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The FDA has developed four distinct approaches
intended to make therapeutically important drugs
available as rapidly as possible, especially when the
drugs are the first available treatment or have
advantages over existing treatments: accelerated
approval, fast track, breakthrough therapy and priority
review.
• Accelerated Approval: The FDA may grant
“accelerated approval” status to products that
treat serious or life-threatening illnesses and
that provide meaningful therapeutic benefits to
patients over existing treatments. Under this
pathway, the FDA may approve a product based
on surrogate endpoints, or clinical endpoints
other than survival or irreversible morbidity.
When approval is based on surrogate endpoints
or clinical endpoints other than survival or
morbidity, the sponsor will be required to conduct
additional post-approval clinical studies to verify
and describe clinical benefit. Under the FDA's
accelerated approval regulations, if the FDA
concludes that a drug
that has been shown to be
effective can be safely used only if distribution or
use is restricted, it may require certain post-
marketing restrictions as necessary to assure
safe use.
In addition, for products approved
under accelerated approval, sponsors may be
required to submit all copies of their promotional
materials, including advertisements, to the FDA
at least 30 days prior to initial dissemination.
The FDA may withdraw approval under
accelerated approval after a hearing if, for
instance, post-marketing studies fail to verify any
clinical benefit, it becomes clear that restrictions
on the distribution of the product are inadequate
to ensure its safe use, or if a sponsor fails to
comply with the conditions of the accelerated
approval.
• Fast Track Status: The FDA may grant "fast track"
status to products that treat a serious condition
and have data demonstrating the potential to
address an unmet
medical need or a drug that
has been designated as a qualified infectious
disease product.
• Breakthrough Therapy: The FDA may grant
“breakthrough therapy” status to drugs designed
to treat, alone or in combination with another
drug or drugs, a serious or life-threatening
disease or condition and for which preliminary
clinical evidence suggests a substantial
improvement over existing therapies. Such drugs
need not address an unmet need, but are
nevertheless eligible for expedited review if they
offer the potential for an improvement.
Breakthrough therapy status entitles the sponsor
to earlier and more frequent meetings with the
FDA regarding the development of nonclinical
and clinical data and permits the FDA to offer
product development or regulatory advice for the
purpose of shortening the time to product
approval. Breakthrough therapy status does not
guarantee that a product will be developed or
reviewed more quickly and does not ensure FDA
approval.
• Priority Review: Priority Review only applies to
applications (original or efficacy supplement) for
a drug that
treats a serious condition and, if
approved, would provide a significant
improvement in safety or effectiveness of the
treatment, diagnosis or prevention of serious
conditions when compared to standard
applications. Priority Review may also be granted
for any supplement that proposes a labeling
change due to studies completed in response to
a written request from the FDA for pediatric
studies, for an application for a drug that has
been designated as a qualified infectious
disease product, or any application or
supplement for a drug submitted with a priority
review voucher.
In December 2016, the FDA issued us a rare
pediatric disease priority review voucher in
connection with the approval of SPINRAZA.
POST-MARKETING STUDIES
Regardless of the approval pathway employed,
the FDA may require a sponsor to conduct additional
post-marketing studies as a condition of approval to
provide data on safety and effectiveness. If a sponsor
fails to conduct the required studies, the agency may
withdraw its approval. In addition, if the FDA
concludes that a drug that has been shown to be
effective can be safely used only if distribution or use
is restricted, it can mandate post-marketing
restrictions as necessary to assure safe use. In such
a case, the sponsor may be required to establish
rigorous systems to assure use of the product under
safe conditions. These systems are usually referred
to as Risk Evaluation and Mitigation Strategies
(REMS). The FDA can impose financial penalties for
failing to comply with certain post-marketing
commitments, including REMS. In addition, any
changes to an approved REMS must be reviewed and
approved by the FDA prior to implementation.
ADVERSE EVENT REPORTING
We monitor information on side effects and
adverse events reported during clinical studies and
after marketing approval and report such information
and events to regulatory agencies. Non-compliance
with the FDA's safety reporting requirements may
result in civil or criminal penalties. Side effects or
adverse events that are reported
during clinical trials
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can delay, impede or prevent marketing approval.
