prices Review Board (PMPRB), 2017, ``Annual
Report 2017: Regulating Prices of Patented Medicines: Continued
Vigilance Necessary, Bilateral Price Comparisons, Average Foreign-
to-Canadian Price Ratios, Bilateral Comparisons,'' accessed July 31,
2019, http://www.pmprb-cepmb.gc.ca/view.asp?ccid=1380&lang=en.
*16. PMPRB, 2018, ``About Us: Mandate and Jurisdiction,'' http://pmprb-cepmb.gc.ca/about-us/mandate-and-jurisdiction, accessed July
31, 2019.
*17. Rachel Bluth, 2016, ``Faced with Unaffordable Drug Prices, Tens
of Millions Buy Medicine Outside U.S.,'' Kaiser Health News,
accessed September 27, 2019, https://khn.org/news/faced-with-unaffordable-drug-prices-tens-of-millions-buy-medicine-outside-u-s/.
*18. Kaiser Family Foundation, 2016, ``Kaiser Health Tracking Poll--
November 2016,'' accessed September 27, 2019, http://files.kff.org/attachment/Kaiser-Health-Tracking-Poll-November-2016-Topline.
*19. FDA, 2018, ``FDA Launches Global Operation to Crack Down on
websites Selling Illegal, Potentially Dangerous Drugs; Including
Opioids,'' accessed September 3, 2019, https://www.fda.gov/news-events/press-announcements/fda-launches-global-operation-crack-down-websites-selling-illegal-potentially-dangerous-drugs.
*20. U.S. Department of Justice, 2017, ``September 25, 2017:
Millions of
[[Page 70826]]
Medicines Seized in Largest INTERPOL Operation Against Illicit
Online Pharmacies,'' accessed September 27, 2019, https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/press-releases/september-25-2017-millions-medicines-seized-largest-interpol-operation-against-illicit-online.
*21. U.S. Department of Justice, 2013, ``April 24, 2013: Paul Daniel
Bottomley Pleads Guilty in U.S. Federal Court,'' accessed August 19,
2019, https://wayback.archive-it.org/7993/20170723081601/https://www.fda.gov/ICECI/CriminalInvestigations/ucm349880.htm.
*22. U.S. Department of Justice, 2018, ``April 13, 2018: Canadian
Drug Firm Admits Selling. Counterfeit and Misbranded Prescription
Drugs Throughout the United States,'' accessed September 3, 2019,
https://wayback.archive-it.org/7993/20180725182130/https://www.fda.gov/ICECI/CriminalInvestigations/ucm605139.htm.
*23. FDA, 2012, FDA Warning Letter to Canadadrugs, accessed
September 27, 2019, https://wayback.archive-it.org/7993/20170723020703/ https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2012/ucm321068.htm.
*24. FDA, 2005, ``FDA Operation Reveals Many Drugs Promoted as
`Canadian' Products Really Originate From Other Countries,''
accessed September 27, 2019, https://wayback.archive-it.org/7993/20170112030444/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm108534.htm.
* 25. Ashley, D. D., 2017, ``Letter to the Editor: The Price of
Crossing the Border for Medications,'' New England Journal of
Medicine, October 26, 2017, 377:1699-1700, doi: 10.1056/NEJMc1711278
(referencing Fralick, M., J. Avorn, A.S. Kesselheim, 2017, ``The
Price of Crossing the Border for Medications,'' New England Journal
of Medicine, July 27, 2017, 377:311-313, doi: 10.1056/NEJMp1704489),
https://www.nejm.org/doi/full/10.1056/NEJMp1704489#article_letters.
* 26. Government of Canada, Archived, ``Consultation: Regulations
Amending the Food and Drug Regulations 1447-Good Manufacturing
Practices,'' accessed September 27, 2019, https://www.canada.ca/en/health-canada/services/drugs-health-products/public-involvement-consultations/compliance-enforcement/regulations-amending-food-drug-regulations-1447.html.
* 27. Government of Canada, Health Canada, ``GMP Drug Establishment
Good Manufacturing Practices Pre-Application Package: Importers,
Distributors and Wholesalers,'' accessed September 27, 2019, https://www.canada.ca/content/dam/hc-sc/migration/hc-sc/dhp-mps/alt_formats/pdf/compli-conform/gmp-bpf/docs/gmp-package-bpf-eng.pdf.
* 28. Government of Canada, Health Canada, 2019, ``Health Canada and
United States Food and Drug Administration Joint Public Consultation
on ICH Guidelines--Update,'' accessed December 10, 2019, https://www.canada.ca/en/health-canada/services/drugs-health-products/public-involvement-consultations/drug-products/notice-international-council-harmonisation-registration-pharmaceuticals-human-use-consultation-update.html.
29. Joanne S. Eglovitch, 2019, ``GS1 Standard Would Speed the Sale
of Returned Drugs After November Deadline,'' Pink Sheet, accessed
September 27, 2019, https://pink.pharmaintelligence.informa.com/PS140811/GS1-Standard-Would-Speed-The-Sale-Of-Returned-Drugs-After-November-Deadline.
30. ASTM E122-17, 2017, Standard Practice for Calculating Sample
Size to Estimate, With Specified Precision, the Average for a
Characteristic of a Lot or Process, www.astm.org.
* 31. FDA, Preliminary Regulatory Impact Analysis: Importation of
Prescription Drugs, http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.
List of Subjects
21 CFR Part 1
Cosmetics, Drugs, Exports, Food labeling, Imports, Labeling,
Reporting and recordkeeping requirements.
21 CFR Part 251
Exports, Labeling, Packaging and containers, Prescription drugs,
Reporting and recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, the Food and
Drug Administration proposes to amend 21 CFR chapter I as follows:
PART 1--GENERAL ENFORCEMENT REGULATIONS
0
1. The authority citation for part 1 continues to read as follow:
Authority: 15 U.S.C. 1333, 1453, 1454, 1455, 4402; 19 U.S.C.
1490, 1491; 21 U.S.C. 321, 331, 332, 333, 334, 335a, 342, 343, 350c,
350d, 350e, 350j, 350k, 352, 355, 360b, 360ccc, 360ccc-1, 360ccc-2,
362, 371, 373, 374, 379j-31, 381, 382, 384a, 384b, 384d, 387, 387a,
387c, 393; 42 U.S.C. 216, 241, 243, 262, 264, 271; Pub. L. 107-188,
116 Stat. 594, 668-69; Pub. L. 111-353, 124 Stat. 3885, 3889.
0
2. Revise Sec. 1.74 to read as follows:
Sec. 1.74 Human drugs.
In addition to the data required to be submitted in Sec. 1.72, an
ACE filer must submit the following information at the time of filing
entry in ACE for drugs, including biological products and eligible
prescription drugs as defined in Sec. 251.2 of this chapter that are
imported or offered for import under section 804 of the Federal Food,
Drug, and Cosmetic Act, intended for human use that are regulated by
the FDA Center for Drug Evaluation and Research.
(a) For a drug intended for human use that is not an eligible
prescription drug covered under paragraph (b) of this section:
(1) Registration and listing. The Drug Registration Number and the
Drug Listing Number if the foreign establishment where the human drug
was manufactured, prepared, propagated, compounded, or processed before
being imported or offered for import into the United States is required
to register and list the drug under part 207 of this chapter. For the
purposes of this section, the Drug Registration Number that must be
submitted at the time of entry in ACE is the unique facility identifier
of the foreign establishment where the human drug was manufactured,
prepared, propagated, compounded, or processed before being imported or
offered for import into the United States. The unique facility
identifier is the identifier submitted by a registrant in accordance
with the system specified under section 510(b) of the Federal Food,
Drug, and Cosmetic Act. For the purposes of this section, the Drug
Listing Number is the National Drug Code number of the human drug
article being imported or offered for import.
(2) Drug application number. For a drug intended for human use that
is the subject of an approved application under section 505(b) or
505(j) of the Federal Food, Drug, and Cosmetic Act, the number of the
new drug application or abbreviated new drug application. For a
biological product regulated by the FDA Center for Drug Evaluation and
Research that is required to have an approved new drug application or
an approved biologics license application, the number of the applicable
application.
(3) Investigational new drug application number. For a drug
intended for human use that is the subject of an investigational new
drug application under section 505(i) of the Federal Food, Drug, and
Cosmetic Act, the number of the investigational new drug application.
(b) For an eligible prescription drug as defined in Sec. 251.2 of
this chapter that is imported or offered for import under section 804
of the Federal Food, Drug, and Cosmetic Act:
(1) Registration and listing. The Drug Registration Number and the
Drug Listing Number. For the purposes of this section, the Drug
Registration Number that must be submitted in ACE is the unique
facility identifier of the Foreign
[[Page 70827]]
Seller. The unique facility identifier is the identifier submitted by a
Foreign Seller registrant under Sec. 251.5 of this chapter. For the
purposes of this section, the Drug Listing Number is the National Drug
Code that the Importer will use when relabeling the eligible
prescription drug as required in Sec. 251.13 of this chapter.
(2) Drug application number. The number of the new drug application
or abbreviated new drug application for the corresponding FDA-approved
drug.
(3) Lot or control number. The lot or control number assigned by
the manufacturer of the eligible prescription drug.
(4) FDA Quantity. FDA Quantity, which is the quantity of each
eligible prescription drug in an import line delineated by packaging
level, including the type of package from the largest packaging unit to
the smallest packaging unit; the quantity of each packaging unit; and
the volume and/or weight of each of the smallest of the packaging
units.
(5) Pre-Import Request number. The Pre-Import Request number
assigned by FDA.
0
3. Add part 251 to read as follows:
PART 251--SECTION 804 IMPORTATION PROGRAM PROPOSAL
Subpart A--General Provisions
Sec.
251.1 Scope of the part.
251.2 Definitions.
Subpart B--Section 804 Importation Program Proposals and Pre-Import
Requests
251.3 SIPproposal submission requirements.
251.4 Review and authorization of importation program proposals.
251.5 Pre-Import Request.
251.6 Limitations on authorized importation programs.
251.7 Suspension and revocation of authorized importation programs.
251.8 Modification or extension of authorized importation programs.
Subpart C--Certain Requirements for Section 804 Importation Programs
251.9 Registration of Foreign Sellers.
251.10 Reviewing and updating registration information for Foreign
Sellers.
251.11 Official contact and U.S. agent for Foreign Sellers.
251.12 Importer responsibilities.
251.13 Labeling of eligible prescription drugs.
251.14 Supply chain security requirements for eligible prescription
drugs.
251.15 Qualifying laboratory requirements.
251.16 Laboratory testing requirements.
251.17 Importation requirements.
251.18 Post-importation requirements.
251.19 Reports to FDA.
251.20 Severability.
251.21 Consequences for violations.
Authority: 21 U.S.C. 351, 352, 353, 355, 371, 374, 381, 384.
