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October 31, 2016
Risk Evaluation and Mitigation Strategies (REMS) and
Generic Drugs
The Food and Drug Administration (FDA) Amendments
Act of 2007 (FDAAA; P.L. 110-85) expanded the risk-
management authority of FDA, authorizing the agency to
require, under specified conditions, a risk evaluation and
mitigation strategy (REMS) for certain drugs. As part of a
REMS, a drug manufacturer may be required to provide
certain information to patients (e.g., a medication guide)
and health care providers, or to impose restriction on a
drug's sale and distribution via one or more Elements to
Assure Safe Use (ETASU). An ETASU is a restriction on
distribution or use that is intended to (1) allow access to
those who could benefit from a drug while minimizing the
risk of adverse events, and (2) block access to those for
whom the risks would outweigh the potential benefits. For
example, an ETASU could require that pharmacies,
practitioners, or health care settings that dispense the drug
be specially certified, or that the patient using the drug be
subject to monitoring. By requiring a REMS, FDA is able
to approve a drug that it otherwise would have to keep off
the market due to safety issues. FDA may determine that a
REMS is required upon the manufacturer's submission of a
new drug application (NDA), after initial approval or
licensing, when a manufacturer presents a new indication or
other change, or when the agency becomes aware of certain
new information.
The law [21 U.S.C.§355-1(i)] requires that a drug that is the
subject of an abbreviated NDA (ANDA; i.e., generic drug)
and the reference listed drug (RLD; i.e., brand drug) use a
single, shared system of ETASU. The Secretary may waive
this requirement for the generic drug if (1) the burden of
creating a single, shared system outweighs the benefit, or
(2) an aspect of the ETASU for the RLD is claimed by an
unexpired patent or is a method entitled to protection, and
the generic applicant certifies that it has sought a license
for use of an aspect of the [ETASU] for the applicable
listed drug and that it was unable to obtain a license.
A REMS restricted distribution program controls the chain
of supply so that the drugs are provided only to patients
with prescriptions from authorized physicians or
pharmacies under specified conditions. Although the law
[21 U.S.C.§355-1(f)(8)] prohibits the holder of an approved
new drug or biologics license application (i.e., the brand
company, which is the RLD sponsor) from using ETASU
to block or delay approval of an application, FDA, the
Federal Trade Commission, generic drug manufacturers,
and various physician, pharmacist, hospital and consumer
groups have expressed concern that some brand companies
are using REMS to prevent or delay generic drugs from
entering the market.
To obtain approval of the generic version of a brand-name
drug, the product developer must demonstrate to FDA that,
among other things, the generic drug is pharmaceutically
equivalent (e.g., has the same active ingredient(s), strength,
dosage form, and route of administration) and bioequivalent
(e.g., absorbed at the same rate and to the same extent) to
the brand drug. To conduct the required bioequivalence
(BE) testing, the generic drug developer must obtain a
sufficient quantity of samples of the brand-name drug. By
restricting distribution of the drug product, the license
holder can delay or prevent the generic developer from
obtaining samples for testing. Some brand companies have
implemented restricted distribution programs for drugs not
covered by REMS. Such restricted access programs are
generally self-imposed rather than FDA-mandated.
Even when a generic product developer has acquired the
necessary samples, conducted the required BE testing, and
obtained FDA approval, the difficulties of negotiating a
single, shared system of ETASU or obtaining entry into a
previously approved system of ETASU can also delay the
generic drug from entering the market.
Generic companies have looked to FDA to intervene when
an RLD sponsor has refused to sell a drug to an eligible
drug developer for testing purposes, citing the REMS with
ETASU as justification. In December 2014, FDA issued
draft guidance, How to Obtain a Letter from FDA Stating
that Bioequivalence Study Protocols Contain Safety
Protections Comparable to Applicable REMS for RLD. This
guidance outlines the steps that a generic drug developer
should take to obtain a letter from FDA to the RLD
sponsor, indicating the generic drug applicant's proposed
protocol is as safe as the REMS and that it would not be a
violation of the REMS to provide the product samples for
BE testing. However, some generic manufacturers have
reported that these practices are continuing even after FDA
has issued such letters.
In the 114th Congress, two bills to keep brand companies
from using REMS to prevent or delay generic drugs from
entering the market have been introduced: the Fair Access
for Safe and Timely Generics Act of 2015 (or the FAST
Generics Act of 2015 [H.R. 2841]) and the Creating and
Restoring Equal Access to Equivalent Samples Act of 2016
(or the CREATES Act of 2016 [S. 3056]). This section
provides an overview of the two bills, as well as a
comparable bill from the 112th Congress, but not a
comprehensive summary.
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