United states securities and exchange commission

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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. 

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