Subpart A--General Provisions
Sec. 251.1 Scope of the part.
(a) This part sets forth the procedures that Section 804
Importation Program sponsors (SIP Sponsors) must follow when submitting
plans to implement time-limited programs to begin importation of drugs
from Canada under section 804 of the Federal Food, Drug, and Cosmetic
Act. This part also sets forth certain requirements that are necessary
for such programs to be authorized by FDA. Additionally, this part sets
forth requirements for eligible prescription drugs and requirements for
entities that engage in importation of eligible prescription drugs.
(b) This part includes provisions that exempt eligible prescription
drugs that meet certain requirements from section 502(f)(1) of the
Federal Food, Drug, and Cosmetic Act. It also includes provisions that
exempt certain transactions involving eligible prescription drugs from
certain requirements in section 582 of the Federal Food, Drug, and
Cosmetic Act.
Sec. 251.2 Definitions.
The definitions of terms in section 804 of the Federal Food, Drug,
and Cosmetic Act apply to the terms used in this part, if not otherwise
defined in this section. The following definitions apply to this part:
Active ingredient means any component that is intended to furnish
pharmacological activity or other direct effect in the diagnosis, cure,
mitigation, treatment, or prevention of disease, or to affect the
structure or any function of the body of man or other animals. The term
includes those components that may undergo chemical change in the
manufacture of the drug product and be present in the drug product in a
modified form intended to furnish the specified activity or effect.
Adverse event means any untoward medical occurrence associated with
the use of a drug product in humans, whether or not it is considered
related to the drug product. An adverse event can occur in the course
of the use of a drug product; from overdose of a drug product, whether
accidental or intentional; from abuse of a drug product (e.g.,
physiological withdrawal); and includes any failure of expected
pharmacological action.
Combination product has the meaning set forth in Sec. 3.2(e) of
this chapter.
Constituent part has the meaning set forth in Sec. 4.2 of this
chapter.
Disability means a substantial disruption of a person's ability to
conduct normal life functions.
Eligible prescription drug means a drug subject to section 503(b)
of the Federal Food, Drug, and Cosmetic Act that has been approved and
has received a Notice of Compliance and a Drug Identification Number
(DIN) from the Health Products and Food Branch of Health Canada (HPFB)
and, but for the fact that it deviates from the required U.S. labeling,
also meets the conditions in an FDA-approved new drug application (NDA)
or abbreviated new drug application (ANDA) for a drug that is currently
marketed in the United States, including those relating to the drug
substance, drug product, production process, quality controls,
equipment, and facilities.
Exclusion. The term eligible prescription drug does not include:
(1) A controlled substance (as defined in section 102 of the
Controlled Substances Act (21 U.S.C. 802));
(2) A biological product (as defined in section 351 of the Public
Health Service Act (42 U.S.C. 262));
(3) An infused drug (including a peritoneal dialysis solution);
(4) An intravenously injected drug;
(5) A drug that is inhaled during surgery;
(6) An intrathecally or intraocularly injected drug;
(7) A drug that is subject to a risk evaluation and mitigation
strategy under section 505-1 of the Federal Food, Drug, and Cosmetic
Act;
(8) A drug that is not a ``product'' for purposes of section 582 as
defined in section 581(13) of the Federal Food, Drug, and Cosmetic Act;
Entry means the information or data filed electronically to the
Automated Commercial Environment (ACE) or any other U.S. Customs and
Border Protection (CBP)-authorized electronic data interchange system
to secure the release of imported merchandise from CBP, or the act of
filing that information or data.
Foreign Seller means an establishment within Canada engaged in the
distribution of an eligible prescription drug that is imported or
offered for importation into the United States. A Foreign Seller must
have an active drug establishment license as a drug wholesaler by
Health Canada. A Foreign Seller must be registered with provincial
pharmacy regulatory authorities to distribute HPFB-approved drugs. A
Foreign Seller must not be licensed by a provincial pharmacy regulatory
authority with an international pharmacy license that allows it to
distribute drugs that are
[[Page 70828]]
approved by countries other than Canada and that are not HPFB-approved
for distribution in Canada. A Foreign Seller must also be registered
with FDA under section 804 of the Federal Food Drug and Cosmetic Act in
accordance with the requirements described in this part.
Illegitimate foreign product means a drug purchased by a Foreign
Seller from a manufacturer, and intended for sale to the Importer in
the United States, where the Foreign Seller has credible evidence that
the product:
(1) Is counterfeit, diverted, or stolen;
(2) Is intentionally adulterated such that the product would result
in serious adverse health consequences or death to humans;
(3) Is the subject of a fraudulent transaction; or
(4) Appears otherwise unfit for distribution such that the product
would be reasonably likely to result in serious adverse health
consequences or death to humans.
Importer means a pharmacist or wholesaler. An Importer must be a
State-licensed pharmacist, or a State or FDA-licensed wholesaler, who
is the U.S. owner of an eligible prescription drug at the time of entry
into the United States. An Importer's pharmacist or wholesaler license
must be in effect (i.e., not expired) and the Importer must be in good
standing with the licensor.
Individual case safety report (ICSR) means a description of an
adverse event related to an individual patient or subject and/or a
description of a medication error.
ICSR attachments means any document related to the adverse event or
medication error described in an ICSR, such as medical records,
hospital discharge summaries, or other documentation.
Life-threatening adverse event means any adverse event that places
the patient, in the view of the initial reporter, at immediate risk of
death from the adverse event as it occurred, i.e., it does not include
an adverse event that, had it occurred in a more severe form, might
have caused death.
Manufacturer means an applicant, as defined in Sec. 314.3 of this
chapter, or a person who owns or operates an establishment that
manufactures an eligible prescription drug. Manufacturer also means a
holder of a drug master file containing information necessary to
authenticate an eligible prescription drug.
Medication error means any preventable event that may cause or lead
to inappropriate medication use or patient harm while the medication is
in the control of a healthcare professional, patient, or consumer. The
medication error may or may not result in an adverse event.
Minimum data set for an adverse event means the minimum four
elements required for reporting an ICSR of an adverse event: An
identifiable patient, an identifiable reporter, a suspect drug product,
and an adverse event.
Minimum data set for a medication error means the minimum three
elements required for reporting an ICSR of a medication error: An
identifiable reporter, a suspect drug product, and a medication error.
Pre-Import Request means a request made to FDA by an Importer that
must be granted by FDA before the Importer can start importation under
a Section 804 Importation Program.
Qualifying laboratory means a laboratory in the United States that
has been approved by FDA for the purposes of section 804 of the Federal
Food, Drug, and Cosmetic Act.
Relabel has the meaning set forth in Sec. 207.1 of this chapter.
Relabeler has the meaning set forth in Sec. 207.1 of this chapter.
Repack or repackage has the meaning set forth in Sec. 207.1 of
this chapter.
Section 804 Importation Program (``SIP'') means a program under
section 804 of the Federal Food, Drug, and Cosmetic Act that has been
authorized by FDA for the importation of eligible prescription drugs
from Canada.
Section 804 Importation Program Sponsor (``SIP Sponsor''): (Option
1): Means a State, tribal, or territorial governmental entity that
regulates wholesale drug distribution and/or the practice of pharmacy,
and a co-sponsor or co-sponsors, if any, that submits a proposal to FDA
that describes a program to facilitate the importation of prescription
drugs from Canada under section 804 of the Federal Food, Drug, and
Cosmetic Act. A co-sponsor must be a State, tribal, or territorial
governmental entity, a pharmacist, or a wholesaler.
Section 804 Importation Program Sponsor (``SIP Sponsor''): (Option
2): Means a State, tribal, or territorial governmental entity that
regulates wholesale drug distribution and/or the practice of pharmacy,
a wholesaler, or a pharmacist, and a co-sponsor or co-sponsors, if any,
that submits a proposal to FDA that describes a program to facilitate
the importation of prescription drugs from Canada under section 804 of
the Federal Food, Drug, and Cosmetic Act. A co-sponsor must be a State,
tribal, or territorial governmental entity, a wholesaler, or a
pharmacist.
Section 804 Serial Identifier (``SSI'') means a unique alphanumeric
serial number of up to 20 characters that is assigned and affixed by
the Foreign Seller to each package and homogenous case of the product
that it intends to sell to the Importer. For purposes of the SSI,
``package'' means the smallest individual saleable unit of product for
distribution that is intended by the Foreign Seller for sale to the
Importer located in the United States, and ``individual saleable unit''
means the smallest container of product sold by the Foreign Seller to
the Importer.
Serious adverse event. (1) An adverse event is considered
``serious'' if it results in any of the following outcomes:
(i) Death;
(ii) A life-threatening adverse event where the patient was at
immediate risk of death at the time of the event; it does not include
an adverse event that might have caused death had it occurred in a more
severe form;
(iii) Inpatient hospitalization or prolongation of existing
hospitalization;
(iv) A persistent or significant incapacity or substantial
disruption of the ability to conduct normal life functions; and/or
(v) A congenital anomaly/birth defect.
(2) Other events that may be considered serious adverse events:
Important medical events that may not result in one of the listed
outcomes in this definition may be considered serious adverse events
when, based upon appropriate medical judgment, they may jeopardize the
patient or study subject and may require medical or surgical
intervention to prevent one of the outcomes listed in this definition.
Examples include: Allergic bronchospasm requiring intensive treatment
in an emergency department or at home, blood dyscrasias, or convulsions
that do not result in inpatient hospitalization, or the development of
product dependency or product abuse.
Statutory Testing means the testing of an eligible prescription
drug for authenticity, degradation, and to ensure that the prescription
drug is in compliance with established specifications and standards, as
required by section 804(d)(1)(J) and (L) of the Federal Food, Drug, and
Cosmetic Act.
Suspect foreign product means a drug purchased by the Foreign
Seller from the manufacturer, and intended for sale to the Importer in
the United States, that the Foreign Seller has reason to believe is:
(1) Potentially counterfeit, diverted, or stolen;
[[Page 70829]]
(2) Potentially intentionally adulterated such that the product
would result in serious adverse health consequences or death to humans;
(3) Is potentially the subject of a fraudulent transaction; or
(4) Appears otherwise unfit for distribution such that the product
would result in serious adverse health consequences or death to humans.
Transaction means the transfer of product between persons in which
a change of ownership occurs.
Unexpected adverse event means an adverse event that is not
included in the current U.S. labeling for the drug product. Events that
may be symptomatically and pathophysiologically related to an adverse
event included in the labeling but differ from the labeled event
because of greater severity or specificity, would be considered
unexpected. ``Unexpected,'' as used in this definition, also refers to
adverse events that are mentioned in the product labeling as occurring
with a class of products or anticipated from the pharmacological
properties of the product but are not specifically mentioned as
occurring with the particular product.