Based on new safety information that emerges after
approval, the FDA can mandate product labeling
changes, impose a new REMS or the addition of
elements to an existing REMS, require new post-
marketing studies (including additional clinical trials),
or suspend or withdraw approval of the product. These
requirements may affect our ability to maintain
marketing approval of our products or require us to
make significant expenditures to obtain or maintain
such approvals.
APPROVAL OF CHANGES TO AN APPROVED
PRODUCT
If we seek to make certain types of changes to
an approved product, such as adding a new indication,
making certain manufacturing changes or changing
manufacturers or suppliers of certain ingredients or
components, the FDA will need to review and approve
such changes in advance. In the case of a new
indication, we are required to demonstrate with
additional clinical data that the product is safe and
effective for a use other than that initially approved.
FDA regulatory review may result in denial or
modification of the planned changes, or
requirements
to conduct additional tests or evaluations that can
substantially delay or increase the cost of the planned
changes.
REGULATION OF PRODUCT ADVERTISING AND
PROMOTION
The FDA regulates all advertising and promotion
activities and communications for products under its
jurisdiction both before and after approval. Pursuant
to FDA guidance, a company can make safety and
efficacy claims from data either in or consistent with
the label. However, physicians may prescribe legally
available drugs for uses that are not described in the
drug's labeling. Such off-label uses are common
across medical specialties, and often reflect a
physician's belief that the off-label use is the best
treatment for patients. The FDA does not regulate the
behavior of physicians in their choice of treatments,
but FDA regulations do impose stringent restrictions
on manufacturers' communications regarding off-label
uses. Failure to comply with applicable FDA
requirements may subject a company to adverse
publicity, enforcement
action by the FDA, corrective
advertising and the full range of civil and criminal
penalties available to the government.
Regulation of Combination Products
Combination products are defined by the FDA to
include products comprising two or more regulated
components (e.g., a biologic and a device). Biologics
and devices each have their own regulatory
requirements, and combination products may have
additional requirements. Some of our marketed
products meet this definition and are regulated under
this framework and similar regulations outside the
U.S., and we expect that some of our pipeline product
candidates may be evaluated for regulatory approval
under this framework as well.
Product Approval and Post-Approval Regulation
Outside the U.S.
We market our products in numerous
jurisdictions outside the U.S. Most of these
jurisdictions have product approval and post-approval
regulatory processes that are similar in principle to
those in the U.S. In Europe, for example, where a
substantial part of our ex-U.S. efforts are focused,
there are several tracks for marketing approval,
depending on the type of product for which approval is
sought. Under
the centralized procedure, a company
submits a single application to the EMA. The
marketing authorization application is similar to the
NDA or BLA in the U.S. and is evaluated by the CHMP,
the expert scientific committee of the EMA
responsible for human medicines. If the CHMP
determines that the marketing authorization
application fulfills the requirements for quality, safety
and efficacy and that the medicine has a positive
benefit risk balance, it will adopt a positive opinion
recommending grant of the marketing authorization by
the EC. The CHMP opinion is not binding, but is
typically adopted by the EC. A marketing application
approved by the EC is valid in all member states of
the E.U. The centralized procedure is required for all
biological products, orphan medicinal products and
new treatments for neurodegenerative disorders, and
it is available for certain other products, including
those which constitute a significant therapeutic,
scientific or technical innovation.
In addition to the centralized procedure, Europe
also has:
• a
national procedure, which requires an
application to the competent authority of an E.U.
country (if an application is to be made in more
than one E.U. country, following approval in the
first country, the applicant must submit
applications in the other countries using the
mutual recognition procedure);
• a decentralized procedure, whereby applicants
submit identical applications to several countries
and receive simultaneous approval, if the
medicine has not yet been authorized in any E.U.
country; and
• a mutual recognition procedure, where applicants
that have a medicine authorized in one E.U.
country can apply for mutual recognition of this
authorization in other E.U. countries.