Risk Evaluation and Mitigation Strategies (REMS) and Generic Drugs
October 31, 2016
Risk Evaluation and Mitigation Strategies (REMS) and
Generic Drugs
Background: REMS
To obtain approval of the generic version of a brand-name
The Food and Drug Administration (FDA) Amendments
drug, the product developer must demonstrate to FDA that,
Act of 2007 (FDAAA; P.L. 110-85) expanded the risk-
among other things, the generic drug is pharmaceutically
management authority of FDA, authorizing the agency to
equivalent (e.g., has the same active ingredient(s), strength,
require, under specified conditions, a risk evaluation and
dosage form, and route of administration) and bioequivalent
mitigation strategy (REMS) for certain drugs. As part of a
(e.g., absorbed at the same rate and to the same extent) to
REMS, a drug manufacturer may be required to provide
the brand drug. To conduct the required bioequivalence
certain information to patients (e.g., a medication guide)
(BE) testing, the generic drug developer must obtain a
and health care providers, or to impose restriction on a
sufficient quantity of samples of the brand-name drug. By
drug’s sale and distribution via one or more “Elements to
restricting distribution of the drug product, the license
Assure Safe Use” (ETASU). An ETASU is a restriction on
holder can delay or prevent the generic developer from
distribution or use that is intended to (1) allow access to
obtaining samples for testing. Some brand companies have
those who could benefit from a drug while minimizing the
implemented restricted distribution programs for drugs not
risk of adverse events, and (2) block access to those for
covered by REMS. Such restricted access programs are
whom the risks would outweigh the potential benefits. For
generally self-imposed rather than FDA-mandated.
example, an ETASU could require that pharmacies,
practitioners, or health care settings that dispense the drug
Even when a generic product developer has acquired the
be specially certified, or that the patient using the drug be
necessary samples, conducted the required BE testing, and
subject to monitoring. By requiring a REMS, FDA is able
obtained FDA approval, the difficulties of negotiating a
to approve a drug that it otherwise would have to keep off
single, shared system of ETASU or obtaining entry into a
the market due to safety issues. FDA may determine that a
previously approved system of ETASU can also delay the
REMS is required upon the manufacturer’s submission of a
generic drug from entering the market.
new drug application (NDA), after initial approval or
licensing, when a manufacturer presents a new indication or
Role of FDA
other change, or when the agency becomes aware of certain
Generic companies have looked to FDA to intervene when
new information.
an RLD sponsor has refused to sell a drug to an eligible
drug developer for testing purposes, citing the REMS with
The law [21 U.S.C.§355-1(i)] requires that a drug that is the
ETASU as justification. In December 2014, FDA issued
subject of an abbreviated NDA (ANDA; i.e., generic drug)
draft guidance, How to Obtain a Letter from FDA Stating
and the reference listed drug (RLD; i.e., brand drug) use a
that Bioequivalence Study Protocols Contain Safety
single, shared system of ETASU. The Secretary may waive
Protections Comparable to Applicable REMS for RLD. This
this requirement for the generic drug if (1) the burden of
guidance outlines the steps that a generic drug developer
creating a single, shared system outweighs the benefit, or
should take to obtain a letter from FDA to the RLD
(2) an aspect of the ETASU for the RLD is claimed by an
sponsor, indicating the generic drug applicant’s proposed
unexpired patent or is a method entitled to protection, and
protocol is as safe as the REMS and that it would not be a
the generic applicant “certifies that it has sought a license
violation of the REMS to provide the product samples for
for use of an aspect of the [ETASU] for the applicable
BE testing. However, some generic manufacturers have
listed drug and that it was unable to obtain a license.”
reported that these practices are continuing even after FDA
has issued such letters.
Reports of Misuse
A REMS restricted distribution program controls the chain
Congressional Action
of supply so that the drugs are provided only to patients
In the 114th Congress, two bills to keep brand companies
with prescriptions from authorized physicians or
from using REMS to prevent or delay generic drugs from
pharmacies under specified conditions. Although the law
entering the market have been introduced: the Fair Access
[21 U.S.C.§355-1(f)(8)] prohibits the holder of an approved
for Safe and Timely Generics Act of 2015 (or the FAST
new drug or biologics license application (i.e., the brand
Generics Act of 2015 [H.R. 2841]) and the Creating and
company, which is the RLD sponsor) from using ETASU
Restoring Equal Access to Equivalent Samples Act of 2016
“to block or delay approval of an application,” FDA, the
(or the CREATES Act of 2016 [S. 3056]). This section
Federal Trade Commission, generic drug manufacturers,
provides an overview of the two bills, as well as a
and various physician, pharmacist, hospital and consumer
comparable bill from the 112th Congress, but not a
groups have expressed concern that some brand companies
comprehensive summary.
are using REMS to prevent or delay generic drugs from
entering the market.