(1) Example of greater severity. Under this definition, hepatic
necrosis would be unexpected if the labeling referred only to elevated
hepatic enzymes or hepatitis.
(2) Example of greater specificity. Cerebral thromboembolism and
cerebral hemorrhage would be unexpected if the labeling included only
cerebrovascular accidents.
Unique facility identifier means the identifier required to be
submitted by the registrant for drug establishment registration under
section 510(b) of the Federal Food, Drug, and Cosmetic Act in
accordance with Sec. 207.25 of this chapter.
Wholesaler means a person licensed as a wholesaler or distributor
of prescription drugs in the United States under section 503(e)(1) of
the Federal Food, Drug, and Cosmetic Act. The term ``wholesaler'' does
not include a person authorized to import drugs under section
801(d)(1).
Subpart B--Section 804 Importation Program Proposals and Pre-Import
Requests
Sec. 251.3 SIP proposal submission requirements.
(a) A SIP Sponsor must only designate one Foreign Seller and one
Importer per initial proposal. Additional Foreign Sellers and Importers
may be added to an authorized SIP through a supplement under Sec.
251.8.
(b) A SIP Sponsor that intends to implement a SIP under this part
must submit a proposal to FDA in electronic form to FDA's Electronic
Submissions Gateway (ESG) or to an alternative transmission point
identified by FDA. The proposal must include:
(1) A cover sheet containing the following:
(i) Name or names of SIP Sponsor and co-sponsors, if any; and
(ii) Name and contact information for a person authorized to serve
as the point of contact with FDA during its review of the proposal;
(2) A table of contents;
(3) An introductory statement that includes an overview of the SIP
Sponsor's SIP Proposal; and
(4) The SIP Sponsor's importation plan.
(c) The overview of the SIP Proposal must include:
(1) The name or names and address or addresses of the SIP Sponsor
and co-sponsors, if any;
(2) The name and DIN of each eligible prescription drug that the
SIP Sponsor seeks to include in the SIP;
(3) The name and address of the applicant that owns the approved
NDA or ANDA for each eligible prescription drug's FDA-approved
counterpart, and the approved NDA or ANDA number;
(4) The name and address of the manufacturer of the finished dosage
form of the drug, if available;
(5) The name and address of the manufacturer of the active
ingredient or ingredients of the drugs, if available;
(6) The name and address of the Foreign Seller;
(7) The name and address of the Importer;
(8) The name and address of the FDA-registered repackager or
relabeler, if different from the Importer, that will relabel the
eligible prescription drugs (including any limited repackaging in
accordance with the requirements in this part), along with evidence of
registration and of satisfactory resolution of any objectionable
conditions or practices identified during its most recent FDA
inspection, if applicable;
(9) A summary of how the SIP Sponsor will ensure:
(i) That the imported eligible prescription drugs meet the
Statutory Testing requirements;
(ii) That the supply chain is secure;
(iii) That the labeling requirements of the Federal Food, Drug, and
Cosmetic Act and this part are met;
(iv) That the post-importation pharmacovigilance and other
requirements of the Federal Food, Drug, and Cosmetic Act and this part
are met; and
(v) That the SIP Proposal would result in a significant reduction
in the cost to the American consumer of the prescription drugs that the
SIP Sponsor seeks to import.
(d) The SIP Sponsor's importation plan must:
(1) Identify the SIP Sponsor, including any co-sponsors, and
identify the finished dosage form manufacturer of each prescription
drug that the SIP Sponsor seeks to include in the SIP, the Foreign
Seller, and the Importer, and explain the legal relationship of each of
these entities to the SIP Sponsor, if any.
(2) Include an attestation containing a complete disclosure of any
past criminal convictions or violations of the State, Federal, or
Canadian laws regarding drugs or devices against the Foreign Seller or
Importer or an attestation that the Foreign Seller or Importer has not
been involved in, or convicted of, any such criminal or prohibited
acts. Such attestation must include principals, any shareholder who
owns 10 percent or more of outstanding stock in any non-publicly held
corporation, directors, officers, and any facility manager or
designated representative of such manager.
(3) Include a list of all disciplinary actions, to include the date
of, and parties to, any action imposed against the Foreign Seller or
the Importer by State, Federal, or Canadian regulatory bodies,
including any such actions against the principals, owners, directors,
officers, or any facility manager or designated representative of such
manager for the previous 7 years prior to submission of the SIP
Proposal.
(4) Include:
(i) The Health Canada inspectional history for the previous 5
years, or if the Foreign Seller has been licensed for less than 5
years, for the duration of its period of licensure; and
(ii) the State and Federal inspectional history for the Importer
for the previous 5 years, or if the Foreign Seller has been licensed
for less than 5 years, for the duration of its period of licensure.
(5) Include the proprietary and established names, the approved
application numbers, and the DIN and National Drug Code (NDC), for each
eligible prescription drug that the SIP Sponsor seeks to import from
Canada and for its FDA-approved counterpart. It must also include as
much of the information that is required by Sec. 251.5 about the HPFB-
approved product and its FDA-approved counterpart as is available,
including the name and quantity of the active ingredient, the inactive
ingredients, and the dosage form.
[[Page 70830]]
(6) Confirm that each HPFB-approved drug's FDA-approved counterpart
drug is currently marketed in the United States.
(7) Describe, to the extent possible, the testing that will be done
to establish that the HPFB-approved drug meets the conditions in the
NDA or ANDA for the HPFB-approved drug's FDA-approved counterpart. It
must also identify the qualifying laboratory that will conduct the
testing, and it must establish that the laboratory is qualified in
accordance with Sec. 251.15 to conduct the tests.
(8) Include a copy of the FDA-approved labeling for the FDA-
approved version of the eligible prescription drug, a copy of the
proposed labeling that will be used for the eligible prescription drug,
and a side-by-side comparison of the FDA-approved labeling and the
proposed labeling including, if applicable, any patient labeling, with
all differences annotated and explained. The SIP Proposal must also
include a copy of the HPFB-approved labeling.
(9) Explain how the SIP Sponsor expects that the SIP will result in
a significant reduction in the cost to the American consumer of the
prescription drugs that the SIP Sponsor seeks to import. The
explanation must include any assumptions and uncertainty, and it must
be sufficiently detailed to allow for a meaningful evaluation.
(10) Explain how the SIP Sponsor will ensure that all of the
participants in the SIP comply with the requirements of section 804 of
the Federal Food, Drug, and Cosmetic Act and this part.
(11) Describe the procedures the SIP Sponsor will use to ensure
that the requirements of this part are met, including the steps that
will be taken to ensure that the:
(i) Storage, handling, and distribution practices of supply chain
participants, including transportation providers, meet the minimum
requirements of part 205 of this chapter and do not affect the quality
or impinge on the security of the eligible prescription drugs;
(ii) Supply chain is secure;
(iii) Importer screens the eligible prescription drugs it imports
for evidence that they are adulterated, counterfeit, damaged, tampered
with, or expired; and
(iv) Importer fulfills its responsibilities to submit adverse
event, medication error, field alert, and other reports.
(12) Explain how the SIP Sponsor will educate pharmacists,
healthcare providers, and patients about the drugs imported under its
SIP.
(13) Include the SIP's recall plan, including an explanation of how
the SIP Sponsor will obtain recall or market withdrawal information and
how it will ensure that recall or market withdrawal information is
shared among the SIP Sponsor, the Foreign Seller, the Importer, and FDA
and provided to the manufacturer; and
(14) Explain how the SIP Sponsor will ensure that any information
that the manufacturer provides to the Importer to allow the Importer to
conduct the Statutory Testing, or information otherwise obtained by the
Importer for such purposes, would be kept in strict confidence and used
only for purposes of testing or otherwise complying with the Federal
Food, Drug, and Cosmetic Act, as required by section 804(e)(2)(B).
Sec. 251.4 Review and authorization of importation program
proposals.
Based on a review of a SIP Proposal submitted under this part, FDA
may authorize, modify, or extend the authorization period of a SIP that
meets the requirements of this part. FDA may deny a request for
authorization, modification, or extension of a SIP in its discretion,
including if a proposed SIP does not meet the standard for authorizing
a SIP under this part. Where a SIP Proposal meets the requirements of
this part, FDA may nonetheless decide, in its discretion, not to
authorize the SIP Proposal.
(a) Among other reasons, FDA may decide not to authorize a SIP
Proposal because of potential safety concerns with the SIP, because of
the degree of uncertainty that the SIP Proposal would adequately ensure
the protection of public health, because, based on the recommendation
of another Health and Human Services (HHS) component as directed by the
Secretary, the relative likelihood that the SIP Proposal would not
result in significant cost savings, or in order to limit the number of
authorized SIP programs so FDA can effectively and efficiently carry
out its responsibilities under section 804 of the Federal Food, Drug,
and Cosmetic Act in light of the amount of resources allocated to
carrying out such responsibilities.
(b) FDA will notify a SIP Sponsor in writing, including through
electronic means, when FDA receives the SIP Sponsor's SIP Proposal.
(c) FDA will make a reasonable effort to promptly communicate to a
SIP Sponsor about any information required by Sec. 251.3 that was not
submitted in a SIP Proposal.
(1) FDA may notify a SIP Sponsor if FDA believes additional
information would help FDA's review of a SIP Proposal.
(2) FDA will notify a SIP Sponsor in writing, including through
electronic means, whether FDA has decided to authorize or not to
authorize the SIP Sponsor's SIP Proposal.
Sec. 251.5 Pre-Import Request.
(a) A prescription drug may not be imported or offered for import
under this part unless the Importer has filed a Pre-Import Request for
that drug, which has been granted by FDA.
(b) The Importer must submit a complete Pre-Import Request at least
30 days prior to scheduled date of arrival or entry for consumption,
whichever occurs first, of an eligible prescription drug covered under
an authorized SIP.
(c) A complete Pre-Import Request must include, at a minimum:
(1) Identification of the Importer including Importer name,
business type (wholesale distributor or pharmacist), U.S. license
number(s) and State(s) of license, business address, unique facility
identifier if required to register with FDA as an establishment under
section 510 of the Federal Food, Drug, and Cosmetic Act or FDA
establishment identification number if not required to register under
section 510 of the Federal Food, Drug, and Cosmetic Act, and name of a
contact person with their email and phone number.
(2) Identification of the FDA-authorized SIP including the name of
the SIP; the name or names of the SIP Sponsor and co-sponsors, if any;
business address; and the name, email address, and phone number of a
contact person.
(3) Identification of the Foreign Seller, including the name of the
Foreign Seller, business address, unique facility identifier, any
license numbers issued by Health Canada or a provincial pharmacy
regulatory body, and the name, email address, and phone number of a
contact person.
(4) Identification and description of the drug(s) covered by the
Pre-Import Request, including the following information:
(i) Established and trade name of the HPFB-approved drug(s), as
applicable, DIN, and complete product description including strength,
description of dosage form, and route of administration.
(ii) Active pharmaceutical ingredient (API) information, including:
(A) Name of API;
(B) Manufacturer of API and its unique facility identifier; and
(C) Amount of API and unit measure in each eligible prescription
drug;
(iii) Established name and trade name, as applicable, of FDA-
approved counterpart drug(s) and NDA or ANDA number.
[[Page 70831]]
(iv) Manufacturer of the eligible prescription drug with the
business address and unique facility identifier.
(v) Copies of the invoice and any other documents related to the
manufacturer's sale of the drugs to the Foreign Seller provided by the
manufacturer to the Importer, and copies of the same documents provided
by the Foreign Seller to the Importer.
(vi) Quantity, listed separately by dosage form, strength, batch
and lot or control number assigned by the manufacturer to each eligible
prescription drug intended to be imported under this Pre-Import Request
compared to the quantity of each batch and lot or control number
originally received by the Foreign Seller from the manufacturer, and
the date of such receipt.
(vii) Expiration date of each HFPB-approved drug, listed by lot or
control number.
(viii) Expiration date to be assigned to the eligible prescription
drug when relabeled by the Importer with a complete description of how
that expiration date was calculated to comply with the FDA-approved NDA
or ANDA.
(ix) NDC proposed for assignment by the Importer.
(x) FDA product code for the eligible prescription drug(s) to be
imported.
(xi) A Statutory Testing plan that includes:
(A) A description of how the samples will be selected from a
shipment for the Statutory Testing;
(B) The name and location of the qualifying laboratory in the
United States that will conduct the Statutory Testing; and
(C) A description of the testing method(s) that will be used to
conduct the Statutory Testing, if the Importer will be conducting the
Statutory Testing, or the description of the testing methods must be
submitted by the manufacturer to FDA directly under Sec. 251.17 if the
manufacturer will be conducting the Statutory Testing.
(xii) Attestation from the manufacturer that must establish that
the drug proposed for import, but for the fact that it bears the HPFB-
approved labeling, meets the conditions in the FDA-approved NDA or
ANDA, including any process-related or other requirements for which
compliance cannot be established through laboratory testing.
Accordingly, the attestation must include:
(A) Confirmation that the HPFB-approved drug has the active
ingredient(s), active ingredient source(s) (including manufacturing
facility or facilities), inactive ingredient(s), dosage form,
strength(s), and route(s) of administration, described in the FDA-
approved drug's NDA or ANDA.
(B) Confirmation that the HPFB-approved drug conforms to the
specifications in the FDA-approved drug's NDA or ANDA regarding the
quality of the drug substance(s), drug product, intermediates, raw
materials, reagents, components, in-process materials, container
closure systems, and other materials used in the production of the
drug.
(C) Confirmation that the HPFB-approved drug was manufactured in
accordance with the specifications described in the FDA-approved drug's
NDA or ANDA, including with regard to the facilities and manufacturing
lines that are used, and in compliance with current good manufacturing
practice requirements set forth in section 501(a)(2)(B) of the Federal
Food, Drug, and Cosmetic Act and parts 4 (if a combination product),
210, and 211 of this chapter.
(D) Original date of manufacture or the date used to calculate the
labeled expiration date based on the HPFB-approved or scientifically
validated expiration period, the expiration period set forth in the
FDA-approved drug's NDA or ANDA, and any other information needed to
label the drug with an expiration date that meets the specifications of
the FDA-approved drug's NDA or ANDA.
(E) Information needed to confirm that the labeling of the
prescription drug complies with labeling requirements of the Federal
Food, Drug, and Cosmetic Act.
(xiii) Information related to the Importation, including:
(A) Location of the eligible prescription drugs in Canada and
anticipated date of shipment (date eligible prescription drug(s) will
leave their location in Canada);
(B) Name, address, email, and telephone number of the Foreign
Shipper;
(C) Anticipated date of export from Canada and Canadian port of
exportation;
(D) Anticipated date and approximate time of arrival at a port
authorized by FDA to import eligible prescription drugs under section
804 of the Federal Food, Drug, and Cosmetic Act;
(E) The name, address, unique facility identifier or FDA
establishment identification number, and telephone number of the
warehouse, location within a specific foreign trade zone, or other
secure distribution facility controlled by or under contract with the
Importer where the eligible prescription drug(s) will be stored pending
testing, relabeling, and FDA determination of admissibility;
(F) Information regarding the facility where the relabeling and any
limited repackaging activities will occur for all eligible prescription
drugs covered by this Pre-Import Request, including:
(1) The facility's unique facility identifier;
(2) The facility's name, address, and FDA establishment identifier
number;
(3) The anticipated date the relabeling and any limited repackaging
will be completed; and
(4) Information about where the relabeled drug will be stored
pending distribution, including the FDA establishment identification
number of the storage facility, if available.
(d) If the manufacturer conducts the Statutory Testing, the
manufacturer must provide the attestation to FDA. If the Importer
conducts the Statutory Testing, the manufacturer must provide the
attestation to the Importer.
(e)(1) The Importer must provide the executed batch record,
including the executed certificate of analysis for at least one
recently manufactured, commercial-scale batch of the HPFB-approved
drug; and at least one recently manufactured, commercial-scale batch of
the FDA-approved drug that was produced for and released for
distribution to the U.S. market under an NDA or ANDA.
(2) The manufacturer must provide these analyses for each
manufacturing line that the manufacturer used to produce either or both
of the drugs.
Sec. 251.6 Limitations on authorized importation programs.
(a) Unless an extension is granted under this section,
authorization for a SIP automatically terminates after 2 years, or a
shorter period of time if a shorter period of time is specified in the
authorization for the SIP.
(b) The 2-year authorization period for a SIP begins when the
Importer files an electronic import entry for consumption for its first
shipment of drugs under the SIP.
(c) Notwithstanding paragraph (a) of this section, authorization
for a SIP terminates if the Importer does not file an electronic import
entry for consumption for a shipment of eligible prescription drugs
under the SIP within 1 year of the date that the SIP was authorized.
(d) FDA will terminate authorization of a SIP upon request from the
SIP Sponsor that includes a notice of the SIP Sponsor's intent to
discontinue its activities.
[[Page 70832]]
Sec. 251.7 Suspension and revocation of authorized importation
programs.
(a) FDA may suspend a SIP under the circumstances set forth in
Sec. 251.18, or under other circumstances in FDA's discretion.
Importation of drugs under a SIP that has been suspended is prohibited.
(b) SIP Sponsors and other SIP participants must agree to submit to
audits of their books and records and inspections of their facilities
as a condition of participation in a SIP. If a SIP Sponsor,
manufacturer, Foreign Seller, Importer, qualifying laboratory, or other
participant in the supply chain delays, denies, or limits an
inspection, or refuses to permit entry or inspection of their facility
or their records, any drug that has been held by such entity will be
deemed to be adulterated and the SIP may be suspended, in whole or in
part, immediately.
(c) FDA may revoke authorization of a SIP, in whole or in part,
including with respect to one or more drugs in the SIP, at any time for
any reason if FDA determines, in its discretion, or on the
recommendation of another HHS component as directed by the Secretary,
that:
(1) The SIP Proposal contained an untrue statement of material
fact;
(2) The SIP Proposal omitted material information;
(3) The SIP no longer meets the requirements of section 804 of the
Federal Food, Drug, and Cosmetic Act, this part, or the SIP, including,
among other things, if the manufacturer, the Foreign Seller, the
Importer, or any other SIP entity is found to be not compliant with
section 501(a)(2)(A) or (B) of the FD&C Act;
(4) Continued implementation of the SIP is likely to pose
additional risk to the public's health and safety;
(5) Confidential manufacturer information was disclosed in
violation of Sec. 251.16;
(6) Continued implementation of the SIP will not result in a
significant reduction in the cost of the drugs covered by the SIP to
the American consumer;
(7) Continued monitoring of the SIP imposes too much of a drain on
FDA or HHS resources or is inconsistent with FDA or HHS prioritization
of resources; or
(8) Continued implementation of the SIP is otherwise inappropriate.
Sec. 251.8 Modification or extension of authorized importation
programs.
(a) A supplement to modify or extend an authorized SIP must be
submitted via the ESG for FDA's consideration.
(b) A SIP Sponsor can propose to add additional Foreign Sellers or
additional Importers to an authorized SIP once it has consistently
imported eligible prescription drugs in accordance with section 804 of
the Federal Food, Drug, and Cosmetic Act and this part.
(c) If FDA authorizes changes to the SIP, the Importer must submit
a new Pre-Import Request in accordance with Sec. 251.5.
(d) A SIP Sponsor must not make any changes or permit any changes
to be made to a SIP without first securing FDA's authorization. If FDA
authorizes changes to a SIP under this section, such authorization does
not change the authorization of the original SIP.
(e) A SIP Sponsor may request that FDA extend the authorization
period of an authorized SIP. Such a request must be submitted via the
ESG for FDA's consideration at least 3 months before the SIP's
authorization period will expire. To be eligible for an extension of
the authorized SIP, a SIP must be up to date on all of the information
and records-related requirements of section 804 of the Federal Food,
Drug, and Cosmetic Act and this part. FDA may, in its sole discretion,
extend the authorization period for up to 2 years at a time.
Subpart C--Certain Requirements for Section 804 Importation
Programs
Sec. 251.9 Registration of Foreign Sellers.
(a) Foreign Sellers must be registered with FDA before FDA will
authorize a SIP Proposal.
(b) To register, a Foreign Seller must provide the following
information:
(1) Name of the owner or operator; if a partnership, the name of
each partner; if a corporation, the name of each corporate officer and
director, and the place of incorporation;
(2) All names of the Foreign Seller, including names under which
the Foreign Seller conducts business or names by which the Foreign
Seller is known;
(3) Physical address, telephone number(s), and email address of the
Foreign Seller;
(4) Registration number, if previously assigned by FDA;
(5) A copy of the Foreign Seller's Health-Canada Drug Establishment
License;
(6) All types of operations performed by the Foreign Seller;
(7) Name, mailing address, telephone number, and email address of
the official contact for the establishment; and
(8) Name, mailing address, telephone number, and email address of:
(i) The U.S. agent;
(ii) The Importer to which the Foreign Seller plans to sell
eligible prescription drugs; and
(iii) Each SIP Sponsor with which the Foreign Seller works.