https://crsreports.congress.gov
Risk Evaluation and Mitigation Strategies (REMS) and Generic Drugs
H.R. 2841
REMS Legislation and Cost-Savings
The House bill seeks to generally limit a “license holder”
Although legislation aimed at reforming FDA REMS has
(defined as the holder of an approved new drug or biologics
been discussed as a means of reducing healthcare spending,
license application) of a covered product (i.e., a drug,
CRS is not aware of any cost estimates (from CBO or other
biologic, or combination thereof, as specified) from
entities) that indicate how H.R. 2841 or S. 3056 would
restricting its availability for testing purposes by an eligible
function as such. However, while CBO has not scored these
product developer. Among other things, it would allow the
two bills (as of the date of this In Focus), the agency has
developer to seek authorization from the Secretary to obtain
scored a comparable provision from the 112th Congress—
a covered product subject to a REMS with ETASU; would
Section 1131 “Drug Development and Bioequivalence
specify the procedure for obtaining authorization from the
Testing” of S. 2516, an early iteration of the Food and Drug
Secretary and access to the product; and would require the
Administration Safety and Innovation Act (FDASIA; P.L.
license holder to publicly designate at least one wholesaler
112-144). Like H.R. 2841 and S. 3056, Section 1131 would
or specialty distributor to fulfill product requests, with
have generally prohibited the use of ETASU to restrict
specified disclosure restrictions. It would allow the
availability of a covered drug for BE testing by an eligible
Secretary to prohibit or limit the transfer of a product if it
product developer, as specified, and it would have allowed
would present an “imminent hazard” to public health. It
the developer to seek authorization from the Secretary to
would also exempt the license holder from liability for any
obtain a covered drug; it would not have addressed the issue
claim arising out of an eligible product developer’s “failure
of developing a single, shared system of ETASU. Unlike
to follow adequate safeguards during development or
H.R. 2841 and S. 3056, the definition of “covered drug”
testing activities.”
under Section 1131 is narrower and would have included
only a drug or biologic subject to a REMS with ETASU, as
In addition, the bill would generally prohibit a license
compared to H.R. 2841 and S. 3056, which seek to
holder from taking any steps to impede the development of
generally limit a license holder from restricting for BE
a single, shared system of ETASU or the entry of a product
testing both covered products subject to REMS with
developer into a previously approved system of ETASU. It
ETASU and covered products not subject to REMS with
would require license holders to negotiate in good faith
ETASU. In May 2012, CBO estimated that the
toward a single, shared system, but would allow the
implementation of Section 1131, with other provisions in S.
Secretary to waive the requirement for a single, shared
2516 aimed at reducing barriers to market entry for lower-
system if the product developer is unable to finalize terms
priced drugs, would have reduced direct spending for
with the license holder. Further, the legislation would also
mandatory health programs by $753 million over the 2013-
allow an eligible product developer that is injured based on
2022 period. Section 1131 was ultimately not included in
certain violations of the legislation to sue the license holder
the final version of the bill signed into law as FDASIA.
for injunctive relief and damages.
Stakeholder Concerns
S. 3056
The generic drug industry has generally supported
Like the House bill, the Senate bill would also establish a
congressional efforts to prevent the use of restricted
mechanism for generic drug manufacturers to obtain the
distribution programs from delaying generic entry, as have
covered product for testing. The legislation would allow the
other stakeholders looking to increase competition to
generic product developer to bring a civil action against the
reduce drug prices. A 2014 study sponsored by the Generic
license holder for failure to provide the product developer
Pharmaceutical Association (GPhA) estimated that misuse
sufficient quantities of the drug on “commercially
of REMS and other restricted distribution programs costs
reasonable, market-based terms.” If the product developer
the United States $5.4 billion annually, with the federal
prevails in the case, the license holder would generally be
government bearing a third of this burden. While some say
required to (1) provide to the product developer, without
that legislation such as S. 3056 is critical to maintaining
delay, sufficient quantities of the product, as specified, and
pharmaceutical competition, other stakeholders, including
(2) award to the developer attorney fees and costs related to
the brand pharmaceutical lobby, oppose the Senate bill,
the lawsuit, as well as a monetary amount, as specified.
arguing that REMS are a necessary regulatory tool for
protecting patient safety. During the June 2016 Senate
The Senate bill would also allow an eligible product
Judiciary Subcommittee hearing on S. 3056, one testimony
developer to bring civil action against the license holder for
expressed concern that the Senate bill does not establish
failing to reach a single, shared system of ETASU, or for
robust criteria that product developers must satisfy to
refusing to allow the product developer to join into a
protect patients and individuals who come into contact with
previously approved system. If the product developer
the drug during its distribution. A paper from the Journal of
prevails in such a lawsuit, the license holder would be
Pharmaceutical Policy and Practice (2016) argues against
required to (1) with the approval of the Secretary, enter into
such legislation, and discusses the importance of
a single, shared ETASU with the developer or allow the
maintaining REMS to ensure that proper safety measures
developer to join a previously approved system, or (2)
are preserved. Further, others refute claims that REMS
demonstrate that the Secretary has waived the requirement
impedes generic competition citing that at least nine drugs
for a single, shared system. It would also require the license
with strict ETASU provisions have generic competitors.
holder to award to the developer attorney fees and costs
associated with the litigation and a monetary amount, as
Agata Dabrowska, Analyst in Health Policy
specified. The Senate bill contains the same limitation of
liability provision as the House bill.
IF10494
https://crsreports.congress.gov
Risk Evaluation and Mitigation Strategies (REMS) and Generic Drugs
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