Sec. 251.10 Reviewing and updating registration information for
Foreign Sellers.
(a) Expedited updates. A Foreign Seller must update its
registration information no later than 30 calendar days after:
(1) Closing or being sold;
(2) Changing their name or physical address; or
(3) Changing the name, mailing address, telephone number, or email
address of the official contact or the U.S. agent. A Foreign Seller,
official contact, or U.S. agent may notify FDA about a change of
information for the designated official contact or U.S. agent, but only
a Foreign Seller is permitted to designate a new official contact or
U.S. agent.
(b) Annual review and update of registration information. A Foreign
Seller must review and update all registration information required
under Sec. 251.9.
(1) The first review and update must occur during the period
beginning on October 1 and ending December 31 of the year of initial
registration, if the initial registration occurs prior to October 1.
Subsequent reviews and updates must occur annually, during the period
beginning on October 1 and ending December 31 of each calendar year.
(2) The updates must reflect new changes not previously required to
be reported along with a summary of the registration updates that were
provided to FDA as required during the calendar year.
(3) If no changes have occurred since the last registration, a
Foreign Seller must certify that no changes have occurred.
Sec. 251.11 Official contact and U.S. agent for Foreign Sellers.
(a) Official contact. A Foreign Seller subject to the registration
requirements of this part must designate an official contact. The
official contact is responsible for:
(1) Ensuring the accuracy of registration information as required
by Sec. 251.9; and
(2) Reviewing, disseminating, routing, and responding to all
communications from FDA, including emergency communications.
(b) U.S. agent. (1) A Foreign Seller must designate a single U.S.
agent. The U.S. agent must reside or maintain a place of business in
the United States
[[Page 70833]]
and may not be a mailbox, answering machine or service, or other place
where a person acting as the U.S. agent is not physically present. The
U.S. agent is responsible for:
(i) Reviewing, disseminating, routing, and responding to all
communications from FDA, including emergency communications;
(ii) Responding to questions concerning those drugs that are
imported or offered for import to the United States; and
(iii) Assisting FDA in scheduling inspections.
(2) FDA may provide certain information and/or documents to the
U.S. agent. The provision of information and/or documents by FDA to the
U.S. agent is equivalent to providing the same information and/or
documents to the Foreign Seller.
Sec. 251.12 Importer responsibilities.
(a) The Importer is responsible for:
(1) In accordance with the procedures set forth in Sec. 207.33 of
this chapter, proposing an NDC for assignment for each eligible
prescription drug imported pursuant to this part;
(2) Examining the Canadian labeling of a sample of each shipment of
eligible prescription drugs to verify that the labeling is consistent
with that of an HPFB-approved drug, and attesting that such examination
has been conducted through reports to FDA required under this part;
(3) Screening eligible prescription drugs for evidence that they
are adulterated, counterfeit, damaged, tampered with, or expired;
(4) Ensuring the eligible prescription drug is relabeled with the
required U.S. labeling, including the container and carton labels;
prescribing information; and patient labeling, such as medication
guides, instruction for use documents, and patient package inserts, in
accordance with Sec. Sec. 251.13 and 251.14(d);
(5) Arranging for an entry to be submitted in accordance with Sec.
251.17;
(6) Collecting and submitting the information and documentation to
FDA about the imported drug(s) pursuant to section 804(d) of the
Federal Food, Drug, and Cosmetic Act, in addition to information about
the Foreign Seller, as set forth in Sec. 251.19; and
(7) Submitting the adverse event, medication error, field alert,
and other reports, and complying with drug recalls, in accordance with
Sec. 251.18.
(b) If the Importer is also relabeling the eligible prescription
drug, the Importer must also:
(1) Register with FDA as a repackager or relabeler under section
510(b) of the Federal Food, Drug, and Cosmetic Act, in accordance with
Sec. 207.25 of this chapter;
(2) Obtain a labeler code from FDA and propose an NDC for each
eligible prescription drug pursuant to Sec. 207.33 of this chapter;
and
(3) List each eligible prescription drug pursuant to Sec. 207.53
of this chapter.
(c) If the Importer is not itself relabeling the eligible
prescription drug, the Importer must:
(1) Obtain its own labeler code from FDA under Sec. 207.33(c) of
this chapter;
(2) Ensure that the eligible prescription drug incorporates the NDC
the Importer proposed for assignment, which must include the Importer's
labeler code; and
(3) Ensure that the entity relabeling an eligible prescription drug
on its behalf proposes an NDC pursuant to Sec. 207.33 of this chapter
and lists each eligible prescription drug pursuant to Sec. 207.53 of
this chapter.
Sec. 251.13 Labeling of eligible prescription drugs.
(a) Upon the request of a SIP Sponsor or Importer, the manufacturer
of a prescription drug must provide an Importer written authorization
for the Importer to use, at no cost, the FDA-approved labeling for the
prescription drug. If the manufacturer fails to do so within a timely
fashion, FDA may deem this authorization to have been given.
(b) In addition to the exemption provided in subpart D of part 201
of this chapter, an eligible prescription drug imported for purposes of
this part is exempt from section 502(f)(1) of the Federal Food, Drug,
and Cosmetic Act if all the following conditions are met:
(1) The Importer or the manufacturer certifies that the drug meets
all labeling requirements under the Federal Food, Drug, and Cosmetic
Act, including the requirements of this part. The Importer of an
eligible prescription drug must either:
(i) Propose an NDC for the drug following the procedures in Sec.
207.33 of this chapter and list the drug following the procedures in
Sec. 207.53 of this chapter, or
(ii) If the Importer is a private label distributor, take
responsibility to ensure that the entity performing relabeling on its
behalf proposes an NDC and lists each eligible prescription drug in
accordance with the applicable requirements of part 207 of this
chapter.
(2) The drug must be:
(i) In the possession of a person (or his agents or employees),
including Foreign Sellers and Importers, regularly and lawfully engaged
in the manufacture, transportation, storage, or wholesale distribution
of prescription drugs;
(ii) In the possession of a retail, hospital, or clinic pharmacy,
or a public health agency, regularly and lawfully engaged in dispensing
prescription drugs; or
(iii) In the possession of a practitioner licensed by law to
administer or prescribe such drugs.
(3) The drug is to be dispensed in accordance with section 503(b)
of the Federal Food, Drug, and Cosmetic Act.
(4) The label of the drug must be the same as the label authorized
by the approved NDA or ANDA of the FDA-approved drug, except that the
label must bear conspicuously:
(i) The Importer's NDC for the eligible prescription drug, and such
NDC must replace any other NDC otherwise appearing on the label of the
FDA-approved drug; and
(ii) The name and place of business of the manufacturer and the
Importer.
(5) The container label must include at a minimum the product's
proprietary and established name (if any); product strength; lot
number; and the name of the manufacturer and the Importer.
(6) Labeling on or within the package from which the eligible
prescription drug is to be dispensed is the same as the labeling
authorized by the NDA or the ANDA of the FDA-approved drug, except
that:
(i) The labeling must bear the statement: ``This drug was imported
from Canada under the [Name of State or Other Governmental Entity and
of Its Co-Sponsors, If Any] Section 804 Importation Program to reduce
its cost to the American consumer.'' If the SIP maintains a website,
the statement could also include the website address. This statement
must be included after the PATIENT COUNSELING INFORMATION section for
products subject to Sec. Sec. 201.56(d) and 201.57 of this chapter, or
after the HOW SUPPLIED section (or after the last section of labeling)
for products subject to Sec. Sec. 201.56(e) and 201.80 of this
chapter. The statement also must be included on the immediate container
and outside package;
(ii) For products subject to Sec. Sec. 201.56(d) and
201.57(c)(17)(iii) of this chapter, the NDC(s) assigned to the eligible
prescription drug in accordance with the procedures in Sec. 207.33 of
this chapter must be included in the HOW SUPPLIED/STORAGE AND HANDLING
section in place of the NDC(s) assigned to the FDA-approved U.S.
versions of the drug; and
(iii) For products subject to Sec. Sec. 201.56(e) and 201.80(k)(3)
of this chapter, the NDC(s) assigned to the
[[Page 70834]]
eligible prescription drug in accordance with the procedures in Sec.
207.33 of this chapter must be included in the HOW SUPPLIED section in
place of the NDC(s) assigned to the FDA-approved U.S. versions of the
drug.
(c) The Importer is responsible for relabeling the drug, or
arranging for it to be relabeled, to meet the requirements of this
part. The relabeling and associated limited repackaging activities must
meet applicable requirements, including applicable current good
manufacturing practice requirements under parts 210 and 211 of this
chapter. Except for repackaging that is necessary to perform the
relabeling described in this part, further repackaging of drugs
imported pursuant to a SIP is prohibited.
Sec. 251.14 Supply chain security requirements for eligible
prescription drugs.
(a) SIP Sponsors. A sponsor of an authorized SIP must ensure that:
(1) Each drug imported under the SIP is HPFB-approved and labeled
for sale in Canada from the point of manufacture until it reaches the
Foreign Seller;
(2) For each drug that is imported under the SIP and that is
manufactured outside Canada, the drug was authorized for import into
Canada by the manufacturer and labeled by the manufacturer for the
Canadian market before importation under the SIP (i.e. the drug was not
transshipped through Canada for sale in another country);
(3) For each drug imported under the SIP, the drug was sold by the
manufacturer directly to a Foreign Seller;
(4) For each drug imported under the SIP, the Foreign Seller ships
the drug directly to the Importer in the United States; and
(5) The Importer(s) and Foreign Seller(s) identified in the SIP
meet the applicable requirements of this part and in section 582(c) and
(d) of the Federal Food, Drug, and Cosmetic Act.
(b) Manufacturer. The manufacturer must provide to the Importer a
copy of any transaction documents that were provided from the
manufacturer to the Foreign Seller.
(c) Foreign Seller.
(1) A Foreign Seller must have systems in place to:
(i) Determine whether a drug in its possession or control that it
intends to sell to the Importer under a SIP is a suspect foreign
product. Upon making a determination that a drug in its possession or
control is a suspect foreign product, or upon receiving a request for
verification from FDA that the Foreign Seller has determined that a
product within its possession or control is a suspect foreign product,
a Foreign Seller must:
(A) Quarantine such product within its possession or control until
such product is cleared or dispositioned;
(B) Promptly conduct an investigation, in coordination with the
Importer and the manufacturer, as applicable, to determine whether the
product is an illegitimate foreign product, and verify the product at
the package level, including the SSI; and
(C) If the Foreign Seller makes the determination that a suspect
foreign product is not an illegitimate foreign product, promptly notify
FDA of such determination (such product may be further distributed).
(ii) Determine whether a drug in its possession or control that it
intends to sell to the Importer under a SIP is an illegitimate foreign
product. Upon making a determination that a drug in its possession or
control is an illegitimate foreign product, the Foreign Seller must:
(A) Quarantine such product within the possession or control of the
Foreign Seller from product intended for distribution until such
product is dispositioned;
(B) Disposition the illegitimate foreign product within the
possession or control of the Foreign Seller;
(C) Take reasonable and appropriate steps to assist a manufacturer
or Importer to disposition an illegitimate product not in the
possession or control of the Foreign Seller; and
(D) Retain a sample of the product for further physical examination
or laboratory analysis of the product by the manufacturer or the
Secretary (or other appropriate Federal or State official) upon request
by the Secretary (or other appropriate Federal or State official), as
necessary and appropriate.
(2)(i) Upon determining that a product in the possession or control
of the Foreign Seller is an illegitimate foreign product, the Foreign
Seller must notify FDA and the Importer that the Foreign Seller
received such illegitimate product not later than 24 hours after making
such determination.
(ii) Upon the receipt of a notification from FDA, the Importer, or
other authorized repackager, wholesale distributor, or dispenser that a
determination has been made that a product that had been sold by the
Foreign Seller is an illegitimate foreign product, a Foreign Seller
must identify all illegitimate foreign product subject to such
notification that is in the possession or control of the Foreign
Seller, including any product that is subsequently received, and
perform the activities to investigate the product described in
paragraph (c)(1) of this section.
(iii) Upon making a determination, in consultation with FDA, that a
notification is no longer necessary, a Foreign Seller must promptly
notify the Importer and person who sent the notification that the
notification is terminated.
(iv) A Foreign Seller must keep records of the disposition of an
illegitimate foreign product for not less than 6 years after the
conclusion of the disposition.
(3) Upon request by FDA, or other appropriate Federal or State
official, in the event of a recall or for purposes of investigating a
suspect foreign product or an illegitimate foreign product, a Foreign
Seller must promptly provide the official with information about its
transactions with the manufacturer and the Importer.
(4) A Foreign Seller, upon receiving a shipment of eligible
prescription drugs from the manufacturer, must:
(i) Separate the portion of drugs intended for sale to the Importer
located in the United States, and store such portion separately from
that portion of product intended for sale in the Canadian market;
(ii) Assign a SSI to each package and homogenous case intended for
sale to the Importer in the United States, unless each such package and
homogenous case contains a manufacturer-affixed or imprinted product
identifier, as such term is defined in section 581(14) of the Federal
Food, Drug, and Cosmetic Act, at the time of receipt by the Foreign
Seller; and
(iii) Affix or imprint the SSI on each package and homogenous case
intended for sale to the Importer in the United States. Such SSI must
be located on blank space on the package or homogenous case and must
not obscure any labeling for the Canadian market, including the DIN.
(5) Upon receiving a request for verification from the Importer or
other authorized repackager, wholesale distributor, or dispenser that
is in possession or control of a product such person believes to be
distributed by such Foreign Seller, a Foreign Seller must, not later
than 24 hours after receiving the request for verification or in other
such reasonable time as determined by the Secretary, based on the
circumstances of the request, notify the person making the request
whether the product identifier, including the standardized numerical
identifier, that is the subject of the request corresponds to the SSI
affixed or imprinted by the
[[Page 70835]]
Foreign Seller. If a Foreign Seller responding to a request for
verification identifies a product identifier that does not correspond
to that SSI affixed or imprinted by the Foreign Seller, the Foreign
Seller must treat such product as suspect foreign product and conduct
an investigation as described in paragraph (c)(1) of this section. If
the Foreign Seller has reason to believe the product is an illegitimate
foreign product, the Foreign Seller must advise the person making the
request of such belief at the time such Foreign Seller responds to the
request for verification.
(6) For each transaction between the Foreign Seller and the
Importer for an eligible prescription drug, the Foreign Seller must
provide:
(i) A statement that the Foreign Seller received the product from
an FDA-registered manufacturer;
(ii) The proprietary or established name of the product;
(iii) The strength and dosage form of the product;
(iv) The container size;
(v) The number of containers;
(vi) The lot number of the product;
(vii) The date of the transaction;
(viii) The date of the shipment, if more than 24 hours after the
date of the transaction;
(ix) The business name and address of the person associated with
the Foreign Seller from whom ownership is being transferred;
(x) The business name and address of the person associated with the
Importer to whom ownership is being transferred;
(xi) The SSI for each package and homogenous case of product; and
(xii) The Canadian DIN for each product transferred.
(7) Upon a request by FDA, or other appropriate Federal or State
official, in the event of a recall or for purposes of investigating a
suspect foreign product or an illegitimate foreign product, the Foreign
Seller must promptly provide the official with information about its
transactions with the manufacturer and the Importer.
(d) Importers. (1) An Importer of an eligible prescription drug
must purchase the drug directly from a Foreign Seller in Canada.
(2) Upon receipt of a product from the Foreign Seller, an Importer
must facilitate the affixation or imprinting of a product identifier,
as defined in section 581(14) of the Federal Food, Drug, and Cosmetic
Act. The Importer must ensure that such affixation or imprinting occurs
at the same time the product is relabeled with the required U.S.-
approved labeling for the drug product and, except for repackaging
necessary to perform the relabeling described in this part, cannot
otherwise relabel or repackage the product. The Importer may contract
with an entity registered with FDA under part 207 of this chapter to
accomplish such relabeling, provided that the entity does not otherwise
relabel or repackage the product, except for repackaging that is
necessary to perform the relabeling described in this part.
(3) The repackager or relabeler that affixes or imprints the
product identifier to each package and homogenous case of an eligible
prescription drug in accordance with section 582 of the Federal Food,
Drug, and Cosmetic Act--
(i) May affix or imprint a product identifier only on a package of
an eligible prescription drug that has a serial number that was
assigned and affixed by the Foreign Seller;
(ii) Must maintain the product identifier information for such drug
for not less than 6 years; and
(iii) Must maintain records for not less than 6 years that
associate the product identifier the repackager affixes or imprints
with the serial number assigned by the Foreign Seller and the Canadian
DIN.
(4) An Importer must retain records, for no less than 6 years, that
allow the Importer to associate the product identifier affixed or
imprinted on each package or homogenous case of product it received
from the Foreign Seller, with the SSI that had been assigned by the
Foreign Seller, and the Canadian DIN that was on the package when the
Foreign Seller received the product from the original manufacturer. An
Importer must also have processes in place to, upon receipt of a drug
and records from a Foreign Seller, compare such information with
information the Importer received from the manufacturer, including
relevant documentation about the transaction that the manufacturer
provided to the Foreign Seller upon its transfer of ownership of the
product for the Canadian market.
(5) An Importer must comply with all applicable requirements of
section 582 of the Federal Food, Drug, and Cosmetic Act, including
requirements that apply to subsequent transactions with trading
partners, unless a waiver, exception, or exemption applies.
(6) For transactions of eligible prescription drugs between
Importers and Foreign Sellers, an Importer is exempt from the following
supply chain security requirements that are otherwise applicable:
(i) An Importer is exempt from the prohibition on receiving a
product for which the previous owner did not provide the transaction
history, transaction information, and transaction statement, under
section 582(c)(1)(A) or (d)(1)(A) of the Federal Food, Drug, and
Cosmetic Act as applicable; provided that the Importer receives from
the Foreign Seller the information required under paragraph (c) of this
section.
(ii) An Importer is exempt from the prohibition on receiving a
product that is not encoded with a product identifier, under section
582(c)(2) or (d)(2) of the Federal Food, Drug, and Cosmetic Act as
applicable, provided that the product the Importer received from the
Foreign Seller has an SSI.
(iii) An Importer is exempt from the prohibition on conducting a
transaction with an entity that is not an ``authorized trading
partner,'' under section 582(c)(3) or (d)(3) of the Federal Food, Drug,
and Cosmetic Act as applicable.
(iv) An Importer is exempt from the requirement to verify that a
product in the Importer's possession or control contains a
``standardized numerical identifier'' at the package level, under
section 582(c)(4)(A)(i)(II) or (d)(4)(A)(ii)(II) of the Federal Food,
Drug, and Cosmetic Act as applicable, provided that the Importer
verifies that each package and homogenous case of the product includes
the SSI affixed or imprinted by the Foreign Seller.
Sec. 251.15 Qualifying laboratory requirements.
(a) To be considered a qualifying laboratory for purposes of
section 804 of the Federal Food, Drug, and Cosmetic Act and this part,
a laboratory must have ISO 17025 accreditation.
(b) To be considered a qualifying laboratory for purposes of
section 804 of the Federal Food, Drug, and Cosmetic Act and this part,
a laboratory must have an FDA inspection history and it must have
satisfactorily addressed any objectionable conditions or practices
identified during its most recent FDA inspection, if applicable.
(c) To be considered a qualifying laboratory for purposes of
section 804 of the Federal Food, Drug, and Cosmetic Act and this part,
a laboratory must comply with the applicable elements of current good
manufacturing practice requirements, including but not limited to
provisions regarding laboratory controls in Sec. 211.160 of this
chapter and laboratory records in Sec. 211.194 of this chapter.
Sec. 251.16 Laboratory testing requirements.
(a) The manufacturer or the Importer must arrange for eligible
prescription drugs to be tested by a qualifying laboratory.
(b) If the tests are conducted by the Importer, the manufacturer of
the
[[Page 70836]]
prescription drug must supply to the Importer all information needed to
authenticate the prescription drug being tested, including any
necessary testing methodologies and protocols that the manufacturer has
developed. The manufacturer must also provide the Importer with
formulation information about the HPFB-approved drug and the FDA-
approved drug to facilitate authentication.
(c) Testing done on a statistically valid sample of the batch or
shipment, as applicable, must be sufficiently thorough to establish, in
conjunction with data and information from the manufacturer, that the
batch or shipment is eligible for importation under a SIP. The size of
the sample must be large enough to enable a statistically valid
statement to be made regarding the authenticity and stability of the
quantity of the batch in the shipment or the entire shipment, as
applicable.
(d) The statistically valid sample of the HPFB-approved drug must
be subjected to testing to confirm that the HPFB-approved drug meets
the FDA-approved drug's specifications, including the analytical
procedures and methods and the acceptance criteria. In addition, to
testing for degradation, a stability-indicating assay provided by the
manufacturer must be conducted on the sample of the drug that is
proposed for import.
(e) If the manufacturer performs the testing required under section
804(e)(1) of the Federal Food, Drug, and Cosmetic Act at a qualifying
laboratory, the testing results, a complete set of laboratory records,
a detailed description of the selection method for the samples, the
testing methods used, complete data derived from all tests necessary to
ensure that the eligible prescription drug meets the specifications of
the FDA-approved drug that are established in the NDA or ANDA, a
Certificate of Analysis, and any other documentation demonstrating that
the testing meets the requirements under section 804(e)(1) of the
Federal Food, Drug, and Cosmetic Act must be submitted in electronic
form directly to FDA via the ESG or to an alternative transmission
point identified by FDA.
(f) Regardless of whether testing under this section is performed
by the manufacturer or Importer, the sample of a batch or shipment of
drugs must be randomly selected for testing or, in the alternative, the
sample must be selected to be representative of the quantity of the
batch in a shipment or of a shipment, as applicable.
(g) Information supplied under this part must be kept in strict
confidence by the recipient and only for the purpose of testing or
otherwise complying with this part.
(h) To ensure that trade secret and commercial or financial
information is protected:
(1) The information that the manufacturer provides must not be
disseminated except to the qualifying laboratory and to FDA; and
(2) The SIP Sponsor must explain how it will ensure that the
information is not disseminated beyond the qualifying laboratory.
(i) FDA may transmit information that the manufacturer is required
to provide to an Importer under this section on the manufacturer's
behalf if the manufacturer has not transmitted such information to the
Importer in a timely fashion and if such information is available to
FDA in the NDA or ANDA.
Sec. 251.17 Importation requirements.
(a) Importers must ensure that each shipment of eligible
prescription drugs imported or offered for import pursuant to this part
is accompanied by an import entry for consumption filed electronically
as a formal entry in ACE, or another CBP-authorized electronic data
interchange system, and designated in such a system as a drug imported
pursuant to this part.
(b) The Importer may make entry for consumption and arrival of
shipments containing eligible prescription drugs only at the CBP port
of entry authorized by FDA to import eligible prescription drugs under
section 804 of the Federal Food, Drug, and Cosmetic Act. The Importer
must keep the product at a designated secured warehouse, and under
appropriate environmental conditions to maintain the integrity of the
products, until FDA issues an admissibility decision. The secured
warehouse must be within 30 miles of the authorized Port of Entry for
examination.
(c) If the entry for consumption is filed in ACE before the testing
and relabeling of the eligible prescription drug, the Importer must
submit an application to bring the drug into compliance and must
relabel and test the drug in accordance with the plan approved by FDA
pursuant to Sec. Sec. 1.95 and 1.96 of this chapter.
(d) Upon arrival in the United States of an initial shipment that
contains a batch of an eligible prescription drug identified in a Pre-
Import Request that has been granted by FDA, the Importer must select a
statistically valid sample of that batch to send to a qualifying
laboratory for Statutory Testing, unless the manufacturer conducts the
Statutory Testing at a qualifying laboratory.
(1) In the case of any subsequent shipment composed entirely of a
batch of an eligible prescription drug that has already been tested in
accordance with this part, the Importer must select a statistically
valid sample of the shipment to send to a qualifying laboratory for
Statutory Testing.
(2) The Importer must send three sets of the samples sent to the
qualifying laboratory in accordance with Sec. 251.16 to the FDA field
lab identified by FDA when the Agency granted the Pre-Import Request.
(3) The Importer must submit to FDA a complete set of laboratory
records, a detailed description of the selection method for the sample
of the eligible prescription drug sent to the qualifying laboratory,
the testing methods used, complete data derived from all tests
necessary to ensure that the eligible prescription drug meets the
specifications of the FDA-approved drug that are established in the NDA
or ANDA, a complete Certificate of Analysis, and all relevant
documentation demonstrating that the testing meets the requirements
under section 804(e)(1) of the Federal Food, Drug, and Cosmetic Act, as
well as any additional information FDA deems necessary to evaluate
whether the drug meets manufacturing, quality, and safety standards.
(e) If the manufacturer conducts the Statutory Testing, upon
arrival in the United States of an initial shipment that contains a
batch of an eligible prescription drug identified in a Pre-Import
Request that has been granted by FDA, the manufacturer must select a
statistically valid sample of that batch to send to a qualifying
laboratory for the Statutory Testing.
(1) In the case of any subsequent shipment composed entirely of a
batch or batches of an eligible prescription drug that has already been
tested in accordance with this part, the manufacturer must select a
statistically valid sample of that shipment to send to a qualifying
laboratory for that Statutory Testing.
(2) The manufacturer must send three sets of the samples the
manufacturer sent to the qualifying laboratory in accordance with Sec.
251.16 to the FDA field lab identified by FDA when the Agency granted
the Pre-Import Request.
(3) The manufacturer must submit to FDA, directly in electronic
form to the ESG or to an alternative transmission point identified by
FDA, a complete set of laboratory records, a detailed description of
the selection method for the sample of the eligible prescription drug
sent to the qualifying laboratory, the testing methods used, complete
data
[[Page 70837]]
derived from all tests necessary to ensure that the eligible
prescription drug meets the conditions in the FDA-approved drug's NDA
or ANDA, a complete Certificate of Analysis, and all relevant
documentation demonstrating that the testing meets the requirements
under section 804(e)(1) of the Federal Food, Drug, and Cosmetic Act, as
well as any additional information FDA deems necessary to evaluate
whether the drug meets manufacturing, quality, and safety standards.
(f) After FDA has reviewed the testing results provided by the
Importer or manufacturer and determined that they are acceptable, FDA
will notify the Importer and then the Importer must cause the eligible
prescription drug to be relabeled with the required U.S. labeling.
(g) After the eligible prescription drug has been shown by testing
and relabeling to meet the requirements of section 804 of the Federal
Food, Drug, and Cosmetic Act and this part, the Importer or the
manufacturer must provide the written certification described in
section 804(d)(1)(K) of the Federal Food, Drug, and Cosmetic Act to
FDA.
Sec. 251.18 Post-importation requirements.
(a) Stopping importation. If at any point a SIP Sponsor determines
that a drug, manufacturer, Foreign Seller, Importer, qualifying
laboratory, or other participant in or element of the supply chain in
the authorized SIP does not in fact meet all applicable requirements of
the Federal Food, Drug, and Cosmetic Act, FDA regulations, and the
authorized SIP, the SIP Sponsor immediately must stop importation of
all drugs under the SIP, notify FDA, and demonstrate to FDA that
importation has in fact been stopped.
(b) Field alert reports. Importers must submit NDA and ANDA field
alert reports, as described in Sec. Sec. 314.81(b)(1) and 314.98 of
this chapter, to the manufacturer and to FDA.
(c) Additional reporting requirements for combination products. For
combination products containing a device constituent part, Importers
must submit the reports to the manufacturer and to FDA described in
Sec. 4.102(c)(1) of this chapter and maintain the records described in
Sec. Sec. 4.102(c)(1) and 4.105(b) of this chapter.
(d) Adverse event and medication error reports. (1) Scope. An
Importer must establish and maintain records and submit reports to FDA
and the manufacturer of all adverse events and medication errors
associated with the use of their drug products imported under this
part.
(2) Review of safety information. The Importer must promptly review
all domestic safety information for the eligible prescription drugs
obtained or otherwise received by the Importer.
(3) Expedited ICSRs. The Importer must submit expedited ICSRs for
each domestic adverse event or medication error to FDA and the
manufacturer as soon as possible but no later than 15 calendar days
from the date when the Importer has both met the reporting criteria
described in this paragraph (d) and acquired a minimum data set for
that adverse event or medication error.
(i) Serious, unexpected adverse events. The Importer must submit
expedited ICSRs for domestic adverse events reported to the Importer
spontaneously (such as reports initiated by a patient, consumer, or
healthcare professional) that are both serious and unexpected, whether
or not the Importer believes the events are related to the product.
(ii) Other adverse event reports to be expedited upon notification
by FDA. Upon notification by FDA, the Importer must submit as expedited
ICSRs any adverse event reports that do not qualify for expedited
reporting under paragraph (d)(3)(i) of this section. The notice will
specify the adverse events to be reported and the reason for requiring
the expedited reports.
(iii) ICSRs for medication errors. The Importer must submit an
expedited ICSR for each domestic medication error. If the report also
involves one or more adverse events, the Importer must comply with all
adverse event reporting requirements in this section and submit one
ICSR describing both the medication error and the adverse event(s).
(4) Followup reports for expedited ICSRs. The Importer must
actively seek any missing data elements under paragraph (d)(7) of this
section or updated information for any previously submitted expedited
ICSR under paragraph (d)(3) of this section. The Importer must also
investigate any new information it obtains or otherwise receives about
previously submitted expedited ICSRs. The Importer must submit followup
reports for expedited ICSRs to FDA and the manufacturer, as soon as
possible, but no later than 15 calendar days after obtaining the new
information. The Importer must document and maintain records of their
efforts to obtain missing or incomplete information.
(5) Nonexpedited ICSRs. The Importer must submit an ICSR for each
domestic adverse event not reported under paragraph (d)(3)(i) of this
section (all serious, expected and nonserious adverse drug experiences)
to FDA and the manufacturer within 90 days from the date when the
Importer has both met the reporting criteria described in this
paragraph (d) and acquired a minimum data set for that adverse event.
(6) Completing and submitting safety reports. This paragraph (d)(6)
describes how to complete and submit expedited ICSRs required under
this section. Additionally, upon written notice, FDA may require the
Importer to submit any of this section's adverse event and medication
error safety reports at a different time period than identified in
other paragraphs.
(i) Electronic format for submissions. (A) ICSR and ICSR
attachments must be submitted in an electronic format that FDA can
process, review, and archive, as described in Sec. 314.80(g)(1) of
this chapter.
(B) The Importer may request, in writing, a temporary waiver of the
requirements in paragraph (d)(6)(i)(A) of this section, as described in
Sec. 314.80(g)(2) of this chapter. These waivers will be granted on a
limited basis for good cause shown.
(ii) Completing and submitting ICSRs.
(A) Single submission. Submit each ICSR only once.
(B) Labeling. Each ICSR must be accompanied by a copy of the
current U.S. labeling as an ICSR attachment unless it is already on
file at FDA as part of the SIP.
(C) Separate ICSR. The Importer must submit a separate ICSR for:
(1) Each patient who experiences an adverse event reportable under
paragraphs (d)(3)(i) or (ii), (d)(4), or (d)(5) of this section.
(2) Each medication error reportable under paragraph (d)(3)(iii) of
this section. For reports that include both a medication error and an
adverse event, the Importer need only submit one ICSR describing both
the medication error and the adverse event.
(D) Coding terms. The adverse event and medication error terms
described in the ICSR must be coded using standardized medical
terminology.
(E) Minimum data set. All ICSRs submitted under this section must
contain at least the minimum data set appropriate to the type of report
(adverse event or medication error). The Importer must actively seek
the minimum data set in a manner consistent with its written procedures
under paragraph (d)(9) of this section. The Importer must document and
maintain records of their efforts to obtain the minimum data set.
(F) ICSR elements. The Importer must complete all available
elements of an
[[Page 70838]]
ICSR as specified in paragraph (d)(7) of this section.
(1) The Importer must actively seek any information needed to
complete all applicable elements, consistent with their written
procedures under paragraph (d)(9) of this section.
(2) The Importer must document and maintain records of their
efforts to obtain the missing information.
(G) Supporting documentation. When submitting supporting
documentation for expedited ICSRs of adverse events, the Importer must:
(1) Submit for each ICSR for a domestic adverse event, if
available, a copy of the autopsy report if the patient died, or a copy
of the hospital discharge summary if the patient was hospitalized. The
Importer must submit each document as an ICSR attachment. The ICSR
attachment must be submitted either with the initial ICSR or no later
than 15 calendar days after obtaining the document.
(2) Include in the ICSR a list of available, relevant documents
(such as medical records, laboratory results, death certificates) that
are held in their drug product safety files. Upon written notice from
FDA, the Importer must submit a copy of these documents within 5
calendar days of the FDA notice.
(7) Information reported on ICSRs. ICSRs must include the following
information:
(i) Patient information, which includes:
(A) Patient identification code;
(B) Patient age at the time of adverse event or medication error,
or date of birth;
(C) Patient gender; and
(D) Patient weight.
(ii) Adverse event or medication error.
(A) Outcome attributed to adverse event or medication error;
(B) Date of adverse event or medication error;
(C) Date of ICSR submission;
(D) Description of adverse event or medication error (including a
concise medical narrative);
(E) Adverse drug event or medication error terms(s);
(F) Description of relevant tests, including dates and laboratory
data; and
(G) Other relevant patient history, including preexisting medical
conditions.
(iii) Suspect medical product(s), which includes:
(A) Name;
(B) Dose, frequency, and route of administration used;
(C) Therapy dates;
(D) Diagnosis for use (indication);
(E) Whether the product is a combination product;
(F) Whether adverse event abated after drug use stopped or dose
reduced;
(G) Whether adverse event reappeared after reintroduction of drug;
(H) Lot number;
(I) Expiration date;
(J) NDC; and
(K) Concomitant medical products and therapy dates.
(iv) Initial reporter information.
(A) Name, address, and telephone number;
(B) Whether the initial reporter is a healthcare professional; and
(C) Occupation, if a healthcare professional.
(v) Importer information, which includes:
(A) Importer name and contact office address;
(B) Importer telephone number;
(C) Date the report was received by the Importer;
(D) Whether the ICSR is an expedited report;
(E) Whether the ICSR is an initial report or followup report; and
(F) Unique case identification number, which must be the same in
the initial report and any subsequent followup report(s).
(8) Recordkeeping.
(i) For a period of 10 years from the initial receipt of
information, the Importer must maintain records of information relating
to adverse events and medication error safety reports under this
section, whether or not submitted to FDA.
(ii) These records must include raw data, correspondence, and any
other information relating to the evaluation and reporting of adverse
events and medication error safety information that is obtained by the
Importer.
(iii) Upon written notice by FDA, the Importer must submit any or
all of these records to FDA within 5 calendar days after receipt of the
notice. The Importer must permit any authorized FDA employee, at
reasonable times, to access, copy, and verify its established and
maintained records described in this section.
(9) Written procedures. The Importer must develop, maintain, and
follow written procedures needed to fulfill the requirements in this
section for the surveillance, receipt, evaluation, and reporting to FDA
and the manufacturer of adverse events and medication error safety
information, including procedures for employee training, and for
obtaining and processing safety information from the Foreign Seller.
(10) Patient privacy. The Importer must not include in reports
under this section the names and addresses of individual patients;
instead, the Importer must assign a unique code for identification of
the patient. The Importer must include the name of the reporter from
whom the information was received as part of the initial reporter
information, even when the reporter is the patient. The names of
patients, individual reporters, healthcare professionals, hospitals,
and geographical identifiers in reports are not releasable to the
public under FDA's public information regulations in part 20 of this
chapter.
(11) Safety reporting disclaimer. (i) A report or information
submitted by the Importer under this section (and any release by FDA of
that report or information) does not necessarily reflect a conclusion
by the Importer or by FDA that the report or information constitutes an
admission that the eligible prescription drug imported under section
804 of the Federal Food, Drug, and Cosmetic Act caused or contributed
to an adverse event or a medication error.
(ii) The Importer need not admit, and may deny, that the report or
information submitted as described in this section constitutes an
admission that the drug product caused or contributed to an adverse
event or a medication error.
(e) Drug recalls. (1) The SIP Sponsor must establish a procedure to
track the public announcements of the manufacturer of each drug they
import under section 804 of the Federal Food, Drug, and Cosmetic Act
and they must also monitor FDA's recall website for recall or market
withdrawal information relevant to the drugs that they import under
section 804.
(2) If FDA or any participant in a SIP determines that a recall is
warranted, the SIP Sponsor must effectuate the recall in accordance
with its written recall plan under paragraph (e)(3) of this section.
(3) A SIP must have a written recall plan that describes the
procedures to perform a recall of the product and specifies who will be
responsible for performing the procedures. The recall plan must cover
recalls initiated by FDA, recalls initiated by the Foreign Seller or by
the Importer, and recalls initiated by a drug's manufacturer, with
which the Foreign Seller and/or Importer must cooperate. The recall
plan must include sufficient procedures for the SIP to:
(i) Immediately cease distribution of the drugs affected by the
recall;
(ii) Directly notify consignees of the drug(s) included in the
recall, including how to return or dispose of the recalled drugs;
(iii) Specify the depth to which the recall will extend (e.g.,
wholesale,
[[Page 70839]]
intermediate wholesale, retail or consumer level);
(iv) Notify the public about any hazard(s) presented by the
recalled drug when appropriate to protect the public health;
(v) Conduct effectiveness checks to verify that all consignees at
the specified recall depth have received notification about the recall
and have taken appropriate action;
(vi) Appropriately dispose of recalled product; and
(vii) Notify FDA of the recall.
(4) In the event of a recall, Importers and Foreign sellers must,
upon request by FDA, provide transaction history, information, and
statement (as these terms are defined in sections 581(25), 581(26), and
581(27) of the Federal Food, Drug, and Cosmetic Act).
Sec. 251.19 Reports to FDA.
(a) A SIP Sponsor must submit a report to FDA each quarter
containing the information set forth in this section, beginning after
the SIP Sponsor files an electronic import entry for consumption for
its first shipment of drugs under the SIP. If the SIP Sponsor specifies
in such report that the information contained in the report is being
transmitted on behalf of the Importer and in order to fulfill the
Importer's obligation under Sec. 251.12, the Importer need not
separately submit such information to FDA.
(b) The report must contain the following information:
(1) The name, address, telephone number, and professional license
number (if any) of the Importer;
(2) The name and quantity of the active ingredient of the imported
eligible prescription drug(s);
(3) A description of the dosage form of the eligible prescription
drugs;
(4) The date(s) on which the eligible prescription drug(s) were
shipped;
(5) The quantity of the eligible prescription drug(s) that was
shipped;
(6) The lot or control number assigned to the eligible prescription
drug(s) by the manufacturer of the eligible prescription drug(s);
(7) The point of origin (i.e., the manufacturer) and the
destination (i.e., the wholesaler, pharmacy, or patient to whom the
Importer sells the drug) of the eligible prescription drug(s);
(8) The per unit price paid by the Importer for the prescription
drug(s) in U.S. dollars; and
(9) Any other information that FDA determines is necessary for the
protection of the public health.
(c) The Importer must also confirm that the eligible prescription
drugs was bought directly from the manufacturer by the Foreign Seller
and that the Foreign Seller sold the eligible prescription drug(s)
directly to the Importer.
(d) The report must include the following documentation:
(1) Documentation from the Foreign Seller specifying the
manufacturer of each eligible prescription drug and the quantity of
each lot of the eligible prescription drug(s) received by the Foreign
Seller from that manufacturer;
(2) Documentation demonstrating that the eligible prescription drug
was received by the Foreign Seller from the manufacturer and
subsequently shipped by the Foreign Seller to the Importer;
(3) Documentation of the quantity of each lot of the eligible
prescription drug(s) received by the Foreign Seller demonstrating that
the quantity being imported into the United States is not more than the
quantity that was received by the Foreign Seller;
(4) Documentation demonstrating that the sampling and testing
requirements described in section 804(d)(1)(J)(i)(III) of the Federal
Food, Drug, and Cosmetic Act were met for each shipment of each
eligible prescription drug.
(e) The report must include certifications from the Importer for
each shipment of each eligible prescription drug that the drug is
approved for marketing in the United States and is not adulterated or
misbranded and meets all labeling requirements under the Federal Food,
Drug, and Cosmetic Act. This certification must include:
(1) That there is an authorized SIP.
(2) That the imported drug is covered by the authorized SIP.
(3) That the drug is an eligible prescription drug as defined in
this part.
(4) That the FDA-approved counterpart of the drug is currently
commercially marketed in the United States.
(5) That the drug is approved for marketing in Canada.
(6) That the drug is not adulterated or misbranded and meets all
labeling requirements under the Federal Food, Drug, and Cosmetic Act.
(f) The report must include laboratory records, including complete
data derived from all tests necessary to ensure that each eligible
prescription drug is in compliance with established specifications and
standards, and documentation demonstrating that the Statutory Testing
was conducted at a qualifying laboratory, unless the manufacturer
conducted the testing and submitted this information directly to FDA.
(g) The report must include data, information, and analysis on the
SIP's cost savings to the American consumer for the drugs imported
under the SIP.
Sec. 251.20 Severability.
The provisions of this part are not separate and are not severable
from one another. If any provision is stayed or determined to be
invalid, the remaining provisions shall not continue in effect.
Sec. 251.21 Consequences for violations.
(a) An article that is imported or offered for import into the
United States in violation of section 804 of the Federal Food, Drug,
and Cosmetic Act or this part is subject to refusal under section 801
of the Federal Food, Drug, and Cosmetic Act.
(b) The importation of a prescription drug in violation of section
804 of the Federal Food, Drug, and Cosmetic Act, the falsification of
any record required to be maintained or provided to FDA under such
section, or any other violation of this part is a prohibited act under
section 301(aa) of the Federal Food, Drug, and Cosmetic Act.
Dated: December 11, 2019.
Brett P. Giroir,
Acting Commissioner of Food and Drugs.
[FR Doc. 2019-27474 Filed 12-18-19; 8:45 am]
BILLING CODE 4164-01-P